KR20020031421A - Oral dosage forms - Google Patents

Abstract

The present invention relates to an oral dosage form in which the total release of the active substance is regulated. The active substance is present in the form of two or more different salts, which are present in the dosage form in solid agglomerated state and the active substance is released differently in vitro.

Description

Oral dosage forms < RTI ID = 0.0 >

The present invention relates to an oral dosage form in which the active substance is present in the form of two or more different salts, the salts of which are present in the form of an aggregate in the solid state of aggregation and whose release in vitro of the active substance is different, .

It is advantageous in many therapies to administer the active substance in a formulation that releases the active substance in a controlled manner. For example, controlled release of an active agent having a relatively short half-life prolongs the usefulness of the active agent in the body. In addition, it can be regulated to a constant blood level in this way, optionally minimizing the unwanted accompanying symptoms and improving adherence to dosage details.

Typically, controlled release of the active substance from the oral dosage form is achieved only through relatively costly formulation procedures, such as emulsifying the oral dosage form containing the active substance into the sustained release membrane or incorporating the active substance into the sustained release matrix . If the same active substance or the same active substance salt is to be separately processed to provide different formulations, if a certain amount of the active substance has to be released differently in order to adjust the overall release profile, then the sustained release and non- It can be combined as a sustained type.

It is therefore an object of the present invention to provide an oral dosage form of the active substance which releases the active substance in a controlled manner without the need for a costly separate formulation step to control the overall release profile of the active substance from the dosage form .

According to the invention, this object is achieved by a process according to the invention, characterized in that the same active substance is present in the form of two or more different salts, these salts are present in the form of an aggregate in the solid state and the active substance is released differently in vitro Is achieved by providing an oral dosage form in which release of the substance is modulated.

In one preferred embodiment of the invention, the various salts of all the active substances present in one dosage form exhibit different water solubilities from each other, which in turn induces different dissolution rates of the active substance.

Preferably, the various active substance salts used in the dosage form according to the present invention are different from each other by a factor of at least two.

In the case of oral dosage forms according to the invention, the total release profile of the active substance concerned can be adjusted to the desired form by selecting the active substance salts contained in the combined dosage forms and their quantitative proportions. This may be achieved by treatment-specific modulation of the plasma level of the active substance, such as achieving a stable plasma level that is as long as possible over a relatively long period of time, pulsing release with a plasma level peak that varies with time of the active substance, Lt; / RTI > to achieve plasma levels of the active substance according to < RTI ID = 0.0 >

In the present invention, the active substance affects all biological, biochemical, chemical, physical or physiological processes or structures in a human or animal body and is capable of forming solid salts at 25 ° C by conversion with an acid or base to be.

This formation of the active substance salts can also be achieved through conversion with other active substances having corresponding acidic or basic functionalities.

Preferably, the salt-forming active substance is selected from the group consisting of pharmaceutically active substances that form salts, vitamins, nutrients, minerals and diagnostic agents, and particularly preferably selected from the group consisting of pharmaceutically active substances that form salts do.

When the active substance is a pharmaceutically active substance that forms a salt, the active substance may preferably be a salt-forming substance selected from the following group of substances: analgesic, insect repellent, arrhythmia, asthma, depression, diabetes An antihypertensive agent, an antihypertensive agent, an antihypertensive agent, a rheumatic agent, an antipyretic agent, an anxiolytic agent, a weight loss drug, a treatment drug for athlete's disease, a dizziness treatment drug, an anti-inflammatory drug, an antiinflammatory drug, an antidote, an antiallergic agent, An antiinflammatory agent, a beta-adrenergic receptor blocker, a calcium-channel blocker, a renin-angiotensin inhibitor, a cough suppressant, an antiinflammatory agent, an antifibrinolytic agent, a hemostatic agent, a hypoglycemic agent, , Bile secretagogue, cholinergic agent, cholinergic agent, corticoid (internal), circulation accelerating drug, detox drug, (Eg, pituitary hormone, hypothalamic hormone), regulatory peptides or their inhibitors, immunomodulators, cardiovascular drugs, anti-inflammatory drugs, antiinflammatory drugs, antiulcer drugs, anti-influenza drugs, cold medicines, gynecological medicines, , Antithrombotic agents, antioxidants, antihypertensive agents, anemia drugs, dementia drugs (brain function enhancers), appetite suppressants, coronary artery anticoagulants, laxatives, chemotherapeutic agents, diuretics, enzymes, fungi growth inhibitors, lipid lowering drugs, A medicament for treating migraine, a drug for migraine, a muscle relaxant, a neuropathic drug, a neuroleptic drug, a neuroleptic drug, a therapeutic agent for osteoporosis, a calcium metabolism modulator, a Parkinson's drug, a therapeutic drug for extrapyramidal symptoms, Tonics, thyroid therapeutic drugs, sex hormones or their inhibitors, antispasmodics, platelet aggregation inhibitors, pneumonics, urological agents, An anti-neoplastic agent or an anti-proliferative agent, a sedative agent, a vasodilator, a viral growth inhibitor or a cell proliferation inhibitor. Particularly preferably, the salt-forming pharmaceutical active is selected from a salt-forming analgesic, an infectious disease agent or a neuroleptic agent.

A salt-forming opiate amount agent or a non-steroidal analgesic agent which is a compound having an opioid action can be preferably used as a salt-forming analgesic agent.

Examples of the salt-forming opioid agent having an opioid action include, but are not limited to, the following: bromotitanyl, carfentanil, pentathienyl, loptentanil, oxfetanil, trepentanil, codeine, dextropropoxyphen Dihydrocodeine, diphenoxylate, 멥taginol, nalbupine, petidine (meperidine), tilidine, tramadol, biminol, butorphanol, dextromomide, dezocine, diacetylmorphine (heroin) But are not limited to, hydrocodone, hydrocodone, hydro morphone, ketobemidone, levomethone, levomadil, levorphanol, morphine, nalolpine, oxycodone, pentazocine, pyritramide, alfentanil, Remyfentanil or ceftetanium. Particularly preferably used is tramadol or morphine.

The prometazine may preferably be used as a salt-forming neuroleptic agent.

Physiologically acceptable active substance salts may be present as the active substance salt in the pharmaceutical oral dosage form according to the invention. Additional active materials may be used as the partner salt in the active material used.

Preferably the salts are selected from the group consisting of chloride, bromide, sulfate, sulfonate, phosphate, tartrate, theoclate, embonate, formiate, acetate, propionate, benzoate, oxalate, succinate, citrate, Diclofenacate, naproxenate, salicylate, glutamate, fumarate, acetylsalicylate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate, ≪ / RTI > cyclamate or acesulfamate. Particularly preferably, these salts can be selected from chloride, sulfate, saccharinate, theoclate, embonate, diclofenacate, naproxenate or salicylate.

Preferably, tramadol hydrochloride, tramadol saccharinate and tramadol diclofenacate or morphine hydrochloride, morphine saccharinate and morphine sulfate may be present together with each other as a salt of the same active substance in the oral dosage form of the present invention. Particularly preferably, tramadol hydrochloride and tramadol saccharinate or tramadol hydrochloride and tramadol diclofenacate may be present together with each other as a salt of the same active substance in the oral dosage form of the present invention.

Alkarin metal salts, alkaline metal salts, ammonium salts, iron salts or aluminum salts of the active substance may be used with comparable preference as the active substance salts. Particularly preferred is an alkaline metal salt, and most preferably sodium or potassium salt of the active substance may be used.

The controlled total release of the active substance from the oral dosage form of the present invention can be further modified such that at least one, preferably several or all of the active substance salts of the active substance salts may be present in the dosage form in sustained release form. Equally preferably, the oral dosage form can be made into a sustained release formulation with all active substance salt formulations to provide dosage forms of the present invention.

In one preferred embodiment of the invention, the sustained release is provided by incorporation into a sustained release coating and / or sustained release matrix.

The sustained-release coating is preferably based on a water-insoluble, optionally modified, natural or synthetic polymer and optionally a conventional softener on a mixture of natural, semi-synthetic or synthetic wax or a fatty or fatty alcohol or a mixture of two or more of the above- do.

In the water-insoluble polymer for producing a sustained-release coating, the following materials are preferably used as coating materials: polymethacrylates, particularly preferably poly (C _1-4 ) -alkyl (meth) acrylates, (Meth) acrylate and / or a copolymer thereof, preferably a 2: 1 molar ratio of monomers, of a poly (C _1-4 ) _{-dialkylamino-} (C _1-4 ) the molar ratio of the copolymer (Eudragit RS ^R), monomer 0.1 ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate-chloride: acrylate copolymer (Eudragit NE30D ^R), the molar ratio of monomers 1: 2 Ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate-chloride-copolymer (Eudragit RL ^R ) of 1: 2: 0.2 or a mixture of two or more of the above polymers.

The film material is available as an aqueous latex dispersion of 30% by weight, i.e., Eudragit RS30D ^R, Eudragit NE30D and Eudragit RL30D ^{R R,} and is also used as a preferred coating material.

The same preferred polyvinyl acetate may optionally be combined with further auxiliaries to be used as a water-insoluble polymer for the preparation of sustained-release coatings of dosage forms according to the invention as a whole or for individual active substance salts. They are available as aqueous dispersions containing 27% by weight of polyvinyl acetate, 2.5% by weight of povidone and 0.3% by weight of sodium lauryl sulfate (Kollicoat SR 30D ^R ).

The sustained release coating may also be based on a water-insoluble cellulose derivative, preferably an alkylcellulose (e.g., ethylcellulose) or a cellulose ester (e.g., cellulose acetate). Coatings made of ethylcellulose are preferably applied from aqueous, pseudo-latex dispersions. The aqueous ethyl cellulose dispersion can be purchased as a 30 wt% dispersion (Aquacoat ^R ) or a 25 wt% dispersion (Surelease ^R ).

With respect to semisynthetic or synthetic waxes, fats and / or fatty alcohols, the sustained release coating is preferably selected from the group consisting of carnauba wax, beeswax, glycerin monostearate, glycerin mono behenate (Compritol ATO 888 ^R ), glycerin ditripalmitostearate (Precirol ATO 5 ^R ), microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of two or more of these components.

If the sustained release coating is based on a water insoluble, optionally modified, natural and / or synthetic polymer, the coating dispersion or solution may be combined with a conventional polymer to reduce the required minimum film temperature or modify the properties of the film, And may contain physiologically acceptable softening agents.

Examples of suitable emollients include lipophilic diesters made from C ₆ -C ₄₀ aliphatic or aromatic dicarboxylic acids and C ₁ -C ₈ aliphatic alcohols (eg, dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl Esters of polyethylene glycol, propylene glycol, glycerine (e. G., Triacetate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate) paroxetine), Myvacet ^R (acetylated mono-and di-glycerides, C ₂₃ H ₄₄ O ₅ to C ₂₅ H ₄₇ O _7), medium-chain triglycerides (Miglyol ^R), oleic acid, or two or more mixture of said softener . Preferably, triethyl citrate is used as a softener for aqueous dispersions of Eudragit RS ^R and optionally Eudragit RL ^R.

Preferably, the sustained release coating contains from 5 to 50% by weight, particularly preferably from 10 to 40% by weight, most preferably from 10 to 30% by weight, based on the amount of polymer used, of a softening agent. In each case, for example in the case of cellulose acetate, a large amount of softening agent can be used, preferably up to 110% by weight.

The sustained release coating may also contain other conventional auxiliary materials known to those skilled in the art, such as a slip agent, preferably talcum or glycerin monostearate, a colorant, preferably iron oxide or titanium dioxide, a surfactant, Tween 80 ^R ) or an auxiliary material for controlling membrane properties, for example, a water soluble pore former such as lactose, polyethylene glycol 1000 (PEG 1000) or saccharose.

Oral dosage forms of the present invention may contain one or more active substance salts, preferably several or all active substance salts, in the sustained release matrix, preferably uniformly distributed. Physiologically acceptable hydrophilic materials known to those skilled in the art can preferably be used as the matrix material. Particularly preferably, the sustained release matrix is selected from the group consisting of cellulose ethers, cellulose esters and / or acrylic resins, most particularly preferably ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) Acids and / or salts, amides and / or esters thereof.

Also preferably, physiologically acceptable hydrophobic materials known to those skilled in the art can be used as the matrix material. Particularly preferably, the matrix comprises a hydrophobic polymer, a wax, a fat, a long chain fatty acid, a fatty alcohol or a corresponding ester or ether or mixture thereof, more particularly preferably a mono- or di-glyceride of a C ₁₂ -C ₃₀ fatty acid and / and the / or C ₁₂ -C ₃₀ fatty alcohols and / or waxes or their mixtures with base.

It is also possible to use a mixture of the hydrophilic and hydrophobic materials as the sustained release matrix material.

When the oral dosage form of the present invention contains active salt of the active acid which is weaker than hydrochloric acid in the gastrointestinal tract of humans or animals, they should preferably have a protective coating resistant to gastrointestinal fluids. These protective coatings may prevent the active substance in the active substance salt present in the oral dosage form of the present invention from being released in the gastrointestinal system in a sustained or permanent manner. The gastric-resistant coating prevents the oral dosage form of the present invention from passing through the gastrointestinal tract in an undissolved state and releasing the active substance until it reaches the intestinal tract. Preferably, the gastric juice-resistant coating is dissolved at a pH of from 5 to 7.5. Thus, one skilled in the art can monitor and control the total-release profile required by simple preliminary in vitro experiments using known measurement methods to determine the release of active substance.

The gastric-resistant film is preferably a methacrylic acid / methyl methacrylate copolymer (Eudragit L ^R ) having a molar ratio of monomers of 1: 1, a methacrylic acid / methyl methacrylate copolymer having a molar ratio of monomers of 1: 2 S ^R), the molar ratio of monomers is 1: methacrylic acid / ethyl acrylate copolymer (Eudragit L30-D55 ^R), the molar ratio of monomers 7: 3: 1 methacrylic acid / methyl acrylate / methyl methacrylate (Eudragit FS ^R ), shellac, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate or a mixture of two or more of these components and optionally poly (meth) acrylate, preferably Eudragit NE 30D ^R and / or Eudragit RL ^R and / / Or Eudragit RS ^R is formulated.

The coating dispersion or solution to which the gastric fluid-resistant coating is applied may contain one of the softening agents in addition to the corresponding polymer. Moreover, the sustained release coating materials described above can also be applied as protective coatings of various thicknesses to gastric acid known to those skilled in the art.

The sustained release and / or protective coatings of the oral dosage forms according to the invention can be prepared by conventional processes suitable for the relevant coatings known to those skilled in the art, for example by spraying solutions, dispersions or suspensions, Process. ≪ / RTI > Solutions, suspensions or dispersions may be used in the form of aqueous or organic solutions or dispersions. In the present invention, it is preferable to use an aqueous dispersion. It is possible to use an alcohol (e.g. ethanol or isopropanol), a ketone (e.g. acetone), an ester (e.g. ethyl acetate), a chlorinated hydrocarbon (e.g. dichloromethane) as an organic solvent and accordingly an alcohol and a ketone are preferably used . It is also possible to use a mixture of two or more of the above solvents.

These processes are described in the prior art (H. Sucker, Georg Thieme Verlag, 1991, pp 347 ff. The contents of this document are incorporated herein by reference and are incorporated herein by reference.

In a preferred embodiment of the present invention, the oral dosage form of the present invention is present in the form of a tablet, a chewing tablet, a chewing gum, a shelf or a powder, optionally filled in a capsule, and a particularly preferred form is a tablet.

In a further preferred embodiment of the invention, the oral dosage form of the invention is in the form of a plurality of particles, preferably microcleaning agents, microcapsules, granules, active substance crystals or pellets, particularly preferably microcleaning agents, granules or pellets ≪ / RTI > and optionally filled into capsules or tableted.

When the oral dosage form of the present invention is present in the form of granules or pellets, they may preferably be 0.1 to 3 mm in size, particularly preferably 0.5 to 2 mm.

When the oral dosage forms of the present invention are present in the form of a detergent, they may preferably have a diameter of from 0.5 to 5 mm, particularly preferably from 1 to 3 mm, and most preferably from 1 to 2 mm.

When the oral dosage form of the present invention is present in the form of active substance crystals, microparticles, micropellets or microcapsules, they may preferably be 10 [mu] m to 1 mm in diameter, particularly preferably 15 [mu] , Most particularly preferably from 30 [mu] m to 200 [mu] m.

Moreover, the dosage forms of the present invention may contain conventional auxiliary materials known to those skilled in the art depending on the design.

When the oral dosage forms of the present invention are present in the form of tablets or detergents, they are preferably microcrystalline cellulose, cellulose ethers, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogen phosphate and other Customary binders, flow-control agents, slip agents, and optionally dispersants known to those skilled in the art.

When the oral dosage form of the present invention is present in the form of pellets, granules or microgranules, they may be used as additional adjuvants, preferably microcrystalline cellulose, cellulose ether, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogen phosphate , Fatty alcohols, esters of glycerin, or fatty acid esters.

When the oral dosage forms of the present invention are in the form of microcapsules or microparticles, they may contain conventional auxiliary substances known to those skilled in the art depending on the type of process used for manufacture.

For the preparation of the oral dosage forms according to the invention, the active substance salts and optionally further auxiliaries are preferably homogenized in a high speed mixer or rotary fluidized bed. After this process, the formulation is carried out according to various methods known to the person skilled in the art and, optionally, a gastric resistant protective coating is applied from the coating material according to the method described above.

When the oral dosage form of the present invention is present in the form of tablets, the various solid active substance salts are preferably homogenized and granulated by means of wet, dry or fusion granulation and compressed to form tablets, The salt may be prepared by direct tableting optionally with additional auxiliary substances. Furthermore, tablets may be prepared by squeezing the pellets, active substance crystals, microparticles or microcapsules, which are optionally coated.

Oral dosage forms according to the invention in the form of pellets may preferably be prepared by mixing the active substance salts, extruding and spheronizing, coagulating pelleting, or pelleting directly in a high speed mixer or rotating fluidized bed. It is particularly preferred to make pellets by extruding the wet compound followed by spheronization. The preparation of microcapsules is carried out according to conventional microencapsulation processes such as spray-drying, spray-curing or coacervation.

When the oral dosage form according to the present invention is present in the form of a plurality of particles, the sustained release coating is preferably formulated with an aqueous and / or organic medium, preferably an aqueous medium, Containing multiparticulates are dispensed with their associated polymers and optionally further auxiliary substances after their preparation and the coatings are applied in such a manner that they are preferably dried simultaneously at conventional temperatures in the fluidized bed but not in subsequent curing of the coating. In the case of a poly (meth) acrylate coating, the coating is preferably dried at an inlet-air temperature of 30 to 50 占 폚, preferably 35 to 45 占 폚.

In the case of a film based on cellulose such as ethyl cellulose or cellulose acetate, the drying is preferably carried out at a temperature of 50 to 80 DEG C, particularly preferably at a temperature of 55 to 65 DEG C.

The wax coating may be applied after cooling to a temperature not exceeding the fusion range of the fluidization bed and completely curing at a temperature below the melting range of the fluidization bed, followed by cooling. The wax coating can also be applied by spraying a solution in an organic solvent.

The amount of active substance to be administered to a patient can vary depending upon the type of active agent used, the weight of the patient, disease symptoms and optionally the severity of the pain and / or disease.

The total amount of active substance to be administered and its total release from a salt of the active substance is preferably adjusted in such a way that the administration of the oral dosage form according to the invention is preferably at most twice a day, preferably once a day do.

The oral dosage forms according to the present invention may be formulated in a controlled manner in accordance with the desired overall release profile, for example, pulsating or multi-phase, for a given period of time, without the need for expensive separate formulation steps for the active substance. And can be discharged in the form of a gas.

This means that it is possible to minimize the time and hence the cost for the preparation of the oral dosage form according to the invention.

The water solubility of the active substance salt was measured as follows.

The relevant active substance salt is added to deionized water at 25 占 폚 in an amount sufficient to provide a saturated solution at this temperature (for example, about 1 g to 10 ml of deionized water in the case of tramadol saccharide) and stirred at 25 占 폚 for 20 hours Saturation state was maintained. The amount of the relevant active substance salt necessary for this purpose can be optionally determined by means of a preliminary experiment. The inactivated active substance salt was allowed to settle and the clear supernatant was removed by pipette and centrifuged at a rate of 3000 rpm or more for 5 minutes. A portion of the supernatant supernatant obtained in this manner was transferred to an HPLC sample tube and the concentration of the active material salt was measured against an appropriate standard.

The release profile of the oral dosage form according to the invention was determined as follows:

The dosage form according to the invention was tested in a European Pharmacopoeia basket instrument for 2 hours at a temperature of 37 + 0.5 [deg.] C and a speed of 50 rpm in 600 ml of synthetic gastric juice of pH 1.2 without enzyme and released. The dosage form was then further tested for 8 hours in 900 ml of synthetic gastric juice at pH 7.2 without enzyme. The amount of active substance released at a given time was determined by means of HPLC in each case. The values shown are average values based on three samples for each case. The present invention will be described with reference to the following examples. This description is for illustrative purposes only and is not intended to limit the inventive concept.

Example 1

Preparation of pellets:

- [2- (2 ', 6'-dichloranyl) - (2-methylpiperazin-1-yl) (Tramadol diclofenacate) and 330 g of microcrystalline cellulose (Avicel PH 101 ^R , FMC) were homogenized in a Kenwood Chef mixer for 10 minutes and granulated with an appropriate amount of water to remove the mineral, Lt; / RTI > The wet granulation was extruded in a NICA E140 extruder equipped with a 1.0 x 2.0 mm extrusion mold and the wet extrudate was spheronized in a NICA spheronizer type S450. The pellets were then dried in a drying cabinet at a temperature of 50 DEG C for 24 hours. The yield of the pellets having a particle size in the range of 800 to 1250 占 퐉 obtained through screen fraction is 90% or more.

Coating application:

500 g of these pellets (800-1250 μm) were homogenized in an aqueous dispersion of the composition below at an inlet-air temperature of 40 ° C. until a weight gain of 7.6% relative to the initial weight of the pellets in the fluidized bed (Huttlin HKC05) Respectively.

Aqueous dispersion for 500 g pellets:

100.0 g of polymethacrylic acid methyl methacrylate

(30% aqueous dispersion, Eudragit L30D ^R , Rohm)

6.0 g of triethyl citrate

Glycerin monostearate 1.8 g

82.2 g of demineralized water

Total amount 190.0 g

The solubility of [1e- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-1 (a) -ol] - [2- (2 ', 6'-dichloroanilino) -phenylacetate] About 0.3 mg / ml. The solubility of tramadol hydrochloride was determined to be greater than 300 mg / ml.

In each case, 710 mg of the treated pellets were filled into 0 gel size hard gelatin capsules using a Zanasi E6 hard gelatin capsule machine.

The release profile was determined according to the method described above using a basket instrument and the results are shown in Table 1 below and in Figure 1 (as a percentage of the total volume calculated with tramadol hydrochloride). The coated pellets without deviating from the above conditions were tested for 18 hours in a synthetic serum at pH 7.2 without enzyme.

Time (minutes) The released tramadol (mg) (calculated as tramadol hydrochloride) 012015024036042060072084096010801200 05076106129138157168179188195198

710 mg of gastric fluid-resistant pellet was prepared by adding 280 mg of [1e- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-1 (a) -Ol] - [2- (2 ', 6'-dichloanilino) -phenylacetate] and 50 mg of tramadol hydrochloride.

Example 2

Preparation of pellets:

(2 ', 6'-dichloroanilino) - [2- (2'-fluoro-phenyl) -2-methyl- phenyl acetate] 280 g, lactose monohydrate 120 g, microcrystalline cellulose ^{90 g (Avicel PH 101 R,} FMC) and colloidal microcrystalline cellulose ^{90 g (Avicel RC 591 R,} FMC) for 10 minutes homogenized in Kenwood champ mixer And granulated with an appropriate amount of water from which the minerals have been removed to obtain granules suitable for extrusion and spheronization. The wet granulation was extruded in a NICA E140 extruder equipped with a 1.0 x 2.0 mm extrusion mold and the wet extrudate was spheronized in a NICA spheronizer type S450. The pellets were then dried in a drying cabinet at a temperature of 50 DEG C for 24 hours. The yield of the pellets having a particle size in the range of 800 to 1250 占 퐉 obtained through screen fraction is 90% or more.

Coating application:

500 g of these pellets (800-1250 占 퐉) were homogenized in a fluidized bed (Huttlin HKC05) with an aqueous dispersion of the composition below at an inlet-air temperature of 60 占 폚 until a weight gain of 2.4% Respectively.

Aqueous dispersion for 500 g pellets:

34.0 g of ethyl cellulose (Aquacoat ECD30, FMC)

2.0 g of dibutyl sebacate

Twin 800.01 g

0.01 g of vesicle emulsion (Fluka)

64.0 g of de-mineralized water

Total amount 100.02 g

The release profile was determined according to the method described above using a basket instrument and the results are shown in Table 2 below and in Figure 2 (as a percentage of the total volume calculated with tramadol hydrochloride). The coated pellets without deviating from the conditions described above were tested for 10 hours in a synthetic serum at pH 7.2 without enzyme.

Time (minutes) The released tramadol (mg) (calculated as tramadol hydrochloride) 030120240480600720 0252856798598

323 mg of the treated pellets were prepared by mixing 140 mg of [1e- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-1 (a) -ol] - [2- (2 ', 6'-dichloanilino) -phenylacetate] and 25 mg of tramadol hydrochloride.

The applied ethylcellulose coating does not cause the sustained release of the active substance salt, but ensures that the [2- (2 ', 6'-dichloroanilino) -phenylacetate ion is not generated by the acid from its salt. The active substance tramadol is released very quickly from the highly water-soluble tramadol hydrochloride. Tramadol is a substantially less water-soluble 1e- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-1 (a) -ol] - [2- (2 ', 6'-dichloroanilino) - < / RTI > phenylacetate over a period of 10 hours.

Example 3

Preparation of pellets:

(2 ', 6'-Dichloroanilino) - [2- (2'H-cyclopentylphenyl) -2,3'-dicyclohexyl] 188 g of lactose monohydrate, 84 g of lactose monohydrate and 332 g of microcrystalline cellulose (Avicel PH 101 ^R , FMC) were homogenized in a Kenwood Chef mixer for 10 minutes and granulated with an appropriate amount of water to remove extrusion and spheronization Lt; / RTI > The wet granulation was extruded in a NICA E140 extruder equipped with a 1.0 x 2.0 mm extrusion mold and the wet extrudate was spheronized in a NICA spheronizer type S450. The pellets were then dried in a drying cabinet at a temperature of 50 DEG C for 24 hours. The yield of the pellet having a particle size in the range of 800 to 1000 [mu] m obtained through screen fraction is 90% or more.

Coating application:

500 g of these pellets (800-1000 [mu] m) were homogenized in a fluidized bed (Huttlin HKC05) with an aqueous dispersion of the composition as described below at an inlet-air temperature of 40 [deg.] C until a weight gain of 5.3% Respectively.

Aqueous dispersion for 500 g pellets:

Aqueous shellac solution 125.0 g

(ASL 125, 20% solids content)

1.25 g of triethyl citrate

48.75 g of demineralized water

Total amount 175.0 g

The release profile was determined according to the method described above using a basket instrument and the results are shown in Table 3 below and in Figure 3 (as a percentage of the total volume determined with tramadol hydrochloride).

Time (minutes) The released tramadol (mg) (calculated as tramadol hydrochloride) 0120130150240360420600 00122540485159

219 mg of the gastric fluid-resistant pellet was prepared by adding 94 mg of 1e- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-1 (a) - Yl] - [2- (2 ', 6'-dichloanilino) -phenylacetate] and 10 mg of tramadol hydrochloride.

The applied gastric-resistant coating ensures that the active substance tramadol is not released during testing in the synthetic gastric juice. During the test in synthetic intestinal juice, the active substance tramadol is released very rapidly from tramadol hydrochloride. Tramadol was obtained from l- (m-methoxyphenyl) -2e-dimethylaminomethyl-cyclohexane-l (a) -ol] - [2- (2 ', 6'-dichloroanilino) In a sustained manner.

Example 4

Preparation of pellets:

(Avicel PH 101 ^R , FMC), 30 mg tramadol hydrochloride, 254 g tramadol saccharinate (about 20 mg / ml water solubility measured according to the method described above) and 284 g microcrystalline cellulose (Avicel PH 101 ^R , FMC) were homogenized in a Kenwood Chef mixer for 10 minutes And granulated with an appropriate amount of water from which the minerals have been removed to obtain granules suitable for extrusion and spheronization. The wet granulation was extruded in a NICA E140 extruder equipped with a 1.0 x 2.0 mm extrusion mold and the wet extrudate was spheronized in a NICA spheronizer type S450. The pellets were then dried in a drying cabinet at a temperature of 50 DEG C for 24 hours. The yield of the pellets having a particle size in the range of 800 to 1250 占 퐉 obtained through screen fraction is 90% or more.

Coating application:

500 g of these pellets (800-1250 占 퐉) were homogenized in a fluidized bed (Huttlin HKC05) with an aqueous dispersion of the composition below at an inlet-air temperature of 40 占 폚 until a 15% weight gain relative to the initial weight of the pellets was achieved Respectively.

Aqueous dispersion for 500 g pellets:

When the ratio of monomers is 1: 2: 0.1

Ethyl acrylate / methyl methacrylate / trimethylammonium

Ethyl methacrylate-chloride-copolymer

(30% aqueous dispersion, Eudragit RS30D ^R , Rohm) 156 g

Monomer ratio of 1: 2: 0.2

Ethyl acrylate-methyl methacrylate-trimethyl

Ammonium ethyl methacrylate chloride copolymer

(30% aqueous dispersion, Eudragit RL30D ^R , Rohm) 44 g

12 g of triethyl citrate

Glycerin monostearate 3 g

160.0 g of demineralized water

Total amount 375.0 g

The release profile was determined according to the method described above using a basket instrument and the results are shown in Table 4 and in Figure 4 (as a percentage of the total volume calculated with tramadol hydrochloride).

Time (minutes) The released tramadol (mg) (calculated as tramadol hydrochloride) 03060120180240360480600 0615364758819599

327 mg of the gastric-resistant pellet contains 127 mg of tramadol saccharinate and 15 mg of tramadol hydrochloride, which is equal to the total amount of active substance of 100 mg of tramadol hydrochloride.

Example 5

Preparation of pellets:

50 mg of tramadol hydrochloride, 526 g of tramadol saccharinate and 384 g of microcrystalline cellulose (Avicel PH 101 ^R , FMC) were homogenized in a Kenwood Chef mixer for 10 minutes and granulated with an appropriate amount of water to remove extrusion and spheronization Lt; / RTI > The wet granulation was extruded in a NICA E140 extruder equipped with a 1.0 x 2.0 mm extrusion mold and the wet extrudate was spheronized in a NICA spheronizer type S450. The pellets were then dried in a drying cabinet at a temperature of 50 DEG C for 24 hours. The yield of the pellets having a particle size in the range of 800 to 1250 占 퐉 obtained through screen fraction is 90% or more.

Coating application:

500 g of these pellets (800-1250 μm) were homogenized in an aqueous dispersion of the composition below at an inlet-air temperature of 40 ° C. until a weight gain of 14.4% relative to the initial weight of the pellets in the fluidized bed (Huttlin HKC05) Respectively.

Aqueous dispersion for 500 g pellets:

When the ratio of monomers is 1: 2: 0.1

Ethyl acrylate / methyl methacrylate / trimethylammonium

Ethyl methacrylate-chloride-copolymer

(30% aqueous dispersion, Eudragit RS30D ^R , Rohm) 177.0 g

Polyethylene glycol 6000 (BASF) 5.3 g

10.6 g of triethyl citrate

3.0 g of glycerin monostearate

164.1 g of demineralized water

Total amount 360.0 g

The release profile was determined according to the method described above using a basket instrument and the results are shown in Table 5 below and in Figure 5 (as a percentage of the total volume calculated with tramadol hydrochloride).

Time (minutes) The released tramadol (mg) (calculated as tramadol hydrochloride) 0306012024036048060072084096010801200 0183954728598112126140155168182

549 mg of the gastric-resistant pellet contains 263 mg of tramadol saccharinate and 25 mg of tramadol hydrochloride, which is equal to the total amount of active substance of 200 mg of tramadol hydrochloride.

Example 6:

Manufacture of tablets

15 g of promethazine hydrochloride, 39 g of promethazine theoclate, 120 g of microcrystalline cellulose, 75 g of methylhydroxypropylcellulose (50 mPa.s, Metholose 60SH), 2.5 g of highly dispersible silicon dioxide and 2.5 g of magnesium stearate were homogenized in a tumbling mixer (Bohle, LM 40) for 10 minutes. This mixture was tableted on a Korsch EKO Centric press equipped with a stirrer to obtain a convex spherical tablet having a diameter of 9 mm.

The release profile was determined according to the method described above. The tablets which had been applied without deviating from the above conditions were tested in the blade mixer apparatus described in European Pharmacopoeia.

Claims (33)

Characterized in that the same active substance is present in the form of two or more different salts and these salts are present in the dosage form in the solid agglomerated state and the in vitro release of the active substance is different, Dosage form. The oral dosage form according to claim 1, characterized in that the salt of the different active substances is different in water solubility. 3. Oral dosage form according to claim 2, characterized in that the water solubilities of all the different active substance salts differ from each other by a factor of two or more. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the active substance is selected from the group consisting of a pharmaceutically active substance which forms a salt, a vitamin, a mineral substance, a nutrient and a diagnostic agent, ≪ / RTI > or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 4, wherein the pharmaceutically active substance that forms a salt is selected from the group consisting of analgesics that form salts, insect repellents, arrhythmia drugs, asthma drugs, antidepressants, An antihypertensive agent, an antihypertensive agent, a hypotensive agent, a therapeutic agent for hypoglycemia, an antihypertensive agent, a sedative agent, an antihypertensive agent, an antihypertensive agent, an anticoagulant, a rheumatic agent, an antithyroid agent, an anxiolytic agent, a weight loss drug, A cholinesterase inhibitor, a corticosteroid, a corticosteroid, a cholinergic agent, a corticosteroid, a corticosteroid, a corticosteroid, a corticosteroid, a cholinergic agent, a corticosteroid, an antiinflammatory agent, Circulatory accelerating drugs, detox drugs, geriatric drugs, gout treatments, anti-influenza drugs, cold medicine, gynecology A medicament, a drug for the treatment of dementia (a brain function enhancer), an appetite suppressant, an antihypertensive drug, a hypnotic drug, a hypnotic drug, a pituitary hormone, a hypothalamic hormone, a regulatory peptide or an inhibitor thereof, an immunomodulator, , Anticancer drugs, laxatives, chemotherapeutic agents, diuretics, enzymes, fungi growth inhibitors, hormones, lipid-lowering drugs, neurotherapeutics, gastrointestinal drugs, migraine treatment drugs, mineral preparations, muscle relaxants, neuropathic drugs, A medicament, a neuroleptic agent, a therapeutic agent for osteoporosis, a calcium metabolism modulating agent, a therapeutic agent for Parkinson's disease, a therapeutic agent for extrapyramidal symptoms, a psychoactive drug, roborants, tonics, a thyroid therapeutic drug, Antihypertensive agents, antispasmodics, platelet aggregation inhibitors, pneumonics, urinary agents, intravenous agents, anti-neoplastic agents or inhibitors, muscle relaxants, , Antispasmodic, vasodilator, virus inhibitors, and cell proliferation is selected from the group consisting of proliferation inhibitors, preferably analgesics, infectious oral dosage form as claimed selected from the group consisting of therapeutic agents and neuroleptics. 6. The oral dosage form of claim 5, wherein the salt-forming analgesic is selected from the group consisting of a salt-forming opiate agent, an opiate-acting compound and a non-steroidal analgesic. 7. The method of claim 6, wherein the salt-forming analgesic is selected from the group consisting of bifentanil, carfentanil, pentathienyl, lofentanil, oxfetanil, trepentanil, codeine, dextrofloxifene, dihydrocodeine, diphenoxylate, But are not limited to, naltrexone, nalbuphine, petitidine (meperidine), tilidine, tramadol, biminol, butorphanol, dextromamide, dezocine, diacetylmorphine (heroin), hydrocodone, hydro morphone, Is selected from the group consisting of levomethanil, levorphanol, morphine, nalorpine, oxycodone, pentazocine, pyritramide, alfentanil, buprenorphine, etorphine, fentanyl, Lt; RTI ID = 0.0 > morphine. ≪ / RTI > 6. The oral dosage form of claim 5, wherein the salt-forming neuroleptic agent is prometagin. 9. The composition of any one of claims 1 to 8 wherein the active substance salt is selected from the group consisting of chloride, bromide, sulfate, sulfonate, phosphate, tartrate, theoclate, embonate, formiate, acetate, propionate, Citrate, diclofenacate, naproxanate, salicylate, acetylsalicylate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate , Lactate, mesylate, saccharinate, cyclamate and acesulfamate, preferably selected from the group consisting of chloride, sulfate, saccharinate, theoclate, embonate, diclofenacate, ≪ / RTI > progesterone, progesterone, procyanate, and salicylate. The method according to any one of claims 1 to 6, wherein the alkaline metal salt, the alkaline metal salt, the ammonium salt, the iron salt or the aluminum salt of the active substance is used as the active substance salt, preferably the alkaline metal salt of the active substance is active Characterized in that it is used as a material salt, particularly preferably sodium or potassium salt of the active substance is used as the active substance salt. 11. A pharmaceutical composition according to any one of claims 1 to 10 in the form of a tablet, a chewing tablet, a chewing gum, a shellac or a powder, optionally in the form filled in a capsule, Or a pharmaceutically acceptable salt thereof. Characterized in that it is in the form of a plurality of particles, preferably in the form of microcleaning agents, microcapsules, granules, active substance crystals or pellets, particularly preferably in the form of microcleaning agents, granules or pellets Wherein these forms are optionally filled into capsules or compressed into tablets. 13. An oral dosage form according to claim 12, characterized in that the granules or pellets are in the range of 0.1 to 3 mm in size, preferably 0.5 to 2 mm. The oral dosage form according to claim 12, characterized in that the detergent has a diameter of 0.5 to 5 mm, preferably 1 to 3 mm, particularly preferably 1 to 2 mm. 13. The method according to claim 12, characterized in that the active substance crystals, microparticles, micropellets or microcapsules have a diameter of 10 [mu] m to 1 mm, preferably 15 [mu] m to 0.5 mm, particularly preferably 30 [ Oral administration form. 16. The oral dosage form according to any one of claims 1 to 15, characterized in that at least one of the active substance salts is present in a sustained release form. 17. An oral dosage form according to claim 16, characterized in that all of the active substance salts are present in sustained release form. 18. The oral dosage form according to any one of claims 1 to 17, characterized in that the associated dosage form is slow-acting. 19. Oral dosage form according to any one of claims 16 to 18, characterized in that it is released by intramuscular injection into the sustained release coating and / or sustained release matrix. 20. The composition of claim 19, wherein the sustained release coating is based on a water-insoluble, optionally modified, natural or synthetic polymer, optionally mixed with a conventional softening agent, or mixed with a natural, semi-synthetic or synthetic wax or a fatty or fatty alcohol, ≪ / RTI > or a mixture thereof. The method of claim 20 wherein the water-insoluble polymer is a poly (meth) acrylates, preferably poly (C _1-4) - alkyl (meth) acrylates, poly (C _1-4) - dialkylamino - (C _{1 -4)} - alkyl (meth) acrylates and / or copolymers thereof, preferably at a molar ratio of monomer 2: 1 ethyl acrylate / methyl methacrylate copolymer (Eudragit NE30D ^R), the molar ratio of monomer 1 : Ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate-chloride-copolymer (Eudragit RS ^R ) having a molar ratio of 1: 2: 0.1, ethyl acrylate / methyl methacrylate / Trimethylammonium ethyl methacrylate-chloride-co-polymer (Eudragit RL ^R ) or a mixture of two or more of said polymers. 21. Oral dosage form according to claim 20, characterized in that the water-insoluble polymer is present as a coating material comprising a cellulose derivative, preferably alkylcellulose, particularly preferably ethylcellulose or cellulose ester, preferably cellulose acetate. The oral dosage form according to claim 21 or 22, characterized in that the polymer is applied from an aqueous medium, preferably an aqueous latex or a pseudo-latex dispersion. The oral dosage form of claim 19, characterized in that the mixture of polyvinyl acetate and polyvinylpyrrolidone is used as a coating polymer, preferably in the form of an aqueous pseudo-latex dispersion. The composition according to claim 20, which is at least one of carnauba wax, beeswax, glycerin monostearate, glycerin mono behenate (Compritol ATO 888 ^R ), glycerin ditrimyl palmitostearate (Precirol ATO 5 ^R ), microcrystalline wax, Wherein the mixture is present as a coating material. 24. The oral dosage form according to any one of claims 21 to 23, characterized in that the polymer is used in combination with conventional softening agents. 27. The process according to claim 26, wherein the lipophilic diester prepared from a C ₆ -C ₄₀ aliphatic or aromatic dicarboxylic acid and a C ₁ -C ₈ aliphatic alcohol (preferably dibutyl phthalate, diethyl phthalate, dibutyl sebacate Or diethyl sebacate), hydrophilic or lipophilic esters of citric acid (preferably triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate), polyethylene glycol, propylene glycol, glycerin Characterized in that a mixture of two or more of esters (preferably triacetin), acetylated mono- and di-glycerides, medium-chain triglycerides, oleic acid or said softening agent is used as a softening agent. 27. A process according to claim 26 or 27, characterized in that the softening agent is present in an amount of 5 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 10 to 30% by weight, based on the polymeric coating material Oral administration form. 29. The composition according to any one of claims 19 to 28, wherein the matrix is a hydrophilic matrix material, preferably a hydrophilic polymer, particularly preferably a cellulose ether, a cellulose ester and / or an acrylic resin, most preferably ethylcellulose, An oral dosage form characterized in that it is based on hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or salts, amides and / or esters thereof. 30. A composition according to any one of claims 19 to 29, wherein the matrix is a hydrophobic matrix material, preferably a hydrophobic polymer, wax, fat, long chain fatty acid, fatty alcohol or a corresponding ester or ether or mixture thereof, Characterized in that it is based on mono- or di-glycerides of C ₁₂ -C ₃₀ fatty acids and / or C ₁₂ -C ₃₀ fatty alcohols and / or waxes or mixtures thereof. 31. The oral dosage form according to any one of claims 1 to 30, characterized in that it has a protective coating, preferably a gastric-resistant protective coating. 31. The composition of claim 31, wherein the gastric-resistant film comprises a methacrylic acid / methyl methacrylate copolymer (Eudragit L ^R ) having a molar ratio of monomers of 1: 1, a methacrylic acid / methyl methacrylate copolymer (Eudragit S ^R), the molar ratio of monomers 1: 1 methacrylic acid / ethyl acrylate copolymer (Eudragit L30-D55 ^R), the molar ratio of monomers 7: 3: 1 methacrylic acid / methyl acrylate / methyl methacrylate (Eudragit FS ^R ), shellac, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate or a mixture of two or more of these components, optionally with a poly (meth) acrylate, preferably Eudragit NE 30D ^R and / or Wherein Eudragit RL ^R and / or Eudragit RS ^R are mixed. 32. The composition according to any one of claims 1 to 32, wherein optionally one or more of the salts is present in a sustained release form and two or more different salts of the same active substance with different in vitro release are mixed, Oral dosage forms obtainable by dissolving in a sustained release and / or gastric-resistant protective coating.