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United States Patent Office Patented Jan 3,557,287 United States Patent Office Patented Jan. 19, 1971 2 3,557,287 teral administration, e.g. tablets, dragées, capsules, Sup COMPOSITIONS AND METHODS FOR TREATING positories and injectable solutions. In order to produce HEADACHES OF WASCULAR ORIGIN WITH Such medicinal preparations the mixture of active con COMBINATIONS OF CAFFEINE, A VASOTONIC stituents is worked up with the usual organic or inorganic, LYSERGEC ACED AND A THOXANTHENE pharmacologically inert adjuvants. Examples of such ad Botond Berde and Albert Fanchamps, Basel, Switzerland, assignors to Sandoz Ltd. (also known as Sandoz AG), juvants are lactose, starch, polyvinyl pyrrollidone, stearic Basel, Switzerland acid, sorbic acid, talc, methyl cellulose, alcohols, glycerin No Drawing. Filed Dec. 31, 1968, Ser. No. 788,351 and natural or hardened oils. The preparations may fur Claims priority, application Switzerland, Jan. 9, 1968, thermore contain suitable sweetening or colouring sub 350/68 10 stances and flavourings. Int, C. A61k 27/00 U.S. Cl, 424-253 6 Claims EXAMPLES OF GALENIC PREPARATIONS Example 1.--Capsules (composition A) ABSTRACT OF THE DISCLOSURE G. 5 Ergostine hydrogen maleate ---------------- 10.0012 The invention relates to a pharmaceutical composition Caffeine (anhydrous) --------------------- 0.10 incorporating as active constituents: Mepithiathene hydrogen maleate ------------ 20.0007 (a) a vasotonic lysergic acid derivative of the peptide Tale ------------------------------------ 0.050 type or a pharmaceutically acceptable acid addition 20 Lactose --------------------------------- 0.1381. salt thereof; (b) caffeine; and Content of the capsule --------------- 0.290 (c) 9-(1-methyl - 4 - piperidylidene)thioxanthene or a Cover about ----------------------- 0.080 pharmaceutically acceptable acid addition salt thereof. For a capsule of about --------------- 0.370 The composition is useful for treating attacks of mi Corresponds to 0.0010 g. of base. graine, or migraine equivalents, and vascular headaches. Corresponds to 0.0005 g. of base. -amaataraum Ergostine hydrogen maleate, caffeine and mepithiathene The present invention relates to a pharmaceutical com 30 hydrogen maleate are mixed with talc and lactose; the position incorporating as active constituents: mixture is mechanically filled into hard gelatine capsules. (a) a vasotonic lysergic acid derivative of the peptide type Example 2.-Suppositories (composition B) G. or a pharmaceutically acceptable acid addition salt Ergostine hydrogen maleate ---------------- 10.0024 thereof; Caffeine (anhydrous) ---------------------- 0.10 (b) caffeine; and Mepithiathene hydrogen maleate ------------ 20.0014 (c) 9-(1-methyl - 4 - piperidylidene)thioanthene or a Zinc sulphate ----------------------------- 0.0001 pharmaceutically acceptable acid addition salt thereof; Colour pigment indigo carmine ------------- 0.0003 the preparation of the constituents (a): (b): (c) being Colour pigment yellow orange S ------------ 0.0020 by weight, from about 1:5:0.05 to about 1:2000:20. 40 Maleic acid ------------------------------ 0.0020 The vasotonic lysergic acid derivative of the peptide Lactose --------------------------------- 0.0918 type, which may be employed in the composition, may be Solid fat -------------------------------- 1.74 ergostine, ergotamine, dihydroergostine, dihydroergota 1.94 mine, ergovaline, 5' - methyl-ergolanine, or a pharma 45 Corresponds to 0.0020 g. of base. ceutically acceptable acid addition salt thereof. For ex * Corresponds to 0.0010 g. of base. ample, ergostine may be employed as its hydrogen male ate, ergotamine as its tartrate, dihydroergostine as its Ergostine hydrogen maleate, caffeine, mepithiathene hydrogen maleate or tartrate, dihydroergotamine as its hydrogen maleate, colour pigments, zinc sulphate, maleic tartrate or methanesulphonate, ergovaline as its sulphate acid and lactose are mixed homogeneously. The mixture and 5'-methyl-ergolanine as its methanesulphonate. 50 is homogeneously suspended in the melted solid fat; the The name "mepithiathene' is hereinafter used for 9 resulting suspension is worked up into suppositories in (1 - methyl-4-piperidylidene)thioxanthene. Mepithiathene accordance with the known molding process. may also be used in the form of a pharmaceutically ac Example 3-Capsules (composition C) ceptable acid addition salt, for example as its hydrogen G. maleate. Ergotamine tartrate ---------------------- 1 0.0010 The ratio, by weight, of constituents (a): (b); (c) Caffeine (anhydrous) --------------------- 0.10 is preferably from about 0.5:30:1 to about 3:300:1. Mepithiathene hydrogen maleate ----------- 20.0007 The pharmaceutical composition, in unit dose form, Dimethylsilicone oil ---------------------- 0.00045 may incorporate from about 0.5 mg. to about 3 mg. 60 Polyethylene glycol 6000 ----------------- 0.00135 of constituent (a), from about 50 mg. to about 300 mg. Magnesium stearate ----------------------- 0.0020 of constituent (b), and from about 0.3 mg. to about Polyvinyl pyrrollidone -------------------- 0.0045 3 mg. of constituent (c). For example, the composition Maize starch ---------------------------- 0.0090 may have the following constitutions: Talc ---------------------------------- 0.01.08 Lactose -------------------------------- 0.1602 A B C D E. F. Ergostine hydrogen maleate, Ing----- 1.2 2.4 ---------------------- Ergotamine taltrate, mg------------------------- 2 2 Content of the capsule -------------- 0.290 Catleine, mg-------------------------- 100 100 100 00 100 100 Cover about ---------------------- 0.060 Mepithia thene hydrogen maleate, mg. 0.7 l. 4 0.7 1.4 2.8 1.4 For a capsule of about ------------- 0.350 The invention also extends to galenic preparations of 1 Corresponds to 0.00089 g. of base. the composition, which are suitable for enteral or paren Corresponds to 0.0005 g.of base. 3,557,287 3. 4. Ergotamine tartrate, caffeine and mepithiathene hydro ed solid fat. The resulting suspension is worked up into gen maleate are mixed with part of the talc and with suppositories in accordance with the usual molding magnesium stearate (I). The remainder of the talc is process. mixed with polyvinyl pyrrollidone, maize starch and lac The toxicity of the new composition is very low. Thus, tose. This mixture is moistened and kneaded with an for example, the DLso values ascertained in mice, rats aqueous suspension of dimethyl silicone oil and poly and rabbits upon peroral administration of mixtures of ethylene glycol 6000 until the mass can be granulated. ergostine, caffeine and mepithiathene are in the same The granulate is dried and crushed (II). order of magnitude as those ascertained for caffeine un I and II are mixed and mechanically filled into hard der the same conditions (animal species, mode of ad gelatin capsules. O ministration): G. Ergotamine tartrate ---------------------- 1 0.0010 DL150 in mg./kg. p.o. Caffeine (anhydrous) -------------------- 0.10 Mice Rats Rabbit Mepithiathene hydrogen maleate ---------- 2 0.0014 Ergostine plus caffeine plus mepithia thene, 2:200:1------------------------------------- 538 600 299 Dimethylsilicone oil --------------------- 0.00045 Ergostine plus caffeine plus mepithia thene, Polyethylene glycol 6000 ----------------- 0.00135 2:100: 1------------------------------------- 458 659 237 Magnesium stearate --------------------- 0.0020 Caffeine-------------------------------------- 465 540 240 Polyvinyl pyrrollidone --------------------- 0.0045 Maize starch --------------------------- O.O090 The new composition is useful for treating headaches Talc ---------------------------------- 0.01.01 20 of vascular origin, inter alia migraine, migraine equiva Lactose -------------------------------- 0.1602 lents or vascular headaches. Contra-indications are preg nancy, peripheral blood circulation disorders, Angina Content of the capsule -------------- 0.290 pectoris and coronary sclerosis as well as hepatic and Cover about ---------------------- 0.060 renal insufficiency; a daily repeated administration of the preparation (i.e. a permanent treatment) is not rec For a capsule of about -------------- 0.350 ommendable. Corresponds to 0.00089 g. of base. A suitable daily dose against an attack of migraine is 2 Corresponds to 0.0010 g. of base. 0.5 to 10 mg. of the vasotonic lysergic acid derivative of Ergotamine tartrate, caffeine and mepithiathene hydro the peptide type, 50 to 1000 mg. of caffeine and 0.5 to 10 gen maleate are mixed with part of the talc and with 30 mg. of mepithiathene. The dose is preferably adminis magnesium stearate (I). The remainder of the talc is tered orally or rectally. For example, one to two capsules mixed with polyvinyl pyrrollidone, maize starch and lac (composition A, C, or D, see Examples 1, 3 and 4) or tose. This mixture is moistened and kneaded with an one suppository (composition B, E or F, see Examples 2, aqueous suspension of dimethylsilicone oil and polyethyl 5 and 6) are administered upon appearance of the first symptoms of an attack; in case of an insufficient effect or ene glycol 6000 until the mass can be granulated. The no esffect the initial dose is repeated every 30 to 45 granulate is dried and crushed (II). minutes. The dose for each attack and each day (24 I and II are mixied and mechanically filled into hard hours) should generally not exceed 6 capsules or 3 gelatine capsules. Suppositories. Example 5.-Suppositories (composition E) 40 A combination preparation of the invention, containing G. as active materials ergotamine, caffeine and mepithiathene Ergotamine
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