WO2017212422A1 - Compositions topiques comprenant un carbomère destiné au traitement et à la prévention d'infections virales et d'états allergiques - Google Patents
Compositions topiques comprenant un carbomère destiné au traitement et à la prévention d'infections virales et d'états allergiques Download PDFInfo
- Publication number
- WO2017212422A1 WO2017212422A1 PCT/IB2017/053367 IB2017053367W WO2017212422A1 WO 2017212422 A1 WO2017212422 A1 WO 2017212422A1 IB 2017053367 W IB2017053367 W IB 2017053367W WO 2017212422 A1 WO2017212422 A1 WO 2017212422A1
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- WIPO (PCT)
- Prior art keywords
- carbomer
- pharmaceutically acceptable
- viscosity
- pharmaceutical composition
- topically administrable
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- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Definitions
- the present invention concerns pharmaceutical compositions for topical, and especially intranasal, application that have rapid, persistent and broad-spectrum antiviral and anti-allergenic activity, and methods of using said compositions for the prevention and treatment of acute viral infections such as the common cold and allergen-induced ailments such as seasonal and/or allergic rhinitis, and the symptoms thereof.
- the antiviral/anti-allergenic effect of such compositions is found to be dose- dependent, and thus the compositions can provide effective clinical regimens for treatment and/or prevention of viral infections such as influenza, and/or allergen induced conditions, in humans, as well as in other mammals.
- the invention comprises methods for treating or preventing viral infections or allergenic conditions or the symptoms thereof in a mammalian subject in need thereof which comprise topically administering to the subject an aqueous composition buffered to approximately neutral pH comprising a therapeutically effective amount of at least one pharmaceutically acceptable carbomer; and compositions therefor.
- FIG. 1 Plot of of inhibition of H V-B14 mRNA (copy number, per well x lO 3 ) in human airway epithelial A459 cells in preventive mode where cells are pre-treated with increasing concentrations of Carbomer 980; Carbomer 980 + HPMC (where the carbomers are in a 1:1 weight ratio) (final concentration of Carbomer 980 only is plotted); and HPMC (expressed as Log[Polymer] in % weight (% w/w)).
- FIG. 2 Plot of HRV-14 mRNA copy number (per well x 10 "3 ) in human airway epithelial A459 cells in preventive mode where cells were pre-treated with Carbomer 980 of increasing carbomer concentration (expressed as Log[Carbomer 980] in % w/w).
- FIG. 3 Lytic plaque formation at Day 3 following incubation of confluent monolayers of human cervical epithelial HeLa cells in curative mode where cells were pre- incubated with HRV-B14 and one of the following applied to the agar overlay: 20 ⁇ g/ml ribavirin; 0.0015% Carbomer 980; and 0.0015% Pemulen ® TR-2, compared to Control. The resulting number of lytic plaques are indicated in the lower left hand corner of each picture.
- FIG. 3 Lytic plaque formation at Day 3 following incubation of confluent monolayers of human cervical epithelial HeLa cells in curative mode where cells were pre- incubated with HRV-B14 and one of the following applied to the agar overlay: 20 ⁇ g/ml ribavirin; 0.0015% Carbomer 980; and 0.0015% Pemulen ® TR-2, compared to Control. The resulting number of lytic plaques are indicated in the lower left hand corner of each picture.
- Viral load (expressed as viral copy number per ml x 10 "5 ) in human airway epithelia infected with Influenza H1N1 (Panel A) or Coronavirus OC643 (Panel B) after 24 hours following treatment with Carbomer 980 (with 0.5% phenylethanol preservative) compositions of increasing carbomer concentration (0.003, 0.01, 0.03, 0.1, 0.3 and 0.5 % w/w).
- the antiviral, oseltamivir, 1 ⁇ is tested against H1N1 (Panel A); and chloroquine is tested against Coronavirus (Panel B).
- Fig. 7 Viscosity (in mPa's) of 1% Carbomer 980 or 981 as a function of pH between 5 and 7; or as a function of pH between 4 and 7 and salt content
- Carbomer 980 composition comprises 150 mM NaCI
- Carbomer 981 compositions comprise 3 concentrations of NaCI: 1.7 mM, 150 mM, or 450 mM).
- Fig. 12 Plot of body weight (bw) (in g) (Panel A) or relative food consumption (g/kg/bw/day) in male and female rats over 14 day Test Period of intranasal administration of Carbomer 980 composition (including 0.5% phenylethanol preservative) as compared with untreated controls, followed by a Recovery Period of 7 days.
- Fig. 13 Plot of HRV-14 mRNA copy number (per well x 10 "3 ) (Panel A) and cell viability (OD at 450 nm) (Panel B) against carbomer concentration (expressed as Log [Carbomer 980] in % w/w) in human airway epithelial A459 cells treated for one hour with Carbomer 980 compositions of increasing carbomer concentration, and subsequently infected with HRV- Fig.
- Fig. 15 Mouse L292 fibroblast cell viability graded by microscopic examination at the indicated times in agar-coated monolayers treated with 5% w/w Carbomer 980, as well as various marketed nasal sprays (Vicks First Defense ® , Anefrin Nasal Spray, and Nostrilla ® Fast Relief), and 0.9% saline, 0.1% Triton and 0.5% phenylethanol controls, and stained with neutral red. (* indicates cytotoxicity)
- the common cold also known as nasopharyngitis, rhinopharyngitis or coryza, is an acute viral respiratory tract infection affecting the nose, throat and sinuses, and also occasionally involving the eyes in the form of conjunctivitis. It is among the most common infectious diseases in man, being endemic to all human populations (Zuckerman, 2007). Adults are typically subject to 2-4 infections annually, with children having as many as 6-10 colds per year (Simasek and Blandino, 2007).
- HRVs human rhinoviruses
- HRVs are a group of picornaviridae enteroviruses with approximately one hundred known serotypes that are subdivided into three subgroups termed HRV-A, HRV-B and HRV- C, with the first two subgroups comprising 74 and 25 serotypes respectively (Palmenberg et al., 2009 and 2010). Among these, HRV-C is noted for causing severe infections in children.
- HRVs are non-enveloped, positive sense, single-stranded RNA viruses with genomes of approximately 7.2-8.5 Kb in length that consist of a single gene that codes for 11 proteins which are transcribed as a single polypeptide that is subsequently cleaved into structural and non-structural proteins.
- Four of these proteins termed VP1, VP2, VP3 and VP4, make up the capsid that encases the viral RNA, while the remaining non-structural proteins are involved in genome replication and assembly.
- Each virion contains 60 copies of each of the four capsid proteins, giving it an icosahedral structure, with each VP1 protein serving as the site of attachment of the virus to cell surface receptors.
- HRV serotypes Approximately 85% of known HRV serotypes, termed “major group HRVs", infect cells by binding to the human cell surface inter-cellular adhesion molecule 1 (ICAM-1), also known as CD45, while the remaining “minor group HRVs” infect cells via the cadherin- related family member 3 (CDHR3) protein.
- IAM-1 human cell surface inter-cellular adhesion molecule 1
- CDHR3 cadherin- related family member 3
- HRVs have also been reported to bind to the low-density lipoprotein receptor (LDL , 15%) or a cell surface sialoprotein to gain entry into cells.
- HRVs are typically transmitted from person to person either via airborne droplets (aerosols), direct contact with infected nasal secretions, or through fomites (i.e.
- HRV infection being particularly well initiated by intranasal and conjunctival inoculation when compared to exposure via the oral route alone.
- HRVs are able to survive in indoor environments for hours to days at ambient temperature, and for approximately 2h on undisturbed skin, which leads to the high transmission and infection rates observed in child day care, preschool and family environments.
- Allergic rhinitis also termed seasonal rhinitis, perennial rhinitis, polinosis or hay fever, is inflammation of the nose that occurs when the immune system overreacts to airborne allergens. Signs and symptoms include sneezing, rhinorrhea and/or nasal congestion that can be accompanied by conjunctival injection and eyelid edema with swelling under the eyes. The fluid from the nose is usually clear, with sinus obstruction sometimes causing frontal headaches. Symptom onset is often within minutes following exposure to allergens, and can affect sleep, the ability to work, and the ability to concentrate.
- Seasonal rhinitis is caused by tree pollens in the spring, grass and weed pollens in the summer, and by other weed pollens in the fall, with seasonal rhinitis also being occasionally caused by airborne fungal spores.
- Perennial rhinitis is caused by year- round exposure to indoor environmental allergens, such as to dust mite or cockroach excretions, animal dander or mold.
- the underlying mechanism leading to rhinitis involves the binding of IgE antibodies to allergens which subsequently causes the release of histamine from mast cells. While the symptoms of allergic rhinitis resemble those of the common cold, they often last for more than two weeks, do not usually include a fever, and can most often be diagnosed by history and symptoms alone.
- Treatment of seasonal and perennial rhinitis or other allergen-induced inflammatory conditions of the upper respiratory tract is generally the same, with its goal being the prevention or reduction of symptoms caused by the inflammation of infected tissues. Measures that are effective include avoiding contact with allergen, with front-line therapies being oral antihistamines with oral decongestants, or nasal corticosteroids with or without oral antihistamines.
- Alternative treatments include nasal mast cell stabilizers such as cromolyn sodium or nedocromil, nasal antihistamines, nasal imatropium to relieve rhinnorhea, nasal saline, or an oral leukotriene receptor antagonist such as monteleukast. Medications, however, are generally insufficient and/or can be associated with side effects such as fatigue and drowsiness.
- Carbomers are widely considered to be non-toxic and well tolerated excipients, as they are unable to permeate the skin or mucosa, and have little-to-no oral bioavailability (CI , 1982). When applied topically, carbomers display little-to-no skin irritation, sensitization, phototoxicity or allergenic effects in mammals.
- Carbomers which are which are white, hygroscopic powders, that typically swell in water when neutralized, are widely used in both pharmaceutical and cosmetic formulations as thickening, suspending, dispersing and emulsifying agents (Windholz M, 1976; ACT, 1982), and are currently classified by the US Food and Drug Administration as inactive pharmaceutical ingredients approved for use in tablets, capsules, solutions, suspensions, emulsions, lotions, ointments, creams and gels at concentrations of up to 3.5% w/w depending on the application (FDA, 2016).
- Typical carbomer use in cosmetics is at concentrations of 0.1-1% w/w in lotion, eyeshadow, lipstick, hair conditioner, hair dye, dentifrice, bath soap, shaving cream and aftershave preparations, and at up to 5% w/w in blushes, face cream, hand cream, fragrance, after shave and suntan gel formulations.
- Their physical properties and relative inertness towards most biological systems further makes them suitable for the controlled the release of drugs from time-release tablets or entrapped systems (Choulis N, 1976 and Elgindy NA, 1976), or, e.g., as bulking agents (Goodrich, 1962).
- Marketed topical formulations containing carbomers include but are not limited to transdermal products within the Voltaren ® brand, such as diclofenac diethylamine 2.32% gel and diclofenac sodium 1% gel (Novartis); ophthalmic formulations such as Viscotears ® Liquid Gel (Bausch& Lomb); and nasal products such as Ocean Nasal Moisturizer Gel ® (Valeant Pharmaceuticals Int'l.), Extra Moisturizing Anefrin Nasal Spray (Walgreen's), and Nostrilla ® Nasal Spray (Insight Pharmaceutical).
- transdermal products within the Voltaren ® brand such as diclofenac diethylamine 2.32% gel and diclofenac sodium 1% gel (Novartis); ophthalmic formulations such as Viscotears ® Liquid Gel (Bausch& Lomb); and nasal products such as Ocean Nasal Moisturizer Gel ® (Valeant Pharmaceuticals Int'l.), Extra Mois
- montelukast sodium nasal spray formulation prepared as a colloid solution using hydroxypropyl cellulose and Carbomer 934 as a mucoadhesive agent were determined and found to meet the requirements for optimum nasal drug delivery (Jullaphant T, 2016).
- Carbopol ® was demonstrated to be a suitable gelling agent in heparin gel; and in concentrations of 1.15 %, 1.20 %, and 1.25 %, used with preservatives, the gelling system showed acceptable microbiological and active ingredient stability (Laze L et al, 2017).
- Carbomer 934 on murine leukemia and avian myoblastosis virus reverse transcriptases at concentrations of 5-30 mg/ml (Bloemers and Van der Horst, 1975; Kumar, 1976).
- Another study reports a protective effect exerted by Carbomer 934 against intravenous vaccinia and intranasal herpes simplex challenge in the mouse when administered by intraperitoneal injection (De Clercq and Luczak, 1976), which appears related to activation of peritoneal macrophages which in turn stimulates interferon production, rather than by direct viral inhibition.
- H V A hallmark of H V is that the viruses are deactivated in acidic environments (Gern et al. 2007). The effect is believed to be due to conformational changes in the viral capsid proteins at pH below about 6.2 which render the virus noninfectious (Giranda et al. 1992). Thus Hull et al., 2007 attempted to treat HRV infections with 1% Carbomer 980 NF in a succinate buffered composition formulated at pH 4.5. See also Rennie P., 2007. However, to applicants' knowledge, no carbomer composition has previously been shown to be clinically effective in the treatment or prevention of acute viral infections such as the common cold.
- CN 101590074 describes a neutralized gel composition of carbomer (e.g., Carbomer 934P), pH 6.0 to 7.0, that is applied intranasally and around the mouth 4-5 times day to prevent and treat allergic rhinitis.
- carbomer e.g., Carbomer 934P
- pH 6.0 to 7.0 pH 6.0 to 7.0
- carbomers are capable of inhibiting H V and influenza infection of human airway epithelial cells, and thus can be particularly useful for the treatment or prevention of virus-induced respiratory infections as well as allergenic) induced conditions such as allergic rhinitis and symptoms thereof in mammals by topical intranasal administration.
- Carbomer 980 or “Carbomer 981” (available as Carbopols ® 980 NF and 981 NF), as well as USP/NF- monographed "Copolymer,” which includes species such as Pemulens ® TR-1 and TR-2 NF are capable of inhibiting viral proliferation in human airway epithelial cells. In in vitro studies, the inhibition was found to be dose-dependent, with maximal inhibition occurring at concentrations consistent with the induction of a barrier effect. Additionally,
- Carbomer 980 has been found to exhibit anti-plaque activity not only against HRV-B14 but also HRV-29, and thus potentially against a broad range of HRV serotypes. Critically, the anti-viral activity is seen when pre-treating HRV with carbomer, rather than when the cells are incubated with carbomer prior to viral inoculation, indicating that the carbomer acts directly on the HRV.
- anionic polymer compositions not only can provide a viscous physical barrier to the binding of pathogens to cell surface receptors such as epithelial cell ICAM-1 receptors , but may also exert a potent anti-viral, anti-allergenic effect through the binding of negatively-charged groups of the 30 polymer existing in the pH neutral compositions of the invention to positively-charged viral antigens, thereby inhibiting viral infection of the cell as well as the dissemination and further expansion of progeny virions.
- the anionic polymer is used for the treatment or prevention of allergic rhinitis
- the negatively-charged strands are able to bind to positively-charged domains of various allergens, thus preventing their ability to induce local histamine release when mucosal and/or epithelial surfaces are exposed to topical preparations designed for use in the prevention and/or treatment of allergic disorders.
- Carbomers also known as carboxyvinylpolymers, are synthetic, high molecular weight non-linear polymers of 2-propenoic acid (i.e. acrylic acid).
- carbomers are flocculated powders of particles having a median diameter of about 2 to 7 microns. Each particle can be viewed as a network structure of polymer chains interconnected by crosslinks. In the absence of the crosslinks, the primary particle would be a collection of linear polymer chains, intertwined but not chemically bonded. Such linear polymers are soluble in a polar solvent, such as water.
- cross-linked carbomers are not soluble due to their crosslinked nature and high molecular weight.
- these polymers swell up to 1000 times their original volume (and ten times their original diameter) to form a viscous gel (e.g., colloidal dispersion) when exposed to a pH environment above 4-6.
- the pKa of the polymers is slightly acidic, i.e. 6 ⁇ 0.5
- the majority of the carboxylate groups on the polymer backbone are ionized at neutral pH and above, with the different variants of Homopolymers, for example, containing between 98.7% and 99.9% acrylic acid and between 56-68% free carboxylic acid groups (USP monograph).
- TAA triethanolamine
- Carbomer Homopolymer is a high molecular weight polymer of acrylic acid cross- linked with allyl ethers of polyalcohols.
- Carbomer Homopolymer previously dried at 80° for one hour, contains not less than 56.0 percent and not more than 68.0 percent of carboxylic acid (-COOH) groups, per USP monograph.
- Homopolymer at 1% concentration in water has a pH of about 3.
- the polymer When neutralized with alkali hydroxides or amines, the polymer swells giving the appearance of dissolving in water; when neutralized with lower amines and alkanolamines, it swells giving the appearance of dissolving in methanol or glycerin; when neutralized with ethoxylated long-chain (C 14 -C is) amines, it swells giving the appearance of dissolving in ethanol.
- Typical cross-linkers are allyl ether of pentaerythritol, allyl ethers of sucrose, or allyl ethers of propylene.
- Carbomer Copolymer is a high molecular weight copolymer of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of polyalcohols. Carbomer copolymer swells in water when a suspension or dispersion of the copolymer is neutralized with sodium hydroxide to a pH within the range of 7.3 to 7.8 (USP monograph). The typical cross-linker is allyl ether of pentaerythritol.
- Carbomer Interpolymer is a Carbomer Homopolymer or Copolymer that contains a block copolymer of polyethylene glycol and a long-chain alkyl acid ester. Carbomer Interpolymer swells in water when a suspension or dispersion of it is neutralized with sodium hydroxide to a pH within the range of 5.5 to 9 (USP monograph).
- the USP monograph further identifies Carbomer Homo-, Co- and Inter-polymers by three sub-category Types (A, B and C) which differ by viscosity range, as set forth in Table 1:
- Carbomers 941, 934P, 934, 940, and 1342 as shown on Table 2 (which are commercially available, e.g., Carbopols ® 941 NF, 934 P NF, 934 NF, 940 NF and 1342 NF, respectively).
- Carbomer 980 NF as used herein, if not otherwise specified, shall be understood to refer to pharmaceutically acceptable, essentially benzene-free, carbomer meeting the viscosity specifications set forth on Table 1 for Carbomer Homopolymer Type C; and similarly, "Carbomer 981" or “Carbomer 981 NF” shall refer to pharmaceutically acceptable essentially benzene-free Carbomer meeting the viscosity specifications set forth on Table 1 for Carbomer Homopolymer Type A.
- carbomer 910 is a white, fluffy hygroscopic powder.
- the pH of a 1 in 100 dispersion is about 3. When neutralized with alkali hydroxides or with amines, it dissolves in water, in alcohol, and in glycerin.
- Carbomer Homopolymer examples include Carbopols ® 71G NF, 971P NF, and 981 NF (Type A); 974 P NF and 5984 EP (Type B); and 980 NF (Type C), (all available from Lubrizol Advanced Materials, Inc., Cleveland, Ohio, hereinafter "Lubrizol”).
- Carbopol ® 980 NF is understood to be a benzene-free alternative to Carbomer 940;
- Carbopol ® 981 NF to USP 941 See, e.g., "Compendial Specifications Applicable to Carbopol ® and Pemulen ® Pharmaceutical-Grade Polymers Based on Individual
- Carbomer Copolymer examples include commercially available Carbomer Copolymer, e.g., as Pemulens ® TR-1 NF and TR-2 NF (Lubrizol), which are Type B and Type A, respectively, copolymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol that contain both hydrophobic and hydrophilic portions within the molecule.
- Pemulens ® TR-1 NF and TR-2 NF Lubrizol
- Type B and Type A respectively, copolymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol that contain both hydrophobic and hydrophilic portions within the molecule.
- carbomers are polymers of acrylic acid crosslinked with divinyl glycol (e.g., Noveon ® polycarbophil, Lubrizol).
- Carbomer Interpolymer examples include Lubrizol under the Carbopol ® tradename (e.g., Carbopol® Ultrez® 10 NF; Carbopol® ETF 2020 NF).
- Carbopol ® s 980 NF amd 981 NF and Pemulen ® TR-1 and TR-2 are polymerized without benzene, and thus are preferred for use in the methods and compositions of the invention:
- ETD2020NF Interpolymer Type B ethyl acetate/ 1.0 wt% mucilage, 47,000 - 77,000 cyclohexane spindle #7 (Test SA-003)
- compositions of the invention comprise at least one pharmaceutically acceptable carbomer in a topically administrable vehicle.
- pharmaceutically acceptable carbomer as employed herein shall be understood to include both the carbomer in its acid form and also the partially or fully neutralized (e.g., alkali metal or ammonium salt) forms thereof.
- compositions of approximately neutral pH comprising, or consisting essentially of, or consisting of: (a) a therapeutically effective amount of one or more pharmaceutically acceptable carbomers,
- terapéuticaally effective refers to an amount effective for the prevention or treatment of viral or allergen-induced conditions or diseases, including the reduction or alleviation of symptoms associated with said conditions or diseases.
- Viral infections treatable or preventable by the compositions of the invention comprise infections arising from one or more of human rhinoviruses (HRVs), coronaviruses influenza viruses (e.g., influenza A and B), adenoviruses, as well as parainfluenza viruses, respiratory syncytial viruses (RSV), metapneumovirus, enteroviruses other than HRV, coxsackievirus, Severe Acute Respiratory Syndrome (SARS), avian and/or swine influenza virus, filoviridae, paramyxovirus, orthomyxovirus, Middle East Respiratory Syndrome (M ERS), and co-infections thereof.
- HRVs human rhinoviruses
- coronaviruses influenza viruses e.g., influenza A and B
- adenoviruses e.g., as well as parainfluenza viruses
- RSV respiratory syncytial viruses
- SARS Severe Acute Respiratory Syndrome
- M ERS Middle East
- Preferred carbomers (a) for use in the methods and compositions of the invention are selected from: Homopolymer of Type A, B or C (allyl pentaerythritol crosslinked); Homopolymer of Type B (allyl sucrose crosslinked); and Copolymer of Types A or B (allyl pentaerythritol crosslinked), and combinations thereof.
- the carbomer is selected from Homopolymer of Type C
- (allylpentaerythritol crosslinked) having a viscosity of 13,000 to 30,000 cP, with reference to a 0.2 wt.% mucilage (spindle 6), and a viscosity of 40,000 to 60,000 cP, with reference to a 0.5 wt.% mucilage (spindle 7), where viscosity is determined with reference to an aqueous dispersion of the carbomer neuturalized to pH 7.3-7.8 at 25°C, using a Brookfield RVT, 20 rpm.
- the carbomer is selected from Homopolymer of Type A (allyl pentaerythritol crosslinked) having a viscosity of 1,000 to 6,000 cp, with reference to a 0.2 wt.% mucilage (spindle 4), and a viscosity of 4,000 to 10,000, with reference to a 0.5 wt.% mucilage (spindle 5), where viscosity is determined with reference to an aqueous dispersion of the carbomer neuturalized to pH 7.3-7.8 at 25°C, using a Brookfield VT, 20 rpm.
- Type A allyl pentaerythritol crosslinked
- the carbomer is selected from Copolymer of Type B, allyl
- pentaerythritol crosslinked having an emulsion viscosity of 6,500 to 15,500 cP, with reference to a 0.2 wt. % emulsion (spindle #5), and a mucilage viscosity of 10,000 to 26,500 cP, with reference to a 1.0 wt.% mucilage (spindle #6), where viscosity is determined with reference to an aqueous dispersion of the carbomer neuturalized to pH 7.3-7.8 at 25°C, using a Brookfield RVT, 20 rpm.
- the carbomer may be selected from Copolymer of Type A, allyl pentaerythritol crosslinked, having an emulsion viscosity of 1,700 to 4,500 cP, with reference to a 0.2 wt.% emulsion (spindle #4), and a mucilage viscosity of 4,000 to 13,500 cP, with reference to a 1.0 wt.% mucilage (spindle #5), where viscosity is determined with reference to an aqueous dispersion of the carbomer neuturalized to pH 7.3-7.8 at 25°C, using a Brookfield RVT, 20 rpm.
- Copolymer of Type A allyl pentaerythritol crosslinked, having an emulsion viscosity of 1,700 to 4,500 cP, with reference to a 0.2 wt.% emulsion (spindle #4), and a mucilage viscosity of 4,000 to 13,
- the carbomer (a) after being dispersed in water, is preferably neutralized. It is preferred that the carboxylic acid groups of the carbomer be maximally deprotenated since these groups are required for the polymer's binding to HRV. Common neutralizers, and the appropriate ratio to use (as compared to one part of carbomer) to achieve exact neutralization at a pH of 7.0, are set out in Table 7: Table 7.
- the concentration of carbomer in the composition may vary widely depending on the application and the desired viscosity.
- the concentration of pharmaceutically acceptable carbomer (a) in the compositions is generally about 0.01 to about 20 wt.%, more preferably about 0.05 to about 10 wt.%, even more preferably from about 0.1 to about 5 wt.%, even more preferably about 0.5 to about 3 wt.%, for example 0.5 wt.%.
- compositions to be administered as a nasal spray would need to be in excess of about 100 mPa's at 25°C. (as measured with a Brookfield Viscometer, spindle 4, 25 °C.) in order to assure sufficient intranasal residency time for clinical efficacy, while not surpassing about 400 mPa.s in order for the preparation to be sprayable using a commonly-employed nasal spray device.
- the tonicity agent, component (b) should be selected to provide an osmolarity to the compositions of between about 200 and about 400 mOsm/L, preferably between about 220 and about 380 mOsm/L, and more preferably between about 250 and about 340 mOsm/L.
- (b) is an ionic agent selected from one or more sources of monovalent cations, such as sodium chloride, potassium chloride, or a balanced salt solution.
- the ionic tonicity agents are typically present in an amount of about 0. 5 to about 0. 9%, preferably about 0. 6 to about 0. 9% by weight based on the total composition.
- an appropriate concentration in a nasal spray composition of the invention may be about 100 to about 200 milimolar (mM), e.g., about 130 to about 150 mM, depending on the buffer.
- the tonicity agent can also be non-ionic.
- Non-ionic tonicity agents include diols, such as glycerol, mannitol, erythritol; and sugars such as sucrose and dextrose.
- Other non- ionic tonicity agents include glycerol, polyethylene glycol, and propylene glycol.
- Yet other non-ionic agents are mannitol, sucrose, and dextrose.
- the non-ionic agents may be present in an amount of about 1% to about 5% by weight based on the total composition.
- Component (c) the buffer or buffering system, preferably comprises any one of the following components:
- buffer systems include acetic acid/acetate, adipic acid/adipate, ascorbic acid/ascorbate, aspartic acid/aspartate, benzoic acid/benzoate, bicine/bicinate, boric acid/borate, camphoric acid/camphorate, carbonic acid/carbonate, citric acid/citrate, formic acid/formate, fumaric acid/fumarate, gluconic acid/gluconate, glutamic acid/glutamate, glutaric acid/glutarate, glycerophosphoric acid/glycero-phosphorate, glycolic acid/glycolate, glycine/glycinate, hippuric acid/hippurate, isobutyric acid/isobutyrate, lactic acid/lactate, male
- phosphoric acid/phosphate citric acid/citrate; succinic acid/succinate; and ascorbic acid/ascorbate
- Sufficient buffer is used to maintain a pH that is preferably in the range of from about 6.5 to about 7.5.
- Other pH ranges considered to be "approximately neutral pH" are: from about 6.5 to about 7.8, e.g., from about 6.5 to about 7.3 and from about 7.3 to about 7.8.
- a suitable concentration of buffer may be 1-100 mM, preferably 5-50 mM, more preferably 5-25 mM, and most preferably 10-20 mM.
- the preferred buffer is phosphate-buffered saline (PBS), which is an aqueous solution comprising sodium hydrogen phosphate, sodium chloride and, in some formulations, potassium chloride and/or potassium dihydrogen phosphate to make up physiological solutions.
- PBS phosphate-buffered saline
- the osmolarity and ion concentrations of the solutions preferably match those of the human body (i.e. are isotonic).
- isotonic PBS shall refer to a 20 mM phosphate buffer solution (“PBS”) (comprising 0. 89g/L Disodium phosphate and 2.26 g/L Monosodium phosphate) in 150 mM sodium chloride.
- PBS phosphate buffer solution
- salt or salt solution functioning as the tonicity agent (b) may be comprised of the anion of the acid employed in buffering system (c).
- a source of monovalent cations is provided to the composition as an ingredient of PBS or other buffer system (c), or otherwise provided to the composition (e.g., as an ingredient contained within an optional component), it shall be considered to fulfill the requirement for component (b) and shall be included in the determination of total monovalent cation concentration for purposes of calculating osmolarity of the composition.
- compositions of the invention comprises 0.5% w/w Carbomer 980 NF or Carbomer 981 NF in isotonic PBS, pH 7.2. It will be within the skill of a worker in the art to prepare compositions of appropriate viscosity and tonicity within the pH range of from about 6.5 to about 7.5, or from about 6.5 to about 7.8, e.g., from about 6.5 to about 7.3 or from about 7.3 to about 7.8, which are suitable for the intended therapeutic application.
- compositions of the invention to be administered to the nasal cavity as a nasal spray are preferably isotonic, non-irritating, and sprayable, yet sufficiently viscous to remain in contact with the surface of the posterior nasal and nasopharyngeal cavities for a prolonged period of time after administration.
- compositions of the invention intended for ocular administration in the form of an eyedrop are preferably isotonic, non-irritating, and dispensable by dropper, yet sufficiently viscous to remain in contact with the ocular (e.g., corneal) surface.
- an optional additional ingredient comprises a viscosity-modulating agent.
- a viscosity-modulating agent as used herein, refers to a compound that when added to a solution increases (or decreases) the viscosity of the solution.
- a viscosity-enhancing agent may be used in a nasal spray to provide sustained mucosal contact time, and reduce the possibility of the formulation to 'drip back' from the nasal cavity to the back of the throat ("post-nasal drip").
- Viscosity-modulating agents typically comprise uncrosslinked polymers such as hydroxypropylmethylcellulose (i.e. hypromellose), methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl- cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.
- a preferred viscosity-enhancing agent is hydroxypropylmethylcellulose.
- the concentration of a viscosity-enhancing agent in the aqueous formulation is in general from about 0. 001 to about 5% (w/v), preferably from about 0. 05 to about 0. 5%, and more preferably from about 0.1 to about 0.3% (w/v).
- the pharmaceutical formulation of the present invention optionally comprises an anti-bacterial preservative, preferably a non-cationic preservative.
- Suitable preservatives for the present invention may be selected, e.g., from phenylethanol, phenoxyethanol, and parabens, methyl parabens, propyl parabens, and mixtures thereof.
- preservatives are employed at a level of about 0. 001 to about 1%, preferably, from about 0. 005 to about 0. 25%, and most preferably from about 0. 05 to about 0. 2% (w/v).
- taste-masking agents e.g., sweeteners, flavoring agents, or other agents.
- compositions are essentially free of divalent or trivalent cations such as Ca 2+ , Zn 2+ Fe 2+ , Fe 3+ and La 3+ , which may cause the carbomer to precipitate due to the due to the high affinity of the carbomer anionic groups for these ions.
- the 1% Carbopof 980 formulation of Hull et al. 2007 comprised Zn 2+ in the presence of succinate buffer at pH 4.5, which is incompatible both with maintaining carbomer in solution and maintaining a maximal number of free deprotonated carboxylic acid groups that are required for the polymer's binding to H V.
- compositions are free of certain cationic preservatives, such as benzalkonium chloride, bromododecinium bromide, benzethonium chloride, methylbenzethonium chloride, cetylkonium chloride, cetylpyridinium chloride, cetrimonium chloride, dofanium chloride, tetraethylammonium bromide, didecyldimethyl- ammonium chloride, domiphen bromide and the like, since the carbomers can react with amine groups to form thick emulsions of oils in water (Windholz M, 1976).
- benzalkonium chloride bromododecinium bromide, benzethonium chloride, methylbenzethonium chloride, cetylkonium chloride, cetylpyridinium chloride, cetrimonium chloride, dofanium chloride, tetraethylammonium bromide, didecyldimethyl- ammonium chloride
- the pharmaceutical formulations of the present invention are preferably stable at room temperature for at least 12 months, preferably 24 months, and more preferably 36 months.
- Stable as used herein, means that carbomer maintains at least 80%, preferably
- compositions of 0.5% w/w Carbomer ® 980 formulated in isotonic PBS containing either of 0.1% phenoxyethanol, 0.5% phenylethanol, or a mixture of parabens as preservative, have been found to inhibit viral replication by 85%, 82% and 92% respectively.
- compositions of the invention preferably comprise viscous aqueous solutions, dispersions (e.g., colloidal gels) or suspensions of carbomer in isotonic salt solution buffered to approximately neutral pH, for topical administration.
- dispersions e.g., colloidal gels
- suspensions of carbomer in isotonic salt solution buffered to approximately neutral pH, for topical administration.
- compositions are applied directly to the nasal cavity by conventional means, for example by use of a dropper, pipette or spray, with said formulation being provided in either single or multidose form.
- a dropper, pipette or spray for example by use of a dropper, pipette or spray, with said formulation being provided in either single or multidose form.
- this may be achieved by the user
- Said formulation may also comprise additional ingredients which have been selected to further: alleviate the symptoms or duration of the common cold, such as in the case of a nasal decongestant, an antihistamine, an anti-inflammatory agent, an antiviral, or a salt of Li + or Zn 2+ in a concentration sufficiently low to avoid precipitating the carbomer ; reduce the occurrence of secondary bacterial infections, such as in the case of an inducer of endogenous antimicrobial peptide production or an antiseptic for use in rhinosinusitis; promote the healing of the nasal mucosa, such as in the case of a cytoprotective moisturizer, and/or increase the retention of the formulation by the nasal mucosa, such as in the case of an additional mucoadhesive and/or thickening agent, and this without limitation and
- compositions of the invention are topically administered for the prevention or treatment of viral infection or allergen-induced conditions such as allergic rhinitis to a mammalian (e.g., human or veterinary) subject in need thereof.
- a mammalian subject e.g., human or veterinary
- an adult human subject may be administered by the nasal route a total dose of from about 17 to about 34 mg of carbomer per day, more preferably about 5 to about 20 mg/day.
- the composition may be administered once a day or in divided doses several times a day.
- the administration protocol may consist of 2-3 metered dose sprays of a 0.5% carbomer composition of the invention per nostril, 3-4 times per day, which provides a maximum number of sprays per day of 24.
- Each spray may consist of about 0.10 to about 0.20 ml (e.g., 0.14 ml) of composition of the invention.
- a typical treatment period may consist of about 1 to 7 days, or shorter or longer as needed.
- a dosing regimen consisting of 3 actuations per nostril (i.e. x 2 nostrils), given up to 4 times per day (approximately 4 hours apart), over a period of 7 days will thus consist of a maximum of 168 nasal spray actuations.
- the rationale for the number of applications and regimen is to maximize the coverage of the nasal epithelium commensurate with consumer acceptability.
- compositions of the invention forms a barrier that reduces the ability of viral pathogens to infect human epithelial cells due to its ability to block the binding of viruses to cell surface receptors, thus providing a useful means for the prevention and treatment of a range of infections including but not limited to upper respiratory, labial, gingival, oropharyngeal, ocular, dermal and genital viral infections.
- compositions of the invention comprise carbomer as the sole active pharmaceutical ingredient, and are devoid of any active pharmaceutical ingredients other than the carbomer.
- Carbomers are unable to permeate the skin or mucosa, and have limited to no oral bioavailability.
- compositions of the invention are systemically available, nor have any expected pharmacologic action other than the anti-viral and/or anti-allergenic activity of the carbomer.
- the compositions of the invention may comprise one or more active pharmaceutical ingredients in addition to the carbomer.
- compositions of the invention are essentially free of oil formation, and thus are not emulsions.
- compositions of the invention include carbomer preparations for the prevention, treatment and/or use in, as applicable: (A) buccal disorders such as labial herpes, cold sores, gingivostomatisis, ulcerative lesions of the oropharyngeal structures and/or oral warts; (B) conjunctivitis, idiopathic anterior uveitis and/or ophthalmic herpes zoster infections; (C) dermal ailments including molluscum contagiosum, common, flat, mosaic, periungual or plantar warts, and/or herpes zoster-induced dermal lesions; (C) sexually-transmitted diseases such as genital herpes and human papilloma virus infections; (D) vaginal candidiasis; (E) reducing the hand-to-hand and surface-to-hand transmission of viruses, and (F) the disinfection of contaminated surfaces.
- buccal disorders such as labial herpes, cold sores
- carbomer compositions for use in a topical labial or intrabuccal application for use in the prevention and/or treatment of herpes simplex labialis, coxsackie virus-induced gingivostomatitis or herpangina (i.e. cold sores, painful gums and mouth, and/or ulcerative lesions of the posterior oropharyngeal structures), and/or human papilloma virus-induced veruciform proliferations (i.e. oral warts).
- herpes simplex labialis i.e. cold sores, painful gums and mouth, and/or ulcerative lesions of the posterior oropharyngeal structures
- human papilloma virus-induced veruciform proliferations i.e. oral warts.
- Anionic polymer (a) preferably consists of 4% or less (w/w) of a cross-linked 2- propenoic acid-derived carbomer listed in Table 1, while buffering agent (c) consists of any buffer that is commonly used in medicinal preparations (ex: phosphate, citrate, succinate, ascorbate, or other), and which also serves to assure a preferred viscosity and antiviral activity of the anionic polymer (a) solution.
- the resulting formulations are applied directly to the oral cavity by conventional means, for example by application of a liquid (i.e. mouthwash), gel, cream, film, eluting strip, dissolving tablet, losange or any similar means of delivery to the surface of the affected labial or buccal mucosa.
- a liquid i.e. mouthwash
- gel i.e. cream, film, eluting strip, dissolving tablet, losange or any similar means of delivery to the surface of the affected labial or buccal mucosa.
- said formulations may also include, for example and without limitation: (d) a local anesthetic such as benzocaine, procaine, tetracaine, lidocaine, prilocaine or other; (e) an antiviral agent such as acyclovir, valacyclovir, penciclovir, famciclovir, docosanol or other; (f) an antiseptic, (g) an essential oil or fragrance such as menthol or eugenol; and (h) an additional mucoadhesive and/or thickening agent, and this without limitation and in any combination(s) thereof for use in the topical treatment of labial, intrabuccal or oral infections.
- a local anesthetic such as benzocaine, procaine, tetracaine, lidocaine, prilocaine or other
- an antiviral agent such as acyclovir, valacyclovir, penciclovir, famciclovir, do
- compositions may also be used in the topical treatment of acute, recurrent and/or chronic ocular infections such as adenovirus, herpes simplex virus, enterovirus, Coxsackie virus, poxvirus and human immunodeficiency virus-induced ocular infections (i.e. "viral conjunctivitis” or “pinkeye"), viral anterior uveitis (i.e. "idiopathic anterior uveitis”) and/or ophthalmic herpes zoster infections.
- acute, recurrent and/or chronic ocular infections such as adenovirus, herpes simplex virus, enterovirus, Coxsackie virus, poxvirus and human immunodeficiency virus-induced ocular infections (i.e. "viral conjunctivitis” or “pinkeye"), viral anterior uveitis (i.e. "idiopathic anterior uveitis”) and/or ophthalmic herpes zoster infections.
- compositions may be liquids or gels that are applied for example by means of a dropper, squeeze bottle or applicator tube.
- said formulations may also include, for example and without limitation: an antiviral drug including but not limited to trifluridine, idoxuridine, vidarabine, ganciclovir or similar; an anti-inflammatory agent such as a glucocorticoid or a non-steroidal antiinflammatory drug; an antibiotic or similar antimicrobial agent for extending the use of formulation to the treatment of infections induced by Staphylococcus aureus, Haemophilius influenza, Streptococcus pneumoniae and/or Pseudomonas aeruginosa (i.e.
- bacterial conjunctivitis a vasoactive constrictor of ocular arterioles, such as but not limited to the alpha adrenergic agonists tetrahydrozoline and naphazoline to reduces eye redness and congestion; an antihistamine; an antiseptic; an additional moisturizer and/or lubricant, and this without limitation and in any combination(s) thereof for use in the topical treatment of ocular infections.
- compositions may be used in the prevention or treatment of dermal ailments such as pox virus-induced molluscum contagiosum, common, flat, genital, mosaic, periungual or plantar warts, and/or herpes zoster-induced dermal lesions.
- dermal ailments such as pox virus-induced molluscum contagiosum, common, flat, genital, mosaic, periungual or plantar warts, and/or herpes zoster-induced dermal lesions.
- the formulations of (a) anionic polymer, (b) tonicity agent, and (c) buffer or buffer system may be a solid, liquid, gel, ointment, cream or paste that is applied for example by means of an adhesive pad, patch, bottle, applicator tube or spray.
- said formulations may also include, for example and without limitation: an antiviral drug such as acyclovir, valacyclovir or other; an antimetabolite or inhibitor of DNA synthesis such as 5-fluorouracil or other; a keratolytic such as salicylic acid, allantoin, hydantoin, urea, glycolic acid or other; a retinoid such as tretinoin; an immunomodulator such as imiquimod, an interferon or other; a blistering agent such as cantharidin; an Hi or H 2 histamine receptor antagonist; an anesthetic such as benzocaine, procaine, tetracaine, lidocaine, prilocaine or other; an antiseptic; and an antibiotic to either kill infected tissue or to limit secondary bacterial infections, and this without limitation and in any combination(s) thereof for use in the topical treatment of dermal lesions and infections.
- an antiviral drug such as acyclovir, valacyclovir or other
- compositions of the invention are used in the prevention of sexually-transmitted diseases, pregnancy and/or in the treatment of intravaginal infections.
- the resulting formulations are applied directly to the vaginal cavity by conventional means, for example by application of a suppository, dissolving tablet, liquid, gel or cream with or without use of an applicator, either as such or combined with the use of a barrier device such as a diaphragm, condom, cervical cap or medicated sponge.
- said formulations may also include, for example and without limitation: an antifungal agent; a spermicide such as nonoxynol-9, octoxynol-9, benzalkonium chloride, sodium cholate, lactic acid, neem oil or other; an antiseptic, a lubricant, a cytoprotective moisturizer, an additional mucoadhesive or thickening agent, and/or an essential oil or fragrance, and this in any combination(s) thereof.
- an antifungal agent such as nonoxynol-9, octoxynol-9, benzalkonium chloride, sodium cholate, lactic acid, neem oil or other
- an antiseptic such as nonoxynol-9, octoxynol-9, benzalkonium chloride, sodium cholate, lactic acid, neem oil or other
- an antiseptic such as nonoxynol-9, octoxynol-9, benzal
- compositions may also include an antiviral agent such as but not limited to compounds used for the prevention or treatment of genital herpes or human papilloma virus infections.
- an antiviral agent such as but not limited to compounds used for the prevention or treatment of genital herpes or human papilloma virus infections.
- compositions are used in the prevention of hand-to- hand and surface-to-hand transmission of H V and other respiratory pathogens.
- the resulting formulations are applied directly to the skin of the hands by conventional means, for example by using a rigid or squeeze bottle, metered dispenser, presoaked wipes or a dispensing tube that are employed by the user as per the manufacturer's instructions.
- said formulations may be gels, foams, creams or liquids that may also include, for example and without limitation: an organic solvent such as ethanol, n-propanol or isopropanol; an antiseptic; an oxidizing agent; a humectant such as glycerol, glycerin, propylene glycol or an organic acid; and an essential oil or fragrance, and this in any combination(s) thereof.
- an organic solvent such as ethanol, n-propanol or isopropanol
- an antiseptic such as ethanol, n-propanol or isopropanol
- an antiseptic such as ethanol, n-propanol or isopropanol
- an antiseptic such as ethanol,
- a further embodiment comprises the compositions for use for the disinfection of contaminated surfaces, including but not limited to its use in home, school, restroom, hospital and industrial settings.
- Bicarbonate may be favored as the buffer for both its antiviral and antimicrobial properties.
- the resulting preparations may be liquids, gels, powders or tablets that are diluted in a volume of water prior to their application to said contaminated surfaces by means of a damp cloth, mop, hose, jet, sprayer or similar device by the user as per the manufacturer's instructions.
- the formulation may also include, for example and without limitation: an organic solvent, including but not limited to ethanol, n-propanol, isopropanol and mixtures thereof; a wetting agent; an oxidizing agent including various acids; a phenolic disinfectant such as phenol, o-phenylphenol, chloroxylenol, thymol or other ; one or more quarternary ammonium compounds; an antiseptic; a chelate or salt of a metal that exhibits antimicrobial properties such as Ag + , Cu + , Cu 2+ , Li + or Zn 2+ (the divalent ions being in a concentration sufficiently low to avoid precipitating the carbomer) and/or an essential oil or fragrance, and this in any combination(s) thereof.
- the diluted preparation is applied to the surface in question, allowed to dry, and either left or subsequently removed from the surface by rinsing with water as per the manufacturer's instructions.
- the invention in its various aspects includes: A method for treating or preventing viral infections or allergenic conditions or the symptoms thereof in a mammalian subject in need thereof which comprises topically administering to the subject a composition comprising a therapeutically effective amount of at least one pharmaceutically acceptable carbomer in an aqueous solution or suspension or dispersion buffered to approximately neutral pH, wherein the composition also comprises a steroidal or non-steriodal anti-inflammatory agent; an antihistamine; a decongestant; an inducer of antimicrobial peptide production; an antibiotic; an antifungal; an antiseptic; and each of these either alone or in any combination thereof for use in the prevention and/or treatment of upper respiratory viral infections, allergic rhinitis or viral, bacterial and/or fungal sinusitis; and/or
- the composition is a liquid, dispersion, suspension, emulsion, gel, cream, ointment, paste or film comprising an antiviral drug, an anesthetic, an antiseptic, a mucoadhesive or a humectant, and each of these either alone or in any combinations thereof for topical use in the prevention and/or treatment of infections of the oral cavity, lips and perilabial surface, including the prevention and/or the treatment of cold sores, gingivostomatitis, painful gums and mouth, herpangina, oral warts, herpes simplex labialis and/or any other ulcerative lesions of the labial, buccal or posterior oropharyngeal structures;
- a steroidal or non-steroidal antiinflammatory agent an antibiotic, a decongestant, an antihistamine or a humectant, and each of these either alone or in any combinations thereof for topical use in the prevention and/or treatment of acute, recurrent and/or chronic infections or allergic diseases of the eye, including viral conjunctivitis or pinkeye, allergic conjunctivitis, viral anterior uveitis, idiopathic anterior uveitis and ophthalmic herpes zoster infections; an antiviral drug, keratolytic, a dermal blistering agent, an antiseptic or a humectant, and each of these either alone or in any combinations thereof for topical use in the prevention and/or treatment of viral infections of the skin, including molluscum contagiosum, common, flat, mosaic, periungual or planar warts, and herpes zoster-induced dermal lesions; an antiviral drug, a spermicide, an antiseptic, a
- composition is a liquid, dispersion, suspension, emulsion or gel used for prevention of the hand-to-hand and surface-to-hand transmission of viral infections comprising an organic solvent, an antiseptic or humectant, and each of these either alone or in any combinations thereof.
- composition is used for the disinfection of contaminated surfaces and comprises an organic solvent, an oxidizing agent, a phenoloic disinfectant, an antiseptic or humectant, and each of these either alone or in any combinations thereof.
- the invention also contemplates a method of preparing a pharmaceutically- acceptable formulation with antiviral and anti-allergenic activity consisting of the combination of a salt or salt solution (a), an anionic polymer with antiviral and/or anti- allergenic action (b), and a buffering system (c), wherein:
- the salt or salt solution is, or is respectively made with, any pharmaceutically- acceptable salt of a monovalent cation, including but not limited to any halide, sulfate or carboxylate salt of Na + , K + , Li + , NhV, an organic amine, or an amino acid, and in any combination(s) thereof;
- the anionic polymer is any pharmaceutically-acceptable, non-linear, cross-linked, Type A, B or C Homo- or Copolymer derived from 2-propenoic acid (i.e. polyacrylic acid) produced in a ethyl acetate/cyclohexane co-solvent system;
- the buffering system consists of any pharmaceutically-acceptable acid/anion pair that is used to maintain the formulation at a given pH, including but not limited to acetic acid/acetate, adipic acid/adipate, ascorbic acid/ascorbate, aspartic acid/aspartate, benzoic acid/benzoate, bicine/bicinate, boric acid/borate, camphoric acid/camphorate, carbonic acid/carbonate, citric acid/citrate, formic acid/formate, fumaric acid/fumarate, gluconic acid/gluconate, glutamic acid/glutamate, glutaric acid/glutarate, glycerophosphoric acid/glycero-phosphorate, glycolic acid/glycolate, glycine/glycinate, hippuric acid/hippurate, isobutyric acid/isobutyrate, lactic acid/lactate, maleic acid/maleate, malic acid/malate, malonic acid/malonate
- the invention further includes the above method, wherein the resulting formulation: (a) is a liquid, dispersion, suspension, emulsion, gel, cream, ointment, paste, film, wax, or solid;
- (b) is administered by means of a bottle, dropper, pipette, spray, tube, sponge, tissue, wipe, eluting strip, suppository, granulated preparation, applicator, tablet, losange, patch, or by any other similar pharmaceutically-acceptable means;
- ( c ) is isotonic compared to tissues, mucosal surfaces and biological fluids, with an osmolarity between 200-400 mOsm/L at 20°C;
- (d) has a pH between 6.0 and 8.0, and more preferably between 7.2 and 7.5.
- the invention even further contemplates the use of the above formulation topically for the prevention and/or treatment the following ailments as applicable, including the prevention and/or treatment of their symptoms, severity, duration and/or sequelae:
- infections of the oral cavity, lips and perilabial surface including the prevention and/or the treatment of cold sores, gingivostomatitis, painful gums and mouth, herpangina, oral warts, herpes simplex labialis and/or any other ulcerative lesions of the labial, buccal or posterior oropharyngeal structures;
- viral infections of the skin including molluscum contagiosum, common, flat, mosaic, periungual or planar warts, and herpes zoster-induced dermal lesions;
- sexually transmitted diseases such as genital herpes and/or human papilloma virus infections.
- the invention also includes the above methods wherein the resulting formulation contains one or more of:
- antifungal agents benzoic acid, abafungin, albaconazole, amorolifin,
- amphotericin B anidulafungin, bifonazole, butenafine, butoconazole, candicidin, caspofungin, cicloprox, clometrizole, crystal violet, ecoconazole, efinaconazole,
- epoxiconazole fenticonazole, filipin, flucocytosine, fluconazole, griseofulvin, haloprogin, hamycin, isoconazole, isovuconazole, itraconazole, ketoconazole, Miconazole, micafungin, miconazole, naftifine, natamycin, nystatin, omoconazole, oxiconazole, posaconazole, propriconazole, ravuconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenic acid, and/or voriconazole;
- steroidal antiinflammatory agents alclometasone, amcinonide, betamethasone, clobetasol, desonide, desoximetasone, diflorasone, fluandrenolide, fluocinonide, fluocinolone, fluticasone, halobetasol, halcinonide, halometasone, hydrocortisone, mometasone and/or triamcinolone, and/or any of their various derivatives;
- non-steroidal anti-inflammatory agents acetylsalicylic acid, aceclofenac, celecoxib, clonoxin, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, flufenamic acid, flurbiprofen, harparagide, ibuprofen, indomethacin, ketoprofen, ketorolac, licofelone, lomoxicam, loxaprofen, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, oxaprozin, paracetamol, phenylbutazone, piroxicam, salicylic acid, salsalate, sulindac, tolfenamic acid, tenoxicam, tolmetin and vitamin D;
- the antiseptics benzalkonium chloride, cetyl trimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, benzododecinium bromide, chlorhexidine, octenidine, boric acid, brilliant green, hydrogen peroxide, acetic acid, peracetic acid, povidone-iodine, phenol, thymol, hexachlorophene, triclosan, polyhexamethylene biguanide, sodium hypochlorite, calcium hypochlorite and/or sodium bicarbonate;
- the antiviral drugs acyclovir, docosanol, famciclovir, idoxuridine, penciclovir, trifluridine, valcyclovir and/or vindarabine;
- cytoprotective moisturizers butylene glycol, ceramide, cetyl alcohol, cyclomethicone, dexpanthenol, dimethicone, glyceryl triacetate, glycerin, glycerol, heparin sulfates, hexylene glycol, hyaluronic acids, maltitol,
- maltodextrose mineral oil, petrolatum, poloxamers, propylene glycol, sorbitol and/or xylitol;
- fenoxazoline levomethamphetamine, levonordefrin, mephentermine, naphazoline, norepinephrine, oxymetazoline, phenylephrine, phenylpropanolamine, propylhexidine, pseudoephedrine, synephrine, tetrahydrozolidine, tramazoline, tuaminoheptane, tymazoline and xylometazoline, with preference being given to naphazoline, oxymetazoline, phenylephrine, pseudoephedrine and/or xylometazoline;
- the essential oils or fragrances including anethole, pinenes, camphor, 1,8-cineole, citral, eugenol, geranial, limonene, linalool, menthol, menthone, and/or thymol;
- the inducers of endogenous antimicrobial peptide production including (l-3)(l-6) beta glucans, vitamin D, isoleucine, butyrate, litocholic acid, lactose, lactulose, quinine, niacinamide, resveratrol, pterostilbene, polydatin, sulforophane, maitake extract, shiitake extract, Brewer's yeast extract, natto and/or hyaluronan;
- the mucoadhesives alginate, carboxymethylcellulose, hyaluronic acid (multiple), hypromellose and/or polycarbophil calcium;
- Carbomer compositions The above-described, commercially available carbomers, Carbopol ® 980 NF and Carbopol ® 981 NF (alternatively referred to herein as”Carbomer 980 [or 981]” or “Carbomer 980 [or 981] NF”), as well as Pemulens ® T -1 and TR-2, were used. Unless otherwise specified, in Examples 1-13 and the Figures, the terms "Carbomer 980" or “Carbomer 980 composition” (and analogously for the other carbomers tested) shall be understood to refer to neutralized dispersions of the commercially sourced USP/NF carbomer in isotonic, phosphate buffered solution.
- Percentages recited in connection with the above-described carbomer compositions refer to the weight percent (w/w %) of carbomer present in the composition.
- the "vehicle” or “Control” or “Ctrl” referred to in the Examples and Figures consisted of isotonic PBS without carbomer, unless otherwise indicated.
- A HRV-B14 Infectivity Studies in Human Airway Epithelial A459 Cells.
- GAPDH Cellular glyceraldehyde 3-phosphate dehydrogenase
- the number of lytic plaques was determined in quadruplicate determinations three days post infection using an ELISpot reader after fixation and staining of monolayers with cristal violet. Non-infected cells were used as baseline controls; virus infected cells were used to define 100% infection; and the antiviral agent ribavirin was used as a positive control in all experiments.
- the supernatants were removed at the end of the 24h incubation period and assayed for viral load by qPCR.
- Oseltamivir was used as a control in H1N1 viral load studies, and chloroquine in Coronavirus OC43 studies.
- Cytotoxicity studies were conducted by measuring transepithelial resistance in Ohm. cm 2 , LDH release as a percentage of Triton- induced cytotoxicity, cilial beating frequency in Hz, and epithelial mucus production in pg/ml.
- Histamine Release Assays were performed in KU812 cells (ATCC No. CRL-2256) propagated in RPMI1640 containing 10% FCS and 20 ⁇ gentamycin. The cultured KU812 cells were gently washed in Tyrode buffer, and samples of 1 x 10 5 cells were incubated with increasing concentrations of carbomer composition for 15 min prior to a lh incubation with 100 ⁇ polymixin B or compound 48/80. The cells were placed on ice, gently centrifuged at 190 g at 4°C for 8 min, and the supernatants collected and centrifuged at high speed to remove any remaining cell fragments.
- OPT o-phthalaldehyde
- the monolayers were coated with culture medium containing less than 2% agar, which was allowed to harden for 30 min after which neutral red was added to the plates (0.01% in PBS). Thirty minutes after coloration, control and test items were applied to the cells by means of circular filters of 5 mm in diameter that were deposited on the solidified agar surfaces, and the cultures were placed in a cell culture incubator for 6, 14 or 24h after which cell viability was assessed by microscopy. Test items were evaluated in quadruplicate and controls in duplicate determinations. (H) Rat nasal tolerability studies.
- the studies were conducted in groups of 20 rats (10 males and 10 females) by administering ⁇ of carbomer composition intranasally at 6h intervals twice per day for a period of 2 weeks followed by a 1 week recovery period to assess the reversibility of any effects observed at Day 14.
- Clinical observations were made daily after each dosing. Body weight, food and water consumption were recorded at time of allocation and/or weekly thereafter throughout the experimental period as applicable.
- All superficial tissues were examined visually and by palpation, and key organs and subcutaneous tissues were inspected visually, then the kidneys, larynx, liver, lungs, trachea, pituitary and samples of the nasal turbinates were collected for histopathological examination. All tissues were stained with hematoxylin and eosin for all animals, with samples of kidney and liver tissue being further processed for Oil Red-0 staining, and subsequently evaluated.
- Example 1 Comparison of viral inhibition by anionic v. nonionic polymer.
- Carbomer 980 compositions certain of which included 0.05% w/w hypromellose (HPMC), were tested for HRV-B14 viral inhibition alongside HPMC, poloxamer 407 and pentosan polysulfate.
- HPMC 0.05% w/w hypromellose
- compositions of the invention are preferably free of non-anionic polymers.
- Example 2 Activity against HRV-B14, Using the methods of (A) above, human airway epithelial A459 cells were treated for lh with 0.5% w/w Carbomer 980, Carbomer 981, and Pemulen * TR-l and TR-2 compositions, followed by incubation with HRV-B14 for an additional 6h, resulting in decreases in viral mRNA copy number.
- the viral mRNA copy number for the two experiments (“Exps. 1 and 2") is shown as follows (% inhibition compared to vehicle controls):
- Carbomer 980 does not penetrate cell membranes, it follows that the pre-incubation of human airway epithelial cells with a Carbomer 980 preparation formulated at pH 7.4 reduces their susceptibility to infection by HRV. This result was supported by repeated cytoxicity testing in the WST- 1/formazan and neutral red membrane integrity assays.
- the above Examples 1-3 demonstrate that carbomer protects cells from infection when applied topically to human airway epithelial A459 cells prior to the exposure of the cell culture to HRV-B14.
- Example 6 Inhibition of Influenza A HlNl and Coronavirus OC63 Virus in Human Airway Epithelia.
- Carbomer 980 compositions were tested for inhibition of coronavirus OC43 viral load in infected human airway epithelia preparations (Panel B, versus buffer control and chloroquine).
- Example 7 Pre-treatment of virus with carbomer prior to infection of human cervical epithelial HeLa cells.
- H V-B14 was pretreated at an MOI of 0.4 with 0.05% w/w Carbomer 980 or 0.015% Pemulen ® TR-2 at pH 7.4 for lh followed by a 10'000-fold (Figure 6, Panel A) or 100'000-fold ( Figure 6, Panel B) dilution of the samples prior to their application to confluent monolayers of human cervical epithelial HeLa cells.
- Carbomer compositions were prepared with the objective of achieving compositions of suitable viscosity for intranasal administration.
- the tested hypo- and isotonic compositions comprised 0.5% w/w Carbomer 980 in 20 mM phosphate-buffered saline, pH 7.2, with 50 mM NaCI; or 0.5% w/w Carbomer 981 in 20 mM phosphate-buffered saline with 150, 450 or 1.7 mM mM NaCI. All of the compositions additionally comprised 0.1-0.5% of a non-cationic preservative.
- the viscosity of carbomer preparations is also dependent on the presence of amines, cationic preservatives and divalent cations, as carbomers form viscous emulsions with amines and cationic preservatives, yet precipitate out in presence of high concentrations of divalent cations.
- Panel A shows that hypo- and isotonic solutions at neutral pH have higher viscosity than solutions containing a high amount of salt at low pH.
- Panel B depicts the compositions of the invention as being able to penetrate deep into the nasal cavity, up to and beyond the area of the nasopharyngeal tonsil (i.e. the adenoid) which is a primary site for H V infections.
- the nasopharyngeal tonsil i.e. the adenoid
- Example 9 Effect on antiviral activity of non-cationic preservatives.
- Carbomer 980 compositions of which three additionally comprise a non-cationic preservative, i.e. phenoxyethanol (0.1%), phenylethanol (0.5%) or paraben (0.5%), were tested for inhibition of H V-B14 infectivity. As shown in Figure 8, each of these formulations inhibited viral replication in human airway epithelial A459 cells, demonstrating that the presence of non-cationic preservatives is not deleterious to the polymer's antiviral action.
- a non-cationic preservative i.e. phenoxyethanol (0.1%), phenylethanol (0.5%) or paraben (0.5%)
- Example 10 Microbial Challenge with P. aeruginosa or S. aureus.
- Example 12 Nasal tolerabilitv in the rat.
- the carbomer composition has no effect on either body weight (Panel A) or food consumption (Panel B), versus as untreated control, in the animals tested.
- Figure 16 supports the lack of adverse effects of 0.5% w/w Carbomer 980 on the weight of kidneys, liver, lungs with bronchi and pituitary glands in both male and female treated animals. No treatment induced effects were apparent in either male or female animals on Day 14. The results indicate that the formulation of 0.5% w/w Carbomer 980 is compliant with ISO 10993 (2009).
- Example 13 Carbomer anti-allergenic activity.
- Figure 14 shows increasing concentrations of Carbomer 980 compositions
- Figure 14 also shows the lack of a cytotoxic effect of Carbomer 980 composition at the same concentrations in the same cells as determined using the formazan/mitochondrial function-based read-out (Panel B).
- An exemplary carbomer composition of the invention, pH 7.2, comprises th following:
- Carbomer was then added and dispersed by using a homogenizer followed by the addition of sodium hydroxide or hydrochloric acid to adjust the pH to 7.2.
- the finished product is a cloudy viscous liquid with a pH of 7.2, osmality of 250-300 mOsm/Kg and a viscosity of 150-300 mPa.s
- the product is for use as a nasal spray to provide a viscous coating of carbomer into the anterior and posterior nasal cavities.
- the following tests may be performed as part of release and stability testing:
- Example 15 Clinical evaluation of Carbomer 980 NF gel delivered as a nasal spray relative to human nasal safety and tolerability (in healthy volunteers) and clinical efficacy and safety in partients with the common cold.
- Study A Safety and Tolerability.
- Study A was a randomized, parallel-group, open label, placebo-controlled, assessment of safety and tolerability of a 0.5 % wt/wt Carbomer 980 NF formulated as described in Example 14, for delivery as a topical nasal spray to healthy human volunteers.
- the composition was filled into 10-mL glass vials fitted with a pump capable of delivering a spray upon actuation.
- Matching placebo consisted of the composition without carbomer.
- nasal spray administered via a nasal spray.
- One dose of the nasal spray consisted of three actuations per nostril. Each actuation was 140 ⁇ (equivalent to 140 mg, and a calculated dose of 0.7 mg of carbomer).
- Administration was four times a day dosing, approximately four hours apart (i.e. 8:00, 12:00, 16:00, and 20:00), for a period of seven days (Days 1-7).
- each subject received in total 28 doses, which was equivalent to 168 actuations.
- the second cohort started (Day -1) following completion of the first cohort. Subject randomization was stratified by gender. Assessment of local nasal tolerability was by nasal examination performed at screening visits, on Day 1 prior to first dosing (before 8:00 dose), on Days 1 to 7 following the 12:00 dose, and at 12:00 during the end of study visit (Day 8).
- Study B Treatment of patients diagnosed with common cold.
- Study B is a multi- center, randomized, parallel group, double-blind, 2-arm, placebo-controlled, multiple-dose study in adults with early symptoms of a common cold ( ⁇ 72 hours duration) to assess efficacy, and safety of the investigational formulation used in Study A.
- Eligibility criteria include the following symptomatic common cold symptoms:
- TSS Total symptom score
- 9 baseline sum of the 8 common cold symptoms
- Score >1 for at least one of the following symptoms: sore throat, runny nose, or blocked nose.
- Nasal symptoms runny nose; blocked nose; sneezing; headache;
- Approximately 170 eligible subjects are randomized to treatment with carbomer nasal spray or placebo (vehicle only, nasal spray) in a 1:1 ratio at multiple sites.
- Subjects perform a baseline self-assessment of common cold symptoms in an e- diary.
- Subjects are instructed to dose for the full seven days irrespective of symptom resolution to avoid inappropriate discontinuation due to misinterpretation of reduced symptomatology as a result of the fluctuation of symptoms that occurs with a common cold.
- Subjects are also instructed to change to a new study treatment device every 2 days and to prime the new device prior to the morning dose.
- the dosing regimen is one dose (consisting of 3 actuations per nostril, where each actuation is 140 ⁇ , equivalent to 140 mg and a calculated dose of 0.7 mg carbomer), administered four times a day (at approximately 8:00, 12:00, 16:00, and 20:00 hours), for 7 days (except for Day 1 where subjects in the 2nd strata receive 3 doses). Subjects are instructed to blow their noses prior to dosing. Subjects are also instructed to alternate nostrils after each actuation. First dosing can occur any time prior to 13:00 on Day 1.
- the study treatment is administered via a nasal spray device containing 12 mL, yielding 50 actuations after an initial one time priming.
- Each subject requires 168 actuations or 4 vials.
- Each subject is assigned a kit containing 4 vials for 7 days of dosing, with instructions to use 1 vial for 2 days (48 actuations), and then to start a new vial.
- Subject randomization is stratified by dosing time on Day 1 by those study subjects receiving the first dose of study treatment between the hours of: 8:00-11:00 and those receiving the first dose between the hours 11:01-13:00.
- subjects dosing between 8:00-11:00 are to dose every 4 hours for 4 doses and subjects dosing between 11:01-13:00 are to dose every 4 hours for 3 doses.
- Days 2-7 all subjects administer their initial morning dose immediately following recording of their common cold symptom assessment at 07:00 hours and the remaining 3 doses every 4 hours.
- Dosing times and number of actuations are recorded in subject's e-diary. Subjects are instructed not to take any additional cough/cold medications, including but not limited to, prescription, OTC, non-drug/nutritional supplement, or procedures throughout the study. Subjects are instructed to use acetaminophen/paracetamol over other OTC medications, but to avoid use if possible. Subjects self-evaluate the severity of the following common cold signs/symptoms before each dose and record their assessment in the e-diary: headache, muscle ache, chills, sore throat, blocked nose, runny nose, cough, and sneezing.
- subjects Upon awakening on the morning of Day 8, subjects complete a self-assessment of common cold symptoms in the e-diary. Subjects are to return to the study sites on Day 8 for the End of study/Visit 2). Adverse events and the use of concomitant medications are recorded by the subjects in e-diaries and monitored by the site personnel throughout the study.
- Efficacy is assessed by subject's evaluation of common cold signs/symptoms. While common cold symptoms manifest for 7-10 days, the most severe symptoms typically present witin the first 4 days of symptom onset. Thus the primary study objective is to assess the efficacy of the carbomer composition in reducing the severity of nasal symptoms on days 1-4, with the endpoint being average nasal symptom score (ANSS1-4), compared to placebo, in adult subjects with the common cold.
- ANSS1-4 average nasal symptom score
- Hayden FG and Gwaltney JM Intranasal interferon-alpha 2 treatment of experimental rhinoviral colds infection. 7. Infect. Dis. 150: 174 -180. (1984). Hayden FG, Kaiser DL and Albrecht JK. Intranasal recombinant alpha-2b interferon treatment of naturally occurring common colds. Antimicrob. Agents Chemother. 32: 224-230 (1988).
- Patick AK Brothers MA, Maldonado F, Binford S, Maldonado O, Fuhrman S, Petersen A, Smith GJ and Zalman LS.
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Abstract
La présente invention décrit des procédés et des compositions topiquement administrables destinés au traitement ou à la prévention d'infections virales ou d'états allergiques ou de leurs symptômes chez un mammifère en ayant besoin qui comprend l'administration de manière topique au sujet d'une composition comprenant une quantité thérapeutiquement efficace d'au moins un carbomère de qualité pharmaceutique dispersé dans une solution aqueuse de sel monovalent tamponnée jusqu'au pH approximativement neutre. Les procédés et les compositions peuvent être utilisés pour la prévention ou le traitement de la grippe et des symptômes du refroidissement courant, ainsi que des états induits par un allergène tels que la rhinite allergique, chez un mammifère (par exemple, un être humain) en ayant besoin.
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Cited By (10)
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CN110279655A (zh) * | 2019-08-09 | 2019-09-27 | 郑州康金瑞健康产业有限公司 | 一种抗过敏鼻炎凝胶 |
WO2019191200A1 (fr) * | 2018-03-27 | 2019-10-03 | American Genomics, Llc | Procédé et formulation pour réaliser une anesthésie d'aspect interne de paroi oculaire par application topique |
KR102217617B1 (ko) * | 2020-08-14 | 2021-02-19 | 비엘엔에이치 주식회사 | 백선의 예방 또는 치료용 약학적 조성물 |
WO2021191800A1 (fr) * | 2020-03-23 | 2021-09-30 | Kerecis Ag | Solutions antimicrobiennes et leurs méthodes d'utilisation dans le traitement ou la prévention d'infections |
WO2021202144A1 (fr) * | 2020-04-03 | 2021-10-07 | Elysium Health Inc. | Méthodes de traitement d'infections virales |
WO2021214626A1 (fr) * | 2020-04-23 | 2021-10-28 | Johnson & Johnson Consumer Inc. | Méthodes et compositions pour l'inhibition de virus de la grippe faisant intervenir des polymères modifiés hydrophobiquement de faible masse moléculaire et des polyalkylène glycols |
WO2021233571A1 (fr) * | 2020-04-30 | 2021-11-25 | Ninoderm Ug (Haftungsbeschränkt) | Agent de traitement pour thérapie antivirale, applicateur et procédé de fabrication d'un agent de traitement |
WO2022003200A1 (fr) * | 2020-07-03 | 2022-01-06 | pHOxgen Limited | Réduction d'infections virales |
KR20220043794A (ko) * | 2020-09-29 | 2022-04-05 | 동아제약 주식회사 | 소독용 겔 조성물 및 이의 제조 방법 |
WO2022112430A1 (fr) * | 2020-11-25 | 2022-06-02 | Phoxbio Limited | Réduction d'infections virales |
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