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WO2012156502A2 - Préparation de type bain de bouche à deux composants - Google Patents

Préparation de type bain de bouche à deux composants Download PDF

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Publication number
WO2012156502A2
WO2012156502A2 PCT/EP2012/059241 EP2012059241W WO2012156502A2 WO 2012156502 A2 WO2012156502 A2 WO 2012156502A2 EP 2012059241 W EP2012059241 W EP 2012059241W WO 2012156502 A2 WO2012156502 A2 WO 2012156502A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
phosphate
calcium
dry
concentration
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/EP2012/059241
Other languages
English (en)
Other versions
WO2012156502A3 (fr
Inventor
Bjørn JOHANSEN
Jan KARLSEN
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.)
Arcoral Pharma AS
Original Assignee
Arcoral Pharma AS
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 Arcoral Pharma AS filed Critical Arcoral Pharma AS
Publication of WO2012156502A2 publication Critical patent/WO2012156502A2/fr
Publication of WO2012156502A3 publication Critical patent/WO2012156502A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0216—Solid or semisolid forms
    • A61K8/022—Powders; Compacted Powders
    • 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
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/22—Gas releasing
    • A61K2800/222—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/882—Mixing prior to application

Definitions

  • the present application relates to a two component preparation useful for preparing a mouth rinse, comprising (a) a first dry component comprising calcium chloride hexahydrate and stabilizing agent and (b) a second dry component comprising phosphate and a stabilizing agent, and optionally fluoride.
  • a dry, two component preparation which upon dissolution in water yield a supersaturated solution of calcium and phosphate ions.
  • Cancer patients undergoing bone marrow transplantation are typically administered immune depressing medicinal agent to depress the immune system and thus avoid rejection of the transplanted tissue or cells. Furthermore, cancer patient undergoing cytotoxic drug treatment may often also have reduced immune system due to the cytotoxic effect on the leucocytes. A patient having a depressed immune system is also susceptible to infection resulting in prophylactic treatment with antibiotics. Repetitive and large use of antibiotics, as well as head and neck radiation, may again result in severe dental caries.
  • Chemotherapeutic treatment may also result in discourage eating and malnutrition due to stomatitis, sore throat, change in taste sensation, stomach cramping, nausea, vomiting, diarrhoea etc.
  • the malnutrition condition may further result in
  • Saliva provides a natural antibacterial protection (due to the fact that saliva provides a tissue coating film). Furthermore, the saliva also has a remineralizing potential due to the lubrication of the mucosa.
  • Non-limiting examples of medicinal agent which may result in dry mouth are e.g.
  • antidepressive medicaments citalopram, fluoxetine, paroxetine
  • carbamazepine anti epilepticum
  • lansoprazol proton pump inhibitor
  • klozapine neurorolepticum
  • topiramate anticonvulsant
  • olanzapine anti schizophrenia
  • the salivary production may also be severely reduced upon radiation therapy as radiation causes atrophy of the salivary glands in the oral cavity, cf. Medical News, 1975, JAMA, Vol 234, no. 6, pp. 577 - 578.
  • Sjogren's syndrome An example of another disease affecting the salivary glands leading to reduced salivary production and dry mouth is Sjogren's syndrome.
  • patients having Sjogren's syndrome are also exposed to developing undesirable conditions of the oral cavity, such as mucositis etc.
  • US 6387352 discloses a mouth wash composition supersaturated with respect to calcium and phosphate, suitable for treating patients having dental caries or other conditions in the oral cavity, e.g. as a result of chemotherapy or radiation therapy. More specifically, US 6387352 discloses a formulation which is effective for use as a dental rinse or mouth wash, wherein said formulation comprises an aqueous calcium component (calcium stock solution); and separated there from, an aqueous phosphate component (phosphate stock solution).
  • a formulation which is effective for use as a dental rinse or mouth wash, wherein said formulation comprises an aqueous calcium component (calcium stock solution); and separated there from, an aqueous phosphate component (phosphate stock solution).
  • US 5993785 disclose an aqueous solution which are supersaturated with respect to calcium and phosphate(s) and which further comprise a stabilizing agent in an amount sufficient to enable the calcium ions and phosphate ions to remain in supersaturated solution so that it may be used as a dental rinse or mouth wash.
  • US 5993785 likewise teaches an aqueous calcium component, and separated there from, an aqueous phosphate component.
  • a composition providing a super saturated solution of calcium and phosphate is at the moment marketed as CaphosolTM http://www.caphosol-us.com/default.asp.
  • CaphosolTM is used to lubricate the mucosa and maintain the integrity of the oral cavity through its mineralizing potential. It is described for inter alia mucositis and dry mouth. CaphosolTM consist of two stock solutions provided in separate, single dosages ampoule, one comprising calcium ions and the other one comprising phosphate ions, which upon mixing yield the super saturated mixture. Upon administration, the calcium component and the phosphate component is mixed by the patient prior to administration.
  • patients undergoing chemotherapy or radiation therapy due to cancer, or patients having a depressed or ineffective immune system patients undergoing bone marrow transplantation, AIDS patients etc
  • patients having Sjogren's syndrome patients having imperfect or non- functioning salivary glands
  • patients being administrated medicines resulting in dry mouth patients with high susceptibility to dental caries or who aims at an increased oral health
  • patients with inflammatory and/or ulcerative lesions in the oral cavity or the susceptibility thereof, etc might benefit from treatment with a supersaturated calcium and phosphate solution.
  • the challenge of preparing mount washes comprising the necessary amounts of calcium and phosphate ions to provide the beneficial effects of the soft and hard tissue of the oral cavity, is to prepare a solution of calcium ions and phosphate ions which to not results in the precipitation of calcium and phosphate complexes thereof.
  • super saturated solutions which do not precipitate within the time needed to rinse the oral cavity are disclosed as referred to above.
  • Said super saturated solutions disclosed in US 6387352 and 5993785 require the patient to mix together two previously prepared and packaged aqueous solutions comprising calcium ions and phosphate ions, respectively.
  • two separate aqueous concentrates are provided that requires dilution by the patient.
  • the aqueous stock solutions come pre-diluted and separately packaged.
  • aqueous solutions as a formulation form necessitates sterilization procedures.
  • a solid formulation avoids labour-intensive sterilization or purified water procedures and most often provides for a longer storage life.
  • the use of such liquid products is inconvenient for the patient, for example requiring the patient to carry large and heavy packaging when traveling.
  • the present application thus provides a two component preparation useful for preparing a mouth rinse, comprising (a) a first dry component comprising calcium chloride hexahydrate and a stabilizer and (b) a second dry component comprising phosphate and a stabilizer, and optionally fluoride.
  • the invention relates to a dry, two component preparation, which upon dissolution of said dry components (a) and (b) yields a supersaturated solution of calcium and phosphate ions.
  • the calcium chloride hexahydrate in component (a) and phosphate in component (b) are present in amounts sufficient to provide, upon dissolution, a super saturated solution thereof having the concentrations of calcium and phosphate ions as described in US 6387352 and US 5993785 (the entire contents of which are hereby incorporated by reference as if repeated verbatim herein for establishing such numerical values), said amounts being derivable by known methods of calculation.
  • a month rinse solution obtained by the dissolution of dry components (a) and (b) according to the present invention is stable in a sufficient period of time to allow for the combined solution to be used as a mouth rinse solution.
  • the stabilizer contained in dry components (a) and (b) of the present two component preparation is an alkali metal such as e.g. earth alkali halides, such as e.g. sodium chloride.
  • the amount of sodium chloride in the two component preparation according to the present invention is sufficient to facilitate dissolution of the calcium and phosphate ions and avoiding precipitation once dry components (a) and (b) are dissolved and mixed.
  • the two component preparation may also optionally comprise other physiologically acceptable excipients such as e.g. flavoring agents, coloring agents, and / or preservatives well known to the skilled person.
  • physiologically acceptable excipients such as e.g. flavoring agents, coloring agents, and / or preservatives well known to the skilled person.
  • a kit comprising unit dosages containers comprising a powder mixture comprising calcium chloride hexahydrate and stabilizer and separated there from unit dosages containers comprising a powder mixture comprising phosphate and a stabilizer, and optionally fluoride and an instruction manual.
  • the two component preparation is provided in the form of two effervescent tablets, and according to yet another aspect as a single effervescent tablet comprising a first segment of the tablet containing the dry calcium component, a second segment of the tablet containing the dry phosphate component, and a layer of an inert material separating the two segments of the tablet.
  • the present invention also provides a method for treating or preventing conditions and disorders of the soft and/or hard tissue of the oral cavity, which method comprises the steps:
  • a first dry component comprising calcium chloride hexahydrate and stabilizer and b) a second dry component comprising phosphate and a stabilizer, and optionally fluoride.
  • component b) in water approximately immediately prior to use, c) administering the solution obtained in c) to a patient in need thereof.
  • the patient in need thereof may be any patient suffering of conditions in the oral cavity due to disorders or disease or being a result of side effect of chemical or radiation therapy, or patients in need of remineralization of the teeth due to e.g. caries or aiming at an increased oral health in general.
  • Dental caries is furthermore a common and undesirable condition, e.g. in the elderly population wherein root surface lesions and recurrent carious lesions are common.
  • the present invention would be beneficial.
  • the term "supersaturated" is to be understood to mean a solution comprising calcium and phosphate ions, and wherein the concentration of said ions are higher than the concentration of said ions presented in a saturated solution thereof.
  • the source of phosphate used in the dry component (b) of the two component preparation according to the present invention may be in the form of
  • disodium hydrogen phosphate dodecahydrate (Na 2 HP0 4 x 12 H 2 0) is used as the phosphate source in component (b) of the two component preparation according to the present invention.
  • sodium phosphate hydrogen dihydrate (NaH 2 P0 4 x 2 H 2 0) is used as the source of phosphate in component (b).
  • a mixture of Na 2 HP0 4 x 12 H 2 0 and NaH 2 P0 4 x 2 H 2 0 is used as the phosphate source in component b).
  • components (a) and (b) may be separately dissolved in water, and thereafter mixed together into the final supersaturated solution.
  • the two components may be directly dissolved into the same container of water.
  • the amount of calcium chloride hexahydrate component (a) is sufficient to provide, upon dissolution of component (a), a concentration of calcium ions in a range of from about 4 mM to about 80 mM, such as e.g. from about 4 mM to about 40 mM, or such as from about 4 mM to about 20 mM, or about 10 mM
  • the concentration of calcium ions provided in the obtained supersaturated solution is in the range of about 2 to about 40 mM, such as e.g. 2 mM to about 21 mM, such as e.g. about 2.5 to about 16 mM.
  • the concentration of calcium ions is suitably in the range of from 2.5mM to about 10 mM, such as e.g. 3mM to 5 mM, for example about 3.87, 4.5 or 5mM.
  • the amount of phosphate in component (b) is sufficient to provide, upon dissolution of component (b) in water, a concentration of phosphate ions in a range of about 1 mM to about 64 mM, such as e.g. 2 mM to about 40 mM, e.g. such as 3 to about 20 mM, such as e.g. 4 mM to about 12 mM.
  • the concentration of phosphate ions provided in the obtained supersaturated solution is in the range of about 0.5mM to about 32 mM, such as e.g. l .mM to about 20 mM, such as e.g. about 1.5 to about 10 mM.
  • the concentration of phosphate is suitably in the range of from about 2 to about 6 mM, such as e.g. 2 to 4mM, for example 2, 3, 3.4 or 3.87 mM.
  • the concentration of phosphate ions is around 2.7 to 3.4 mM, for example 2.96 mM.
  • the pH of the super saturated solution obtained after dissolution of powder components (a) and (b) and upon mixing thereof is within the area from about 5 to about 8, more preferably from about 6 to about 7.5, such as about 6.5 to about 7.5; especially preferable is when the pH is about neutral such as 7.0 +/- 0.2.
  • a pH adjuster could be used to provide the desired pH.
  • stabilizing agent is a compound or compounds which facilitate the dissolution of calcium and phosphate upon dissolution of dry components (a) and (b).
  • the stabilizer agent contained in the dry components (a) and (b) of the present two component preparation may be one or more alkali metals such as e.g. earth alkali halides, such as e.g. sodium chloride or potassium chloride, preferably sodium chloride.
  • Ammonium salts such as e.g. ammonium chloride may also be used as a stabilizing agent according to the present.
  • the amount of stabilizer in dry components (a) and (b) is sufficient to, upon dissolution, allow the use of calcium and phosphate which are higher than the amount obtained in a saturated solution of calcium and phosphate ions.
  • the amount of sodium chloride should provide an isotonic solution due to the aim of avoiding bad taste, possible irritation and/or pain in the oral cavity caused by sodium chloride.
  • the concentration of sodium chloride upon dissolution of dry components (a) and (b) in the final mouth rinse solution is according to one aspect of the present invention in a range of about 40 mM to about 400 mM, such as e.g. 80 mM to 200 mM, such as about 100 mM.
  • the two component preparation according to the present invention may also comprise fluoride, in which is preferably comprised in component (b).
  • zinc may as well be added to component (a) and/or component (b), preferably zinc is added to component (a).
  • a mouth rinse solution obtained by the dissolution of dry components (a) and (b) of the present two component preparation is the same as for super saturated mouth rinse preparation well known to the skilled person, e.g. such as for CaphosolTM as described in US 6387352 and US 5993785 (the entire contents of which are hereby incorporated by reference as if repeated verbatim herein for establishing such regime).
  • the present preparation may be used together with other dental health products and treatment methods, such as e.g. tooth brushing, methods and preparations for the application of fluoride, salivary gland stimulation methods and preparations etc. Examples
  • Example 1 Manufacturing of a two component preparation.
  • Calcium chloride hexahydrate and sodium chloride may be weighed out in the amounts given in table 1 and mixed to provide powder mixture (a).
  • Sodium phosphate and sodium chloride may be weighed out in the amounts given in table 1 and mixed to provide powder mixture (b).
  • the powder mixture (a) and (b) may be filled in airtight, single dose containers to be used for the preparation of two separate solution which upon mixing provide a mouth rinse solution ready to use.
  • a powder mixture of calcium chloride hexahydrate and sodium chloride and a powder mixture of sodium phosphate and sodium chloride as provided in table 1 were added to 50 ml water respectively, to yield a solution (a) comprising calcium ions and a solution (b) comprising phosphate ions. The two solutions were then combined to yield the final super saturated mouth rinse solution.
  • Normal tapwater can be used provided the water is of low hardness.
  • the amounts of the solid refer to the w/w % and correspond to the mixed volume of 100 ml.
  • the amount of solids has been tested against the already available CaphosolTM product in order to verify the concentration of the compounds in the final solution. If a smaller volume is needed the amount of solids can be reduced accordingly. Here we have given amounts corresponding to 100 ml final solution.
  • CaphosolTM provides 0,052% (w/w) of CaCl calculated as without crystal water.
  • CaCl 6H20 In the solid preparation according to the present invention we use CaCl 6H20.
  • Example 3 Manufacturing of a two component effervescent tablet.
  • Calcium chloride hexahydrate and sodium chloride may be weighed out in the amounts given in table 1 and mixed to provide a dry component (a).
  • Sodium phosphate and sodium chloride may be weighed out in the amounts given in table 1 and mixed to provide a dry component (b).
  • the components (a) and (b) may be mixed with binders and effervescent agents and formed into a tablet, with component (a) arranged in one segment of the tablet, component (b) arranged in a second segment of the tablet, with a layer of inert material separating the two components.
  • the components may be arranged as two separately packaged effervescent tablets.
  • Table 1 Amounts and ingredient of a two component preparation

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Birds (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La préparation à deux composants ci-décrite, utile pour préparer un bain de bouche, comprend (a) un premier composant anhydre d'hexahydrate de chlorure de calcium et un stabilisant et (b) un second composant anhydre de phosphate et un stabilisant, et éventuellement un fluorure. Lors de la dissolution desdits composants anhydres (a) et (b) dans une quantité d'eau prédéfinie, la préparation à deux composants donne une solution sursaturée en ions calcium et phosphate.
PCT/EP2012/059241 2011-05-18 2012-05-18 Préparation de type bain de bouche à deux composants Ceased WO2012156502A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161487294P 2011-05-18 2011-05-18
US61/487,294 2011-05-18

Publications (2)

Publication Number Publication Date
WO2012156502A2 true WO2012156502A2 (fr) 2012-11-22
WO2012156502A3 WO2012156502A3 (fr) 2013-08-01

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PCT/EP2012/059241 Ceased WO2012156502A2 (fr) 2011-05-18 2012-05-18 Préparation de type bain de bouche à deux composants

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180318191A1 (en) * 2017-05-04 2018-11-08 Phoenix Dental, Inc. Dental Composition and Method
US11090259B2 (en) 2012-11-16 2021-08-17 Eusa Pharma (Uk) Ltd Effervescent tablet

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5993785A (en) 1996-09-18 1999-11-30 Erling Johansen Mouthwash compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4606912A (en) * 1981-07-22 1986-08-19 Caries Research Group Of Rochester, Inc. Method of making a clear, stable aqueous mouthwash solution and the solution made by that method for the enhancement of cells of the oral cavity and the remineralization of teeth

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5993785A (en) 1996-09-18 1999-11-30 Erling Johansen Mouthwash compositions
US6387352B1 (en) 1996-09-18 2002-05-14 Erling Johansen Mouthwash compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Medical News", JAMA, vol. 234, no. 6, 1975, pages 577 - 578
PAPAS ET AL., BONE MARROW TRANSPLANTATION, vol. 00, 2003, pages 1 - 8

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11090259B2 (en) 2012-11-16 2021-08-17 Eusa Pharma (Uk) Ltd Effervescent tablet
US20180318191A1 (en) * 2017-05-04 2018-11-08 Phoenix Dental, Inc. Dental Composition and Method

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