United States Patent Office Patented Nov
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3,066,075 United States Patent Office Patented Nov. 27, 1962 2 the water at a temperature not in excess of about 150 C. 3,066,075 COMPOST ONS COMPRISING AMPHETAMINE and in such manner as not to discolor the product. Vac AND CARBOXYMETHYL CELLULOSE IN CHEMi uum drying, including spray drying, is a preferred mode CALLY COMBINEO FORM of drying. Marshall E. Deutsch, Whippany, N.J., assignor to G. W. The resulting salt is a hard light colored solid, very Carnrick Co., Newark, N.J., a corporation of New soluble in water, and yields viscous solutions in water at - Jersey concentrations of about 1% or more. Amphetamine may No Drawing. Filed July 25, 1960, Ser. No. 44,897 be recovered from the salt by making a solution alkaline 19 Claims. (Cl. 167-65) with strong alkali, such as sodium hydroxide, and then 10 steam distilling to recover the amphetamine. The present invention relates to a novel therapeutic The various optical forms of amphetamine, i.e., the d-, product and to therapeutic compositions made therefrom. l- and dil-forms, may be used. It will, therefore, be un It is well known that in recent years the medical arma derstood that wherever the context so requires or admits, mentarium has been enhanced by the introduction of drugs the term "amphetamine' includes each of its aforemen in what may be referred to as time-released form. U.S. 5 tioned forms, perse or inadmixture. patents which disclose medication in such form include The ordinary carboxymethyl cellulose of commerce Nos. 2,736,682; 2,738,303; and 2,809,916-8. may be employed in accordance with this invention. It Briefly stated, time-release refers to the fact that the is an especial advantage of this invention that carboxy drug is in such form as to give not only a fairly immedi methyl cellulose having a wide range of average molec ate effect but, in addition, the drug is in such form as to 20 ular weight is useful. Illustrative of such a range is that be released for effectiveness either more or less continu between about 10,000 and about 600,000. ously or at intervals over an extended period of time, e.g., Any cationic-exchange resin which is capable of replac 8 hours or so. When the drug is in a form effective more ing a metallic ion such as sodium with hydrogen is suit or less continuously over a period of time it may be able in the aforementioned process. Such resins include, referred to as being in "trickle” form. When the drug is for example, polystyrene sulfonic acid and carboxylic acid effective at intervals, e.g., in two bursts, it may be referred resins such as those marketed in the U.S.A. under the to as in “two shot' form. designations: Duolite C-25 (made by Chemical Process, It can easily be appreciated that the timed-release form Redwood City, Calif.), Amberlite IR-120H and IRC-50 possesses advantages in the administration of drugs. For (made by Rohm & Haas, Philadelphia, Pa.), DoweX 50 one thing, the patient is not required to go through the 30 (made by Dow Chemical Company, Midland, Mich.), drug ingesting process as often as otherwise. Then too, and Zeocarb 225 (made by Pfaudler-Permutit, New it is especially important in certain cases that either sus York, N.Y.). tained or repeated effectiveness be provided. For exam As aforementioned, the ratio of the amphetamine equiv ple, in the case of sedatives it is desirable to control sleep alent to that for carboxymethyl cellulose in the novel over an extended period of around 8 hours. A "trickle' salt is from about 1 to about 30 parts by weight of the form would appear to be indicated. In the case of appe former to about 72 parts by weight of the latter. Espe tite suppression, the "two shot" or "three shot" type of cially desirable results are obtained when the ratio is from time-release form may be desirable, so timed as to be ef about 20 to about 30 parts of amphetamine equivalent to fective at the patient's normal eating times. about 72 parts of carboxymethyl cellulose equivalent. One of the drugs employed in time-released form is 40 Therapeutic compositions in accordance with this in amphetamine, in the form of its organic and inorganic vention are made by combining the novel salt of this in acid addition salts, such as the succinate, tartrate, citrate, vention with a sedative and/or a tranquilizer, in accord hydrochloride, phosphate and sulfate salts. While this ance with medical indications and considerations as to drug has utility as an appetite depressant or anoretic, un compatibility, etc. toward side effects such as jitteriness and insomnia often 45 Sedatives which may be used include barbiturates, such result from its use. as phenobarbital, barbital, amobarbital, butabarbital and It has been surprisingly found, in accordance with this secobarbital; and/or other sedatives, such as ethinamate, invention, that dosage effective to retain the desirable methylparafynol, methylprylon, glutethimide and ethchlor anoretic qualities of amphetamine, without any Substan Wynol. tial untoward side effects, can be realized by combining 50 Tranquilizers which may be used include meprobamate, amphetamine with carboxymethyl cellulose to form a chlorimethazanone, phenaglycodol, hydroxyzine, ectyl salt wherein about 1 to about 30 parts by weight are the urea, captodiamine hydrochloride, buclyzine, methamino amphetamine residue per about 72 parts by weight of the diazepoxide, deserpidine, thiopropazate, 1-piperidine carboxymethyl cellulose residue. Moreover, to obtain 55 ethanol benzilate hydrochloride, benactyzine hydrochlo the same anoretic effect as yielded by amphetamine in the ride, oxanamide and chlorpromazine. form of its known salts, only two thirds as much am The ratio of novel salt to barbiturates employed in the phetamine is needed in the form of the novel salt of this instant therapeutic compositions is within the range from invention. about 1 to about 2 parts of the salt to about 1 part of When the aforementioned novel salt was incorporated 60 the barbiturate, by weight. Especially satisfactory re in timed-release tablets, capsules, etc., in accordance with sults are obtained when said ratio is about 4 parts of this invention, it was further found, surprisingly, that the novel salt to about 3 parts of barbiturate. drug, in combination with sedatives or tranquilizers, not As will be understood in the art, the amounts of the only exhibited "bursts' of effectiveness as an appetite sup other sedatives and of the tranquilizers which can be pressant at intervals of about 3%-4 hours, but that it also 65 used vary over wide limits. These amounts, expressed exhibited a trickle effect over an extended period, i.e., as ratios relative to the dosage of barbiturates, are given 7-8 hours. below: In preparing the novel salt of this invention, an aque Ethinamate-1 ous solution of sodium carboxymethyl cellulose is passed Methylparafynol-5 through a cation-exchange resin in the hydrogen form. 70 Methprylon-4 Amphetamine is added to the resulting suspension and a Glutethimide-5 solution is again obtained. The salt is dried by removing Ethchlorvynol-5 8,066,075 3. Meprobamate-5 EXAMPLE I - Chlormethazanone-2 Phenaglycodol-2 Preparation of Salt of Amphetamine and Carboxymethyl Hydroxyzine-2 Cellulose Ectylurea-5 S. One hundred milliliters of an aqueous solution, 1% Captodiamine hydrochloride-1 strength, of sodium carboxymethyl cellulose (Hercules Bticlyzine-/3 Powder Company, CMC7HP), having an approximate Methaminodiazepoxide-4 average molecular weight of 350,000 and a degree of Deserpidine-400 substitution, i.e., number of hydroxyl groups in each Thiopropazate-/3 O anhydroglucose unit which has combined with acetate, of 1-piperidine-ethanol benzilate hydrochloride-Ao 0.75, was passed at a rate of one ml. per minute through Benactyzine hydrochloride-A0 a column 1' high containing 4 grams of polystyrene Sul Oxanamide-3 fonic acid cation-exchange resin (Amberlite IR-120H). Chlorpromazine The carboxymethyl cellulose, which formed, went into The above numbers are termed the barbiturate equivalents 5 suspension and was collected in a separate container. The of the indicated materials. column was rinsed with 2 five ml. portions of distilled In preparing compositions incorporating sedatives other water which was added to the suspension. To 110 milli than barbiturates and/or tranquilizers, with or without liters of the resulting suspension was added 0.36 gram of barbiturates, it is a simple matter to calculate the correct dextro-amphetamine free base, giving rise to the disap amounts to be used, making due allowance for the above pearance of the suspension and formation of a solution. dosage strengths and for all of the sedatives and/or The solution of the salt of carboxymethyl cellulose and tranquilizers employed. For example, if methylparafynol d-amphetamine was dried by heating to 140 C. for half is used to replace all barbiturates, then 5 times as much an hour. of the former, compared with the effective amount of There was obtained a hard, faintly off-white solid, 25 which could be ground into a powder. The solid was barbiturate, should be used. Or, if it is desired to use very soluble in water and formed a viscous 1% solution equal dosages of a barbiturate, another sedative, e.g., when dissolved in water. It assayed 27.6% amphetamine methprylon, and a tranquilizer, e.g., deserpidine, then the when tested by weighing out a sample, dissolving it in parts of each to employ, on the basis of 1-2 parts by water, adding excess 20% sodium hydroxide solution, weight of the novel salt of this invenion are as follows: 30 steam distilling in a Kjeldahl distillation apparatus into Barbiturate-/3 part of 1=%.