2,408,289 Patented Sept. 24, 1946 UNITED STATES PATENT orrlcs BARBITURIC ACID COMPOSITIONS Milton '1‘. Bush, Nashville, Tenn., assi'gnor to Mallinckrodt. Chemical Works, St. Louis, Mo., a corporation of Missouri - No Drawing. Application‘ July 17, 1942,. Serial No. 451,311 4' Claims. (Cl. 167-52) . 1 2 , , the desired hypnosis or anaesthesia without irri This invention relates to. barbituric acid com tation. They can be sterilized and kept for long positions, and more particularlyto non-aqueous periods of time without loss of activity. _ solutions of barbituric acids suitable .for paren The solutions of the present invention comprise terai administration. barbituric acids dissolved in a non-aqueous sol; Among the. objects of this. invention arev the vent. The organic solvents employed must act provisionv of barbituric acid solutions of the type as such for the barbituric acid. or acids utilized‘; indicated which are stable, non-alkaline and non‘ that- is, the barbituric acids must be soluble to irritating; the provision of barbituric acid- solu produce the required concentration of hypnotic tions which. may be. utilized for intramuscular injections; and the provision of stable barbituric 10 or anaesthetic component in the organic solvent; The solubility of the barbituric acid in the or acid solutions which may be administered orally ganic solvent must not be substantially less than or intravenously, as well as intramuscularly. 10% and preferably is at least 30%. The-re isno Other objectswill be in part obvious and in part upper limit for this solubility. pointed out hereinafter. The invention accordingly comprises the in 15 Moreover, the solvent itself must not be too soluble in or be miscible with water. Solubilities gredients and combinations of ingredients, the of the organic solvents in water of the order of proportions thereof, and features of composition, 10% are, for example, satisfactory, and may be which will be exempli?ed in the products herein even higher without unduly detracting from the after described, and the scope of the application of which will be indicated in the following claims. 20 effectiveness ,of the barbituric acid. Zero is the lower limit for this solubility. If the solvent possesses too great a solubility in water the effectiveness of the resulting barbi they are customarily employed in the form of turic acid composition is markedly decreased. strongly alkaline aqueous solutions of their so dium or other salts. These solutions are gen 25 Solubilities as high as 15% of the organic solvent in water are permissible. The preferred type of erally unstable, must be prepared fresh from solvent, however, has a solubility in water of previously sterilized components and decompose approximately 10% or less. rapidly on heating- Moreover, they are very Typical of the solvents which may be em irritating to human tissue due both to their alka-‘ ployed are paraldehyde, triacetin, and olive oil, linity and the osmotic effect that such hypertonic although other organic solvents possessing the solutions produce and consequently their use is requisite low solubility in water and having a pH strictly limited to oral or intravenous adminis value in aqueous solution of substantially 7 may tration. a be substituted. 1 In many instances it is impossible to admin A wide range of barbituric acids may be uti ister these barbituric acids either orally or intra lized. as the active hypnotic or anaesthetic agent venously. For example, where the patient is suf in the instant compositions. For example: fering from shock, or where there is little time to carry out the operation, it may be difficult to 1-methyl-5-allyl-5-isopropyl ?nd the patient’s veins. The veins collapse in 5-ethyl-5-n-butyl 40 shock and are, therefore, difficult to locate, while K 5-.allyl-5-isopropyl Barbituric acids are useful as hypnotics and anaesthetics. When administered by injection if the administration is to be carried out on a battle?eld or under other difficult conditions, it 5-ethyl-5 -sec-butyl may likewise be hard to quickly determine the position of the patient’s veins. It may be impos sible to attempt oral administration due to the failure of the patient to cooperate or to many. other conditions. On the other hand, the intra muscular route is always available and it would be possible to utilize these barbituric acids if 1 -methyl-5-ethyl-5- ( l-methylbutyl) 5-allyl-5- ( l -methylbutyl) Barbituric acids have been utilized either alone solutions suitable for intramuscular injection ' were obtainable. According to the present invention, solutions of the barbituric acids are provided. These solu tions can be injected intramuscularly without detrimental effect upon the patient, producing 5-ethyl-5 - ( l-methylbutyl) or in combination with each other or with other hypnotics. All of the compositions listed above possess suf?cient solubility in paraldehyde and triacetin, for example, to enable the injection intramuscularly of effective hypnotic and/0r anaesthetic doses without the utilization of det rimentally large quantities of solution. In general it is desirable to inject only a small volume of solution so the solubility and neces~ 2,408,289 3 sary dosage will usually as a practical matter de—, termine suitable combinations for use. Likewise, where the solution is injected intramuscularly, a barbituric acid is preferably selected which is not too rapidly inactivated in vivo so that there may be the required time for absorption before inactivation. The preferred barbituric acids are 5-al1yl-5-(l-methyl-butyl) barbituric acid, 1 methyl-57allyl-5-isopropyl barbituric acid, and N-methyl-5 -ethyl-5- (1 -methylbuty1) barbituric 4 Although the barbituric acid solutions of the present invention are of especial value for intra muscular injection, they may also be injected intravenously. If such an injection is made with the usual slowness, no detrimental symptoms are encountered. As indicated above, two or more of the barbi turic acids may be used in the same solution or one or more of such acids may be used in a so 10 lution with another narcotic, hynotic or anaes acid. thetic, such as morphine, dilaudid, etc. It has been found that the median fatal dose In view of the above, it will be seen that the and the median anaesthetic dose on intramuscu several objects of the invention are achieved and lar or intravenous injection of the solutions of other advantageous results attained. the present invention in concentrations of the‘ 15 As many changes could be made in the above order of, for example, 250 mg./m1. are very close products without‘ departing from the scope of to the corresponding doses required of the cus the invention, it is intended that all matter con tomarily employed 10% aqueous solutions of the 'tained in the above description shall be inter sodium salt of the corresponding barbituric acid. preted as illustrative and not in a limiting sense. The organic solvent employed must not itself 20 I claim: be toxic or irritating to human beings. Paral 1. A hypnotic composition for intramuscular injection comprising a solution of a barbituric acid dehyde is an instance of a solvent which is not in paraldehyde. toxic and has even been employed as a hypnotic. 2. A hypnotic composition for intramuscular However, its hypnotic activity is only a fraction ' (about 1&0 or 1a,) that of allyl-(l-methylbutyl) 25 injection comprising a solution of 5-allyl-5-(l methylbutyl) barbituric acid in paraldehyde. barbituric acid, for example, so that this solvent 3. A hypnotic composition for intramuscular plays only a negligible part in the activity of injection comprising a solution of 1-methyl-5 such a solution. A 30% solution of allyl-(l ally1-5-isopropyl barbituric acid in paraldehyde. methylbutyl) bar-bituric acid in paraldehyde is ‘ 4. A hypnotic composition for intramuscular stable. This is true even when such a solution 30 injection comprising a solution of N-methyl-5 is heated to 120° C. for as long as four hours. ethy1-5-(1-methylbuty1) barbituric acid in par Such stability makes it possible to sterilize the solution with heat. aldehyde. MILTON T. BUSH.