we 2,853,418 United States Patent 0 ICC Patented Sept. 23, 1958‘ _

1 2 Kingdom were for barbiturates or preparations contain ing barbiturates. 6.4% of all prescriptions under the 2,853,418 National Health Scheme in the United Kingdom in Octo HYPNOTIC COMPOSITION COMPRISING A BAR ber 1954 contained barbiturates as the sole or principal BITURATE ‘AND (QB-METHYL ETHYL GLUTAR therapeutic agent. IMIDE ' ' Since 1949 barbiturate poisoning in general has in Robert’ Grenville Smith, .Croydon, Victoria, Australia, as creased tremendously. The number of patients treated signor to Nicholas Proprietary Limited, Melbourne, for barbiturate poisoning in England and Wales was Victoria, Australia, a company oflVictoria 2800 in 1949; 3950 in 1951; and 4200 in 1953. Suicidal . NoDrawing. Application April 17, 1956: '10 and accidental deaths from barbiturates have increased Serial No. 578,575 even more spectacularly. In 1946, the number of suicides was 78 and accidental deaths was 54, totalling 132; whilst Claims priority, application Australia April 20, 1955 in 1954 the suicides numbered 391 and accidental deaths . 181, totalling 575. Since 1945 the total suicide rate from ‘ 4 Claims. (c1. 161-52) '15 all agents has tended to oscillate but does not show a signi?cant upward trend. Suicides from barbiturates, This invention relates to barbiturate pharmaceutical however, have increased approximately six times and it preparations, for example, tablets, capsules, elixirs, sus has been concluded that a preference has been shown v pensions and the like, containing barbiturates. _ lately for using barbiturates as suicidal agents rather Thebarbiturates comprise an important and valuable 20 than some other lethal means. group of central nervous system‘depressants frequently Research has recently disclosed a substance which ex prescribed by physicians and widely used by the laity. hibits outstanding antagonism towards barbiturates. This Reference to this appears in the textbook entitled, “The barbiturate antagonist is ?,?-methyl ethyl glutarimide, Pharmacological Basis of Therapeutics,” vby Goodman and having the structural formula as follows: Gilman, page 126, published 1941 by the Macmillan 25 Company, New York, U. S. A. The barbiturates are used medically for several purposes, the most important of which are for producing sleep, inhibiting convulsions, anaesthesia, and sedation. The general properties of barbiturates are possessed in varying degrees by indi 30 The above identi?ed glutarimide is outstanding for the vidual members of the group andthis has led to a large purpose of treating barbiturate poisoning, and, unlike number of different compounds being employed in medi other aneleptics used in the treatment of barbiturate cine. Some are long acting, others intermediate and still poisoning, appears to be a closer approach than hitherto others very short acting. Administration'may be oral or to a true barbiturate antagonist. This has been shown parenteral, but much more frequently the former. 35 to be the case with animal experiments and has since Chemically, the barbiturates are derivatives of barbi been con?rmed clinically with success in curing many turic acid, having the general structural formula as cases of barbiturate poisoning in humans both in Aus follows: ‘ tralia and England. The discovery has now been made that barbiturate 151-0 E 40 poisoning can be prevented, rather than cured, by em / ploying as a source of barbiturate a pharmaceutical prep aration comprising a barbiturate and essentially a propor \H tion of 5,,8-methyl ethyl glutarimide, insu?‘icient to inter- ‘ fere with a therapeutic dose of barbiturate but sufficient wherein one or both'of the hydrogen atoms attached to to overcome the toxic effect of overdose. Thus, it is the'carbon atom numbered 5 or the hydrogen atom at possible to make the barbiturates commonly used in gen tached to the nitrogen atom numbered 3 are replaced by eral medical practice much safer by removing the risk‘ another group to produce a compound having special of coma which follows ingestion of high doses at present. property in the ?eld. Examples are diethyl barbituric By combining with the barbiturate a‘ proportion of [8,5 acid or barbital,phenylethyl-barbituric acid or pheno 50 methyl ethyl glutarimide such that the effectiveness of barbital, and S-phenyl-S-ethyl-3-methyl barbituric acid or the barbiturate at normal dosages is unimpaired but at - methyl-phenobarbitone. .Salts of these compounds‘can high dosage levels approaching the usual coma dose, vital be formed and are often employed, e. g. sodium ethyl body functions are maintained-the usual depressive toxic (l-methyl butyl) barbiturate or pento-barbital sodium. 55 effects of the barbiturate ‘on such functions as pulse rate, The wide use of the barbiturates has resulted in many blood pressure, and the like are reduced to a safe level. cases of overdosage, either accidental or suicidal. vThis In this way it is possible to protect patients from acci overdosagehas frequently ended fatally. An authorita dental or deliberate overdosage of barbiturate. tive review of the current usage of barbiturates in suicide Clinical trials have shown that 18,;3-methyl ethyl glu and accidental death due to barbiturate poisoning in 60 tarimide may be present in the pharmaceutical prepara England has appeared in Lancet, January 21, 1956 at page ~ tion in a proportion of 5% to 30% by weight of the 150. This paper estimates that between 80,000 and barbiturate without interfering with the therapeutic effect 100,000 lbs. of barbiturates are prescribed annually in the of the barbiturate, to overcome the toxic effects of over United Kingdom. Approximately 9% of all prescrip dose. The (MS-methyl ethyl glutarimide is, in this way‘ tions under the National Health Scheme in the United 65 Simultaneously ingested with the barbiturate to act as an 2,853,418 4 e?cie'nt antidotel and-prevent the toxic effect ofan acci Example 11 dental or deliberate overdose of barbiturate. In the clinical work 15%, 20%, 25% and 30% by Tablets again were prepared consisting of the fol; weight of ,B,B-methyl ethyl glutarimide has been used. lowing: It is preferred to use 15% to 20% proportion to {3,5 Grams methyl ethyl glutarimide as this does not interfere with Pentobarbitone __ 60 normal barbiturate effect at low dosages, but does satis {LB-methyl ethyl glutarimide ______12 factorily prevent coma at high dosage levels. The over Lactose .___ -___ 78 all useful proportion of tip-methyl ethyl glutarimide can Sucrose __ -___ 35 be expected to vary according to the circumstances of 10 Sodium carboxy methyl cellulose ______10 use. Magnesium stearate ______5 C‘e‘rtain‘barbiturates; such. as .phenobarbitone, are pro longed in' action‘, henc‘e'it is possible that the‘ ?nd-methyl" 200 ethyl glutarimide would be absorbed and perhaps‘ ex creted'in‘s'om'e instances before being'active. Because of 15 The method of Example 1 was adopted,,th_e pentobarrbi-i this the pharmaceutical preparation of the‘ invention may tone being of 40' mesh particles. Each 200 mgn'ntabletv embody an agent’ delaying the‘ release of ‘the 5,;8-rnethyl contains 60 mgm. of Pentobarbitone. ethyl glutarimide in the" human gastro-intestinal. tract. Thus, the‘ preparation may compriz'e granules havingin Example III " soluble coatings for delaying the absorption of the 5,6 20 Capsules (hard gelatine) were prapared containing the methyl ethyl glutarimide constituent of the mixture. An‘ following: other procedure which may be employed consists‘in pre paring multi-layer tablets in which a layer containing the Grams barbiturate is compressed over a core containing the Amyl'obarbitone ______200 glutarimide, asv hereinafter fully described in certain of 25 mil-methyl ethyl glutarimide ______25 the‘ practical examples. Absorption rates (or release) of Lactose 15 the drugs may thereby bearti?ciallyv controlled, depend ing upon the rate of absorption, excretion and detoxi 240 cationof the {Le-methyl ethyl glutarimide in relation to the barbiturate prescribed. 30 Mix the constituentsaeach‘of‘ whichis of- 40 mesh. size Pharmaceutical preparations in‘ accordancewith the particles and ?ll capsulesof suitable .size with.240. mgm'. invention may comprise; for example, any of the follow of'the: mixture. Each capsule.vv will contain.200 mgm. ing medicinal barbiturates: Phenobarbitone (British Phar arnylobarbitone. macopoeia) or Phenobarbital (U. S. Pharmacopoeia‘); Example IV Amylobarbitone (British Pharmacopoeia) or Amobar bital (U. S. Pharmacopoeia); Butobarbitone (British An elixir‘was: prepared consisting of they following: Pharmacopoeia); Pentobarbitone Sodium (British Phar Phenobarbitone ______grams__... 4.00.. macopoeia) or Pentobarbital Sodium (U. S. Pharma [LB-methyl ethyl- glutarimide ______do_..__ 0.400 copoeia); Quinalbarbitone Sodium (British Pharmaco poeia) or Secobarbital Sodium (U. S. Pharmacopoeia); 40 Tartrazine ______do____ 0.100 Orange oil ______-___ _.____ ml 2.5 and Hexobarbitone Sodium (British Pharmacopoeia) or Alcohol 95%; ______ml__ 150' Hexobarbital Sodium (U. S. National Fo-rmulary Vol. Glycerin ______ml__ 450 X, 1955). “Tween 80”___ ml 35 Practical examples of‘ pharmaceutical compositions in Syrup (sweetening) ______ml__. 150.‘ accordance with the invention are as follows, but it is to Distilled water to make up ______ml__ 1000: be understood that the invention is in no way limited thereto: Dissolve thephenobarbitone, ?,?-methyl ethyl. glutarimide Example I and orange oil in the alcohol and “Tween 80,” add the 50 glycerin and syrup. Dissolve the tartrazine in sufficient distilled water, mix into the solution, make product up Tablets consisting of the following mixture were pre to volume with distilled water and ?lter. Each 5 ml. of pared: this preparation contains 20 mgm. of phenobarbitone. Grams Example V Phenobarbitone ______30 55 [Shit-methyl ethyl glutarimide ______4.5 Multi-layer tablets for the‘ delayed release or absorption Lactose ______100‘ of the drugs as indicated, were‘ prepared consisting of the Sucrose ______50.5 following‘: Sodium carboxy methyl cellulose ______10 Magnesium stearate (60 mesh) ______5.0 60 Core A: Grams [LB-methyl ethyl glutarimide ______9.2 200 Lactose .___ _ 26.55 Icing sugar 16.8 The phenobarbitone, 5,}3-methyl ethyl glutarimide, Lac Dextrin ___ 2.4 tose andlsucrose all of 40 mesh size particles were mixed 65 Magnesium stearate ______. 0.05 throughly in a blender, then massed by addinga mixture of equalparts of Industrial Spirit (alcohol 95%) and 55., water. The moistened mass‘ was passed through a 16 The pL?-methylethyl glutarimide, lactose, icing sugar and‘ mesh'sieve and-granules dried at 50° C. The dried gran! 70 dextrin'are mixed thoroughly in‘ a blender, then massed by, ules were passed through a 16 mesh sieve then mixedwith adding a mixture’ of equal parts of industrial spirit and sodium carboxy methyl cellulose (40 mesh size particles) water. The moistened mass was passed through a' 16 and magnesium stearate (.60 mesh size particles). Tablets mesh and the granules dried at 50° C. The dried granules‘ were made 5/16" diameter, weighing 200 mgm., and con were passed through a’ 16' mesh then mixed with mag taining 30 mgm. of phenobarbitone. . 75 nesium stearate. Tabletsi weighing 55 mgmz, and con 2,853,418

. » » 5 ' . 6 , taining 9.2 mgm. of Ftp-methyl ethyl glutarimide were which the lip-methyl ethyl glutarimide and'barbiturate so produced. (phenobarbitone or pentobarbitone) were available simultaneously for ingestion. Results in both animals Layer B: , Grams and man showed that the particular barbiturate deriv Phenobarbitone ______65.75 atives above identi?ed act satisfactorily. Medicinal Lactose ' 77 barbiturates generally may be employed in the composi- , Gum acacia 1.5 tions of the invention but persons concerned with the Magnesium stearate ______0.75 art will appreciate that no practical advantage will accrue with .those ultra-short acting barbiturates used for 145.0 10 anaesthetic purposes only and administered by a quali The phenobarbitone and lactose were mixed thoroughly ' ?ed medical practitioner. in a blender, then massed by adding gum acacia in aqu Persons concerned with the art will appreciate that eous solution. The moistened mass was passed through the invention may also be applied in various kinds of 16 mesh and the granules dried at 50° C. The dried barbiturate pharmaceutical compositions in which the granules were passed through a 16 mesh, then mixed with v15 ‘barbiturate content normally constitutes a potential magnesium stearate. Layer B was compressed on Core hazard in accidental or deliberate overdosage of bar A to form a tablet weighing 200 mgm. and containing biturate. Examples of types of compositions contain- . 9.2 mgm. of lip-methyl ethyl glutarimide and 66.75 mgm. ing barbiturates to which the invention may thus be of phenobarbitone. adapted, to the extent that risk of death from over Example VI 20 dosage may be minimised, are as follows: _ Multi-layer delayed release tablets similar to Example (a) Compositions comprising two or more barbiturates, V were prepared consisting of the following: ' such barbiturates being mixtures of short-acting, inter mediate-acting, and/or long-acting drugs, e. g., mixtures Core A: ' Grams of phenobarbitone and pentobarbitone. The glutarimide 18,;8-methyl ethyl glutarimide ______.. 65 25 should be incorporated in these compositions in an Lactose 39 amount which is the desired percentage of the total weight Icing sugar 18.2 of the mixture of barbiturates. Sodium carboxy methyl cellulose ______5.2 (b) Compositions comprising one or more barbiturates Magnesium stearate ______.._ 2.6 with mild stimulants such as caffeine or amphetamine to 30 reduce the post-barbiturate depression usually encountered 130 as an aftermath of barbiturate administration. The The fL?-methyl ethyl glutarimide, lactose and icing sugar glutarimide should be incorporated in an amount which were granulated as in Example V and the dried granules is the desired percentage of the weight of the barbiturate passed through a 16 mesh then mixed with the sodium drug or drugs in the composition. carboxy methyl cellulose and magnesium stearate. 35 (c) Compositions comprising one or more barbiturates Tablets weighing 130 mgm. were so prepared. with other mild sedatives as, for example, sodium bro mide. The glutarimide should be incorporated in an Layer B: . Grams amount which is the desired percentage of the weight of Amylobarbitone ______2,00 the barbiturate drug or drugs in the composition. Lactose 150 40 (d) Compositions comprising one or more barbiturates Icing sugar 56 with other hypnotics as, for example, chloral or paralde Sodium carboxy methyl cellulose '______.._ 16 hyde. The glutarimide should be incorporated in an Magnesium stearate ______8 amount as already indicated. In compositions of this kind it will be appreciated that the advantage of the “N 430 45 glutarimidemust- be assessed relative to any risk of death The granules were prepared as in Core A. Layer B 'as a result of overdose of the other hypnotic. was compressed on Core A to form a tablet weighing (e) Compositions comprising one or more barbiturates 560 mgm. and containing 200 mgm. amylobarbitone and with analgesics as, for example, aspirin, phenacetin, code 65 mgm. 5,5-methyl ethyl glutarimide. ine. The glutarimide should be incorporated in an 50 amount as already indicated. In compositions of this Example VII kind it will be appreciated that the presence of the glu tarimide is limited to removing the toxic effect of the bar Capsules (hard gelatine) were prepared containing the biturate in case of overdosage. The toxic effect of the following: overdosage of the analgesic or analgesics remains. In Grams 55 practise compositions of this kind are usally such that Phenobarbitone 130 this risk is very much less than the risk of barbiturate B,?-methyl ethyl glutarimide ______.. 19.5 toxicity in the case of overdosage. Lactose 30.25 (f) Compositions comprising one or more barbiturates Icing sugar - 5 with antiasthmatics as, for example, ephedrine. The glu Dextrin 3 60 tarimide should be incorporated in an amount as already The tap-methyl ethyl glutarimide, lactose, icing sugar indicated. and dextrin were granulated as in Example V. The (g) Compositions comprising one or more barbiturates dried granules of 16 mesh size were coated with a solu with anticholinergic drugs acting on autonomic e?ector tion of cellulose acetate phthalate 10% w/v in acetone. cells as, for example, atropine. The glutarimide should The amount of coating was such that when the granules’ 65 be incorporated as already indicated. ' were tested in arti?cial intestinal juice, ‘they disintegrated (h) Compositions comprising one or more barbiturates within one hour. The dried, coated granules were mixed with anticonvulsants as, for example, the hydantoins. thoroughly with the phenobarbitone and the mixture was The glutarimide should be incorporated as already in ?lled into hard gelatine capsules so that each capsule con dicated. tained 19.5 mgm. 5,;3-methyl ethyl glutarimide and 130 70 What is claimed is: mgm. phenobarbitone. l. A pharmaceutical preparation comprising a medici Experimental work with animals and humans has been nal barbiturate and a proportion of fLp-methyl ethyl carried out employing phenobarbitone and pentobarbitone, glutarimide within the range of 5% to 30% by weight of which are the most widely used barbiturates. In all the barbiturate. such clinical work the preparations were of the kind in 75 2. A pharmaceutical preparation comprising a medici- ' 2,853,418 (9 7 - 0 nal barbiturate and aproportion of [3,}3-methyl ethyl glu portion of pig-methyl ethyl glutarirnide Within the range tarimidewithin the rangeyof 15%‘ to 20%“ by Weight-of" of 15% to"20%‘>b‘y weight of the barbiturate. thepbarbiturate. 3'. A pharmaceutical preparation comprising-a barbitu References Cited in the ?le of this patent rate selected from the‘group' consisting of phenobarbital UNITED. STATES PATENTS. amobarbitol, butobarbitone, pentobarbital'sodiurn, seco Hermelin ______Feb. 28; 1956 barbital sodium andhexobarbital sodium, and a propor 2,736,682" tion of 13,,8-rnethyl ethyl glutarimide within the’range of OTHER REFERENCES 5%‘ to 30% byrweight of the barbiturate. Science News Letter, Apr. 25, 195 3, p. 259. 4; A pharmaceutical‘preparation comprising a. barbi 10 Harris: Lancet (London), vol. 268, Jan. 22, 1955. turate selected from the group consisting of phenobarbi p. 181. tal, amobarbital, butabarbital, pentobarbital sodium, Shaw et.al.:. Nature,v vol. 174, No..4426, Aug. 28, secobarbital sodium, and hexobarbital. sodium, and’a pro 1954, pp. 402-403.