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
  • A61K9/0053—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
  • 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
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a composition for the treatment of hypoptyalism comprising pilocarpine.
• This composition has direct multiple effects in the buccopharyngeal cavity.
• Radiotherapy is one of the main treatments in the case of cancers of the ORL cavity that leads to significant undesirable effects.
• the origins of the hypoptyalism can be broken down into:
• the origins of the hypoptyalism can be broken down into:
• pilocarpine that is an alkaloid extract from the leaves of pilocarpus of the different varieties jaborandi, pennatifolius, and microphyllus is known.
• the pilocarpine of composition C 11 H 16 N 2 O 2 is a liquid that is oily, viscous, and sensitive to light and that exhibits an amphiphilic nature that allows dissolution both in water and much more easily in a solvent or a composition of organic solvents.
• This parasympathomimetic active ingredient stimulates the secretions of the exocrine glands and therefore the secretions of the salivary glands and the sweat glands.
• the Jaborandi dye is obsolete and never received marketing approval because it is impossible to determine with precision the content of active ingredient. Moreover, as for any dye, other elements or components or substances that are exogenic and that are not the object of any study will be found to be present. The stability of the product and the preservation methods can also be discussed.
• pilocarpine is known as an active ingredient in oral form and medicines are currently marketed.
• the dose is 5 mg of pilocarpine per tablet to be administered 3 ⁇ per day, or 15 mg of pilocarpine per day, and even up to 30 mg per day for certain more severe cases.
• this taking of large doses conducted over several weeks is at the origin of significant undesirable secondary effects such as nausea, excessive sweating, sensations of dizziness, hot flashes or asthenias.
• a primary consequence of the oral method is the passage through the digestive tract that leads to variable absorption and bioavailability because the first hepatic passage subjects the active ingredient to a significant degradation in the form of metabolites that no longer have pharmacological activities. It is therefore necessary to provide an overdosage so that the effect of the existing portion reaches the oral and submaxillary activity zones.
• Another consequence is a delayed effect of the active ingredient since the first action of the pilocarpine is exerted only with a delay of 0.45 to 1 hour after intake.
• composition that includes the pilocarpine according to this invention makes it possible to greatly limit the secondary effects that are linked to an absorption by an oral path, improves the dose/effect ratio and imparts a strong improvement of the bioavailability.
• composition according to this invention consists in administering pilocarpine in basic form or in the form of salts, chlorohydrate or nitrate, in a specific galenical form of a tablet with sublingual usage with slow disintegration allowing it:
• the pilocarpine is combined with at least one bioadhesive polymer, at least one buffer, and at least one lubricant.
• a softener and a hydrophilic substance can be combined with these agents, and the formulation in tablet form can provide dimensions that can prevent the act of swallowing and the direct passage to the digestive tract.
• a formulation example of a tablet for sublingual use is:
• pilocarpine that is basic or in salt form 2.5 mg magnesium stearate: 10.0 mg sodium or disodium hydrogen phosphate: 90.0 mg K 100 methocel: 50.0 mg 6 000 polyethylene glycol: 40.0 mg hyaluronic acid: 20.0 mg lysozyme chlorohydrate: 15.0 mg compressed sorbitol qsp for 1000 mg: 772.5 mg
• the pH buffer with a sodium or disodium hydrogen phosphate base can be replaced by sodium carbonate or sodium bicarbonate.
• Magnesium stearate is a lubricant that is suitable for the production of tablets, and PEG, in addition to its lubricating properties, is hydrophilic, imparting a softening effect to the composition.
• the family of cellulose derivatives comprises in particular:
• Polymers that are suitable for this application comprise:
• the lysozyme chlorohydrate can advantageously be added so as to compensate for the deficit of physiological salivary lysozyme in the case of the hypoptyalism.
• the dosage can be adapted but a range of proportions is between 5 and 30 mg for a 1000 mg tablet.
• Another element for better use of the pilocarpine in the local application according to this invention is the use of a mass substrate that has low molecular weight and is preferably hygroscopic.
• composition according to this invention leads to positive consequences that are now listed.
• the pilocarpine creates a first direct effect because it is immobilized upon direct contact of the muscarine-like receptors that are present within various salivary gland structures, endobuccal submucous glands and submaxillary glands.
• the pilocarpine thus kept in contact, is well-enough dissolved and bioavailable to be absorbed through the phospholipid structures of the walls of the cells of the stratified epithelium of the mucous membrane.
• This first effect that is obtained is direct but not only does the pilocarpine access the saliva production groups, but it also passes partly into the sublinqual and perlingual venous microvascularization.
• the pilocarpine is found distributed in several minutes to submaxillary glandular bundles, which constitutes a second action that is slightly offset over time and arises from a different mechanism.
• This formulation thus makes it possible to avoid the passage through the liver and the associated metabolization.
• the amount can be reduced and the dose/effect ratio is greatly increased.
• the dose reduction induces a potential economy of secondary effects.
• the effective concentration thresholds of the composition according to this invention are much lower and often less than the triggering thresholds on the digestive, cardiovascular or urinary level and the thresholds for creating excessive sweating, hot flashes or nausea.
• the pilocarpine remaining circulating in the arterial path necessarily in a very small amount, it always rejoins the hepatic system via the hepatic artery and is ultimately metabolized. This makes it possible to comply with the detoxification metabolism.
• the treatment with small doses and a perfectly stable formulation also makes it possible to use a very adjustable dosage, more specifically adapted to each patient based on requirements that are often very variable, with values adjusted to nearly 0.5 mg.
• Such a formulation thus allows an intake of pilocarpine in a permanent manner because the side effects are reduced.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Physiology (AREA)
• Nutrition Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Microbiology (AREA)
• Biotechnology (AREA)
• Botany (AREA)
• Medical Informatics (AREA)
• Alternative & Traditional Medicine (AREA)
• Mycology (AREA)
• Natural Medicines & Medicinal Plants (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Hydrogenated Pyridines (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Citations (4)

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• 2004
  • 2004-01-09 FR FR0450050A patent/FR2864901B1/fr not_active Expired - Fee Related
• 2005
  • 2005-01-07 PL PL05717659T patent/PL1701721T3/pl unknown
  • 2005-01-07 EP EP20050717659 patent/EP1701721B1/fr not_active Not-in-force
  • 2005-01-07 US US10/585,335 patent/US20080241120A1/en not_active Abandoned
  • 2005-01-07 DK DK05717659T patent/DK1701721T3/da active
  • 2005-01-07 SI SI200530909T patent/SI1701721T1/sl unknown
  • 2005-01-07 PT PT05717659T patent/PT1701721E/pt unknown
  • 2005-01-07 WO PCT/FR2005/050012 patent/WO2005067924A1/fr active Application Filing
  • 2005-01-07 ES ES05717659T patent/ES2336578T3/es active Active
  • 2005-01-07 DE DE200560018159 patent/DE602005018159D1/de active Active
  • 2005-01-07 AT AT05717659T patent/ATE451101T1/de active
• 2011
  • 2011-08-12 US US13/208,556 patent/US9119775B2/en not_active Expired - Fee Related

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