HK1064035B - Pharmaceutical salts of 1-phenyl-3-dimethylamino-propane compounds - Google Patents

Description

The present invention relates to pharmaceutical salts consisting of an active substance and at least one sugar substitute, medicinal products containing these salts and the use of these salts in the manufacture of medicinal products.

A wide range of pharmaceutical active substances with excellent efficacy cause a strongly bitter, often disgusting taste sensation in the patient when administered orally.

The formulation of pharmaceutical active substances with very good water solubility into medicinal products often poses problems in pharmaceutical practice, so the production of controlled-release drug forms is often difficult due to the very good water solubility of active substance salts. While a delay of these active substances can be achieved, for example, by coating the drug forms with retardant film coatings, this type of delay is associated with a relatively high cost, since retardant film coatings from aqueous supersoluble systems very good for aqueous active substances often only provide an insufficient diffusion delay. The production of these formulated active substance extracts therefore requires relatively more rapid chemical reactions.

According to the invention, this task is solved by the provision of pharmaceutical, i.e. physiologically compatible salts from a pharmaceutical active substance and at least one sugar substitute, the active substance being a salt-forming compound selected from the group The following substances are to be classified in the same heading as the active substance: sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, and sulphur dioxide and sulphur dioxide, respectively, and their salts and products, and their sulphur dioxide and their sulphur dioxide concentrations, and their sulphur dioxide and their products, and their sulphur dioxide and their products, sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their products, and their sulphur dioxide and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and, and,

The present invention therefore relates to pharmaceutical salts consisting of a pharmaceutical active substance and at least one sugar substitute, the active substance being a salt-forming compound selected from the group of The following substances are to be classified in the same heading as the active substance: sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, sulphur dioxide and sulphur dioxide, and sulphur dioxide and sulphur dioxide, respectively, and their salts and products, and their sulphur dioxide and their sulphur dioxide concentrations, and their sulphur dioxide and their products, and their sulphur dioxide and their products, sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their sulphur dioxide and their products, and their products, and their sulphur dioxide and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their products, and their sulphur dioxide and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and their products, and, and,

In a preferred embodiment of the present invention, the solubility of the pharmaceutical salts according to the invention in water is ≤ 250 mg/ml water, preferably ≤ 200 mg/ml, particularly preferred ≤ 150 mg/ml, most particularly preferred ≤ 100 mg/ml. This is also shown in particular by the reduction in the water solubility of the pharmaceutical salts according to the invention in relation to the water solubility of the best water soluble salt of the corresponding active substance according to the Pharmaceutical List, 12th edition ABDATA Pharma-Daten-Service, 65735 Asch/Taunus, preferably in relation to the corresponding hydrochloride by at least 50%, preferably by at least 65%, particularly preferred by at least 75%, preferably by at least 85%.

The present invention covers all sugar substitutes which, if formed in a form which is at least simply negatively charged, can form a salt with the respective active substance. The present invention also covers pharmaceutical salts in which the active substance has two or more different sugar substitutes as salt partners. The pharmaceutical salts of the present invention contain saccharin, cyclamate or acesulfamarin, especially saccharin, as salt-forming sugar substitutes.

The invention covers all pharmaceutical active substances of the above group which, when formed into a form at least simply positively charged, can form a salt in anionic form with the sugar substituent (s) concerned.

The manufacture of the pharmaceutical salts of the invention may be carried out by conventional methods known to the professional. Preferably, in order to manufacture the pharmaceutical salts of the invention, at least one salt of the active substance and at least one salt of the sugar substitute are dissolved separately in the smallest possible quantity of solvent or mixture of solvents, if necessary, under heating.

The two solutions are then added together, where necessary mixed and where necessary cooled. If the solution, if any, is cooled and the pharmaceutical salt of the invention falls at least partially from the active substance and the sugar substitute, it is separated by the usual methods, preferably by suction filtration. The separated pharmaceutical salt is then, if necessary, cleaned by the usual methods known to the professional, such as recrystallization, washing or stirring in an appropriate solvent. If the pharmaceutical salt has not yet completely evaporated, the remaining solution should preferably be completely compressed in the rotary evaporator and the pharmaceutical salt of the invention extracted from the residue by usual methods known to the professional and cleaned as described above.

The solvent or mixture of solvents suitable for manufacture and the appropriate conditions of application, such as temperature or duration of application, can be determined by the professional by simple preliminary tests. If both the active substance and the salt of the sugar substitute are sufficiently soluble in water, water is preferred as solvent. The salt of the active substance is preferably its hydrochloride, hydrobromide, phosphate, hydrogen phosphate, hydrogen sulphate, sulphate, nitrate or methyl sulphate. The salt of the sugar substitute is preferably its sodium, potassium, calcium or ammonium salt.

It is also possible, of course, to incorporate the active substance itself with the free acid of a sugar substitute in a suitable transfer medium and to isolate and, if necessary, purify the resulting pharmaceutical salt by usual methods known to the professional.

The present invention also relates to medicinal products containing at least one pharmaceutical salt of the invention and, where appropriate, physiologically compatible excipients, which may be used to treat the indications known for the active substances concerned.

Preferably, the drugs of the invention for the control of pain contain at least one pharmaceutical salt of the invention, and preferably contain the corresponding saccharinates as pharmaceutical salts of these active substances.

For the treatment of urinary incontinence, preferably, medicinal products of the invention shall be used which contain at least one pharmaceutical salt of the invention.

The medicinal products of the invention may be in solid, semi-solid or liquid form, and are preferably for oral administration.

In a preferred embodiment, the product is available as a gel, gum, juice, spray, tablet, chewable tablet, dragee, powder, if any, in capsule form, easily reconstitutable dry preparations, preferably in gel, aqueous or oily juice, sublingual spray, tablets or chewable tablets.

Preferably, the medicinal product may also be in multi-particle form, preferably in the form of milk-based tablets, microcapsules, granules, crystals or pellets, preferably in the form of micro-tablets, granules or pellets, whether or not packaged in capsules or sold as tablets.

If the medicinal product is presented in the form of granules or pellets, they may preferably be in the range of 0.1 to 3 mm, and preferably in the range of 0.5 to 2 mm.

If the medicinal product is in the form of micro-tablets, they may preferably be of a diameter in the range of 0,5 to 5 mm, preferably in the range of 1 to 3 mm and preferably in the range of 1 to 2 mm.

If the medicinal product is in the form of active substance crystals, microparticles, micropellets or microcapsules, these may preferably be in the range of 10 μm to 1 mm, preferably in the range of 15 μm to 0,5 mm and preferably in the range of 30 μm to 200 μm.

The medicinal products of the invention may also contain, as additional components, the usual physiologically compatible excipients known to the practitioner, depending on the form of manufacture.

Where the medicinal products of the invention are in the form of tablets or micro-tablets, they may preferably contain microcrystalline cellulose, cellulose ether, lactose, starch, starch derivatives, sugar alcohols, calcium hydrogen phosphate and the usual binders, flow regulators, lubricants and/or explosives known to the professional as physiologically compatible excipients.

If the medicinal products of the invention are available in the form of gels or chewing gum, they may preferably contain methylparabens, propylparabens, xylitol and/or xanthan gum as physiologically compatible excipients.

If the medicinal products of the invention are in the form of pellets, granules or micropellets, they may preferably contain microcrystalline cellulose, cellulose ether, lactose, starches and starch derivatives, sugar alcohols, calcium hydrogen phosphate, fatty alcohols, glycerol esters or fatty acid esters as physiologically compatible excipients.

Where the medicinal products of the invention are in the form of microcapsules or micro-particles, they may contain the usual physiologically compatible excipients known to the practitioner, depending on the method of manufacture used.

The manufacture of the medicinal products in accordance with the invention may be carried out by conventional methods known to the professional.

Where the medicinal products are in the form of tablets, preferably the pharmaceutical salt and, where appropriate, the physiologically compatible excipients of the invention are mixed homogeneously, granulated and pressed into tablets by wet, dry or melting granulation or by direct tabletisation of the pharmaceutical salt with further excipients.

The preparations of the medicinal products according to the invention in the form of pellets may preferably be prepared by mixing the pharmaceutical salt and physiologically compatible excipients, extrusion and spheronisation, by building-up pelletisation or by direct pelletisation in a high-turn mixer or in the rotor spindle layer.

The microcapsules are produced by conventional microencapsulation methods, such as spray drying, spray hardening or coalescence.

The medicinal products of the invention in semi-permanent form, such as gels or chewing gum, are preferably suitable for application of the pharmaceutical salt of the invention through the oral mucosa, the medicinal products of the invention in solid or liquid form, such as oily or liquid juices, tablets or multiparticle forms are preferably suitable for application of the pharmaceutical salt of the invention through the gastrointestinal tract.

If the medicinal product in solid form is intended to be taken up by the intestinal tract, it must have at least a gastric-resistant coating, which ensures that it passes through the intestinal tract undissolved and that the pharmaceutical salt is not released until the intestinal tract.

The pharmaceutical product of the invention may also contain the pharmaceutical salt of the invention in a partial or complete delayed form.

The delay of drug delivery is preferably based on the application of a delay coating, embedding in a delay matrix, attachment to an ion exchange resin or a combination of these delay methods.

Preferably, the retarder coating shall be based on a water-insoluble, modified natural or synthetic polymer, or on a natural, semi-synthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of the above components.

The water-insoluble polymers used to produce the retarder coating are preferably poly (meth) acrylates, preferably poly (C1-4) alkyl (meth) acrylates, poly (C1-4) di-alkylamino (C1-4) alkyl (meth) acrylates and/or their copolymers, preferably ethyl acrylate/methyl methacrylate copolymers with a molar monomer content of 2 : 1, ethyl acrylate/methyl methacrylate/trimethylammonium methacrylate copolymers with a molar monomer ratio of 1: 2: 0,1, ethyl acrylate/methyl methacrylate/trimethyl methacrylate copolymers with a molar monomer ratio of 1 : 2 or more, or one or two of the following polymers:

These coating materials are available on the market as 30% by weight aqueous latex dispersions under the names Eudragit RS30D®, Eudragit NE30D® and Eudragit RL30D® respectively and are therefore also used as coating materials.

Polyvinyl acetate may also be used as a water-insoluble polymer for the production of the retardant coating for the medicinal products of the invention, where appropriate in combination with other excipients, which are available on the market as aqueous dispersions containing 27% by weight of polyvinyl acetate, 2.5% by weight of povidone and 0.3% by weight of sodium lauryl sulphate (Kollicoat SR 30 D®).

In another preferred embodiment, the retarder coatings of the medicinal products of the invention are based on water-insoluble cellulose derivatives, preferably alkyl cellulose, such as ethyl cellulose, or on cellulose esters, such as cellulose acetate, as coating material. The coatings of ethyl cellulose or cellulose acetate are preferably applied from aqueous pseudolate dispersion.

As natural, semi-synthetic or synthetic waxes, fats or fatty alcohols, the retardant coating in the medicinal product of the invention may contain, preferably, carnauba wax, beeswax, glycerin monostearate, glycerin monobhenate (Compritol ATO888®), glycerin tri-palmitostearate (Precirol ATO5®), microcrystalline wax, cetyl alcohol, cetyl stearyl alcohol or a mixture of at least two of these components.

If the retardant coating is based on a water-insoluble, modified natural and/or synthetic polymer, the coating dispersion or solution may contain a common physiologically compatible plasticizer known to the professional in addition to the corresponding polymer to reduce the minimum film temperature required.

Suitable plasticizers are, for example, lipophilic diester of an aliphatic or aromatic dicarboxylic acid with C6-C40 and an aliphatic alcohol with C1-C8, such as dibutylphthalate, diethylphthalate, dibutylsebacate or diethylsebacate, hydrophilic or lipophilic ester of citric acid, such as triethylcitrate, tributylcitrate, acetyltributylcitrate or acetyltriethylcitrate, polyalkyleneglycols, such as polyethylene glycol or propylene glycols, ester of glycerin, such as triacetin, Eryvacet® (accelerated mono- and diglycerides, C44H23O525H47O to C47O7), with Tritritol (Methylbutylbutyrate) or at least two varieties of Eryvacetine, and, where appropriate, Erymacetol® (Tritol) or Erymacetol®, containing at least two of the following:

The retarder coating preferably contains the plasticizer (s) in quantities of 5 to 50% by weight, preferably 10 to 40% by weight and preferably 10 to 30% by weight, depending on the amount of polymer used.

In individual cases, for example for cellulose acetate, higher amounts of plasticizers, preferably up to 110% by weight, may be used, depending on the amount of cellulose acetate.

In addition, the retarder coating may contain other common auxiliaries known to the professional, such as lubricants, preferably talc or glycerin monostearate, colouring pigments, preferably iron oxides or titanium dioxide, or surfactants, such as Tween 80®.

The release profile of the delayed active substance can be adjusted by the usual methods known to the practitioner, such as by the thickness of the coating or by the use of additional excipients as coating components. Suitable excipients are, for example, hydrophilic or pH-dependent pore formers such as sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose acetate succinate, lactose, polyethylene glycol or mannitol or water-soluble polymers such as polyvinylpyrrolidone or water-soluble polymers, preferably hydroxymethylpropylcellulose or hydroxypropylcellulose. The retarder coating may also contain insoluble or lipophilic excipients, such as alkylated silicon dioxide, marketed as aerosol R972®, or magnesium stearate to further enhance the retarder.

The particular formulation of the medicinal product according to the invention may, where appropriate, have at least one additional coating in addition to the delay coating, such as a flavour enhancer coating or a stomach-resistant coating.

The gastric-resistant coating is preferably based on methacrylic acid/methyl methacrylate copolymers with a molar ratio of 1:1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers with a molar ratio of 1:2 (Eudragit S®), methacrylic acid/ethyl methacrylate copolymers with a molar ratio of 1:1 (Eudragit L30D-55®), methacrylic acid/methyl methacrylate copolymers with a molar ratio of 1:1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers with a molar ratio of 1:3 (Eudragit FS®), methacrylic acid/ethyl methacrylate copolymers with a molar ratio of 1:1 (Eudragit S®), methacrylic acid/ethyl methacrylate copolymers with a molar ratio of 1:1 (Eudragit RED®), and may also be used in combination with at least one of these compounds, and may be used in combination with Eudragit Eudragit Neucet®, Eudragit Neucet®, Hydroxy/acetyl cellulose, or Eudragit RED®, and/or Eudragitroacethanol.

The coatings may be applied by usual methods suitable for the particular coating and known to the professional, such as by spraying solutions, dispersions or suspensions, by melting or by powder ordering. The solutions, dispersions or suspensions may be used in the form of aqueous and/or organic solutions or dispersions, with preference being given to aqueous dispersions. Organic solvents may be alcohols, e.g. ethanol or isopropanol, ketones, e.g. acetone, esters, e.g. ethyl acetate, chlorinated hydrocarbons, e.g. dichloromethane, alcohol chloride or a special mixture.

If the medicinal product is in multi-particle form and the active substance is to be administered at least partially delayed, the delayed coating shall preferably be applied by coating the coating with the water and/or organic media, preferably water, using the swirling process and drying the coating preferably at the same time at normal temperature in the water and, if necessary, at the same temperature in the water, after the preparation of the active salt containing the multiparticle forms with the corresponding polymers and, where appropriate, another active substance and/or the same active salt and, where appropriate, other physiologically compatible excipients.

Preferably, the coating for poly (meth) acrylate coatings shall be dried at a sulphur temperature in the range of 30 to 50 °C, preferably in the range of 35 to 45 °C.

For cellulose based coatings, such as ethyl cellulose or cellulose acetate, drying is preferably carried out at a temperature in the range of 50 to 80 °C, and particularly preferably in the range of 55 to 65 °C.

Wax coatings can be applied by melt coating in the back layer and cooled to complete solidification at temperatures below the respective melting range after coating.

To modify the drug release profile, the medicinal product of the invention may also contain the pharmaceutical salt to be delayed in a delay matrix, preferably evenly distributed.

The matrix materials may be physiologically compatible, hydrophilic materials known to the professional. Preferably, polymers, especially cellulose ether, are used as hydrophilic matrix materials. Cellulose esters and/or acrylic resins are used.

Matrix materials made from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures of at least two of the above materials, are also preferred; in particular, mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures of at least two of the above materials are preferred as hydrophobic materials.

It is also possible to use mixtures of the above hydrophilic and hydrophobic materials as a retarder matrix material.

The retarder matrix can be produced by the usual methods known to the skilled person.

The invention also relates to the use of at least one pharmaceutical salt and, if necessary, physiologically compatible excipients in the manufacture of a medicinal product, which may be used to treat the indications known for the active substances concerned.

It is preferable to use at least one pharmaceutical salt of the invention to produce a medicinal product for the treatment of pain, preferably using saccharinates as salts.

It is also preferable to use at least one pharmaceutical salt of the invention for the manufacture of a medicinal product for the treatment of urinary incontinence, preferably using saccharinates as salts.

The dose of the pharmaceutical salt to be administered to the patient varies, for example, according to the patient's weight, the indication and the severity of the pain or illness.

The pharmaceutical salts of the invention consisting of a pharmaceutical active substance and a sugar substitute are usually less soluble in water than the salts of these active substances used in the conventional formulations, preferably the saccharinates of the respective active substances, the water solubility of which is usually ≤ 250 mg/ml water and is usually at least 50% lower than the water solubility of the conventional salts of the corresponding active substance.

This also simplifies the formulation of these pharmaceutical salts into medicinal products, e.g. the production of granules by extrusion. The pharmaceutical salts of the invention also allow a more effective delay of the active substance by means of conventional delaying methods, due to the altered solubility, compared to salts of conventional use.

In addition, the pharmaceutical products of the invention used for application of the respective pharmaceutical salt through the oral mucosa or intestinal tract achieve a largely controlled release of the respective active substance without the use of a delay matrix and/or delay coating, but with a gastric-resistant coating if necessary.

The medicinal products of the invention, in the form of oral doses, which release the active substance already at or immediately after application, continue to have the advantage of compensating for their strongly bitter or disgusting taste by the simultaneous release of the sugar substitute, which improves patient compliance with the dosage regulation and increases acceptance of medicinal products containing the active substance as salt.

For a large number of active substances, the water solubility of conventional active substance salts is known, e.g. from the Pharmaceutical List, 12th edition ABDATA Pharma-Data-Service, 65735 Eschborn/Taunus.

If the water solubility of an active substance salt is not known, it may be determined by the following method, which has also been used to determine the water solubility of pharmaceutical salts of the invention:

In a clear, colourless container made of a transparent material such as glass or plastic, 1 ml of ion-free water or a fraction thereof (amount A in ml) is placed at 20 °C and the conventional salt of the active substance or the pharmaceutical salt of the invention is added by portion under stirring with a magnetic stirrer.

If the added amount of salt B (in mg) had completely dissolved, further amounts of the salt were added slowly. Each further addition was documented and the behaviour of the solution observed. Once the first turbidity of undissolved salt was detected by observation against a suitable background, another 10 minutes were stirred. If then any undissolved components remained, the sum C (in mg) of the amount of substance used was determined. When stirring again, a clear solution was obtained, further small amounts of each salt were added and each time again stirred for 10 minutes until a first turbidity of undissolved salt was detected. $\mathrm{Wasserlöslichkeit\; des\; Wirkstoffsalzes\; in\; mg}/\mathrm{ml\; Wasser}=\frac{(C/A)+\left(C,/,D\right)}{2}$

If the added amount B (in mg) of the salt did not dissolve immediately and cloudiness occurred, the salt was stirred for another 10 minutes after addition. If still undissolved salt remained, the unsolved amount was dissolved by adding small amounts of water under stirring. After obtaining a clear solution, the sum E (in ml) of the amounts of water used was determined. The solubility of the salt per 1 ml of water was then calculated according to the following formula: $\mathrm{Wasserlöslichkeit\; des\; Wirkstoffsalzes\; in\; mg}/\mathrm{ml\; Wasser}=\frac{B}{E}$

The following illustrations illustrate the invention.

Examples: Example 1:

The optically pure compound (+) - ((1 S,2S) -3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol was produced and subsequently separated in accordance with DE-A-4426245 and the corresponding part of the disclosure is hereby introduced by reference and is therefore considered to be part of the disclosure.

To produce (+) - 1S,2S) - 3-dimethylamino-1-ethyl-2-methylpropyl) phenolsaccarinate, 2.58 g (10 mmol) (+) - 1S,2S) - 3-dimethylamino-1-ethyl 2-methylpropyl) phenol hydrochloride and 2.42 g (10 mmol) of saccharin sodium dihydrate were fully dissolved in the smallest amount of water possible, heated, and then mixed in a stirrer and then cooled overnight. The resulting (+) - 1S,2S) - 3-dimethylamino-1-ethyl-2-propyl) -methylsaccarinate was separated from the parent material, washed with ethanol and purified after treatment.

The following is a list of the types of vehicles used:

To produce diphenhydramine saccharinate, 5.0 g (17.1 mmol) of diphenhydramine hydrochloride and 4.13 g (17.1 mmol) of saccharin sodium dihydrate were heated in the lowest possible amount of water and completely dissolved.

The following is a list of the types of vehicles used:

To produce verapamil saccarinate, 415 mg (0.845 mmol) verapamil hydrochloride and 204 mg (0.845 mmol) saccharin sodium dihydrate were heated in the lowest possible amount of water and completely dissolved.

The following is a list of the types of vehicles used:

To produce morphine saccharinate, 285 mg (0.76 mmol) of morphine hydrochloride trihydrate and 183 mg (0.76 mmol) of saccharin sodium dihydrate were dissolved completely in the lowest possible amount of water under heating, then mixed together under stirring and then refrigerated overnight. The failed morphine saccharinate was separated from the remaining mother's milk, cleaned with ethanol and isolated by conventional methods.

The following is a list of the types of vehicles used:

To prepare an oral gel, 0,33 g of methylparaben, 0,05 g of propylparaben and 75,0 g of xylitol were first dissolved at 80 °C in 198,0 g of purified water and then cooled to 40 °C. Then, 0,94 g of diphenhydramine saccharinate obtained in accordance with REFERENCE example 2 and 2 g of xanthan gum were added to the mixture by stirring, stirred for one hour and added to evaporated water. After cooling to a temperature of 20 to 25 °C, the mixture was flavoured by stirring with 0,625 g of Tutti Frutti 9/008897 (Dragoco Gerberding & Co. AG, 37603 Holzminden)

The following is a list of the types of vehicles used:

5 g of crushed gum paste (Popeye Amural Confections, Yorkville, Illinois, USA) was heated in a fantasy bowl to a temperature of 30 to 40 °C. The sticky gum paste was then infused with a 187.5 mg PISTLE of the obtained Diphenhydramine Saccharinate according to REFERENCE Example 2.

The taste test showed that the chewing gum containing the diphenhydramine saccharinate had an excellent taste at first and was still enjoyable after a long time.

Example 7:

To make an aqueous juice, 0,33 g of methylparaben, 0,05 g of propylparaben and 75,0 g of xylitol were dissolved at 80 °C in 199,22 g of purified water The mixture was cooled to 40 °C and stirred to give 78,5 mg of the obtained (+) - 1S,2S) - 3-dimethylamino-1-ethyl-2-methylpropyl) phenolsaccharinate as described in Example 1.

Example 8:

In this example, the water solubility of certain pharmaceutical salts and of conventional salts of the active substance concerned was determined by the method described above.

Vergleich der Wasserlöslichkeiten von bestimmten erfindungsgemäßen pharmazeutischen Salzen und entsprechenden herkömmlichen Salzen dieser Wirkstoffe. Das jeweils eingesetzte herkömmliche Salz ist In Klammem angegeben.

Wirkstoff	Löslichkeit des Wirkstoffsalzes in mg/ml Wasser	Löslichkeit des Wirkstoffsacdiarinats in mg/ml Wasser
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)phenol	261 (Hydrochlorid)	31
	500 (Hydrochlorid)	71
(+)-(1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol	650 (Hydrochlorid)	55
(-)-(1S,2S)-3-(3-Dimethylamino-1-ethyl-1-fluoro-2-methyl-propyl)-phenol	568 (Hydrochlorid)	130
(-)-(2S,3S)-1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol	2000 (Hydrochlorid)	90
	33 (Hydrochlorid)	10
	52 (Hydrochlorid-Trihydrat)	25
	25 (metilsulfat)	8
	1250 (Hydrochlorid)	380
	200 (Hydrochlorid)	7
	1000 (Hydrochlorid)	7
	500 (Hydrochlorid)	<2
	250 (Phosphat-hemihydrat)	200
	330 (Hydrochlorid)	130
	14 (Hydrochlorid)	2

As shown by the solubility values in Table 1, the solubility of the respective saccharinates is reduced compared to the corresponding conventional salts.

Claims (16)

1. A pharmaceutical salt of a pharmaceutical active compound and at least one sugar substitute characterized in that the active compound is a salt-forming compound selected from the group consisting of

   (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

   (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,

   (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,

   (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,

   (-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)phenol,

   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

   (+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and

   (-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
2. The pharmaceutical salt as claimed in claim 1, characterized in that the solubility of the salt in water is ≤ 250 mg/ml of water, preferably ≤ 200 mg/ml, particularly preferably ≤ 150 mg/ml, very particularly preferably ≤ 100 mg/ml.
3. The pharmaceutical salt as claimed in claim 1 or 2, characterized in that the salt-forming sugar substitute is saccharin, cyclamate or acesulfam, preferably saccharin.
4. Medicament comprising at least one pharmaceutical salt as claimed in one of Claims 1 to 3 and, if appropriate, physiologically tolerable excipients.
5. Medicament comprising at least one pharmaceutical salt as claimed in one of Claims 1 to 3 for the control of pain.
6. Medicament comprising at least one pharmaceutical salt as claimed in one of Claims 1 to 3 for the control of urinary incontinence.
7. Medicament as claimed in one of Claims 4 to 6, characterized in that it is present formulated in the form of gels, chewing gums, juices, sprays, tablets, chewable tablets, coated tablets, powders, if appropriate filled into capsules, easily reconstitutable dry preparations, preferably in the form of gels, aqueous or oily juices, sublingual sprays, tablets or chewable tablets.
8. Medicament as claimed in one of Claims 4 to 6, characterized in that it is present formulated in multiparticulate form, preferably in the form of microtablets, microcapsules, granules, active compound crystals or pellets, particularly preferably in the form of microtablets, granules or pellets, optionally filled into capsules or compressed to give tablets.
9. Medicament as claimed in one of Claims 4 to 8, characterized in that the salt is present at least partially in delayed-release form.
10. Medicament as claimed in Claim 9, characterized in that delaying of the release is carried out by applying a release-delaying coating, embedding in a release-delaying matrix, binding to an ionexchange resin or by a combination of at least two of these methods.
11. Medicament as claimed in Claim 10, characterized in that the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer, optionally in combination with a customary plasticizer, or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or Mixture of at least two of these components.
12. Medicament as claimed in Claim 10, characterized in that Matrix is based on a hydrophilic matrix material, preferably hydrophilic polymers, particularly preferably on cellulose ethers, cellulose esters and/or acrylic resins, very particularly preferably on ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or their their salts, amides and/or esters.
13. Medicament as claimed in Claim 10, characterized in that Matrix is based on a hydrophobic matrix material, preferably hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or appropriate esters or ethers or their mixtures, particularly preferably on mono- or diglycerides of C₁₂-C₃₀ fatty acids and/or C₁₂-C₃₀-fatty alcohols and/or waxes or their mixtures.
14. Medicament as claimed in one of Claims 4 to 13, characterized in that it has a protective coating, preferably an enteric protective coating.
15. Use of at least one pharmaceutical salt as claimed in one of Claims 1 to 3 for the production of Medicament for the control of pain.
16. Use of at least one pharmaceutical salt as claimed in one of Claims 1 to 3 for the production of Medicament for the treatment of urinary incontinence.