US3140233A - Tasteless pharmaceutical composition and process - Google Patents

Description

United States Patent 1 3,140,233 TASTELESS PHARMACEUTICAL COMPOSITION AND PROCESS Peter Rieckmann, Mannheim-Waldhof, Germany, assignor to C. F. Boehringer & Soelme G.m.b.H., Mannheim-Waldhof, Germany, a corporation of Germany No Drawing. Filed Apr. 19, 1962, Ser. No. 188,901 Claims priority, application Germany July 21, 1959 Claims. (Cl. 16782) The present invention relates to a process of producing tasteless pharmaceutical compositions and more particularly to a process of using the cetyl sulfate of the fi-dimethyl amino ethyl ether of (Z-methyl phenyl) benzylalcohol, for producing tasteless pharmaceutical compositions, and compositions containing same.

The present application is a continuation-in-part of copending application Serial No. 43,746, filed July -19, 1960, and entitled Water-Insoluble Salts of Basic Antihistaminic Compounds, and Process of Making Same.

It is of considerable importance in therapy, and especially in pediatry, to make administration of a pharmaceutical agent as easy as possible for the patient. This may be a rather decisive factor in achieving satisfactory results in psychiatry, where the patient should not become aware of receiving a drug.

In a number of instances, however, it has been found A impossible to neutralize completely the intensely bad and disagreeable taste of pharmaceutical compounds by the addition of taste-correcting agents. A conventional 3,140,233 Patented July 7, 1 964 ice effective because they are rapidly and completely split erty renders the salt especially suitable for certain kinds of drug preparations. Ondissolving the salt in an organic solvent which is miscible with water, for instance, 'in ethyl alcohol and pouring the resulting solution in Water,

'the acid addition salt of the antihistaminic compound is precipitated in the form of a stable emulsion so that addition of an emulsifier is not necessary. The resulting emulsion is tasteless. Due to this property the new salt can readily be used in the form of preparations to be applied by means of medicine droppers and as juices.

The acid addition salt according to the present invention can be prepared according to known methods by reacting the water-soluble salts of the ,B-dimethylamino ethyl ether of (Z-methylphenyl) benzylalcohol, for instance, its hydrochloride, with the alkali metal salts of the acid cetyl ester of sulfuric acid in an aqueous solution. It is also possible to react said' antihistaminic compound with the free cetyl sulfuric acid in a suitable organic solvent and to distill off the solvent.

The following examples serve to illustrate thepreparation of the new cetyl sulfate without, however, limiting the same thereto:

method of improving the taste of pharmaceutical compounds consists in providing water-insoluble derivatives thereof. These derivatives must meet with the following conditions:

The water-soluble salts of basic antihistaminic compounds, in particular, have a very bitter, harsh, and tart taste and exert an anesthesizing effect. Attempts have been made to eliminate the disagreeable taste of basic antihistaminic compounds by converting them into their insoluble salts. Such almost insoluble salts are the acid addition salts of fatty acids of high molecular weight and the salicylates. However, these compounds are not completely free of a disagreeable taste. Salts of basic antihistaminic compounds with tannic acid have also been prepared (German Patent No. 1,001,455). However, such salts can be obtained in a pure state only with some difiiculties. Furthermore, tannic acid, which is split off in the gastro-intestinal tract, is certainly not inert.

It is one object of the present invention to provide pharmaceutical compositions, containing as active agent, the substantially tasteless water-insoluble cetyl sulfate of the B-dimethylamino ethyl ether of the (2-methyl phenyl) benzylalcohol.

Another object of the present invention is to provide such compositions which may contain other drugs.

These and other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

According to the present invention it has been found that compositions which contain the cetyl sulfate of B- dirnethylamino ethyl ether of the (2-methyl phenyl) benzylalcohol are substantially tasteless and are highly Example 1 V 30.55 g. of the hydrochloride of the B-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol are dissolved in about ten times its amount of cold water. 34.4 g. of sodium cetyl sulfate are dissolved in about ten times its amount of hot water. Both solutions are combined while stirring. A white oil precipitates which accumulates ,at the bottom-of the vessel and solidifies, after standing for some time in a refrigerator. The supernatant liquid is poured ofl. The solid cake is triturated with cold water and washed, until free of sodium chloride, on a Buechne'r funnel. The resulting salt is dried in a vacuum at room temperature. Melting point: 43-45 C.

. Analysis.-Found:- 68.00% C.; 9.51% H; 5.6% S; 2.1l%'N. Calculated: 68.99% C.; 9.71% H; 5.42% S; 2.37% N (N determined by the Kjeldahl method: 2.25%

The'stoichiometric content of base in said salt is 45.57%. A content of 45.3% was calculated from the ultraviolet absorption at 259 mp.

' Example 2 26.9 g. of the fi-dimethylamino ethyl ether of (2 methyl phenyl) benzylalcohol are dissolved in 200 cc. of carbon tetrachloride. The solution is mixed with a "solution of 32.2 g. ofcetyl sulfuric acid in 300 cc. of carbon tetrachloride; After evaporation of the solvent the cetyl sulfate of Example 1 is obtained.

- In place of the sodium salt, theremay be employed the potassium salt or other alkali metal salts of said acid ester.

In place of the hydrochloride of the antihistaminic ba'se,there may be used other Water soluble acid addition salts, such as the hydrobromides, phosphates, maleates, succinates.

In place of carbon tetrachloride used 'as solvent for the antihistaminic base and cetyl sulfuric acid, there may be employed othersolvents wherein the base as well as the cetyl sulfate is soluble,-such as chloroform, methylene chloride, methanol, ethanol, acetone. I

As stated above, the new acid addition salt is characterized by its extreme insolubility in water, so that it is absolutely tasteless; by its rapid cleavage in the gastrointestinal tract so that'it exertsits'antihisaminic acivity shortly after administration; by its propery of yielding on cleavage, in addition to the antihistaminic agent, substantially nontoxic, well tolerated degradation products; and by its high solubility in organic solvents such as ethanol.

The new acid addition salt is administered in the form of solid shaped preparations such as tablets, pills, dragees, and the like, or in the form of aqueous emulsions and emulsions in sugar sirup, fruit juices, and the like, which do not require the addition of emulsifying agents.

Especially valuable pharmaceutical compositions of the cetyl sulfate according to the present invention are obtained, for instance, by combining the same with reserpine. Such a composition of the cetyl sulfate of the fi-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol and reserpine has proved to be an excellent psychotropic agent useful in many disorders such as vegetative and neurocirculatory dystonias, climacteric, preclirnacteric, and pregnancy disorders, and many others.

It is frequently of importance to administer such compositions in liquid form. This is not possible when using the fl-dimethylamino ethyl ether of (Z-methyl phenyl) benzylalcohol as such or in the form of its hydrochloride because the bitter taste of these compounds prevents its use. In such instances the combination of reserpine with the cetyl sulfate of said ether has proved of special advantage.

The following example illustrates such compositions without, however, being limited thereto.

Example 3 1 g. of the di-sodium salt of ethylene diamine tetraacetic acid is dissolved in 100 cc. of distilled water. The resulting solution is added to 50 l. of 96% ethanol. 50 g. of a mixture of 2,5-di-tertiary butyl-4-methyl phenol, ascorbyl palmitate and citric acid, sold under the trademark Oxynex 2004 by the firm E. Merck of Darmstadt, Germany, 53 g. of monocetyl sulfate, and 100 g. of reserpine are successively added thereto while stirring. Solution is achieved by heating of 50 C. with stirring. 30 kg. of polyethylene glycol 300 and finally 9.670 kg. of the cetyl sulfate of the B-dimethylamino ethyl ether of (Z-methyl phenyl) benzylalcohol obtained according to Example 1 or 2 are admixed thereto while stirring and the mixture is filled up to a volume of 100 liters by the addition of 96% ethanol. The resulting solution is a substantially tasteless preparation which contains 1 mg. of reserpine and 96.7 mg. of the cetyl sulfate of the B-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol (corresponding to 50 mg. of said base) per cc., Le. 40 drops.

Mono-cetyl sulfate is added to prevent splitting up of the cetyl sulfate of the p-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol by the reserpine base. Addition of said mono-cetyl sulfate thus is of considerable importance in the preparation of stable liquid compositions.

Such a liquid composition is preferably administered by adding 5 drops to 30 drops thereof into tea or other liquids, depending on the seriousness of the symptoms. Administration is repeated three times daily. The effective single dose thus is between about 0.2 mg. and about 0.75 mg. of reserpine and between about 6.2 mg. and about 27.5 mg. of the ether base (in the form of its cetyl sulfate) while the effective daily dose is between about 0.6 mg. and about 2.25 mg. of reserpine and between about 18.6 mg. and about 82.5 mg. of the ether base (in the form of its cetyl sulfate).

The preferred solvent is the mixture of polyethylene glycol and ethanol used in Example 3. Other non-toxic solvents and solvent mixtures may, of course, also be used.

Due to the insolubility of the cetyl sulfate of fl-dimethyl aminoethyl ether of (2-methyl phenyl) benzyl alcohol in water or aqueous liquids such as tea and the like and its capability of being readily and uniformly emulsified therein, the composition is substantially tasteless and thus free of the disadvantages of the bitter tasting Water-soluble salts of said basic ether and of their unwanted anesthetizing effects.

Such compositions, furthermore, are substantially free of the undesirable side-effects observed on administration of reserpine alone, such as bradycardia and excessive hypotension, disturbances of the voluntary nervous system such as Parkinsons symptoms and hypersalivation, and of the autonomic nervous system, such as diarrhea, edema, pains in the limbs While the sedative effect of reserpine is not reduced but actually increased.

I claim:

1. In a process of producing a substantially tasteless pharmaceutical composition, the steps which comprise dissolving the cetyl sulfate of the ,B-dimethylamino ethyl ether of (Z-methyl phenyl) benzyl alcohol in a substantially non-toxic, watermiscible organic solvent and adding the resulting solution to a drinkable aqueous liquid, thereby forming an emulsion of said cetyl sulfate in said liquid.

2. The process according to claim 1, wherein the organic solvent is a mixture of polyethylene glycol and ethanol.

3. In a process of producing a substantially tasteless pharmaceutical composition, the steps which comprise dissolving reserpine and mono-cetyl sulfate in ethanol, adding thereto polyethylene glycol and the cetyl sulfate of the ,B-dimethylamino ethyl ether of (Z-methyl phenyl) benzyl alcohol, and stirring said mixture to cause dissolution of the components.

4. In a process of producing a substantially tasteless pharmaceutical composition, the steps which comprise dissolving reserpine and mono-cetyl sulfate in a substantially non-toxic, water-miscible, organic solvent, adding thereto the cetyl sulfate of the fl-dimethylamino ethyl ether of (Z-methyl phenyl) benzyl alcohol, and stirring said mixture to cause dissolution of the components.

5. In a process of producing a substantially tasteless pharmaceutical composition, the steps which comprise dissolving reserpine and mono-cetyl sulfate in ethanol, adding thereto polyethylene glycol and the cetyl sulfate of the B-dimethylamino ethyl ether of (2-rnethyl phenyl) benzyl alcohol, stirring said mixture to cause dissolution of the components and adding the resulting solution to a drinkable aqueous liquid, thereby forming an emulsion of said cetyl sulfate in said liquid.

6. In a process of producing a substantially tasteless pharmaceutical composition, the steps which comprise dissolving reserpine and mono-cetyl sulfate in a substantially non-toxic, water-miscible, organic solvent, adding thereto the cetyl sulfate of the fi-dimethylamino ethyl ether of (2- methyl phenyl) benzyl alcohol, stirring said mixture to cause dissolution of the components, and adding the resulting solution to a drinkable aqueous liquid, thereby forming an emulsion of said cetyl sulfate in said liquid.

7. A substantially tasteless pharmaceutical composition comprising a solution of the cetyl sulfate of the [3- dimethylamino ethyl ether of (Z-methyl phenyl) benzylalcohol in a substantially non-toxic, water-miscible organic solvent.

8. A substantially tasteless pharmaceutical composition comprising a solution of the cetyl sulfate of the fl-dimethylamino ethyl ether of (Z-methyl phenyl) benzylalcohol in a mixture of polyethylene glycol and ethanol.

9. A substantially tasteless pharmaceutical composition comprising a solution of reserpine, mono-cetyl sulfate, and the cetyl sulfate of the fl-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol in a substantially non-toxic, water-miscible organic solvent.

10. A substantially tasteless pharmaceutical composition comprising a solution of reserpine, mono-cetyl sulfate, and the cetyl sulfate of the B-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol in a mixture of polyethylene glycol and ethanol.

No references cited.

Claims (1)

1. IN A PROCESS OF PRODUCING A SUBSTANTIALLY TASTELESS PHARMACEUTICAL COMPOSITION, THE STEPS WHICH COMPRISE DISSOLVING THE CETYL SULFATE OF THE B-DIMETHYLAMINO ETHYL ETHER OF (2-METHYL PHENYL) BENZYL ALCOHOL IN A SUBSTANTIALLY NON-TOXIC, WATERMISCIBLE ORGANIC SOLVENT AND ADDING THE RESULTING SOLUTION TO A DRINKABLE AQUEOUS LIQUID, THEREBY FORMING AN EMULSION OF SAID CETYL SULFATE IN SAID LIQUID.