US2893915A - Pharmaceutical compositions containing quaternary ammonium compounds and a steroid - Google Patents

Description

This invention relates to the adsorption of quaternary ammonium salts and is more particularly concerned with a composition whereby the oral administration of quaternary ammonium salts results in greatly increased physiological effects.

Many quaternary ammonium organic compounds have been shown to have useful pharmaceutical properties. However, these materials are usually administered direct 1y into the blood stream, because their relatively poor and erratic absorption from the gastro intestinal tract results in varying characteristics for the same drug when administered orally. Additionally, the effect usually expected from the quaternary ammonium compound is considerably less, due to the poor absorption. Of course, ;such limitations on the use of these pharmaceutical quaternary ammonium compounds has constituted a limitling factor in their wide overall acceptance. Generally speaking, the use of quaternary ammonium compounds for the purpose of lowering blood pressure (hypotensive agents) has gained significant recognition in recent years. Necessarily, much of the administration of these hypotensive agents should be accomplished orally, to eliminate the necessity for the careful control and professional assistance required where such materials are administered directly into the blood stream. In the field of antispasmodics, there are quaternaries which show a higher degree of activity than the corresponding tertiary amine, upon comparison by certain quantitative test methods. In practice however, the quaternary antispasmodics are relatively poorly absorbed when administered orally and have not generally been found suitable for practical application. In general then, it may be said that many quaternary compounds with useful activities when administered by parenteral routes are limited in their application, be-

cause the generally more convenient oral route is unavailable due to the relatively poor degree of absorption of these materials and the erratic effects that result.

It is, therefore, a principal object of the present invention to provide a composition which allows markedly improved absorption of quaternary ammonium compounds upon oral administration. Still another object of the present invention is the provision of such a composition which allows certain quaternary ammonium compounds to be administered orally with generally uniform results. Another object of the present invention is to provide a composition of matter containing a therapeutically active quaternary ammonium compound in admixture with a steroid acid. Another object of the present invention is to provide such a composition which contains between and 400 milligrams per dose of such steroid acid, in intimate mixture with a therapeutic quantity of a quaternary ammonium compound. Other objects will become apparent hereinafter.

The present invention contemplates a mixture of therapeutically active quaternary ammonium compounds in intimate mixture with steroid acids, such as bile acids or a mixture of the bile acids or their salts, all of which contain a cyclopentanopolyhydrophenanthrene nucleus with a moiety containing a carboxy group attached to the 17-position. Representative steroid acids, of which the so-called bile acids are examples, included within the tes Patent scope of the present invention include, for example, cholic acid, dehydrocholic acid, lithocholic acid, dihydroxycholanic acid, isodesoxycholic acid, norcholanic acid, diketocholanic acid, cholanic acid, allocholanic acid, choleic acid, dihydroxycholenic acids, desoxybilianic acid, glycocholic acid, ketocholanic acid and other bile acids, etc., mixtures of these and other steroid acids containing a cyclopentanopolyhydrophenanthrene nucleus and the carboxy group somewhere attached to or through the 17-position, as well as readily hydrolizable salts of these acids. Representative salts which are suitable include, for example, sodium, potassium, calcium, magnesium, lithium, etc. that is, salts which are water-soluble, and readily hydrolizable by the digestive tract.

Quaternary ammonium salts which are suitable include monoquaternary and di-quaternary organic compounds having pharmacologic activity as antispasmodic agents, cardiovascular agents, hypotensive agents, curarimimetic agents, and in general those materials which are quaternary organic compounds, suitable for oral administration. The germicidal surface-active type of quaternary compounds are not included within the scope of the present invention, since they are normally administered topically. Included wtihin the scope of the mono-quaternary and di-qu aternary 'organic compounds particularly suitable for the combination are, for example, tetraethylamrnonium, hexamethonium, pentamethonium, pentapyrrolidinium salts, homatropine methylbromide, hexamethylene bis [2 (1 methyl 9 pyrid 3,4b indolium) ldibromide, hexamethylene bis [2 (1,2 dimethyl 1,2,3,4- tetrahydro 9 pyrid 3,4b indolium)]dibromide, tetramethylene bis [2 (1 methyl 9 pyrid 3,4bindolium)]dibromide, pentamethylene bis [2 (1- methyl 9 pyrid 3,4b indolium)]dibromide, pentamethylene bis [2 (1,9 dimethyl 9 pyrid 3,4bind'olium) Jdiiodide, pentamethylene bis [2 (1 propyl- 9 pyrid 3,4b indolium)]dibromide, hexamethylene bis [2 (1,9 dimethyl 9 pyrid 3,4b indolium)] dibromide, 1 (1 methyl 9 pyrid 3,4b indolium) 3 (diethylmethylammonium)propane dibromide, 1 (1- methyl 9 pyrid 3,4b indolium) 6 (trimethylammonium)hexane dibromide, 1 isoquinolinium 6 (trimethylammonium)hexane dibromide, 1 (1,9 dimethyl- 9 pyrid 3,4b indolium) 3 (trimethylammonium) propane dibromide, l (1 methyl 9 pyrid 3,4bindolium) 3 (trimethylammonium) propane dibromide, 1 isoquinolinium 3 trimethylammonium propane dibromide, 1 (1 methyl 9 pyrid 3,4b indolium) 3- (N methylpyrrolidinium) propane dibromide, l (1- methyl 9 pyrid 3,4b indolium) 5 (trimethylammonium)pentane dibromide, 1 (1 methyl 9 pyrid- 3,4b indolium) 3 (N methylpi-peridinium)propane dibromide, 1 (9 pyrid 3,4b indolium) 3 (trimethylammonium)propane dibromide, l atropinium 3- (trimethylammonium)propane dibromide, l (isoquinolinium) 3 (N methylpyrrolidinium)propane dibromide, l tropinium 3 (trimethylammonium)propane dibromide, 1 (2 methyl 1,2,3,4 tetrahydroisoquinolinium) 3 (trimethylammonium)propane dibromide, 1 (4 bromoisoquinolinium) 3 trimethylammonium propane dibromide, l [4 -'(phenylthioethyl) pyridinium] 3 (trimethylammonium)propane dibromide, 1- (1,2 dimethyl l,2,3,4 tetrahydro 9 pyrid 3,4bindolium) 3 (trimethylammonium)propane dibromide, 1 (l methylisoquinolinium) 3 trimethylammonium propane dibromide, 1 (1,9 dimethyl 9 pyrid 3,4bindolium) 3 (N methylpyrrolidinium)propane dibromide, 1 [4 (3 indoleethenyl) pyridinium] 3- (trimethylammonium) propane dibromide, 1 (2- ethyl 1,2,3,4 tetrahydroisoquinolinium) 3 (trimethylammonium)-propane dichloride, 1 (2 methyl 1,2,3, 4 tetrahydroisoquinolinium) 3 (N methylpyrrolidinium) propane dibromide, 1 [4 (naphthylethenyl)- pyridinium-l 3 (trimethylammonium) -propane dibromide, 1 (4 benzylpyridinium) 3 (trimethylammonium)-propane dibromide, 1 [4 (3 i ndolethyl) pyr d iu r m hy m n m) r pane dibronude, 1 [4 (phthalamidoethyl) pyridinium] 3 (trimethylammonium) propane dibromide, 1 (tropinonium) 3 trimethylam'monium-propane dibromide, 1- (isoquinolinium') 4: (N methylpyrrolidinium) -butane dibromide, 1- (4 stilbazolium) 3 (trimethylammonium) propane dibromide, 1 (N methyl 4 benzylpiperidinium) 3 trimethyl-ammonium-propane dibromide, 1 (1,2 dimethyl 1,2,3,4 tetrahydroisoquinolinium) 3 trimethylammonium propane dibromide, 1- tropanium 3 trimethylammonium propane dibromide, 1 (4 indeneethylpyridinium) 3 (trimethylammonium) propanedibromide, 1 [4' (3 benzoxypropyl) pyridinium] 3- ('trimethylammonium) propane dibromide, 1 t-ropinium 3 (N --methylpiperidinium) propane dibromide, l' (tropinium) 3 (N- methylpyrrolidinium) propane dibromide, 1- [2 (3- indoleethyl)pyridinium-] 3 trimethylammonium propane dibromide, 1 (2 ethyltetrahydroisoquinolinium)- 4 (trimethylammonium) butane dibromide, 1 (2- methyltetrahydroisoquinolinium) 2 (trimethylamm'onium) ethane diodide, 1 (1 methyl 4 benzylpiperidinium) 2 (trimethylammonium) ethane diiodide, l- [4 1 methyl 3 indoleethyl-)pyridinium] 3 trimethylammonium propane dibromide, 1' (2 ethylisoindolinium) 3 (trimethyl'ammonium) propane dibromide, 1 [2 (1 naphthylethyl)pyridinium] 3 trimethylammonium propane dibromide, 1 [2 1 indeneethyl) pyridinium] 3 trimethylammonium propane dibromide, 2 diphenylmethylisoquinolinium bromide, 9 fiuorenyl isoquinolinium bromide, 2 diphenylmethyl; 1 methyl 9 pyrid 3,4b indoliumbromide, etc.

The combination is usually administered as a capsule, tablet or solution. Because of the bitter taste which is normally associated with the steroid acids, administration by solution is not as desirable as it is by tablet or capsule. The amount of steroid acid which will be used per dose, that is, per tablet, per capsule, or per volume of liquid-dose, is most suitably between the range. of 25 milligrams to 400 milligramsdepending tosome extent on the weight dosage of the therapeutic agent. Normally between 100 to 300 milligrams per capsule or dose is the more preferred. In; the case of I-(Z-ethyl-l,2,3,4-tetrahydroisoquinolinium) 3-(trimethylammonium)propaue disalt, 200 milligrams of the quaternary ammonium bromide or chloride and'ZQO milligrams of cholic acid constitutes a desirable ratio. Hexamethonium chloride may be used in tablets ranging from 100 to 300 milligrams of quaternary in combinationwith quantities ranging from 100 to 300-grams 'of' one of the steroid acids. Of. course the [particular anion associated with the therapeutic quaternary ammonium compound should be stable and non-toxic, but is otherwise not critical. Pentapyrrolidiniummay beused in 50 to 100 milligram tablets combined with 50 to 200 milligrams of the steroid acid. In the case of 1-[4-( l-methyl-3-indoleethyl)pyridinium]-3- trimethylammonium-propane dibromide, between 25 and 75 milligrams of the quaternary and 50 to 200 milligrams of asteroid acid per dose is adesirable ratio.

Preparation of the composition of the present invention is readily accomplished by intimately mixing the steroid acid and the quaternary. Conventional equipmentv may be employed. Where tableting is to be the end result, the use of excipients, fillers, coloring matter, etc., is contemplated. With capsules, the addition of the mixture directly to the capsule is usually satisfactory. Where solutions are used, the mixture is dissolved. in a suitable sol-. vent, which may contain other solutes suclras buffers, and the concentration regulated. Both pharmacological and-clinical studieshavelindicated that the absorption of 4 the quaternary ammonium compound compounded as discussed above and administered orally'is enhanced greatly: For example, in animals, upon the oral administration of hexamethonium, in an amount of 5 milligrams per kilogram of body weight, with 10 milligrams per kilogram of steroid acid, a blood pressure fall of 50 percent with 4.5 hours required'to return to pre-fall level was noted. This is in direct contrast to the oral administration of 5 milligrams per kilogram of hexamethonium without the steroid acid: which resulted in: a 45 percent blood pressure fall with only 1.0 hour required to return to pre-fall level.

Various modifications'may be made in the composition of the present invention wtihout departing from the spirit or scope thereof and I'- limit myself only as defined in the appended claims.

I claim: L

1. A composition of matter having enhanced pharmacologic action upon oral administration comprising: a physiologically-active, non-surface-active, quaternary arn-' monium compound per se pharmacologically effective upon oral administration in intimate mixture with a compound selected from the group consisting of cyclopentanopolyhydrophenanthrenes having a moiety. attached at the 17-position, said moiety comprising a carboxyl group, and hydrolyzable salts, of said cyclopentanopolyhydrophenanthrenes. 2. A composition of matter having enhanced pharmacologic action upon oral administration comprising: a

' physiologically-active, non-surface-active, quaternary ammonium, compound per se pharmacologically efiective upon oral administration in intimate mixture with between 25 and 400 milligrams per dose of a cyclopentanopolyhydrophenanthrene having a moiety attached at the 1 7-position, said moiety comprising a carboxyl group.

3. A composition of matter having enhanced. pharmacologicv action upon oral administration comprising: a physiologically-active, non=surface-active, bis-quaternary ammonium salt per se pharmacologically effective upon oral administration in intimate mixture with between and 300 milligrams per dose of a cyclopentanopolyhydrophenanthrene having a moiety attached at the 17-position, said moiety comprising a carboxyl group.

4. A, composition of matter having enhanced pharmacologic, action upon oral administration comprising: between about 25 and about 300'milligrams per dose of a physiologically-active, non-surface-active, bis-quaternary ammonium salt per sepharmacologically eifective upon oral administration. in intimate mixture with between about. 100 and about 300 milligrams per dose of a bile acid.

5. A composition of matter having enhanced therapeutic; action upon oral administration comprising: hexamethonium in intimate mixture with bile acid.

6. A composition of matter having enhanced thera-. peutieproperties which comprises: 1-(2-ethyll,2,3,4-tetrahydroisoquinolinium) 3 (trimethylammonium)-propane dibromide in intimate mixture with cholic acid.

7. A process comprising orally administering to an animal a composition of matter comprising: a physiologically-active, non-surface-active, quaternary ammonium compound per se pharmacologically effective upon oral administration in intimate mixture with a compound selected from the group consisting of cyclopentanopolyhydrophenanthrenes having a moiety attached at the 17- position,-said,moiety comprising a carboxyl group, and hydrolyzable' salts of said cyclopentanopolyhydrophenanthrenes.

24th ed., 1947, p. 807, Lippincott

Claims (1)

1. A COMPOSITION OF MATTER HAVING ENHANCED PHARMACOLOGIC ACTION UPON ORAL ADMINISTRATION COMPRISING: A PHYSIOLOGICALLY-ACTIVE, NON-SURFACE-ACTIVE, QUATERNARY AMMONIUM COMPOUND PER SE PHARMACOLOGICALLY EFFECTIVE UPOM ORAL ADMINISTRATION IN INITMATE MIXTURE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF CYCLOPENTANOPOLYHDROPHENANTHRENES HAVING A MOIETY ATTACHED AT THE 17-POSITION, SAID MOIETY COMPRISING A CARBOXYL GROUP, AND HYDROLYZABLE SALTS OF SAID CYCLOPENTANOPOLYHYDROPHENANTHRENES.