The present invention relates to a topical administration form with virucidal properties. The present invention also relates to the topical administration form for use in prevention of infection with an enveloped virus.

Summary of the Invention

A first aspect of the invention relates to a topical administration form comprising at least two components selected from a. triclosan (CAS NO 3380-34-5); b. a plant component containing monoterpene hydrocarbon and/or monoterpene alcohol and/or sesquiterpene hydrocarbon and/or phenylpropanoid and/or capryl aldehyde and/or lauryl aldehyde and/or methyl nonyl ketone; and c. a metal compound, wherein the metal is selected from zinc, silver and copper, wherein the metal compound is an ionic salt or the elementary form of the metal.

A second aspect of the present invention relates to a topical administration form according to the first aspect for use in prevention of infection with an enveloped virus.

In another embodiment, the present invention relates a pharmaceutical composition comprising at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

Detailed Description of the Invention Terms and definitions

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

The terms “comprising,” “having,” “containing,” and “including,” and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of” or “consisting of.”

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictate otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

As used herein, including in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and biochemistry). Standard techniques are used for molecular, genetic and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (2002) 5th Ed, John Wiley & Sons, Inc.) and chemical methods.

As used herein, the term pharmaceutical composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition according to the invention is provided in a form suitable for topical, parenteral or injectable administration.

As used herein, the term pharmaceutically acceptable carrier includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington: the Science and Practice of Pharmacy, ISBN 0857110624).

As used herein, the term virucidal relates to a property of a compound or formulation, which leads to destruction, deactivation or substantial reduction of transmissibility or infectivity of a virus when brought in contact with the compound or formulation. In the context of the specification, this quality is particularly used in connection with deactivation of an enveloped virus. There is a difference between antiviral drugs and virucidal drugs or agents. Antiviral drugs do not destroy their target pathogen; instead they inhibit their development. They are mostly taken orally. Virucidal drugs or agents deactivate or destroy viruses. For topical administration, virucidal drugs or agents are needed, which not only inhibit the growth of the virus, but rather destroy the virus, thus, it cannot spread to other tissues and infect the host.

A first aspect of the invention relates to a topical administration form comprising at least two components selected from a. triclosan (CAS NO 3380-34-5); b. a plant component containing or essentially consisting of a compound selected from the group comprising a monoterpene hydrocarbon and/or monoterpene alcohol and/or sesquiterpene hydrocarbon and/or phenylpropanoid and/or capryl aldehyde and/or lauryl aldehyde and/or methyl nonyl ketone, or a mixture of two or more of the aforementioned group; and c. a metal compound, wherein the metal is selected from zinc, silver and copper, and wherein the metal compound is an ionic salt or the elementary form of the metal.

In certain embodiments, the metal compound is a nanoparticle, particularly a nanoparticle of elementary silver, copper or zinc.

In the context of the present specification, the term “nanoparticle” relates to a particle of matter that is between 1 and 100 nm in diameter. The most important property of metal nanoparticles is their large surface area to volume ratio, which increases their interaction with other molecules.

In certain embodiments, the topical administration form comprises all three components, triclosan, the terpene compound and the metal compound.

In certain embodiments, the plant component is a plant-derived essential oil. In certain embodiments, the plant component is selected from Pinus mugo pumilio twig leaf oil, Matricaria recutita/German chamomile, Melissa officinalis/lemon balm, Melaleuca alternifolia /tea tree, Aloysia gratissima/whitebrush/common Beebrush, Artemisia arborescen/great mugwort, Artemisia arborescens/great mugwort, Artemisia douglasiana/Californian mugwort, Cinnamonum verum/cinnamon leaf, Cymbopogon citratus/lemongrass, Eucalyptus globulus/eucalyptus, Eupatorium patens/Little Joe, Hyssopus officinalis/hyssop, lllicium verum/star anise, Juniperus oxycedrus/cade, Lavandula latifolia/lavender, Leptospermum scoparium/manuka, Mentha x piperita/peppermint, Origanum majorana/sweet majoram,

Pinus mugo/dwarf pine, Rosmarinus officinalis/rosemary, Santalum album/sandalwood, Santolina insularis/Santolina, Tessaria absinthioides, Thymus vulgaris/thyme, Zingiber officinale/ginger. In certain embodiments, the plant component is Pinus mugo pumilio twig leaf oil (CAS-Number: 90082-73-8).

Pinus mugo pumilio twig leaf oil (pine oil) is an essential oil obtained by the steam distillation of twigs and needles of the dwarf pine tree. There is evidence that it has properties inactivating an enveloped virus in vitro (Dellanno et al. Am J Infect Control. 2009 Oct;37(8):649-52). Pine oil has a relatively low toxicity level in human patients.

In certain embodiments, the concentration of triclosan in the topical administration form is 0.1-2% (w/w). In certain embodiments, the concentration of triclosan in the topical administration form is 0.3-1% (w/w). In certain embodiments, the concentration of triclosan in the topical administration form is 0.4% (w/w).

Triclosan is used as a biocide in hospitals and medical practice. It is effective against bacteria, fungi, and enveloped viruses. There is evidence that it has properties inactivating an enveloped virus in vitro (Dellanno et al. Am J Infect Control. 2009 Oct;37(8):649-52).

In certain embodiments, the plant component is in a concentration in the topical administration form of 0.1-2% (w/w). In certain embodiments, the plant component is in a concentration in the topical administration form of 0.3-1% (w/w). In certain embodiments, the plant component is in a concentration in the topical administration form of 0.5% (w/w).

Terpenes are a large and diverse class of organic compounds, produced by a variety of plants. Monoterpene hydrocarbon, monoterpene alcohol, and sesquiterpene hydrocarbon belong to the class of terpenes. Terpenes are derivatives of isoprene units, derived biosynthetically from units of isopentenyl pyrophosphate. Monoterpenes consist of two isoprene units and sesquiterpenes consist of three isoprene units.

Limonene and b-pinene (which both are monoterpenes) reduced viral infectivity of herpes simplex virus, which is an enveloped virus, in vitro (Astani et al. Iran J Microbiol. 2014;6(3):149-155.). The main chemical components of pine oil are limonene, pinene, dipentene, and camphene.

The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their function is to defend plants against herbivores and pathogens. The most well-known phenylpropanoids are anethole, apiole, cinnamaldehyde, dillapiole and estragole.

Capryl aldehyde, also known as octanal, is an organic compound, with the chemical formula CH ₃ (CH ₂ ) ₆ CHO. Lauryl aldehyde, also known as dodecanal or dodecyl aldehyde, is an organic compound with the chemical formula CH3(CH2) _IO CHO.

Methyl nonyl ketone, also known as 2-undecanone and IBI-246, is the organic compound with the formula CH3C(0)CgHi9. In certain embodiments, the zinc salt concentration in the topical administration form is 0.5- 5% (w/w). In certain embodiments, the zinc salt concentration in the topical administration form is 1-3% (w/w). In certain embodiments, the zinc salt concentration in the topical administration form is 2% (w/w).

There is evidence that zinc salt has antiviral properties in vitro (te Velthuis et al. PLoS Pathog. 2010 Nov 4;6(11):e1001176). Te Velthuis et al. do not assess the virucidal properties of zinc salts.

In certain embodiments, the copper salt concentration in the topical administration form is 0.3-5% (w/w). In certain embodiments, the copper salt concentration in the topical administration form is 0.5-2% (w/w). In certain embodiments, the copper salt concentration in the topical administration form is 1% (w/w).

In certain embodiments, the metal salt is a sulphate salt.

In certain embodiments, the metal salt is a sulfide.

In certain embodiments, the metal salt is a sulphite salt.

In certain embodiments, the metal salt is an oxide. In certain embodiments, the metal is in an elementary form.

In certain embodiments, the topical administration form is composed of cetylstearylalcohol 11 ,0 (w/w)

Cremophor® A 25 2,5 (w/w) silicon oil 1000 4,0 (w/w) propylene glycol 5,0 (w/w) triclosan 1 ,0 (w/w) pine oil 0.5 (w/w) zinc sulphate 2.0 (w/w) copper sulphate 1.0 (w/w) water 73,0 (w/w).

In certain embodiments, the topical administration form also comprises preservative. The amount of preservative is adapted to fulfil the needed function.

A second aspect of the present invention relates to a topical administration form according to the first aspect of the invention, for use in prevention of infection with an enveloped virus.

Enveloped viruses have viral envelopes as their outer layer, which are composed of phospholipids and proteins and which are typically derived from portions of the host cell membranes, but include some viral glycoproteins. This type of virus can be inactivated by destroying the viral envelope.

In certain embodiments, the enveloped virus is of the family Coronaviridae, Herpesviridae, Poxviridae, Hepadnaviridae, Asfarviridae, Flaviviridae, Alphaviridae, Togaviridae, Hepatitis D, Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Filoviridae, Retroviridae. In certain embodiments, the enveloped virus is of the family Coronaviridae.

In certain embodiments, the topical administration form is selected from a hand cream, a hand ointment, a hand lotion, a hand soap, and an aqueous solution. In certain embodiments, the topical administration form is a hand cream.

A hand cream has several advantages over common disinfectant liquids. It remains on the skin for a much longer time and it prevents drying and possibly also injury of the skin.

Medical treatment Dosage Forms and Salts

Similarly, within the scope of the present invention is a method of preventing viral infection in a patient in need thereof, comprising administering to the patient a compound according to the above description.

The skilled person is aware that any specifically mentioned drug may be present as a pharmaceutically acceptable salt of said drug. Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion. Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate. Non-limiting examples of pharmaceutically acceptable cationic salt forms include aluminium, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine and zinc. Topical administration is also within the scope of the advantageous uses of the invention. The skilled artisan is aware of a broad range of possible recipes for providing topical formulations, as exemplified by the content of Benson and Watkinson (Eds.), Topical and Transdermal Drug Delivery: Principles and Practice (1st Edition, Wiley 2011 , ISBN-13: 978-0470450291 ); and Guy and Handcraft: Transdermal Drug Delivery Systems: Revised and Expanded (2 ^nd Ed., CRC Press 2002, ISBN-13: 978-0824708610); Osborne and Amann (Eds.): Topical Drug Delivery Formulations (1 ^st Ed. CRC Press 1989; ISBN-13: 978-0824781835).

Pharmaceutical Compositions and Administration

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.

In certain embodiments of the invention, the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

In embodiments of the invention relating to topical uses of the compounds of the invention, the pharmaceutical composition is formulated in a way that is suitable for topical administration such as aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like, comprising the active ingredient together with one or more of solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives that are known to those skilled in the art.

The dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. In certain embodiments, the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The pharmaceutical compositions of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892).

Wherever alternatives for single separable features such as, for example, a compound or medical indication are laid out herein as “embodiments”, it is to be understood that such alternatives may be combined freely to form discrete embodiments of the invention disclosed herein. Thus, any of the alternative embodiments for a compound may be combined with any medical indication mentioned herein.