Pharmaceutical salts

Abstract

The invention relates to pharmaceutical salts comprised of a pharmaceutical active substance and of at least one sugar substitute, to medicaments containing these salts, and to the use of these salts for producing medicaments.

Claims

1. A pharmaceutical composition comprising a delayed-release formulation of a therapeutically effective amount of a pharmaceutical salt and one or more physiologically tolerable excipients, wherein the pharmaceutical salt is selected from the group consisting of: (a) ()-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol saccharinate; (b) (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol saccharinate; and (c) ()-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol saccharinate.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical salt is ()-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol saccharinate.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical salt is (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol saccharinate.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical salt is ()-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol saccharinate.

5. The pharmaceutical composition according to claim 1, which comprises one or more of the following release-delaying methods: (a) a release-delaying coating; or (b) the pharmaceutical salt embedded in a release-delaying matrix; or (c) the pharmaceutical salt bound to an ion-exchange resin.

6. The pharmaceutical composition according to claim 1, which is formulated as a tablet other than a chewable tablet, or as a capsule.

7. The pharmaceutical composition according to claim 6, which is formulated as a tablet other than a chewable tablet.

8. The pharmaceutical composition according to claim 6, which is formulated as a capsule.

9. A method of controlling pain comprising administering to a patient in need thereof a pain-controlling effective amount of the pharmaceutical composition of claim 1.

10. A method of controlling urinary incontinence comprising administering to a patient in need thereof an urinary incontinence-controlling effective amount of the pharmaceutical composition of claim 1.

Description

EXAMPLES

Example 1

(1) The preparation and the subsequent separation of the optically pure compound (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol was carried out according to DE-A-4426245. The corresponding part of the disclosure [sic] is hereby inserted as reference and is thus regarded as part of the disclosure.

(2) For the preparation of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol saccharinate, 2.58 g (10 mmol) of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol hydrochloride and 2.42 g (10 mmol) of saccharin-sodium dihydrate were in each case completely dissolved with warming in an amount of water which was as small as possible. Both solutions were then mixed with one another with stirring and then placed in a cool place overnight. The precipitated (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol saccharinate was separated off from the supernatant mother liquor, purified with ethanol and isolated according to conventional methods.

Example 2

(3) For the preparation of diphenhydramine saccharinate, 5.0 g (17.1 mmol) of diphenhydramine hydrochloride and 4.13 g (17.1 mmol) of saccharin-sodium dihydrate were in each case completely dissolved with warming in an amount of water which was as small as possible. Both solutions were then mixed with one another with stirring and then placed in a cool place overnight. The precipitated diphenhydramine saccharinate was separated off from the supernatant mother liquor, purified with ethanol and isolated according to conventional methods.

Example 3

(4) For the preparation of verapamil saccharinate, 415 mg (0.845 mmol) of verapamil hydrochloride and 204 mg (0.845 mmol) of saccharin-sodium dihydrate were in each case completely dissolved with warming in an amount of water which was as small as possible. Both solutions were then mixed with one another with stirring and then placed in a cool place overnight. The precipitated verapamil saccharinate was separated off from the supernatant mother liquor, purified with ethanol and isolated according to conventional methods.

Example 4

(5) For the preparation of morphine saccharinate, 285 mg (0.76 mmol) of morphine hydrochloride trihydrate and 183 mg (0.76 mmol) of saccharin-sodium dihydrate were in each case completely dissolved with warming in an amount of water which was as small as possible. Both solutions were then mixed with one another with stirring and then placed in a cool place overnight. The precipitated morphine saccharinate was separated off from the supernatant mother liquor, purified with ethanol and isolated according to conventional methods.

Example 5

(6) For the preparation of an oral gel, 0.33 g of methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol were first dissolved in 198.0 g of purified water at a temperature of 80 C. and the mixture was then cooled to 40 C. Then, initially 0.94 g of diphenhydramine saccharinate obtained according to example 2 and subsequently 2 g of xanthan gum were added with stirring, stirring was continued for one hour and evaporated water was replaced. After cooling to a temperature of 20 to 25 C., the mixture was flavored with 0.625 g of Tutti-Frutti 9/008897 (Dragoco Gerberding & Co. AG, 37603 Holzminden) while stirring.

Example 6

(7) 5 g of comminuted chewing gum mass (Popeye Amural Confections, Yorkville, Ill., USA) were warmed to a temperature of 30 to 40 C. in a Fanta dish. 187.9 mg of diphenhydramine saccharinate obtained according to example 2 were then incorporated into the viscous chewing gum mass using a pestle. The homogeneous mass was then portioned into teflonized molds to give portions of 1 g each.

(8) The taste test showed that the chewing gums which contained the diphenhydramine saccharinate had an excellent taste at the start and were still enjoyable even after a relatively long chewing time.

Example 7

(9) For the preparation of a juice on an aqueous basis, 0.33 g of methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol were dissolved in 199.22 g of purified water at a temperature of 80 C. The mixture was cooled to 40 C. and 78.5 mg of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol saccharinate obtained according to example 1 were added with stirring. 0.25 g of xanthan gum was then added, stirring was continued for one hour and evaporated water was replaced. After cooling to [lacuna] temperature of 20 to 25 C., the mixture was flavored while stirring with 0.075 g of orange-mandarin flavor 10888-56 (Givaudan Roure Flavors Ltd. CH 8600 Dbendorf).

Example 8

(10) In this example, the water solubility of certain pharmaceutical salts and of conventional salts of the corresponding active compound was determined according to the method indicated above. The solubility values thus obtained are presented in table 1 below:

(11) TABLE-US-00001 TABLE 1 Comparison of the water solubilities of certain pharmaceutical salts according to the invention and corresponding conventional salts of these active compounds. The conventional salt employed in each case is indicated in brackets. Solubility of Solubility of the active the active compound compound salt saccharinate in mg/ml of in mg/ml of Active compound water water ()-(1R,2R)-3-(3- 261 31 dimethylamino-1-ethyl- (hydrochloride) 2-methylpropyl)phenol (1RS,3RS,6RS)-6- 500 71 dimethylaminomethyl-1- (hydrochloride) (3-methoxy- phenyl)cyclohexane- 1,3-diol [sic] (+)-(1S,2S)-3-(3- 650 55 dimethylamino-1-ethyl- (hydrochloride) 2-methylpropyl)phenol ()-(1S,2S)-3-(3- 568 130 dimethylamino-1-ethyl- (hydrochloride) 1-fluoro-2-methyl- propyl)phenol ()-(2S,3S)-1- 2000 90 dimethylamino-3-(3- (hydrochloride) methoxyphenyl)- 2-methylpentan-3-ol (+)-(1R,2R,4S)-2- 33 10 dimethylaminomethyl-4- (hydrochloride) (4-fluorobenzyl-oxy)- 1-(3-methoxy- phenyl)cyclohexanol Morphine 52 25 (hydrochloride trihydrate) Amezinium 25 8 (metilsulfate) Phenylephrine 1250 380 (hydrochloride) Verapamil 200 7 (hydrochloride) Diphenhydramine 1000 7 (hydrochloride) Benzalkonium 500 <2 (hydrochloride) Codeine 250 200 (phosphate hemihydrate) Hydromorphone 330 130 (hydrochloride) Buprenorphine 14 2 (hydrochloride)

(12) As can be seen from the solubility values according to table 1, the solubility of the respective active compound saccharinates is lowered compared with the corresponding conventional active compound salts.