WO2019025599A1 - Gel comprenant de la chlorhexidine - Google Patents

Gel comprenant de la chlorhexidine Download PDF

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Publication number
WO2019025599A1
WO2019025599A1 PCT/EP2018/071155 EP2018071155W WO2019025599A1 WO 2019025599 A1 WO2019025599 A1 WO 2019025599A1 EP 2018071155 W EP2018071155 W EP 2018071155W WO 2019025599 A1 WO2019025599 A1 WO 2019025599A1
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WIPO (PCT)
Prior art keywords
gel composition
chlorhexidine
gel
salt
pharmaceutically
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Application number
PCT/EP2018/071155
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English (en)
Inventor
Joaquín BALASCH RISUEÑO
Marta EMBID LÓPEZ
Original Assignee
Laboratorios Kin, S.A.
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 Laboratorios Kin, S.A. filed Critical Laboratorios Kin, S.A.
Priority to MX2020001363A priority Critical patent/MX2020001363A/es
Priority to PE2020000181A priority patent/PE20200698A1/es
Priority to CR20200058A priority patent/CR20200058A/es
Priority to EP18746958.0A priority patent/EP3661480A1/fr
Priority to CN201880052414.5A priority patent/CN110996891B/zh
Priority to BR112020002106-7A priority patent/BR112020002106B1/pt
Publication of WO2019025599A1 publication Critical patent/WO2019025599A1/fr
Priority to PH12020550032A priority patent/PH12020550032A1/en

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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
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A61K8/416—Quaternary ammonium compounds
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/43—Guanidines
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the invention relates to the field of oral cavity hygiene and to compositions with active principles and ingredients for preserving oral cavity health. Thus, it relates to compositions usable in odontoiatric or odontostomatological field.
  • oral health is a state of being free from several disorders that affect the oral cavity, including chronic mouth and facial pain, oral and throat cancer, oral sores, birth defects such as cleft lip and palate, periodontal (gum) disease, tooth decay and tooth loss.
  • Risk factors are the unhealthy diet, tobacco, harmful alcohol use, and poor oral hygiene. It is widely recognized that oral health contributes to total health and is an essential component of the quality of life.
  • Oral tissues require the maintenance of proper oral hygiene by tooth brushing, dental floss, dentifrices, gels, mouth rinses, etc.
  • mouth rinses are used in addition to conventional tooth brushing, and for reducing accumulation of oral plaque. These mouth rinses are also used for patients.
  • compositions for oral care are also used for treating malodor, mainly by controlling the growth of microorganisms in the oral cavity.
  • the compositions comprise compounds that allow reducing plaque formation and the activity of
  • microorganisms at the same time they are safe and respectful for gingival and dental tissues.
  • Chlorhexidine is by now the most commonly used oral antiseptic, acting as bactericidal and bacteriostatic. It is a biguanide. Chlorhexidine (CHX) has some side effects, such as the staining of the teeth and lingual mucosa with an increased formation of supragingival calculus; additionally, taste disturbances have been reported as well as discoloration of some restorative materials.
  • hyaluronic acid (HA) is the main component of the extracellular matrix of many tissues, and it is present in human saliva acting as a lubricant. HA possesses a role in healing both acute and chronical oral lesions, especially periodontal alterations. HA forms a protective superficial film over oral mucosa. In vivo, the plaque growth inhibition activity of HA in 4-day plaque regrowth model is comparable to CHX. HA is also known as a mucoadhesive agent.
  • Liquid compositions comprising both compounds are known. These are mouth rinses aiming preserving oral hygiene. Examples of these compositions are marketed and also disclosed in patent literature, such as in PCT application W09852612, wherein water- based antiseptic compositions comprising among others hyaluronic acid and chlorhexidine are reported. Other examples of said compositions are the marketed products EllaDent Perio 020 mouthwash and the CURASEPTOADS Perio mouthwash. Using rinses implies the drawback that they have to be retained in mouth for a
  • compositions for delivering actives are formulated as gels with appropriate consistency. The gels are applied onto gums and actives are released gradually.
  • Gels comprising only chlorhexidine include hydroxyethylcellulose for example as gelling agent (e.g.: Curasept ADS 350 Gingival Gel; TrisDent Dental Gel; and Oralsan Gingival Gel).
  • sodium hyaluronate in gel formulations can be manufactured, for example, with carbopol (also termed carbomer) (e.g.: Neutrogena Hydro Boost Gel de Agua; Ultimate Hydration Gel; Bionect Gel; and Theaioz Duo Gel).
  • carbopol also termed carbomer
  • Neutrogena Hydro Boost Gel de Agua Ultimate Hydration Gel
  • Bionect Gel and Theaioz Duo Gel
  • gels comprising both chlorhexidine and hyaluronic acid.
  • An example is the gel for feminine hygiene of the Swiss patent
  • CH691030 wherein sodium hyaluronate and chlorhexidine, among other ingredients, are ingredients of a mixture comprising carragenan as gelling agent.
  • Carragenan is mentioned as a proper gelling agent that together with hyaluronate provides a sliding, compact, filamentous, transparent, clean and incolour gel.
  • Inventors of CH691030 propose the gel also for disinfecting oral cavity, although no specific examples are provided.
  • Another gel composition comprising chlorhexidine and hyaluronic acid is disclosed in the Russian patent RU2286764.
  • the gel is particularly mentioned for use in the treatment of inflammatory diseases of the oral cavity, and it comprises a combination of polyvinyl alcohol with sodium alginate as gelling agent.
  • compositions with both ingredients are not stable for a long time. It is for this reason that there are no gel compositions in the market with chlorhexidine and hyaluronic acid, although it is a request made by dentists and surgeons.
  • gelling agents are pH sensitive and do not perform its function at the final desired pH, generally about 7-8, for oral compositions. Also, some gelling agents can alter the final pH of compositions making them not useful for oral cavity treatment. Thus, it is evident that there is still in the field a need of alternative formulations avoiding the above referred drawbacks while being effective for oral hygiene.
  • chlorhexidine, or a salt thereof, and hyaluronic acid, or a salt thereof can be formulated together as a transparent gel composition with good adherence properties to oral cavity (in particular to tooth enamel and gums) and also to skin surfaces, if a carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof is used as gelling agent in the gelling matrix conforming the gel.
  • the compositions have high moisturing properties and are versatile in terms that a wide range of concentrations of chlorhexidine and of hyaluronic acid can be embedded in the gel.
  • a first aspect of the invention is a gel composition comprising:
  • an effective amount of chlorhexidine (CHX) and/or a pharmaceutically or cosmetically acceptable salt thereof said effective amount being a percentage by weight comprised from 0.05 % w/w to 1 .5 % w/w, in relation with the total weight of the gel composition;
  • HA hyaluronic acid
  • a gelling matrix comprising water, and a cellulose derivative, said cellulose derivative comprising carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, together with
  • the carboxy(C 1 -C 3 )alkyl-cellulose in the gelling matrix acts as thickening or gelling agent and forms, optionally with other excipients or carriers, a hydrophilic matrix embedding the actives chlorhexidine and/or a pharmaceutically acceptable salt thereof, and the hyaluronic acid and/or a pharmaceutically acceptable salt thereof.
  • hyaluronic acid and/or a pharmaceutically or cosmetically salt thereof contributes also to conform the gel for being a polymeric compound that behaves as so when dissolved in water from the gelling matrix.
  • it is also a thickening agent.
  • this HA also acts as muco-adhesive.
  • This gel composition supposes a widely requested need for practitioners and citizens as a whole, since it allows the simultaneous administration of an antiseptic and of a compound for healing any tissue lesions (i.e. for oral cavity or for other injured cavities, including mucosa-containing cavities).
  • the gel composition not only solves the problem of the precipitation of chlorhexidine in hyaluronic acid or of both when they are together in gels, but also that of maintaining pH at the desired values for oral use (namely pH from 7 to 8). Further and surprisingly, the gel composition maintains its consistency and transparency in case it is colorless (which means that at least no chlorhexidine precipitation is present) with a wide range of chlorhexidine and hyaluronic acid concentrations. Thus, no precipitation occurs. This later opens the option of preparing a wide variety of compositions with these active ingredients. Moreover, as will be depicted in the examples below, the gel composition has the adequate adhesive properties allowing its use for a long period of time. Hence, if the gel is well-adhered onto the gums and/or teeth, or even in other surfaces, such as topically on skin surfaces, then low numbers of daily applications are required for achieving the desired effect.
  • the invention encompasses a method for preparing a gel composition as defined in the first aspect and its embodiments, the method comprising:
  • step (b) adding to the homogenized aqueous dispersion of step (a), a cellulose derivative, said cellulose derivative comprising carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, to obtain a gel composition.
  • the method comprises the gelation of carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof in an homogenized aqueous dispersion comprising hyaluronic acid and/or a pharmaceutically or cosmetically acceptable salt thereof, dissolved in water and chlorhexidine and/or a pharmaceutically or cosmetically acceptable salt thereof, dispersed in a solvent selected from the group consisting of polyalkylene glycol, glycerin, propylene glycol and mixtures thereof.
  • Gel compositions as defined above allow treating many of the oral cavity diseases, injuries or disorders, for which hyaluronic acid is effective and in which antiseptic conditions are required or desired.
  • the gels of the invention are useful for preserving good oral cavity health, in particular of the gums, after brushing.
  • Another aspect of the invention is a gel composition as defined above for use as a medicament.
  • the invention also relates, thus, to the use of the gel compositions as defined above as pharmaceutical or cosmetic topical compositions.
  • the gel compositions can be applied to any skin or mucosa surface, where they rest enough time to allow all actives perform their effects.
  • said gels, as above indicated are colorless and transparent within the established stability test is the cosmetic and pharmacological field. If not colorless, no precipitation of chlorhexidine and/or of a salt thereof takes place.
  • Another aspect of the invention is the use of a gel composition as defined above as cosmetic care agent (or simpler as a cosmetic). This applies in particular when no diseases is present, but administration of the gel ameliorates appearance of the surface to which it is applied.
  • ameliorating skin elasticity or oral cavity appearance leading to an appearance of healthy gums and of mouth mucosa.
  • This cosmetic effect also aids to have a proper condition of the tissues that avoid or minimize risk of diseases (in particular or oral cavity), and/or allows an improved healing in case of tissue damage for any reason (i.e. exodontia).
  • Yet another aspect of the invention is the use of a gel composition as defined above as oral cosmetic care agent for hydrating, strengthen and ameliorating appearance of oral mucosa and gums , wherein said gel comprises cosmetically effective amounts of hyaluronic acid and/or a cosmetically acceptable salt thereof, and cosmetically effective amounts of chlorhexidine, said effective amount being a percentage by weight comprised from 0.05 % w/w to 1.5 % w/w, in relation with the total weight of the gel
  • a gel composition as defined above comprising chlorhexidine, or a salt thereof; hyaluronic acid, or a salt thereof; and a carboxy(C 1 -C 3 )alkyl-cellulose in the gelling matrix, as oral cavity cosmetic agent.
  • the cosmetic use of the gel composition of the invention implies using cosmetically acceptable excipients or carriers that can be coincident with pharmaceutically acceptable excipients or carriers.
  • Another aspect of the invention is the use of carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof as chlorhexidine suspending agent in hyaluronic acid containing compositions in form of gels.
  • FIG. 1 is a comparative graph of the mucoadhesion levels of a gel of the invention over time, registered by means of a gravimetric test on an inclined temperature-controlled plane treated with mucin. Error bars show the standard deviation for each data set. Adhesion score percentage (abbreviated AS (%)) in the Y-axis is indicated as percentage of adhesion. X-axis shows the time (T) in minutes (min).
  • Each data set include data from water (first column in the set), data from water in a mucin containing inclined plane (second column in the set), sample (third column in the set) and sample in a mucin containing inclined plane (forth column in the set).
  • a “gelling agent” is a thickening agent that forms a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure.
  • a thickening agent or thickener is a substance which can increase the viscosity of a liquid without substantially changing its other properties.
  • Thickening agents used in cosmetics, pharmaceutical or personal hygiene products include viscous liquids such as polyethylene glycol, synthetic polymers such as carbomer (a trade name for polyacrylic acid) and vegetable gums.
  • a gel is a solid jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state.
  • Carboxy(C 1 -C 3 )alkyl-cellulose is often used as its sodium salt, such as the sodium carboxymethyl cellulose.
  • the properties of the cellulose derivative can be modulated. For example, assuming concentration stays the same; adding more substitutions also increases viscosity.
  • a compound that avoids precipitation of other compounds in a particular matrix for example in a gelling matrix.
  • carboxy(C 1 -C 3 )alkyl-cellulose in particular carboxymethyl cellulose is used as suspending agent of CHX in an aqueous gel comprising hyaluronic acid or a salt thereof.
  • Carboxy(C 1 -C 3 )alkyl-cellulose is also used as thickening or gelling agent.
  • oral cavity encompasses, according to this description, the two regions of mouth; the vestibule and the oral cavity proper. The vestibule is the area between the teeth, lips and cheeks.
  • the oral cavity is bounded at the sides and in front by the alveolar process (containing the teeth) and at the back by the isthmus of the fauces. Its roof is formed by hard palate and soft palate and the floor is formed by the mylohyoid muscles and is occupied mainly by the tongue.
  • a mucous membrane - the oral mucosa lines the sides and under surface of the tongue to the gums, lining the inner aspect of the jawbone (mandible). It receives the secretions from the submaxillary and sublingual salivary glands.
  • each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the excipients are orally acceptable, which means that they can be used without problems or complications in case they are finally swallowed and reach the digestive tract.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • the particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and the similar considerations.
  • cosmetically acceptable refers to that excipients or carriers suitable for use in contact with oral cavity mucosa and enamel without undue toxicity, incompatibility, instability, allergic response, among others.
  • skintological acceptable including excipients or carriers suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, among others.
  • a first aspect of the invention is, briefly, a gel composition comprising chlorhexidine and/or a pharmaceutically acceptable salt thereof, hyaluronic acid and/or a pharmaceutically acceptable salt thereof, and a gelling matrix comprising carboxy(Cr C 3 )alkyl-cellulose and/or a salt thereof, together with pharmaceutically excipients and/or carriers.
  • Chlorhexidine and/or a pharmaceutically acceptable salt thereof, hyaluronic acid and/or a pharmaceutically acceptable salt thereof are both in the gel composition in therapeutically effective or cosmetically effective amounts.
  • the salts of carboxy(Cr C 3 )alkyl-cellulose are selected from alkali metal salts, alkaline-earth metal salts, quaternary ammonium salts, and mixtures thereof.
  • the salts are alkali metal salts selected from sodium, potassium, and mixtures thereof.
  • the carboxy(C 1 -C 3 )alkyl-cellulose is carboxymethylcellulose or a salt thereof.
  • the carboxy(Cr C 3 )alkyl-cellulose salt is an alkali metal salt of carboxymethylcellulose.
  • the carboxy(C 1 -C 3 )alkyl-cellulose salt is sodium carboxymethylcellulose. In another particular embodiment the carboxy(C 1 -C 3 )alkyl-cellulose salt is an alkaline earth metal salt of carboxymethylcellulose.
  • carboxymethylcellulose is used in combination with xanthan gum or sodium alginate for promoting adhesion to mucous membranes and so releasing pharmaceutical actives of interest in a controlled way.
  • xanthan gum or sodium alginate for promoting adhesion to mucous membranes and so releasing pharmaceutical actives of interest in a controlled way.
  • carboxymethylcellulose grade and amount can be adjusted in toothpaste according to desired paste viscosity.
  • Gels of the invention are conceived and aimed to stay on the desired surface of application for a period of time allowing the actives in the gel to be released and then to perform their effect.
  • Carboxymethylcellulose, or carboxy(C 1 -C 3 )alkyl-cellulose and salts thereof provides to the gel of the invention this required adhesion and surprisingly, it results in an ingredient that allows the join administration of two active ingredients that tend to precipitate when mixed together in gelling matrixes.
  • carboxy(C 1 -C 3 )alkyl-cellulose in the gelling matrix wide ranges of key ingredients are allowed, in particular wide ranges of concentrations of hyaluronic acid or of a salt thereof and of chlorhexidine or of a salt thereof.
  • the gel composition of the present invention is one wherein the carboxy(C 1 -C 3 )alkyl-cellulose has a carboxy(C 1 -C 3 )alkyl- moiety content from 15% to 30% by weight of the weight of the carboxy(C 1 -C 3 )alkyl-cellulose; preferably from 19% to 24% by weight of the weight of the carboxy(C 1 -C 3 )a lkyl-cellulose.
  • Measurement of the content of the carboxy(C 1 -C 3 )a lkyl- moieties can be performed by any method known in the art.
  • the gel composition of the present invention is one wherein the carboxy(Cr)
  • C 3 )alkyl-cellulose in particular carboxymethylcellulose, has a degree of substitution from 1.15 to 1.45 measured according to American Standard ASTM D1439 .
  • the carboxy(C 1 -C 3 )alkyl-cellulose is Blanose 12M31 P, a
  • the composition of the present invention is one wherein the carboxy(C 1 -C 3 )alkyl-cellulose has a viscosity from 1500 mPa.s to 6500 mPa.s; preferably from 3100 mPa-s to 6500 mPa-s.
  • viscosity refers to the resistance of a fluid to shear, also called dynamic or shear viscosity and defined mathematically as a stress-to- shear rate quotient.
  • the viscosity is measured by using devices such as rotational viscometers or rheometers which measure the torque exerted on an axis in contact with the sample when it is rotated at a precisely controlled angular velocity. Converting torque and velocity to stress and share rate respectively is straight forward by multiplication by calibration constants.
  • viscosity measurements are performed using a (Brookfield Viscometer, #2 spindle (SP2), operating at 0.3 rpm).
  • the percentage by weight of carboxy(C 1 -C 3 )a lkyl- cellulose, in relation to the total weight of gel composition is from 1 .0 % to 5.0%. More in particular it is from 1 .0% to 4.0 %. Even more in particular, it is from 2.0 % to 3.0 %.
  • the gel formulations comprise a pharmaceutically acceptable salt of chlorhexidine selected from the group consisting of chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine chlorhydrate (or hydrochloride) and chlorhexidine base ,and mixtures thereof.
  • the pharmaceutically acceptable salt of chlorhexidine is chlorhexidine gluconate.
  • Chlorhexidine gluconate is also known as chlorhexidine digluconate (used herewith interchangeably).
  • the chlorhexidine and/or its salts are in a percentage by weight from 0.05 to 1 .5 %, in relation to the total weight of the gel formulation. More in particular, it is from 0.10 to 1 .0% by weight. Also more in particular from 0.1 % to 0.5%, even more in particular from 0.1 % to 0.3% by weight. Also more in particular, it is from 0.10 to 0.25 % by weight.
  • hyaluronic acid is the main component of the extracellular matrix of many tissues, and it is present in human saliva acting as a lubricant.
  • Hyaluronic acid is also a mucoadhesive agent that acts as healing agent in cases where tissues are injured due to surgical interventions or due to certain diseases. Therefore, hyaluronic acid is not only one of the active ingredients in the formulation when tissue is to be repaired, but also promotes adhesion. In the present invention adhesion to mucosa and/or enamel is also achieved due to the presence of the carboxy(C 1 -C 3 )alkyl-cellulose, as above exposed.
  • hyaluronic acid and/or one of its salts has a molecular weight of at least 1.3 MDa. More in particular it is from 1.3 to 2.5 MDa.
  • the percentage by weight of hyaluronic acid or of a salt thereof, in relation to the total weight of the gel composition is from 0.1 to 1.0 %. More in particular is from 0.1 to 0.8 %, in particular 0.75 %. In another particular embodiment it is from 0.1 to 0.5 %, and even more in particular it is from 0.1 to 0.30 %. More in particular, it is from 0.10 to 0.25 %. Even more in particular, it is selected from 0.10 %, 0.15%, 0.20%, 0.21 %, 0.22%, 0.23%, 0.24 % and 0.25%.
  • the gel composition according to the first aspect comprises:
  • This particular embodiment is a gel composition adequate to be an oral gel composition, more in particular for oral cavity application.
  • it is a gel to be used in oral cavity for the treatment of disorders, diseases or any condition, such as to promote tissue repair or regeneration after dental extraction (exodontia).
  • the gel widely adheres to oral tissue (mainly gums and dental alveolus in case of exodontia) and allows the controlled deliver of both chlorhexidine and hyaluronic acid (or any of their salts), both active compounds in being effective since they do not precipitate in the gel composition.
  • the gelling matrix with carboxy(C 1 -C 3 )alkyl-cellulose or a salt thereof, but also the hyaluronic acid or a salt thereof do contribute to the gel consistency of the composition, mainly due to its polymeric nature and behavior in water.
  • the gelling matrix comprises, besides the water and the cellulose derivative comprising carboxy(C 1 -C 3 )a lkyl- cellulose or a salt thereof as gelling agent, in particular carboxymethylcellulose, additional gelling agents selected from the group consisting of propylene glycol, carbomers (such as Carbopol®), other cellulose derivatives (such as ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), magnesium aluminum silicate (such as Veegum®), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, and mixtures thereof.
  • the gel composition according to the invention comprises,:
  • an effective amount of chlorhexidine (CHX) and/or a pharmaceutically or cosmetic acceptable salt thereof said effective amount being a percentage by weight comprised from 0.05 % w/w to 1 .5 % w/w, in relation with the total weight of the gel composition;
  • gelling matrix comprising in addition a compound selected from the group consisting of polyalkylene glycol, glycerin, propylene glycol and mixtures thereof.
  • the gel further comprises a solvent selected from the group consisting of polyalkylene glycol, glycerin, propylene glycol and mixtures thereof.
  • a solvent of polyol nature selected from the group consisting of propylene glycol, glycerin and mixtures thereof chlorhexidine or one of its salts could be dispersed and mixed with an aqueous solution of hyaluronic acid or its salts, avoiding chlorhexidine precipitation.
  • carboxy(C 1 -C 3 )alkyl-cellulose or a salt thereof allowed high stable gel compositions in which both, chlorhexidine and hyaluronic acid, are suspended and no precipitation occurs.
  • carboxy(C 1 -C 3 )alkyl-cellulose or a salt thereof enhances adhesion to the surfaces on which the gel composition is applied. In particular, enhances adhesion to animal skin and to oral cavity tissues (tooth enamel and gums).
  • the gel composition is a highly stable topical gel composition for skin and for oral cavity tissues.
  • the gel composition comprises, in a particular embodiment, additional compounds aiding to avoid precipitation when the gel compositions comprise a great amount of ingredients.
  • the gel compositions of the first aspect comprise chelating compounds selected from the group consisting of EDTA, phosphonate compounds, gluconate compounds, citrate compounds and combinations thereof. In a particular embodiment, optionally in
  • the chelating compound is comprised in a percentage by weight in relation to the total weight of the gel composition from 0.05 % to 1 %. More in particular, it is from 0.1 % to 0.40 %. More in particular, it is from 0.1 % to 0.20%. More in particular, the chelating compound is ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as disodium EDTA. Even more in particular, EDTA or its sodium salt, are comprised in a percentage by weight from 0.1 % to 0.20%.
  • EDTA ethylenediaminetetraacetic acid
  • the gel compositions of the present invention further comprise one or more compounds selected from the group consisting of an essential oil, a preservative, a flavor, an humectant, an emulsifier, a chelating agent, and additional gelling agent besides the carboxy(C 1 -C 3 )alkyl-cellulose , an antimicrobial agent, an aqueous vehicle (i.e. water), and mixtures thereof.
  • the gel composition of the first aspect of the invention comprises in a particular embodiment oil selected from the group consisting of thyme oil, eugenol, eucalyptus oil, rosmarine oil, mint oil, cinnamon leaf oil, clover leaf oil, tea tree oil and origanum oil.
  • the gel composition has a pH from 7.0 to 8.0. At this pH range, the gel is adequate for the particular use in oral cavity, as above indicated.
  • the gelling agent carboxy(C 1 -C 3 )alkyl-cellulose does not alter this pH, which means that at the adequate pH no precipitation of chlorhexidine and/or one of its salts will take place.
  • the invention encompasses also a method for preparing a gel composition as defined above and comprising the steps of:
  • step (b) adding to the homogenized aqueous dispersion of step (a), a cellulose derivative, said cellulose derivative comprising carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, to obtain a gel composition.
  • the solvent in which chlorhexidine and/or a salt thereof is dispersed is selected from the polyols propylene glycol, glycerin and mixtures thereof.
  • the solvent is selected from the polyethers polyethylene glycol, polypropylene glycol and mixtures thereof, which are also termed in this description as polyalkylene glycols.
  • the solvent in which chlorhexidine and/or a salt thereof is dispersed is a mixture of one or more polyols and one or more polyalkyleneglycols. More in particular the solvent is a mixture of
  • hyaluronic acid and/or a pharmaceutically or cosmetically acceptable salt thereof is dissolved in deionized water.
  • a pre-mixture can be prepared with a solvent of polyol nature, more in particular with propylene glycol, glycerin or a mixture of both, said polyol acting as dispersant of chlorhexidine or of a salt thereof.
  • said aqueous pre-mixture is in another particular embodiment derivatized with polyalkylene glycols, said polyalkylene glycols soluble in water and with a molecular weight from 50 to 200 Da.
  • the solvent is in another particular embodiment optionally derivatized with oils. Examples of oils to be added in the pre-mixture include Castor oil. This pre-mixture is further completed with the carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, which evolves to a gel consistency once it contacts the aqueous pre-mixture.
  • this carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, in particular carboxymethylcellulose allows chlorhexidine and hyaluronic acid and/or their salts be stably suspended in the aqueous gel.
  • the invention relates in particular to the use of the gel composition in the treatment of oral cavity diseases affecting gums and/or teeth and/or the oral mucosa.
  • Dental plaque is a biofilm or mass of bacteria that grows on surfaces within the mouth. It is a sticky colorless deposit at first, but when it forms tartar (also known as calculus), it is often brown or pale yellow. It is commonly found between the teeth, on the front of teeth, behind teeth, on chewing surfaces, along the gumline, or below the gumline cervical margins. Dental plaque is also known as microbial plaque, oral biofilm, dental biofilm, dental plaque biofilm or bacterial plaque biofilm.
  • Progression and build-up of dental plaque can give rise to tooth decay - the localised destruction of the tissues of the tooth by acid produced from the bacterial degradation of fermentable sugar - and periodontal problems such as gingivitis and periodontitis; hence it is important to disrupt the mass of bacteria and remove it.
  • Plaque control and removal can be achieved with correct daily or twice- daily tooth brushing and use of interdental aids such as dental floss and interdental brushes.
  • Oral hygiene is important as dental biofilms may become acidic causing demineralization of the teeth (also known as dental caries) or harden into dental calculus. Decay is or tooth decay, also known as dental caries or cavities, is a breakdown of teeth due to acids made by bacteria. The cavities may be a number of different colors from yellow to black.
  • Gingivitis ulceration of the gum tissue
  • gingivitis is a non-destructive disease that occurs around the teeth.
  • the most common form of gingivitis, and the most common form of periodontal disease overall, is in response to bacterial biofilms (also called plaque) that is attached to tooth surfaces, termed plaque-induced gingivitis. While some cases of gingivitis never progress to periodontitis, data indicates that periodontitis is always preceded by gingivitis.
  • Gingivitis is reversible with good oral hygiene; however, without treatment, gingivitis can progress to periodontitis, in which the inflammation of the gums results in tissue destruction and bone resorption around the teeth. Periodontitis can ultimately lead to tooth loss.
  • Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (Gl) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment. Oral and gastrointestinal (Gl) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy.
  • HSCT hematopoietic stem cell transplantation
  • Oral ulcers or mouth ulcers are ulcers that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanisms, but usually there is no serious underlying cause. The two most common causes of oral ulceration are local trauma (e.g. rubbing from a sharp edge on a broken filling) and aphthous stomatitis ("canker sores"), a condition characterized by recurrent formation of oral ulcers for largely unknown reasons. Mouth ulcers often cause pain and discomfort, and may alter the person's choice of food while healing occurs (e.g. avoiding acidic or spicy foods and beverages).
  • Tooth sensitivity or dentin hypersensitivity (abbreviated to DH, or DHS, and also termed sensitive dentin, dentin sensitivity, cervical sensitivity, and cervical hypersensitivity) is dental pain which is sharp in character and of short duration, arising from exposed dentin surfaces in response to stimuli, typically thermal, evaporative, tactile, osmotic, chemical or electrical; and which cannot be ascribed to any other dental disease.
  • a degree of dentin sensitivity is normal, but pain is not usually experienced in everyday activities like drinking a cooled drink. Therefore, although the terms dentin sensitivity and sensitive dentin are used interchangeably to refer to dental hypersensitivity, the latter term is the most accurate.
  • the main cause of DH is gingival recession (receding gums) with exposure of root surfaces, loss of the cementum layer and smear layer, and tooth wear. Receding gums can be a sign of long-term trauma from excessive or forceful toothbrushing, or brushing with an abrasive toothpaste (dental abrasion), or a sign of chronic periodontitis (gum disease).
  • the gels of the invention are, in another particular embodiment, for use in the treatment of oral cavity tissues after a process of exodontia.
  • said oral cavity tissues include the gums.
  • a dental extraction (also referred to as tooth extraction, exodontia, exodontics, or informally, tooth pulling) is the removal of teeth from the dental alveolus (socket) in the alveolar bone. Extractions are performed for a wide variety of reasons, but most commonly to remove teeth which have become unrestorable through tooth decay, periodontal disease or dental trauma, especially when they are associated with toothache. Sometimes wisdom teeth are impacted (stuck and unable to grow normally into the mouth) and may cause recurrent infections of the gum (pericoronitis). In orthodontics if the teeth are crowded, sound teeth may be extracted (often bicuspids) to create space so the rest of the teeth can be straightened.
  • Tooth extraction is usually relatively straightforward, and the vast majority can be usually performed quickly while the individual is awake by using local anesthetic injections to eliminate painful sensations. After the tooth is removed, stitches are used to replace the gum into the normal position. Nonetheless, exodontia is a surgical act performed in oral cavity producing tissue damage. Post-operative in exodontia is a challenging process, affecting life quality of the patient due to pain and inflammation in the area associated with cicatrisation events. So that, after a dental extraction a blood clot is formed in dental alveolus and regeneration and recovery of the tissue starts. Early cicatrisations processes include granulocyte tissue formation in dental alveolus that is progressively replaced by new bone tissue.
  • the gels defined above comprising chlorhexidine (or a salt thereof), hyaluronic acid (or a salt thereof) and a gelling matrix with carboxy(C 1 -C 3 )alkyl-cellulose are, according to another aspect, for use as oral cavity cosmetic care. This means, that they are in particular for use in ameliorating appearance of gums and teeth.
  • the gel compositions of the invention are used as cosmetic care agents. More in particular they are used as cosmetic topical compositions.
  • the gel composition as defined above is used, according to another aspect of the invention, as an oral cavity cosmetic care agent. Therefore, the invention relates also to gel compositions for use in cosmetics.
  • These cosmetic gel compositions comprise an effective amount of chlorhexidine and/or a salt thereof; hyaluronic acid and/or a salt thereof; and a gelling matrix comprising water and a cellulose derivative, said cellulose derivative comprising carboxy(C 1 -C 3 )alkyl-cellulose and/or a salt thereof, together with appropriate cosmetically orally acceptable excipients and/or carriers.
  • the gel is used as oral cosmetic care agent for hydrating, strengthen and ameliorating appearance of oral mucosa and gums, said gel comprising as above indicated
  • cosmetically effective amounts of hyaluronic acid and/or a cosmetically acceptable salt thereof and cosmetically effective amounts of chlorhexidine and/or a cosmetically acceptable salt thereof, said effective amount of chlorhexidine or salt being a percentage by weight comprised from 0.05 % w/w to 1 .5 % w/w, in relation with the total weight of the gel composition.
  • the gel as oral cosmetic care agent is for daily cosmetic care and for protection of the mucosa and gums
  • These cosmetic effect is achieved in any of the tissues of oral cavity, in particular in gums, teeth and oral mucosa, but the cosmetic gel compositions of the invention can also be applied onto the skin, since due to the gel consistency it remains appropriate time to the surface and there allows absorption of any of the actives that the gel contains.
  • topical cosmetic gel compositions as defined above are used also as a skin care agent, wherein the skin care comprises ameliorating at least one of the following symptoms: roughness, flakiness, dehydration, tightness, chapping, scar reduction, and lack of elasticity.
  • safe and effective amounts is defined as any amount sufficient to significantly improving the cosmetic appearance of the skin and/or oral cavity tissues without substantial irritation, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement.
  • the safe and effective amount of chlorhexidine and/or a salt thereof and of hyaluronic acid and/or a salt thereof will vary with the age and physical condition of the consumer, the condition of the oral mucosa or skin, the duration of the treatment, the nature of any concurrent treatment, the specific combination of active ingredients employed, the particular cosmetically
  • Table 2 shows the appearance and consistency of several gel compositions comprising chlorhexidine and hyaluronic acid. The presence of the carboxymethyl cellulose gave proper gel consistency (colorless or white) but with no precipitation observed. Table 2_ Other gel compositions of the invention.
  • FORMULA for colorless gel composition comprising 0.50 % by weight of hyaluronic acid. Composition for 100 g
  • compositions with higher amounts of hyaluronic acid did not show any precipitate of chlorhexidine and/or hyaluronic acid. They were supplemented with a sweetener (sucralose) in order to mask bitter taste of hyaluronic acid. Addition of sweetener did not alter de consistency and transparency of the gel.
  • Example 2 Assay for evaluation of the mucoadhesive properties of a topical product
  • the colorless gel of Example 1 (Table 1 ; gel composition with 0.24% of hyaluronic acid) was tested in order to evaluate the mucoadhesion properties through gravimetric test on an inclined temperature-controlled plane treated with mucin.
  • the goal of the test is evaluating the mucoadhesive properties of a topical product through the analysis of kinetic detachment of the sample from a steel inclined plane, with and without a mucin biofilm.
  • the actual mucoadhesion of the sample is determined from the delay in sample slipping and in the detachment from the plane caused by the mucin.
  • the sample was tested undiluted. Each run was performed in three replicas and the performed runs included: Deionized water without mucin; deionized water with mucin; analyzed sample without mucin; and analyzed sample with mucin.
  • the plane was accurately cleaned and prepared before each run.
  • the plane was pre-coated with a 8 % suspension in water of porcine gastric mucin type II (Sigma-Aldrich) spread to make an evenly film.
  • the test conditions for the sample were as follows:
  • P t is the weight of the sample detached from the steel plane at each endtime t.
  • sample of example 1 showed a mucoadhesion of 46.1 % when stabilized vs. a percentage of deionized water equal to 12.33 %.
  • the corresponding percentage of the sample's adhesion without mucin was 22.37 %. Since the differential adhesion vs. the negative control was statistically significant (p ⁇ 0.0001 ), it could be concluded that the tested sample (Example 1 ) did show mucoadhesion properties.
  • the mixture comprising sodium hyaluronate and chlorhexidine gluconate had a gel consistency in which no precipitation of chlorhexidine was observed. Thus, it was a colorless gel composition.
  • the gel had mucoadhesive properties, thus being able to be topically applied in any surface, such as skin or even mucin-containing surfaces such as the gums of the oral cavity.
  • Example 3 Clinical trial of the efficacy of the gel of the invention comprising chlorhexidine and hyaluronic acid
  • Example 4 Cosmetic use of the gel of the invention An oral gel composition as disclosed in Example 1 (Table 1 ), was tested in a group of volunteers with several ages and not suffering any oral disease (healthy). The aim was to evaluate the cosmetic (aesthetic) effect of the oral gel composition in terms of gums appearance, mainly due to hydration linked to the presence of hyaluronic, and strengthen of the gums.
  • Volunteers include 30 people who took part in the study (informed of not to use any kind of antihistamines or pharmacological agents). They were given one package of the hyaluronic-containing oral gel composition, and were obliged to using it regularly for 3 weeks by: spread on the clean gums with circular, massaging movements; do not use another products of the same or similar endpoint, stopping immediately in case of any side effects in tested area and reporting them to dermatologist, observation and recording of remarks.
  • the cosmetic formulation does not cause any symptoms that would demonstrate its harmful i.e. allergic or toxic-irritant effects to mucous, membranes or gums as people involved in the tests didn't report any serious symptoms i.e. itching, contradiction, or others that might suggest a negative impact of the assessed product on skin.
  • oral gel is a cosmetic product that can be recommended for daily care and protection of the mucosa and gums of people of all ages.
  • the gel was characterized by: the right consistency, pleasant taste, high efficiency in use, adequate durability of the effect, which does not change during application and which encourage regular use of the preparation.
  • the persons participating in the study stated that the tested product has a suitable consistency, acceptable aesthetic color and fragrance.
  • the well- composed, active substances contained in the evaluated product with each application ensured proper care of mucous membranes and gums of people of different ages.

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Abstract

L'invention concerne une composition de gel comprenant de la chlorhexidine et/ou un sel pharmaceutiquement acceptable de celle-ci; de l'acide hyaluronique et/ou un sel pharmaceutiquement acceptable de celui-ci; et une matrice gélifiante, la matrice gélifiante comprenant de l'eau, et des dérivés de cellulose. L'invention concerne également un procédé de préparation des gels et des utilisations particulières des gels dans le domaine cosmétique, l'hygiène de la cavité buccale, la prévention de maladies de la cavité buccale et le traitement desdites maladies.
PCT/EP2018/071155 2017-08-04 2018-08-03 Gel comprenant de la chlorhexidine WO2019025599A1 (fr)

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MX2020001363A MX2020001363A (es) 2017-08-04 2018-08-03 Gel que comprende clorhexidina.
PE2020000181A PE20200698A1 (es) 2017-08-04 2018-08-03 Gel que comprende clorhexidina
CR20200058A CR20200058A (es) 2017-08-04 2018-08-03 Gel que comprende clorhexidina
EP18746958.0A EP3661480A1 (fr) 2017-08-04 2018-08-03 Gel comprenant de la chlorhexidine
CN201880052414.5A CN110996891B (zh) 2017-08-04 2018-08-03 包含氯己定的凝胶
BR112020002106-7A BR112020002106B1 (pt) 2017-08-04 2018-08-03 Composição em gel, método de preparo e uso da mesma
PH12020550032A PH12020550032A1 (en) 2017-08-04 2020-01-21 Gel comprising chlorhexidine

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EP17382547 2017-08-04
EP17382547.2 2017-08-04
IE20170230A IE87094B1 (en) 2017-08-04 2017-11-02 Gel comprising chlorhexidine
IE2017/0230 2017-11-02

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WO2020249040A1 (fr) * 2019-06-14 2020-12-17 The Procter & Gamble Company Compositions de soins buccaux sans rinçage
US20200390677A1 (en) * 2019-06-14 2020-12-17 The Procter & Gamble Company Leave-on oral care compositions
IT202000029288A1 (it) 2020-12-01 2022-06-01 Altergon Sa Sali di microbiocidi biguanidinici con glicosamminoglicani
WO2022251438A1 (fr) * 2021-05-26 2022-12-01 Colgate-Palmolive Company Compositions de soins bucco-dentaires
RU2806865C1 (ru) * 2022-06-28 2023-11-08 Общество с ограниченной ответственностью "СТОМАТОЛОГИЧЕСКИЙ МАГАЗИН "РОМАШКА" Стоматологический гель
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CN113440441B (zh) * 2021-07-29 2022-09-16 山东福瑞达生物股份有限公司 一种含精油的口腔抑菌组合物及其制备方法

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WO2020249042A1 (fr) * 2019-06-14 2020-12-17 The Procter & Gamble Company Compositions de soins bucco-dentaires sans rinçage
WO2020249040A1 (fr) * 2019-06-14 2020-12-17 The Procter & Gamble Company Compositions de soins buccaux sans rinçage
US20200390677A1 (en) * 2019-06-14 2020-12-17 The Procter & Gamble Company Leave-on oral care compositions
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IT202000029288A1 (it) 2020-12-01 2022-06-01 Altergon Sa Sali di microbiocidi biguanidinici con glicosamminoglicani
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RU2806865C1 (ru) * 2022-06-28 2023-11-08 Общество с ограниченной ответственностью "СТОМАТОЛОГИЧЕСКИЙ МАГАЗИН "РОМАШКА" Стоматологический гель

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IE87094B1 (en) 2020-05-13
EP3661480A1 (fr) 2020-06-10
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MX2020001363A (es) 2020-03-20
PE20200698A1 (es) 2020-06-16
PH12020550032A1 (en) 2021-02-15
BR112020002106A8 (pt) 2020-12-01
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CL2020000293A1 (es) 2020-08-14
BR112020002106A2 (pt) 2020-08-04

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