FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to pharmacology, more particularly, but not exclusively, to novel pharmaceutical composition and devices for delivering same, and to uses thereof in the treatment of ceruminosis (ear wax blockage) and associated diseases and/or disorders.

Cerumen, or ear wax, is a mixture of secretions from the ceruminous and pilosebaceous glands as well as squamae of epithelium, dust, and other debris. Cerumen forms a protective layer on the skin of the external ear canal. The consistency of, and thus the difficulty in removing, cerumen varies from individual to individual and is at least partially genetically determined.

Cerumen (ear wax) lubricates and cleans the ear canal, and forms part of the defense mechanism of the external ear against foreign bodies and infectious agents. Cerumen is a combination of epithelial cells, foreign material and lipid products, the latter formed by the sebaceous glands and apocrine glands. The lubricating effect is the effect of such lipids, found in high concentration in the sebum, produced by the sebaceous glands. The cleaning function is the result of constant migration of the cerumen towards the outer part of the external auditory canal. On its way out, foreign bodies, dust and dirt adhere to the cerumen, and are thus prevented from plugging the ear or reaching the tympanic membrane.

Cerumen impaction is a common problem, encountered on a daily basis by general and family physicians, and otolaryngologists. It has been estimated that each week 150,000 cerumen removals take place in the United States [Grossan M. Ear Nose Throat J 1998; 77:541-546]. Cerumen impaction has important clinical implications on the general well-being of the patient, since its associated symptoms and complications include hearing loss, pain, itching, tinnitus, vertigo, external otitis and chronic cough.

Cerumen build-up and impaction in the external ear canal is a significant problem, especially for the infant and geriatric populations of the world. In the United States about 8 million cerumen removals take place each year, and in the United Kingdom the number is 2 million. Individuals possessing hairy ear canals, narrow ear canals, or osteoma are more disposed to such build-up or impaction. In addition, some literature suggests that the use of cotton buds to clean the external ear canal interferes with the body's normal shedding of ear wax and epithelium and increases the chance of such build-up and impaction. Build-up and/or impaction of ear wax may cause irritation, itching, pain, infection, hearing loss, tinnitus, vertigo, external otitis and chronic cough. Wax removal is necessary to alleviate these conditions. Cerumen removal is also required when it is necessary to examine the tympanic membrane.

Conventional methods of removing cerumen from the external auditory canal include physical methods, chemical methods (ceruminolysis) and various combinations thereof. The currently practiced methods, however, are associated with numerous disadvantages. For example, physical removal of cerumen must be carried out by an experienced physician and requires instruments such as a loop, curette, forceps, suction apparatus, syringe or irrigation apparatus. For ear irrigation, a jet of warm water or other liquid is sprayed from a syringe or other apparatus into the ear canal in an effort to dislodge impacted cerumen. Ear irrigation devices are disclosed for example, in U.S. Patent Nos. 4,206,756; 5,364,343; 6,210,358 and 6,949,088.

These methods are time consuming, uncomfortable (and often painful) for patients, and can result in complications, such as laceration and/or infection of the external auditory canal, vertigo, tinnitus, abscess and tympanic membrane perforation. In particular, ear irrigation is associated with a high rate of complication, as well as failure to remove cerumen (Sharp JF, Wilson JA, Ross L, Barr-Hamilton RM. Ear wax removal: a survey of current practice. BMJ 1990; 301(6763): 1251-3).

Self treatment by patients using cotton swabs or other means is not recommended by health professionals, since it generally results in greater impaction and can lead to skin irritation and infection.

Chemical methods typically involve ceruminolytic products which act by softening the cerumen and lubricating the canal, thus facilitating cerumen removal. Over the years, a large number of agents have been proposed and tested, including sodium bicarbonate, hydrogen peroxide, acetic acid, glycerin, acetone, triethanolamine polypeptide, various forms of docusate sodium and a combination of aluminum acetate, dichlorobenzene and benzethonium chloride. After softening with one of these agents, irrigation with body temperature water or saline is often performed to remove the softened cerumen. None of these compounds are associated with a high degree of efficacy in dissolving wax, and some have been associated with ear irritation.

Several products contain carbamide peroxide (6.5 %) in an anhydrous glycerin vehicle as defined in the FDA monograph part 344. These include products such as Murine® Ear Drops available from Abbott Laboratories of Columbus, Ohio; Debrox® Drops Earwax Removal Aid available from SmithKline Beecham of Pittsburgh, Pa.; Bausch & Lomb Earwax Remover available from Bausch & Lomb of Rochester, N.Y.; and Flents® Earwax Remover available from Flents Products Co. of Yonkers, N.Y. Another commercially available product is Cerumenex® Eardrops, which is a prescription product containing triethanolamine polypeptide oleate-condensate (10 %) available from the Purdue Frederick Company of Norwalk, Conn. Cerumenex® sometimes results in irritation of the ear canal.

Compositions that facilitate the removal of ear wax are also disclosed in, for example, U.S. Patent No. 3,422,186, which discloses ceruminolytic compositions comprising ethylene oxide-polyoxypropylene glycol condensates; U.S. Patent No. 4,895,875, which discloses stabilized peroxide solutions comprising urea peroxide and glycerin and methods of preparation and use useful for cerumen removal; U.S. Patent No. 5,296,472, which discloses compositions comprising cyclodextrins and methods of use for cerumen removal; U.S. Patent No. 5,380,711, which discloses oil-free "empty" cyclodextrin compositions and methods of use for cerumen removal; and U.S. Patent No. 5,480,658, which discloses compositions comprising acetic acid and boric acid in a water base useful for cleaning the external ear canal of pets.

In some publications, it has been indicated that non-water, non-oil-based ceruminolytic agents are clinically more effective than oil-based preparations [see, for example, Hand C and Harvey I. Br J Clin Pract 2004; 54: 852-867]. In other publications, it has been indicated that ceruminolytic products based on triethanolamine peptide, carbamide peroxide or sodium bicarbonate are no more clinically effective than saline placebo in removing cerumen [see, for example, Roland PS et al. Arch Otolaryngol Head Neck Surg. 2004; 130(10): 1175-1177; Burton MJ and Doree CJ. Cochrane Database Syst Rev 2003; (3):CD004400].

Nonetheless, organic compounds such as liquid paraffin and olive oil are widely used in clinical practice as ceruminolytics or as components of ceruminolytic preparations. Their use is associated with certain disadvantages however, notably difficulty in administration due to inherent messiness, slow action, and the concomitant requirement for mechanical wash procedures.

Yet other disclosures relating to in vitro assessment of ceruminolytic agents indicate that olive oil is ineffective as a wax dispersant [Andaz C and Whittet HB. J Otorhinolaryngol Relat Spec 1993;55(2):97-99; Chalishazar U and Williams H. Br J Nurs 2007; 16(13): 806-808].

Squalane (CAS No. 111-01-3) is chemically named 2,6,10,15,19,23- hexamethyltetracosane, is liquid at ambient temperature, and is a widely used ingredient for the preparation of cosmetics, soaps and pharmaceutical preparations including ointments, suppositories and medical lubricants.

U.S. Patent No. 6,723,689 discloses an antimicrobial composition comprising inter alia a moisturizer and/or emollient. Among others, squalane and mineral oil are mentioned as possible moisturizers and/or emollients.

U.S. Patent No. 6,656,928 discloses a composition for topical administration in the form of a shake lotion, gel or spray, the composition comprising inter alia a corticosteroid; an anti-fungal agent, and optionally an emollient. Among many others, squalane and mineral oil are mentioned as possible emollients.

U.S. Patent Nos. 5,976,521 and 5,470,884 disclose an anti-acne cosmetic composition comprising inter alia an emollient. Among many others, squalane and mineral oil are mentioned as possible emollients.

U.S. Patent No. 5,308,526 discloses a liquid cleansing composition comprising inter alia an emollient. Among many others, squalane and mineral oil are mentioned as possible emollients.

Squalane has been used as one ingredient in ear cleaning products, for example, Miracell® intended for human use and marketed as drops, and Cerumene® intended for veterinary use, and marketed as a liquid.

U.S. Patent No. 3,821,375 discloses compositions for treating otitis in dogs and cats, which are hydrocarbon-based suspensions that comprise chloramphenicol and squalane. According to the teachings of this patent, the squalane serves for accelerating the penetration of the active ingredients since it removes the accumulated ear wax and dirt.

U.S. Patent No. 5,176,654 discloses a spray apparatus for the delivery of fluid substances, such as medicaments, to an ear, and a method for delivering fluid substances to an ear.

Additional background art includes U.S. Patent Application having Publication

No. 2004/0126436.

SUMMARY OF THE INVENTION

The present inventor has now designed and successfully practiced novel ceruminolytic preparations, which are safe, effective and easy to use, particularly in humans. Exemplary such formulations comprise specific combinations of olive- squalane in an oily vehicle.

Embodiments of the present invention therefore relate to pharmaceutical compositions, designed for local administration to the ear, and useful for the treatment of ceruminosis and associated symptoms. In some embodiments, the formulations comprise specific combinations of olive-squalane and additional natural oils, the latter of which contribute fragrance, disinfecting and/or moisturizing properties. Advantageously, the compositions are prepared in a mineral oil and/or vegetable oil vehicle, which contributes a washing medium. Further according to some embodiments of the present invention there is provided a device for administering the disclosed compositions, which enables pressured topical application directly to the ear canal and enhances the ceruminolytic activity of the compositions.

Without wishing to be bound by any particular theory or mechanism of action, the efficacy of the disclosed compositions may be attributed to the combined use of a natural non-irritating ceruminolytic agent with an oily vehicle and device to provide a mechanical wash.

Further according to some embodiments of the present invention there are provided methods which advantageously combine a ceruminolytic agent, preferably that from a vegetable source such as olive-squalane, with an oily vehicle, into a composition that is administered in the form of a spray. The oily vehicle serves to fix the ceruminolytic agent on the impacted cerumen and/or the surface of the ear canal for prolonged activity, and as well, provides a wash vehicle for removing the softened cerumen after the ceruminolytic agent has taken effect. As the course of therapy continues and the cerumen becomes softened, the spray provides a mechanical wash for removing the softened and loosened cerumen from the ear canal.

According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition comprising olive-squalane and pharmaceutically acceptable carrier, the carrier being substantially consisted of an oil, the composition being is in a form of liquid spray particles.

According to some embodiments of the invention, the liquid spray particles are formed upon subjecting the liquid composition that comprises the olive-squalane and the carrier to a pressure of at least 5 bars.

According to some embodiments of the invention, the liquid spray particles have a kinetic energy sufficient to transform at least a portion of a substantially solid cerumen into a liquid cerumen upon impacting the substantially solid cerumen.

According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition comprising olive-squalane and pharmaceutically acceptable carrier, the carrier being substantially consisted of an oil, the composition being packaged in a container and pressurized under a pressure of at least 5 bars.

According to an aspect of some embodiments of the present invention there is provided a container and a pharmaceutical composition being packaged in the container and pressurized under a pressure of at least 5 bars, the pharmaceutical composition comprising olive-squalane and pharmaceutically acceptable carrier, the carrier being substantially consisted of an oil.

According to some embodiments of the invention, the container is configured to release therefrom the pharmaceutical composition in a form of the liquid spray particles.

According to some embodiments of the invention, the liquid spray particles have a kinetic energy sufficient to transform at least a portion of a substantially solid cerumen into a liquid cerumen upon impacting the substantially solid cerumen.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the oil is selected from the group consisting of a mineral oil and a vegetable oil. According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the vegetable oil is selected from the group consisting of almond oil, canola oil, coconut oil, corn oil, cottonseed oil, peanut oil, saffron oil, sesame oil, soybean oil, and any combination thereof.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the mineral oil is light mineral oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the carrier comprises light mineral oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the carrier comprises almond oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the carrier comprises a mixture of light mineral oil and almond oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the olive- squalane is derived from a vegetable oil refining product.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the vegetable oil refining product is obtained in the course of manufacture of an oil selected from the group consisting of olive oil, palm oil, palm kernel oil, coconut oil, soybean oil and sunflower oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the olive- squalane ranges from 5 to 30, or from 15 to 30, or from 20 to 30 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the olive- squalane is about 25 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the carrier ranges from 60 to 80 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the carrier is about 75 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the pharmaceutical composition further comprises an additive.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the additive ranges from 0.5 to 15 or from 0.5 to 10 or from 0.5 to 5 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the additive is selected from the group consisting of a fragrant oil, a moisturizing oil, a disinfecting oil and any combination thereof.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the additive comprises a fragrant oil.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the fragrant oil is selected from the group consisting of mint oil, peppermint oil, pine oil, spearmint oil, spruce oil and any combination thereof.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the fragrant oil ranges from 0.1 to 5 or from 0.1 to 1 weight percent, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the fragrant oil is 0.5 weight percent, based on the total weight of the composition.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, the disinfecting oil and/or the moisturizing oil is selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil, tea tree oil, eucalyptus oil, lavender oil, rosemary oil and any combination thereof.

According to some embodiments of the invention, in any one of the pharmaceutical compositions as described herein, a concentration of the disinfecting oil and/or the moisturizing ranges from 1 to 15, or from 1 to 10, or from 1 to 5, or from 1 to 3 weight percents, based on the total weight of the formulation.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition comprises:

olive- squalane, in a concentration that ranges from 15 to 30 weight percents, based on the total weight of the composition; and

a pharmaceutically acceptable carrier comprising light mineral oil, almond oil or a combination thereof, in an amount of about 70 to 80 weight percents, based on the total weight of the composition, and may further comprise a fragrant oil, in a concentration that ranges from 0.1 to 1 weight percent, based on the total weight of the composition; and/or an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and any combination thereof, in an amount that ranges from 0.5 to 5 weight percents, based on the total weight of the composition.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition is consisting essentially of:

olive- squalane, in an amount of 24.5 weight percents, based on the total weight of the composition;

spearmint oil, in an amount of about 0.5 weight percent, based on the total weight of the composition;

light mineral oil in an amount of 74 weight percents, based on the total weight of the composition; and

an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and combinations thereof, in an amount of 1 weight percent, based on the total weight of the composition.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition is consisting essentially of:

olive- squalane, in an amount of 24.5 weight percents, based on the total weight of the formulation;

spearmint oil, in an amount of 0.5 weight percent, based on the total weight of the composition;

light mineral oil, almond oil or a combination thereof, in an amount of 72 weight percents, based on the total weight of the composition; and

a combination of turmeric oil, oregano oil and black cumin seed oil, each present in an amount of about 1 weight percent, based on the total weight of the composition.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition comprises:

olive- squalane, in a concentration that ranges from 15 to 30 weight percents, based on the total weight of the composition; and

a pharmaceutically acceptable carrier comprising light mineral oil, almond oil or a combination thereof, in an amount of about 70 to 80 weight percents, based on the total weight of the composition, and may further comprise a fragrant oil, in a concentration that ranges from 0.1 to 1 weight percent, based on the total weight of the composition and/or an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and any combination thereof, in an amount that ranges from 0.5 to 5 weight percents, based on the total weight of the composition.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition is consisting essentially of:

olive- squalane, in an amount of 24.5 weight percents, based on the total weight of the composition;

spearmint oil, in an amount of about 0.5 weight percent, based on the total weight of the composition;

light mineral oil in an amount of 74 weight percents, based on the total weight of the composition; and

an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and combinations thereof, in an amount of 1 weight percent, based on the total weight of the composition.

According to some of any of the embodiments of the invention, an exemplary pharmaceutical composition is consisting essentially of:

olive- squalane, in an amount of 24.5 weight percents, based on the total weight of the formulation;

spearmint oil, in an amount of 0.5 weight percent, based on the total weight of the composition;

light mineral oil, almond oil or a combination thereof, in an amount of 72 weight percents, based on the total weight of the composition; and

a combination of turmeric oil, oregano oil and black cumin seed oil, each present in an amount of about 1 weight percent, based on the total weight of the composition.

According to some embodiments of the invention, any one of the exemplary compositions described herein is in a form of liquid spray particles.

According to some embodiments of the invention, the liquid spray particles are formed upon subjecting the composition to a pressure of at least 5 bars.

According to some embodiments of the invention, the liquid spray particles have a kinetic energy sufficient to transform at least a portion of a substantially solid cerumen into a liquid cerumen upon impacting the substantially solid cerumen.

According to some embodiments of the invention, any one of the exemplary compositions described herein is packaged in a container and pressurized under a pressure of at least 5 bars.

According to some embodiments of the invention, the container is configured to release therefrom the pharmaceutical composition in a form of liquid spray particles.

According to some embodiments of the invention, the liquid spray particles have a kinetic energy sufficient to transform at least a portion of a substantially solid cerumen into a liquid cerumen upon impacting the substantially solid cerumen.

According to some embodiments of the invention, any one of the compositions as described herein is identified for use in the treatment of ceruminosis in a subject in need thereof.

According to some embodiments of the invention, the treatment is effected by administering the composition to an ear canal of the subject.

According to some embodiments of the invention, any one of the compositions as described herein is being packaged in a spray dispenser configured to dispense the composition as liquid spray particles at a pressure of at least 5 bars.

According to an aspect of some embodiments of the present invention there is provided a use of any one of the pharmaceutical composition as described herein in the manufacture of a medicament for treating ceruminosis in a subject in need thereof..

According to an aspect of some embodiments of the present invention there is provided a method of treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject, the method comprising administering a therapeutically effective amount of any one of the compositions as described herein to an ear canal of a subject in need thereof, thereby treating the ceruminosis and/or ceruminosis-associated disease or disorder.

According to an aspect of some embodiments of the present invention there is provided a dispensing device comprising any one of the pharmaceutical compositions as described herein and configured for dispensing the composition as liquid spray particles at a pressure of at least 5 bars.

According to an aspect of some embodiments of the present invention there is provided a dispensing device comprising a pharmaceutical composition, the device being configured for dispensing the composition as liquid spray particles at a pressure of at least 5 bars, the pharmaceutical composition comprising a ceruminolytic agent and a pharmaceutically acceptable carrier being essentially consisted of an oil.

According to some embodiments of the invention, the ceruminolytic agent is selected from the group consisting of saline, sodium bicarbonate, hydrogen peroxide, acetic acid, glycerin, acetone, triethanolamine polypeptide, docusate sodium, aluminum acetate, benzethonium chloride, liquid paraffins, olive oil, menthol oil, squalane, olive- squalane, isopropyl myristate, jojoba oil and any combination thereof.

According to some embodiments of the invention, the oil is selected from the group consisting of a mineral oil, a mineral oil replacement, a vegetable oil, and a combination thereof.

According to some embodiments of the invention, the dispensing device comprises a nozzle having an outlet aperture, the nozzle being configured to cause the pharmaceutical composition to be dispensed through the outlet aperture as liquid spray particles at the pressure.

According to some embodiments of the invention, any one of the devices as described herein is selected from the group consisting of an aerosol spray dispenser and a pump-type spray dispenser.

According to some embodiments of the invention, for any one of the devices as described herein, the device is a metered dose spray dispenser.

According to an aspect of some embodiments of the present invention there is provided a method of treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject, the method comprising administering to an ear canal of a subject in need thereof a therapeutically effective amount of a pharmaceutical composition that comprises a ceruminolytic agent upon subjecting the composition to a pressure of at least 5 bars, thereby treating the ceruminosis and/or ceruminosis-associated disease or disorder.

According to some embodiments of the invention, the ceruminolytic agent is selected from the group consisting of saline, sodium bicarbonate, hydrogen peroxide, acetic acid, glycerin, acetone, triethanolamine polypeptide, docusate sodium, aluminum acetate, benzethonium chloride, liquid paraffins, olive oil, menthol oil, squalane, olive- squalane, isopropyl myristate, jojoba oil and any combination thereof.

According to some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier that consists essentially of an oil.

According to some embodiments of the invention, the oil is selected from the group consisting of a mineral oil, a mineral oil replacement, a vegetable oil, and a combination thereof.

According to some embodiments of the invention, the administering is effected by means of a dispensing device that comprises the composition and is configured to dispense the composition as liquid spray particles at the pressure.

According to some embodiments of the invention, the administering is effected for a time period of from 2 to 14 days.

According to some embodiments of the invention, the administering is effected from one to three times a day.

According to some embodiments of the invention, the therapeutically effective amount comprises from 0.1 to 1 ml of the pharmaceutical composition.

According to some embodiments of the invention, a method as described herein further comprises, subsequent to the administering, removing cerumen from the ear of the subject.

According to some embodiments of the invention, the removing is effected by a means selected from the group consisting of forceps, a loop, a curette and a suction apparatus.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIGs. 1A-B present schematic illustrations of an exemplary embodiment of a pump-type spray dispensing device. The dispensing device comprises a container (FIG. IB) for holding the formulation; and a pump mechanism, a nozzle, and additional means for operating the device (FIG. 1A). DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to pharmacology, and more particularly, but not exclusively, to novel pharmaceutical composition and devices for delivering same, and to uses thereof in the treatment of ceruminosis (ear wax blockage) and associated diseases and/or disorders.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

In a search for novel formulations for effecting cerumen removal and thereby treating ceruminosis, the present inventor has recognized that olive squalane, a widely acceptable component in a variety of cosmetics, soaps and pharmaceutical preparations, has a chemical composition that resembles cerumen (see, for example, U.S. Patent Application having Publication No. 2004/0126436), yet, as opposed to the highly viscous/solid consistency of cerumen, olive-squalane is liquid at ambient temperature. The present inventor has thus envisioned that by effecting a collision of the liquid particles of olive-squalane with the solid cerumen particles, kinetic energy would be transformed to the solid particles, resulting in increasing the distances between the solid particles and thus in facilitated removal of cerumen.

The present inventors have thus designed a ceruminolytic composition that comprises olive-squalane as a ceruminolytic agent, which can be applied in a form of a spray. When such a composition is subjected to pressure, spray particles are produced, and the composition has been designed so as to produce such spray particles that have a kinetic energy sufficient to transform at least a portion of a substantially solid cerumen into a liquid cerumen upon impacting the solid cerumen.

The designed compositions utilized olive-squalane in an oily vehicle, namely a carrier that consists essentially of oil, which is non-irritating and further, can be used as a washing medium. Due to their oily nature, the designed compositions are not conducive to the growth of microorganisms and accordingly, do not require the inclusion of preservatives, which may cause or contribute to irritation and/or allergy.

In several clinical studies conducted by spraying such olive- squalane-containing compositions, it was demonstrated that when administered as a spray, exceptional performance in cerumen removal is observed.

According to an aspect of some embodiments of the present invention, there are provided pharmaceutical compositions comprising a ceruminolytic agent and pharmaceutically acceptable carrier. In some embodiments, the carrier is substantially consisted of an oil. In some embodiments, the ceruminolytic agent is olive-squalane.

In some embodiments, there is provided a pharmaceutical composition that comprises olive-squalane and a pharmaceutically acceptable carrier substantially consisting of an oil.

As used herein, a "ceruminolytic agent" is an agent which has activity in eliminating or reducing the amount of impacted cerumen in a mammalian ear canal. Elimination or reduction of impacted cerumen by a ceruminolytic agent can be effected by facilitating the removal of the impacted cerumen from the ear canal, with in turn, can be effected by softening, melting or dissolving the impacted cerumen, or by otherwise transforming the impacted cerumen into liquid particles.

As used herein, the term "impacted cerumen" describes an accumulated cerumen that has a solid or highly viscous (semi-solid) consistency.

The term "olive-squalane", which is also referred to herein and in the art as "plant squalane", denotes the saturated triterpene compound having the formula C30H62, chemically named 2,6,10,15,19,23-hexamethyltetracosane (CAS No. 111-01-3), which is derived from a vegetable source or a refining product thereof. In some embodiments, the term "olive-squalane" does not encompass squalane which is solely the product of in vitro chemical synthesis, and squalane which is derived from liver oils of sharks. In some embodiments, the olive-squalane may be that produced using methods that involve chemical methods such as hydrogenation, but the required starting material is a vegetable source or a refining product thereof, and not a synthetic chemical compound.

Olive-squalane is known as a high value biological material, that has been widely used as an ingredient for the formulation of cosmetics, as well as a carrier of lipid soluble drugs.

An olive-squalane that is suitable for use as a ceruminolytic agent according to some embodiments of the invention may be derived from any plant source, or refining product thereof. Exemplary plant oil refining products suitable for use in the context of some embodiments of the present invention are those which contain significant concentrations of phytosqualene, which is the unsaturated triterpene compound having the formula C30H50, chemically named 2,6, 10,15, 19,23-hexamethyl-2,6, 10, 14,18,22- tetracosahexaene (CAS No. 7683-64-9). Phytosqualene may be readily converted to olive-squalane by hydrogenation processes, as is known in the art.

Plant oil refining products suitable for the production of olive-squalane from phytosqualene, include for example, condensation products from the refining of olive oil, palm oil, palm kernel oil, coconut oil, soybean oil and sunflower oil.

In particular, phytosqualene is found in high concentration in waste residues from the final step in olive oil manufacturing, known as olive oil deodorizer distillates (ODD). The extraction of phytosqualene from ODD using supercritical fluid extraction with carbon dioxide to obtain nearly pure squalene, and its subsequent hydrogenation to squalane in supercritical carbon dioxide has been described in the art. In addition, U.S. Patent Publication No. 2004/0015033 describes a method for the production of squalane which involves extraction, using a compressed gas, of intermediate products from the processing of vegetable oils to obtain squalene, and its subsequent hydrogenation to squalane.

Additional methods for the production of plant squalane from residues of vegetable oils are described in the prior art. Spanish Patent application No. ES 2002428 relates to a process for the production of vegetable squalane in which a pressing residue from olive oil production is first partly hydrogenated to give a mixture of squalene, squalane, hydrocarbons and unsaturated fatty acids; the resultant mixture is converted by fractional crystallization into a liquid concentrate of which the free fatty acids are saponified by addition of a base and removed; the remaining fraction is then hydrogenated to convert squalene into squalane. Paraffins still present in the fraction may reportedly be removed by distillation. Spanish Patent application No. ES 2011259 describes a similar process, in which the acidic pressing residue is freed from fatty acids by distillation and saponification; the residue is hydrogenated, the paraffins are frozen out ("winterizing") and pure olive-squalane is obtained by distillation. Spanish Patent No. ES 2063697 describes carrying out deparaffination by washing with sulfuric acid. Japanese Patent application No. JP-A Hei 09/176057 describes a process for squalane production, starting from a distillation product accumulating in the purification of olive oil, which contains 35% by weight of squalene and 50% by weight of free fatty acids, which is freed from the acids and hydrogenated. The squalane-containing fraction is then dissolved in isopropyl alcohol and deparaffinized by addition of urea. Japanese Patent application No. JP-A Hei 06/306387 describes hydrogenation of residues of squalene-containing oils, such as olive oil, soybean oil or palm oil, and subsequent purification by fractional crystallization. Additional methods are described in Japanese patent application No. JP-A Hei 06/306388 and German Patent application No. DE 4316620.

In some embodiments of the invention, the olive-squalane present in the formulation is derived from olive (Olea europaea). In some embodiments, the olive- squalane is derived from a vegetable oil refining product, such as that produced in the course of manufacture of olive oil, palm oil, palm kernel oil, coconut oil, soybean oil or sunflower oil.

As used herein, a "pharmaceutically acceptable carrier" describes a vehicle, diluent and/or an exipient that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered pharmaceutically active ingredient (herein a ceruminolytic agent, e.g., olive-squalane). A pharmaceutically acceptable vehicle generally facilitates any one or more of administration, delivery, absorption and pharmacokinetic profile of the pharmaceutically active ingredient with which it is combined, and usually does not have any pharmaceutical activity of its own.

According to embodiments of the present invention, the pharmaceutically acceptable carrier substantially consists of one or more oils. Such a carrier is also referred to herein as a "pharmaceutically acceptable oily vehicle" or simply as "oily carrier" or "oily vehicle".

By "substantially consisted of" or any grammatical diversion of this expression, it is meant that the carrier includes at least 80 , at least 90 , at least 95 , at least 98 , at least 99 , at least 99.5 , at least 99.9 % or even 100 , by weight, of one or more oils, of the total weight of the carrier. The carrier may include minute amounts of organic solvents or other organic materials, and/or minute amounts of water or an aqueous solution, however, such minute amounts are no more than 20 , preferably no more than 10 , no more than 5 , no more than 1 , no more than 0.5 , and preferably no more than 1 , by weight, of the total weight of the carrier.

In the context of the present embodiments, the major functions of the pharmaceutically acceptable oily vehicle are to assist in administration of the ceruminolytic agent and to provide a washing medium for removal of impacted cerumen.

Pharmaceutical compositions according to embodiments of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, as described herein. Proper formulation is dependent upon the route of administration chosen.

In some embodiments, the oil consisting the carrier is a mineral oil, a vegetable oil or a combination thereof.

The term "mineral oil", as used herein, describes a clear colorless nearly odorless and tasteless liquid obtained from the distillation of petroleum. It may also be referred to as white oil, white mineral oil, liquid petrolatum, liquid paraffin or white paraffin oil. In some embodiments of the invention, the mineral oil is light mineral oil. In some embodiments, light mineral oil is a commercially available product which may be obtained either as a NF (National Formulary) grade product or as a USP (US Pharmacopoeia) grade product. In some embodiments, the mineral oil is preferably free of aromatics and unsaturated compounds.

Non-limiting examples of vegetable oils suitable for use in the context of the present embodiments include almond oil, canola oil, coconut oil, corn oil, cottonseed oil, peanut oil, saffron oil, sesame oil, soybean oil, and any combination thereof.

In some embodiments, the vegetable oil comprises almond oil.

In some embodiments, the vegetable oil is almond oil.

In some embodiments, the oily vehicle comprises light mineral oil.

In some embodiments, the oily vehicle comprises light mineral oil or almond oil.

In some embodiments, the oily vehicle consists of light mineral oil.

In some embodiments, the vehicle consists of almond oil.

In some embodiments, the oily vehicle consists of a mixture of light mineral oil and almond oil

The oily vehicle may alternately or in addition comprise a mineral oil replacement. Mineral oil replacements include alkanes having at least 10 carbon atoms (e.g., isohexadecane), benzoate esters, aliphatic esters, noncomodogenic esters, volatile silicone compounds (e.g., cyclomethicone), and volatile silicone substitutes. Examples of benzoate esters include C^Qs alkyl benzoate, isostearyl benzoate, 2-ethyl hexyl benzoate, dipropylene glycol benzoate, octyldodecyl benzoate, stearyl benzoate, and behenyl benzoate. Examples of aliphatic esters include CnCis alkyl octonoate and dioctyl maleate. Examples of noncomodogenic esters include isononyl isononanoate, isodecyl isononanoate, diisostearyl dimer dilinoleate, arachidyl propionate, and isotridecyl isononanoate. Examples of volatile silicone substitutes include isohexyl decanoate, octyl isononanoate, isononyl octanoate, and diethylene glycol dioctanoate.

Isohexadecane may be included in the oily vehicle to help reduce excess greasiness of the formulation.

Cyclomethicone is an evaporative silicone which may be included in the oily vehicle to assist in making the formulation amenable to ejection from a pump-type spray dispenser. Furthermore, due to its evaporative property, cyclomethicone may assist in retaining and fixing the formulation on the surface to which it is sprayed e.g. the ear canal.

According to some embodiments of the invention, a concentration of the olive- squalane in the composition ranges from 5 to 30 weight percents, or from 10 to 30 weight percents, or from 15 to 30 weight percents or from 20 to 30 weight percents, or from 22 to 28 weight percents, based on the total weight of the composition. Any value within the indicated ranges is contemplated.

In some embodiments, a concentration of the olive- squalane is about 25 weight percents, based on the total weight of the composition.

According to some embodiments of the invention, a concentration of the oily carrier, as described herein, is at least 50 weight percents, at least 60 weight percents or at least 65 weight percents, based on the total weight of the composition. According to some embodiments of the invention, a concentration of the oily carrier, as described herein, ranges from 60 to 80 weight percents, or from 70 to 80 weight percents, or from 70 to 75 weight percents, based on the total weight of the composition. Any value within the indicated ranges is contemplated.

In some embodiments, a concentration of the oily carrier is about 75 weight percents, based on the total weight of the composition.

Thus, according to some embodiments of the present invention, the olive- squalane is present in the composition in an amount that ranges from 15 to 30 weight percents, or from 20 to 30 weight percents, or from 22 to 28 weight percents, or is 25 weight percents, based on the total weight of the composition; and the pharmaceutically acceptable carrier which consists of an oil (the oily vehicle) is present in the composition in an amount that ranges from 60 to 80 weight percents, or from 70 to 80 weight percents, or from 70 to 75 weight percents, based on the total weight of the composition.

In some embodiments, the pharmaceutical composition as described herein further comprises one or more additional compounds, also referred to herein as additives.

In some embodiments, a concentration of the one or more additives ranges from

0.5 to 15 or from 0.5 to 10 or from 0.5 to 5 weight percents, based on the total weight of the composition.

Exemplary additional components include, but are not limited to, a fragrant oil, a moisturizing oil, a disinfecting oil and any combination thereof.

In some embodiments, the pharmaceutical composition further comprises a fragrant oil.

A "fragrant oil" describes an oil which produces an olfactory effect. Fragrant oils include perfume oils and natural aroma mixtures, such as those accessible from plant sources, for example citrus oil, jasmine oil, mint oil, patchouli oil, peppermint oil, pine oil, rose oil, spearmint oil, spruce oil and ylang-ylang oil. Also suitable are muscatel oil, salvia oil, chamomile oil, clove oil, lemon balm oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, and labdanum oil, orange blossom oil, neroli oil, orange peel oil, and sandalwood oil. Other suitable fragrant oils include, but are not limited to, oils derived from fruits such as almond, apple, cherry, grape, pear, pineapple, orange, strawberry, raspberry; and oils derived from flowers such as lavender, iris, and carnation. Other fragrant oils include musk, rosemary, thyme and sage. Lists of suitable fragrant oils are provided, for example, in U.S. Patent Nos. 4,534,891, 5,112,688 and 5,145,842, which are incorporated by reference as if fully set forth herein.

Representative examples of fragrant oils usable in the context of the present embodiments include, but are not limited to, mint oil, peppermint oil, pine oil, spearmint oil, spruce oil and any combination thereof. In some embodiments, the fragrant oil is spearmint oil.

In some embodiments, a concentration of the fragrant oil ranges from about 0.1 to 10 weight percents, or from 0.1 to 5 weight percents or from 0.1 to 1 weight percent or is about 0.5 weight percent, based on the total weight of the formulation.

In some embodiments, the additive comprises an additional oil which has disinfecting and/or a moisturizing properties, referred to herein as a disinfecting oil or a moisturizing oil. Exemplary oils which can act as disinfecting and/or moisturizing oil include, but are not limited to, turmeric oil, oregano oil, black cumin seed oil, tea tree oil, eucalyptus oil, lavender oil, rosemary oil and any combination thereof.

In some embodiments, the composition comprises turmeric oil as an additive.

In some embodiments, the composition comprises one or more of turmeric oil, oregano oil and black cumin seed oil, as additives.

The disinfecting and/or moisturizing oil is suitably present in the formulation in an amount of from about 0.5 to about 15 weight percents, or from about 0.5 to about 10 weight percents, from about 0.5 to about 5 weight percents, based on the total weight of the composition. In some embodiments, the disinfecting and/or moisturizing oil is present in the formulation in an amount of about 1 weight percent, or in an amount of about 3 weight percents, based on the total weight of the composition.

In some embodiments, the composition comprises an additive and the additive comprises both a fragrant oil and a disinfecting and/or moisturizing oil, as described herein.

In some embodiments, the additive comprises one or more ingredients which provide an additional therapeutic activity and/or assist in the dispensing and delivery performance of the formulation. Suitable such ingredients include, but are not limited to, an antibiotic, an antimycotic agent, an anti-inflammatory agent, a thickener, a dispersing agent, a disinfectant, an emulsifier and any combination thereof. The selection and combination of such ingredients may be readily determined by one of skill in the art.

It is to be understood that a single ingredient can perform more than a single function in the compositions according to the present embodiments. Thus, it should be understood in applying the claims to a given composition that because an ingredient of the composition may perform more than one function, that one ingredient may thereby satisfy more than one limitation of a claim. For example, mineral oil, which forms a part of the oily vehicle as described herein, may also act as ceruminolytic. If mineral oil is present in a formulation in at least the minimum concentration for a ceruminolytic agent specified by the limitation of a given claim, then the mineral oil of that formulation meets the claim limitation relating to a ceruminolytic agent. According to some embodiments of the present invention, an exemplary pharmaceutical composition as described herein comprises:

olive- squalane, in a concentration that ranges from 15 to 30 weight percents, based on the total weight of the composition; and

a pharmaceutically acceptable carrier that comprises, or is consisted essentially of, light mineral oil, almond oil or a combination thereof, in an amount of about 70 to 85 weight percents, based on the total weight of the composition.

According to some embodiments of the present invention, an exemplary pharmaceutical composition as described herein comprises:

olive- squalane, in a concentration that ranges from 15 to 30 weight percents, based on the total weight of the composition;

a pharmaceutically acceptable carrier that comprises, or is consisted essentially of, light mineral oil, almond oil or a combination thereof, in an amount of about 70 to 80 weight percents, based on the total weight of the composition; and

a fragrant oil, as described herein, in a concentration that ranges from 0.1 to 1 weight percent, based on the total weight of the composition.

According to some embodiments of the present invention, an exemplary pharmaceutical composition as described herein comprises:

olive- squalane, in a concentration that ranges from 15 to 30 weight percents, based on the total weight of the composition;

a pharmaceutically acceptable carrier that comprises, or is consisted essentially of, light mineral oil, almond oil or a combination thereof, in an amount of about 70 to 80 weight percents, based on the total weight of the composition;

a fragrant oil, as described herein, in a concentration that ranges from 0.1 to 1 weight percent, based on the total weight of the composition; and

an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and any combination thereof, in an amount that ranges from 0.5 to 5 weight percents, based on the total weight of the composition.

According to some embodiments of the present invention, a pharmaceutical composition as described herein comprises a ceruminolytic agent such as olive- squalane, as described herein; a fragrant oil, as described herein; and a pharmaceutically acceptable oily vehicle, as described herein, which comprises, or consists essentially of, a mineral oil, a vegetable oil, and any combination thereof, as described herein.

The following lists examples of pharmaceutical compositions according to some embodiments of the invention.

According to some embodiments, a pharmaceutical composition as described herein comprises:

olive- squalane, present in an amount of about 15 to 30 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.1 to 1 weight percent, based on the total weight of the composition; and

light mineral oil, almond oil or a combination thereof, present in an amount of about 70 to 80 weight percents, based on the total weight of the composition,

and optionally further comprises:

an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and combinations thereof, present in an amount of about 0.5 to 5 weight percents, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

light mineral oil, present in an amount of about 74 weight percents, based on the total weight of composition; and

an additional oil selected from the group consisting of turmeric oil, oregano oil, black cumin seed oil and combinations thereof, present in an amount of about 1 weight percents, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition; light mineral oil, present in an amount of about 74 weight percents, based on the total weight of composition; and

turmeric oil, present in an amount of about 1 weight percent, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

light mineral oil, present in an amount of about 74 weight percents, based on the total weight of composition; and

oregano oil, present in an amount of about 1 weight percent, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

light mineral oil, present in an amount of about 74 weight percents, based on the total weight of composition; and

black cumin seed oil, present in an amount of about 1 weight percent, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

light mineral oil, almond oil or a combination thereof, present in an amount of about 72 weight percents, based on the total weight of composition; and a combination of turmeric oil, oregano oil and black cumin seed oil, each present in an amount of about 1 weight percent, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

almond oil, present in an amount of about 72 weight percents, based on the total weight of composition; and

a combination of turmeric oil, oregano oil and black cumin seed oil, each present in an amount of about 1 weight percent, based on the total weight of the composition.

In some embodiments, a pharmaceutical composition as described herein consists essentially of:

olive- squalane, present in an amount of about 24.5 weight percents, based on the total weight of the composition;

spearmint oil, present in an amount of about 0.5 weight percents, based on the total weight of the composition;

a combination of light mineral oil and almond oil, each present in an amount of about 36 weight percents, based on the total weight of composition; and

a combination of turmeric oil, oregano oil and black cumin seed oil, each present in an amount of about 1 weight percent, based on the total weight of the composition.

It is to be noted that unless otherwise specified, percentages stated herein are in relation to the final weight of the total formulation. It is further to be noted that all numerical values stated herein include a standard deviation that is acceptable in the pharmaceutical arts, and appropriate for any particular component.

As discussed hereinabove, the present inventor has envisioned and demonstrated that when a ceruminolytic agent such as olive squalane is used in the form of spray particles, it efficiently facilitates cerumen removal by interfering within the solid cerumen particles, increasing the distance therebetween and thus transforming at least a portion of impacted cerumen into liquid particles and softening the impacted cerumen.

Thus, according to some embodiments of the present invention, each of the pharmaceutical compositions described herein is in a form of a spray.

As used herein and in the art, the term "spray" describes a jet or mass of finely divided liquid particles or droplets.

Accordingly, in some embodiments, each of the pharmaceutical compositions described herein is in a form of liquid spray particles.

As further known in the art, liquid spray particles are formed upon subjecting a liquid to pressure.

Accordingly, in some embodiments, liquid spray particles of the pharmaceutical composition as described herein are formed upon subjecting any of the pharmaceutical compositions described herein, when in a liquid form, to a pressure.

Preferably, subjecting the composition to pressure is effected so as to provide particles with kinetic energy for effecting the desired ceruminolytic activity, e.g., softening the impacted cerumen.

Without being bound by any particular theory, it is assumed that when the composition is utilized in a form of liquid spray particles, a collision occurs between these particles and the impacted cerumen, which has a substantially solid consistency. Since the chemical composition of olive- squalane resembles that of the cerumen, the collision between these materials results in "slamming" of the composition liquid particles within the solid cerumen particles. As a result of the collision, some of the kinetic energy of the spray particles is transferred to the cerumen solid particles, and thus, the distance between the solid cerumen particles in increased (due to the transferred kinetic energy) and as a result, the mixture of the liquid spray particles and the distanced solid particles, which has a less viscous consistency compared to the impacted cerumen, and even a liquid consistency, is obtained.

In some embodiments, the liquid spray particles have a kinetic energy sufficient to transform at least a portion of an impacted (substantially solid) cerumen into a liquid cerumen upon impacting the cerumen.

As discussed hereinabove, "a kinetic energy sufficient to transform at least a portion of an impacted (substantially solid) cerumen into a liquid cerumen" is an energy sufficient to allow the liquid spray particles of the composition as described herein to collide with, and thereby to transfer energy to, at least a portion of cerumen particles, whereby the result of this collision and energy transfer is an increased distance between the cerumen particles, and liquid consistency of at least a portion of the impacted cerumen.

By "at least a portion" it is meant at least 20 , at least 30 , at least 40 , at least 50 , at least 60 , at least 70 , at least 80 , at least 90 , and even more weight percents of the impacted cerumen.

In some embodiments, the required kinetic energy of the liquid spray particles is achieved by subjecting the composition, when in a liquid form, to a pressure of at least 5 bars.

In some embodiments, the pressure is of at least 6 bars or at least 6.5 bars. In some embodiments, the pressure ranges from 5 bars to 9 bars, or from 6 bars to 9 bars, or from 6.5 bars to 9 bars, or from 7 bars to 9 bars.

In some embodiments, subjecting the pharmaceutical composition to a pressure as described herein is performed by means of pressurizing the composition within a container.

According to some embodiments, any of the pharmaceutical compositions described herein is a pressurized composition.

In some embodiments, any of the pharmaceutical compositions described herein is packaged in a container and is pressurized within the container at a pressure of at least 5 bars, as described herein.

In some embodiments, the container is configured to release therefrom the pharmaceutical composition in a form of liquid spray particles, as described herein.

Thus, in some embodiments, the container is a spray dispenser, as is further described in detail hereinbelow.

According to an aspect of some embodiments of the present invention, there is provided a pharmaceutical composition as described herein, preferably in a form a pressurized composition or in a form of liquid spray particles, as described herein, which is identified for use in the treatment of ceruminosis and/or a ceruminosis- associated disease or disorder in a subject in need thereof.

In some embodiments, the treatment is effect by administering the composition to an ear canal, e.g., an external ear canal, of the subject.

According to an aspect of some embodiments of the present invention, there is provided a use of the pharmaceutical composition as described herein, preferably in a form a pressurized composition or in a form of liquid spray particles, as described herein, in the manufacture of a medicament for treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject in need thereof.

According to an aspect of some embodiments of the present invention, there is provided a method of treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject, which is effected by administering a therapeutically effective amount of the composition as described herein, preferably in a form a pressurized composition or in a form of liquid spray particles, as described herein, to an ear canal (e.g., an external ear canal) of a subject in need thereof.

While some embodiments of the present invention concern a use of olive- squalane as a ceruminolytic agent, it can be readily recognized that the effect of the spray particles as described herein can be exhibited also by compositions comprising other ceruminolytic agents.

According to an aspect of some embodiments of the present invention, there is provided a method of treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject, which is effected by administering to an ear canal of a subject in need thereof a therapeutically effective amount of a pharmaceutical composition that comprises a ceruminolytic agent, upon subjecting the composition to a pressure of at least 5 bars, as described herein.

Similarly, according to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition which comprises a ceruminolytic agent and a pharmaceutically acceptable carrier, which is identified for use in treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject in need thereof upon subjecting a liquid form of the composition to a pressure of at least 5 bars, as described herein.

According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition, in a form of liquid spray particles, or in a pressurized form, as described herein, which comprises a ceruminolytic agent and a pharmaceutically acceptable carrier, which is identified for use in treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject in need thereof.

According to an aspect of some embodiments of the present invention there is provided a use of pharmaceutical composition which comprises a ceruminolytic agent and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject in need thereof upon, wherein the medicament comprises the composition in a form of liquid spray particles or in a pressurized form, as described herein.

According to an aspect of some embodiments of the present invention there is provided a use pharmaceutical composition which comprises a ceruminolytic agent and a pharmaceutically acceptable carrier, which is identified for use in treating ceruminosis and/or a ceruminosis-associated disease or disorder in a subject in need thereof, wherein the treatment is effected by subjecting a liquid form of the composition to a pressure of at least 5 bars, as described herein.

Exemplary ceruminolytic agents that are suitable for use in some embodiments of the invention include, but are not limited to, saline, sodium bicarbonate, hydrogen peroxide, acetic acid, glycerin, acetone, triethanolamine polypeptide, docusate sodium, aluminum acetate, benzethonium chloride, liquid paraffins, olive oil, menthol oil, squalane, olive-squalane, isopropyl myristate, jojoba oil and any combination thereof.

In some embodiments, the pharmaceutically acceptable carrier consists essentially of an oil, as described herein (e.g., of a mineral oil, a mineral oil replacement, a vegetable oil, or a combination thereof).

In some embodiments of any of the methods and uses described herein administering the composition is effected by subjecting the composition to a pressure, to thereby form liquid spray particles of the compositions.

In some embodiments of any of the methods and uses described herein administering the composition is effected by means of a dispensing device that comprises a composition (e.g., a pressurized composition) and is configured to dispense the composition as liquid spray particles at the indicated pressure.

As used herein, the term "ceruminosis" describes excessive or disordered formation of impacted cerumen in an ear (e.g., in an external ear canal) of a subject.

Ceruminosis is associated with diseases, disorders or symptoms such as hearing loss, pain, itching, tinnitus, vertigo, external otitis and chronic cough.

As used herein, the term "subject" refers to a vertebrate, preferably a mammal

(e.g., a dog, a cat, a horse), more preferably a human being (male or female) at any age.

A "subject in need thereof" is one who exhibits at least one clinical sign or symptom of ceruminosis i.e. impaction of cerumen in the outer ear canal. Such signs and symptoms may include any of hearing loss, feeling of fullness in ear, pain, pruritis, tinnitus, vertigo, external otitis and cough.

Pharmaceutical compositions suitable for use in context of the present embodiments include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose, described herein as a therapeutically effective amount.

Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

For any composition used in the methods and uses of the present embodiments, the therapeutically effective amount or dose can be estimated initially from activity assays in animals or from clinical studies in animals or humans. Such information is presented hereinbelow in the Examples section that follows, can be used to more accurately determine useful doses in humans.

The exact formulation and dosage can be chosen by the individual physician in view of the patient's condition.

Dosage amount and interval may be adjusted individually to provide an amount of the active moiety which is sufficient to maintain the desired effects.

Depending on the severity and responsiveness of the condition to be treated, the course of treatment can last from several days to several weeks or until cure is effected or diminution of the condition being treated is achieved.

The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the judgment of the prescribing physician, etc.

In some embodiments, the administering is carried out for a time period of from

2 to 30 days, or from 2 to 14 days, or from 2 to 7 days. In some embodiments, the administering is carried out for one week.

During the treatment period, in some embodiments, administering is effected from one to three times a day, preferably 3 times a day.

In some embodiments, each administration comprises a dose of from 0.1 to 1 ml of the pharmaceutical composition, or from 0.1 to 5 ml of the composition (e.g., 0.2 ml of the composition). In some embodiments, upon treating ceruminosis as described herein, the cerumen spontaneously exits the ear canal.

In some embodiments, treatment with the compositions as described herein is followed by removing cerumen from the ear of the subject.

Any of the currently known methods for removing cerumen in contemplated, include, for example, removal by a means of forceps, a loop, a curette and/or a suction apparatus.

In any of the methods and uses described herein, the pharmaceutical compositions disclosed herein are preferably utilized by means of a dispensing device, which is configured to contain the composition and to dispense the composition in a form of spray, as described herein.

According to an aspect of some embodiments of the present invention, there is provide a dispensing device comprising a pharmaceutical composition and being configured for dispensing the composition as liquid spray particles at a pressure of at least 5 bars.

In some embodiments, the pharmaceutical composition comprising a ceruminolytic agent, as described herein.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, as described herein. In some embodiments, the carrier is essentially consisted of an oil, as described herein.

In some embodiments, the pharmaceutical composition comprises olive- squalane and an oily vehicle, as described herein.

As used herein, a "dispensing device", also referred to herein as a "spray dispenser" describes a container which holds the composition as described herein, and includes a mechanism for releasing or ejecting the composition in a form of a spray, as defined herein.

In some embodiments, the dispensing device comprises a nozzle having an outlet aperture, the nozzle being configured to cause the pharmaceutical composition to be dispensed through the outlet aperture as liquid spray particles at the indicated pressure.

In some embodiments, the dispensing device is a hand-held dispensing device. The hand held dispensing device may be any type of spray dispenser known in the art, which typically includes a nozzle having an outlet aperture through which the composition is expelled or ejected in the form of a spray upon depression of the nozzle, for example, by application of finger pressure. The activation of the device by depression of the nozzle may also be referred to as "actuation".

The dispensing device may be a pump-type dispensing device or an aerosol dispensing device.

A pump-type spray dispenser dispenses the formulation under normal atmospheric pressure; application of finger pressure temporarily pressurizes the formulation to cause a portion of it to leave the dispenser as a spray. The pressure in the mechanism returns to atmospheric soon after the portion of formulation has been dispensed. Pump-type spray dispensers are disclosed, for example, in U.S. Patent Nos. 3,159,316; 4,034,900, and 4,050,860. A pump-type spray dispenser for administering medicaments to the ear is disclosed for example, in U.S. Patent No. 5,176,654.

An "aerosol" spray dispenser describes a spray dispenser that contains the formulation to be dispensed, and a gas under pressure. Such a dispenser typically comprises a metal container (made for example, from aluminum or tinplate) for holding the composition and gas, so that the dispenser can withstand pressure higher than atmospheric pressure. The composition is typically a liquid mono-phasic solution (i.e. homogeneous solution) or in bi-phasic solution (i.e. aqueous solution and oil solution). The container is tightly closed with a valve orifice, and then an aerosol propellant (i.e. a liquefied gas), such as butane, propane, a hydrofluoroalkane mixture or any other propellant as is known in the art, is inserted, thus creating pressure inside the container (e.g. of at least 5 bars). Agitation of the container, even minimally, causes the gas and liquid to mix; depression of the nozzle results in the ejection of the pressurized composition. Aerosol spray dispensers are disclosed, for example, in U.S. Patent Nos. 5,322,683; 5,397,564; and 6,730,288.

The dispensing device may be a metered dose dispensing device. Such a dispenser expels a pre-determined volume of the composition i.e. a metered dose, with each actuation of the device. Advantageously, a metered dose dispensing device prevents the waste and messiness of excess dosing, and ensures that a precise amount of the composition is inserted to the ear canal. Metered dose dispensing may be accomplished using either a pump-type spray dispenser or an aerosol spray dispenser. The amount of formulation ejected per actuation of the dispensing device is suitably in the range of about 0.1 to 1.0 ml, for example, about 0.2 ml. The specific amount ejected may be adjusted according to the age and approximate ear canal volume of the subject. For example, the ear canal volume of infants from birth to age one month is about 0.2 ml; that of a six month old infant is about 0.5 ml, and that of children older than twenty four months and of adults is about 2.0 ml. The determination of the appropriate volume per actuation is within the skill of the art.

Metered dose devices are known in the art for different applications, described for example, in U.S. Patent Nos. 6,032,836; 5,697,532; 5,502,076, and 6,702,155, and in U.S. Patent Application No. 2003/0178022.

It can be advantageous that the dispenser comprises an extension means mounted on the nozzle so as to be positioned over the outlet aperture. The extension means is adapted to access the outer ear of the subject since it provides a means of directing the composition into the ear canal upon actuation of the dispenser, without having to hold the dispenser in extremely close proximity to the ear of the subject. The shape of the extension means is suitably substantially cylindrical, and the length may be selected for ease of handling and administration. A suitable length is in the range of about 4 to 8 cm. The proximal terminal portion of the extension means is that which is disposed over the outlet aperture of the nozzle. The distal terminal portion is that which is adapted to access the outer ear of the subject. Depression of the nozzle causes the composition to be ejected through the distal terminal portion of the extension means, so as to be dispensed in the form of a spray, as described herein.

The extension means may be fixed in a single position i.e. stationary, or it may be capable of changing position i.e. articulating. The advantage of an articulating extension means is that it may be positioned in the closed position so as to prevent accidental ejection of the composition, and to provide ease of storage. In some embodiments, the angle of the articulating extension means may be altered so as to provide ease of administration to the ear canal of the subject.

In some embodiments, the distal terminal portion of the extension means has a substantially larger diameter than the proximal portion of the extension means, so as prevent entry of the extension means deeply into the ear canal. Advantageously, this embodiment provides a means of avoiding inadvertent mechanical damage to the ear canal upon administration of the formulation.

In some embodiments, the dispensing device is configured to release the composition in a form of a microspray or an aerosol.

Referring now to the drawings, Figure 1 shows an exemplary dispensing device according to some embodiments of the invention. A pump-type spray dispenser comprises a tube-shaped container (Figure IB) to hold the composition, a pump mechanism and a nozzle comprising an outlet aperture, as depicted in Figure 1A and is further described in the Examples section that follows.

The dimensions of the dispensing device, including that of the container, the nozzle, the extension means and additional parts, and the materials comprising same may be readily determined by those of skill in the art.

It is expected that during the life of a patent maturing from this application many relevant dispensing devices and spray dispensers will be developed and the scope of the term dispensing device is intended to include all such new technologies a priori.

As used herein the term "about" refers to ± 10 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to".

The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

The word "exemplary" is used herein to mean "serving as an example, instance or illustration". Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.

The word "optionally" is used herein to mean "is provided in some embodiments and not provided in other embodiments". Any particular embodiment of the invention may include a plurality of "optional" features unless such features conflict.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

EXAMPLE 1

Olive-squalane-containing ceruminolytic formulations Materials and Methods:

Olive squalane was obtained from (Helion Ltd.)

Light mineral oil was obtained from (Helion Ltd.)

Almond oil was obtained from (Helion Ltd.)

Turmeric oil was obtained from (Helion Ltd.)

Spearmint oil was obtained from (Helion Ltd.)

Oregano oil was obtained from (Helion Ltd.)

Nigella sativa oil was obtained from (Helion Ltd.)

Various ceruminolytic formulations, containing olive-squalane as a ceruminolytic agent, and oil vehicle (a light mineral oil and/or almond oil), a fragrance and optionally additional active or non-active ingredients, were prepared by mixing the ingredient with Silverson Multipurpose Batch Mixer equipped with a special rotor/stator mixing head. The following lists exemplary formulations, comprising olive-squalane in a light mineral oil vehicle, prepared as described hereinabove:

Formulation 1

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 24.5 Ceruminolytic agent

Turmeric oil 1.0 Natural disinfectant

Spearmint oil 0.5 Fragrance

TOTAL 100 -

Formulation 2

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 24.5 Ceruminolytic agent

Oregano oil 1.0 Natural disinfectant

Spearmint oil 0.5 Fragrance

TOTAL 100 -

Formulation 3

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 24.5 Ceruminolytic agent

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 0.5 Fragrance

TOTAL 100 - Formulation 4

The following lists an exemplary formulation comprising, olive-squalane in an almond oil vehicle, prepared as described hereinabove:

Formulation 5

Ingredient Concentration (%w/w) Function

Almond oil 72.0 Vehicle and washing agent

Olive-squalane 24.5 Ceruminolytic agent

Turmeric oil 1.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 0.5 Fragrance

TOTAL 100 -

The following lists an exemplary formulation, comprising olive- squalane in a light mineral oil/almond oil vehicle, prepared as described hereinabove:

Formulation 6

Ingredient Concentration (%w/w) Function

Light mineral oil 36.0 Vehicle and washing agent

Almond oil 36.0 Vehicle and washing agent

Olive-squalane 24.5 Ceruminolytic agent

Turmeric oil 1.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 0.5 Fragrance

TOTAL 100 -

The following lists additional exemplary formulations:

Formulation 7

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Turmeric oil 11.0 Natural disinfectant

Spearmint oil 10.0 Fragrance

TOTAL 100 -

Formulation 8

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Oregano oil 11.0 Natural disinfectant

Spearmint oil 10.0 Fragrance

TOTAL 100 - Formulation 9

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Nigella sativa oil 11.0 Moisturizer

Spearmint oil 10.0 Fragrance

TOTAL 100 -

Formulation 10

Ingredient Concentration (%w/w) Function

Light mineral oil 72.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Turmeric oil 10.0 Natural disinfectant

Oregano oil 2.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 10.0 Fragrance

TOTAL 100 -

Formulation 11

Ingredient Concentration (%w/w) Function

Almond oil 72.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Turmeric oil 11.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 10.0 Fragrance

TOTAL 100 - Formulation 12

Ingredient Concentration (%w/w) Function

Light mineral oil 36.0 Vehicle and washing agent

Almond oil 36.0 Vehicle and washing agent

Olive-squalane 5.0 Ceruminolytic agent

Turmeric oil 11.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 10.0 Fragrance

TOTAL 100 -

Formulation 13

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 14.5 Ceruminolytic agent

Turmeric oil 6.0 Natural disinfectant

Spearmint oil 5.5 Fragrance

TOTAL 100 -

Formulation 14

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 14.5 Ceruminolytic agent

Oregano oil 6.0 Natural disinfectant

Spearmint oil 5.5 Fragrance

TOTAL 100 - Formulation 15

Ingredient Concentration (%w/w) Function

Light mineral oil 74.0 Vehicle and washing agent

Olive-squalane 14.5 Ceruminolytic agent

Nigella sativa oil 6.0 Moisturizer

Spearmint oil 5.5 Fragrance

TOTAL 100 -

Formulation 16

Ingredient Concentration (%w/w) Function

Light mineral oil 72.0 Vehicle and washing agent

Olive-squalane 14.5 Ceruminolytic agent

Turmeric oil 6.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 5.5 Fragrance

TOTAL 100 -

Formulation 17

Ingredient Concentration (%w/w) Function

Almond oil 72.0 Vehicle and washing agent

Olive-squalane 14.5 Ceruminolytic agent

Turmeric oil 6.0 Natural disinfectant

Oregano oil 1.0 Natural disinfectant

Nigella sativa oil 1.0 Moisturizer

Spearmint oil 5.5 Fragrance

TOTAL 100 - Formulation 18

EXAMPLE 2

Dispensing Device

An exemplary pump-type spray dispensing device for administering the compositions (formulations) as described herein, in a form of a spray, to an ear of a subject, is depicted in Figures 1A and IB

Figure 1A presents a pump mechanism and nozzle, which to be deposited onto a container that holds the formulation. Figure IB presents an exemplary, tube-shaped container 20, at least partially filled with a formulation 30 (a pharmaceutical composition as described herein, in a liquid form).

As depicted in Figure 1A, the pump mechanism and nozzle can be mounted onto container 20 by means of mounting cap 6. The pump mechanism is composed of a tube 17, which, when the pump mechanism is mounted in container 20, is in fluid communication with formulation 30; actuator 4; upper piston 5 and lower piston 11; springs 10 and 13; stem insert 12; and ball 16, all configured as depicted in Figure 1A for generating a pump mechanism (e.g., for generating a formulation in a form of liquid spray particles at outlet aperture 3). The pump mechanism and the mounting cap can further comprise matting 15; housing 14; gaskets 7 and 9; and collar 8, all as depicted in Figure 1A. The nozzle is depicted in Figure 1A as composed of canal 1; linker 2 and outlet aperture 3, all being in fluid communication with tube 17, as depicted in Figure 1A. It is to be noted that the heights, lengths, widths, and any other dimensions of the components composing the device can be modified as desired, and are not to be limited by the values as depicted in Figures 1A-B.

EXAMPLE 3

Clinical study I

The objective of the study was to evaluate the clinical efficacy of a ceruminolytic formulation comprising olive- squalane, for the removal of earwax. The results showed that following treatment, more than two thirds of the 38 ears treated showed complete to near-complete resolution of obstruction.

Study Protocol:

The study was approved by the institutional ethics review board of the Department of Otolaryngology-Head and Neck Surgery, Edith Wolfson Medical Center, Holon, Israel.

A total of 23 volunteers were examined during a 5-months period. All subjects signed informed consent. Subjects enrolled in the study were over 18 years old, without any previous ear disease, and none had any ear examination or treatment during the previous 6 months. Nineteen subjects were eventually included in the study: two patients were lost for follow up; one patient discontinued treatment after 5 days due to otalgia, and another completed full treatment, had no adverse effects, but refused follow up. The age range of the 19 patients was 65 to 88 years (mean age 75.7 years). There were 10 males and 9 females. All together, 38 ears were studied.

All gradings and treatments were done by the same physician. The degree of occlusion by cerumen was determined using a scale of 0 to 3:

0 = no obstruction

1 mild obstruction

2 moderate obstruction

3 complete obstruction,

as is further detailed in Table 1 below. Table 1

The type or the consistency of the cerumen was determined prior to treatment and afterwards in order to assess the effect of the medication on the cerumen, following the coding presented in Table 2 below.

Table 2

Otologic signs and symptoms and any possible adverse effects of the treatment were monitored.

The formulation investigated was composed of olive- squalane (25%), light mineral oil (74.5%), and spearmint oil (0.5%). The formulation was administered by means of a spray dispenser (e.g., as described in Example 2 hereinabove), for one week, 3 times a day. For each treatment, 2 puffs from the spray dispenser were instilled into the ear. Each puff contained approximately 0.2 ml of the formulation. After 1 week of treatment, the ears were examined and if any cerumen remained, it was removed using suction or Hartman's ear forceps. The duration of the removal procedure was timed, the suction size was documented and the subjects were asked to score their satisfaction on a 1 to 5 scale. Results:

The results are presented in Tables 3-5 below and in Figure 4.

Before treatment, 27 ears were completely occluded (score: 3), 5 ears had moderate occlusion (score: 2), 2 ears were mildly occluded (score: 1) and 4 ears had no obstruction (score:0). After completion of the treatment, there was no obstruction in 17 ears, mild obstruction (score: 1) in 10 ears, moderate obstruction (score: 2) in 4 ears and complete obstruction (score: 3) in 7 ears (see, Table 3 and Figure 4).

The consistency of the cerumen, when present, was found to be type A in 5 ears, type B in 15 ears and type C in 14 ears. Following treatment, the distribution was type A in 3 ears, type B in 6 ears and Type C in 12 ears (see, Table 4), showing that in remaining occlusion, of any degree, the cerumen tended to become softer.

The remaining cerumen was completely removed using suction (#13), within less than one minute, in 10 ears; Using suction (#14), within less than one minute, in 1 ear; Using suction (#13), within 1 minute to 5 minutes, in 2 ears; Using Hartman's ear forceps and suction (#13), within 1 minute to 5 minutes, in 6 ears; And using Hartman's ear forceps, within less than one minute, in 2 ears.

The otologic symptoms prior to the treatment with the formulation and afterwards (before complementary cerumen removal) are described in Table 5. Most symptoms in the study resolved after the treatment period.

All the patients described the use of the preparation as very satisfactory (5 on a 1 to 5 scale).

During the treatment period, 2 patients had some degree of pain in their ears during the application of the preparation, 1 described ear discharge and the other 16 patients had no symptoms during the use of the preparation.

Table 3

Pre-treatment and post-treatment obstruction scores

Obstruction Pre-Treatment Post-Treatment Score n (%) n (%)

0 4 (10.5) 17 (44.7)

1 2 (5.2) 10 (26.3) 2 5 (13.2) 4 (10.5)

3 27 (71.1) 7 (18.4)

Total 38 (100) 38 (100) number of ears; =percent of all ears)

Table 4

Pre-treatment and post-treatment cerumen type

number of ears; =percent of all ears)

Table 5

Pre-treatment and post-treatment otologic symptoms

(n=number of ears)

Discussion:

In the herein described study, complete or near-complete resolution of the ear obstruction was achieved in more than two thirds of the ears.

For comparison, in previous studies [Mehta AK. Br J Clin Pract 1985;39:200-3; Chaput de Saintonge DM and Johnstone CI. Br J Clin Pract 1973;27:454-5; Lyndon et al. Curr Med Res Opin 1992;13:21-5; and Hand C and Harvey I Br J Gen Prac 2004; 54: 862-867], the efficacy of ceruminolytic agents was evaluated by the need for syringing or other method of cerumen removal after their use. Such a need was found in 70 % to 80 % of the ears, as compared to only 55.3% in the present study.

The type of cerumen prior to treatment was dry in most ears. After treatment with the tested formulation, most of the cerumen was soft and amenable to removal.

While there are several commercially available products for removing cerumen, none so far has been shown to be reliably effective [Hand C and Harvey I Br J Gen Prac 2004; 54: 862-867; Browning G. Clin Evid 2002;7: 490-497; and Roland et al. Head Neck Surg 2004;130: 1175-7].

The superior efficacy of the formulation presented herein might be attributed to its combined mode of action: ceruminolysis and lubrication. In addition, spray administration appears to assist in efficiency, possibly due to deeper penetration of the ceruminolytic agent to the cerumen layers.

EXAMPLE 4

Clinical study II

The objective of the study was to evaluate the clinical efficacy of a ceruminolytic formulation comprising olive- squalane, for the removal of earwax. The results showed that following treatment, more than 80 % of the 148 ears treated showed complete to near-complete resolution of obstruction.

Study Protocol:

A prospective study involving 74 patients (148 ears) was conducted at the Department of Otolaryngology-Head and Neck Surgery, Bikur Cholim Hospital, Jerusalem, Israel.

The complaints, degree of obstruction and type of cerumen were recorded before and after treatment, substantially as described in Example 3 hereinabove. Patients were treated with the formulation as described in Example 3 hereinabove (dispensed from a device as described in Example 2 hereinabove), twice a day for one week.

Results:

Results after treatment were recorded by ease of external ear cleaning or spontaneous exit of cerumen.

The results may be summarized as follows: 12.2 % of patients had spontaneous extrusion of cerumen; 70.3 % of patients had an easy post-treatment ear cleaning and 17.5 % of patients had a moderate to difficult post-treatment ear cleaning.

The obtained data demonstrate that treatment of impacted cerumen with the tested formulation comprising olive-squalane in a spray dispenser facilitated easy ear cleaning of ears in the majority of patients (70.3 %) and provided spontaneous cleaning in more than 10 % (12.2 %) of the patients. Poor patient compliance may have contributed to cases of treatment failure.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.