Tramadol pharmaceutical salts

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical salts of the biologically active substance tramadol and at least one sugar substitute chosen from a group comprising saccharin, cyclamate or acesulfam, and a medicament comprising these salts, and its using in treatment of enuresis and pains. The claimed tramadol pharmaceutical salt and sugar substitute possesses the delayed release that provides prolonged curative effect.

EFFECT: improved and valuable medicinal and pharmaceutical properties of salts.

12 cl, 8 ex

 

The present invention relates to pharmaceutical salts of biologically active substances tramadol and at least one sugar substitute to medicines containing these salts, to the use of these salts to obtain drugs and dosage forms containing these salts.

Tramadol hydrochloride - (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride - suitable for dealing with strong and moderate pain and for the treatment of urinary incontinence. In the patent US 3652589 and in the application WO 98/46216 described the use of other salts of the active substance tramadol with inorganic acids such as sulfuric acid, nitric acid and phosphoric acid, and with organic acids, such as benzoic acid, salicylic acid and phthalic acid, to obtain the corresponding medicines designed to combat pain, respectively, for the treatment of urinary incontinence.

Despite the high effectiveness of these salts in the fight against pain pronounced bitter taste of the active substance tramadol and its soluble salts leads to non-compliance of patients prescribed dosage and makes them not quite adequate with respect to medicines, from which this active substance is released during the reception./p>

With regard to the methods of application of the respective shell and any additional processing, such as deposition of thin film coatings, i.e. methods designed to improve the taste, the result of this deteriorating immediate release of the active substance from the dosage form.

Getting the dosage forms with prolonged action (retardirovannah dosage forms) due to the high water solubility of tramadol hydrochloride is also associated with certain difficulties and necessitates the use of expensive methods of retardation, such as application retardery shells or sealing of the active substance in retardiculous matrix.

With regard to the foregoing, the present invention was based on the task to receive pharmaceutical compounds on the basis of the active substance tramadol, which would not have inherent tramadol bitter taste and which would ensure more effective retardation in tramadol compared to conventional, used primarily for these purposes, salt, namely, tramadol hydrochloride.

This problem is solved with the help of pharmaceutical salts of the active substance tramadol and at least one sugar substitute. The solubility of these salts in water and/or aqueous liquid is the awn is preferably ≤ 100 mg/ml, particularly preferably ≤30 mg/ml and most preferably ≤10 mg/ml

As substitutes for sugar are all suitable acid sugar substitutes that during the formation of at least a singly charged negative form capable of combining with the active substance tramadol corresponding salt. Preferred as sweeteners saccharin, cyclamate, Acesulfame, or a mixture of at least two of these substances.

To obtain the proposed invention the pharmaceutical salts of tramadol and/or at least one highly water-soluble salt of tramadol is subjected to interaction with at least one free acid and/or at least one water-soluble salt of at least one sugar substitute. This interaction of such salt tramadol with a water-soluble salt of a sugar substitute, it is advisable to carry out in aqueous medium at neutral pH. As the salt of tramadol preferable to use tramadol hydrochloride. As a salt of a sugar substitute, it is preferable to use sodium, potassium, calcium or ammonium salt of saccharin and/or cyclamate or Acesulfame and/or as the free acid substitute for sugar - free acid saccharin and/or cyclamate or Acesulfame. If tramadolcan such is subjected to interaction with a free acid of the sugar substitute, the latter should be used in an appropriate organic solvent, preferably alkanols and particularly preferably in ethanol.

Another object of the invention is a medicinal product, containing in its composition as a pharmaceutical active substance is at least one salt of tramadol according to the invention and optionally other active substances and/or excipients. Preferably these medicines are used for treating pain, urinary incontinence, cough, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, diseases of the cardiovascular system, respiratory diseases, mental disorders and/or epilepsy.

The object of the invention is also the use of at least one of the proposed salt of tramadol for receiving a corresponding medicinal product intended for treating pain, urinary incontinence, cough, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, diseases of the cardiovascular system, respiratory diseases, mental disorders and/or epilepsy.

Assigned to a particular patient, the amount of the active substance varies depending on such factors as body weight, met the dick introduction indications for use and the severity of the disease. Usually with the introduction of at least one salt of tramadol according to the invention it is administered in amounts, based on the content of active substance in the dosage range from 1 to 600 mg/day.

Another object of the invention is a pharmaceutical form, containing in its structure at least one salt of tramadol according to the invention.

Number of tramadol and sugar substitute in the proposed medicines, dosage forms, should be selected so that the bitter taste of the active substance tramadol be offset by the taste properties of the used sugar substitute. Preferably proposed in the invention dosage forms contain a sugar substitute in equimolar amounts relative to tramadol, in other words, both components are presented almost entirely in the form of a complex salt. Depending on the degree of sweetness of used sugar substitute and/or required for the release mechanism tramadol dosage forms according to the invention can contain tramadol and sugar substitute in various molar quantities.

The proposed dosage form may be a solid, semi-solid or liquid, preferably oral pharmaceutical composition, containing in its sustainab salt of the active substance tramadol and at least one sugar substitute, optional other active substances, as well as conventional auxiliary substances and additives.

Solid dosage forms according to the invention is preferably presented in the form of compositions from a variety of particles, particularly preferably in the form of granules, microparticles, microtablets or balls (pellets), optional packaged in capsules or in the form of tablets, preferably rapidly disintegrating tablets or effervescent tablets, and the tablets are preferably pressed from pellets or are made by extrusion from the melt.

Since the release of active substances from a solid dosage form according to the invention is provided in the intestinal tract, the latter must have at least one resistant to gastric juice membrane, dissolving depending on pH. This shell dosage form, bypassing the gastrointestinal tract into the intestines, where the release of the active (s) substance (s).

Also preferably the proposed dosage form can be represented in the form of a gel, chewing gum, mixtures, particularly preferably in the form of oil or water mixtures, or in aerosol form, particularly preferably in the form of a sublingual spray.

According to one preferred options of the dosage form according to the invention for the selection of tramadol if prohozhdenie is through the gastrointestinal tract serves to produce, for example, in the form of oil or water mixtures, the release of which is active (s) substance (s) occurs without delay.

Retardation, and thereby also the implementation of yet another modification regarding the release of the active substance tramadol and optionally used other active substances can be enhanced by applying at least reagiruya shell, sealing the salt of the active substance in at least retardiculous matrix or a combination of both.

Retardation reach preferably by providing a prolonged action (retardery) membranes. As such membranes can be used water-insoluble waxes or polymers, such as acrylic resin, preferably a poly(meth)acrylates, or water-insoluble types of cellulose, preferably ethylcellulose. These materials are known from the prior art and are described, in particular, Bauer, Lehmann, Osterwald and Rothgang "Überzogene Arzneiformen", p.69 and then published by Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart (1988), which publication is included in this part of the present description by reference.

To achieve the desired rate of release of the active substance reagiruya shell along with water-insoluble polymers may contain also does not have such a property of the retardation is preferably soluble in emery in the amount up to 30 wt.%, for example polyvinylpyrrolidone or water-soluble types of cellulose, preferably the hypromellose or hydroxypropylcellulose, and/or hydrophilic pore, such as sucrose, sodium chloride and mannitol, and/or known plasticizers.

Also preferably the dosage form according to the invention for the purpose of retardation salt of the active substance can contain this salt in reagiruya matrix, preferably uniformly distributed in it.

As materials of the matrix can be used physiologically acceptable hydrophilic materials known to specialists in this field. Preferred as the hydrophilic material of the matrix polymers, particularly preferred ethers and esters of cellulose and/or acrylic resin. Most preferably be used to obtain matrix materials such as ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or its derivatives such as its salts, amides or esters.

Equally preferred to obtain the matrix and hydrophobic materials such as hydrophobic polymers, waxes, fats, fatty acids long chain fatty alcohols or corresponding complex and ethers, or their mixtures. Particularly preferable to apply the as hydrophobic materials mono - or diglycerides With 12With30fatty acids and/or C12-C30fatty alcohols and/or waxes or a mixture thereof.

There is another option, namely to apply the material reagiruya matrix mixture of the above-mentioned hydrophilic and hydrophobic materials.

Proposed in the invention the dosage form can be produced using various methods known to experts in this field. These methods are known from the prior art: see, for example, Pharmaceutical Pelletization Technology, Drugs and the Pharmaceutical Sciences, volume 37, publishing house Verlag Marcel Decker or "Remington''s Pharmaceutical Sciences, published by Mack Publishing Company, Easton, Pennsylvania. These publications included in this part of the present description by reference.

If according to the invention at the proposed dosage forms such as tablets or pellets (pellets), requires the presence of the shell, the shell can be applied using conventional methods, such as drazhirovanie, plating solutions, dispersions or suspensions, by drawing from the melt or by the application of powder coating.

In the case of dosage forms according to the invention, such as gel, chewing Reznik or sublingual spray intended for release tramadol under the action of the mucous membranes of the mouth, almost stable allocation tramadol can achieve without using reagiruya matrix and/who do reagiruya shell.

In the case of dosage forms according to the invention, such as capsules, tablets, granules or pellets intended for release tramadol in the intestinal tract, a stable allocation tramadol is also possible to achieve without using reagiruya matrix and/or reagiruya shell, however, if you have a shell that is resistant to the action of gastric juice.

Another advantage of the proposed invention dosage forms is that pronounced bitter taste of tramadol could be offset by the simultaneous release of sugar substitute. Due to this patients more accurately comply with the prescribed dosage, and their relation to medicines containing the active substance tramadol is changed in a positive way.

Medicinal product according to the invention can be applied also for diabetics. The formation of the salt of tramadol and sugar substitute and/or excipients solubility ≤100 mg/ml in water and/or aqueous body fluids provides compared to tramadol hydrochloride the possibility of more effective retardation of the active substance tramadol using commonly used for this purpose methods. This approach contains the salt of tramadol drug prolonged action allows AET therefore, to simplify the technology of their production and thereby reduce production costs. This also applies to other versions of medicines according to the invention, such, for example, which requires the presence of membranes that are resistant to the action of gastric juice.

Solubility of salts of tramadol and sugar substitute was defined as follows.

Salt (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and the corresponding sugar substitute at 25°added to deionized water in such a quantity (for example, in the case of tramadol saharinata approximately 1 g per 10 ml of deionized water)that at this temperature formed a saturated solution, saturation, which persisted after 20 hours stirring at 25°C. Necessary for these purposes the amount of the salt of tramadol and the corresponding sugar substitute can be determined when necessary, experimental way.

After deposition of nerastvorimaya part of the salt of tramadol and the corresponding sugar substitute transparent supernatant was removed with a pipette, and then for 5 min, centrifuged at at least 3000 rpm part of the thus obtained clear supernatant was transferred into a test tube for GHWR and was determined by the salt concentration of tramadol and the corresponding sugar substitute in comparison with this indicator tramadol HYDR who chloride as standard.

Below the invention is explained in more detail by way of examples, which in no way limit its scope.

Example 1

To obtain tramadol of saharinata of 30.0 g (0.1 mole) of tramadol hydrochloride and 20,53 g (0.1 mole) of saccharin sodium or 24,13 g (0.1 mole) of saccharin sodium dihydrate, respectively, were completely dissolved by heating in an extremely small amount of water. Then both the solution with stirring mixed with each other. Tramadol saccharinate cooling precipitated from aqueous solution in the form of crystals already after a short period of time, after which it was isolated according to conventional methods and purified by ethanol. The water thus obtained of tramadol saharinata, which was determined by the above method was 22.5 mg/ml

Example 2

30,0 g (0.1 mole) of tramadol hydrochloride was dissolved in 20 g of water and stirring was slowly mixed with a solution of 20,13 g (0.1 mole) of sodium cyclamate in 36 grams of water. Then the resulting solution for 16 h and kept at 5°C. resulted tramadol cyclamate in crystalline form, which by conventional methods were isolated and purified by ethanol.

Example 3

30,0 g (0.1 mole) of tramadol hydrochloride was dissolved in 13 g of water and stirring was slowly mixed with a solution of 20,13 g (0.1 mole) of Acesulfame potassium in 53 g of water. Then the resulting solution in the tech what the night held at 5° C. resulted tramadol Acesulfame in crystalline form, which by conventional methods were isolated and purified by ethanol.

Example 4

To obtain oral gel first dissolving 0.33 g of methylparaben, 0.05 g propyl paraben and 75.0 g of xylitol at a temperature of 80°in 197,63 g of purified water, after which the mixture was cooled to 40°C. Next, under stirring was added first, 0.75 g of tramadol saharinata, and then 2 g of xanthene gum, was stirred for 1 h and evaporated water compensated for the new addition. After cooling to room temperature the mixture under stirring was added 0.625 g of orange-tangerine Orange flavor-Mandarine Flavor 10888-56 (firm Givaudan Roure Flavors Ltd. CH 8600 Duebendorf).

Example 5

5 g of the crushed mass, designed to take chewing gum (firm Popeye Amural Confections, Yorkville, PCs Illinois, USA), was heated in the pot from under forfeits to a temperature of 30-40°With, then this plastic mass with Molchanovo of the pestle was mix up to 150 mg of tramadol saharinata. Then the homogeneous mass was poured into Teflon molds with results in doses of 1 g each.

In order to compare the taste of the properties by the same method carried out an appropriate test, which received a chewing gum with the same stoichiometric quantity of tramadol (equivalent to 100 mg of tramadol hydrochlo the IDA).

The results of this test showed that chewing gum containing tramadol hydrochloride, already after a short period of time was so strong bitter taste that chewing her further was impossible. In contrast, chewing gum, containing tramadol saccharinate, had great taste, not only initially, but basically kept them in the further process of mastication.

Example 6

To get medicine on the basis of water, 0.33 g of methylparaben, 0.05 g propyl paraben and 75.0 g of xylitol was dissolved at a temperature of 80°in 198,37 g of purified water, after which the mixture was cooled to 40°and with stirring was added 0.75 g of tramadol saharinata. Then added 0.25 g xanthene gum, was stirred for 1 h and evaporated water compensated for the new addition. After cooling to room temperature the mixture was added with stirring 0.075 g of the flavor of candied fruit Tutti Frutti 9/008897 (company Dragoco Gerberding & Co. AG, 37603 Hoizminden).

Example 7

To get medicine on the basis of oil, 0.33 g of methylparaben and 0.05 g of propyl paraben were dissolved at 80°in 200,88 g glycerol esterified with saturated esters of C8-C10fatty acids, after which the mixture was cooled to 25°and suspended under stirring in her 37,5 g of powdered xylitol, 1,25 g vysokokapit the aqueous silicon dioxide and 0.75 g of tramadol saharinata. Then to the mixture was added with stirring 0.0125 g of flavouring, orange ″Wren″ Blutorange 9/028658 (company Dragoco Gerberding & Co. AG, 37603 Hoizminden).

Example 8

To get sublingual aerosol first dissolving 0.33 g of methylparaben, 0.05 g propyl paraben and 75.0 g of xylitol at a temperature of 80°in 197,37 g of distilled water, after which the solution was cooled to 40°and was mixed with 0.75 g of tramadol saharinata. Then added 0.15 g xanthene gum, was stirred for 1 h and evaporated water compensated for the new addition. In the end the solution was cooled to 25°and added 0.75 g of grapefruit Grapefruit flavor 14391786 (firm IFF, International Flavors & Fragrances GmbH, 46446 Emmerich).

1. Pharmaceutical salt of tramadol and at least one sweetener selected from the group including saccharin, cyclamate or Acesulfame.

2. The pharmaceutical salt according to claim 1, characterized in that the solubility of salt in water and/or aqueous body fluids ≤100 mg/ml, preferably ≤30 mg/ml and particularly preferably ≤10 mg/ml

3. The drug is designed to treat pain and incontinence of urine, containing in its structure at least one salt of tramadol in claims 1 and 2, and optionally other active substances and/or auxiliary substances.

4. The connection representing a pharmacist is ical salt of tramadol and sweetener, selected from the group including saccharin, cyclamate or Acesulfame for the treatment of pain and urinary incontinence.

5. The compound according to claim 4 to obtain medicines designed to fight the pain.

6. The compound according to claim 4 to obtain a medicinal product intended for the treatment of urinary incontinence.

7. Dosage form, containing in its structure at least one salt of tramadol according to any one of claims 1 to 3, and optionally other active substances and/or auxiliary substances.

8. Dosage form according to claim 7, characterized in that it represent the composition of the set of particles, preferably in the form of granules, microparticles, microtablets, balls (pellets), optional packaged in capsules or in the form of tablets, fast disintegrating tablets or effervescent tablets, or in the form of pellets, compressed into tablets.

9. Dosage form of claim 8, characterized in that it has at least one shell, resistant to gastric juice.

10. Dosage form of claim 8, characterized in that it is a composition in the form of a gel, chewing gum, medicine, preferably oily or aqueous mixtures, or in the form of an aerosol, preferably sublingual spray.

11. Dosage form according to any one of claims 7 to 9, characterized in that it has at least the least one providing a prolonged action matrix.

12. Dosage form according to any one of claims 7 to 9 or 11, characterized in that it has at least one providing a prolonged effect of the shell.



 

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5 cl, 1 dwg, 2 tbl, 1 ex

FIELD: medicine, namely, andrology and physiotherapy, possible use for treatment of chronic prostatitis.

SUBSTANCE: in accordance to method, low intensity infrared laser irradiation of projection of duodenum is performed, also of cistern of pectoral lymphatic canal for 3 minutes, of points J1 and J2 for 4 minutes each in conjunction with rectal effect of electromagnetic radiation of extremely high frequency spectrum in "noise" generation mode in frequency range 52-78 GHz with density of output power flow of 10-9Wt/cm2. Length of laser radiation wave is 0,95 micrometers, generation frequency is 80-120 Hz, energy of impulse - 4-6 mWt. Effect is performed under condition of phyto-correction with use of specified biologically active food additive daily or every second day. Course consists of 10-14 procedures.

EFFECT: improved lymph-draining function, amplified processes of regeneration and local recirculation of tissue of prostate gland, increased local and general immune resistance.

FIELD: medicine, urology.

SUBSTANCE: method involves retrograde administration of gel of the following composition into ureter, wt.-%: hydroxyethylcellulose, 0.80-1.20; papaverin, 0.80-1.20; prednisolon or hydrocortisone, 0.50-1.00, and water, up to 100. Method enhances effectiveness of removing stones based on improved stone slipping and elimination of topical spasm and inflammation with retaining ureter peristalsis and reducing period of treatment and amount of complications. Invention can be used in treatment of urinary calculosis.

EFFECT: improved method for removing stones.

2 cl

FIELD: medicine.

SUBSTANCE: method involves prescribing drinking radon-containing mineral water distinguished by radon activity of 185-370 kBq/l in the amount of 100 ml 3 times a day. Then, radon baths are given where radon activity is of 0.75-2.25 kBq/l, temperature is 36-37°C, procedure duration is 10-15 min. Then, vacuum depression of 4-9 atm with succession frequency of 15-25 pulses per 1 min and alternating sinusoid current of 100-200 Hz, current intensity of 20-40 mA and duration of 12-15 min is applied to kidney region and injured ureter segment region in everyday mode with 10-12 procedures long treatment course.

EFFECT: increased stimulated action to functional renal pacemaker and neuromuscular apparatus; higher percent of stone excretion.

4 cl

FIELD: otolaryngology.

SUBSTANCE: invention is intended to treat pseudoallergic rhinosinusopathy against a background of parasitic invasion of hepatobiliary system. Elimination of parasites is effected simultaneously with administration of hepatoprotectors and all-purpose membrane stabilizers until clinical is achieved, while cryoconchotomy is performed not later than elimination of parasites is ended.

EFFECT: achieved complete restoration of nasal respiration, reduced incidence of parasitic malady recurrences, and reliably eliminated symptoms of rhinosinusopathy owing to combination of cryoconchotomy and purposive action on hepatobiliary system.

5 cl, 2 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pantohematogen-base medicinal formulation for external using that comprises the following components, wt.-%: dry pantohematogen, 0.01-6; polymeric gel-forming composition, 0.1-20, and water, the balance. Proposed medicinal formulation provides using pantohematogen an aqueous solution without addition of alcohol and therefore it can be used in cases wherein alcohol-containing formulations are contraindicative - in burns of different degree, small skin damages and others and can be used in treatment of patients showing intolerance to alcohol-containing preparations. Method for preparing the pantohematogen medicinal formulation for external using involves preparing "dry" pantohematogen aqueous solution in the ratio limits pantohematogen : water = (1:50)-(1:200) by weight and solution is kept under normal conditions for 1 h and filtered. Additionally an aqueous solution of rare-linked polymer is prepared in the ratio = (1:10)-(1:200) and an aqueous solution of neutralizing agent in the amount necessary for providing slightly alkaline medium of final solution. In the volume ratio of pantohematogen aqueous solution and rare-linked polymer in the ranges = (3:1)-(1:10) components are mixed and stirred to obtain the homogenous solution. Then neutralizing agent aqueous solution is added to a mixture and stirred to obtain homogenous solution with slightly alkaline reaction (pH = 6-8). The advantage of proposed technology in preparing the medicinal formulation involves its simplicity and providing prolonged fitness period.

EFFECT: improved preparing method.

6 cl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes an orally administrated liquid composition used in treatment of respiratory diseases and comprising from 2% to 40% of guaifenesin and a filling agent comprising from 5% to 25% of polyoxyalkylene block-copolymer, from 30% to 90% of hydrophilic solvent, and from 5% to 45% of water. The composition shows high physical stability in delivery of the concentrated doses of pharmaceutically active component, in particular, the active component doesn't show precipitation from solution for the prolonged times. Also, the composition remains in a liquid form in the mouth cavity that provides the effect of the pharmaceutically active agent of the composition on large areas in the mouth cavity mucosa.

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

6 cl, 16 tbl, 1 dwg, 16 ex

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