UmtedD States Patent [19] {111 E Re. 29,875 Mercer et al. [45} Reissued Jan. 2, 1978

[S4] BRONCHODILATOR EXPECI'ORANT [52] US. Cl...... 424/253; 424/254; ELIXIR 424/278; 424/315; 424/330; 424/340; 424/341 [75] Inventors: Neil B. Mercer; Hugh D. B both [58] Field of Search ...... 424/253 of Evansville, Ind. [56] References Cited [73] Assignee: Mead Johnson & Company, US. PATENT DOCUMENTS Evmvme' Ind- Re. 29,359 8/1977 Mercer at a]...... 424/253 [21] APPI' No“ “6,873 Primary Examiner—Lconard Schenkman [22] Filed; m 31, 1977 Attorney. Agent, or Firm-Robert E. Camahan; Robert H‘ Uloth Related US. Patent Documentl [57] mgr Reissue of’ A bronchodilator expectorant composition containing a [54] Patent No" 3367:,“ sympathomimctic amine bronchodilator, the xanthine fa?dko _ 23:25" 196’ bronchodilator theophylline, guaiacol or a water solu Filcd: Aug’. m, 1966 ble form thereof and a aedatlve.

[51] Int. 0.1 ...... A611: 31/52 3(L'laimmNoDnwiap Re. 29,875 1 2 certainty of uniform resuspension of insoluble ingredi BRONCHODILATOR EXPECI‘ORANT ELIXIR ents is an ever-present problem in the administration of drugs as liquid suspensions. Matter enclosed in heavy brackets [ ] appears in the We have found that certain barbiturates form clear original patent but forms no part of this reissue speci?ca solutions when employed in combination with theoph tion; matter printed in italics indicates the additions made yiline, ephedrine hydrochloride, and glyceryl guaiaco late. The reason for the specific compatibility which we by reissue. have discovered is not known since the operability of certain barbiturates does not appear to be a function of U.S. Pat. 3,109,773, dated Nov. 5, 1963 of Neil H. 10 their water or alcohol solubilities. Mercer and Robert J. Bequette deals with a bron There is provided according to the present invention chodilator-expectorant elixir containing theophylline in a bronchodilator expectorant composition containing a highly concentrated liquid dosage form made possible sympathomimetic amine bronchodilator such as ephed through the solubilizing effect of glyceryl guaiacolate, rine, pseudophedrine, methoxyphenamine, or protoky or other water-soluble form of guaiacol, on the theoph lol or an acid addition salt thereof; the xanthine bron ylline. Those compositions have the advantage of pro chodilator theophylline; glyceryl guaiacolate, or a viding a therapeutic dose of theophylline and glyceryl water soluble form thereof such as guaiacol itself, or guaiacoiate or equivalent water soluble form of guaia potassium guaiacol sulfonate; and a sedative compo col in a relatively small volume of elixir which may nent, cyclopal, aprobarbital, butabarbital, or pentobar contain alcohol in sufficient amount to assist in absorp- 20 bital. These ingredients are contained in an aqueous tion of the theophylline, but in insufficient amount to alcoholic vehicle to provide ?nal composition which interfere with patient acceptance. The compositions contains at least 40% by volume of water and up to 20% have solution stability over a wide pH range including by volume of ethanol, which shares the advantage of acidic conditions. The latter is desirable since consider pH stability, palatability, freedom from gastric irrita ably more latitude is thereby afforded the flavorist in 25 tion, and effective absorption with the compositions of compounding an acceptably flavored product and be U.S. 3,109,773. cause the theophylline remains in solution even under The compositions are designed to contain a therapeu the strongly acid conditions met in the stomach, thus tically effective dosage of each active ingredient in a reducing the possiblity of gastric irritation. dosage volume of up to 2 tablespoons (30 ml.) of elixir. The present invention provides the solution to a diffi 30 Each 5 ml. unit contains from about 1/6 up to a full cult problem encountered in preparing an elixir of the therapeutic dose of each ingredient, or more particu foregoing type retaining each of the advantages thereof larly from 16.6 to 175 mg. of theophylline; from 7.5 to relative to palatability, absorption, tolerance, and ac 350 mg. of glyceryl guaiacolate, or an equivalent solubi ceptability, but including therein as additional active lizing weight of potassium guaiacol sulfonate or guaia ingredients a sympathomimetic amine bronchodilator 35 col; from 4 to 25 mg. of ephedrine hydrochloride, component, such as ephedrine hydrochloride, and a ephedrine sulfate, or a pharmacologically equivalent barbiturate sedative. amount of one of the previously mentioned sympatho Bronchodilator compositions containing both adren mimetic bronchodilators; from 2 to 35 mg. of one of the ergic and xanthine-type bronchodilator agents to coun barbiturates listed above, preferably butabarbital. For teract bronchospasrn, and a sedative are widely used the latter, concentrations in the range of 2 to 15 mg./ 5 because of their effectiveness, despite the disadvantages ml. are employed. A soluble form of ephedrine, pseudo of certain side effects. The sedative serves the purpose ephedrine, methoxyphenamine, or protokylol is, of of relieving the anxiety to which patients suffering from course, used. Ephedrine sulfate and ephedrine hydro bronchial asthma are frequently subject and also coun chloride may be used interchangeably in the amount teracting the central nervous system stimulating side 45 specified. The concentrations of other adrenergic bron effects of the sympathomimetic amines which serves as chodilators for use in the present elixirs are adjusted in adrenergic bronchodilator components. Phenobarbital accordance with accepted dosage practice for each is the most widely used sedative in such compositions, drug. although other barbiturates have been used in tablet or In its broadest concept, the present bronchodilator capsule dosage forms. expectorant compositions are clear aqueous or aqueous Phenobarbital is generally preferred for such compo alcoholic solutions containing at least 40% by volume sitions because of its relatively long duration of action of water and up to 20% by volume of alcohol, and providing a continuous calming effect during dosage for having dissolved therein 0.83 g. to 4.37 g. of theophyl chronic conditions. Unfortunately a physical incompati line per 100 ml. of water in the composition, sufficient bility between phenobarbital and theophylline is oper 55 guaiacol or pharmaceutically acceptable water soluble ant which results in their precipitation from solution form thereof to serve as solubilizer for the theophylline, when it is attempted to incorporate phenobarbital in a pharmacologically effective dose of a sympathomi sedative effective amounts into a theophylline-glyceryl metic bronchodilator, and a sedative dose of a barbitu guaiacolate elixir of the type described in U.S. rate selected from 5-allyl-5-cyclopentenylbarbituric 3,109,773. Apparently the phenobarbital interferes with 60 acid (cyclopal), S-allyl-S-isopropylbarbituric acid (apro~ the solubilizing action of the glyceryl guaiacolate on the barbital), S-ethyl-5-(2-butyl)barbituric acid (butabarbi theophylline, resulting in precipitation thereof. Further tall), and S-ethyl-5-(2-pentyl)barbituric acid (pentobarbi more, the phenobarbital is itself rendered insoluble. It is ). thus impossible to formulate a clear solution free from The foregoing concentration range of theophylline insoluble suspended ingredients. Solutions are preferred 65 exceeds that of a saturated solution thereof in the sol in accordance with the object of providing rapid and vents selected as vehicles in this invention. It is solubi uniform absorption without gastric irritation and for lized in accordance with the invention set forth in U.S. convenience and accuracy of administration. The un 3,109,773. The aforementioned barbiturates in the con Re. 29,875 3 4 centrations given, in company with the sympathomi metic amine ingredient, are soluble in the composition -continued Con and surprisingly do not themselves precipitate nor cause A- centra precipitation of the theophylline. In order to illustrate 11:12:31! tron the speci?city required of the barbiturate for use in the 5 llarbltunc. . acid. 506"ml. 1:31elixir ' present compositions, the following experiment is de derivative (g.) (mg) Stability result scribed. 5-alll5henl' ‘P Y - us- 200 (1) Wk‘ EXAMPLE (Jimmy!) ‘Clear solution failed to form on mixing the ingredients, and no stability studies Stock solutions as follows were prepared. were therefore initiated. not then with such sample. The solutions which formed satisfactorily were ?ltered to remove any Solution No. l-Sm bale foreign material, and put aside and stored in paired lots Ingredient: Amount/5m ml. of solution at 0' C. and at room temperature. They were examined Theophylline g 5.1 after 4 weeks for crystallization. Glyceryl guaiaeolate g 3.0 In the preceding table there are identi?ed the various Sucrose g 250.0 Sodium saccharin g 0.5 barbiturates tested, the amounts used, and the dose Sodium cyclamste g 3.0 thereof contained in 15 ml. of the ?nal composition, to 70% sorbitol solution ml 25.0 which the amount employed corresponds. In each in Citric acid g 2.0 stance this dose is a sedative dose of the barbiturate as Sodium Citrate g 1.5 Distilled water, q.a. ml 4G) speci?ed in either the Merck Index. U.S.P. XVI, NF X Solution Hal-Alcohol solution or NF XI. Methylparaben g 0.6 It is apparent from the foregoing that the results ob Propylbaraben g 0.15 tained with cyclopal, aprobarbital, and butabarbital are Ethyl vanillin g 0.10 truly unexpected in view of the similarity of the chemi Menthol (4% in ethanol) ml 0.08 Grenadine ?avor ml 0.04 25 cal structures properties of these substances to closely Ethyl alcohol ml 78.95 related barbiturates which were found to be unsatisfac Solution Dial-Ephedrine hydrochloride solution tory. Refer, for instance, to itobarital, diallylbarbituric Ephedrine hydrochloride 3 0.8 acid, secobarbital, barbital, butethal, and the S-pheny] Distilled water q.s. ml 10.0 barbiturates. Pentobarbital at a concentration of 10 mg./ l 5 ml. provided a clear solution of the composition The amounts of barbiturates speci?ed in the follow 30 given in the foregoing example. This concentration of pentobarbital is slightly less than a sedative dose (the ing list were then weighed and dissolved in a 79 ml. recommended dose is 30-500 mg.) Stable clear solutions portion of the alcohol solution (Solution No. 2). This having a sedative dose of 15 mg. of pentobarbital per 15 was then mixed with 400 ml. of Solution No. l and 10 II; of elixir can, however, be formulated as outlined ml. of Solution No. 3 was added thereto. The mixture 35 a ve. was then diluted to 500 ml. with distilled water. In some Attempts were made to formulate elixirs as described instances the ingredients did not dissolve and stability in the foregoing example using various concentrations studies were of the barbiturates listed below. They proved to be unsatisfactory for failure to form clear solutions con taining effective sedative amounts in volumes of 5-30 Con ml. of the elixir. A- centre‘ 5-allyl-5-ethylbarbituric acid mount tion 5-methyl-5-phenylbarbituric acid per per 15 ml. S-cyclohex-l-enyl-l,5-dimethylbarbituric acid (hexo Barbituric acid 5(1) ml elixir barbital) derivative (g.) (mg) Stability result 45 S-cyclohex-l-enyI-S-ethylbarbituric acid (cyclobarbital) 5,5-diethyl- 9.9 :00 (') S-ethyl-S-phenylbarbituric acid (phenobarbital) (bsrbltal). What is claimed is: 5-a.Ilyl-5-(2-pentyl)- 3.3 100 (1) (secobarbital 1. A bronchodilator-expectorant composition com S-ethyl-S-isoamyl 1.65 50 Precipitation occurred prised of a solution containing at least 40% by volume (amobarbital). within 1 wk. of water and characterized by containing in each 5 S-ethyl-S-n-butyl- 3.3 I“) (') milliliters thereof 16.6 to 175 mg. of theophylline, 7.5 to (butothal) S-ethyl-methyl-S- 1.98 60 ( ’) 350 mg. of glyceryl guaiacolate or an equivalent solubi henyl lizing weight of potassium guaiacol sulfonate or guaia (mephohsrbital). col, and from V6 to a full therapeutic dose of ephed S-ethyl-S-(Z-butyl} 0.99 30 Solution clear after 4 wks. rine, pseudoephedrine, methoxyphenamine, or protoky (butabarbital). storage at room temp. 55 crystallization occurred lo], and from 2 to 35 mg. of cyclopal, aprobarbital, at 0‘ C. a?er 4 wire. butabarbital, or pentobarbital [.1 wherein the amount of 5,5~diallyl 0.99 30 Solution remained clear theophylline dissolved in said solution exceeds the satu for l wk. but slight rated solution amount thereof in the solvents employed in crystallization occurred both at room temp. and said solution. and the theophylline in solution which ex at 0‘ C. alter 4 wks. ceeds said saturated solution amount is solubilized and 5-sllyl-5-cyclopent- 3.3 I00 Solution remained clear held in solution by said glyceryl guaiacolate or equivalent l-onyl(cyclopsl). at room temp. for 4 solubilizing weight ofpotassium guaiacol sulfonate or guai Mia, but light crystalli zation occurred at 0' C. acol. 5-allyl~5-isobutyl- 6.6 200 2. The composition of claim 1 containing up to 20% (itobarbital) _ by volume of alcohol. S-allyl-S-isopropyl- L98 60 Solution remained clear 65 3. The composition of claim 1 containing 4 to 25 mg. (aprobarbital). at room temp. for 4 wks. but slight crystalliza of ephedrine hydrochloride or ephedrine sulfate and tion occurred at 0' C. from 2 to 15 mg. of butabarbital per 5 milliliters of elixir. after 4 wks., but not * I U i I