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Publication numberUS2753288 A
Publication typeGrant
Publication dateJul 3, 1956
Filing dateJan 12, 1953
Priority dateJan 12, 1953
Publication numberUS 2753288 A, US 2753288A, US-A-2753288, US2753288 A, US2753288A
InventorsFrank E Visscher
Original AssigneeUpjohn Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Scopolamine lower-alkyl halide therapeutic composition
US 2753288 A
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Description  (OCR text may contain errors)

United States Patent SCOPQLAMINE LOWER-ALKYL HALIDE THERAPEUTIC COMPOSITIBN Frank E. Visscher, Kalamazoo Township, Kalamazoo County, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application January 12, 1953,

Serial No. 330,916

6 Claims. (Cl. 16755) This invention relates to therapeutic compositions and to a process for their administration. More particularly, it relates to compositions which are primarily intended for oral use in the treatment of gastro-intestinal disorders and to a process for their administration to human beings. This application is a continuation-in-partof my application Serial No. 325,041, filed December 9, 1952, now abandoned.

Gastro-intestinal disorders are common afllictions of the human race, peptic ulcer being one of the commonest manifestations thereof. Many types of surgical operations have been devised as a treatment for ulcer, but surgery involves serious risks, incurs post-operative disability, and is certainly not always regarded as the best way to treat such internal problems. Moreover, recurrence .of ulcer after surgery is not uncommon. For a considerable number of years, investigators have made a determined eltort to find a satisfactory drug therapy for such disorders. Some of the results of these investigations have been encouraging, and several promising drugs have appeared on the market and are now in common use. These include ,B-diethylaminoethyl 9-xanthenecarboxylate methobromide, pa-phenyibenzylidene) 1 ldimethylpiperidinium methyl sulfate, and phenyl cyclohexyloxy acetic acid diethyl amino ethyl ester brommethylate. However, all of these drugs leave much to be desired. The need for other and superior drugs for the alleviation of gastro-intestinal disorders is apparent.

One of the principal objects of the present invention is to provide therapeutic compositions which are effective in the treatment of gastro-intestinal disorders. Another object of this invention is to provide such compositions in which the active ingredient is a scopolamine lower-alkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms, and the halogen has an atomic weight greater than nineteen. A further object of this invention is to provide such scopolamine lower-alkyl halide compositions which are selectively active in the treatment of peptic ulcer and ulcerative colitis. Still another object of this invention is to provide novel scopolamine lower-alkyl halide compositions which are particularly well-adapted for the oral treatment of gastrointestinal disorders associated with hypersecretion and hypermotility. Still another object of this invention is to provide a process of counteracting gastric hypersecretion and hypermotility and thus combating gastro-intestinal disorders in human beings. Other objects of this invention will be apparent to those skilled in the art to which the invention pertains.

The foregoing and additional objects have been ac complished by the provision of novel scopolamine loweralkyl halide compositions and a novel process for their administration to human beings.

The active ingredients of the novel compositions of the present invention are quaternary ammonium derivatives of scopolamine (l-hyoscine). These materials are the N-lower-alkyl halides of the tropic acid ester of epoxytropine, being closely related structurally to atropine, to

warrant further exploitation.

Novatrin (the metho-bromide of homatropine), and to Eumydrin (the metho-nitrate of atropine).

These materials can be represented by the following structural formula:

wherein R is a lower-alkyl group having not more than two carbon atoms, and X is a halogen having an atomic weight greater than nineteen. As used throughout this specification, the term active ingredient refers to such scopolamine lower-alkyl halide.

The novel compositions of the present invention have proven clinically to have advantages over all of the products mentioned above in the treatment of gastrointestinal disorders. The novel compositions of the present invention, for example, demonstrate fewer sideefiects than either B-diethylaminoethyl 9-xanthenecarboxylate methobromide or phenyl cyclohexyloxy acetic acid diethyl amino ethyl ester brommethylate when used in clinically prescribed doses, and are far more efiective as gastric anti-secretory agents than either of'the above or p (wphenylbenzylidene) 1,1 dimethylpiperidinium methyl sulfate. In addition, the novel process and compositions of the present invention have been used successfully in treating patients after all other commercially available drugs of this type have failed.

The active ingredient of the novel compositions of the present invention is a scopolamine lower-alkyl halide, wherein the alkyl group contains not more than two carbon atoms, and the halogen has an atomic weight greater than nineteen. Some scopolamine alkyl halides are old compounds, the methyl bromide being known at least as early as 1902 (German Patent 145,996, issued September 27, 1902). Since that time several investigators have attempted to determine its pysiological properties, but, so far as is known, it has never been made commercially available, primarily because the results of the investigations were not sufiiciently encouraging to Up to the time of the present invention, scopolamine methyl bromide has never been administered orally because of the reported appearance of undesirable side-effects when administered parenterally even at very low dosage. The most serious was the 19 to 63 percent increase in heart rate after subcutaneous dosage reported by Ebbe Nyrnan in Acta Physiol. Scand. 6, 256 (1943). For the same or similar reasons, related drugs have either not been given orally or have been limited to dosages not in excess of one milligram and a total daily dosage of no more than three milligrams. Likewise, since scopolamine methyl bromide is structurally and pharmacologically related to atropine, it would be expected that scopolamine methyl bromide, when administered in higher dosages, would also produce uniformly more severe side-effects, such as extreme stimulation of the central nervous system, commonly referred to as atropine jag or acute toxic psychosis. Since scopolamine methyl bromide is even more closely related to scopolamine and scopolamine hydrobromide, it would also be expected that scopolamine methyl bromide would have marked central nervous system etiects. Scopolamine and scopolamine hydrobromide, usually administered in the form of scopolamine hydrobromide trihydrate, are especially stimulatory in lower animals, such as rats, while they are generally sedative or depressive in man. However, one to three milligram doses of these compounds in man have produced sleep on the one hand and hallucinations on the other, and in some patients as low as .2 to .75 milligram doses of scopolamine hydrobromide trihydrate have produced serious poisoning with cardiac and respiratory collapse.

It has now been found that, within certain limits, hereinafter fully set forth, increased dosages of certain scopolamine alkyl halides, e. g., scopolamine methyl bromide, do not produce the expected untoward side-reactions, but upon oral administration in the form of the novel compositions of the present invention, remarkably reduce the volume and acidity of gastric secretion. This activity coupled with reduction in motility renders the novel compositions of the present invention, as fully borne out by clinical observation, extremely useful in the treatment of peptic ulcer and other gastro-intestinal disorders associated with hypersecretion and hypermotility. In the course of clinical trials, the novel compositions of the present invention also exhibited utility in the relief of ulcerative colitis and regional enteritis. The favorable selective activity without untoward side-reactions within the limits specified for the novel compositions of the present invention is of the essence of the present invention. The remarkable oral activity demonstrated for the novel compositions of the present invention has not been suggested for scopolamine alkyl halides by the prior art during the period of the past fifty years of their availability, and the absence of untoward side-effects is most surprising in view of what would ordinarily be expected with increase in dosage to within what may now be called the therapeutic range.

According to the present invention, a scopolamine lower-alkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms, and the halogen has an atomic weight greater than nineteen, is associated with a non-toxic carrier which may be either a solid material or a liquid. Bland carriers are of course much preferred. The compositions can take the form of tablets, powders, capsules, liquid suspensions, or other dosage forms which are particularly useful for oral administration. Liquid diluents are employed for oral use. Such a medium can be a solvent such as water. The only basic limitations on the liquid diluent used are compatability and palatability. The compositions can take the form of scopolamine lower-alkl halide, admixed with solid diluents and/or tableting adjuvants such as cornstarch, lactose, talc, stearic acid, magnesium stearate, gums, or the like. Any of the tableting materials used in pharmaceutical practice can be employed where there is no incompatability with the scopolamine lower-alkyl halide. The material can be tableted with or without coactive materials. Alternatively, the scopolamine lower-alkyl halide with its adjuvant material can be placed in the usual capsule of resorbable material, such as the usual gelatin capsule, and administered in that form. In yet another embodiment, a powdered scopolamine lower-alkyl halide composition can be put into powder packets. Other examples are as follows: the scopolamine lower-alkyl halide composition can be prepared in the form of a suspension in a material in which it is not soluble; the scopolamine loweralkyl halide can be combined with human or animal feeds of various kinds; the scopolamine lower-alkyl halide composition can be prepared in the form of a laminated tablet for prolonged action; the scopolamine lower-alkyl halide can be combined with an antacid to provide a more complete therapy for peptic ulcer and the like; the scopolamine lower-alkyl halide can be combined with phenobarbital to provide relief for nervous reactions as well as peptic ulcer; the scopolamine lower-alkyl halide can be combined with an anti-proteolytic agent such as protamine sulphate, soy bean trypsin inhibitors, trypsin inhibitor fraction from blood, or the like; the scopolamine lower-alkyl halide can be combined with an anti-hemorrhagic and coagulant preparation such as thrombin, gelatin, vitamin K, carboxy-methylcellulose, methylcellulose or the like for use in the acute hemorrhagic stage of gastro-intestinal ulcer; the scopolamine lower-alkyl halide can be combined with hormonal substances, such as cortisone, ACTH, or the like, which have a tendency to produce or aggravate gastro-intestinal ulcers; the scopolamine lower-alkyl halide can be combined with local anesthetics effective in the gastro-intestinal tract, such as procaine hydrochloride, benzocaine, or the like; the scopolamine lower-alkyl halide can be combined with a carbonic anhydrase inhibitor, such as 2-acetylamino- 1,3,4-thiadiazole-5-sulfonamide; the scopolamine loweralkyl halide may be combined with any other adjuvant; or, combinations of the foregoing can be provided. High concentrations of scopolamine lower-alkyl halide, e. g., up to about 67 percent, can be obtained by utilizing tablet triturates.

The proportion of scopolamine lower-alkyl halide in the compositions of the present invention can be varied. It is necessary that the active ingredient constitute an amount such that a suitable dosage will be obtained consistent with the dosage form employed. Obviously several unit dosage forms may be administered at about the same time. Not less than about 2.5 milligrams and about .01 percent of active ingredient is used per unit dose, since the use of less than such dosage has not demonstrated any practical value in attaining the desired results. Likewise, it has been found that although an amount greater than twenty milligrams and about 67 percent of active ingredient is effective in relieving hypersecretion and hypermotility, side-effects may become serious at higher dosage levels. It is preferred to use from four to ten milligrams and from about .04 to about 12.15 per cent of active ingredient per dosage unit in order to obtain almost complete selectivity of action, achieving relief from gastric hypersecretion and hypermotility free from untoward side-reactions. It has also been found by actual clinical tests that the minimum total daily oral dosage required to achieve the desired result is about ten milligrams and, for optimum results, between about fifteen and about fifty milligrams of active ingredient per patient treated. Expressed in terms of percentages, the active ingredient in the novel compositions of the present invention comprises from about 0.01 to about 67 percent, preferably from about 0.04 percent to about 12.15 percent.

The novel compositions of the present invention have been prepared with solid and liquid diluents suitable for oral administration. Examples 1, 2, and 3 illustrate some of the solid forms. Example 4 represents a more special: ized solid form, namely, a laminated tablet. This type of laminated tablet is prepared to accomplish either one or both of two objectives: more efficiently to utilize the active material and to obtain more prolonged or delayed action. The enteric coating serves to resist disintegration of the tablet or pill in the acid juices of the stomach and permits some of the active ingredient to pass intact into the duodenum and thus have a more delayed action. Among the large variety of substances which can be used for enteric coatings are salol (phenyl salicylate), tolu balsam, shellac, casein, keratin, stearic acid, salol-shellac, salol-benzonaphthol, salol-tolu balsam, salol-stearic acidshellac, stearic acid-carnauba wax-soft paraflin-agar-elm bark, magnesium stearate-mastic, shellac-wool fat, shellac-castor oil, myristic acid-hydrogenated castor oil, cetyl alcohol, cetyl alcohol-shellac, cetyl alcohol-mastic, cel? lulose acetate phthalate, carboxymethyl cellulose (Ty: lose), poly-vinyl alcohol, shellac-ammonia, shellac-ammonia-alcohol, polycarboxylic acid esters of cellulose, cellulose phthalate, and the like.

Such enteric coated tablets may be prepared in several different forms. For example, they may consist of a tablet containing a scopolamine lower-alkyl halide uniformly coated with a sufficient amount of enteric material l0 p rmit the tablet to pass into the duodenum before dissolving and give a delayed reaction; a similarly coated tablet may in turn be coated with scopolamine loweralkyl halide to obtain immediate and prolonged activity; or in yet another embodiment a similarly coated tablet may in turn be coated with a combination of ascopolamine lower-alkyl halide and an antacid to obtain combined as well as immediate and prolonged activity. More explicitly, the latter form will not only permit delayed absorption and possibly greater efliciency of action, but also has the advantage of combined antacid and anticholinergic therapy and provides immediate and prolonged relief for gastric hypersecretion and hypermotility by acting immediately upon entry of the outer dose (the dose outside the enteric coat) into the stomach and at some time later upon entry of the inner core intothe duodenum.

Since liquid oral preparations are sometimes preferred to dry compositions, the liquid preparations illustrated by Examples 5, 6 and 7 were prepared and found to be similarly useful.

Since scopolamine methyl bromide compositions are most effective in the treatment of peptic ulcer as an adjunct to antacid therapy, the compositions shown by Examples 8 and 9 were formulated to permit such combined therapy. Among the antacids which are operative in the compositions of the present invention are aluminum hydroxide gel, magnesium oxide, calcium carbonate, aminoacetic acid (Glycine), dihydroxy aluminum aminoacetate, magnesium trisilicate, calcium caseinate, alkali metal bicarbonates, monocalcium phosphate, sodium carboxymethylcellulose, aluminum phosphate gel, bismuth subcarbonate, disodium phosphate, tricalcium phosphate, gastric mucin, non-toxic anion exchange resins, and the like. These antacids may be used alone or in combination. Possible combinations include magnesium trisilieate, aluminum hydroxide and mucin; calcium carbonate and glycine; aluminum hydroxide and sodium carboxymethylcellulose; magnesium oxide and sodium carboxymethylcellulose; and the like.

Since ulcer patients often have a nervous condition as a result of their ulcer, formulations shown by Examples 10, 11 and 12 were prepared and found to permit satisfactory combined therapy in that event. These examples illustrate the combination of scopolamine methyl bromide and a sedative barbiturate. Among the barbiturates useful in such a combination are allylisopropylbarbituric acid, isoarnylethylbarbituric acid, diethylbarbituric acid, diallylbarbituric acid, calcium ethylisopropylbarbiturate, n butylethylbarbituric acid, isopropyl bromallyl barbituric acid, sodium n-hexylethylbarbit'urate, sodium ethyl (l-methylbutyl) barbiturate, l-methylpropyl-p-bromallyl barbituric acid, phenylethylbarbituric acid, cyclohexenylethyl barbituric acid, isobutylallyl barbituric acid, sodium allyl (l-methylbutyl)-barbiturate, and the like.

The novel process of the present invention is the process of counter-acting gastric hypersecretion and hypermotility, and thus combating gastro-intestinal disorders, which comprises orally administering to a living human being from about 2.5 to about twenty milligrams, preferably four to ten milligrams, of scopolamine loweralkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms, and the halogen has an atomic weight greater than nineteen, preferably scopolamine methyl bromide, per unit dose, in the form of an oral therapeutic composition, preferably containing from about .01 percent to about 67 percent and especially from about .04 percent to about 12.15 percent of active ingredient. The daily dose per patient is usually from about ten to about fifty milligrams preferably between about fifteen and fifty milligrams, in terms of the active ingredient. Examples 1, 2 and 3 illustrate the manner in which the process of the present invention has been carried out utilizing the novel compositions of the present invention.

In general, the active ingredients of the novel compositions and process of the present invention can be prepared by reacting the commercially available scopolamine hydrobromide with a base, such as sodium hydroxide, extracting the resulting scopolamine by the use of solvent, such as ether, reacting the thus-produced scopolamine with a lower-alkyl halide, wherein the loweralkyl group contains not more than two carbon atoms, and the halogen has an atomic weight greater than nineteen, and separating the thus-produced scopolamine lower-alkyl halide. Although the reaction can be conducted in the absence of a solvent, it is preferred to use a solvent, such as ether, benzene, toluene, methyl ethyl ketone, or tetrahydrofuran. Although the reaction may under some conditions require between. about eight and about 500 hours to attain completion, depending upon the temperature of the reaction, between about eight and about hours is usually sufiicient.

The following compounds are operative as active ingredients in the novel compositions and process of this invention, with scopolamine methyl bromide being preferred: scopolamine methyl bromide, scopolamine methyl chloride, scopolamine ethyl bromide, scopolamine ethyl iodide, scopolamine methyl iodide, scopolamine ethyl chloride, and mixtures of the foregoing.

The following preparations and examples are illustrative of the compositions and processes of this invention but are not to be construed as limiting.

PREPARATION 1.SCOPOLAMINE METHYL BROMIDE in a one-liter separatory funnel, 94 grams (0.215 mole) of scopolamine hydrobromide trihydrate was dissolved in 250 milliliters of water, made alkaline by shaking with forty grams (1 mole) of sodium hydroxide in milliliters of water, and the free base immediately extracted with ether. As scopolamine is somewhat soluble in water, the aqueous layer was saturated with potassium carbonate and again extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate and the ether removed by distillation, leaving 65 grams (0.214 mole; 100 percent yield) of nearly colorless oil. Then 100 grams (1.05 moles) of cold methyl bromide was added to a chilled, SOD-milliliter pressure flask containing the 65 grams of scopolamine, the flask stoppered tightly with a clamp, and allowed to stand at room temperature for 96 hours. The flask was cooled before opening, excess methyl bromide removed by filtration, and the white solid washed thoroughly with dry ether. The yield of crude scopolamine methyl bromide was eighty grams (94 percent yield; 93.5 percent over-all yield). The salt was recrystallized from 550 milliliters of alcohol; first crop, seventy grams, melting point 212- 214 degrees Centigrade; second crop, six grams, melting point -200 degrees centigrade. The combined crops were again recrystallized from 500 milliliters of 3 -A alcohol; melting point 210-212 degrees centigrade. The third recrystallization from 600 milliliters of alcohol yielded 64 grams, melting point 214-2l6 degrees centigrade, 21 75 percent yield based on scopolamine hydrobromide trihydrate starting material.

PREPARATION 2.-Scor oLAMINE ETHYL CHLORIDE In the manner shown in Preparation 1, scopolamine ethyl chloride can be prepared by reacting scopolamine with more than one equivalent of ethyl chloride and separating the thus-produced scopolamine ethyl dnloride.

PREPARATION 3.--SCOPOLAMINE METnYr. CHLORIDE In the manner shown in Preparation 1, scopolamine '7 methyl chloride-can be prepared by reacting scopolarnine with more than one equivalent of methyl chloride and separating the thus-produced scopolamine methyl chloride.

PREPARATION 4.SCOPOLAMINE ETHYL IODIDE In the manner shown in Preparation 1, scopolamine ethyl iodide can be prepared by reacting scopolamine with more than one equivalent of ethyl iodide and separating the thus-produced scopolamine ethyl iodide.

Example 1.Tablet (five milligrams; ca. 5.1 percent) For a batch of 1000 tablets, five grams of scopolamine methyl bromide and 84 grams of lactose were intimately mixed as fine powders, and granulated with an aqueous solution of 2.6 grams of sucrose. After drying, the granules were lubricated with 4.9 grams of starch and 1.3 grams of calcium stearate and compressed into tablets on a tablet machine.

The individual tablets thus-produced contained the following quantities of ingredients:

Scopolamine methyl bromide milligrams Lactose grains 1.3 Sucrose do 0.04 Starch do 0.075 Calcium stearate do 0.02

Example 2.--Tablet (ten milligrams; ca. 9.0 percent) In a manner similar to that shown in Example 1, ten milligram dosages can also be prepared.

Scopolamine methyl bromide milligrams 1O Lactose grains 1.4 Sucrose do 0.04 Starch do 0.1 Calcium stearate do 0.02

In the manner shown in Example 1, numerous other oral dosages of the novel compositions of the present invention have also been prepared. The following tables summarize the effects of clinical trial on humans of these novel compositions. Oral dosage responses in the dosage range from five to ten milligrams of scopolamine methyl bromide per human subject are seen to be strongly antisecretory and usually without subjective or objective sideelfects. These doses produce 53 to 81 percent average reduction of clinical free acidity, as shown by Tables I and II. These reductions of free acidity are associated with reductions of volume of gastric secretion of roughly similar magnitude. It is therefore probable that oral doses of five to ten milligrams of scopolamine methyl bromide produce seventy to 95 percent decreases of acid output. Further, Table I shows an almost complete absence of side-effects in the dosage range of five to ten milligrams of scopolamine methyl bromide, and indicates that side-effects, while sometimes present, are not serious following dosages of fifteen and twenty milligrams.

TABLE I.ORAL DOSAGE C. U. in Table I refers to clinical units of free acidity, and is said to be significantly affected when a decrease of fifty percent or more is demonstrated in two consecutive fifteen minute periods. These units are numerically equivalent to the number of milliliters of one-tenth normal sodium hydroxide which is required to neutralize to pH 4 milliliters of gastric juice. The pH is said to be afiected when a rise of 0.5 is detected. The numbers in the Side effects column refer to the presence and severity of side effects in the patients treated. For example, 1 x 1+ means that one patient reported a side eifect of 1+ severity, severity being gauged by the clinician on an arbitrary scale ranging from 1+ for minimal to 4+ for intolerable. Thus 1 refers to mini-- TABLE II.

Inhibition Average Subjects of Free Duration Single Oral Dose, Mg. No. Acidity, of Ana-cid- Av. Perity, Hrs.

cent

Absence of side-effects in the specified dosage range is also demonstrated by the following data. Accommodation was measured by using the distance from the eyes to the point of bluring of a dot on a sheet of paper. Single values for pre-drug and post-drug periods were obtained.

TABLE III.OBJEOTIVE SIDE-EFFECTS Accommodation Scopolarnine Methyl Bromide Pro-drug Post-drug Impairment, No. x cm. No. x cm. Percent K 5t020mg 11x16.1 10x15.1 ncg. 6

Subjective side-effects (dryness of mouth, urinary retention, headache, weakness, etc.) were usually not encountered 'by administering scopolamine methyl bromide compositions.

This information is summarized in Table IV.

TABLE IV.INOIDENOE OF SUBJEOTIVE SIDE-EFFECTS A more thorough test was made to determine the incidence and severity of side effects of five milligram oral doses of scopolamine methyl bromide, with special regard for antisalivary action. Spearmint chewing gum stick) was used half-hourly for five minutes both morning and afternoon as a sialogogue. The drug was administered as 0.5 milliliter of ten milligrams per milliliter solution (one percent scopolamine methyl bromide) in a gelatin capsule at 11:30 a. m. No values for salivary TABLE V.-SUMMARY OF ANTISALIVARY ACTION OF. 6

resulted in dryness of the mouth beginning one to one and a half hours after dosage and lasting in one case for about five hours. There was no significant effect on heat rate and no interference with vision or urination. There was no indication of either stimulation or depression of the central nervous system nor has any such effect ever been observed with scopolamine methyl bromide compositions with either single doses or the repeated doses that have been administered. 1

MG. ORAL DOSES OF SCOPOLA- MINE METHYL BROMIDE Pre-drug Saliva- Post-drug Salivation Values (5 tion Values (Be- Time of min. collection) ginning 90 min. Post Max. Subjective Best Hr. Dose, mg. Subject after dosage) Drug Dryness Dryness Salivation Inhibn., (hrs. after (Ito 4 Inhib11., Percent dosage) Percent N 0. Av. VoI. N 0. Av. Vol.

(ml.) (mL) 6- I 13. 2 7 (i. 6 50 2% +2 64 t ta 2. 1 2 7 5, 12; 8 8 14. 3 -12 -6 7 12.2 8 12. 8 0 0 7 j 8. 8 8, 7. 6 l3 3% 0 7 8. 3 6 8.3 0 0 0 8. 12. 9 7 8. 8 32 5 +1 40 6 16.0 5 18.0 12 0 -10 7 7.9 9 7. 1 l0 0 3 14.3 8" 14.6 0 0 7 8 14. 3 7 11. 8 17 0 5 8. 2 7 9. 1 -11 0 9' 7 9. 6 7 8. 5 12 0 22 6 13. 8 6 11. 2 l9 3 +1 29 7 12.2 7 10. 9.- 11 ca. 3 +0. 5 21. 5 8 8. 7 9 8.1 7. 0 l4 5 14. 1 7 12. 12 0 18 flow were reported until ninety minutes after drug dosage.

As shown by Table V, averages of seven pre-drug and seven post-drug values for salivary flow were reported by thirteen volunteer subjects. Fifteen trials of five milligram oral doses in the thirteen subjects have yielded for the best. hour of inhibition an average reduction of salivary flow of 21.5 percent. Two trials of placebos led to reduction of fourteen and eighteen percent. On the basis of the. available data, no statistically significant evidence of antisalivary action for the drug administered group over that of the control group was apparent. No individual reporting less than twenty-nine percent. decrease in salivation reported subjective dryness of the mouth or nose.

It is evident that: (1) oral dosage with five milligrams of scopolamine methyl. bromide, given thirty minutes before lunch, produces on the average a moderate decrease in average salivary flow; (2) there is a good correlation between subjective dryness of mouth or nose and objective dryness as measured by decrease inrate of salivary flow; (3) there is a delay in onsetof maximum antisalivary action, when this action was manifest, of approximately three hours.

Other tests of side-effects oforal dosage in human subjects were also conducted. Tests of efiects of oral doses of scopolamine methyl bromide. in theproduction the side-effects have been made by three. volunteer subjects, at nine dosage levels as follows: 0.5, 1.0, 2.0, 3.0, 5.0, 7.5, 10, 15 and 20 milligrams. Record was made of sitting and standing pulse rates and of subjective symptoms, if any, including. drynessof month. No effects were observed at dosages below fifteen milligrams. At this level one of three subjects noted dryness of the mouth beginning about two hoursafter dosage; and con.- tinuing. for. approximately. three hours. Twoother subjects noteddryness onone occasionbut not. on a. second later occasion. Two trials of twenty milligram doses Further clinical testing has demonstrated the eifectiveness of the scopolamine lower-alkyl halide compositions of this invention fortreating gastro-intesinal disorders. Besides being eifective as gastric anti-secretory agents, the compositions of this invention have demonstrated extremely favorable selective activity as anti-spasmodic agents. Cliinical testing has also shown, in addition the absence of untoward side-reactions, that there is developed no tolerance to gastric anti-secretory and anti-spasmodic etfects of these compositions.

Example 3.Anim al preparation I Because animal experiments are. easier to carry out under controlled conditions than human experiments, considerable animal work has been done. The results thereof correspond favorably with the human data; given above. The animal data. reported below also. show the superiority of scopolamine methyl bromide over other products; reputed to have similar activity. Administration. by the intra-intestinal route isindieative oforal etfectiveness. 'I-The. scopolamine methyl bromide was ad,- ministeredin water solution throughout theanimal experiments. These solutions contained up toabout 12.15 percent of scopolamine methyl bromide.

In Table VI is, collected data, on. gastric secretion; in pyloric ligation rats. Mature male. rats were: starved for two daysandt operated. on under ether anesthesia. The pylorus was ligated and three cubic. centimeters of air were injected intragastricly. Intra-intestinal dosages of test compound were given immediately following; pyloric ligation, and priorto. woundclosure. The rats were thereafter deprived. of water. for two hours, Whereafter; they were sacrifiedwith the aid of chloroform. The stomachs were removed, and the volume of gastric juice, in; each was determined. Since noagentsthavetthus far. beenfound to exert: a. difierential effect on volume. and: acidityof gastric. secretion in rats, the volume of. juice was. taken as the basis for determining the rate of gastric acid secretion. A comparison was made with untreated controls, the amount of inhibition being calculated.

demonstrate in vivo antispasmodic action of scopolamine methyl bromide. Thirty minutes after oral dosage [Collection period 3 hr. following intra-lntestinal dosage.]

Experimentals Controls Compound Dose, Percent rug/kg. No. Av. Vol. No. Av. Vol. Inhibn. Rats Gastric Rats Gastric Juice .Tuice scopolamine Methyl Brornlde 1 0. 005 5 7. 3 5 7. 1 neg. Do 0. 01 5 8. 6 5 7. 1 neg. 1 0. 05 5 7.0 5 7.1 neg. 1 0. 1 5 7. 5 5 7.1 neg. 1 4 3.1 5 4. 5 31 l 1 6 3. 1 5 4. 5 31 5 5 1. 9 5 4. 5 58 1 5 l1 2. l1 3. 6 50 10 6 0. 9 G 4. 4 80 1 10 6 1. 0 6 4. 4 77 15 6 1. 0 6 4. 4 77 9 l 6 0.6 6 4. 4 88 11 5. 8 12 7. 3 2O 15 10 3. 7 1O 5. 8 47 6 O. 5 6 4. 5 90 40 6 0. 2 4 6. 8 97 0. 6 5 5.1 5 7.0 27 1. 0 5 3. 1 5 7.0 56 2. 5 3 1. 2 6 4. 4 73 5. 0 3 0. 7 6 4. 4 83 l Incubated with rat gastric juice for hour at 37 degrees centigrade.

I Compound A is fi-diethylaminoethyl 9-xanthenecarboxylate methobromide. Compound B is atropine sulfate. They are identified in a similar manner throughout the balance of this specification.

Toxicity was tested in mice and dogs at a dose of fifty milligrams per kilogram, and comparative results are summarized in Table VII. LD50" is the dosagein milligrams per kilogram which will kill fifty percent of the animals to which it is given.

TABLE VII.-ACUTE TOXICITY 1 Central nervous system.

Chronic toxicity tests to determine long-term effects of the drug have been made in groups of six rats dosed twice daily for eleven days. Three dosage levels were employed, depending on a predetermined value for the oral LD50 in mice (1414 mg./kg.). These levels were A, equal to the LD50; B, one-half the 1.1350; and C, one-fourth the LDso. The daily dose was divided into two portions and administered morning and afternoon. It was found that two of six rats in group A failed to survive. The average gain of weight per day for groups A, B and C was respectively 2.0, 2.1 and 5.5, while controls gained 4.8 grams per day. Neither the white nor the red blood cell count was decreased below normal in any group. 'The hemoglobin concentration was normal. No evidence of antisecretory activity in the blood plasma was found on the day following the last dose. tions were found to show no significant morphological variations.

It can be safely concluded from these toxicity tests that the equivalent toxic doses for human treatment are greatly in excess of the doses required to achieve the therapeutic results claimed herein for the novel compositions and process of the present invention.

A modification of the procedure of Brown et al., J. Am. Pharm. Assn. 39, 305 (1950) has been employed to Liver and kidney secwith the test compound, a charcoal mixture (five percent charcoal, three percent methylcellulose, ten percent gum acacia in water) was fed. After twenty minutes the rats were sacrificed, and the small intestines removed and measured. The distance traversed by the charcoal was measured and expressed as percent of total length of small intestine. The difference between the value for treated rats and controls is expressed as percent inhibition and is taken as a measure of antispasmodic activity. Compound scopolamine methyl bromide appears to be about one-eighth as potent as atropine, by the oral route. It is much more eliective than compound A.

TABLE VIII.ANTISPASMODIC ACTIVITY Does, Percent Percent Approx. Compound rug/kg. No. Intestine Inhibi- Atropine Oral Rats Travtion Index ersed scopolamine Methyl Bromi e 3 g 33 it, is

0. 5 6 50 31 Compound B 1.0 22 36 50 l 2.0 6 32 55 10 4 64 11 Compound A 30 6 52 26 lo 4 56 21 Controls 94 72 On the basis of the foregoing animal data it can be concluded (1) that scopolamine methyl bromide was approximately four times as potent as compound A in inhibiting gastric secretion in polyoric ligation rats; (2) that scopolamine methyl bromide is much more effective than compounds A as an antispasmodic; (3) that orally in mice, scopolamine methyl bromide was much less toxic than compound A; in dogs, fifty milligrams per kilogram doses had no observed ill effects other than mydriasis when given orally; in rats ten milligrams per kilogram doses showed comparable central nervous system stimulant ac tivity to compound A. On the basis of greater antispasmodic and gastric antisecretory activities plus somewhat lesser toxicity, scopolamine methyl bromide has demonstrated its superiority to compound A.

To determine the effects of scopolamine methyl bromide on gastric motility, the radiographic method described by Cannon, Am. J. Physiol. 12: 387 (1904). was used. Four dogs Weighing about ten kilograms were selected and trained to lie quietly on the X-ray machine. Prior to each study they were fasted for twenty hours. Thirty minutes after scopolamine methyl bromide was administered orally, thirty grams of barium sulfate in 150 milliliters of water was given by stomach tube. Thereafter, at thirty or sixty minute intervals, X-ray photographs of the dog were taken to determine the passage of the barium from the stomach. Scopolamine methyl bromide was assessed on the basis of its activity in increasing gastric emptying time. The results are tabulated in Table IX.

TABLE IX.-GASTRIC EMPTYING TIME IN DOGS One dog was used on a chronic study of the compound. The control gastric emptying time on this dog was 1.0 hour. After giving 1.5 milligrams subcutaneously, the gastric emptying time was 4.5 hours. The dog was then given 1.5 milligrams subcutaneously daily for three weeks. At the end of this period the gastric emptying time was found to be 4.0 hours after administration of 1.5 milligrams subcutaneously. There would appear to be no tolerance developed to this compound. 1

To illustrate further the superiority of the compositions of the present invention over compound A, the therapeutic ratios of the two drugs were calculated and are shown in Table X. A therapeutic ratio is the ration of the dose causing undesirable effects to the dose causing desirable effects. Mathematically, the larger the resulting quotient, the more favorable is the ratio.

Example 4.-Laminatd tablets (a) A typical laminated tablet can be prepared by compressing 2.5 milligrams of scopolamine methyl bromide into a tablet in a manner similar to that shown in Examples 1 and 2, and coating it with ammoniated shellac as disclosed in U. S. Patent 1,907,203. Other suitable .coatings are disclosed in U. S. Patents 2,196,768 and 2,433,244. A 2.5 milligram dose of scopolamine methyl Example 5.-Liquid preparation (a) Scopolamine methyl bromide was dissolved in water; sucrose, sucaryl, sodium phosphate and citric acid were added; and the mixture stirred until all dissolved. The glycerin was added, and all were mixed thoroughly to produce an oral liquid preparation.

Each milliliter 1,000 milliliters c0ntains containscopolamine methyl bromide 1 milligram. 1.0 gram. Sucrose U. S. P percent 650.0 grams. Sucaryl Sodium 0.228 percent.. 2.28 grams. Sodium Phosphate Dibasi 0.15 percent... 1.5 grams.

(NazHIOs) Citric Acid U. S. P 0.1 percent... 1.0 gram. Glycerin 10 percent..-.. 100.0 millilicrs. Deionizcd Water, q. s. ad 1,000.0 milliliters.

One teaspoon of this preparation gives about a fivemilligram dose and amounts to about 0.1

weight of scopolamine methyl bromide.

(b) In the manner shown in 5(a) supra, a liquid preparation containing scopolamine ethyl chloride is prepared by substituting scopolamine ethyl chloride for scopolamine methyl bromide.

Example 6.--Elixir The dry ingredients listed below were dissolved in a mixture of alcohol, glycerin, and water and mixed thoroughly to produce a high alcoholic content elixir.

percent by Each milliliter 1,000 milliliters contaihscontainscopolamine methyl bromide 1 mg 1.0 gram. Alcohol (95 percentlU. S. P 18 percent.. 190 milliliters. Glycerin 9.3 percent... 93 milliliters. Sucrose U. S. P" 11 percent...- 110 grams. Sodium Benzoate--- 0.22 percent... 2.2 grams. Deionized Water, q. s. ad 1,000.0 milliiters.

TABLE X.-THERAPEUTIC RATIOS OF COMPOUND A AND SOOPOLAMINE. METHYL BROIVIIDE Side Efiects Toxicity Effects in Acute Tox- Eftects in dogs-Cardioaccelerator Efiects in rabbits Effects 111 ratsrats-ONS Acute Toxicity icity in Action, Antisialogogne Antichmmo Stimulant in Mice0ral, Dogs ED card. a n 1 ggg g ffig Action 1c D50 50 mgJkg. y a is c at 50311188. 6 tivityin cx S. 0. Le-

DBO nt e (r S) 5, T (rats) ED antisec. at l0smg/kg. antisec thal Efiects Oomplund A-0.3 1 1. 5 22 no. scopolamine methyl bromide-3..- 3 8 2.0 280 no. Atropine 11.2

1 Measure of the central nervous system activity of a rat by a modification of the method or Schulte, Rcif et al., .1

PharmacoL, 70, 62 (1941), shown by motion of the cage in which I influence of a drug is the resulting quotlent, the less 1s the central nervous system stimulating effect of the drug used. These from the ratio of movement while under the the rat is confined and expressed as the quotient resulting to movement while not under its influence. The smaller data are not strictly therapeutic ratios but indicate superiority over atropine.

bromide is then coated on the outside of the ammoniated shellac coat. The outer dose is released immediately in the stomach, and the inner dose becomes effective only after the ammoniated shellac coated tablet has passed into the duodenum and disintegrated.

(b) In the manner shown in 4(a) supra, laminated tablets containing scopolamine methyl chloride are prepared by substituting scopolamine methyl chloride for scopolamine methyl bromide.

(LOW ALCOHOLIC) ELIXIR OF SCOPOLAMINE METHYL BROMIDE 500 milliliters 0.1 percent scopolamine methyl bromidegrams 0.5

1.5 percent alcohol 95 percent U. S. P -milliliters 7.9

61 percent sucrose (cane sugar) -grams 305.0 15 percent glucose syrupy U. S. P do 75.0 0.15 percent methylparaben do 0.75 0.037 percent propylparaben do 0.185

Deionized water, q. 5. ad 500 milliliters.

One teaspoon of this preparation gives about a 'fivemilligram dose of scopolamine methyl bromide.

Example 8.-Antacid tablets (a) Tablets of scopolamine methyl bromide and an antacid are prepared as follows: The scopolamine methyl bromide, aluminum hydroxide gel dried, magnesium trisilicate, saccharin and dextrin are intimately mixed as fine powders and granulated with an aqueous solution of starch and sucrose. After drying, the granules are lubricated with starch and magnesium stearate and compressed into tablets on a tablet machine.

Per tablet scopolamine methyl bromide -milligrams- 2.5 Aluminum hydroxide gel dried U. S. P grains 13.07 Magnesium trisilicate powder U. S. P -do 5.0 Saccharin soluble powder U. S. P -do-- 0.01 Dextrin white bolted do 2.0 Starch --d-- 0.28 Sucrose do 0.9 Magnesium stearate powder -do 0.12

One tablet supplies about a 2.5 milligram dose and contains about .18 percent by weigh-t of scopolamine methyl bromide.

b) In the manner shown in 8(a) supra, antacid tablets containing scopolamine ethyl iodide are prepared by substituting scopolamine ethyl iodide for scopolamine methyl bromide.

Example 9.-Liquid antacid preparation A liquid oral preparation of scopolamine methyl bromide and an antacid is prepared by dissolving scopolamine methyl bromide in part of the water containing glycerin, and propylene glycol. The hydrated alumina gel and magnesium trisilicate are added and passed through a .colloid mill until uniform. The resulting colloidal suspension is assayed. The product is standardized to thirty grains Al(OH)3 and sixty grains magnesium trisilicate with q. s. deionized water to make up one fluid Since the water content of alumina gel varies, a quantity of hydrated gel equivalent to thirty grains per fluid ounce of Al(OH)3 in the final product is used.

In order to obtain the most eliective doses of the antacids in the above preparation, about one tablespoon is given. This supplies about 6.25 milligrams and amounts to about .04 percent by weight of scopolamine methyl bromide.

Example 10.-Phen0barbital tablets Each compressed tablet contains: scopolamine methyl bromide 2.5 milligrams.

Phenobarbital 0.25 grain (or 0.5 grain). Calcium carbonate bolted 0.9 grain.

Lactose 0.5 grain.

Magnesium stearate 0.0035 grain.

Starch 0.05 grain.

Acacia 0.000262 grain.

White mineral oil 0.00196 grain.

Sucrose 0.231 grain.

The tablets were prepared as follows: The scopolamine methyl bromide, phenobarbital, calcium carbonate and lactose were intimately mixed as fine powders and granulated with acacia and sucrose. After drying, the granules were lubricated with starch, white mineral oil and mag- 15 nesium stearate, and compressed into tablets on a tablet machine with a fl t-inch scored punch. One tablet provides 2.5 milligrams or about 1.9 percent by weight of scopolamine methyl bromide.

Example 11.Liqaid phenobarbital preparation Phenobarbital and scopolamine methyl bromide were dissolved in alcohol. Propylene glycol and deionized water were added to make up 500 milliliters. The remaining ingredients were added and stirred into the mixture, with water being mixed in thoroughly to make up 1000 milliliters The recommended minimum dose is approximately one teaspoon which contains about five milligrams or 0.1 percent of scopolamine methyl bromide.

Example 12.Phen0barbital tablet triturate Each tablet triturate contains:

Scopolamine methyl bromide 5 milligrams. Phenobarbital U. S. P 0.25 (or 0.5) grain. Lactose U. S. P 0.41 (or 0.6) grain. Calcium carbonate bolted 0.82 (or 1.0) grain. Sucrose 0.231 grain.

Starch 0.05 grain.

White mineral oil U. S. P 0.00196 grain.

The tablet triturates were prepared as follows: The scopolamine methyl bromide, phenobarbital, lactose and calcium carbonate were intimately mixed as fine powders, granulated with a paste of starch and syrup, and dried at 130 degrees Fahrenheit. The granules were lubricated with starch and white mineral oil and compressed on a rotary tablet machine with a -inch fiat punch. One tablet is the recommended minimum dosage of this composition and supplies about five milligrams (about 4.2 percent by weight) of scopolamine methyl bromide.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. An oral therapeutic composition, having selective gastric antisecretory and antispasmodic activity, which is useful in combating gastro-intestinal disorders, comprising, in unit dosage, from about 2.5 to about twenty milligrams and from about 0.01 to about 67 percent of scopolamine lower-alkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms and the halogen has an atomic weight greater than nineteen, an

antacid, and a pharmaceutical diluent.

2. An oral therapeutic composition, having selective gastric antisecretory and antispasmodic activity, which is useful in combating gastro-intestinal disorders, comprising, in unit dosage, from about 2.5 to about twenty milligrams and from about 0.01 to about 67 percent of scopolamine lower-alkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms and the halogen has an atomic weight greater than nineteen, calcium carbonate, and a pharmaceutical diluent.

3. An oral therapeutic composition, having selective gastric antisecretory and antispasmodic activity, which is useful in combating gastrointestinal disorders, comprising, in unit dosage, from about 2.5 to about twenty milligrams and from about 0.01 to about 67 percent of scopolamine lower-alkyl halide, wherein the lower-alkyl I? group contains not more than two carbon atoms and the halogen has an atomic weight greater than nineteen, a sedative barbituric acid compnund, and a pharmaceutical diluent.

4. An oral therapeutic composition, having selective gastric antisecretory and antispasmodic activity, which is useful in combating gastro-intestinal disorders, comprising, in unit dosage, from about 2.5 to about twenty milligrams and from about 0.01 to about 67 percent of scopolamine lower-alkyl halide, wherein the lower-alkyl group contains not more than two carbon atoms, and wherein the halogen has an atomic weight greater than nineteen, and a pharmaceutical diluent.

5. An oral therapeutic composition in dosage unit form, having selective gastric antisecretory and antispasmodic activity, which is useful in combating gastro-intestinal disorders, comprising from about 2.5 to about twenty milligrams of scopolamine methyl bromide per dosage unit and a solid tableting adjuvant.

6. An oral therapeutic composition, having selective gastric antisecretory and antispasmodie activity, which is useful in combating gastro-intestinal disorders, comprising from about 0.01 to about 67 percent of scopolamine methyl bromide and a member selected from. the group consisting of a syrup and an elixir, the scopolamine methyl bromide being present in a concentration such that a unit dose of the composition provides between about 2.5 and twenty milligrams of scopolamine methyl bromide.

References Cited in the file of this patent FOREiGN PATENTS Germany Nov. 2, 1903 OTHER REFERENCES Howard: Modern Drug Encyclopedia, 5th ed., February 1952, pp. 26, 27, 97.

Merck Index, 6th ed. (1952), pages 852, 853. Malmberg: Acta Paediatricia, vol. 38 (1949), pp. 472 to 483.

U. S. Dispensatory, 24th ed. (1947), pp. 1178, 1179. Merck Index, 4th ed. (1930), p. 454. Frankel: Die Arzneirnittel-Synthese (1927), p. 363. Nyman: Acta Physiol. Scandinav., vol. 6 (1943), pp. 256 to 265.

New and Nonofficial Remedies (1949), page 447. Shepherd: Washington Post, Dec. 24, 1951, page 5B. Trade Reg. No. 573,713 registered April 28, 1953. Nyman (2): Acta Med. Scand. Suppl, vol. 206 (1946), pp. 506 to 509.

Kimbel: Neue Medizinische Welt, vol. 1, Sept. 16, 1950, pp. 1200, 1201.

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2881085 *Nov 9, 1953Apr 7, 1959Abbott LabThin film coating for tablets and the like
US3065142 *Jul 30, 1958Nov 20, 1962Armour PharmaGastric resistant medicinal preparation
US3131123 *Jan 12, 1960Apr 28, 1964Lab Francais De TherapeutiqueEnteric tablets and manufacture thereof
US3198827 *May 9, 1961Aug 3, 1965Boehringer Sohn IngelheimHydroxy-benzoic acid ethers and salts thereof
US3405070 *Jan 30, 1961Oct 8, 1968IbmProcess for preparation of microcapsules
US3764675 *Sep 27, 1972Oct 9, 1973Arnar Stone LabMethod of treatment of cardiac bradyarrhythmias
US3886084 *Aug 23, 1971May 27, 1975Champion Int CorpMicroencapsulation system
US4016279 *Jan 13, 1976Apr 5, 1977Boehringer Ingelheim GmbhN-ethyl-norscopolamine methobromide or n-methyl-scopolammonium bromide
US5057317 *Mar 22, 1988Oct 15, 1991Chugai Seiyaku Kabushiki KaishaSlow-release pharmaceutical agent
WO1992016528A1 *Mar 5, 1992Sep 16, 1992Boehringer Ingelheim IntNew bi- and tricyclic aminoalcohol esters, their preparation and their use in medicaments
Classifications
U.S. Classification514/271, 424/683, 514/291, 424/476, 424/480, 424/477, 424/481, 424/687, 424/606, 424/690
International ClassificationC07D451/10
Cooperative ClassificationC07D451/10
European ClassificationC07D451/10