Classifications

• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
  • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
• • 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
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
  • A61K9/0058—Chewing gums

Definitions

• the present invention relates to novel pharmaceutical compositions for suppressing pain and hyperthermia and a method for preparing them.
• analgesic and antipyretic pharmaceutical compositions intended to be sucked or to be chewed and the disintegration of which is prolonged.
• compositions intended for the oral route in the form of tablets or sucking tablets or chewing gums, characterized in that they contain, as active ingredient, lysine etylsalicylate in combination or in mixture with one or more excipients or diluents suitable for producing a pharmaceutical form capable of being sucked or chewed.
• the pharmaceutical compositions according to the invention are in the form of tablets or tablets, the disintegration of which in the oral cavity is progressive and prolonged.
• buffering agents such as for example urea or glycine, non-reactive flavoring and bulking agents such as mannitol or sorbitol, adhesion agents with low dissolution rate such as alkylcelluloses, for example methyl cellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose, or copolymers of acrylic acid or methacrylic acid, binding agents such as polyvinyl-pyrrolidone, gum arabic, guar, adraganth or karaya, inert diluents such as lactose, calcium carbonate, phosphate magnesium or calcium sulfate, skim milk powder, sodium caseinate, sweetening agents such as calcium saccharinate, ammonium cyclamate, ammonium glycyrrhizinate or aspartame, lubricating agents such as magnesium stea
• the active ingredient is lysine acetylsalicylate. It can be DL-lysine acetylsalicylate or L-lysine or D-lysine acetylsalicylate. Preferably, the product used is DL-lysine or L-lysine acetylsalicylate.
• Lysine acetylsalicylate is presented as a fine white, hygroscopic crystalline powder, easily soluble in water, very slightly soluble in alcohol and in ether.
• DL-lysine acetylsalicylate melts at around 199 ° C (instant melting).
• lysine mono-acetylsalicylate described in French patent 1,295,304 has a melting point determined in the Maquenne block of 154-166 °. It is a fairly unstable active principle which combines in its olecule a weak acid easily hydrolyzed and a basic amino acid capable of causing undesirable chemical reactions.
• compositions of a buffering agent such as glycine which is able to avoid hydrolysis reactions of the acetyl group. It has actually been found that compression of lysine acetylsalicylate tablets without a buffering agent leads to the formation of -N-acetyllysine, of -N-acetyllysine and -diacetyllysine. This reaction is of the autocatalytic type. The presence of a buffering agent is likely to avoid or to stop this reaction.
• a buffering agent such as glycine
• lysine carries the risk of a Maillard reaction with sugars present in the formulation leading to strongly colored products, most often brown. It is therefore necessary to carry out the formulation without the addition of reducing sugars such as glucose, capable of reacting with lysine and of replacing them either with non-reducing sugars, that is to say, having no free aldehyde function. , or by glucitols such as inositol, mannit ⁇ l, sorbitol or dulatol which are not liable to react with the amino function of lysine.
• the pharmaceutical compositions according to the invention are intended to produce a form which gradually releases this active principle in the oral cavity where it is almost completely absorbed. A more effective antipyretic and analgesic pharmaceutical form is thus produced, since it ensures higher measured salicylic acid blood levels than by the usual compositions.
• the pharmaceutical compositions according to the invention contain a quantity of lysine acetylsali cylate calculated as acetylsalicylic acid varying from 200 to 600 mg per unit dose, ie from 360 to 1080 mg of lysine acetylsalicylate.
• the dose of lysine acetylsalicylate calculated as acetylsalicylic acid varies from 250 to 500 mg, or 630 mg to 810 mg of lysine acetylsalicylate.
• the invention also relates to a process for preparing the pharmaceutical compositions according to the invention in which the active principle is mixed or combined with one or more diluents, excipients, adhesion agents, buffering agents, bulking agents, lubricating agents and / or flavoring agents for producing a pharmaceutical form capable of being chewed, such as tablets, tablets or gums.
• This preparation is carried out according to the usual methods of pharmacotechnology.
• sorbitol for direct compression marketed under the name NEOSORB 60 .. 660 g
• Palatinite is the trademark to designate an equi mixture of isomers of -D-glucopyranosi to 1,6 mannitol and -D-glucopyranosi to 1,6-glucitol crystallized with 2 molecules of ea.
• EXAMPLE II SUGAR TABLETS
• polyvinylpyrrolidone of PM greater than 30,000 ........ briefly 20 g
• hydroxypropylcellulose having a determined viscosity at 20 ° C.
• a 2% aqueous solution of 2,080 centipoises and a particle diameter of less than 0.25 mm 15 g of a copolymer of acrylic acid sold on the market under the brand Carbopol 934 (product essentially consisting of a copolymer of acrylic acid and allylsaccharose), 110 g of tricalcium phosphate, 140 g of palatinite and 725 g of acetylsali cylys lysine.
• 5 g of magnesium stearate and 15 g of talc and mint essence are added.
• the powder is sieved and then compressed by direct compression into tablets having a diameter of 10 mm, a thickness of 1.1 mm, a weight of approximately 1,100 mg and a hardness of 5.6 kg.
• the amount of lysine acetylsalicylate increases with contact time in a quasi-linear fashion.
• Salicylemia is determined on a batch of healthy volunteers absorbing a solution prepared with 900 mg of commercial lysine acetylsalicylate dissolved in 90 ml of water. Each subject maintains the solution for 4 minutes in his oral cavity. The dosage of lasalicylemia is practiced ten minutes later. It shows a rate of 4 mg / l. This rate is therefore very low.
• the determination of salicylemia is practiced after ingestion of the tablets according to the invention. Subjects keep the tablets in the mouth for 4 minutes. Salicylemia is determined ten minutes and then 30 minutes after administration. The values obtained are more than ten times higher than those obtained after injection of the lysine acetylsalicylate solution.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Zoology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1987
  • 1987-03-04 FR FR8702939A patent/FR2611501B1/fr not_active Expired - Lifetime
• 1988
  • 1988-03-04 WO PCT/FR1988/000127 patent/WO1988006449A1/fr not_active Ceased
  • 1988-03-04 ZA ZA881571A patent/ZA881571B/xx unknown
  • 1988-03-04 EP EP88902497A patent/EP0305464A1/de not_active Ceased
• 1989
  • 1989-07-20 US US07/383,027 patent/US4988683A/en not_active Expired - Fee Related

Non-Patent Citations (1)

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