WO2016205574A1 - Formulations antimicrobiennes - Google Patents

Formulations antimicrobiennes Download PDF

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Publication number
WO2016205574A1
WO2016205574A1 PCT/US2016/037947 US2016037947W WO2016205574A1 WO 2016205574 A1 WO2016205574 A1 WO 2016205574A1 US 2016037947 W US2016037947 W US 2016037947W WO 2016205574 A1 WO2016205574 A1 WO 2016205574A1
Authority
WO
WIPO (PCT)
Prior art keywords
acrylic acid
polymer
pharmaceutical formulation
crosslinked
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/037947
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English (en)
Inventor
Bahram Memarzadeh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Common Pharma Inc
Original Assignee
Common Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Common Pharma Inc filed Critical Common Pharma Inc
Priority to CN201680046713.9A priority Critical patent/CN108367026A/zh
Priority to EP16812480.8A priority patent/EP3310363A4/fr
Publication of WO2016205574A1 publication Critical patent/WO2016205574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K33/22—Boron 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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

Definitions

  • This invention relates to antimicrobial compositions and formulations that provide local anti-fungus, anti-viral and antibacterial, anti-gram-positive and gram negative, activity when infected human or animal skin, tissue, nail and hair is treated.
  • the composition can also be used for vaginal and oral infections or diseases.
  • Jublia® is a newly approved nail topical solution with limited efficacy and is sold as a prescription medication.
  • the primary ingredient in Jublia® is efinaconazole which is present in a concentration of 10%.
  • Jublia® is expensive due to the high concentration of the efinaconazole. In addition, it has a limited efficacy of about a 20% complete cure rate.
  • KERYDIN® is another newly approved product which is from Anacor Corporation. It is a 5% solution of tavaborole. It also has a similar efficacy and cost to that of Jublia®.
  • OH tavaborole Medications for athlete's foot are mostly over-the-counter but severe cases are treated by the use of oral prescription medication.
  • topical products are Lotrimin® which contains the drug clotrimazole in a 1% formulation and Lamisil®, a 1% terbinafine hydrochloride solution.
  • Lotrimin® which contains the drug clotrimazole in a 1% formulation
  • Lamisil® a 1% terbinafine hydrochloride solution.
  • the majority of marketed products are costly and not very effective or have side effects such as dr skin, rash and irritation
  • Noveon® AA-1 Polycarbophil, USP is a high molecular weight acrylic acid polymer crosslinked with divinyl glycol and is manufactured by Lubrizol Corporation of Wickliffe, Ohio. It provides excellent bioadhesive properties and has been used extensively to enhance the delivery of active ingredients to various mucous membranes.
  • Polycarbophil can be used for the formulation of buccal, nasal, ophthalmic, vaginal and rectal bioadhesive products.
  • Noveon AA-1 Polycarbophil can also be used as a controlled release polymer in oral solid dose applications. Typical usage levels for achieving controlled release characteristics in tablets manufactured by aqueous granulation are 5 - 10 wt. %.
  • Noveon AA-1 product line has a limited, acceptable pH range for proper gelling and stability. This pH range is between pH 5 and pH 8. More specifically, the recommended range is pH 6 to pH 7.
  • the current invention is based upon the use of boric acid and borate compounds in combination with a polymer which facilitates the application to topical sites and is relatively inexpensive.
  • Boric acid and borate compounds have known anti-microbial characteristics but have never been used at a low pH with a polyacrylic polymer.
  • the primary effective ingredients of this composition are homo- and copolymers of acrylic acid polymers hydrated in water and added boric acid.
  • the preferred polymers are cross-linked acrylic acid polymers that are marketed under the brand names such as
  • a polycarbophil is a generic drug used as a stool stabilizer. Chemically, it is a synthetic polymer of polyacrylic acid cross-linked with divinyl glycol or other cross-linking reagents. Carbopol® and Noveon® are trademarks of Lubrizol Advanced Materials, Inc. These polymers are referred to as polyacrylic acid or poly(acrylic acid).
  • the most effective pH range of this formulation is about equal to or greater than 2 and about equal to or less than 5.
  • the pH of the formulation can be achieved by the addition of small amounts of a dilute acid such as hydrochloric acid, acetic acid, ascorbic acid or citric acid. Most preferably the acid is 0. IN HC1.
  • boric acid has known anti-inflammatory properties. Such properties, in combination with anti-bacterial properties help in the effectiveness of the proposed composition in the treatment of Acne vulgaris.
  • the current invention is further distinguished by formulating the composition at a low pH (less than or equal to about pH 5.0) which is outside the normal range of use as recommended by the various manufacturers of the polyacrylic polymers.
  • the most effective pH range of this formulation is between about 2.0 and about 5.0 inclusive.
  • the pH of the formulation can be lowered by the addition of small volumes of a dilute hydrochloric acid solution. This product is more effective at the low end of this pH range.
  • Formulation at this pH range requires a special method of preparation so that the gel formed by the polyacrylic polymer doesn't break, become clumpy and become non- homogeneous. Simple pH adjustment can result in the breaking of the polymer gel.
  • the solution to the problem is to add boric acid to a solution of the polymer which has not had its pH previously adjusted. This will result in a stable gel and the ability to adjust the pH to ⁇ pH 3 (with a 1% boric acid and a 2% polymer concentration).
  • All references to concentrations of any components of the various embodiments of the instant invention are references to percentage based on a W/W basis.
  • a more accurate and desired pH can be achieved by adjusting the concentration of boric acid to a lower or higher concentration as needed to properly adjust the pH.
  • a pH lower than 3.0 can be achieved by adding small amounts of dilute hydrochloric acid (for example HCl at 0. IN) until the desired pH is reached.
  • boric acid with a polycarbophil especially at a pH of ⁇ 5.0 is challenging since any addition of base (sodium borate or sodium hydroxide) will cause a dramatic reduction in viscosity (visible to the human eye) and a phenomena called the "crashing of the gel". It is also important to emphasize that the pH of boric acid solutions are just below pH 5.
  • the pH of hydrated polycarbophil polymers, without any pH adjustment, is about 2.0. If the pH of a hydrated solution of the polyacrylic polymer is adjusted prior to the addition of boric acid, then sodium hydroxide or sodium borate would need to be added which runs the risk of crashing the gel or obtaining a pH outside of the accepted pH range.
  • the formulation and method of the present invention results in a boric-acid- containing gel-like formulation at a pH equal to or lower than about 5.0. Once applied on the skin, the formulation will dry in a short time (typically 5-10 minutes). The short drying time is far more convenient for the patient and enhances the retention of the formulation on the tissue and thus increases patient compliance and therapeutic effectiveness.
  • Noveon AA-1 was hydrated in distilled water by simple addition and mixing. Hydration can be determined by inspecting the solution. Full hydration was indicated by the optical uniformity of the solution. After full hydration, boric acid, in solution or as a powder, was added to achieve a concentration of borate from as little as about 0.5% up to about 5.5%. The solution was then mixed until the solution was visually clear. The pH was measured and was typically between 3 and 4 depending on the concentration of borate in the solution. The anti-microbial efficacies of boric and acrylic acid polymers are also enhanced by a lower pH.
  • the resulting gel was transferred into plastic or glass containers for use.
  • the formulation was brushed or directly applied on a fungus infected nail (onychomycosis), skin or any infected area.
  • the gel was then allowed to dry for 5 to 10 minutes.
  • the treatment was repeated several times a day and for as many days as required. For example, if the formulation was used to treat onychomycosis, generally, the formulation will need to be applied for as long as it takes for an entire new nail to grow which is often 6-12 months.
  • the same process was used to produce the mixture but a pH adjustment step had been added.
  • a low concentration borate buffer was added drop wise to adjust the pH to be above pH 3.
  • the resulting gel was transferred into vials, tubes or other suitable storage devices for topical, dermal or ophthalmic treatment.
  • the low concentration borate buffer was typically made up of a 1.0 mM solution of sodium borate with the pH adjusted with boric acid to a pH of about 8.0. The most important factor is that the Na + concentration of the low concentration borate buffer is at or below 0.1%. Other concentrations may be used as long as the Na + ion concentration is at or below 0.1%.
  • the present invention is based upon three new and non-obvious discoveries.
  • the present invention includes formulations composed of polyacrylic polymers and boric acid without pH adjustment resulting in a pH of about 3.2.
  • the present invention also includes formulations of the same composition in which the pH was adjusted to a higher value by using diluted borate buffer solutions (sodium borate and boric acid) and having the pH adjusted upwards to a maximum of pH 5.0.
  • diluted borate buffer solutions sodium borate and boric acid
  • diluted hydrochloric acid could be used to adjust the pH of initial formulation (polyacrylic acid and boric acid) to as low as 2.0.
  • the present invention integrates the anti-microbial effectiveness of boric acid and the gel formation properties of a polyacrylic acid and its related cross-linked polymers in one, convenient, stable, safe, and effective formulation in which the pH is equal to or greater than about 2.0 and the pH is equal to or less than about 5.0.
  • This formulation can also integrate additional pharmaceutically accepted excipients, polymers, fragrances, viscosity modifying agents, coloring substances, additional anti-microbial agents and antibiotics to have improved efficacy and/or patient compliance.
  • the present invention can be stored and utilized in a variety of containers, with or without brushes, delivery nozzles, applicators and performance containers such as atomizers, pumps, metered dosing or massaging tools.
  • the viscosity of the formulation can be adjusted to be between 500 centipoises (cps) and 20,000 cps as needed in order to be compatible with the delivery or application device.
  • the gel can be dispersed by an atomizer or metered dosing device since the gel is has sheer thinning properties and application of a mechanical delivery device will reduce the viscosity and enable it to be delivered from the container.
  • This disclosure describes a co-formulation of boric acid and polyacrylic acid polymers such as polycarbophil and specifically Noveon AA-1 and other members of the same family of polymers.
  • the formulations are preferably produced only in water.
  • One preferred embodiment has the following composition:
  • the pH of the above solution can be acidic or basic.
  • an emulsion was made with a 20% acetone in water solution using a pharmaceutical grade of acetone and a surfactant, either non-ionic or ionic such as Poloxamer 188 (0.1 to 5%) or sodium dodecyl sulfate (0.1% to 1%). Poloxamers are nonionic triblock copolymers. Equal volumes of this emulsion and a 2X mixture of a polycarbophil polymer and boric acid in water (4% polycarbophil and 2% boric acid) were mixed to form a stable emulsion. This mixture can be applied on the tissue or nail and will dry faster due to the organic content.
  • a surfactant either non-ionic or ionic such as Poloxamer 188 (0.1 to 5%) or sodium dodecyl sulfate (0.1% to 1%). Poloxamers are nonionic triblock copolymers. Equal volumes of this emulsion and a 2X mixture of a polycarbophil polymer and boric
  • any of the following solvents can be used in place of acetone:
  • any of the following polyacrylic acid polymers shown II can be used in place of Noveon AA-1.
  • Carbopol® homopolymers are polymers of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol.
  • Carbopol® copolymers are polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allylpentaerythritol.
  • Carbopol® interpolymers are carbomer homopolymers or copolymers that
  • PemulenTM polymers are polymers of acrylic acid, modified by long chain
  • Noveon® polycarbophil is a polymer of acrylic acid crosslinked with divinyl glycol.
  • the listed polymers are all of the same class as Noveon AA-1 but have different degrees of cross-linking and/or different cross-linkers.
  • any of the above listed polymers can be substituted for Noveon AA-1. Adjustments in concentration may be needed to achieve the desired pH.
  • Example 1 300 grams of purified water was put in a glass bottle.
  • 3.3 gms of boric acid was added to 20 gms of purified water and mixed for 20 minutes to obtain a suspension.
  • the boric acid suspension was added to the polymer mixture and mixed for one hour to fully dissolve the boric acid.
  • the container holding the boric acid suspension was rinsed with 10 grams of purified water and added to the polymer mixture.
  • Two additional aliquots of Noveon AA-1 (2.2 gms and 2.3 gms) were added to the mixture.
  • a formulation of the invention was applied to the left and right big toe of a patient having fungus infected toe nails.
  • the formulation was placed in a small plastic bottle with a brush attached to the cap.
  • the formulation was brushed on to fully coat the nail of the big toe and underneath the expose part of the nail and the nail bed.
  • the exposed big toes were allowed to dry for 5-10 minutes.
  • shoes and socks were put on and the patient went about normal daily activities.
  • Application was repeated every morning from 12-Dec-2014 to 20-Mar-2015. Measurements were made of the full length of each toe nail and the length of the healthy part of the nail. The ratio of healthy nail to total length of the nail is given below.
  • Example 2 20 grams of Noveon AA-1 was added to 970 grams of water and
  • Example 3 The above formulation was used on a person with moderate acne vulgaris that had inflammatory and yellow-head lesions on the face. Most of the lesions were on the front of the face. In four days, 80% improvement was obtained and sustained with once per day application of the formulation with a small brush directly on the lesions.
  • microorganisms a. Aspergillus brasiliensis (fungus)
  • Candida albicans (fungus)
  • Candida albicans fungus
  • Escherichia coli bacteria
  • the test was performed according to ISO 10993-10:2010.
  • the test sample was 2% Noveon and 2% boric acid in water.
  • a placebo was also tested which was only 2% Noveon in water. All testing was under GLP conditions.
  • a negative control was used which was 0.9% Sodium Chloride for Injection, USP and a positive control was used which was 20% W/V of sodium dodecyl sulfate (SDS) in water.
  • SDS sodium dodecyl sulfate
  • test animals were inspected at times 1, 24, 48 and 72 hours. All animals in the test, placebo and negative control groups showed no irritation at all.
  • the positive control showed observational rankings of 2-4 with the rankings assigned as follows:
  • test sample was analyzed and showed a pH of 3.0 and a viscosity of 6,000 cps when measured at 25°C RVT, Spindle 27 at 20 rpm.
  • placebo was analyzed which showed a pH of 3.2 and a viscosity of 11,625 cps when measured at 25°C RVT, Spindle 27 at 20 rpm.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation pharmaceutique qui comprend un polymère d'acide acrylique et d'acide borique à un pH inférieur à environ 5,0 et supérieur à environ 2,0.
PCT/US2016/037947 2015-06-18 2016-06-17 Formulations antimicrobiennes Ceased WO2016205574A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201680046713.9A CN108367026A (zh) 2015-06-18 2016-06-17 抗微生物配制品
EP16812480.8A EP3310363A4 (fr) 2015-06-18 2016-06-17 Formulations antimicrobiennes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562181202P 2015-06-18 2015-06-18
US62/181,202 2015-06-18

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WO2016205574A1 true WO2016205574A1 (fr) 2016-12-22

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EP (1) EP3310363A4 (fr)
CN (1) CN108367026A (fr)
WO (1) WO2016205574A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019239352A1 (fr) * 2018-06-13 2019-12-19 Kyoto Biopharmaceuticals, Inc. Amélioration d'actions antibactériennes d'un antibiotique depsipeptide à l'aide de quantités synergiques d'acide borique
WO2020180272A1 (fr) * 2019-03-04 2020-09-10 Kahramanmaraş Sütçü İmam Üni̇versi̇tesi̇ Solution de bore potable

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019239352A1 (fr) * 2018-06-13 2019-12-19 Kyoto Biopharmaceuticals, Inc. Amélioration d'actions antibactériennes d'un antibiotique depsipeptide à l'aide de quantités synergiques d'acide borique
CN112236163A (zh) * 2018-06-13 2021-01-15 京都生物制药株式会社 使用协同量的硼酸增强缩酚酸肽抗生素的抗菌作用
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WO2020180272A1 (fr) * 2019-03-04 2020-09-10 Kahramanmaraş Sütçü İmam Üni̇versi̇tesi̇ Solution de bore potable

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EP3310363A1 (fr) 2018-04-25
CN108367026A (zh) 2018-08-03
EP3310363A4 (fr) 2019-02-13

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