Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics

Definitions

• the present invention relates to the pharmaceutical, cosmetic and nutraceutical field and more particularly to that of bio-adhesive systems with programmed release of active ingredients in the human body.
• the human body is constituted by a certain number of cavities accessible from the exterior and covered with mucous membranes. These mucous membranes are the site of a certain number of diseases or local infections. This is the case of:
• These mucous membranes have the characteristic of being permanently moistened by liquids specific to the mucous membrane in question.
• the local treatment is generally coupled with a systemic treatment.
• systemic treatment we mean the supply via the blood of an active ingredient to the inside of the entire organism. This supply can be carried out by direct administration in blood circulation (intravenous administration) or by oral administration.
• Herpes is caused by a virus that develops at the oral, vaginal and ocular area.
• the prolongation of the action is obtained by injection of a suspension of particles intended to be solubilized gradually in the organism.
• the best-known example is that of insulin: intramuscular injection of particles of insulin for a 24 hours action minimum.
• a second example is that of the administration of implants in the case of hormone therapy: deposit of small hormone (progestins) tablets under the skin that are intended to dissolve slowly.
• small hormone progestins
• the best-known example is the nicotine patch for the weaning of smokers.
• the route that has received great attention in this field is the ocular route.
• gels are generally based on water-soluble polymeric molecules such as polyvinyl alcohol, cellulose derivatives, and acrylic derivatives.
• the emulsions or pseudo-latexes as well as the inserts are not defined as bio-adhesive systems with prolonged release. Their prolonged activity comes from the fact they are maintained in place in the eye in the conjunctival cul-de-sac, which plays in this case the role of storing active ingredients. In this situation, no physical or chemical combination is used with one of the biological components of the eye.
• bio-adhesives are introduced in the form of gel or creams.
• the forms known as bio-adhesives for the oral route could be mostly introduced in the form of tablets or patches.
• the ingredients known as bio-adhesives tested within this application framework are:
• the forms applied locally in the rectal area are generally creams or gels for the treatment of hemorrhoids.
• This route can also be used with the aim of a systemic action of the active ingredients which, administered by oral route, are quickly degraded hepatically.
• the rectal route avoids this problem.
• the invention offers an original concept of viscous liquid compositions intended for the realization of pasty forms having prolonged action and/or release for local applications. These compositions are characterized in that long lasting and/or prolonged action and/or release of the active ingredient is obtained by the in situ formation of a matrix film having reinforced bio-adhesive capacity, more or less viscous and biodegradable.
• the aforementioned reinforced bio-adhesive character is obtained by a complexation reaction of the matrix agent with one of the components of the local secretions or of the mucous membrane, leading, under the effect of a permanent washing of the mucous membranes by the secretions, to an action and/or release, on a period greater than 2 hours, of the active ingredient previously dissolved or dispersed with the aid of a solvent, this action and/or release being changeable by incorporation of appropriate additives.
• the purpose of the present invention is to realize in situ, after application of the preparation, a matrix film having reinforced and biodegradable bio-adhesive capacity, of which the action and/or release of the active ingredient is, as far as possible, independent of the pH and/or independent of the action of the secretions of the mucous membranes, depending on the excipients used to reinforce the solidity of the aforesaid bio-adhesive matrix film.
• the reinforced bio-adhesion is such that it is quasi-instantaneous from the moment of application on the mucous membranes.
• bio-adhesion we mean the capacity that a biological or synthetic substance has to “stick” to a biological or mucous membrane.
• matrix film we mean the formation of a three-dimensional network, more or less solid, more or less thick, and more or less porous, in which is included the active substance.
• biodegradable we mean the degradation of a support generated by a biological mechanism such as the action of enzymes but also by a mechanical erosion mechanism due to the “washing” secretions of the organism.
• washing we mean a repeated passage of a solution on the same support until total exhaustion of the latter.
• This invention is applicable to the preparations intended for the oral mucous membrane, as well as the nasal, vaginal and rectal mucous membranes; and the cornea.
• This invention is based on the fact that certain substances in the solid state or the liquid state have the property to complex with certain molecules of the mucous membranes when they are applied to the latter.
• the matrix agent to the surface of the mucous membranes thus forming a three-dimensional network from which the action and/or from which the active ingredient diffuses gradually over time.
• the substances used are mostly materials of natural origin much used in the pharmaceutical, cosmetic and dietetic field.
• complex we mean the formation of a chemical bond other than the hydrogen bonds encountered with the majority of the other agents known as bio-adhesives. This bond is characterized in that energy is intermediate between the energy of a covalent bond and the energy of a hydrogen bond thus leading to a structure more resistant to the phenomenon of “washing”.
• the invention has as the aim a viscous liquid composition with reinforced bio-adhesive capacity, for a local application in pasty form having prolonged release of an active ingredient, characterized in that it includes at least a matrix agent, a hydration medium of matrix agent and at least one active ingredient.
• bio-adhesive matrix films having prolonged release being the subject of the present invention calls for substances known as matrix agents, which, in contact with the mucous membranes, offer a reinforced bio-adhesive capacity.
• These substances can be used alone and create a viscous film or a more or less solid structure, in which the active ingredient(s) are dissolved or dispersed.
• binder we mean substances acting as cements between the particles of a network with the aim of reinforcing a more or less solid structure.
• these matrix substances avoid the dispersion of the other excipients within the secretions of the organism by their imprisonment in the viscous gangue or the spongy structure formed at the surface of the mucous membrane.
• the action of the aforesaid film or the release of an active ingredient included in such a system can vary between 1 to 48 hours according to the action site of the aforementioned preparation.
• the release time of the active ingredient is between 2 and 12 hours for the oral, nasal, and ocular administration and the release time of the active ingredient is greater than 12 hours for vaginal administration.
• Matrix agents allowing attainment the aforementioned films and playing the role of “binder” belong to the class of the natural polymers, polysaccharides:
• the polysaccharides retained within the framework of this invention are the carrageenans.
• the carrageenans have been known for more than 600 years in the medical field and in the nutritional field in particular for their original property, which consists of gelifying milk by simply heating it.
• They are polysaccharides, polymers of galactose more or less sulfated.
• the carrageenans are extracted from different algae: Chondrus crispus, Gigartina stellata, Gigartina acicularis, Gigartina skottsbergii, Gigartina pistillata, Gigartina chamissoi, Iridea, Eucheuma cottoni, Eucheuma spinosum.
• the proportion of the different sulphates groups and the anhydrogalactose bridge at 3,6 allowed isolation of different types of carrageenans. They are the iota-, kappa-, lambda-, beta-, nu-, and mu-carrageenans.
• the lambda-forms exhibit many sulfurated groups compared to the kappa-forms.
• the iota-forms are intermediate.
• the mu- and nu-forms are in lesser quantities and are considered as impurities decreasing the gelifying effect of the iota- and kappa-forms.
• carrageenans retained for the present invention are the lambda- and the iota-carrageenans.
• the lambda- and the iota-carrageenans offer no syneresis phenomenon.
• Lambda-carrageenans offer no gelifying properties, but thickening.
• the gelifying property develops only if the preparation is subjected to heat.
• these substances will have the possibility of developing bio-adhesive properties like the conventional excipients bio-adhesive such as Carbopol® or carboxymethylcellulose defined as polymers suitable for forming more or less solid three-dimensional networks also.
• bio-adhesive such as Carbopol® or carboxymethylcellulose defined as polymers suitable for forming more or less solid three-dimensional networks also.
• bio-adhesives The conventional bio-adhesive mechanism of the excipients known as bio-adhesives is defined as being an interaction of the aforesaid excipient with mucus covering the mucous membranes of the organism. This mucus is generally highly hydrated and offers a certain viscosity due to the presence of a glycoproteine, mucin.
• bio-adhesives are hygroscopic.
• these polymers expand quickly with the formation of hydrogen bonds between the hydrophilic groups of the polymer and those of the mucus and inter alia those of the mucin. Consequently there is formation of a three-dimensional network from a polymer/mucin interaction.
• the hydrogen bonds are bonds of weak energy. Consequently a dilution of the medium or the constant “washing” of a support will lead to a rapid breaking of these bonds thus decreasing the bio-adhesive character of these excipients.
• the bio-adhesive character is known as “reinforced” because besides the creation of the hydrogen bonds observed with the conventional excipients, other bonds are formed with the support.
• the iota- and lambda-carrageenans possess sulphate groups on the skeleton of the molecule. These chemical groups are very reactive and create complexing reactions with certain molecules having free protons on some of their atoms such as nitrogen and sulphur. Because of the presence of these free protons, N 2+ or S 4+ , anionic groups, such as the sulphate groups of the carrageenans, SO 4 2 ⁇ , react very strongly with these molecules.
• the study is based on the realization of 2 solutions having a defined viscosity of 3000 mPa.
• the viscosity of the solution was not chosen arbitrarily but according to the final mechanical properties of the solution: easily diffusible solution (sprayable).
• the concentrations in agents bio-adhesives are:
• the impregnation of the membrane is effectuated in the 30 seconds before the deposit of the solutions.
• the impregnation of the membrane is such that a liquid film is formed at the surface of the latter thus simulating what occurs in the area of the different mucous: wetness of the mucous membranes.
• the “reinforced” character of the bio-adhesivity is tested by “washing” the deposit with a pH 6.8 buffered medium simulating the different secretions of the organism.
• This apparatus sketches out a back and forth movement from top to bottom at the ratio of 30 per minute and with an amplitude of 12 cm.
• the impregnated membrane is attached to a rigid support (glass plate), itself vertically attached to the lever drawing out the back and forth movement.
• the disintegration apparatus as well as a chronometer are activated when the deposit surplus begins to drain to the inferior part of the membrane.
• liquid-based carrageenan preparations are characterized as Newtonian products that is to say that they flow freely under the effect of only their mass, which is not the case of Carbopol
• these same products are also characterized as thixotropic solutions, that is to say that these aforementioned solutions, having the appearance of a solid at rest, liquefy rapidly, under the effect of an agitation. This property is not observed with Carbopol.
• Hercules in his U.S. Pat. No. 6,358,525 shields different hydroxypropylcellulose and hydrocolloid based compositions such as the carrageenans, in order to slow down the availability of the active substances to the organism.
• the patent application US2004019010 uses the carrageenan gels as substitute for the vitreous humour of the eye during ocular surgeries, such as cataract.
• the vitreous humour is replaced by these gels which, gradually over time, see their viscosity diminished to avoid an excessively strong intra-ocular pressure.
• These gels can be combined with active substances such as anti-inflammatory drugs, antibiotics, etc, which thus avoid any post-operative complications.
• U.S. Pat. No. 5,403,841 shields carrageenans for the ophthalmic application of certain active ingredients.
• a bio-adhesion of the carrageenans is not claimed but, instead, a quasi-instantaneous increase of the viscosity carrageenan-based solution instilled in the eye.
• patent EP424043 clearly refers to the use of the carrageenans to increase the release time of the ingredients in the eye. This result would be due to an increase in the viscosity of the lachrymal liquid by interaction of the carrageenans with the proteins of the tears, the lysozymes among others. In no case is the interaction process described. In fact no mention is made:
• U.S. Pat. No. 6,610,667 shields a composition of which the principal agent of bio-adhesion is alginate and has a lesser degree of other hydrocolloids such as the xanthan gum, galactomananes, glucomananes and carrageenans.
• the application is mainly centered around the combination alginate/gum xanthane or alginate/galactomananes or glucomananes.
• the esophagus is far from being a cavity of easy access from the exterior.
• the international application WO2004/075920 uses the carrageenans as vector of active ingredients in the pulmonary area with the aim of delaying their release.
• the lungs are far from being considered as a cavity in the same fashion as the oral, vaginal, or rectal, cavity therefore far from being easily accessible from the exterior.
• the pulmonary secretions are definitely less substantial than those observed to exit from the salivary or lachrymal glands.
• patent EP1452168 concern cutaneous applications of the carrageenans.
• the patent application US2002071861 makes use of the carrageenans but the bio-adhesive aspect of these preparations is supplied by carboxymethylcellulose, hydroxypropylmethylcellulose and Carbopol®.
• U.S. Pat. No. 6,159,491 makes use of a combination of Carbopol® (Polycarbophil®) with carrageenans and agarose of high purity with the aim of having a release twice.
• Carbopol® Polycarbophil®
• the carrageenans are used as gellants, delaying the release of the active substances and Carbopol® as bio-adhesive.
• the concentration in matrix agent, especially carrageenans, in the medium varies from 0.5% to 30% in relation to the final mass of the preparation.
• the hydrating solvent of the matrix agent can be aqueous or hydro-alcoholic.
• the proportion of the alcoholic phase can vary from 10% to 90% in mass in relation to the total volume of the hydrating phase.
• the alcoholic phase can be embodied by ethylic alcohol and isopropyl alcohol.
• the agents supporting this hydration belong to the class of alkalines and the alkaline-earths. They are inter alia:
• the proportion of alkaline and alkaline-earth ions introducible into the medium varies between 0% to 50% in mass in relation to the total mass of the preparation.
• the aqueous phase used can be buffered to support the stability of the active substances but also the stability of the matrix agent.
• compositions can be as follows:
• the buffer solutions that can be thus used respond to the following compositions:
• the value of the pH of the buffered medium can vary from 5 to 12.
• the present invention is intended for the administration of a certain number of active substances.
• the active substances that can be in such a form belong to certain pharmacological categories, namely analgesics, anti-inflammatories antispasmodics, cytotoxics, antibiotics, antifungals, disinfectants, pesticides, hormones, antivirals, antimigraine agents, anti-allergics, analeptics, respiratory agents, spermicides, anti-hemmorrhoidal agents, vasoconstrictors, vasodilators, antipruritics, uterorelaxants, antiglaucoma agents, mydriatics, antiasthmatics.
• analgesics namely analgesics, anti-inflammatories antispasmodics, cytotoxics, antibiotics, antifungals, disinfectants, pesticides, hormones, antivirals, antimigraine agents, anti-allergics, analeptics, respiratory agents, spermicides, anti-hemmorrhoidal agents, vasoconstrictors, vasodilators,
• These substances can be incorporated in the dissolved state in the aqueous or hydro-alcoholic phase of the preparation subject to the present invention or in the solid state dispersed in the matrix film.
• the proportion of these different solvents, used in these preparations depends on the solubility of the active ingredients and can vary from 1% to 50% in volume in relation to the total volume of the hydrating phase.
• these solvents require the use of surface-active agents to avoid any phase separation between the hydrating phase and the organic solution of actives.
• the surface-active agents usable in the present invention are:
• the surface-active agents can be used to reinforce the bio-adhesive properties of the carrageenans, among them the phospholipides such as the phosphatidylcholine.
• the quantity of these substances used to promote the solubilization or the dispersion of the active ingredients as well as increase the bio-adhesive capacity of the carrageenans can vary from 0 to 50% in weight in relation to the total mass of the excipients.
• the active ingredients can be solubilized in the hydrating phase or in another solvent, these can also be incorporated in the solid state creating a bio-adhesive suspension.
• the active ingredients must satisfy a particle size criterion.
• the granulometric distribution of the powders can spread from 1 ⁇ m to 1000 ⁇ m, preferably ranging between 1 ⁇ m and 250 ⁇ m.
• the carrageenans created a viscous film, of gelatinous appearance and of soft to firm consistency according to the concentration.
• a reinforcement of this structure can be effectuated by introduction into the medium substances that, with contact with the secretions, are going to increase the solidity of this network.
• starches have been retained, in particular their derivatives, because they are products that are more or less soluble in the hydration medium that reinforce the matrix structure of the carrageenans with the aid of their aptitude to form viscous networks in contact with the water.
• These different structuring agents can be obtained from starches of wheat, rice, corn, manioc and potato.
• the quantities used in order to obtain an action and/or a release of the active ingredient between 2 and 48 hours can vary from 0 to 50% in mass in relation to the total mass of the preparation
• the particle size of the starches and modified starches making such results attainable must range between 1 ⁇ m and 1000 ⁇ m with a preference for a size ranging between 1 ⁇ m and 100 ⁇ m.
• Preservation additives and dyes can be introduced into the composition.
• the proportion of preservative can vary from 0% to 10% in mass in relation to the total mass of the preparation.
• the dyes can be water-soluble or fixed on alumina lacquer or another support.
• the optimum percentage of required dye ranges between 0.01% and 5% in mass in relation to the total mass of the preparation.
• moistening products can be added to the bio-adhesive medium.
• moisture we mean substances that bring a certain moisture to the medium in which they are present by way of their intrinsic hygroscopic properties, namely fixation of the moisture of the surrounding atmosphere moisture.
• polyols such as glycerin, sorbitol, maltitol, xylitol, mannitol, etc.
• compositions being intended, among other things, to be applied to the oral mucous membrane, flavors as well as sweetening substances can be added in the bio-adhesive medium.
• the flavors can be of natural or synthetic origin same as the sweetening substances.
• saccharose conventionally used as a sweetening substance
• aspartame acesulfam
• sodium saccharin sodium cyclamate
• sweetening agents Besides saccharose conventionally used as a sweetening substance, aspartame, acesulfam, sodium saccharin and sodium cyclamate can be retained as sweetening agents.
• the concentration in the medium can vary from 0.1% to 30% in mass in relation to the total mass of the preparation.
• solutions or suspensions thus realized, creating in situ matrix systems with prolonged release, have viscosities going from 100 mPa and 500,000 mPa.
• Such systems after application, lead to an action and/or the progressive release of the active ingredient over a period that can go from 1 hour to 48 hours, this kinetic release being little or not dependent on surrounding biological factors.
• This dissolution kinetic can be of the order of zero or 1 depending on the type of excipients used to obtain such a release.
• these same systems are of interest from a mechanical standpoint and, inter alia, regarding the lubrication of the mucous membranes when these are subject to dryness, such as oral dryness in the oligoptyalism, vaginal dryness, nasal dryness and corneal dryness in the case of Sjôgren disease.
• Lambda-carrageenans 2.50% Miconazole 2.00% Pre-gelatinized starch 2.50% Polysorbate 20 2.00% Sodium methyl parahydroxybenzoate 0.08% Sodium propyl parahydroxybenzoate 0.02% Ethanol with 96% V/V 1.50% Demineralized water 89.40%

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• 2004
  • 2004-10-20 FR FR0411156A patent/FR2876581B1/fr not_active Expired - Fee Related
• 2005
  • 2005-10-19 PT PT05815499T patent/PT1807114E/pt unknown
  • 2005-10-19 AT AT05815499T patent/ATE403441T1/de not_active IP Right Cessation
  • 2005-10-19 WO PCT/FR2005/050869 patent/WO2006043005A2/fr active IP Right Grant
  • 2005-10-19 AU AU2005297009A patent/AU2005297009A1/en not_active Abandoned
  • 2005-10-19 EP EP05815499A patent/EP1807114B1/fr active Active
  • 2005-10-19 JP JP2007537351A patent/JP5979466B2/ja active Active
  • 2005-10-19 US US11/577,503 patent/US20080274191A1/en not_active Abandoned
  • 2005-10-19 CN CN2005800439056A patent/CN101084017B/zh active Active
  • 2005-10-19 PL PL05815499T patent/PL1807114T3/pl unknown
  • 2005-10-19 ES ES05815499T patent/ES2314738T3/es active Active
  • 2005-10-19 DE DE602005008760T patent/DE602005008760D1/de active Active
• 2016
  • 2016-04-22 US US15/136,446 patent/US10646435B2/en active Active

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