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WO2015082172A1 - Polydimethylsiloxane for the treatment of viral infections - Google Patents

Polydimethylsiloxane for the treatment of viral infections Download PDF

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Publication number
WO2015082172A1
WO2015082172A1 PCT/EP2014/074143 EP2014074143W WO2015082172A1 WO 2015082172 A1 WO2015082172 A1 WO 2015082172A1 EP 2014074143 W EP2014074143 W EP 2014074143W WO 2015082172 A1 WO2015082172 A1 WO 2015082172A1
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WO
WIPO (PCT)
Prior art keywords
polydimethylsiloxane
herpes
treatment
dimethicone
formulation
Prior art date
Application number
PCT/EP2014/074143
Other languages
French (fr)
Inventor
Mario Dominik Nicolaas Oldani
Original Assignee
Zzip Ag
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Publication date
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Publication of WO2015082172A1 publication Critical patent/WO2015082172A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • the present invention relates to the use of polydimethylsiloxane, also designated as dimethicone, for the topical treatment of viral infections, such as herpes infections caused by Herpes simplex (HSV) type 1 and type 2.
  • HSV Herpes simplex
  • dimethicone is especially suitable for the topical treatment of herpes labialis or cold sores, orofacial herpes or herpes genitalis.
  • the present invention further relates to topical formulations and kits of parts comprising polydimethylsiloxane, or dimethicone, for the treatment of herpes labialis, orofacial herpes or herpes genitalis.
  • Herpes labialis also designated as cold sores, herpes simplex labialis, recurrent herpes labialis, or orolabial herpes is a type of viral infection occurring on an around the lip.
  • An outbreak typically causes small blisters or sores on or around the mouth commonly known as cold sores or fever blisters.
  • the sores typically heal within 2 to 3 weeks, but the herpes virus remains dormant in the facial nerves, following orofacial infection, periodically reactivating (in symptomatic people) to create sores in the same area of the mouth or face at the site of the original infection.
  • labia is a general term for "lip”.
  • the term “herpes labialis” does generally not refer to the labia of the genitals, though the etymology of the infection is the same.
  • the broader term “orofacial herpes” is generally used to describe the condition, whereas the term “herpetic stomatitis” is used to specifically describe infections of the mouth.
  • Herpes infections usually show no symptoms and when symptoms appear they typically resolve within two weeks.
  • the main symptom of an oral infection is inflammation of the mucosa of the cheek and gums known as acute herpetic gingivostomatitis.
  • Other symptoms may also develop including headache, nausea, dizziness and painful ulcers.
  • Cold sores or blisters are generally caused by reactivation of HSV after a primary infection. Once a primary HSV has occurred, it remains latent in the body for life. During latency, the virus migrates from the primary site of infection to the central nervous system where the virus can remains latent for a period of several weeks to many years. When reactivation occurs, the virus migrates back from the nerves to the mucosa or skin where it causes blisters (cold sores).
  • Reactivation of HSV can be influenced by stress, menstruation, sunlight, sunburn, fever, dehydration, or local skin trauma.
  • Herpes genitalis refers to a genital infection by Herpes simplex virus, the most common sexually transmitted infection by the number of current cases. Following the classification HSV into two distinct categories of HSV-1 and HSV-2 in the 1960s, it was established that "HSV-2 was below the waist, HSV-1 was above the waist". Although genital herpes was previously primarily caused by HSV-2, genital HSV-1 infections are increasing and now cause up to 80% of infections. Genital HSV-1 infection recurs at rate of about one sixth of that of genital HSV-2.
  • HSV-1 or HSV-2 genital infection When symptomatic, the typical manifestation of a primary HSV-1 or HSV-2 genital infection is clusters of genital sores consisting of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores.
  • Genital Herpes is believed to be asymptomatic in the majority of cases, thus aiding contagion and hindering containment.
  • the lesions may occur on the glans penis, shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus.
  • lesions may appear on or near the pubis, labia, clitoris, vulva, buttocks or anus.
  • Antiviral medications against HSV include docosonol, acyclovir and penciclovir. Famciclovir or valaciclovir, taken in pill form, can be effective using a single day, high-dose application and are more cost effective and convenient than the traditional treatment of lower doses for 5 to 7 days. Lysine has been suggested as a treatment for herpes labialis based on in vitro studies, but the evidence is inconclusive in humans.
  • medicaments provide alternative mechanisms of action to treat the infection thereby avoiding the development of resistance, provide a significant faster cure rate thereby shortening the infectious phase of the infection cycle, provide a more patient compliant treatment regime or provide a more effective treatment in general.
  • herpes in immune- compromised patients such as cancer, MS or HIV patients. Because of the life long latency associated with a herpes infection, defects in the immune system can result in that the virus remains no longer restricted to the central nervous systems and a spread of the virus into vital organs is likely ultimately with lethal results.
  • This object of the present invention is met by a method of treating topical viral infections as outlined in the appended claim 1.
  • this object of the present invention is, according to a first aspect, met by the use of polydimethylsiloxane, also designated as dimethicone, in the treatment of topical, mucosal or dermal viral infections.
  • dimethicone has a beneficial effect on the treatment of topical, mucosal or dermal viral infections, especially with respect to the duration of the treatment. Only one or a limited amount of topical applications of dimethicone, such as 5, 4, 3 or 2 suffice to completely cure the infection. Further a treatment period of 1, 2, 3, 4 or 5 days suffices to completely cure the infection.
  • Polydimethylsiloxane belongs to a group of polymeric organosilicon compounds that are commonly referred to as silicones.
  • PDMS is a widely used silicon-based organic polymer, and is particularly known for its unusual rheological (or flow) properties.
  • PDMS is optically clear, and, in general, inert, non-toxic, and non-flammable. It is also called dimethicone and is one of several types of silicone oil (polymerized siloxane). Its applications range from contact lenses and medical devices to elastomers; it is also present in shampoos (as dimethicone makes hair shiny and slippery), food (antifoaming agent), caulking, lubricating oils, and heat- resistant tiles.
  • the chemical formula for PDMS is CH 3 [SiO(CH 3 ) 2 ] n Si(CH 3 ) 3 , where n is the number of repeating monomer [SiO(CH 3 ) 2 ] units.
  • Industrial synthesis can begin from
  • the polymerization reaction produces hydrogen chloride.
  • a process was developed in which the chlorine atoms in the silane precursor were replaced with acetate groups.
  • the polymerization produces acetic acid, which is less chemically aggressive than HC1.
  • Hydrolysis of Si(CH 3 ) 2 Cl 2 generates a polymer that is terminated with two silanol groups (-Si(CH 3 ) 2 OH]). These reactive centers are typically "capped” by reaction with trimethylsilyl chloride.
  • Silane precursors with more acid-forming groups and fewer methyl groups such as methyltrichlorosilane, can be used to introduce branches or cross-links in the polymer chain. Under ideal conditions, each molecule of such a compound becomes a branch point. This can be used to produce hard silicone resins. In a similar manner, precursors with three methyl groups can be used to limit molecular weight, since each such molecule has only one reactive site and so forms the end of a siloxane chain. According to a preferred embodiment of this first aspect of the present the invention, the present polydimethylsiloxane or dimethicone is simultaneously administered with copper(II)sulphate.
  • the present viral infection is a herpes viral infection such as a Herpes simplex type 1 or Herpes simplex type 2 infection.
  • herpes viruses are considered within the context of the present invention such as Varicella zoster virus (VZV), Epstein-Barr virus (EBV),
  • CMV Cytomegalovirus
  • Roseolovirus Herpes lymphotropic virus
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • the treatment is a treatment of herpes virus caused sores or blisters both around the mouth and the genitals.
  • the present treatment preferably comprises one or more topical applications of polydimethylsiloxane or dimethicone, preferably in combination with the simultaneous topical application of copper(II)sulphate.
  • the present invention relates to formulations for topical treatment of a herpes infection, the formulations comprise:
  • the above formulation preferably comprises 0.1 to 3 (wt) polydimethylsiloxane, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1, 1.5, 2 or 2.5 (wt) and 1 to 10 (wt) copper(II)sulphate, such as 2, 3, 4, 5, 6, 7, 8, 9 (wt).
  • a preferred range copper(II) sulphate is 5 to 10 (wt) such as 6 to 8% (wt).
  • the (wt) of an ingredient is calculated as percentage of the total weight of all ingredients of the present formulation.
  • the present formulations of this second aspect of the present invention preferably further comprise one or more plant extracts selected from the group consisting of Opuntiaficus- indica extract, Rhododendron ferrugineum extract, Aloe barbadenis extract, Hypericum perforatum extract, St John's wort and Calendula Officinalis flower extract.
  • Calendula officinalis is a plant in the genus Calendula belonging to the family of Asteraceae. It is probably native to southern Europe, though its long history of cultivation makes its precise origin unknown, and it may possibly be of garden origin. It is also widely further naturalised north into Europe (north to southern England) and elsewhere in warm temperate regions of the world.
  • the petals and pollen of Calendula officinalis contain triterpenoid esters and the carotenoids flavoxanthin and auroxanthin (antioxidants, and the source of the yellow -orange coloration).
  • the leaves and stems contain other carotenoids, mostly lutein (80%) and zeaxanthin (5%), and beta-carotene.
  • Plant extracts are widely used in cosmetics presumably due to presence of compounds such as saponins, resins and essential oils.
  • the flowers of Calendula officinalis contain flavonol glycosides, triterpene oligoglycosides, oleanane-type triterpene glycosides, saponins, and a sesquiterpene glucoside.
  • Calendula extracts may have anti-viral, anti-genotoxic and anti-inflammatory properties.
  • the methanol extract of C. officinalis exhibited antibacterial activity and both the methanol and the ethanol extracts showed antifungal activities.
  • Hypericum perforatum also known as Tipton's weed, rosin rose, goatweed, chase- devil, or Klamath weed, is a species of flowering plant in the genus Hypericum.
  • St John's wort is used to refer to any species of the genus Hypericum. Therefore, H. perforatum is sometimes called common St John's wort or perforate St John's wort to differentiate it.
  • Hypericum is classified in the family Hypericaceae having previously been classified as Guttiferae or Clusiaceae. Approximately 370 species of the genus Hypericum exist worldwide with a native geographical distribution including temperate and subtropical regions of Europe, Turkey, Ukraine, Russia, Middle East, India, and China. St John's wort is widely known as an herbal medicine for treating depression.
  • Herb and flowers contain various polyphenols: flavonoids (epigallocatechin, rutin, hyperoside, isoquercetin, quercitrin, quercetin, 13, II8-biapigenin, amentoflavone, astilbin, miquelianin, phenolic acids (chlorogenic acid, 3-O-coumaroylquinic acid), and various naphtodianthrones: (hypericin, pseudohypericin, protohypericin, protopseudohypericin), phloroglucinols (hyperforin, adhyperforin). The naphthodianthrones hypericin and
  • pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be the active components. It also contains essential oils composed mainly of sesquiterpenes.
  • St John's wort is widely known as a herbal treatment for depression. In some countries, such as Germany, it is commonly prescribed for mild depression, especially in children and adolescents. It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.
  • the present formulation is preferably an aqueous formulation. Accordingly, the present formulation preferably comprises 50 to 90% (wt) water such as 55, 60, 65, 70, 75, 80, or 85 %(wt). A preferred range water is 60 to 80 %(wt).
  • the present formulation comprises glycerine in a preferred amount of 5 to 20%(wt) such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 %(wt).
  • the present invention relates to kit of parts for the treatment of virally caused sores or blisters comprising:
  • a container comprising an aqueous solution comprising dimethicone or a present formulation as defined above;
  • An aqueous formulation comprising: a) 0.9 wt% polydimethylsiloxane;
  • 0.002 wt(%) sodium benzoate was prepared wherein 100 wt(%) was provided by further addition of suitable pharmaceutically acceptable diluents and excipients.
  • 20 healthy volunteers with frequently recurrent herpes labialis were recruited and provided with the above formulation and an applicator. Once the first signs of fever blisters or cold sores appeared the volunteers were asked to apply the present formulation once a day on the site of infection until the fever blisters or cold blisters disappeared.
  • An aqueous formulation comprising: a) 0.3 wt( ) PEG-14 dimethicone (polydimethylsiloxane); b) 73 wt( ) based on the total weight of the formulation water; c) 7 wt( ) based on the total weight of the formulation

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Abstract

The present invention relates to the use of polydimethylsiloxane, also designated as dimethicone, for the topical treatment of viral infections, such as herpes infections caused by Herpes simplex (HSV) type 1 and type 2. The present use of polydimethylsiloxane, or dimethicone, is especially suitable for the treatment of herpes labialis or cold sores, orofacial herpes or herpes genitalis. The present invention further relates to topical formulations and kits of parts comprising polydimethylsiloxane, or dimethicone, in combination with copper for the treatment of herpes labialis, orofacial herpes or herpes genitalis.

Description

POLYDIMETHYLSILOXANE FOR THE TREATMENT OF VIRAL INFECTIONS
Description The present invention relates to the use of polydimethylsiloxane, also designated as dimethicone, for the topical treatment of viral infections, such as herpes infections caused by Herpes simplex (HSV) type 1 and type 2. The present use of polydimethylsiloxane, or
dimethicone, is especially suitable for the topical treatment of herpes labialis or cold sores, orofacial herpes or herpes genitalis. The present invention further relates to topical formulations and kits of parts comprising polydimethylsiloxane, or dimethicone, for the treatment of herpes labialis, orofacial herpes or herpes genitalis.
Herpes labialis, also designated as cold sores, herpes simplex labialis, recurrent herpes labialis, or orolabial herpes is a type of viral infection occurring on an around the lip. An outbreak typically causes small blisters or sores on or around the mouth commonly known as cold sores or fever blisters. The sores typically heal within 2 to 3 weeks, but the herpes virus remains dormant in the facial nerves, following orofacial infection, periodically reactivating (in symptomatic people) to create sores in the same area of the mouth or face at the site of the original infection.
In medical context, "labia" is a general term for "lip". The term "herpes labialis" does generally not refer to the labia of the genitals, though the etymology of the infection is the same. When the viral infection affects both face and mouth, the broader term "orofacial herpes" is generally used to describe the condition, whereas the term "herpetic stomatitis" is used to specifically describe infections of the mouth.
Primary Herpes infections usually show no symptoms and when symptoms appear they typically resolve within two weeks. The main symptom of an oral infection is inflammation of the mucosa of the cheek and gums known as acute herpetic gingivostomatitis. Other symptoms may also develop including headache, nausea, dizziness and painful ulcers.
Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy). Primary HSV infections in adults often results in pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely.
Cold sores or blisters are generally caused by reactivation of HSV after a primary infection. Once a primary HSV has occurred, it remains latent in the body for life. During latency, the virus migrates from the primary site of infection to the central nervous system where the virus can remains latent for a period of several weeks to many years. When reactivation occurs, the virus migrates back from the nerves to the mucosa or skin where it causes blisters (cold sores).
Reactivation of HSV can be influenced by stress, menstruation, sunlight, sunburn, fever, dehydration, or local skin trauma.
Herpes genitalis, or genital herpes, refers to a genital infection by Herpes simplex virus, the most common sexually transmitted infection by the number of current cases. Following the classification HSV into two distinct categories of HSV-1 and HSV-2 in the 1960s, it was established that "HSV-2 was below the waist, HSV-1 was above the waist". Although genital herpes was previously primarily caused by HSV-2, genital HSV-1 infections are increasing and now cause up to 80% of infections. Genital HSV-1 infection recurs at rate of about one sixth of that of genital HSV-2. When symptomatic, the typical manifestation of a primary HSV-1 or HSV-2 genital infection is clusters of genital sores consisting of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores.
Genital Herpes is believed to be asymptomatic in the majority of cases, thus aiding contagion and hindering containment. In males, the lesions may occur on the glans penis, shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions may appear on or near the pubis, labia, clitoris, vulva, buttocks or anus.
Antiviral medications against HSV include docosonol, acyclovir and penciclovir. Famciclovir or valaciclovir, taken in pill form, can be effective using a single day, high-dose application and are more cost effective and convenient than the traditional treatment of lower doses for 5 to 7 days. Lysine has been suggested as a treatment for herpes labialis based on in vitro studies, but the evidence is inconclusive in humans.
Although treatment of symptoms of topical viral infections, and especially Herpes infections such as those caused by HSV-1 and HSV-2, is available, there is a continuing need in the art for additional medicaments. These medicaments provide alternative mechanisms of action to treat the infection thereby avoiding the development of resistance, provide a significant faster cure rate thereby shortening the infectious phase of the infection cycle, provide a more patient compliant treatment regime or provide a more effective treatment in general.
In the art, there is a special need for an effective treatment of herpes in immune- compromised patients such as cancer, MS or HIV patients. Because of the life long latency associated with a herpes infection, defects in the immune system can result in that the virus remains no longer restricted to the central nervous systems and a spread of the virus into vital organs is likely ultimately with lethal results.
It is an object of the present invention, amongst other objects, to at least partly, if not completely, fulfill the above needs of the prior art.
This object of the present invention, amongst other objects, is met by a method of treating topical viral infections as outlined in the appended claim 1. Specifically, this object of the present invention, amongst other objects, is, according to a first aspect, met by the use of polydimethylsiloxane, also designated as dimethicone, in the treatment of topical, mucosal or dermal viral infections.
The present inventor surprisingly discovered that dimethicone has a beneficial effect on the treatment of topical, mucosal or dermal viral infections, especially with respect to the duration of the treatment. Only one or a limited amount of topical applications of dimethicone, such as 5, 4, 3 or 2 suffice to completely cure the infection. Further a treatment period of 1, 2, 3, 4 or 5 days suffices to completely cure the infection.
Polydimethylsiloxane (PDMS) belongs to a group of polymeric organosilicon compounds that are commonly referred to as silicones. PDMS is a widely used silicon-based organic polymer, and is particularly known for its unusual rheological (or flow) properties. PDMS is optically clear, and, in general, inert, non-toxic, and non-flammable. It is also called dimethicone and is one of several types of silicone oil (polymerized siloxane). Its applications range from contact lenses and medical devices to elastomers; it is also present in shampoos (as dimethicone makes hair shiny and slippery), food (antifoaming agent), caulking, lubricating oils, and heat- resistant tiles.
The chemical formula for PDMS is CH3[SiO(CH3)2]nSi(CH3)3, where n is the number of repeating monomer [SiO(CH3)2] units. Industrial synthesis can begin from
dimethyldichlorosilane and water by the following net reaction: n Si(CH3)2Cl2 + n+1 H20→ HO[-SiO(CH3)2-]n H + 2n HC1
The polymerization reaction produces hydrogen chloride. For medical and domestic applications, a process was developed in which the chlorine atoms in the silane precursor were replaced with acetate groups. In this case, the polymerization produces acetic acid, which is less chemically aggressive than HC1. Hydrolysis of Si(CH3)2Cl2 generates a polymer that is terminated with two silanol groups (-Si(CH3)2OH]). These reactive centers are typically "capped" by reaction with trimethylsilyl chloride.
Silane precursors with more acid-forming groups and fewer methyl groups, such as methyltrichlorosilane, can be used to introduce branches or cross-links in the polymer chain. Under ideal conditions, each molecule of such a compound becomes a branch point. This can be used to produce hard silicone resins. In a similar manner, precursors with three methyl groups can be used to limit molecular weight, since each such molecule has only one reactive site and so forms the end of a siloxane chain. According to a preferred embodiment of this first aspect of the present the invention, the present polydimethylsiloxane or dimethicone is simultaneously administered with copper(II)sulphate.
According to another preferred embodiment of this first aspect of the present invention, the present viral infection is a herpes viral infection such as a Herpes simplex type 1 or Herpes simplex type 2 infection. Other herpes viruses are considered within the context of the present invention such as Varicella zoster virus (VZV), Epstein-Barr virus (EBV),
Cytomegalovirus (CMV), Roseolovirus, Herpes lymphotropic virus or Kaposi's sarcoma-associated herpesvirus (KSHV).
According to an especially preferred embodiment of this first aspect of the present invention, the treatment is a treatment of herpes virus caused sores or blisters both around the mouth and the genitals.
The present treatment preferably comprises one or more topical applications of polydimethylsiloxane or dimethicone, preferably in combination with the simultaneous topical application of copper(II)sulphate.
According to a second aspect, the present invention relates to formulations for topical treatment of a herpes infection, the formulations comprise:
a) polydimethylsiloxane; and
b) copper(II) sulphate;
The above formulation preferably comprises 0.1 to 3 (wt) polydimethylsiloxane, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1, 1.5, 2 or 2.5 (wt) and 1 to 10 (wt) copper(II)sulphate, such as 2, 3, 4, 5, 6, 7, 8, 9 (wt). A preferred range copper(II) sulphate is 5 to 10 (wt) such as 6 to 8% (wt).
Within the context of the present invention, the (wt) of an ingredient is calculated as percentage of the total weight of all ingredients of the present formulation.
The present formulations of this second aspect of the present invention preferably further comprise one or more plant extracts selected from the group consisting of Opuntiaficus- indica extract, Rhododendron ferrugineum extract, Aloe barbadenis extract, Hypericum perforatum extract, St John's wort and Calendula Officinalis flower extract.
Calendula officinalis (pot marigold, ruddles, common marigold, garden marigold, English marigold, or Scottish marigold) is a plant in the genus Calendula belonging to the family of Asteraceae. It is probably native to southern Europe, though its long history of cultivation makes its precise origin unknown, and it may possibly be of garden origin. It is also widely further naturalised north into Europe (north to southern England) and elsewhere in warm temperate regions of the world.
The petals and pollen of Calendula officinalis contain triterpenoid esters and the carotenoids flavoxanthin and auroxanthin (antioxidants, and the source of the yellow -orange coloration). The leaves and stems contain other carotenoids, mostly lutein (80%) and zeaxanthin (5%), and beta-carotene. Plant extracts are widely used in cosmetics presumably due to presence of compounds such as saponins, resins and essential oils. The flowers of Calendula officinalis contain flavonol glycosides, triterpene oligoglycosides, oleanane-type triterpene glycosides, saponins, and a sesquiterpene glucoside.
Plant pharmacological studies have suggested that Calendula extracts may have anti-viral, anti-genotoxic and anti-inflammatory properties. In an in vitro assay, the methanol extract of C. officinalis exhibited antibacterial activity and both the methanol and the ethanol extracts showed antifungal activities.
Hypericum perforatum, also known as Tipton's weed, rosin rose, goatweed, chase- devil, or Klamath weed, is a species of flowering plant in the genus Hypericum. With qualifiers, St John's wort is used to refer to any species of the genus Hypericum. Therefore, H. perforatum is sometimes called common St John's wort or perforate St John's wort to differentiate it. Hypericum is classified in the family Hypericaceae having previously been classified as Guttiferae or Clusiaceae. Approximately 370 species of the genus Hypericum exist worldwide with a native geographical distribution including temperate and subtropical regions of Europe, Turkey, Ukraine, Russia, Middle East, India, and China. St John's wort is widely known as an herbal medicine for treating depression.
Herb and flowers contain various polyphenols: flavonoids (epigallocatechin, rutin, hyperoside, isoquercetin, quercitrin, quercetin, 13, II8-biapigenin, amentoflavone, astilbin, miquelianin, phenolic acids (chlorogenic acid, 3-O-coumaroylquinic acid), and various naphtodianthrones: (hypericin, pseudohypericin, protohypericin, protopseudohypericin), phloroglucinols (hyperforin, adhyperforin). The naphthodianthrones hypericin and
pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be the active components. It also contains essential oils composed mainly of sesquiterpenes.
St John's wort is widely known as a herbal treatment for depression. In some countries, such as Germany, it is commonly prescribed for mild depression, especially in children and adolescents. It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.
Other medical uses of St John's wort include the treatment of certain somatoform disorders and alcoholism, St John's wort shows antibacterial properties against gram-positive bacteria. In herbal medicine, St John's wort has also been employed as a topical remedy for wounds, abrasions, burns, and muscle pain. The positive effects that have been observed are generally attributed to possible antibacterial and anti-inflammatory effects. The present formulation is preferably an aqueous formulation. Accordingly, the present formulation preferably comprises 50 to 90% (wt) water such as 55, 60, 65, 70, 75, 80, or 85 %(wt). A preferred range water is 60 to 80 %(wt).
According to another preferred embodiment of this second aspect of the present invention, the present formulation comprises glycerine in a preferred amount of 5 to 20%(wt) such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 %(wt).
According to a third aspect, the present invention relates to kit of parts for the treatment of virally caused sores or blisters comprising:
a) a container comprising an aqueous solution comprising dimethicone or a present formulation as defined above;
b) an applicator for application of the aqueous solution of dimethicone or a present formulation on a virally caused sore or blister;
c) instructions for use.
The present invention will be further detailed in the following examples of preferred embodiments of the present invention.
Example 1
An aqueous formulation comprising: a) 0.9 wt% polydimethylsiloxane;
b) 76 wt(%) based on the total weight of the formulation water;
c) 0.1 wt(%) based on the total weight of the formulation
Copper(II) sulphate ;
d) 0.002 wt(%) based on the total weight of the formulation
Calendula officinalis extract;
e) 0.002 wt(%) based on the total weight of the formulation
Hypericum perforatum extract;
f) 0.002 wt(%) 200x freeze dried Aloe vera;
g) 0.003 wt(%) Abil B 8843; and
h) 0.002 wt(%) sodium benzoate was prepared wherein 100 wt(%) was provided by further addition of suitable pharmaceutically acceptable diluents and excipients. 20 healthy volunteers with frequently recurrent herpes labialis were recruited and provided with the above formulation and an applicator. Once the first signs of fever blisters or cold sores appeared the volunteers were asked to apply the present formulation once a day on the site of infection until the fever blisters or cold blisters disappeared.
18 volunteers reported the disappearance of fever blisters or cold blisters within three to four days. Of this group, 11 volunteers reported the disappearance of fever blisters or cold blisters within 2 days and 5 reported the disappearance of fever blisters or cold blisters within 1 day.
Example 2
An aqueous formulation comprising: a) 0.3 wt( ) PEG-14 dimethicone (polydimethylsiloxane); b) 73 wt( ) based on the total weight of the formulation water; c) 7 wt( ) based on the total weight of the formulation
Copper(II) sulphate ;
d) 0.01 wt( ) based on the total weight of the formulation
Calendula officinalis extract;
e) 0.03 wt( ) based on the total weight of the formulation
Opuntia ficus-indicia stem extract;
f) 0.02 wt( ) Rhododendron ferrugineum extract; and
g) 11 wt( ) glycerine; and was prepared wherein 100 wt( ) was provided by further addition of suitable pharmaceutically acceptable excipients.
46 healthy volunteers with frequently recurrent herpes labialis were recruited and provided with the above formulation and an applicator in the form of a cotton bud. Once the first signs of developing fever blisters or cold sores were detected (pain, itching) the volunteers were asked to apply the present formulation once a day on the site of infection until the fever blisters or cold blisters disappeared.
38 volunteers reported the disappearance of fever blisters or cold blisters within three to four days. Of this group, 19 volunteers reported the disappearance of fever blisters or cold blisters within 2 days and 9 reported the disappearance of fever blisters or cold blisters within 1 day. Of the 8 volunteers not reporting a disappearance of fever blisters or cold blisters, 6 volunteers reported decreased symptoms of the infection such as reduced blister formation or pain.

Claims

1. Polydimethylsiloxane, dimethicone, for use in the treatment of topical, mucosal or dermal viral infections.
2. Polydimethylsiloxane for use according to claim 1 in combination with copper(II)sulphate.
3. Polydimethylsiloxane for use according to claim 1 or claim 2, wherein said viral infection is a herpes viral infection.
4. Polydimethylsiloxane for use according to any of the claims 1 to 3, wherein said viral infection is a Herpes simplex type 1 or Herpes simplex type 2 infection.
5. Polydimethylsiloxane for use according to any one of claims 1 to 4, wherein said treatment comprises the treatment of herpes caused cold sores or fever blisters.
6. Polydimethylsiloxane for use according to any one of claims 1 to 5, wherein said treatment comprises one or more topical applications, preferably one or twice a day.
7. Formulation for topical treatment of a herpes infection, said formulation comprises:
a) polydimethylsiloxane; and
b) copper(II) sulphate;
8. Formulation according to claim 7 comprising:
a) 0.1 to 3 (wt) polydimethylsiloxane; and
b) 1 to 10 (wt) copper(II)sulphate, preferably 5 to 10 (wt);
9. Formulation according to claim 7 or claim 8 further comprising one or more plant extracts selected from the group consisting of Opuntia ficus-indica extract, Rhododendron jerrugineum extract, Aloe barbadenis extract, Hypericum perforatum extract, St John's wort, and Calendula Officinalis flower extract.
10. Formulation according to any of the claims 7 to 9, further comprising 5 to 20 (wt) glycerin.
11. Formulation according to any of the claims 7 to 10 further comprising 50 to 90 (wt) water, preferably 60 to 80 (wt).
12. Formulation according to any of the claims 7 to 11, wherein said polydimethylsiloxane is a polymer of dimethicone and polyoxyethylene or polyoxypropylene, preferably PEG- 14 dimethicone.
13. Formulation according to any one of claims 7 to 12 for the topical treatment of virally caused cold sores or fever blisters.
14. Kit of parts for the treatment of virally caused cold sores or fever blisters, comprising:
a) a container comprising an aqueous solution comprising dimethicone or a formulation according to any one of claims 7 to 12;
b) an applicator for topical application of the aqueous solution of dimethicone or a formulation according to any one of claims 7 to 12 on a virally caused cold sore or fever blister;
instructions for use.
PCT/EP2014/074143 2013-12-03 2014-11-10 Polydimethylsiloxane for the treatment of viral infections WO2015082172A1 (en)

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