RU2292877C2 - Medicinal retard-formulation containing tramadol saccharinate - Google Patents

Abstract

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a medicinal formulation of tramadol with delayed-release. Proposed medicinal formulation possesses the high effectiveness in treatment of pains of different etiology and can be used in treatment of diseases chosen from the following group: enuresis, cough, inflammatory processes and/or allergic responses, depression states, abuse and/or alcoholism, gastritis, diarrhea, cardiovascular diseases, diseases of respiratory ways, psychic diseases, epilepsy.

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

38 cl, 11 tbl, 4 dwg, 11 ex

Description

The present invention relates to retard-coated dosage forms that contain tramadol as its saccharinate as an active ingredient, as well as optionally other excipients.

Water-soluble tramadol hydrochloride, i.e. hydrochloride (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, often used to relieve severe pains and moderate pain.

The introduction of tramadol hydrochloride in the form of retard preparations can improve the therapeutic effect of this active substance. Retardation (delayed release) allows, including for this active substance with a relatively short half-life in the body, to obtain a drug with a long-lasting effect, and by maintaining its concentration in the blood at a more even level, it also helps minimize side effects effects and create conditions for patients to comply with the prescribed dosage regimen.

Retardation of the active substance of tramadol hydrochloride can be achieved, for example, by applying retardation film coatings to dosage forms containing tramadol hydrochloride. However, ensuring the retardation of this active substance by means of film coatings is associated with relatively high costs, since film coatings applied from aqueous systems often create an insufficiently effective diffusion barrier for such active substances that are readily soluble in water, and the permeability of these film coatings to tramadol hydrochloride during long-term storage in most cases varies (R. B. O'Donnell, JWMcGinity, "Mechanical Properties of Polymeric Films, Prepared from Aqueous Polymeric Dispersions in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", Drugs and the Ph armaceutical Science, Vol. 79, edited by J.W. McGinity, Marcel Decker, New York, Basel, Hong Kong, 1997).

Therefore, the manufacturing technology of these retard preparations based on tramadol hydrochloride requires the use of relatively complex methods of coating in the form of multilayer films or lengthy heat treatment methods described, for example, in US Pat. No. 5,645,858, US 5,580,578, US 5,681,585, US 5,472,712, and also at K. Bauer, "Coated Pharmaceutical Dosage Forms", Medpharm Scientific Publishers, Stuttgart, 1998, at B. Sutter, Thesis defended at the University of Düsseldorf, 1987, or at FNChristensen, Proceed. Intern. Symp Contr. Rel. Bioact. Mater., 17: 124 (1990). If such coatings are applied from solutions in organic solvents, the environmental costs associated with this when disposing of solvent residues additionally increase the cost of technology for ensuring the retardation of tramadol hydrochloride.

Based on the foregoing, the present invention was based on the task of developing a retardable coating drug retard form with tramadol as an active substance, which immediately after its manufacture would have a stable release profile for the active substance during long-term storage without the need for complex and expensive coating methods or prolonged and thereby associated with high costs of heat treatment.

According to the invention, this problem is solved by using retard-coated drug retard forms, which contain tramadol in the form of its saccharinate as an active substance, as well as optionally other auxiliary substances.

When creating the invention, it was unexpectedly found that the medicinal retard forms proposed therein, immediately after their manufacture, exhibit a stable release profile of the active substance during long-term storage, to achieve which, after normal drying, the retarder coating does not need to be subjected to heat treatment.

Upon receipt of the tramadol saccharinate, this tramadol, i.e. (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, and / or at least one of its corresponding, preferably water-soluble, salt is reacted with saccharin and / or at least one its preferably water soluble salt. As the salt of tramadol, it is preferable to use its hydrochloride, and as the salt of saccharin, it is preferable to use its sodium, potassium, calcium or ammonium salt, more preferably its sodium salt.

Tramadol saccharin can also be formed in situ during the manufacture of dosage retard forms.

The term "in situ education" in the context of the present invention means that the slightly water-soluble salt of tramadol is mixed with the water-soluble saccharin salt, repeatedly moistened and granulated, if necessary extruded and / or processed into a dosage form by applying other energy, preferably under pressure and / or with heat input.

To form tramadol saccharinate in situ, tramadol can be used in the form of a water-soluble, pharmaceutically acceptable salt, preferably in the form of its hydrochloride, and saccharin can be used in the form of its water-soluble, pharmaceutically acceptable salt, preferably sodium, potassium, calcium or ammonium salt, more preferably in the form of sodium salt.

The retardable film-coated dosage forms of the invention are preferably suitable for oral administration.

In one preferred embodiment of the present invention, the dosage forms of the invention are presented in the form of tablets, capsules or suspensions.

In another preferred embodiment of the present invention, the dosage forms provided therein are presented in a multi-particle form, preferably in the form of microtablets, microcapsules, micropellets, granules, crystals of active substances or small spherical granules (pellets), optionally packaged in capsules or compressed into tablets or in the form of a hydrophilic or lipophilic liquid, preferably in the form of a homogeneous suspension, most preferably in the form of mixtures or dispersions for the oral nogo introduction.

If the dosage forms of the invention are presented in the form of granules or pellets, then their size is preferably from 0.1 to 3 mm, more preferably from 0.5 to 2 mm.

If the dosage forms of the invention are presented in the form of microtablets, then their diameter is preferably from 0.5 to 5 mm, more preferably from 1 to 3 mm and most preferably from 1 to 2 mm.

If the dosage forms of the invention are presented in the form of crystals of active substances, microparticles, micropellets or microcapsules, then their diameter is preferably from 10 μm to 1 mm, more preferably from 15 μm to 0.5 mm, and more preferably from 30 to 200 μm.

In addition, the composition of the dosage forms proposed in the invention, depending on the form of their release, may include, as additional components, ordinary excipients well known to those skilled in the art.

If the dosage forms according to the invention are presented in the form of tablets or microtablets, it is preferable to include microcrystalline cellulose, cellulose ether, lactose, starch and its derivatives, sugar alcohols, calcium hydrogen phosphate, as well as ordinary, well-known specialists in their composition as other auxiliary substances binders, flow regulators, lubricants, and optionally disintegrants.

If the dosage forms according to the invention are presented in the form of pellets, granules or micropellets, it is preferable to include microcrystalline cellulose, cellulose ether, lactose, starch and its derivatives, sugar alcohols, calcium hydrogen phosphate, aliphatic alcohols, esters as their other excipients glycerol or fatty acid esters.

If the dosage forms proposed in the invention are presented in the form of microcapsules or microparticles, then, depending on the technology used for their manufacture, they may contain ordinary excipients well known to those skilled in the art.

The dosage forms of various types according to the invention can be prepared by various methods well known to those skilled in the art.

If the dosage forms of the invention are presented in the form of tablets, they can be prepared, for example, by compression of granules obtained by wet granulation, dry granulation or granulation from a melt, or by direct tabletting of tramadol saccharinate, optionally with additional excipients. In addition, tablets can be made by pressing coated pellets, crystals of active substances, microparticles or microcapsules.

The dosage forms of the invention in the form of pellets can be produced by extrusion and spheroidization by layer-by-layer (build-up) granulation (pelletization) or by direct pelletization in a high-speed mixer or in a swirl fluidized bed. It is most preferable to produce pellets by extrusion of a wet mass followed by spheroidization. Microcapsules are made by conventional microencapsulation methods, for example by spray drying, spray crystallization (spray curing) or coacervation.

In one of the preferred embodiments of the invention, it is preferable to use a water-insoluble, optionally modified natural and / or synthetic polymer or natural, semi-synthetic or synthetic wax, fat or aliphatic alcohol or a mixture of at least as the base of the retarding film coating applied to the proposed dosage forms at least two of these components.

To obtain a retardation coating, it is preferable to use poly (meth) acrylates, more preferably poly (C ₁ -C ₄ ) alkyl (meth) acrylates, poly (C ₁ -C ₄ ) dialkylamino (C _1, as water-insoluble polymers to obtain a coating -C ₄ ) alkyl (meth) acrylates and / or their copolymers, most preferably copolymers of ethyl acrylate and methyl methacrylate with a molar ratio of monomers 2: 1 (product Eudragit NE30D ^® ), copolymers of ethyl acrylate, methyl methacrylate and chloride of trimethylammonium ethyl methacrylate with a molar ratio of 2 monomers: 1 0.1 (Eudra product git RS ^® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride with a molar ratio of monomers of 1: 2: 0.2 (product of Eudragit RL ^® ) or a mixture of at least two of these copolymers. These coating materials are marketed in the form of 30% (by weight) aqueous latex dispersions, i.e. in the form of products Eudragit RS30D ^® , Eudragit NE30D ^® , respectively Eudragit RL30D ^® , and as such they are mainly used as coating material.

Polyvinyl acetates are also preferably used as water-insoluble polymers to provide a retardation coating for the dosage forms of the invention, optionally in combination with other excipients. They are marketed as an aqueous dispersion containing 27% by weight of polyvinyl acetate, 2.5% by weight of povidone and 0.3% by weight sodium lauryl sulfate (product Kollicoat SR30D ^® ).

According to another preferred embodiment of the invention, water-insoluble cellulose derivatives, preferably alkyl cellulose, such as ethyl cellulose, or cellulose esters, such as cellulose acetate, can be used as the basis for retarding coatings of the dosage forms of the invention. Coatings of ethyl cellulose or cellulose acetate are preferably applied from an aqueous pseudolatex dispersion. Aqueous pseudo-lattic ethyl cellulose dispersions are marketed as 30% (by weight) dispersions (Aquacoat ^{® product} ) or 25% (by weight) dispersions (Surelease ^{® product} ).

As natural, semisynthetic or synthetic waxes, fats, respectively, aliphatic alcohols for controlled release coating of the invention formulations preferably use carnauba wax, beeswax, glycerol monostearate, glitserinmonobegenat (Compritol ATO888 ^® product) glitserinditripalmitostearat (product Precirol ATO5 ^®), microcrystalline wax, cetyl alcohol, cetyl stearyl alcohol, or a mixture of at least two of these components.

If a water-insoluble, optionally modified, natural and / or synthetic polymer is used as the base for the retarder coating, then in addition to the corresponding polymer, in addition to the corresponding polymer, an ordinary, physiologically acceptable physiologically acceptable polymer may be added to the dispersion or coating solution to lower the minimum film coating temperature acceptable plasticizer.

Examples of suitable plasticizers include lipophilic diesters of an aliphatic or aromatic dicarboxylic acid with C ₆ -C ₄₀ and an aliphatic alcohol with C ₁ -C ₈ , for example dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, for example hydrophilic or lipophilic acids, for example triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyethylene glycols, propylene glycol, glycerol esters such as triacetin, Myvacet ^{® product} (acetylated mono- and diglycerides from C _{2 3} H ₄₄ O ₅ to C ₂₅ H ₄₇ O ₇ ), medium chain triglycerides (product of Miglyol ^® ), oleic acid or mixtures of at least two of these plasticizers. Triethyl citrate is preferably used in the aqueous dispersions of the Eudragit RS ^{® product} and optionally the Eudragit RL ^® product.

The preferred amount of plasticizer (s) in the retarding coating of the dosage form of the invention is from 5 to 50 wt.%, More preferably from 10 to 40 wt.% And most preferably from 10 to 30 wt.%, Based on the amount used (s) ) polymer (s). In some cases, for example, when using cellulose acetate, plasticizers can also be used in higher amounts, preferably up to 110% by weight.

In addition, the composition of the retardation coating may include other ordinary excipients well known to those skilled in the art, for example, lubricants, preferably talc or glycerol monostearate, pigments, preferably iron oxides or titanium dioxide, or surfactants, for example, Tween 80 ^® .

The release profile of tramadol, achieved immediately after the manufacture of the dosage form of the invention, can be controlled by conventional methods well known to those skilled in the art, for example by varying the thickness of the coating or by using other excipients as coating components. Suitable excipients for this purpose include, for example, hydrophilic or pH-dependent pore formers, for example sodium carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, lactose, polyethylene glycol or mannitol, or water-soluble polymers, such as polyvinyl vinyl polyl vinyl or preferably hydroxypropyl methylcellulose or hydroxypropyl cellulose.

The retarder coating to further enhance its retarder effect may also contain insoluble, respectively lipophilic, auxiliary substances, for example, alkyl silica, which, for example, is marketed as an Aerosil R972 ^{® product} , or magnesium stearate.

The dosage forms of the invention for the release of tramadol saccharinate can additionally also have a gastric juice-resistant coating, the solubility of which depends on the pH value. Thanks to this coating, the dosage forms of the invention pass through the stomach without being dissolved in it and begin to release tramadol saccharin only in the intestine. Preferably, the gastric juice resistant coating dissolves at a pH of from 5 to 7.5. To obtain a gastric juice-resistant coating, it is preferable to use copolymers of methacrylic acid and methyl methacrylate with a molar ratio of monomers 1: 1 (product Eudragit L ^® ), copolymers of methacrylic acid and methyl methacrylate with a molar ratio of monomers 1: 2 (product Eudragit S ^® ), methacrylic copolymers acid and ethyl acrylate with a molar ratio of monomers of 1: 1 (product Eudragit L30-D55 ^®), methacrylic acid copolymers, methyl acrylate and methyl methacrylate with a monomer molar ratio of 7: 3: 1 (product Eudragit FS ^®), shell , Hydroxypropylmethylcellulose acetate succinate, methylcellulose phthalate, cellulose acetate or mixtures of at least two of these components, optionally also in combination with the above-described water-insoluble poly (meth) acrylates, preferably in combination with the product Eudragit NE30D ^® and / or product Eudragit RL ^® and / or Eudragit RS ^{® product} .

The coatings of the dosage forms of the invention can be applied by conventional methods suitable for preparing each particular coating, well known to those skilled in the art, for example by spraying solutions, dispersions or suspensions, by melt spraying or by powdering. These solutions, dispersions or suspensions can be used in the form of aqueous or organic solutions or dispersions. It is preferable to use aqueous dispersions. As organic solvents, alcohols, for example ethanol or isopropanol, ketones, for example acetone, esters, for example ethyl acetate, chlorinated hydrocarbons, for example dichloromethane, can be used, while alcohols and ketones are preferably used. Mixtures of at least two of the above solvents may also be used. Such coating methods are known in the art, for example, from H. Sucker, Georg Thieme Verlag, 1991, p. 347 et seq. All such methods are incorporated herein by reference.

If the oral dosage forms of the invention are presented in a multi-particle form, then the retarder coating is preferably applied so that after manufacturing the multi-particle multi-particle forms containing tramadol saccharin can be coated with the corresponding polymers and optionally other excipients from aqueous and / or organic media, preferably from aqueous media, and dry the resulting coating, preferably simultaneously, with cing temperatures in the fluidized bed without exposing the coating followed by heat treatment. Drying the coating of poly (meth) acrylate is preferably carried out at a supply air temperature in the range from 30 to 50 ° C, more preferably from 35 to 45 ° C.

The drying of cellulose-based coatings, for example ethyl cellulose or cellulose acetate, is preferably carried out at a temperature in the range from 50 to 80 ° C, more preferably from 55 to 65 ° C.

Wax coatings can be applied from the melt in the fluidized bed and, after coating, cool to a temperature below the corresponding melting point of the wax in order to completely solidify it. Wax coatings can also be applied by spraying their solutions in organic solvents.

To further modify the release profile of the active substance, the drug retard forms according to the invention may also contain tramadol saccharin in a retardation matrix, preferably in a uniformly distributed form.

Physiologically acceptable hydrophilic materials well known to those skilled in the art can be used as matrix materials. Preferably, cellulose ethers, cellulose esters and / or polyacrylates are used as the base of the retarding matrix. Most preferably, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or its derivatives such as its salts, amides or esters are used as a matrix.

Similarly, hydrophobic materials such as hydrophobic polymers, various types of waxes, fats, long chain fatty acids, aliphatic alcohols or the corresponding esters or ethers or mixtures thereof are preferably used as matrix materials. The most preferred hydrophobic materials are mono- or diglycerides of fatty C ₁₂ -C ₃₀ acids and / or aliphatic C ₁₂ -C ₃₀ alcohols and / or various types of wax or mixtures thereof.

Mixtures of the above hydrophilic and hydrophobic materials can also be used as the material of the retarding matrix.

The retardation matrix can be obtained by conventional methods well known to those skilled in the art.

According to another preferred embodiment, the dosage forms according to the invention comprise the active substance tramadol in both retarded and non-retarded forms, for example, in the form of tramadol hydrochloride. Combination with an immediately released active ingredient allows the patient to enter a high initial dose to quickly relieve pain. Subsequently, the slow release of the active substance from the retard form prevents the weakening of the analgesic effect.

The dose of tramadol prescribed to the patient varies, for example, depending on the weight of the patient, indications for use, as well as on the severity of the pain, respectively the disease. The dose of tramadol administered, as well as its release profile, is preferably selected so that the drug is required to be taken at most twice, preferably only once, per day.

The content of tramadol in the dosage forms according to the invention for a single daily intake is preferably from 10 to 1200 mg, more preferably from 20 to 1000 mg, and most preferably from 100 to 800 mg.

The content of tramadol in the dosage forms according to the invention, calculated to be taken twice daily, is preferably from 5 to 600 mg, more preferably from 10 to 500 mg, and most preferably from 50 to 400 mg of tramadol.

The dosage forms of the invention are preferably used to relieve pain or treat diseases such as urinary incontinence, cough, inflammation, allergies, depression, abusus, alcoholism, gastritis, diarrhea, cardiovascular disease, respiratory diseases, mental illness or epilepsy more preferably for relieving pain or treating urinary incontinence or coughing.

An advantage of the dosage forms proposed in the invention is that immediately after their manufacture they are characterized by a storage stable release profile of the active substance without the need to expose the form obtained usually after drying to heat treatment or to coat it with a complicated method. This advantage allows you to reduce the duration, and thereby the cost of manufacturing proposed in the invention dosage forms.

In addition, when creating the invention, it was unexpectedly found that the release of the active substance of tramadol from the dosage forms of the invention with a retarding coating applied from an aqueous medium is much slower compared to dosage forms that are provided with a retarding coating of an identical composition or structure, but which contain tramadol as an active substance in the form of its hydrochloride. In addition, another advantage associated with the application of a retarding film coating from an aqueous medium is that there is no need for complex regeneration of organic solvents, and also that the dosage forms of the invention do not contain more residual solvents.

In addition, the dosage forms of the invention are characterized in that the nature of the release of the active substance of tramadol from them does not depend on usually variable release conditions, for example, on the ionic concentration of the buffer, on the presence of surfactants or on changes in mechanical stress.

The release profile of the active substance from the dosage forms of the invention was determined as follows.

The dosage form proposed in the invention was studied in a basket device or in a paddle mixer in accordance with the European Pharmacopoeia for 2 hours in 600 ml of artificial gastric juice with a pH of 1.2 at a temperature of the medium into which the active substance is released, 37 ± 0.5 ° C and at a rotation speed of 100 rpm, respectively 50 rpm when using a paddle mixer. Then the dosage form was examined for 8 hours in 900 ml of artificial intestinal juice with a pH of 7.2. In each case, the amount of tramadol saccharinate released at a specific point in time was determined by HPLC. Three samples were used in each experiment, and the results obtained for three such samples were averaged.

Below the invention is illustrated in examples 1-11, which do not limit its scope.

Examples

Example 1

To obtain tramadol saccharinate, equimolar amounts of tramadol, i.e. (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol hydrochloride and saccharin sodium salt or saccharin sodium dihydrate are completely dissolved by heating in the smallest possible amount of water. After that, both solutions by mixing are combined with each other. Tramadol saccharin, which, after a short period of time, crystallizes upon cooling from an aqueous solution, is isolated by conventional methods and purified using ethanol.

Pellet production

2500 g of tramadol saccharinate and 2500 g of microcrystalline cellulose (Avicel PH 105 from FMC) are mixed in a high-speed Diosna P25 mixer for 10 minutes and then granulated with 3300 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in an extruder of the NICA E140 type with an extrusion matrix of 1.0 × 2.0 mm and then the wet extrudate is spheroidized in 2.7 kg portions in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Then the obtained pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

3 kg of the obtained pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Hüttlin HKC05 installation) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until the mass increases by 16 wt.% (In terms of initial weight of pellets). This coating corresponds to a polymer coating content of 13 wt.% (In terms of the initial weight of the pellets). Finally, the pellets are dried in a fluidized bed for 10 min at 45 ° C.

The composition of the aqueous dispersion based on 3 kg of pellets: Eudragit RS30D ^® 1049.0 g Eudragit RL30D ^® 296.0 g Triethyl citrate 80.7 g Glycerol monostearate 20.2 g Tween 80 1.9 g demineralized water 1074.2 g Total: 2522.0 g

345 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile is determined by the above method in a basket device, while the results obtained are shown in table 1, as well as in figure 3.

Table 1 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 60 eleven 120 32 180 46 240 57 300 67 360 76 480 93 600 105

In addition, according to the method described above, the release characteristics of the active substance from pellets with a retarding coating obtained in this way in media of various compositions under the conditions indicated in Table 2 were also determined.

table 2 but) 2 hours in gastric juice at pH 1.2 and 10 hours in intestinal juice at pH 7.2 b) 10 hours in gastric juice at pH 1.2 at) 10 h in intestinal juice at pH 6.0 d) 10 h in intestinal juice at pH 7.2 e) 2 hours in gastric juice at pH 1.2 and 10 hours in intestinal juice at pH 7.2 in each case with 0.1% Tween 80 ^®

The results obtained in these experiments are presented in figure 1. As follows from their graphs shown in Fig. 1, the different composition of the medium into which the active substance is released has practically no effect on the release profile of tramadol saccharinate from retarding coated pellets containing it. Thus, neither the pH value, nor the ionic strength, nor the presence of surfactants affect the release profile of the active substance from pellets with a retarding coating.

Comparative Example 1

Obtaining pellets containing tramadol hydrochloride

275 g of tramadol saccharinate, 75 g of microcrystalline cellulose (Avicel PH 105 from FMC) and 105 g of low substitution hydroxypropyl cellulose (1-HPC LH31 ^® ) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated using 250 g of demineralized water for 10 minutes The wet granulate is extruded in an extruder of the NICA E140 type with an extrusion matrix of 1.0 × 2.0 mm and then the wet extrudate is spheroidized in a NICA spheroidizer for 15 minutes at a speed of 800 rpm. Then the obtained pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

320 g of the obtained pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Acromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C to increase the mass by 25 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 16 wt.% (In terms of the initial weight of the pellets). Finally, the pellets are dried in a fluidized bed for 10 min at 45 ° C.

The composition of the aqueous dispersion based on 320 g of pellets Eudragit RS30D ^® 152.8 g Eudragit RL30D ^® 13.9 g triethyl citrate 15.0 g talc 15.0 g demineralized water 203.3 g Total: 400.0 g

228 mg of retarding coated pellets contain 100 mg of tramadol hydrochloride.

The release profile was determined by the above method in a basket device. The results obtained in this experiment, as well as the results obtained for the pellets of the invention of Example 1, are shown in FIG. 4.

As follows from the graphs shown in Fig. 4, the active substance tramadol saccharinate is released from the containing pellets with retardation coating within 10 hours, while the release of the active substance tramadol hydrochloride from the containing pellets with retardation coating after a short delay time is almost completely completed already 4 hours despite a thicker polymer coating and lower permeability of the polymer composition of this coating.

In addition, we determined our own characteristics of the release of the active substance of tramadol hydrochloride, respectively, of tramadol saccharinate.

The self-release characteristics of the active substance for both tramadol hydrochloride and tramadol saccharinate are determined in demineralized water (37 ° C ± 0.5 ° C) in accordance with the "<1087> intrinsic dissolution" method published in USP 24-NF19, first application (p. 2706 ff.). For each of the two active substances own release was calculated from the slope of the tangent to the curve of the cumulative release of the active substance up to the point in time at which release of active substance from the compressed sample is 10%, and the results are expressed as release rate with the dimension mg-min ^{- 1} cm ^-2 .

Own release in water:

tramadol hydrochloride: 21 mg-min ^-1 · cm ^-2 ,

Tramadol saccharin: 2 mg-min · cm ^-2 .

The difference in the characteristics of the self-release of active ingredients clearly indicates that tramadol saccharin is released from dosage forms much slower compared to tramadol hydrochloride and therefore also penetrates more slowly through diffusion barriers.

Example 2

Pellet production

505 g of tramadol saccharinate and 505 g of microcrystalline cellulose (Avicel PH 105 ^® from FMC) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated with 630 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in a NICA E140 type extruder with a 1.0 × 2.0 mm extrusion die, and then the wet extrudate is spheroidized in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Next, the pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

200 g of the obtained pellets (particle size from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic unit, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until the mass increases by 27 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 21 wt.% (In terms of the initial weight of the pellets). Finally, coated pellets are dried in a fluidized bed for 10 minutes at 45 ° C.

The composition of the aqueous dispersion based on 200 g of pellets: Eudragit RS30D ^® 108.6 g Eudragit RL30D ^® 30.6 g triethyl citrate 8.3 g glycerol monostearate 2.1 g Tween 80 ^® 0.2 g demineralized water 111.2g Total: 261.0 g

379 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile was determined by the above method in a basket device, while the results obtained are shown in table 3, as well as in figure 3. However, unlike the conditions described above, coated pellets were examined for 10 hours in artificial intestinal juice with a pH of 7.2.

Table 3 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 60 3 120 fourteen 180 26 240 35 300 46 360 56 480 74 600 91 720 one hundred

Example 3

Pellet production

505 g of tramadol saccharinate and 505 g of microcrystalline cellulose (Avicel PH 105 ^® from FMC) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated with 630 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in a NICA E140 type extruder with a 1.0 × 2.0 mm extrusion die, and then the wet extrudate is spheroidized in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Finally, the pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

200 g of the obtained pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C to an increase in mass by 21 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 14 wt.% (In terms of the initial weight of the pellets). Then, coated pellets are tested for the release of the active substance either immediately after coating and conventional drying, or after heat treatment, which consists in holding in an oven at 40 ° C for 15 hours.

The composition of the aqueous dispersion based on 200 g of pellets: Eudragit RS30D ^® 80.0 g Eudragit RL30D ^® 20.0 g triethyl citrate 6.0 g talc 6.0 g demineralized water 88.0 g Total: 200.0 g

361 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The corresponding release profiles were determined by the method described above in a basket device, while the results obtained are shown in table 4, as well as in figure 3 for pellets not subjected to heat treatment.

Table 4 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance, without heat treatment The amount of tramadol saccharinate released in% of the total dose of the active substance, exposure for 15 hours at 40 ° C 0 0 0 60 16 fifteen 120 29th 27 180 37 34 240 45 41 360 63 57 480 79 73 600 92 87

The differences between the release rates of active substances from non-subjected and heat-treated forms are about 5%, which corresponds to the usual scatter of measurement results. Thus, the heat treatment carried out after coating does not affect the release profile of the active substance.

Example 4

Pellet production

252.5 g of tramadol saccharinate and 252.5 g of microcrystalline cellulose (Avicel PH 105 ^® from FMC) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated with 338.0 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in a NICA E140 type extruder with a 1.0 × 2.0 mm extrusion die, and then the wet extrudate is spheroidized in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Finally, the pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

170 g of the obtained pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C to an increase in mass by 28 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 20 wt.% (In terms of the initial weight of the pellets). Then the coated pellets are dried in a fluidized bed for 10 min at 45 ° C.

The composition of the aqueous dispersion based on 170 g of pellets: Eudragit RS30D ^® 68.1 g EudragitRL30D ^® 45.4 g triethyl citrate 6.8 g talc 6.8 g demineralized water 99.9 g Total: 227.0 g

381 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile was determined as described above in a basket device, while the results obtained are shown below in table 5, as well as in figure 3. However, unlike the conditions described above, coated pellets were examined for 6 hours in artificial intestinal juice with a pH of 7.2.

Table 5 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 thirty four 120 62 240 94 300 99 480 one hundred

Example 5

Pellet production 505.0 g of tramadol saccharinate and 505.0 g of microcrystalline cellulose 20 (Avicel PH 105 ^® from FMC) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated with 630.0 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in a NICA E140 type extruder with a 1.0 × 2.0 mm extrusion die, and then the wet extrudate is spheroidized in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Finally, the pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

200 g of the obtained pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic unit, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C to increase the mass by 20 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 16 wt.% (In terms of the initial weight of the pellets). Then the coated pellets are dried in a fluidized bed for 10 min at 45 ° C.

The composition of the aqueous dispersion based on 200 g of pellets: Eudragit RS30D ^® 106.1 g triethyl citrate 6.4 g glycerol monostearate 1.6 g Tween 80 ^® 0.2 g demineralized water 84.7 g Total: 199.0 g

358 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile was determined by the above method in a basket device, while the results obtained are shown in table 6, as well as in figure 3. However, unlike the conditions described above, coated pellets were examined for 14 hours in artificial intestinal juice with a pH of 7.2.

Table 6 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 60 0 120 0 180 0 240 2 300 3 360 5 420 7 480 8 600 10 720 12 840 fourteen 960 fifteen

Example 6

Study of storage stability of tramadol-containing pellets with retarding coating containing saccharinate

The retarding-coated pellets obtained according to Example 1 were kept in closed glass vessels, respectively, for 1, 2 weeks, respectively, at 30 ° C and 70% relative humidity, either at 40 ° C in a dry atmosphere, or at 40 ° C and 75% relative humidity and after the appropriate storage time according to the method described above, the release profile of the active substance was determined. However, unlike the conditions described above, coated pellets were examined for 10 hours in artificial intestinal juice with a pH of 7.2.

The results obtained in each of these experiments are presented in figure 2. As follows from the graphs shown in figure 2, storage at 30 ° C and 70% relative humidity, as well as at 40 ° C in a dry atmosphere does not affect the release profile of the active substance. Storage at 40 ° C and 75% relative humidity also only leads to a slight slowdown in the release of partially sticky pellets. Therefore, the dosage forms of tramadol saccharinate proposed in the invention immediately after their manufacture have a retarding active substance release profile that is stored during storage and without heat treatment.

Example 7

Pellet production

250 g of tramadol saccharinate and 250 g of microcrystalline cellulose (Avicel PH 105 ^® from FMC) are mixed in a Kennwood Chef planetary mixer for 10 minutes and then granulated with 443 g of demineralized water for 10 minutes. Next, the wet granulate is extruded in a NICA E140 type extruder with a 1.0 × 2.0 mm extrusion die, and then the wet extrudate is spheroidized in a NICA type spheroidizer for 15 minutes at a speed of 800 rpm. Finally, the pellets are dried overnight in an oven at 50 ° C. The yield of pellets with a particle size of 800 to 1250 microns is more than 90%.

Coating

170 g of the obtained pellets (particle size from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 35 to 40 ° C to increase the mass by 5 wt.% (In in terms of the initial mass of pellets). Then, coated pellets are dried in an oven for 2 hours at 60 ° C.

The composition of the aqueous dispersion based on 170 g of pellets: Surelease E-7-7050 ^{® *} 34.0 g demineralized water 23.0 g Total: 57.0 g

^* 25% pseudolatex dispersion of ethyl cellulose. This commercially available finished dispersion contains dibutyl sebacate as a plasticizer and silicon dioxide as a lubricant.

313 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile was determined as described above in a basket device, while the results obtained are shown in table 7, as well as in figure 3.

Table 7 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 thirty fifteen 120 58 240 69 300 71 480 76 600 79

Example 8

Pill making

Composition per 1 tablet:

tramadol saccharin 149 mg cellactose 146 mg magnesium stearate 3 mg

Cellactose and magnesium stearate are sieved and then mixed for 10 min until homogeneous with tramadol saccharinate in a free-fall mixer (Bohle, LM 40). From this mixture, round, convex pellet-like tablets with a diameter of 10 mm, a height of about 5 mm and a radius of convexity of 8 mm are pressed on a Korsch EK0 type eccentric press using a punch.

Coating

The 2000 tablets obtained are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until a weight increase of 6.5 wt.% (In terms of the initial weight of the tablets). This coating corresponds to a polymer coating content of 5.0 wt.% (In terms of the initial weight of the tablets). Finally, the coated tablets are dried in an oven for 10 minutes at 40 ° C.

The composition of the aqueous dispersion based on 2000 tablets: Eudragit RS30D ^® 69.7 g Eudragit RL30D ^® 29.8 g triethyl citrate 6.0 g glycerol monostearate 1.5 g Tween 80 ^® 0.1 g demineralized water 92.4 g Total: 199.5 g

The release profile was determined as described above in a paddle mixer, and the results are shown in table 8.

Reference Example 2

Pill making

Composition per 1 tablet:

tramadol hydrochloride 100 mg cellactose 98 mg magnesium stearate 2 mg

Cellulose and magnesium stearate are sieved and then mixed for 10 min until homogeneous with tramadol hydrochloride in a free-fall mixer (Bohle, LM 40). Round, convex pellet-like tablets with a diameter of 9 mm, a height of about 5 mm and a radius of convexity of 8 mm are pressed from this mixture on a Korsch EK0 eccentric press using a punch.

Coating

2000 of these tablets are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until the mass increases by 6.5 wt.% (In terms of the initial weight of the tablets). This coating corresponds to a polymer coating content of 5.0 wt.% (In terms of the initial weight of the tablets). Finally, the coated tablets are dried in an oven for 10 minutes at 40 ° C.

The composition of the aqueous dispersion based on 2985 tablets: Eudragit RS30D ^® 69.7 g Eudragit RL30D ^® 29.8 g triethyl citrate 6.0 g glycerol monostearate 1.5 g Tween 80 ^® 0.1 g demineralized water 92.4 g Total: 199.5 g

The release profile was determined as described above in a paddle mixer, and the results are shown in table 8.

Table 8 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance Tramadol hydrochloride released in% of the total dose of the active substance 0 0 0 thirty one 2 240 9 91 480 17 96 720 25 98

If the active substance tramadol hydrochloride is already> 90% released from coated tablets within 4 hours, then the release of tramadol saccharinate from coated tablets is much slower and at a constant rate, with only 25% of the total dose being released after 12 hours.

In this case, we can also conclude that the slower dissolution of tramadol saccharinate at identical diffusion barriers leads to a significantly more pronounced retardation compared to the release of tramadol hydrochloride and, in contrast, even with a thinner film coating provides a kinetics of 0-order release .

Example 9

Pellet production

500 g of tramadol hydrochloride, 345 g of sodium saccharinate and 845 g of microcrystalline cellulose (Avicel PH 101 ^® ) are mixed for 10 minutes and then granulated with demineralized water in an amount sufficient for granulation for 10 minutes. After granulation, the granulate is extruded in an extruder of the NICA E140 type with an extrusion matrix of 0.8 × 1.6 mm and the extrudate is again granulated using a sufficient amount of water to obtain a plastic mass. This mass is extruded again. The wet extrudate is then spheroidized in a NICA type S450 spheroidizer. After drying in an oven, pellets are classified, while the yield of pellets with a particle size of 0.63 to 1.0 mm is> 90%.

Coating

For 1000 g of the obtained pellets, a fluidized bed coating (Hüttlin HKC05 installation) is applied from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until the mass increases by 20 wt.% (In terms of the initial weight of the pellets). This coating corresponds to a polymer coating content of 16 wt.% (In terms of the initial weight of the pellets). Finally, the pellets are dried in a fluidized bed for 10 min at 45 ° C.

The composition of the aqueous dispersion based on 1000 g of pellets: Eudragit RS30D ^® 499.5 g Eudragit RL30D ^® 166.5 g triethyl citrate 40.0 g glycerol monostearate 10.0 g Tween 80 ^® 1.1 g demineralized water 612.9 g Total: 1330 g

Packing of coated pellets in capsules

406 mg of pellets with a retarding coating (which corresponds to a dose of 100 mg of tramadol hydrochloride) are packaged on a machine for assembling detachable Zanasi E6 capsules into size 0 hard gelatine capsules.

The release profile was determined as described above in a basket device, while the results obtained are shown in table 9, as well as in figure 3. However, unlike the conditions described above, coated pellets were examined for 10 hours in artificial intestinal juice with a pH of 7.2.

Table 9 Min time The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 60 7 120 22 240 53 480 91 600 99 720 one hundred

Example 10

Pellets receive analogously to example 4.

400 g of these pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 26 to 30 ° C until a mass increase of 25 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 20% (in terms of the initial weight of the pellets). Finally, coated pellets are dried in a fluidized bed for 10 minutes at 40 ° C.

The composition of the aqueous dispersion based on 400 g of pellets: Eudragit RS30D ^® 200.0 g Eudragit RL30D ^® 66.7 g triethyl citrate 16.0 g glycerol monostearate 4.0 g Tween 80 ^® 0.5 g demineralized water 212.8 g Total: 500.0 g

373 mg of pellets with a retarding coating contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

Pill making

Composition per 1 tablet coated pellets 373 g Kollidon CL ^® 22.4 g Avicel PH 101 ^® 142.0 g magnesium stearate 2.6 g Total: 540.0 g

Retardable coated pellets are mixed for 5 minutes in a free-fall mixer (Bohle, LM 40) with Kollidon CL ^® (crosslinked polyvinylpyrrolidone) and then mixed for 10 minutes with microcrystalline cellulose (Avicel PH 101 ^® ) and magnesium stearate. Round biaxial tablets with a diameter of 12 mm, each weighing 500 mg and a hardness of 100 to 130 N are pressed from this mixture on a tablet machine (Fette, P 1200).

In the aquatic environment, these tablets disintegrate into individual pellets within 1-2 minutes.

The release profile was determined as described above in a paddle mixer, while the results obtained are shown in table 10, as well as in FIG.

Table 10 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 thirty 8 120 22 240 46 300 57 480 86 600 102

Example 11

Pellets receive analogously to example 2.

200 g of these pellets (particle sizes from 800 to 1250 μm) are coated in a fluidized bed (Aeromatic installation, Strea 1) from an aqueous dispersion of the composition indicated below at a product temperature of 35 to 40 ° C until an increase in mass by 20 wt.% (In in terms of the initial mass of pellets). This coating corresponds to a polymer coating content of 15 wt.% (In terms of the initial weight of the pellets). Finally, coated pellets are dried in a fluidized bed apparatus for 10 minutes at 45 ° C.

The composition of the aqueous dispersion based on 200 g of pellets: Kollicoat RS30D ^® 100.0 g propylene glycol 3.0 g talc 7.0 g demineralized water 90.0 g Total: 200.0 g

358 mg of retarding coated pellets contain 149 mg of tramadol saccharinate, which corresponds to a dose of 100 mg of tramadol hydrochloride.

The release profile was determined as described above in a basket device, while the results are shown in table 11.

Table 11 Time (min) The amount of tramadol saccharinate released in% of the total dose of the active substance 0 0 thirty 6 120 37 180 54 240 61 300 71 480 76 600 92 720 98

Figure 3 presents the sample characteristics of various profiles of the release of the active substance of tramadol saccharinate from extruded pellets, which were coated with an aqueous dispersion. Varying the composition and thickness of the film coating makes it possible to appropriately adjust the release profile of the active substance from the composition intended for single administration per day, respectively, twice administration per day, as well as shifting the kinetics of release from 1st-order kinetics to 0-order kinetics. This indicates a large variety of indicators of the release profile of the active substance achieved using the solution proposed in the invention, using only commercially available polymer dispersions processed according to the technology recommended by the manufacturer, without taking additional measures or using special additives.

Claims (38)

1. A dosage form for an oral administration agent having an analgesic effect, comprising tramadol with at least one retarding coating and optionally other excipients, characterized in that it contains tramadol in the form of its saccharinate. 2. The dosage form according to claim 1, characterized in that the tramadol compound is present in the form of an in situ compound. 3. The dosage form according to claim 1 or 2, characterized in that the tramadol compound is prepared using a water-soluble, pharmaceutically acceptable salt of tramadol, preferably tramadol hydrochloride, and a water-soluble, pharmaceutically acceptable salt of saccharin, preferably its sodium, potassium, calcium or ammonium salt, more preferably sodium salt. 4. The dosage form according to claim 3, characterized in that it is presented in the form of tablets, capsules. 5. The dosage form according to claim 4, characterized in that it is presented in a multi-particle form, preferably in the form of microtablets, microcapsules, micropellets, granules, crystals of active substances or pellets, optionally packaged in capsules or compressed into tablets, or in the form of a hydrophilic or lipophilic liquid, in suspended form. 6. The dosage form according to claim 5, characterized in that the size of the granules or pellets is from 0.1 to 3 mm, preferably from 0.5 to 2 mm. 7. The dosage form according to claim 6, characterized in that the diameter of the microtablets is from 0.5 to 5 mm, preferably from 1 to 3 mm, more preferably from 1 to 2 mm. 8. The dosage form according to claim 5, characterized in that the diameter of the crystals of the active substance, microparticles, micropellets or microcapsules is from 10 microns to 1 mm, preferably from 15 microns to 0.5 mm, more preferably from 30 to 200 microns. 9. A dosage form according to any one of claims 1 to 8, characterized in that the base of the retarder coating is a water-insoluble, optionally modified, natural or synthetic polymer or a natural, semi-synthetic or synthetic wax, fat or aliphatic alcohol or a mixture of at least these two components. 10. The dosage form according to claim 9, characterized in that the water-insoluble polymers as the coating material are poly (meth) acrylates, preferably poly (C ₁ -C ₄ ) alkyl (meth) acrylates, poly (C ₁ -C ₄ ) dialkylamino (C ₁ -C ₄ ) alkyl (meth) acrylates and / or their copolymers, preferably copolymers of ethyl acrylate and methyl methacrylate with a molar ratio of monomers 2: 1 (product Eudragit NE30D ^® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride monomer ratio 1: 2: 0.1 (product Eudragit RS ^® ), ethyl acryl copolymers ilate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride with (and a molar ratio of monomers 1: 2: 0.2 (product of Eudragit RL ^® ) or a mixture of at least two of these polymers. 11. The dosage form according to claim 9, characterized in that the water-insoluble polymers as the coating material are cellulose derivatives, preferably alkyl cellulose, more preferably ethyl cellulose, or cellulose esters, preferably cellulose acetate. 12. A dosage form according to claim 10 or 11, characterized in that the polymers are applied from an aqueous medium, preferably from aqueous latex or pseudolatex dispersions. 13. The dosage form according to claim 9, characterized in that the polymer coating is made from a mixture of polyvinyl acetate and polyvinylpyrrolidone, preferably in the form of aqueous pseudolatex dispersions. 14. The dosage form according to claim 9, characterized in that the wax as a coating material, preferably applied by a melt method, is carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate (product Compntol AT0888 ^® ), glycerol nitrite tripalmitostearate (product Precirol ATO5 ^® ), microcrystalline wax or a mixture of at least two of these components. 15. The dosage form of claim 10 or 12, characterized in that the polymers are used in combination with conventional plasticizers. 16. The dosage form according to claim 15, characterized in that the plasticizers are lipophilic diesters of aliphatic or aromatic dicarboxylic acids with C ₆ -C ₄₀ and aliphatic alcohols with C ₁ -C ₈ , preferably dibutyl phthalate, diethyl phthalate, dibutyl sebacetate or diethyl sephylate, citric acid esters, preferably triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, preferably triacetin, acetylated mono- and digly eridy triglycerides with an average chain length of oleic acid or a mixture of at least two of said plasticizers. 17. The dosage form according to claim 15 or 16, characterized in that the amount of plasticizer is from 5 to 50 wt.%, Preferably from 10 to 40 wt.%, More preferably from 10 to 30 wt.% In terms of the amount of polymer material coverings. 18. The dosage form according to any one of claims 1 to 17, characterized in that it has a retarding matrix. 19. The dosage form of claim 18, wherein the matrix is based on a hydrophilic material, preferably hydrophilic polymers, more preferably cellulose ethers, cellulose esters and / or polyacrylates, most preferably ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth ) acrylic acid and / or its salts, amides and / or esters. 20. The dosage form according to p. 18 or 19, characterized in that the matrix is a hydrophobic material, preferably hydrophobic polymers, various types of wax, fats, long chain fatty acids, aliphatic alcohols or the corresponding esters or ethers, or mixtures thereof, more preferably mono- or diglycerides of fatty C ₁₂ -C ₃₀ acids and / or aliphatic C ₁₂ -C ₃₀ alcohols and / or various types of wax or mixtures thereof. 21. The dosage form according to any one of claims 1 to 20, characterized in that, as an additional coating, it has a coating resistant to the action of gastric juice. 22. The dosage form according to item 21, wherein the gastric juice resistant coating consists of copolymers of methacrylic acid and methyl methacrylate with a molar ratio of monomers 1: 1 (product Eudragit L ^® ), from copolymers of methacrylic acid and methyl methacrylate with a molar ratio of monomers 1: 2 (product Eudragit S ^®), copolymers of methacrylic acid and ethyl acrylate with a molar ratio of monomers of 1: 1 (product Eudragit L30-D55 ^®), copolymers of methacrylic acid, methyl acrylate and metilmetakridata a molar ratio of monomer 7: 3: 1 (product Eudragit FS ^®), shellac, gidrokeipropilmetiltsellyulozy acetate succinate, cellulose acetate phthalate or of a mixture of at least two of these components, optionally also in combination with poly (meth) acrylates, preferably with the product Eudragit NE30D ^® and / or an Eudragit RL ^{® product} and / or an Eudragit RS ^{® product} . 23. A dosage form according to any one of claims 1 to 22, characterized in that it additionally contains the active substance tramadol in unhard form. 24. A dosage form according to any one of claims 1 to 24, characterized in that the retarder coating is applied from aqueous media and is not subjected to heat treatment after normal drying. 25. The dosage form according to any one of claims 1 to 24 for a single administration per day, characterized in that it contains from 10 to 1200 mg, preferably from 20 to 1000 mg, more preferably from 100 to 800 mg of tramadol. 26. A dosage form according to any one of claims 1 to 24 for double administration per day, characterized in that it contains from 5 to 600 mg, preferably from 10 to 500 mg, more preferably from 50 to 400 mg of tramadol. 27. Dosage form according to any one of claims 1 to 26 for the relief of pain. 28. Dosage form according to any one of claims 1 to 26 for the treatment of urinary incontinence. 29. Dosage form according to any one of claims 1 to 26 for the treatment of cough. 30. Dosage form according to any one of claims 1 to 26 for the treatment of inflammatory processes and / or allergic reactions. 31. A dosage form according to any one of claims 1 to 26 for the treatment of a depressed state. 32. Dosage form according to any one of claims 1 to 26 for the treatment of abusus and / or alcoholism. 33. The dosage form according to any one of claims 1 to 26 for the treatment of gastritis. 34. The dosage form according to any one of claims 1 to 26 for the treatment of diarrhea. 35. Dosage form according to any one of claims 1 to 26 for the treatment of cardiovascular diseases. 36. Dosage form according to any one of claims 1 to 26 for the treatment of diseases of the respiratory tract. 37. Dosage form according to any one of claims 1 to 26 for the treatment of mental illness. 38. Dosage form according to any one of claims 1 to 26 for the treatment of epilepsy.

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