US3188273A - Composition comprising salt of 1, 1'-methylene-bis-(2-hydroxy-3-naphthoic acid) and 1-diphenylmethyl-4-methyl-piperazine - Google Patents

Description

United States Patent COMPOSITION COMPRISENG SALT OF LldadETi YLENE-BES-(Z-HYDROXY-SNAPHTHOIC AGED) AND 1-DiPHENYLh lETHYL- i-METHYL-PLERA= ZiNE Emanuel Kroll and Herbert A. Lieberman, Dover, Del, assignors to International Latex Corporation, Eover, Del, a corporation of Delaware No Drawing. Filed Apr. 20, 1961, ar. No. 104,245

5 Claims. (Cl. MST-o5) This invention is tasteless salts of cyclizine, l-diphenyl- 4-methylpiperazine.

Cyclizine is effective in combating motion sickness and in its usual forms is readily soluble in the fluids of the mouth and stomach. Even very slight solubility in the mouth causes its extremely bitter taste to be exhibited while ready solubility in the stomach is desirable to give it quick drug action. The compound and its usual salts, however, are so ottensively bitter that they have to be made into tablets designed to be swallowed whole. Many people are not able to conveniently swallow Whole tablets and therefore cannot protect themselves against motion sickness with cyclizine unless they chew the tablets. The bitterness of the drug is so pronounced that few people care to chew the tablets and therefore the benefits of this drug cannot be enjoyed by all. The unpleasant taste is shown not only by the base form of the drug but also by all its heretofore known compounds such as the hydrochloride, cyclohexylsulfamate, tartrate, etc.

The present inventors have found that the revolting bitterness of this compound may be eliminated or reduced practically to zero by reacting it with l,1'-methylene-bis- (Z-hydroxy-B-naphthoic acid), otherwise known as pamoic acid, to form salts which are palatable because they are so insoluble in the month they do not exhibit any bitterness. While this is an important advance, the cyclizine parnoate salts take so long to dissolve in the stomach that their efiicacy is less than desired. The inventors have unexpectedly found that they can increase the solubility of the cyclizine pamoate salts in the stomach without affecting their insolubility in the mouth. By this invention the cyclizine drug remains tasteless in the mouth but fast acting in the stomach and it is thus possible for the first time to administer cyclizine in a tasteless form having a quick drug action comparable to that obtained from the objectionable, bitter form of the drug.

These desirable results are obtained by first converting the cyclizine to insoluble cyclizine pamoate and then com bining it with a suitable surfactant to selectively increase its solubility in aqueous acid solutions. Many difierent types of surfactants will serve the purpose, but not all. The surfactant chosen should be miscible or soluble in aqueous acid solutions; be compatible with the cyclizine pamoate salt in that it should not react with it to form salts which are physiologically inert or insoluble in dilute hydrochloric acid; be non-toxic and tasteless in the quantities used; and be capable of reducing the surface tension of aqueous 0.1 N hydrochloric acid. Surfactants which reduce the surface tension below 70 dynes per centimeter are operative; those which reduce the surface tension below 50 dynes per centimeter constitute a preferred group, and those which reduce the surface tension below 35 dynes per centimeter give optimum results. As used in this specification tasteless means that for most people there is no taste whatever or so little taste as to be completely unobjectionable.

Pamoic acid has two carboxyl groups which may participate in the salt-forming reaction with cyclizine. One mol equivalent of parnoic acid will react with one mol equivalent of cyclizine .to give a monocyclizine compound Where one carboxyl group only of the pamoic acid has ice reacted. By using two mols of cyclizine for one mol of pamoic acid, a double cyclizine compound is obtained Where both carboxyl groups have reacted. The salt where two mols of cyclizine have reacted with one mol of pamoic acid has a higher concentration of cyclizine and may be more advantageous than the mono-cyclizine salt in certain situations. Both the monoand di-cyclizine pamoate salts, however, are free from bitterness and are efiective in motion sickness. The reaction between the two components may be carried out in various ways. Salts containing one mol of cyclizine and one mol of pamoic acid may be prepared by reacting the monopotasslum salt of pamoic acid with one mol of cyclizine hydrochloride in an aqueous solution or other suitable solvent medium includes mixtures of solvents. By using the dipota-ssium salt of pamoic acid and two mols of cyclizine hydrochloride, a double cyclizine salt of pamoic acid is obtainable. The two components may also be reacted by treating the free acid with the free cyclizine base in a suitable solvent such as methanol, isopropanol, or N,N-dimethyltormam-ide and precipitating the product with a nonsolvent such as water it necessary. Other reaction media may be chosen from solvents which are neutral and polar such as the alkanols, etc. The reaction to form the desired salt occurs as soon as the ingredients are mixed but heat is effective in ensuring completeness of the reaction.

EXAMPLE 1 3.88 gm. of pamoic acid, 0.01 mol, were suspended in 200 ml. of methanol. 5.65 gm. of cyclizine base, 0.02 mol, were added and the mixture warmed to approximately 60 C. for A2 hour, the resulting precipitate of 4.7 gm. (102% of theory) being collected on a filter. The precipitate was thoroughly washed with hot methyl alcohol and then dried overnight at 60 C. Tasteless dicyclizine salt of pamoic acid melting at 168-17l C. was obtained.

EXAMPLE 2 3.88 gm. or 0.01 mol of pamoic acid Were suspended in 200 ml. of methyl alcohol, To this suspension was added 6.05 gm. or 0.02 mol of cyclizine hydrochloride and the whole warmed as in Example 1. 1.12 gm. or 0.02 mols of KOH dissolved in 10 ml. of water were then added with additional heating. The resulting precipitate of 4.4 gms. was washed with hot methanol and then with water, after which it was dried overnight at 60 C. The dicycliz-ine salt of pa-rnoi'c acid was tasteless and had a melting point range as in Example 1.

EXAMPLE 3 8.52 gm. or 0.02 mol of monopotassium pamoate were allowed to react with 8.04 gm. or 0.02. mol of cyclizine hydrochloride in 300 ml. of methanol. The precipitated reaction product of 12.3 gm. was collected on a Buchner tunnel, washed with methanol and dried overnight at 60 C. The monocycliz-ine salt melted at 211212 C.

EXAMPLE 4 Suspend homogeneously 430 grams or about 1.0 mol of finely powdered l,l'-methy1ene-bis-(Z-hydroxy 3 naphthoic acid) in 6000 ml. of methyl alcohol. Dissolve 309.5 grams or 1.1 mob of cyclizine base in 2000 ml. of methyl alcohol and add to the pamoic acid mixture with constant stirring. Mix well for at least one hour. Collect the precipitate in a Buchner funnel and wash oil the excess cyclizine base with about 3000 m1. of methyl alcohol. Dry overnight at 45 C. in oven. Yield is 705 grams, 97.3% of theory, of the monocyclizine salt of 1,1-meth ylene-bis-(2-hydroxy-3-naphthoic acid) having a melting point of 208209 C. Other solvents in which the reactants are at least partially soluble and which do not enter into the reaction may be used.

The cyclizine pamoate salts are generally tasteless greenish-yellow powders insoluble in water or alcohol but soluble in hydrochloric acid. They may be made as a suspension in flavored syrups for administration in liquid doses or dispensed in any pharmaceutically acceptable carrier. They may be made into chewable tablets or incorporated in lozenges, lollypops, chewing gum, etc. by methods known in the art.

Surfactants having the characteristics enumerated earlier herein and suitable for the purpose of this invention fall into many chemical classifications. They may be cationic, anionic, amphoteric or non-ionic. Included for example are alkyl sulfonates such as octylsulfonate and dodecyl sulfonate; quaternary ammonum compounds such as cetyl dimethyl benzyl ammonium chloride and the alkyl trimethyl ammonium chlorides sold by Armour as Arquads; alkyl aryl sulfonates such as dodecyl benzene sulfonate and sodium ethyl naphthalene sulfonate; fatty acid esters of hydroxy compounds, exemplified by glycerin, sorbitol and sugars, including esters such as sorbitol oleate and polyglyceryl oleate; alkylene oxide surfactants; alkyl benzene alkali metal sulfates such as isopropyl benzene sodium sulfonate and dodecyl benzene sodium sulfonate; di(n-octyl) sulfosuccinic acid, its salts and esters; fatty alcohol sulfates such as sodium lauryl sulfate, and the like. It is to be understood that the examples are illustrative only since any surfactant having the specified characteristics will work.

Particularly useful are polyalkylene oxide ethers obtained by condensing alkylene oxides such as ethylene oxide, propylene oxide, glycide and the like with organic compounds having at least one active hydrogen atom, for example at least one carboxyl, hydroxyl, amino, or amido group, etc. The amount of alkylene oxide condensed with the organic compound used in the preparation of the particular surfactant is not critical so long as suflicient alkylene oxide is used to make the surfactant miscible or soluble in water and aqueous acid solutions. This class of surfactants may be represented by the general formula where R represents the residue of an organic carboxy, hydroxy, amino or amido compound, etc. containing an active hydrogen, R and R represent hydrogen or a lower alkyl and n is an integer. Surfactants of this type are well known in the art and include, among others, those disclosed in U.S. Patents 1,970,578; 2,085,706; and 2,213,477.

Examples of suitable organic compounds are acids such as caproic, capryllic, capric, lauric, myristic, palmitic, oleic, linoleic, ricinoleic, stearic, dihydroxy stearic, eleostearic, erucic, behenic acid and the like; hydroxy compounds as hexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, cetyl, oleyl alcohols and diethylene glycol, octodecanediol, octomethyl glycol, decamethyl glycol, gycerine, propylene glycol, butylene glycol, mannitol, mannitan, sorbitol, sorbtian and the like. Esters containing an active hydrogen such as esters of the above acids with alcohols may also be used, including monoglycerides and diglycerides and partial esters of hexahydric alcohols such as the mono and poly fatty acid esters of sorbitol and mannitol, etc. disclosed in U.S. Patents 2,322,820 and 2,322,821, Phenols shown in U.S. 2,213,477 are additional examples of useful hydroxy compounds. Amino compounds are hexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, cetyl, oleyl amine, etc. Arnides include hexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, cetyl, oleyl amide and the like. Suitable also are the compounds disclosed in U.S. 2,674,619 where the organic compound containing an active hydrogen is first condensed with propylene oxide and then reacted with ethylene oxide to form the final surfactant.

Specific examples of these alkylene oxide surfactants which may be used include polyoxyethylene stearate (Atlas Powders Myrj 45) polyoxyethylene palmitate, polyoxyethylene ester of coco fatty acids (Armours Ethofat C-), polyoxyethylene oleate, polyoxyethylene lauryl ether (Atlas Brij and polyoxyethylene oleyl ether (Atlas Brij 30 and 35) polyoxyethylene oleyl ether (Atlas G3920), polyoxyethylene glyceryl ether, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween polyoxyethylene sorbitan tristearate (Tween polyoxyethylene sorbitan trioleate (Tween polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene ether of isooctyl phenol, polyoxyethylene ether of butylphenol, polyoxyethylene ether of octadecyl phenol, polyoxyethylene ether of hexyl amine, polyoxyethylene ether of octyl amine, polyoxyethylene ether of coco amine, polyoxyethylene ether of soybean amine, polyoxyethylene ether of stearyl amine (Armours Ethomeen), polyoxyethylene ether of stearamide, poly oxyethylene ether of oleyl amide (Armours Ethomid 0/15), polyoxyethylene ether of hydrogenated tallow amide (Armours Ethomid HT/60) polyoxyethylene ether of coco amine (Armours Ethomeen C-20), polyoxyethylene ether of polyoxyproylene (Wyandottes Pluronics F-68), polyoxyethylene ether of dodecyl alcohol, polyoxyethylene ether of diethylene glycol, polyoxyethylene ether of glycerol monooleate, polyoxypropylene ether of isooctyl phenol, and polyglycidyl ether of isododecylphenol.

The amount of undersurfactant depends upon the particular surfactant used. With some surfactants a quantity as low as 0.1% by weight based on the weight or volume of the dosage form containing the cyclizine pamoate has been found sufiicient, whereas with others as much as 0.5% or more may be required. The surfactant chosen should not have any unpleasant taste of its own in the concentration used and should be soluble or miscible in aqueous acid solutions. The end result is that an effective quantity reduces the time needed for the cyclizine pamoate salts to dissolve in acid media without materially influencing their tastlessness.

Representative examples illustrating the present invention are shown in the following table where an acidic aqueous solution corresponding to the acidity of synthetic gastric juice U.S.P., was prepared and the cyclizine salt, with and without the surfactant, was stirred into ml. of the acid solution at a constant rate. The time needed for solution was noted.

TAB LE I Salt Surfactant Amount, Minutes Cyclizine HOL Monoeyclizine Parnoete.

Myrj 45. Tween 20. Tween 40- Tween 60 Tween 65 Tween 80. Tween 85. Pluronie F- Brij30 Brij 35 Ethofat 0/25 Ethomeen C/ZO. do 01101242 PN PPFQQPPPFPQP mencncnenovcnenmoiencxm Dicyelizino Pamoate.

Myrj 45 Tween 60 Tween 65.

1 Equivalent to 100 mg. cyclizine HCl. Ethylene glycol bis(amino ethylether) tetraaeetic acid.

The following examples are illustrative of palatable formulations containing the products of this invention and are not to be construed as limiting.

Water, qs. to make 100.00 gm.

The cyclizine pamoate is suspended in about 20 ml. water. The sucrose is dissolved in sufficient water to make a syrup and the surface active agent, syrup, glycerin, saccharin sodium and sorbic acid are all then added to the pamoate suspension and mixed well. The suspending agent, Kelgin LV, which has been wetted in a separate container with some of the water, is then added, followed by the addition of the coloring agent and the flavor. Sufficient water is then added to make the total volume of 100 m1.

EXAMPLE 6 Cyclizz'ne pamoate suspension Cyclizine monopamoate gm 1.10 Guar gum gm .60 Sucrose gm 34.00 Glycerin ml 10.00 Sorbic acid em .05 Saccharin sodium gm .10 Tween 60 gm .50 Colors, qs.

Flavors, qs.

Water, qs. to make 100.00 gm.

A procedure similar to that of Example is used.

EXAMPLE 7 Cyclizine pamoate suspension Grams Cyclizine monopamoate 1.10

- Karayagum .50

Methylparaben .05

Saccharin sodium .10

Myrj 51 .50 Flavor qs. Water, qs. to make 100.00 ml.

A procedure similar to that of Example 5 is used. The monocyclizine pamoate of the above examples may be substituted by 0.77 gm. of dicyclizine pamoate.

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 herein as modifications and equivalents may be made within the teaching of our invention, and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 7

1. A pharmaceutical composition comprising the salt of 1,1-methylene-bis-(2-hydroxy-3-naphthoic acid) and 1- diphenylmethyl-4-methylpiperazine and a non toxic tasteless surfactant which reduces the surface tension of aqueous 0.1 N hydrochloric acid below dynes per centimeter and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1 wherein the surfactant is polyalkylene oxide ether.

3. A composition as defined in claim 2 wherein the polyalkylene oxide surfactant is polyoxyethylene stearate.

4. A composition as defined in claim 2 wherein the polyoxyethylene oxide surfactant is polyoxyethylene sorbitan monolaurate.

5. A composition as defined in claim 2 wherein the polyalkylene oxide surfactant is polyoxyethylene lauryl ether.

References Cited by the Exner UNITED STATES PATENTS 2,630,435 3/53 Baltzly et al 260-268 2,647,121 7/53 Jacoby 260-268 2,667,493 1/ 54 Slack 260-313 2,834,782 5/58 Schlesinger et a1 260-268 2,890,985 6/59 Marsh et a1. 167-65 2,925,417 2/60 Worth et al 260-240 2,976,213 3/61 Murphey 167-65 FOREIGN PATENTS 154 12/52 Phillipines.

' OTHER REFERENCES Chinn et al.: Journal Investigative Dermatology, vol. 20, pp. 177-84 (1953).

Chun: J. of Pharm. Science, vol. 50, No. 9, pp. 732-736, 1961, presented at A. Ph. A. Meeting, 1960.

Cooper, J. Am. Pharm. Assoc., Science Ed., vol. 46, No. 9, pp. 520-524, 1957.

Fuhrmann: Chem. Abst., vol. 50, pp. 6653-6654, 1956.

Jowdy: Carolina I. of Pharmacy, vol. 33, p. 465, 1952.

McCutcheon: Soap and Chemical Specialities, vol. 34,

,No. 2, p. 62, February 1958.

Nakamura: Chem. Abst, v01. 53, p. 4661, 1959.

Steck: J. Am. Pharm. Assoc., vol. 41, 1952, p. 455.

Wilson: American Drug Index, 1961, p. 430.

LEWIS GOTTS, Primary Examiner.

IRVINGNIARCUS, M. O. WOLK, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,188,273 June 8, l9

Emanuel Kroll et a1.

It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 30, for "5.65 gm." read 5.64 gm. column 4, line 4, strike out "ether (Atlas Brij 30 and 3S) polyoxyethylene oleyl; line 23, for po1yoxyproylene" read polyoxypropylene same column 4, line 29, for "undersurfactant" read surfactant Signed and sealed this 30th day of November 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Atteating Officer Commissioner of Patents

Claims (1)

1. A PHARMACEUTICAL COMPOSITION COMPRISING THE SALT OF 1,1''-METHYLENE-BIS-(2-HYDROXY-3-NAPHTHOIC ACID) AND 1DIPHENYLMETHYL-4-METHYLPIPERAZINE AND A NON TOXIC TASTELESS SURFACTANT WHICH REDUCES THE SURFACE TENSION OF AQUEOUS 0.1 N HYDROCHLORIC ACID BELOW 70 DYNES PER CENTIMETER AND A PHARMACEUTICALLY ACCEPTABLE CARRIER.