Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
  • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• • 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
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to lowering risk factors such as human papillomavirus (HPV) , pl6 and Ki-67 in the vaginal secretion as well as to prevention or treatment of a high-risk HPV infection of an internal reproductive organ such as the vagina or the cervix uteri .
• HPV human papillomavirus
• Papillomaviruses are highly diverse (De V Amsterdam, E. M., et al . (2004). Classification of papillomaviruses. Virology,
• Gardasil® is a widely used recombinant HPV vaccine targeting HPV6, HPV11, HPV16 and HPV18, the latter of which are deemed to be high-risk.
• this vaccine is only suitable for prophylaxis and may hence be ineffective in older individuals who are more likely to have already been infected with one of these HPV types before vaccination.
• the risk of side effects of vaccinations tends to be higher than the risks of side effects in connection with local therapies.
• achieving vaccination compliance is challenging, as a portion of the general public is presently critical towards vaccination in general and HPV vaccines in particular.
• HPV16 or HPV18 a high-risk HPV such as HPV16 or HPV18, in particular a therapy which is effective in patients already having an infection with one of these HPV types and/or can be applied locally.
• the present invention relates to a pharmaceutical
• composition containing a selenite-containing compound and a pharmaceutically acceptable acid selected from citric acid, acetic acid, malic acid, carbonic acid, sulfuric acid, nitric acid, hydrochloric acid, fruit acids (e.g. malic acid, citric acid, tartaric acid, oxalic acid and fumaric acid, in particular citric acid) and mixtures thereof.
• a pharmaceutically acceptable acid selected from citric acid, acetic acid, malic acid, carbonic acid, sulfuric acid, nitric acid, hydrochloric acid, fruit acids (e.g. malic acid, citric acid, tartaric acid, oxalic acid and fumaric acid, in particular citric acid) and mixtures thereof.
• composition is for use in lowering risk factors such as HPV, pl6 and/or Ki-67 in the vaginal secretion of a female patient, and/or for use in the (additional) prevention or treatment of an infection of an internal reproductive organ of a female patient with at least one HPV selected from HPV16, HPV18, HPV31, HPV33 and HPV58, in particular wherein the HPV is HPV16 and/or HPV18.
• composition is applied intravaginally to the patient.
• US 2003/0180387 Al relates to a method for increasing the antioxidative potential of selenium-containing aqueous
• a preparation comprising a pharmaceutically administrable or food-compatible form of selenium, namely selenite, and a pharmaceutically acceptable or food-compatible acid, selected from citric acid, acetic acid, malic acid, carbonic acid, various fruit acids and mixtures thereof, can be used to prevent or treat herpes simplex
• the document neither discloses intravaginal application nor that the target organ is an internal reproductive organ of a female patient nor the use of a composition against papillomavirus.
• US 2005/0048134 Al concerns the use of a selenite-containing compound to be topically or buccally administered. Treatment or prophylaxis of infections with papilloma viruses, particularly in the genital region, is disclosed as one among many
• US 2013/0323328 A1 relates to a pharmaceutical preparation containing selenite or selenite-containing compounds for
• HPV infections may be specifically detected e.g. by
• PCR polymerase chain reaction
• TMA transcription-mediated amplification
• pl6 also known as pl6 INK4a or cyclin-dependent kinase inhibitor 2A
• pl6 INK4a cyclin-dependent kinase inhibitor 2A
• Overexpression of pl6 is a biomarker of certain
• Ki-67 also known as KI-67 or MKI67
• MKI67 is a protein that is encoded by the MKI67 gene in humans. Ki-67 is a biomarker for cell proliferation. Both of these biomarkers may be tested for instance with the CINtec® PLUS test (Roche, Switzerland) which is a commercially available, approved cytological assay (see e.g. Ravarino, A., et al . (2012). CINtec PLUS
• the inventive therapy is especially effective against infections of HPV16, HPV18, HPV31, HPV33 or HPV58 when they are associated with biomarkers pl6 and Ki-67.
• the patient is pl6- positive, preferably pl6-positive and Ki-67-positive, at least in a region of the internal reproductive organ.
• the pharmaceutical composition is applied until the patient has become pi 6-negative, preferably pl6-negative and Ki-67-negative, in said region.
• reproductive organ is defined as pl6-positive if at least one cell, preferably at least two adjoining cells, more preferably at least three adjoining cells, even more preferably at least five adjoining cells, in particular at least ten adjoining cells over-express pl6 compared to healthy control tissue, such as healthy adjoining cells in the biopsy sample, preferably wherein each of said cells are epithelial cells.
• a biopsy sample is preferably defined as pl6-negative if less than ten adjoining cells, preferably less than five adjoining cells, more preferably less than three adjoining cells, even more preferably less than two cells, in particular no cell over expresses pl6 compared to healthy control tissue, such as healthy adjoining cells in the biopsy sample, preferably wherein each of said cells are epithelial cells.
• a biopsy sample obtained from the region of the internal reproductive organ is defined as Ki-67-positive if at least one cell, preferably at least two adjoining cells, more preferably at least three adjoining cells, even more preferably at least five adjoining cells, in particular at least ten adjoining cells over-express Ki-67 compared to healthy control tissue, such as healthy adjoining cells in the biopsy sample, preferably wherein each of said cells are epithelial cells.
• such a biopsy sample is preferably defined as Ki-67- negative if less than ten adjoining cells, preferably less than five adjoining cells, more preferably less than three adjoining cells, even more preferably less than two cells, in particular no cell over-expresses Ki-67 compared to healthy control tissue, such as healthy adjoining cells in the biopsy sample, preferably wherein each of said cells are epithelial cells.
• pi 6-positive and Ki-67- positive is defined as a positive result in the established CINtec® PLUS test (Roche, Switzerland) , especially as disclosed in CINtec® PLUS Interpretation Guide (Roche, 2016) .
• a positive result is defined as the presence of at least one dual-stained cervical epithelial cell (the cytoplasm stains brown (pl6) and the nucleus stains red (Ki-67) ) .
• composition is 0.01 mg - 1.25 mg, preferably 0.025 mg - 1.00 mg, more preferably 0.05 mg - 0.75 mg, even more preferably 0.10 mg - 0.50 mg, yet even more preferably 0.15 mg - 0.40 mg, especially 0.20 mg - 0.30 mg, per 5 ml of the
• total selenium content does not imply that selenium has to be present as elemental selenium in the composition.
• 0.83 mg sodium selenite as the only selenium-containing compound per 5 ml of composition corresponds to a total selenium content ("selenium-equivalent content") of 0.25 mg per 5 ml.
• the selenium dose per application can be low and still be effective.
• the total selenium dose is 0.01 mg - 1.25 mg, preferably 0.025 mg - 1.00 mg, more preferably 0.05 mg - 0.75 mg, even more preferably 0.10 mg - 0.50 mg, yet even more preferably 0.15 mg - 0.40 mg, especially 0.20 mg - 0.30 mg, per application.
• total selenium dose does not imply that selenium has to be present as elemental selenium in the dose.
• 0.83 mg sodium selenite as the only selenium-containing compound of a dosage unit applied corresponds to a total selenium dose ("selenium-equivalent dose”) of 0.25 mg per application.
• the pharmaceutical composition is applied at least once per day, preferably for at least 30 days, more preferably for at least 60 days, even more preferably for at least 90 days.
• a further preferred embodiment relates to the inventive pharmaceutical composition for use wherein the composition is applied once per day, preferably for at least 30 days, more preferably for at least 60 days, even more preferably for at least 90 days.
• the application of the pharmaceutical composition may be discontinued during menstruation of the patient.
• the composition is applied until the infection of the internal reproductive organ or the region thereof cannot be detected any more.
• composition for use according to the present invention may additionally contain further suitable ingredients and/or pharmaceutically acceptable excipients.
• the pharmaceutical composition for use according to the present invention contains selenite in the form of sodium selenite (which is mostly present as a pentahydrate compound which starts to release crystal water at 40°C) .
• the composition contains one or more acids in a total amount between 1 mg and 10 g acid, more preferably between 10 mg and 5 g acid, in particular between 100 mg and 1 g acid, per 100 g of the composition (in particular if the acid is added in its solid form) .
• the acid may also be added in its liquid form (e. g. with water, i.e. as an aqueous solution) .
• Water and aqueous solutions, respectively, optionally containing further ingredients may be added to the composition according to the present invention in an amount between 0 and (about) 99.9 g, preferably between 50 and 99 g, in particular between 80 and 98g, per 100 g of the composition.
• the composition is present in the form of a gel, a suspension, an emulsion, a suppository such as gelatine capsules or gelatine-free capsules, a spray or a powder.
• the pharmaceutical composition for use according to the present invention When present in the form of a gel, the pharmaceutical composition for use according to the present invention
• a gelling agent preferably contains a gelling agent. Both inorganic and organic aqueous gelling agents may be used as a gelling agent.
• Particularly suitable gelling agents are cellulose derivatives, in particular carboxymethylcellulose, methylcellulose,
• hydroxypropyl cellulose and, in particular, hydroxyethyl
• the gelling agents in particular
• hydroxyethyl cellulose are used at a total concentration of between 0.1 g and 30 g, more preferably between 0.5 g and 5 g, in particular between 1 g and 3 g, per 100 g of the composition.
• the composition especially when the composition is present in the form of a gel, contains silicon dioxide, in particular highly dispersed silicon dioxide, e. g. according to WO 2001/85852 Al, as a technological suspension medium and/or as an adsorbent.
• silicon dioxide in particular highly dispersed silicon dioxide, e. g. according to WO 2001/85852 Al, as a technological suspension medium and/or as an adsorbent.
• an amount between 100 mg and 50 g, more preferably between 500 mg and 10 g, in particular between 1 g and 5 g, Si02 per 100 g of the composition is used.
• composition for use according to the present invention preferably has a pH-value of less than 7.0, more preferably less than 5.0, in particular between 4.0 and 2.5.
• composition may contain further
• excipients and/or further active ingredients in particular buffer substances, colouring agents, stabilizers, preservatives, carrier substances or combinations thereof.
• preservatives are potassium sorbate and sodium benzoate.
• composition may additionally comprise further active agents such as antibiotics, antiviral agents,
• antimycotics , pain inhibitors, anti-inflammatory agents or combinations thereof.
• the present invention also relates to a method for delaying the onset of or treating an infection of an internal reproductive organ of a female patient with at least one HPV selected from HPV16, HPV18, HPV31, HPV33 and HPV58, comprising
• composition is applied intravaginally .
• preventing means to stop a disease state or condition from occurring in a patient or subject completely or almost completely or at least to a
• the patient (who preferably has an infection of an internal reproductive organ with at least one HPV selected from HPV16, HPV18, HPV31, HPV33 and HPV58 (in particular HPV16 and/or HPV18), and especially has been diagnosed with said infection) is in need of the inventive treatment.
• the patient may be a patient that does not have the HPV
• the patient to be subject to inventive prevention or treatment is preferably older than 20 years, preferably older than 30 years, even more preferably older than 40 years, yet even more preferably older than 50 years.
• the inventive treatment has been found to be not as
• the patient is preferably not immunosuppressed.
• the patient is preferably not immunosuppressed.
• the patient preferably does not have cancer and/or chronic viral disease (other than HPV infection) .
• the internal reproductive organ mentioned herein is the vagina or the cervix uteri of the patient.
• the term "over-express" or similar in regard to a gene (product) A typically can mean that the expression level of A (as e.g. measured by Western blot or immunohistochemistry or immunocytochemistry) e.g. in a biopsy sample is higher than the expression level of an appropriate control (such as healthy tissue of the same type), by a factor of at least 1.2 (i.e. an increase of at least 20%), preferably at least 1.4, more
• Fig. 1 Clearance of HPV types 16, 18, 31, 33 and 58.
• HPV Negative no presence of HPV16, HPV18, HPV31, HPV33 and HPV58 detected.
• HPV Positive presence of HPV16, HPV18, HPV31, HPV33 and/or HPV58 detected, "at Screening”: initial screening of the
• Fig. 2 Improvement of pl6/Ki-67 status. Compared to the non-treated control arm, a much larger remission rate from pl6/Ki-67 double-stain positive was observed in the active arm treated with the inventive therapy. "pl6/Ki-67-stain -":
• Example 1 Pharmaceutical composition for intravaginal therapy of infection with HPV types 16, 18, 31, 33 and 58
• composition is an aqueous vaginal gel having the following ingredients (per 5ml of gel) :
• Daily dose was 5 ml of the composition of example 1
• composition applied intravaginally .

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• Health & Medical Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Inorganic Chemistry (AREA)
• Virology (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• Gynecology & Obstetrics (AREA)
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• Oncology (AREA)
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• 2018
  • 2018-08-28 EP EP18191289.0A patent/EP3616693A1/en not_active Withdrawn
• 2019
  • 2019-08-20 TW TW108129683A patent/TWI827652B/zh active
  • 2019-08-28 HR HRP20231470TT patent/HRP20231470T1/hr unknown
  • 2019-08-28 HU HUE19765421A patent/HUE064691T2/hu unknown
  • 2019-08-28 MD MDE20210608T patent/MD3843715T2/ro unknown
  • 2019-08-28 WO PCT/EP2019/072926 patent/WO2020043762A1/en not_active Ceased
  • 2019-08-28 SM SM20230340T patent/SMT202300340T1/it unknown
  • 2019-08-28 AU AU2019332079A patent/AU2019332079B2/en active Active
  • 2019-08-28 AR ARP190102447A patent/AR116027A1/es unknown
  • 2019-08-28 BR BR112021003360-2A patent/BR112021003360A2/pt unknown
  • 2019-08-28 CN CN201980055480.2A patent/CN112584828A/zh active Pending
  • 2019-08-28 IL IL281080A patent/IL281080B2/en unknown
  • 2019-08-28 GE GEAP202215586A patent/GEAP202215586A/en unknown
  • 2019-08-28 RS RS20231165A patent/RS64916B1/sr unknown
  • 2019-08-28 CA CA3107691A patent/CA3107691C/en active Active
  • 2019-08-28 ES ES19765421T patent/ES2958808T3/es active Active
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  • 2019-08-28 JP JP2021510859A patent/JP7420791B2/ja active Active
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  • 2019-08-28 EP EP19765421.3A patent/EP3843715B1/en active Active
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  • 2019-08-28 US US17/264,210 patent/US20210299163A1/en not_active Abandoned
• 2021
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• 2025
  • 2025-05-21 US US19/214,622 patent/US20250281524A1/en active Pending

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