Matrix tablet with modified neramexane release

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims per oral drug form of neramexam with modified release, which is applied for long therapy of patients with such diseases and states as dimentia in Alzheimer's disease and neuropathic pain. Neramexane is dispersed inside hard matrix, which contains release-regulating filler. Filler is selected from copolymer of polyvinylpyrrolidone and vinyl acetate, hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is present in mixture with microsrystalline cellulose. Content of said filler is selected in such a way as to obtain profile of neramexan release in vitro, characterised by dissolution time of, at least, 1 hour for amount of neramexane, constituting 50 wt %.

EFFECT: profile of release ensures concentrations of neramexane in plasma with fluctuation index 0,4 or lower with introduction of matrix tablet of neramexane one time per day at steady state.

23 cl, 4 tbl, 7 ex

 

The technical field to which the invention relates

The invention relates to pharmaceutical dosage forms, particularly for medicinal forms with modified release formulation suitable for oral administration. In another aspect the invention relates to new applications of active compounds neramexane and to therapeutic methods associated with such applications.

The prior art inventions

Neramexane, also known as 1-amino-1,3,3,5,5-pentamethyldisiloxane, is a member of the class of orally active 1-aminocyclohexanol and how it was discovered, is effective in the treatment of various diseases, particularly certain neurological diseases, including Alzheimer's disease and neuropathic pain. The compound and its derivatives are described in U.S. patent No. 6034134 and 6071966, the contents of these patents thus introduced here by reference. I believe that therapeutic action neramexane associated with inhibition of the action of excess glutamate from receptors N-methyl-D-aspartate (NMDA) of nerve cells, for this reason, the connection is also classified as an NMDA antagonist or antagonist of the NMDA receptor. More specifically, neramexane, apparently, has affinity from low to moderate in this regard, I believe that non-competitive antagonist of cocktail recipes. who and NMDA selectively blocks causing toxicity actions associated with abnormal transmission of glutamate, which is a neurotransmitter that carries out integral role in the neural pathways associated with learning and memory, and which is believed to play a role in Alzheimer's disease.

Neramexane, apparently, shows therapeutic effect after oral administration. In clinical trials it can be administered orally in the form of dosage forms with immediate-release. Usually neramexane administered at least twice daily during prolonged therapy in order to maintain therapeutically effective plasma concentration.

Solid oral dosage forms with modified release allow for the modified release of active ingredient over an extended period of time in emergency mode to maintain therapeutically effective plasma levels over the same extended time intervals and/or to modify other pharmacokinetic properties of the active ingredient. Solid dosage form immediate-release provide the greatest release of part or all of the active ingredient within a short period of time, such as 60 minutes or less, provide an opportunity would be the Troy of absorption of the drug. Multi-phase release profile (i.e., the composition comprising at least one composition with the immediate-release and at least one composition with modified release) can be applied to achieve one or more combinations of the speed of release, in order to achieve more specific therapeutic objective functions, so that part of the drug would be released immediately, followed by a prolonged release. However, the modulation speed of release of the active ingredient, of course, does not ensure that effective long-term levels of concentrations in the blood will be consistently achievable or that the pharmacological action will be based solely on the release of the drug.

Found that the low frequency of administration, such as a single daily dose, is required for most long-term drug treatment. Many studies have found a negative correlation between the two parameters, with respect to the treatment of the studied patients and the frequency of dosing. I also think that especially those patients who suffered from dementia, may find difficulty in adherence to the treatment regimen requiring multiple doses each day.

The usual way of the modified h is obozrenie receptor antagonists N-methyl-D-aspartate (NMDA) described in U.S. patent No. 6194000. This method also includes obtaining instantly disposable component and the component with modified release to obtain the final product. The patent describes a ball (not a grain), consisting of a core with a coating, and the coating can be any suitable coating systems based on an organic solvent. However, not all NMDA antagonists act thus, and in this patent does not specifically described compositions containing neramexane.

Currently using the dosage neramexane twice a day using tablets with immediate release. This may not be desirable, because the regard to the treatment of the patient is reduced due to the increased frequency of administration of the medicine. In addition, the introduction of tablets with immediate release may lead to an increase in the frequency of adverse events due to higher rate of absorption. For the treatment of pain is very important to maintain the pain without additional discomfort. Therefore, there exists a continuing need to accept once a day medication with modified release containing neramexane or pharmaceutically acceptable salt neramexane guaranteed a slower absorption in a given period of time is I.

Despite the fact that there is a need for dosage forms with modified release, suitable for introduction neramexane, which, apparently, is useful in the treatment of some patients with Alzheimer's disease, such dosage forms are not described or unsuccessfully developed. Requires development of dosage forms with modified release for neramexane due to the high solubility of the molecule in an aqueous environment in a wide range of pH. In particular, there is a need for dosage forms with modified release neramexane, which are suitable for use once a day and are well tolerated. In addition, there is a need for dosage forms with modified release neramexane that are sustainable and solubility does not depend on the state of digestion or transit of the dosage form through the gastrointestinal tract.

These and other challenges are addressed by the present invention, which is disclosed in the following description, examples and claims.

The invention

In the first aspect, the invention provides dosage forms for oral administration neramexane, new NMDA antagonist, which has been found useful for treatment of diseases of the al is chamera (including weak moderate or severe dementia in Alzheimer's disease and other disorders. Dosage forms have characteristics of the modified release and are suitable for long-term therapeutic dosing regimen. High peaks in the plasma concentration is not allowed.

Slow release of the active ingredient over an extended period of time leads to lower peak concentrations at the beginning of dosing and at steady state and the slower absorption. Slower absorption of reach, when the dissolution rate is slower than absorption, and thus the dissolution sets the speed of the implementation stage. Slow absorption, as can be expected, will improve the tolerability of the active ingredient.

In the following embodiment are designed dosage forms in the form of tablets comprising an active ingredient dispersed in a matrix formed by at least one excipient governing the release, and optionally, one or more additional pharmaceutically acceptable excipients. Dosage forms show the time of the dissolution of at least about 1 hour for part of the dose from 10 to 70 wt.% the included active connection.

In addition, the invention offers the pen is real dosage forms with modified release, includes a therapeutically effective amount of an active compound that is very soluble in water, selected from neramexane and its pharmaceutically acceptable salts, solvate, isomers, conjugates, prodrugs, and derivatives, and at least one excipient governing the release, where the content of excipient chosen to achieve the in vitro release profile of the active compounds, characterized by the time of the dissolution of at least about 1 hour for part 50 wt.% the number of active connections.

In accordance with another aspect of the invention provides oral dosage forms with modified release neramexane, which include at least one regulating the release of excipient and where regulatory release excipient chosen to achieve the in vitro dissolution profile of the medicinal product, which essentially is independent of pH for dissolution.

The following aspects of the proposed oral dosage forms with modified release neramexane in the form of pressed pellets. Tablets include at least one regulating the release of excipient that is selected to achieve the dissolution profile of the medicinal product, which is, essentially, not the head of the Sith from the hardness of the tablets.

The following aspects of the proposed dosage forms with modified release neramexane in the form of pressed pellets. Tablets include at least one regulating the release of excipient that is selected to achieve the dissolution profile of the medicinal product, which essentially is independent across a wider area of the mixing environment for dissolution.

The following aspects of the proposed oral dosage forms with modified release neramexane that demonstrate low index fluctuations of the concentration neramexane in the plasma in the steady state after administration once a day. Specifically, the index fluctuations is about 0.4 or less.

In addition, the proposed use neramexane and methods of treatment, including the introduction of twice a day or once a day dosage forms of the invention. The methods can be used for the treatment of mild, moderate, or severe dementia in Alzheimer's disease or neuropathic pain. Then the methods can be used for the treatment of diabetic neuropathic pain, amyotrophic lateral sclerosis, multiple sclerosis, irritable bowel syndrome, disorders of appetite, obesity, disorders, due to compulsive overeating, autism, syndrome of deficiency of NR is mania, syndrome disorders of attention and hyperactivity, bipolar disorders, tinnitus, fungal infection or psoriasis.

In addition, the methods can be used for the treatment of conditions associated with deterioration in cognitive abilities, such as dementia, neurodegenerative dementia, mild, moderate or severe dementia in Alzheimer's disease, dementia in Parkinson's disease, dementia in AIDS, schizophrenia, attention deficit disorder, attention deficit disorder and hyperactivity, Korsakov's syndrome, dementia associated with cerebrovascular, fronto-temporal dementia, autism, corticobasal degeneration, including dementia when corticobasal degeneration, a disease of the bullock, Levi, weak deterioration of cognitive abilities, dementia due to inflammation or infection, multiple sclerosis or amyotrophic lateral sclerosis.

The following aspects of the invention will become apparent based on the following detailed description and claims.

Detailed description of the invention

The invention provides oral dosage forms with modified release formulation comprising a therapeutically effective amount of the active compounds are well soluble in aqueous medium and at least one regulating the release of excipient. The active compound selected from lexana and its pharmaceutically acceptable salts, the solvate, isomers, conjugates, prodrugs and derivatives. The content of regulating the rate of release of excipient chosen to achieve the in vitro release profile of the medicinal product, which is characterized by the time of the dissolution of at least about 1 hour for the part from 10 to 70 wt.%, as, for example, 50 wt.% the number of active compounds present in the dosage form.

Neramexane can be applied according to the invention in the form of any of its pharmaceutically acceptable salts, solvate, isomers, conjugates, prodrugs, and derivatives, any links to neramexane in this description should be clear, as well as such salts, solvate, isomers, conjugates, prodrugs and derivatives.

In one embodiment of the invention neramexane entered in the dosage form of the invention in the form of one of its salts, and such salts typically have significant solubility in water.

Potentially suitable salt neramexane include, but are not limited to the above, the acid additive salts such as the salts formed with hydrochloric, methylsulfonate, Hydrobromic, idiscovered, perarnau, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, Winne the th, citric, benzoic, carbonic, cinnamic, almond, methansulfonate, econsultancy, hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic and 2-acetoxybenzoic acid.

A therapeutically effective dose neramexane determine, taking into account such factors as the particular condition that is subjected to treatment, the weight of the patient, the patient's condition, the dosage, etc. it is Usually assumed that the cumulative oral daily dose of from about 5 to 150 mg, such as from about 5 mg to 120 mg, or from about 5 mg to 100 mg, neramexane or salt neramexane, such as neramexane mesilate is therapeutically effective to treat at least some of the States for which neramexane, apparently, is useful. Further preferred is cumulative oral daily dose from about 10 mg to 90 mg neramexane or salt neramexane, such as neramexane mesilate.

In addition, the cumulative daily dose from about 5 mg to 50 mg, such as 5 mg, 6.25 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg to 22.5 mg, 25 mg, 27.5 mg, 30 mg, or 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42,5 mg, 45 mg, and 47.5 mg and 50 mg, neramexane nelfinavir or equimolar amount neramexane, other pharmaceutically pickup is integral salt, the MES, isomer, conjugate, prodrug or derivative, such as neramexane hydrochloride, is therapeutically effective and at the same time prevents excessive side effects. In addition, you can also apply a cumulative daily dose from about 5 mg to 40 mg, or from about 10 mg to 30 mg neramexane nelfinavir or equimolar amount neramexane, other pharmaceutically acceptable salts of MES, isomer, conjugate, prodrug or derivative. Specified the number and spacing of the active compounds used in the treatment or alleviation of conditions, including deterioration of cognitive abilities and the following conditions are associated with deterioration in cognitive abilities (e.g., dementia; neurodegenerative dementia; weak, moderate or severe dementia in Alzheimer's disease, dementia in Parkinson's disease; schizophrenia, attention deficit disorder, attention deficit disorder and hyperactivity; Korsakov's syndrome, dementia associated with cerebrovascular; fronto-temporal dementia; autism, corticobasal degeneration, including dementia when corticobasal degeneration, a disease of the bullock, Levi, weak deterioration of cognitive abilities, dementia as a result of inflammation or infection, multiple sclerosis or amyotrophic lateral SCR the roses). If oral solid dosage forms with modified release intended for administration twice a day, the data amount of the active ingredient can be reduced by half. A lower or higher dosage also may be appropriate and therapeutically effective in the treatment of other conditions.

The dosage form with a modified release dosage form is from which you entered the active compound is slowly released over a period of time, which is essentially longer than about 15 minutes and shorter than 24 hours, and usually within a period of at least approximately 4 to 12 hours, as determined in accordance with the established and generally accepted methods, for example, dissolution testing in vitro U.S.Pharmacopeia, USP 28 or European Pharmacopeia, EP 5, using typical buffers with pH intervals from 1.0 to 7.2 as the environment for dissolution. This definition does not depend on the shape of the release profile, i.e. does not depend on whether the dependence of the kinetics from time linear, nonlinear, according to the first order, second order or square root, Sigourney etc. Accordingly, it should be clear that the modified release includes delayed release, prolonged high is obozrenie, continuous-release, slow release and similar expressions for similar release characteristics of the drug.

In one embodiment, dosage form of the invention is a composition that releases neramexane nonlinear manner over a period of at least about 6 hours with a speed of release, which decreases over time. In another embodiment, neramexane released essentially linearly (linear way) for at least 6 hours. The time of dissolution to 50 wt.% the administered dose of the active compounds to release is usually at least 1 hour and can be at least 1.5 hours.

In another embodiment, the time of the dissolution of 40 wt.% the administered dose of the active compounds to release is usually at least 1 hour and can be at least 1.5 hours.

In another embodiment, the time of dissolution 60 wt.% the administered dose of the active compounds to release is usually at least 1 hour and can be at least 1.5 hours.

In another embodiment, the time of dissolution from 10 to 70 wt.% the administered dose of active connections for the release of approximately from 1 to 8 hours.

In the following embodiment, wysw the leave is non-linear and time of dissolution to 50 wt.% the administered dose of active connections for the release is from 1 to 5 hours, or from about 1 to 4 hours, or from about 1.5 to 3 hours. In contrast, if the release profile is essentially linear, the time of dissolution to 50 wt.% dose is approximately at least 2 hours or approximately at least 3 hours, as, for example, from about 4 hours to 8 hours.

In one embodiment of the invention, the release profile in vitro active compounds characterized by the time of the dissolution in the range from about 1 hour to 3 hours for part 50 wt.% the number of active connections.

Non-linear release profile that is appropriate for dosing twice a day and especially once a day, further characterized by the time of the dissolution of 4 hours for part of the dose in the range from about 50 wt.% to 95 wt.% the number of active connections.

In another embodiment of the doses released after 4 hours, varies from about 65 wt.% to 95 wt.%. In another embodiment of the doses released after 4 hours, varies from about 55 wt.% to 85 wt.%. Alternatively, part of the dose released after 4 hours, varies from about 70 wt.% to 85 wt.%. Found that this type of release is used to achieve and maintain therapeutic is oncentrate neramexane in the plasma in the steady state even for a single daily administration.

In another embodiment of the doses in the range of from about 75 wt.% to 95 wt.% released through the time of the dissolution of 6 hours, as, for example, from about 80 wt.% up to 90 wt.%.

Found that dosage forms with modified release, which show the release profile of the medicinal product, as described above, are particularly suitable for the continuous treatment of neramexane, as, for example, the continuous treatment of patients suffering from conditions and disorders selected from weak, moderate or severe dementia in Alzheimer's disease and neuropathic pain. In addition, conditions such as diabetic neuropathic pain, amyotrophic lateral sclerosis, multiple sclerosis, irritable bowel syndrome, disturbances of appetite, obesity, disorders, due to compulsive overeating, autism, bipolar violation, attention deficit disorder, attention deficit disorder and hyperactivity, tinnitus, mycosis fungoides and psoriasis can be treated dosage forms with modified release, which show the release profiles of the medicinal product, as described above.

Dosage forms particularly applicable for therapeutic dosing regimen, which includes a lengthy introduction, twice a day, or one of RA is a day.

In fact, as used here, long-term therapy is understood as the period of regular treatment over a time interval of at least 2 weeks and often for at least about one month. Dosage form of the invention is also suitable for long-term therapy for several months or even years, because it provides the active component, neramexane patient, well-tolerated way, creating a therapeutically effective levels in the plasma in the steady state, with only moderate fluctuation.

Dosing regimens twice a day and once a day, as understood here, include repeated introduction of active compounds in approximately regular intervals. Typically, the time of administration (day by day) do not differ by more than a few hours. Specifically, in the case of the dosage once a day relatively flat profiles in the plasma with moderate fluctuations reach only if daily time introducing similar, for example, always in the morning or always night, and is not changed (the previous day from the next) more than 3 or 4 hours.

In fact, as used here, the stationary state means that regular dosing hold for a sufficiently long period of time such that cf is dnaa plasma concentration of the active compound after administration was similar to the average concentration in the plasma after the previous injection. Similarly, plasma concentrations in the area of the peak and trough are similar to the corresponding concentrations after the last dosing.

The time to reach steady state mainly depends on the half-life of the active component. After 4 half repeated the dose in the same intervals of time usually leads to the average concentrations in plasma, which are approximately 93-94% average concentrations in plasma in the steady state. Knowing the significant biological differences even in the body similar to individuals, you can put that in 4-5 elimination half-life in plasma concentrations are almost the same as the concentration in the plasma in the steady state.

The use of dosage forms of the invention may include long-term therapy with the introduction of once a day. Introduction once a day compositions immediate-release neramexane leads to fluctuations in plasma concentrations, which may increase the risk of side effects due to high peak levels and/or increase the risk of achieving only subtherapeutic concentrations in the area of depression. Index fluctuations concentrations in plasma, according to the mode once a day with the use of conventional drugs is in the range from 0.4 to 0.5, which will bring the LNO two times higher when compared with dosing twice a day preparations immediate-release.

In fact, as used here, the index fluctuations expresses the fluctuation between the concentration in the area of the peak and troughs relative to the average concentration in plasma:

where IFis an index fluctuations, Withss(max)represents the peak concentration in the steady state, Withss(min)represents the concentration of plasma in the area of depression in the steady state and withss(av)denotes the average or arithmetic mean plasma concentrations at steady state. It is usually assumed that the index fluctuations of more than approximately 0.45 in particular cannot be used with continuous therapy neramexane. According to the invention the profile of the release neramexane of the dosage forms specifically designed to get the index of the fluctuations of not more than approximately 0,45 during long-term therapy once a day in the steady state, which reach the relevant selections in relation to nature, class, and the relative amount regulating the release of excipient (or excipients) are presented here according to the methodical recommendations. Usually the index fluctuations of no more than about 0.4 during long-term therapy once a day. In the following embodiments, the implementation of the index is fluktuacii, achievable dosage form of the invention, is not more than about 0.38 or even not more than about 0.35 to repeated application of the same therapeutic regime.

Property release dosage forms of the invention can be achieved by various means, as, for example, several types of structures dosage forms and methods of manufacture. Not considered as a critical mechanism through which regulate the release of the drug. For example, the release of drug can be controlled by the diffusion neramexane through the diffusion barrier, such as through the polymer film, the diffusion through the matrix, the destruction of the matrix in which is embedded or dispersed active compound, or a combination of more than one of these mechanisms.

For example, the dosage form can be developed or manufactured as a disposable solid dosage form coated, as, for example, a tablet with a coating, where the coating acts as a diffusion barrier and provides a prolonged release of the drug. In this case, the coating contains at least one regulating the release of excipient, the quality and quantity of choice to achieve the above properties released the I.

In fact, as used here, excipients is pharmaceutically acceptable, physiologically inactive ingredient dosage form. Excipients governing the release is excipient, which is able to significantly reduce the rate of release of the active compound from the dosage form or product. If coated tablets are designed to achieve the characteristics of the modified release regulating the release of excipients coverage is usually water-insoluble polymer. Potentially suitable polymers are usually well-known specialist in the field of pharmaceutical preparations. Examples of such polymers include alginates, ethylcellulose, acetate cellulose, acetate butyrate cellulose, copolymer of ester methacrylate, polyoxyethylenated polymers, Zein, a copolymer of polyvinyl acetate and polyvinylpyrrolidone, and the like. The polymers can be offered as organic solutions or aqueous dispersions and spray on tablets using conventional equipment for coating. Usually the solution coating or dispersion will also contain a plasticizer, such as glycerin, propylene glycol, polyethylene glycol, diethylphthalate, dibutyl phthalate, dibutylsebacate, triacetin, triethylcitrate, aceti triethylcitrate, acetyltributyl, castor oil, mono - and diglycerides, etc. are Examples of additional possible excipients are dyes, corrigentov, sweeteners, agents which impart opacity, and agents against adhesion.

However, under typical variant implementation of the dosage form of the invention develop as a solid matrix with modified release, which introduced or in which the active ingredient is dispersed and from which it is slowly released over an extended period of time. In this case, the coating with modified-release is not required, and the matrix includes at least one regulating the release of excipient.

Typically, the matrix is not quickly dissolves in aqueous media at physiological temperatures. The release of the active compounds from the matrix can be controlled by the diffusion of active compounds through the matrix, the destruction of the matrix, or both.

In one embodiment, the matrix is designed for compressed tablets. In order tablet matrix type is not quickly broken up, but influenced the modified release of active compounds, it includes at least one regulating the release of excipient, which is preferably selected from the group consisting of insoluble the x in water lipids, waxes, water-insoluble polymers and swelling in water of the polymers. If the matrix is present in more than one excipient governing the release, you can also combine the excipients of various chemical subgroups.

Regulating the release of excipient or mixture of excipients chosen in sufficient quantity to achieve the above text characteristic release. Depending on the type of the typical contents of excipient in the solid matrix comprises from about 10 wt.% up to 80 wt.%.

Suitable regulating the release of water-insoluble polymers include, for example, ethylcellulose, acetate cellulose, acetate butyrate cellulose, copolymer of ester methacrylate, Zein, polyvinyl acetate and a copolymer of polyvinyl acetate and polyvinylpyrrolidone. Suitable regulating the release of lipids and waxes include, for example, beeswax, natural or synthetic mono-, di - and triglycerides of medium and fatty acids with long chain, as, for example, hydrogenated vegetable oil, Carnauba wax, petroleum wax, microcrystalline wax, fatty acids long chain fatty alcohols, long chain esters of fatty acids and fatty alcohols, etc. are Additional examples of pharmaceutically acceptable water-insoluble polymers, lipids and waxes is in, which can also be used in the manufacture of a matrix, a well-known specialist in the field of technology of medicinal forms.

Depending on hydrophilic (destructible or indestructible) or hydrophobic nature of the matrix, the matrix may be a substance which swells upon contact with gastric fluid to a size that is large enough to promote retention in the stomach as long as the subject is in a state of digestion. In addition to these matrices, based on diffusion, can also be a matrix in destructible form. The state of digestion is stimulated by ingestion of food and begins with a rapid and strong changes in the characteristics of movement in the upper region of the gastro-intestinal (GI) tract. The change is to reduce the amplitude of contractions, which is exposed to the stomach, and the smaller opening of the pylorus to the partially closed state. The result is a separation process that allows liquids and small particles to pass through the partially open the pylorus is preserved, while nevereverever particles, which are larger than the pylorus is preserved, are trapped and retained in the stomach. In other words, biological fluids migrate through the matrix and dissolve the active ingredient that is released by diffusion through the matrix which simultaneously modulates the rate of release. Therefore, a matrix with controlled release of these versions of the invention is chosen such that can swell up to a large enough size to linger and thereby be retained in the stomach, causing the implementation of the prolonged release of the drug in the stomach is preferable in the gut. Descriptions of oral dosage forms, swelling to a size that will prolong the time of their stay in the stomach found in U.S. patent No. 5007790, 5582837 and 5972389, and in international patent applications (PCT) WO 98/55107 and WO 96/26718. Each of the documents cited in this section are entered here as a reference in full.

In this embodiment, the solid matrix develop as nabuhay in water, a hydrophilic matrix comprising regulating the release agent selected from the group of swelling in water of the polymers. Suitable forming matrix polymers can be soluble or insoluble in water. Suitable polymers absorb significant amounts of water after contact with aqueous environments, which usually leads to the formation of an aqueous gel. The strength aqueous gel depends on the type and amount of polymer and the presence of other compounds in the matrix. The release of the medicinal product m which may occur through diffusion of active compounds through the water micropores or microchannels within a three-dimensional polymer network of the gel, and through continuous destruction or disintegration of the greater part of the surface layers of the gel matrix.

Usually the gel formation in the hydrophilic matrix with modified release is a process that begins in the outer areas of the pills and slowly moves to the nucleus. Thus, I believe that some of the zones or layers can coexist in the matrix at the time of release of the medicinal product, i.e. UN-hydrated region of the core, an intermediate layer surrounding the core area, and destroy the outer region. However, these arguments should be considered only as a theoretical model; they should not be construed as limiting the scope of any of the subjects of the claims.

Among suitable nabukenya in water of the polymers corresponding to the invention are polymers of cellulose and their derivatives, including, but not limited to the above, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylmethylcellulose, hypromellose, carboxymethylcellulose, carboximetilzellulozu and microcrystalline polysaccharides cellulose and their derivatives, polyalkylene, polyethylene glycols, chitosan, alginate, curagen, galactomannan, traakan is, agar, Arabic gum (acacia), guar gum, xanthan gum, pectin, carboxymethylaminomethyl, chitosan, copolymers of maleic anhydride, polyacrylate, polymethacrylate, a copolymer of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), poly(ethylenimine), polyurethane hydrogels, crosslinked polyacrylic acids and their derivatives, and mixtures of any of these agents.

Additional examples are copolymers mentioned above polymers, including block copolymers and graft polymers. Specific examples of copolymers are PLURONIC and TECTONIC, which are block copolymers of polyethylene oxide and polypropyleneoxide, available from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA. Additional examples are graft copolymers of hydrolyzed starch and polyacrylonitrile, commonly known as “Super Slurper” and is available from the Illinois Corn Growers Association, Blumington, III., USA.

Among the above nabukenya in the water of some polymers, as you can assume, are non-ionic polymers, such as, for example, nonionic simple cellulose ether. An example of such a polymer is hypromellose (receiver array), also called hypromellose, which can be used single or in combination with other polymers.

Suddenly discovered the, that hypromellose, even without adding another regulating the release of excipient, capable of forming nabuhay matrix, from which is released soluble in water form neramexane, as, for example, neramexane mesilate, over a long period of time. This is contrary to the generally accepted assumption that it is difficult to produce a matrix with the modified release essentially with water-soluble active agents on the basis of one nabukelevu in water polymer such as only one hydroxypropylmethylcellulose.

Different brands of hydroxypropylmethylcellulose corresponding to the invention, includes a receiver array 2208, a receiver array 2906 and a receiver array 2910. These brands differ in the degree of substitution in respect of a methyl (or metaxylene)and hydroxypropyl (or hydroxypropoxy) groups. In a receiver array 2208, on average, about 22% (in the range of from 19 to 24%) of the original hydroxyl groups of cellulose into metaxylene group and an average of approximately 8% (in the range of from 7 to 12%) turn into hydroxypropoxy group. A receiver array 2906 includes approximately 29% metaxylene groups and approximately 6% hydroxypropoxy groups, and a receiver array 2910 includes approximately 29% metaxylene groups and approximately 10% hydroxypropoxy groups. Typical mark g is droxyprogesterone is a receiver array 2208, as, for example, commercially available is this brand as Methocel K 100M CR. This trademark Methocel also characterized by a relatively high molecular weight, as shown by the apparent viscosity of approximately 100,000 centipoise for aqueous 2 wt.% at 20°C.

The relative amount of nabukelevu in water of polymer required to achieve the desired release characteristics, depends also on the type or brand of the selected polymer, the presence or absence of other excipients that affect the release of drug, and the required load of the drug in the matrix. If hydroxypropylmethylcellulose ratio of the polymer to the active compound is usually chosen in the range from about 10:1 to 1:10 and may be from about 5:1 to 1:5. If high-viscosity receiver array, such as Methocel K 100M CR selected as the master excipient governing the release, the typical relationship between the receiver array and the active compound is from about 4:1 to 1:4, or from about 2:1 to 1:2. For example, if the matrix is designed to accommodate a dose of approximately 50 mg neramexane nelfinavir, content Methocel K 100M CR according to this variant implementation is in the range from about 5 mg to 100 mg, or from about 12.5 mg to 200 mg

It was also OBN is hidden, it is useful to combine the medicinal substance and nabuhay in water the polymer with additional excipients selected from the class of dry binding agents or auxiliary tools for pressing, which are also sometimes referred to as subsidiary means for the manufacture of tablets, excipients, diluents or agents to create volume. Such excipients are able to increase the internal strength of the binding matrix after pressing. Usually they have a high degree of plastic deformability. Their influence on the dissolution of the medicinal product or the release of a medicinal product may be relatively small. Examples of suitable representatives of this category excipient include anhydrous lactose, lactose monohydrate, calcium phosphate, dibasic calcium phosphate, calcium phosphate, calcium sulfate, sucrose, dextrose, mannitol, sorbitol, cellulose, microcrystalline cellulose and jointly processed mixture of lactose and microcrystalline cellulose (commercially available as, for example, Cellactose). Typical dry binding agent is microcrystalline cellulose, such as, for example, commercially available Avicel PH.

Various types of microcrystalline cellulose are suitable for carrying out the invention. Brand products, which are to mirceski available mainly differ in particle size and moisture content and should be selected depending on the method of obtaining the matrix. For example, we discovered that Avicel PH 102 and some other marks Avicel, particularly suitable for obtaining a matrix tablets by direct compression.

The content of dry binding agent or auxiliary means for pressing in the dosage form of the invention chosen according to various criteria of the drug, as, for example, the type and brand of dry binding agent or auxiliary tools for pressing, type, brand, and quantity nabukelevu polymer in water, load the active compounds, the presence of additional excipients that affect the compressibility etc. Usually their content is at least about 10 wt.% relative to the weight matrix and often at least about 15 wt.%. In the following embodiments, the implementation of the content is from about 15 wt.% up to 60 wt.%, as, for example, from about 15 wt.% up to 50 wt.%.

Attitude nabukelevu in water of the polymer and the dry binding agent or auxiliary means for pressing the matrix is usually in the range from about 6:1 to 1:6, as, for example, from about 5:1 to 1:5 and in particular embodiments, the implementation of approximately 3: 1:3 and about 2:1 to 1:2, respectively. In another embodiment, Nauheim in water polymer is hypromellose, specifically Methocel K 100M CR, and a dry binding agent or an auxiliary means for pressing is microcrystalline cellulose, and they are present in the matrix in the ratio of approximately 2:1 to 1:2, and the total content of both excipients in matrix, from about 50 wt.% to 85 wt.%, as, for example, from about 60 wt.% up to 75 wt.%.

As indicated above, there is a variant of implementation of the dosage form, which is designed as a molded matrix, i.e. extruded matrix tablets. Various methods are available and appropriate for such tablets, and typical methods are compressing the granules obtained wet or dry granulation, and direct pressing of powder mixtures in a compact mass. Both methods are well-known specialist in the field of engineering.

Methods wet granulation include weighing of ingredients, including the active connection and the majority of excipients, plus liquid binder, mixing, agglomerating them, check their moisture, drying, checking, dryness, blurring and pressing the mixture into tablets. The advantage of wet granulation involves improved the giving of cohesively and pressuemosti powders, a useful distribution of particle sizes, suitable for pressing, reducing dust and aerosol pollution and preventing separation of the components.

When dry granulating the ingredients are weighed, mixed and subjected to pressing, as, for example, the pressing roller, and subsequently crushed or sieved. The sieved granules were lubricated and compressed into tablets. As the liquid binder solution is not used for sintering, powder mixture, which granularit in the dry form, which must include at least one binding agent, such as microcrystalline cellulose, polyvinylpyrrolidone or co-processed mixture of lactose and microcrystalline cellulose. One advantage of the methods of dry granulation is that they can be suitable for processing sensitive substances, such as moisture - and heat-sensitive ingredients, because during processing, do not add water and do not need heat to dry the granules.

Direct pressing includes pressing powder mixtures in pill without prior granulation. This method is potentially cost-effective, as it avoids the sequential stages of a method associated with obtaining granules, and it is also suitable for processing the TCI sensitive active compounds. The presence of the dry binding agent or auxiliary means for pressing the product is usually necessary or desirable to achieve the useful strength tablets. However, the immediate pressing may not always be possible. For example, some of the powder mixture does not exhibit sufficient fluidity of the product in the pressing of the tablet or not have suitable for tablet physical characteristics, so in these cases it is preferable to use granulation.

Found that the powder mixture nabukelevu in water of the polymer, agent for dry binding or excipients for pressing and soluble salts neramexane and, optionally, additional excipients are suitable for direct pressing. Usually three components (i.e. nabuhay in water polymer, agent for dry bonding and salt neramexane) constitute at least about 75 wt.% powder mixture and optional additional excipients are not more than about 25 wt.%. In another embodiment, nabuhay in water, the polymer (or mixture nabukenya in water of the polymers), agent for dry binding or auxiliary means for pressing (or a mixture of more than one member of this class) and an active link is, together, represent at least about 85 wt.% matrix preparation, as, for example, from about 85 wt.% to 99.9 wt.% or from about 90 wt.% up to 99.5 wt.%. In the following embodiment, they comprise from about 95 wt.% up to 99 wt.% matrix.

According to another variant implementation of the invention includes direct pressing a powder mixture comprising hypromellose, as, for example, Methocel K 100V CR, microcrystalline cellulose, such as Avicel PH 102 and neramexane mesilate. Typically, each of these three components represents from about 10 wt.% up to 50 wt.% powder, which is pressed to form a matrix. In another embodiment, the ratio neramexane nelfinavir to the other two components together is from about 1:1 to 1:5 and more preferably from about 1:1 to 1:3, as, for example, approximately 1:2.

The powder mixture may include one or more additional excipients. Other excipients are members of classes lubricating agents, such as magnesium stearate, stearic acid, calcium stearate, sodium fumarate, mineral oil, gidrirovannoe vegetable oil, and polyethylene glycol; and agents for slide, as, for example, colloidal silicon dioxide, KRA is small, calcium stearate or magnesium and talc.

Lubricating agent is usually used at levels from about 0.1 wt.% up to 2 wt.% relative to the weight matrix. Representative lubricating agent is magnesium stearate, which also has some properties of slip agents. If you choose the stearate, the interval used content is from about 0.2 wt.% up to 1.5 wt.%, especially approximately from 0.25 wt.% up to 1 wt.%.

Similarly, the number of agent for slip must be selected with a relatively low level, such as approximately less than 5 wt.%. Among the representative agent slip are colloidal silicon dioxide and talc. If you enter one or both of these slip agent, the content of the slip agent in the matrix is typically in the range from about 0.25 wt.% up to 2.5 wt.% or about 0.5 wt.% up to 1.5 wt.%.

Unexpectedly discovered that such a matrix dosage forms are extremely favorable properties of the tablets. For example, we discovered that the profile of release of the active compounds is relatively free from compressive forces, at least in all the wide interval practically applied compression forces. A mixture of Methocel K 100M CR, Avicel PH 102, neramexane nelfinavir, magnesium stearate and colloidal silicon dioxide tabletirujut on standard p is operating the press to tablets with the use of the main forces of the compression ratio in the range from about 5 to 21 kN kN. The obtained tablets essentially differ in their tensile strength, from about 30 N to 100 N, with higher compression forces result in a more solid tablets. However, the dissolution profiles of these tablets were essentially the same, even when the solid tablets was compared with the most soft tablets with identical composition, indicating great strength of the drug. Specifically, it was found that in the range of hardness from about 40 N 80 N profiles dissolution essentially do not depend on the hardness or resistance tensile strength of tablets. The stretch resistance may vary from about 30 N to 500 N, as, for example, from about 40 N to 200 N. In addition, the stretch resistance film-coated tablets can be over 120 N.

Another very useful feature of the tablets of the invention is that despite the fact that neramexane mesilate is an acid additive salt neramexane, which you would expect the pH-dependent behavior when dissolved mentioned above matrix release the active compound, relatively independently of pH of dissolution.

Used here, the terms "relatively independent" and "essentially independent" means that the release profiles in vitro of two tablets or matrices do not differ more than in listello 10% of the administered dose at any time after the initial phase of release of the medicinal product (from 0 to 1 hour).

According to the next result of the implementation of the dosage form of the present invention is designed as a molded matrix, which is covered with a coating, such as sugar or polymer coating, to provide taste masking of the active compounds, which usually has a bad taste.

In fact, as used here, taste mask coating is a coating that essentially does not affect the profile of release of drug from the matrix with modified release. In other words, eliminating the possibility of release of drugs in the initial phase, there will be significant differences at any time between the release of part of the dose of the uncoated matrix and identically manufactured and processed matrix, which has a coating, masking the taste. On the other hand, a significant difference is understood as a difference of 10% or more doses of active compounds introduced into the matrix. I believe that the greatest influence of the coating, taste masking, on the configuration of the profile of release of drug was observed in the initial phase of release of the medicinal product, as, for example, within the first 15 or 30 minutes, which is not true of all characteristics of dosage forms with modified release.

Typically, the coating matrix is p the polymer film coating. The composition of films suitable for taste masking, widely known in the field relating to pharmacy, and they can be based on different types of polymers. Usually, taste mask coating prevents direct contact of the active connection with the saliva during the introduction and rapidly dissolves or disintegrates after dosage form swells.

Suitable polymers for such coatings include, for example, cationogenic methacrylate copolymers, such as copolymers of dimethylaminoethylmethacrylate and methyl methacrylate (D-MMA), which is not soluble in aqueous media at pH above 5 (as, for example, in the saliva), but dissolves in acid environments, such as in gastric fluid). Other potentially suitable polymers include hydroxypropylcellulose, hypromellose, hydroxyethylmethylcellulose, copolymers of methacrylic acid, other than DMM-MMA copolymer of polyvinyl alcohol and polyethylene glycol, a copolymer of acrylate and methacrylate, polyvinyl alcohol, carrageenan and mixtures thereof.

The coating composition may include additional excipients to improve the properties of the coating or its machinability, as, for example, one or more excipients selected from the classes of plasticizers, stabilizers, dyes, abrasivos the x agents dispersing agents, surface-aktivnaya substances, sugars, fillers, release agents, agents that modify the permeability of water vapor, etc. Commercially available compositions of the coatings are often premix of one or more film-forming polymer and at least one additional excipient. Used commercial coating composition include water-soluble brand Sepifilm, as, for example, Sepifilm 002, Sepifilm 003, Sepifilm 752, brand Sepifilm LP, includes Sepifilm LP 770; soluble in water brand Kollicoat, such as Kollicoat IR and Kollicoat Protect; in addition, Opadry, perhaps all brand Instacoat, LustreClear and similar substances.

Taste mask coating may have other functions. For example, the coating potentially improves mechanical or even chemical stability of the matrix tablets and it can also improve the appearance of the tablet, its attractiveness to the patient, the ability to swell and other properties.

Coatings can be applied to the matrix using any conventional method and device, as, for example, the coverage of the cell or coverage in the fluidized layer. Usually aqueous, aqueous-alcoholic or organic liquid comprising dispersed or dissolved film-forming polymer(s) and any optional additional the additional excipients, ground and precipitated on the pre-formed core tablets, which are optional dust-free, continuous flow of warm air for drying the coating composition on the core tablets.

In accordance with the present invention dosage forms with modified release offer for administration once a day neramexane or its pharmaceutically acceptable salt in the body of a subject, human or animal. Drugs neramexane of the present invention are suitable for treating diseases of the Central nervous system, including, but unlimited listed, the treatment of Alzheimer's disease, Parkinson's disease, dementia in AIDS, neuropathic pain, diabetic neuropathic pain, cerebral ischemia, epilepsy, glaucoma, hepatic encephalopathy, multiple sclerosis, cerebral circulation, depression, delayed psoriasis, amyotrophic lateral sclerosis, irritable bowel syndrome, appetite disorders, disorders due to cumulative overeating, autism, attention deficit disorder, attention deficit disorder and hyperactivity, bipolar disorders, tinnitus, mycosis, psoriasis, malaria, Bourne virus and hepatitis C. Additional pathology for which treatment neramexane is appropriate, described in the technical field. CCA is military interest is the ability to provide continuous pain relief. Accordingly, the present invention additionally provides a method of therapeutic or prophylactic treatment of disorders of the Central nervous system in the body of a subject, human or animal, the method includes the introduction of the subject of the dosage forms in accordance with the present invention.

"Therapeutically effective amount" means an amount of compound that after administration to a mammal for the treatment of painful disorders, disorders or condition is sufficient to affect such treatment. "Therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to treatment. According to the present invention in one embodiment, a therapeutically effective amount of neramexane is the amount effective for the treatment of CNS disorders, including Alzheimer's disease or Parkinson's disease. In another embodiment, therapeutically effective amount is an amount effective for treating neuropathic pain or other pain conditions, such as increased visceral sensitivity. Other applications include, but are not limited to the above, treatment of dementia and depression. Efficiency is the number of drugs for the pharmacological actions and consequently, the effectiveness of the pill depends on the disease.

Used herein, the term "treat" is used here to refer to mitigate or alleviate at least one symptom in the body of a subject, including, for example, pain, Alzheimer's disease, vascular dementia or Parkinson's disease. The term "treat" may refer to a reduction or relief intensity and/or duration of the illness endured by the subject in response to the stimulus (e.g., pressure, tissue damage, low temperature etc). For example, in relation to dementia, the term "treat" may mean the reduction or relief of symptoms of deterioration of cognitive abilities (such as memory impairment and/or orientation), or deterioration in the global functioning (activity of daily living, ADL) and/or the slowing or reversal of the progressive deterioration of ADL or deterioration of cognitive abilities. In the meaning of the present invention, the term "treat" also means include delay, delay start (i.e. the period prior to clinical manifestation of the disease) and/or reducing the risk of development or progression of the disease. The term "protect" is used here to refer to the prevention, delay or treatment of, or all, as appropriate, manifestations Il the duration or exacerbation of the disease in the subject. In the meaning of the present invention dementia is associated with impaired Central nervous system, including without limitation neurodegenerative diseases, such as Alzheimer's disease (AD), down's syndrome and dementia associated with cerebrovascular (VaD).

The invention is additionally illustrated by the following examples, which, however, should not be interpreted as limiting the scope of the invention.

Examples

Example 1: matrix tablets with modified release neramexane

Matrix tablets comprising about 25 mg, or 50 mg, or 75 mg, or 100 mg neramexane nelfinavir, obtained as follows. The appropriate number neramexane nelfinavir, hydroxypropylmethylcellulose (receiver array, here: Methocel K 100M CR), microcrystalline cellulose (MCC, here: Avicel PH 102), magnesium stearate and colloidal silicon dioxide (SiO2here: Aerosil 200) are weighed and mixed using a mixer free fall (gravity)(Bohle PTM 200). In the alternative case, the appropriate number neramexane nelfinavir, hydroxypropylmethylcellulose, microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide sieved before mixing using the mixer free fall. The appropriate number for each batch of tablets is calculated according to the target issue for lighting the m contents per unit dose as given in Table 1. The optical characteristics of the powder mixture does not show a lack of homogeneity such scales, pieces or trends of division. All mixtures show useful properties for deformation of the powder and to move freely. Three-dimensional and discrete density of all mixtures is slightly different.

Table 1
IngredientDrug And
[mg/tablet]
Drug
[mg/tablet]
Drug
[mg/tablet]
The drug D [mg/tablet]
Neramexane mesilate50,050,050,050,0
A receiver array25,050,075,0200
MCC72,7547,7522,7545,50
SiO21,51,5 1,53,0
Magnesium stearate0,750,750,751,50
The total number of150,0150,0150,0300,0
IngredientDrug
[mg/tablet]
Drug F
[mg/tablet]
The product G
[mg/tablet]
Preparation H [mg/tablet]
Neramexane mesilate25,025,075,0100,0
A receiver array50,0125,0300,0400
MCC48,12547,068,2591,0
SiO21,252,04,5 6,0
Magnesium stearateof 0.6251,02,253,0
The total number of125,0 mg200.0 mgto 450.0 mgof 600.0 mg

The powders separately extruded in lenticular matrix tablets using a conventional rotary press to tablets with the use of the primary compression force of from about 10 to 20 kN. For example, we discovered that after receiving the average content neramexane nelfinavir for drugs 50 mg is of 47.5 to 52.5 mg/tablet, as, for example, from 50 to 52 mg/tablet for all parts with homogeneous content that meets the requirements of the European Pharmacopeia and the US Pharmacopeia.

Example 2: Coating of matrix tablets with modified release neramexane

Matrix tablets obtained according to Example 1 was covered with a white water-soluble composition for coating, white Sepifilm LP 770, with the use of perforated or non-perforated standard device for coating, with a tray and air regulation. Before coating, the tablets were weighed and obespylivanie. Then the dispersion for coating raspily and on tablets using the spray nozzle 1,0 mm The temperature of the cores of the tablets during the coating ranged from 34 to 39°C. the Temperature at the inlet ranged from 59 to 64°C. and a spray rate of approximately 40-53 g/min Spraying continued up until the increase in weight of tablets was approximately 4%. Visually the appearance of the tablet coating is very good. It turned out that there is no stickiness, surface is smooth, shiny and very smooth, without any cracks or damage.

Example 3: the Release of drug from matrix tablets with modified release

For tablets prepared according to Example 1, was determined by the release profiles of the medicinal product with the use of the device for dissolving type "baskets" according to USP XXVII with a stirring speed of 100 rpm and phosphate buffer pH 6.8 as a medium for dissolution. Through certain time intervals samples environment for dissolution was extracted and analyzed for the content neramexane. For drugs A-D results are summarized in Table 2.

Table 2
Time (min)Drug And
(% wisweb-statement)
Drug
(% vysvobozhdeny is)
Drug
(% release)
The drug D
(% release)
6042343325
12061504836
18075646145
24085747352
30091827959
36095888565
48099959475

The results demonstrate how the release profile of the medicinal product this dosage form of the invention the mod is but precisely controlled simply by changing the relative content of nabukelevu in water of the polymer matrix tablets.

Example 4: Production of matrix tablets neramexane with different tensile forces

Matrix tablets with modified release neramexane produced according to Example 1, having the same qualitative and quantitative composition as the drug (table 1), except that the main force of the compression varies: one batch of tablets (soft) extruded with a small force of approximately 5 kN and the second party (solid) with great force about 21 kN. The hardness or tensile strength of the resulting tablets is changing significantly: pill party In-soft have a hardness in the range from 33 to 38 H, while the party In the solid have a hardness in the range from 85 to 96 H.

Example 5: the Release of drug from tablets neramexane with different tensile forces

The tablets obtained according to Example 4, was tested for evaluation of release properties of the medicinal product, as described in Example 3. The results show a remarkably strong drug, are summarized in table 3.

Table 3
Time (min)Party-soft
(% release)
Party-hard< / br> (% release)
603937
1205755
1806967
2407876
3008584
3609090
4809697

Example 6: pH-Independent release of drug from matrix tablets neramexane

Matrix tablets with modified release neramexane according to the drug produced as described in Example 1. Then tablets were coated film as described in Example 2. The release profiles medicines tablets, film-coated, and examined with the use of the device with the "basket" and the stirring speed of 100 rpm, at pH of 1.2, pH 4.5 and pH 7.4.

Configuration of release profiles are very similar, and there are only small differences between the profiles, indicating remarkably durable ven is at and very low dependence on pH in all the wide range of pH values. In fact, the greatest observed difference in the release of part of the dose at any point in time between the two pH values is only 6%. The results are summarized in table 4.

Table 4
Time (min)pH of 1.2 (% release)pH 4.5 (% release)pH 7.4 (% release)
60353633
120535450
180676863
240767772
300848579
360889185
4809498Example 7: Calculation of profiles neramexane in plasma achieved matrix tablets neramexane

Concentration neramexane in plasma over time was determined after a single dose of 25 mg neramexane nelfinavir in drug immediate-release several volunteers. From the concentration profiles in plasma was calculated by the average value of absorption and rate constants of elimination. Using these data, calculate the expected concentration profiles neramexane in the plasma in the steady state for the following treatment regimen: (a) the introduction of twice-daily 25 mg neramexane nelfinavir as drug immediate-release, (b) introduction once a day 50 mg neramexane nelfinavir as drug immediate-release, and (C) introduction once a day 50 mg neramexane nelfinavir in the form of the preparation In Example 1. From the simulated profiles in the plasma was calculated relative index fluctuations.

Discovered that therapeutic regime (a) is associated with an index fluctuations about 0,22, mode (b) with index fluctuations approximately 0.47, and the mode (s) with index fluctuations approximately 0,33. These results reflect the fact that the regime (a) and (C), but not the mode (b) is considered as valid on the basis of the risk of side effects and the risk of subtherapeutic concentration what's depressions. Although the mode (a) includes only small fluctuations in plasma concentrations, it requires dosing twice a day, which is seen as less convenient than once a day, at least for long-term therapy.

The present invention is not limited to the scope described here, the specific implementation options. Indeed, various modifications of the invention, also described herein will become apparent to experts in the field of technology from the preceding description and accompanying drawings. Such modifications are within the scope of appended claims.

It is also clear that all values are approximate and are intended to describe.

Patents, patent applications, publications, descriptions of matter and protocols are cited throughout this application, the descriptions of which are introduced here by reference in its entirety for all purposes.

1. Oral pharmaceutical form modified-release formulation comprising: a therapeutically effective amount of an active compound selected from neramexane, its isomers and soluble in water and pharmaceutically acceptable salts, solvate, conjugates, prodrugs, and derivatives, where the active compound dispersed within a solid matrix containing d is uliuli release filler, selected from a copolymer of polyvinylpyrrolidone and vinyl acetate, polyvinyl acetate, hydroxypropylmethylcellulose where hypromellose is present in a mixture with microcrystalline cellulose, and the content of the filler is chosen so as to obtain the profile of release of the active compound in vitro, characterized by the time of dissolving at least 1 h to part 50 wt.% the number of active connections.

2. Dosage form according to claim 1, where the profile of release of the active compounds in vitro is characterized by the time of the dissolution of from about 1 to 3 hours for the part of drug 50 wt.% the number of active connections.

3. Dosage form according to claim 1, where the profile of release of the active compounds in vitro is characterized by the time of the dissolution of 4 h for part of the drug from about 65 to 95 wt.% the number of active connections.

4. Dosage form according to claim 1, where the profile of release of the active compounds in vitro is characterized by the time of the dissolution of 4 h for part of the drug from about 70 to 85 wt.% the number of active connections.

5. Dosage form according to any one of claims 1 to 4, where the active compound is neramexane mesilate.

6. Dosage form according to claim 1, additionally containing one or more fillers.

7. Drug is the first form according to claim 6, where the content of regulating the release of filler in the solid matrix is from about 10 to 80 wt.%.

8. Dosage form according to claim 6, where the additional filler selected from the dry binding agents, lubricating agents, and agents to slip.

9. Dosage form of claim 8, where the dry binding agent selected from lactose, lactose monohydrate, calcium phosphate, calcium hydrogen phosphate, calcium sulphate, sucrose, dextrose, mannitol, sorbitol, cellulose, polyvinylpyrrolidone and microcrystalline cellulose.

10. Dosage form of claim 8, where the lubricating agent is selected from magnesium stearate, stearic acid, calcium stearate, sodium fumarate, mineral oils, hydrogenated vegetable oils and polyethylene glycol.

11. Dosage form of claim 8, where the lubricating agent selected from colloidal silicon dioxide, starch, calcium stearate or magnesium and talc.

12. Dosage form according to claim 6, where the solid matrix is in the form of compressed tablets.

13. Dosage form according to item 12, where the compressed tablet is directly pressed tablet.

14. Dosage form according to item 12, where the pressed tablet cover coating, masking the taste.

15. Dosage form by 14, where the coating is a polymer.

16. Dosage form according to claim 1, where R is guiraudie release the filler is selected to achieve the dissolution profile of the active compounds in vitro, which, essentially, does not depend on pH for dissolution.

17. Dosage form according to claim 1, where the filler regulating the rate of release, is a copolymer of polyvinylpyrrolidone and vinyl acetate.

18. Dosage form according to claim 1, where the filler regulating the rate of release is a polyvinyl acetate.

19. Dosage form according to claim 1, where the filler regulating the rate of release is a hypromellose, present in a mixture with microcrystalline cellulose.

20. Dosage form according to claim 1, where the mass ratio of active compound to the filler regulating the rate of release is from about 10:1 to 1:10.

21. Dosage form according to claim 19, where the mass ratio of active compound to the filler regulating the rate of release is approximately 2:1 to 1:2.

22. Dosage form according to claim 1, where the active compound dispersed in the matrix in the form of compressed tablets and where regulatory release the filler is selected to achieve the dissolution profile of the active compounds in vitro, which essentially does not depend on the hardness of the molded tablets, where hardness is from about 40 to 80 N.

23. Oral dosage form with modified release, what with: a therapeutically effective amount of an active compound, selected from neramexane and its pharmaceutically acceptable salts, solvate, isomers, conjugates, prodrugs, and derivatives, and at least one regulating the release of a filler selected from a copolymer of polyvinylpyrrolidone and vinyl acetate, polyvinyl acetate, hydroxypropylmethylcellulose where hypromellose is present in a mixture with microcrystalline cellulose, where regulatory release the filler is selected to achieve index fluctuations of the concentration neramexane in the plasma of about 0.4 or less with the introduction of once a day in the steady state.



 

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13 cl, 12 dwg, 4 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, which are HSP90 (heat-shock proteins) inhibitors and can be used to prepare a medicinal agent for treating tumorous diseases affected by HSP90 inhibition. In formula I R1 denotes Hal, H, OA or A, R2, R3 each independently denotes -O-(X)s-Q, -NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -NHSOr(X)s-Q, NHCOA, Hal, Het or H, where, if R2=H, then R3≠H, or if R3=H, then R2≠H, R4 denotes H, R5 denotes H, Hal, A, OA, (CH2)nCOOH, (CH2)nCOOA, O(CH2)oCONH2, NHCOOA, NHCO(CH2)nNH2, NHCONHA or O(CH2)oHet1, A denotes a straight or branched alkyl containing 1-10 carbon atoms, in which 1-5 hydrogen atoms may be substituted with F, Cl and/or Br, X denotes a straight or branched C1-C10 alkylene which is unsubstituted or substituted once, twice or thrice by A, O A, OH, Hal, CN, COOH, COOA, CONH2, NH2, NHCOA, NHCOOA, Q denotes H, Ar or Het, Ar denotes phenyl which is unsubstituted or substituted once, twice or thrice with A, OA, OH, NO2, Hal, CN, (CH2)nCOOH, (CH2)nCOOA and/or tetrazole, Het denotes a cyclic saturated or aromatic 5-6-member heterocycle containing 1-2 N and/or O atoms, optionally condensed with a benzene ring which may be substituted once, twice or thrice with A, OA, OH and/or =O (carbonyl oxygen), Het1 denotes a monocyclic saturated, unsaturated or aromatic heterocycle containing 1-2 N and/or O atoms, which may be mono- or disubstituted with A, OA, OH, Hal and/or =O (carbonyl oxygen), Hal denotes F, Cl, Br or I, n equals , 1, 2, 3 or 4, o equals 1, 2 or 3, s equals 0, 1 or 2.

EFFECT: high efficiency of using said derivatives.

4 cl, 4 dwg, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: compound is ((S)-1-phenyl-propyl)-amide 3-(methane sulphonyl amino)-2-phenyl- quinoline-4-carboxylic acid, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on the disclosed compound.

EFFECT: novel derivative of methyl sulphonamide quinoline which can be used to modulate the NK-3 receptor.

2 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: compound is ((S)-1-phenyl-propyl)-amide 3-(methane sulphonyl amino)-2-phenyl- quinoline-4-carboxylic acid, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on the disclosed compound.

EFFECT: novel derivative of methyl sulphonamide quinoline which can be used to modulate the NK-3 receptor.

2 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: compound is ((S)-1-phenyl-propyl)-amide 3-(methane sulphonyl amino)-2-phenyl- quinoline-4-carboxylic acid, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on the disclosed compound.

EFFECT: novel derivative of methyl sulphonamide quinoline which can be used to modulate the NK-3 receptor.

2 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: compound is ((S)-1-phenyl-propyl)-amide 3-(methane sulphonyl amino)-2-phenyl- quinoline-4-carboxylic acid, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on the disclosed compound.

EFFECT: novel derivative of methyl sulphonamide quinoline which can be used to modulate the NK-3 receptor.

2 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of pharmaceutical composition in form of hard peroral drug form for treatment of gastrointestinal tract diseases. Pharmaceutical composition contains the following ingredients: trimebutin maleate, lactose, colloidal silicon dioxide, talc, corn starch, magnesium stearate.

EFFECT: obtained pharmaceutical composition ensures high clinical effect.

5 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and solid dosage form of calcium atorvastatin. Solid dosage form consists of core containing the following components, wt %: calcium atorvastatin - 1.5-25; microcrystalline cellulose - 2-30; calcium carbonate - 5-30; croscarmellose sodium - 0.5-5; stearic acid and/or its salt - 0.5-1.04; lactose "Lactopress Spraydry" - balance; and shell containing the following components, wt %: polyethylene glycol - 6-28; titanium dioxide - 10-35; talc - 5-25; silicon emulsion - 0.05-4; dye - 0-3; polyvinyl alcohol - balance.

EFFECT: invention provides for production of calcium atorvastatin pills satisfying requirements of National pharmacopeia XI.

4 cl, 5 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a solid oral dosage form composition containing therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in amount exceeding 46 wt %. The oral dosage form represents a tablet or a film-coated tablet. Aliskiren tablet is made by wet granulation with using mixed organic solvents or organic binding solutions.

EFFECT: elimination of aqueous granulation provides high stability of the dosage form of aliskiren and prolonged shelf-life.

18 cl, 2 ex

FIELD: food industry.

SUBSTANCE: present invention relates to gastral retentive composition containing active agent granulated together with the mixture of the first and the second gelatinating agents and mentioned composition production method the first gelatinating agent is a mixture of microcrystalline cellulose and sodium-carboxymethyl cellulose the second gelatinating agent is a compound with viscosity of 1% water solution which makes at least 600 centipoise at 25°C active agent is chosen from antibacterial compounds such as fluoroquinolones, antidiabetic compounds and antihypertensive medicinal agents.

EFFECT: invention provides gastral retentive composition with sustained release effect, which stays in stomach; medical agent has maximal absorption with improved therapeutic action there.

24 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical dosed form, which contains pharmaceutically active substance, unstable in presence of acid, which includes central nucleus, containing active substance and loosening agent, swelling coating, surrounding central nucleus, and enterosoluble coating, surrounding swelling coating. Swelling coating includes prolamin, preferably, zein. Pharmaceutically active substance includes benzimidazole, selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.

EFFECT: invention ensures fast release of pharmaceutically active substance in medium, which has pH value at least 5.

33 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical chemistry, namely to the method of obtaining of a medical product with a covering from a Pioglitazone hydrochloride which can be used as a therapeutic agent for treatment of diabetes, lipidemias, and also can be an antihypertensive agent, an antiobesity agent, diuretic or an antithrombotic agent.

EFFECT: medical product covered with a hydrochloride pioglitazon, possesses larger stability of an agent at storage, and also improved properties, such as solubility of a Pioglitazone hydrochloride.

11 cl, 30 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed composition contains core including Rabeprasol or pharmaceutically acceptable salt thereof as acid secretion inhibitor in stomach and basic compound, intermediate coat coating the core, and overcoat applied on intermediate layer and containing water insoluble polymer and enterosoluble polymer. Also described is method for production of composition containing said preparation.

EFFECT: composition of prolonged storage time providing effective concentration of Rabeprasol in blood for long period of time.

16 cl, 5 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered a prolonged release composition for regional depot fat reduction containing a therapeutically effective amount of at least one glucocorticosteroid in the form of a crystalline microparticle suspension, and a therapeutically effective amount of at least one selective beta-2-adrenergic receptor agonist and a respective combined preparation of the same purpose.

EFFECT: glucocorticosteroid reduced beta-adrenergic receptor desensitisation to provide a synergetic action with the beta-2-adrenergic receptor agonist (eg, with formoterol) to enable fat amount reduction.

18 cl, 11 dwg, 5 tbl, 7 ex

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