Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
• • 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
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1258—Pills, tablets, lozenges
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• the compounds to be used to attain the above described new and unexpected result are represented by three derivatives of cyclohexanol, namely by the sodium salt of cyclohexanol succinate, by cyclohexanol palmitate, and cyclohexanol stearate.
• the rats were submitted to a total radiation of 600 R. administered in one treatment only, and with the following values: 200 kv., l8 ma., filter 0.5 cu., dpf 50 cm., r./m. 57.5.
• the tests were carried out on three rat groups, each formed by ten. rats, having an average Weight of 200 gr. per rat.
• the first of said groups was treated with peritoneally administered doses of sodium cyclohexanol succinate amounting to 300 mg. per kg.; the second group was treated, over a five consecutive day period, with a dose of 300 mg./kg., while the third group was treated with physiological solution (control group).
• the mode of administering the products to patients was as follows:
• Tablets.-Two tablets of active product 250 mg. each) at intervals of 6 hours, (total dose per day: 2 g.). The administration was always effected in the course of 24 hrs. preceding radiation treatment.
• This daily dose was maintained during the whole course of radium-therapy and sometimes even for longer periods to act also on the restoration phaenomena of the tumor cells.
• Phials.l g. of active product was intramuscularly administered on the day preceding the radiation treatment, and one phial (l g.) directly before said treatment or, in the case of radium therapy, a phail daily during the whole treatment. Phails were used also for intraand peritumoral infiltrations, directly before radium therapy, or for cases which required a quicker and more intense action.
• the products with which the invention is concerned may be considered valuable therapeutic aids since for a given therapeutic effect they allow the use of lesser amounts of radiating energy, with consequent lesser damage to the connective tissues of the tumor bed and furthermore they render radiation-resistant forms of cancer capable of being treated and improved by usual radiation treatments.
• cyclohexanol derivatives with which the invention is concerned appear suitable as potentiating agents in the radiotherapy of epitheliomas as well as for decreasing or minimizing radioresistance which arises in cases of recurrence after a first actinic treatment.
• the method by which the sodium cyclohexanol succinate (this being the preferred product) can be obtained consists of having succinic anhydride reacted with cyclohexanol alcohol, thereby obtaining the cyclohexanolsuccinic acid which is then reacted with sodium hydroxide.
• the cyclohexilic acid is to be gradually added in stoichiometric amounts to the succinic anhydride under rather mild temperature conditions (i.e. about 110 C.), whereafter the reaction product is extracted with water and benzene, avoiding any treatment with acids or bases which, owing to the extreme facility with which the cyclohexanol succinic acid is saponified, would unavoidably result in the formation of undesirable products.
• the final crystallization is preferably carried out from ligroin.
• the above method allows to obtain a product (melting point 50-51 C.) which shows a practically theoretical centesimal content of carbon-hydrogen and which can be converted into a salt with an accurate equivalent amount of sodium hydroxide, using phenolphthalein as indicator.
• the corresponding sodium salt was obtained by adding at room temperature an accurate equivalent of sodium hydroxide to an alcoholic solution of the acid, whereupon the resulting solution was concentrated to dryness under vacuum. Since, as already stated, the thus-obtained substance is rather sensitive with respect to acids and alkaline agents the solution is preferably adjusted to a pH value lower than 8 prior to being concentrated.
• the pulverized sodium salt is repeatedly washed with acetone.
• the final product is obtained in the form of a white powder, ve-ry soluble in water, soluble in alcohol at 90 C., and insoluble in the usual organic solvents.
• the product can be further purified by dissolving it in alcohol at 90 0., followed by precipitation with ether. Melting point: 178-l80 C.
• the aqueous solutions of said product after an adjustment of pHvalue to 7.2 by means of citric acid or phosphoric acid, do not undergo any changes as consequence of heating at 110 C. for a period of one hour.
• the methods for preparing the cyclohexanol derivatives will be disclosed in more detail in the following examples, of which the first one relates to the preparation of a high purity cyclohexanol succinic acid, the second relates to the conversion thereof into a sodium salt, the third to the preparation of cyclohexanol palmitate, and the fourth to the preparation of cyclohexanol stearate.
• Example I g. of succinic anhydride were put into a three-necked, round bottomed fiask, equipped with a cooler, a stirrer and a separating funnel, and heated up to melting temperature (120 C.). Then 50 g. of cyclohexanolic acid were gradually added, while stirring and keeping the inside temperature of the flask at 100-110 C. After the end of such addition, the reaction mass was kept for about half an hour at 100 C., and then cooled. Subseqeuntly the mass was alternately taken up with equal volumes of water and benzene, until the entire substance was dissolved. The benzene layer, dehydrated with sodium sulphate, was evaporated to dryness, and the residue was taken up in boiling ligroin.
• the ligroin solution was filtered, and after cooling, the separated crystals were collected on a filter, under vacuum.
• Example 2 50 g. of cyclohexanolsuccinic acid, obtained according to Example 1, were dissolved in 200 cc. of abs. ethyl alcohol, and then added to an equivalent amount (10 g.) of sodium hydroxide in the form of a concentrated aqueous solution. The resulting solution was evaporated under vacuum to dryness, and the residue, consistingof a white mass, was pulverized and repeatedly washed with acetone.
• Example 3 200 cc. anhydride pyridine and 20 g. cyclohexanol (2 moles) were poured in a 500 cc. flask equipped with a stirrer. To the thus obtained solution were added under stirring g. (0.2 mole) of palmitoil chloride. The addition has to be effected slowly since the reaction is of strongly exothermic nature. Thereafter the reactive mixture was kept at room temperature for 36 hours. -On completion of the reaction the reaction mixture was introduced drop by drop through a separating funnel into 700 cc. of strongly agitated cold water.
• the precipitate was filtered under vacuum, washed with a great amount of Water and then dried under vacuum.
• the product obtained melts at 30.5-320 C. and can contain up to 9% of palmitic acid. It crystallizes from alcohol (7 volumes) with a -82% yield. Melting point 33.5-34.5 C. Free palmitic acid being absent.
• Example 4 To 300 cc. of anhydrous pyridine containing 40 g. (0.4 mole) cyclohexanol were added through a separating funnel under stirring 121 g. (0.4 mole) stearoyl chloride strong heating occurs and the mixture becomes yellow. After this addition, the reaction vessel was closed and kept at room temperature for 36 hours. Then the reaction mixture was poured under strong agitation into 1500 cc. of very cold water. The precipitate was filtred under vacuum and repeatedly washed with a cold 4% solution of bicarbonate, then with a great amount of cold water until the alkalinity disappeared. Then it was dried under vacuum. The dried product (-140 g.) was free from free stc-aric acid. Melting point: 37-38 C.
• a method of enhancing the effect of X-ray and radium treatment of a patient which comprises first administering to said patient an effective amount of sodium cyclohexanol succinate, and thereafter subjecting said patient to X-ray or radium treatment, whereby the eifect of the X-ray or radium treatment is enhanced by the preceding administration of said sodium cyclohexanol succinate.

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Cited By (6)

• 1963
  • 1963-04-03 FR FR7719A patent/FR2625M/fr not_active Expired
  • 1963-04-03 US US270189A patent/US3265574A/en not_active Expired - Lifetime

Non-Patent Citations (1)

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