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
  • A61K31/74—Synthetic polymeric materials
  • A61K31/765—Polymers containing oxygen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the purpose of the present invention is to create a new surface anaesthetic which has a low toxicity.
• injectable local anaesthetics as surface anaesthetics.
• examples of such are procaine, tetracaine, hostacaine, lidocaine and carbocaine.
• the last-mentioned compound has the following formula:
• R designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms
• R designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms, R and R, then together having not more than three carbon atoms, and
• R R are chosen among hydrogen groups, alkyl groups with a maximum of two carbon atoms, R R then together having not more than four carbon atoms.
• a common characteristic. for the said injectable local anaesthetics is that they are toxic to a certain extent. When they are to be used as surface anaesthetics on for instance skin and mucous membranes, it can sometimes occur that they are to be used on large surfaces, and large quantities will then be required. It is then desirable that the concentration of the local anaesthetic is kept as low as possible with consideration to the toxicity. This involves that the duration is reduced considerably and in many cases does not attain the value required. It is thus a desire to be able to increase the duration while maintaining a low toxicity. It is, consequently, the toxicity which sets the upper limit for the duration of the injectable local anaesthetic. It is not advisable to use concentrations of more than 4% with consideration to the toxicity.
• n has a value lying between 4 and 16 or preferably between 6 and 14.
• the said compound has very little toxicity but iias the disadvantage that the depth of this anaesthetic is not satisfactory.
• the compound should not be used in concentrations higher than 6%, as otherwise dermatological secondary etfects can occur. In most cases it is recommendable not to use concentrations lower than 2%. It is not advisable to exceed a molecular weight of 800 and not even to set a lower limit for the molecular weight than 500.
• An appropriate relation between the number of carbon atoms in the group R and the number of oxyethyl groups is about 4-3.
• Tests have now shown that if, when using surface anaesthetics, an injectable local anaesthetic or its salt are combined in a concentration which keeps the toxicity within permissible limits with a surface anaesthetic according to the last-mentioned formula and in a concentration which does not give rise to any secondary effects, a surface anaesthetic is obtained with an effect which exceeds the total effect of the two preparations. Tests have also shown that if an injectable local anaesthetic is chosen in a concentration which does not cause surface anaesthesia and this is combined with a surface anaesthetic of the abovementioned formula, the combination preparation obtains an effect which as regards the toxicity is considerably higher than that of the said surface anaesthetic.
• the combination preparation formed is to be regarded as a mixture of the said injectable local anaesthetic and the said surface anaesthetic.
• the two parts which have been mixed can be dissolved in an appropriate solvent, for instance water, or can be mixed into an appropriate carrier so that an ointment, a gel or a tablet is obtained.
• Concentrations of the components of the combination preparation can of course be varied within wide limits on the condition that the toxicity of the combination preparation does not amount to such values that the preparation is not appropriate as a surface anaesthetic.
• Example 1 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6- dimethyl anilide in a pulverized form and 0.25 g. of hydroxy ethoxy polyethoxy dodecane in the form of an oil and with a molecular weight of approx. 600 are dissolved in g. of distilled water with an isotonic addition of salt.
• the said mixture has the character of a liquid. If 0.25 ml. of the said liquid is placed on a rabbit cornea a duration of approx. 20 minutes is obtained.
• a 0.25% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 when applied to a rabbit cornea in a quantity of 0.25
• a concentration of 0.25% hydroxy ethoxy polyethoxy dodecane when applied to a rabbit cornea and in a quantity of 0.25 ml. gives a duration of 10 minutes.
• Example 2 If in Example 1, 0.25 g. of 1-methyl-2-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.50 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea gives a duration of 21.2 minutes. A 0.50% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 in a rabbit cornea.
• Example 3 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.25 g. of w-diethyl amino-2,6-dimethyl acetanilide, a combination preparation is obtained which in a rabbit cornea gives a duration of 18.9 minutes. A 0.25% solution of w-diethyl amino-2,6-dimethyl acetanilide gives a duration of 0 in a rabbit cornea test.
• Example 4 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.10 g. of 2-diethyl aminoethyl ester of p-aminobenzoic acid a combination preparation is obtainedwhich in a rabbit cornea test gives a duration of 18.4 minutes. A 0.1% solution of the said ester gives a duration of in a rabbit cornea test.
• Example 5 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy benzene a combination preparation is obtained which in a rabbit cornea test gives a duration of 14.5 minutes. A potentiation is obtained as the anaesthetics alone only give durations of 0 and 6.5 minutes, respectively.
• Example 6 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy octenyl dirnethyl benzene, a combination preparation is obtained which in a rabbit cornea test gives a duration of 15.3 minutes. A concentration of 0.25% of hydroxy ethoxy polyethoxy octenyl dimethyl benzene gives a duration of only 4.5 minutes in the same test.
• Example 7 If in Example 1 the injectable local anaesthetic is replaced by 01 g. of (1-cyclopentyl-2-piperidine carboxylic acid)2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea test gives a duration of 23.5 minutes. A potentiation is obtained as the anaesthetics individually give durations of only 3.0 and 6.5 minutes, respectively.
• Example 8 If in Example 1 the injectable local anaesthetic is replaced by 0.1 g. of (1-methyl-5-ethyl-2-piperidine carboxylic acid)2,4,6-trimethyl anilide, a combination preparation is obtained which in a cornea test gives a duration of 21.0 minutes. A potentiation is obtained, as the an aesthetics individually only give durations of 0 and 6.5 minutes, respectively.
• a surface active anesthetic composition comprising a member of the group consisting of injectable local anesthetics and salts thereof and a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
• R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms
• R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms;
• R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R does not exceed 4 carbon atoms.
• Method of producing surface active anmthetic compositions of low toxicity which comprises mixing a member of the group consisting of injectable local anesthetics and salts thereof with a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
• the local anesthetic is a member of the group consisting of lmethyLZ-Piperidine carboxylic acid-2,6-dimethyl anilide, (l-cyclo-pentyl-Z- iperidine car-boxylic acid)2,6-dimethyl anilide, (1-methyl-5-ethyl-2-piperidine carboxylic acid)- 2,4,6-trirnethyl anilide, w-diethyl amino-2,6-dimethyl acetanilide and Z-diethyl aminoethyl ester of p-amino benzoic acid.
• R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms
• R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms;
• R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R does not exceed 4 carbon atoms.

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

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Citations (3)

• 0
  • GB GB889225D patent/GB889225A/en active Active
• 1959
  • 1959-07-01 SE SE6204/59A patent/SE306139B/xx unknown
• 1960
  • 1960-06-27 DE DEA34981A patent/DE1299796B/de active Pending
  • 1960-06-28 US US39211A patent/US3038835A/en not_active Expired - Lifetime
  • 1960-06-29 FR FR831499A patent/FR13M/fr not_active Expired

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