Galenical preparations of organic compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: claim describes a standard solid dosage form for oral administration which represents a mini-tablet having a core and an outer coating, wherein the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, while the outer coating represents a film coating containing a taste masking material specified in polyacrylates, and/or a release modifying ingredient of the coating specified in cellulose derivatives and acryl copolymers, and a mixture thereof. The above mini-tablet has a size of 1 mm to 4 mm and contains aliskiren in an amount making 2 mg/tablet to 4 mg/tablet. The oral solid dosage form is preferentially applied in paediatrics.

EFFECT: according to the invention, the dosage form of aliskiren can be dosed and possesses a taste that makes it applicable for children, and maintains a biological availability at a level comparable to that of the available medicinal product for adults.

19 cl, 13 dwg, 5 tbl, 3 ex

 

The present invention relates to a solid oral dosage form that contains as the active substance with activity during oral administration of an inhibitor of the renin aliskiren or its pharmaceutically acceptable salt, preferably its profumata, in a suitable environment-carrier, and which has an outer coating in the form of a film coating. In particular, the present invention proposed solid oral dosage form that contains aliskiren or its pharmaceutically acceptable salt, preferably profumata, individually or in combination with another active substance, intended for use in the treatment of diseases or conditions in children and/or in patients who have experienced problems with swallowing, caused by disease or associated with age. The present invention relates also to methods for the specified solid oral dosage forms and to its use as a medicine.

It is implied that used below in the present description the term "aliskiren" if it is not specifically defined, refers to the specified compound in free base form and in salt form, preferably in the form of a pharmaceutically acceptable salt, first of all, profumata.

Renin release from the kidney, splits present in the bloodstream angiotensinogen education Decapeptide angiotensin I. In turn, this compound is cleaved angiotensinamidum enzyme (ACE) in the lungs, kidneys and other organs with the formation of oktapeptid of angiotensin II. Oktapeptid increases blood pressure as a direct result of arterial vasoconstriction and indirectly result in the release of adrenal retaining sodium ions by the hormone aldosterone, which is accompanied by increase in the volume of extracellular fluid. Inhibitors of the enzymatic activity of renin leads to reduce the formation of angiotensin I. as a result, the angiotensin II is produced in smaller quantities. The decrease in the concentration of the specified active peptide hormone is the direct cause, for example, the antihypertensive effect of inhibitors of renin. Therefore, inhibitors of renin or their salts can be used, for example, as antihypertensive drugs or in the treatment of congestive heart failure.

It is known that the inhibitor of the renin aliskiren, especially his profumata, has efficacy in the treatment carried out with the aim of lowering blood pressure, and is also well-tolerated. Aliskiren in free base form is described by the following formula

and has the chemical name 2(S),4(S) 5(S),l(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxypropane)phenyl]octanamide. As stated above, it is preferable salt is profumata, which is specifically described in example 83 EP 678503 A.

To date, no studies concerning the application of aliskiren as monotherapeutic funds or in combination with other antihypertensive agents in the treatment of children suffering from hypertension. Because aliskiren is the first representative of a new class of antihypertensive drugs (Daugherty and others, 2008), we should expect that it may have advantages over other currently used therapies suitable for children aged 0.5 to 17 years, suffering from hypertension.

Because there is an increase in the incidence of hypertension in children (Sorof and others, 2004), approaches to its treatment, alternative present, must acquire increasing importance. The use of aliskiren can be particularly important for children aged 6-17 years with primary arterial hypertension as it was found that aliskiren has comparable efficacy when used to treat adult patients, the article is adusa obesity, and adult patients with normal body mass index (BMI) (Jensen and others, 2008). It is believed that obesity is a major contributor to the development of essential hypertension in school-aged children and adolescents (Weinberger and others, 2008).

Hypertension in children, although it is less common than hypertension in adults, is a disease that requires the development of medical devices, because for sick children suffering from hypertension in combination with renal dysfunction, heart disease or diabetes are more likely to have to require therapy with pharmacological agents. In addition, the increase in the number of cases of obesity in school-aged children and adolescents, observed all over the world, is causing an increasing number of cases of hypertension in children (Weinberger and others, 2008). This situation is further complicated by the fact that there are no recommendations by the values of the doses for children, supported by the results of a controlled randomized clinical trials, and is suitable for children preparative forms of medicines.

The currently used tools include ACE inhibitors, calcium channel blockers, β-blockers and angiotensin receptor blockers (ARB). In a recently published review, which cover the work indicates 438 pediatric nephrologists in North America, it is noted that as a drug first-line treatment of essential hypertension most commonly used angiotensin converting enzyme inhibitors (ACEI), followed by calcium channel blockers (47% and 37%, respectively). Beta-blockers as drugs first-line use only 7% of respondents, and as a second-line drugs - 17% (Chesney and Jones 2007). In the treatment of hypertension in children is also used diuretics, such as hydrochlorothiazide (HCTZ), but so far have not been conducted controlled studies on the use of HCTZ for the treatment of hypertension in children.

New treatment options for hypertension, such as the use of aliskiren, can help clinicians solve some of the problems listed above, characteristic of adults. To date, no studies of the use of Aliskiren for the treatment of hypertension in children; this drug has an action mechanism different from the mechanism of action of other funds and, therefore, may be an alternative drug for people suffering from hypertension children aged 0.5 to 17 years.

In the case of use in Pediatrics oral introduction of pharmaceutical products in the form of solutions, consisting of powder, granules or tablets, or that the notches are film-coated, or capsules, has certain advantages in comparison with other routes of administration such as parenteral administration, i.e. i.v.- or i.m.-introduction. It is believed that the disease requiring treatment with painful injection preparative forms should be more severe than the conditions that can be treated using oral dosage forms. However, the main advantage of oral preparative forms lies in their suitability for introduction by the patient, while for parenteral preparative forms in most cases require that their introduction was carried out by a physician or paramedical personnel.

Marketed aliskiren available in the form of oral dosage forms, which is a tablet with a film coating with quick release, having a content of active substance 150 mg. It is an indivisible round tablet with a diameter of about 11 mm and a thickness of about 4 mm, which does not meet the requirements for preparative forms for children from the point of view of the content of the active substance, the possibility of dosing, acceptability to the patient (in terms of its ability to swallow) and size.

Thus the physico-chemical properties and very bitter taste of the drug substance exclude the possibility of the awn create a liquid oral formulation, which is the standard in the implementation of child care by age of 0.5-17 years.

Thus, there is a need for the development and implementation of treatment of hypertension in children and in creating intended for children preparative form containing aliskiren, which does not have the disadvantages inherent in marketed tablet film-coated quick release containing aliskiren, from the point of view of application for children, this means that the new form should be sized to be capable of dispensing and taste, which are required in its application to children, and to preserve the biological availability at a level comparable with the biological availability of marketed medicinal product.

However, most commonly used in Pediatrics preparative forms that are suitable for children, such as syrups and other liquid formulation, are unacceptable due to the physico-chemical properties and very bitter taste of aliskiren, which prevent the development of such commonly used in Pediatrics preparative forms. It was found, for example, that it is impossible to create a liquid formulation containing aliskiren, because you cannot find sweeteners and/or corrigentov, and/or a viscosity modifier, which provide the Wali would be the degree of masking of taste, sufficient to achieve acceptable for children to taste. In addition, it was found that for the development of a liquid formulation, for example, representing a suspension, which would have a less bitter taste, the barrier is very high solubility of aliskiren in water (>350 g/l at pH values from 1 to 8). In addition, in earlier clinical study, it was found that the bioavailability of a liquid formulation containing aliskiren was lower bioavailability of solid oral forms.

Powder coated or granules coated, designed to restore, also was regarded as unsuitable because of the expected large amount of polymer required to provide taste masking in the case of large surface area, would be unacceptable for use in Pediatrics for the specified age groups.

In addition, physico-chemical properties of aliskiren are also not favorable for obtaining powder coated or granules coated due to the high hygroscopicity of the connection.

The specified high hygroscopicity of aliskiren may be an obstacle for the development of the medicinal product/formulation with such a large surface area as a result is their absorption of moisture and its impact on stability, that, as it has already been established, is a problem for marketed containing aliskiren preparative forms in the form of film-coated tablets, which are intended for the population of adults.

In addition, containing aliskiren granules coated with a film coating also was not considered as a suitable form of the medicinal product, because changing the polymorphic state of the drug substance in amorphous can have a negative effect on the stability of the drug product.

It was found that the preparation of oral formulations in the form of tablets reliable and efficient method is technically difficult to implement.

One such difficulty is due, for example, that the crystals of aliskiren have a needle shape, which has a negative effect on the bulk properties of the drug substance, for example, on the characteristics of fluidity and bulk density. The compressibility of the drug substance is insufficient, which leads to weak linkages between the particles and changes of polymorphism at pressing. Aliskiren has a pronounced elasticity, which also leads to a weakening of the ties between the particles. The quality of the drug substance is not constant, which affects the technology is the cue properties pills, for example, the distribution of particle size, bulk density, flowability, wettability, surface area and tend to stick together.

In addition, aliskiren is highly hygroscopic. Upon contact with water polymorphic state of the drug substance is changed to an amorphous, as evidenced by reduced stability compared to the crystalline state. The combination of these obstacles makes the process of producing a standard tablet extremely difficult.

Direct extrusion is unsuitable method for manufacturing standard containing aliskiren dosage forms due to technological problems, due to the needle-like particle shape, low turnover, and problems associated with ensuring uniformity of dose.

Another form of the medicinal product, which is sometimes considered for use in Pediatrics, are the preparative form, representing the mini-pill, which can be introduced in combination with a small amount of soft food such as pudding or mashed vegetables, or without it. However, the combination of the above technical difficulties makes extremely difficult the application of the process of making standard tablets to get mini-tablets such as described in WO 2005/089729. Su is bedstvie of these technical difficulties could not be expected this method will allow you to obtain an acceptable result.

Despite the technical difficulties associated with the preparation containing aliskiren preparative form when creating the present invention have been developed appropriate modifications of the production process, which helped to overcome many technical difficulties and create containing aliskiren standard solid dosage form suitable for oral administration in the form of mini-tablets having a core and outer cover, in which:

- tablet core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt,

- the outer coating is a coating with taste masking properties and/or function of supervised release, first film coating that has the ability to mask the bitter taste of aliskiren.

In particular, the present invention is proposed containing aliskiren standard solid dosage form for oral administration, representing the mini-coated tablets, as a formulation suitable for children of a certain age, which satisfies the necessary requirements with regard to technical characteristics, the introduction and pharmacokinetic characteristics.

Standard medicines is nnow form proposed in the present invention, it is possible to introduce not only the children, but it can be used, for example, in General, for patients who have difficulty swallowing due to illness or age of the patient.

One of the embodiments of the invention relates to the above-described standard solid dosage form, where the size of the mini-pill is from 1 to 3 mm, preferably from 1.25 to 2.5 mm, and most preferably from 1.5 to 2.5 mm

In one of the embodiments of the invention the size of the mini-pill is 2 mm.

One of the embodiments of the invention relates to a solid standard dosage form, representing the above-described mini-pill, where mini-tablet contains as active substance only aliskiren or its pharmaceutically acceptable salt in an amount constituting from about 2 to about 4 mg in terms of free base on a standard dosage form, preferably from about 2.5 to 3.5 mg in terms of free base by standard pharmaceutical form.

In one variant of the invention, the mini-tablet contains aliskiren or pharmaceutically acceptable salt in a quantity amounting to 3.125 mg/tablet.

One of the embodiments of the invention relates to the above-described solid article is Hartnoll dosage form, in which film coating has the function of controlled release.

In one variant of the invention, the film coating has a pH-dependent release profile.

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating provides a level of dissolution of aliskiren in vitro at a pH value of about 2, approximately 75% or less for 10 min, about 96% or less for 20 min and about 98% or less for 30 min (option a).

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating provides a level of dissolution of aliskiren in vitro at a pH value of about 4.5, approximately 70% or less for 10 minutes, about 95% or less for 20 min and about 98% or less for 30 min (option a).

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating provides a level of dissolution of aliskiren in vitro at a pH value of about 6.8%, with the bringing about 4% or less for 10 min, approximately 32% or less for 20 min and about 70% or less for 30 min (option a).

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating contains as the film-forming substance is basically the copolymer butylated methacrylate.

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating contains as the film-forming substance to an aqueous dispersion of ethyl cellulose and optional hypromellose as a pore-forming substances present in the film-forming substance.

One of the embodiments of the invention relates to a solid standard dosage form proposed in the invention and represented in the present description, in which the film coating contains as the film-forming substance is a copolymer of ammoniojarosite, preferably a copolymer of ammoniojarosite type a and/or copolymer of ammoniojarosite type Century.

One of the embodiments of the invention refers to standard solid dosage form for oral administration, containing terapeutiche the key effective amount aliskiren or its pharmaceutically acceptable salt, preferably profumata, which is designed for use in the treatment of diseases or conditions in children, preferably by standard solid dosage form for oral administration, proposed in the invention and represented in the present description.

One of the embodiments of the invention refers to standard solid dosage form intended for use in the treatment of hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricle hypertrophy, disorders of cognitive abilities, stroke, headache and chronic heart failure, it is preferable to solid oral form of the drug proposed in the invention and represented in the present description.

Definitions:

The concept of "effective amount" or "therapeutically effective amount" refers to the amount of active substance or agent that stops or reduces the progression of the condition to be treated, or which otherwise leads to complete or partial cure, or has a palliative effect on the state.

The concept of "aliskiren" refers to soedinenii, which is represented by the following formula

and which has the chemical name 2(5),4(5),5(5'),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxypropane)phenyl]octanamide.

Assume that occurring above and below in the present description the term "aliskiren" if it is not specifically defined, refers to him in the form of free base or in salt form, primarily in the form of its pharmaceutically acceptable salts, such as profumata, bisulfate, orotate or nitrate, most preferably in the form of profumata.

As stated above, the most preferred salt is profumata, which is specifically described in example 83 EP 678503 A.

Aliskiren, especially his profumata is a renin inhibitor, in respect of which it is known that it is effective in the treatment carried out with the aim of reducing blood pressure regardless of age, gender or race, and also has good tolerability.

The concept of "release" in the context of the present description refers to the process by which a pharmaceutical oral dosage form is brought into contact with the liquid, and the liquid transports the drug(s) tool(s) from the dosage form, causing it enters the LM the bone, surrounding dosage form. The combination of the arrival rate and duration of exposure of the patient, provide consider dosage form, can be described as its release profile in vivo. Release profiles, provide dosage forms, may have different speeds and duration of the release, and can also be continuous. Continuous release profiles include release profiles, in which there is a continuous release of one or more active substances either with constant or variable speed.

For the purposes of the present invention can be considered that the preparative form with quick release is a preparative form in which the release of the current/active substances/substances not intentionally modified by using special design formulation or method of manufacture.

For the purposes of the present invention the term "preparative form with modified release" refers to the preparative form in which the release of the current/active substances/substances intentionally modified by using special design formulation or method of manufacture. This modified-release, as the rights of the lo, provide by delaying the starting time of the release of the active substance. As a rule, for the purposes of the present invention, a modified release refers to the release, the detainee 30-60 minutes

The concept of "time delay" in the context of the present description refers to the period of time between the introduction of the dosage form containing the composition proposed in the invention, and the release of active substance from its component.

In the context of the present description the term "latency" refers to the period of time between the release of the active substance from one component of the dosage form and release of active substance from another component of the dosage form.

In the context of the present description the term "disintegration" refers to the process in which the pharmaceutical oral dosage form disintegrates, as a rule, the pressure of the liquid, to separate particles and dispersed. It is believed that the disintegration is achieved when the solid oral dosage form is in this state, when according to USP <701> the rest of solid oral dosage forms except fragments of insoluble coating or shell of the capsule, if present, remains in the sieve test devices in view of the soft weight in which there is no palpable solid core. Liquid to characterize raspadaemosti represents water, such as tap water or deionized water. The disintegration time was measured using standard methods known to the person skilled in the art (see procedure with the use of harmonic oscillations, which are described in the Pharmacopoeia USP <701> and EP 2.9.1, and JP).

In the context of the present description the term "dissolution" refers to the process by which a solid substance, in this case the active substance is dispersed in the form of molecules in the environment. The dissolution rate of the active substance, which is present in the pharmaceutical oral dosage form proposed in the invention is determined by the amount of the drug substance, which goes into solution per unit time in the standardized conditions of the contacting liquids and solids at standard temperature and a standard composition of the solvent. The dissolution rate is measured by standard methods known to the person skilled in the art (see procedure with the use of harmonic oscillations, which are described in the Pharmacopoeia USP <711> and EP 2.9.3, and JP). For the purposes of the present invention test, designed to determine the dissolution of the individual active substance, Khujand who are according to the Pharmacopoeia USP < 711> at a pH of 2.0 using basket method at 100 rpm (revolutions per minute). Environment for dissolution is preferably a buffer, typically a phosphate buffer, the first buffer, which is described in the example entitled "Test solubility". The both molarity of the buffer is preferably of 0.1 M

In the context of the present description the term "mini-pill" refers to a small tablet with a total weight (excluding the weight of the coating) from about 2 to 30 mg, for example, from about 4 to 9 mg, for example, about 7 mg of Mini-tablets are a special form consisting of many particles of the products presented in this description. You can get them as described in the present description method, including from other consisting of smaller particles products, such as particles, granules, or beads. The mini-pill may have any shape, which are known to the person skilled in the art, have a tablet, for example round, for example with a diameter of from about 1.25 to 3 mm; cylindrical, for example with a convex top face and a convex lower face, where, for example, the diameter and height of the cylinder independently of each other can be from 1 to 3 mm; or may be a lenticular mini-tablets, for example, the mini-pill with about the same height and diameter, and components of the 1.25 to 3 mm.

The core of the mini-pill offered in the invention may contain additives or excipients suitable for the preparation of solid oral dosage forms proposed in the present invention. You can apply substances that facilitate tableting, which are commonly used in the formulation in the form of tablets, which are described in numerous publications on this subject (see, in particular, Fiedler, "Lexikon der Hilfstoffe", 4th ed., publishing house ECV Aulendorf, 1996, the contents of the specified directory is included in the present description by reference). Such substances include, but is not limited to, fillers, binders, disintegrating agents, sizing, substances that improve slip, stabilizers, fillers or diluents, surfactants, film-forming substances, softeners (plasticizers), pigments, etc.,

The present invention relates to solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active ingredient and filler as an additive. Other additives can serve as (but not limited to, binders, disintegrating agents, sizing, substances that improve slip, stabilizers, diluents, surfactants, p is incobrasa substances, pigments, plasticizers and antiadhesive, etc., Preferably the active ingredient and other additives used in the above in the present description.

The present invention relates to solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active ingredient and a carrier, and the baking powder as additives. Other additives can serve as (but not limited to, binders, sizing, substances that improve slip, stabilizers, diluents, surfactants, film-forming agents, pigments, plasticizers and antiadhesive, etc., Preferably the active ingredient and other additives used in the above in the present description.

The present invention relates to solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active ingredient and filler, baking powder and sizing as additives. Other additives can serve as (but not limited to, a binder, a substance that improves slip, stabilizers, diluents, surfactants, film-forming substances is TBA, pigments, plasticizers and antiadhesive, etc., Preferably the active ingredient and other additives used in the above in the present description.

The present invention relates to solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active ingredient and filler, baking powder, a lubricant and a substance that improves slip, as additives. Other additives can serve as (but not limited to, binders, stabilizers, diluents, surfactants, film-forming agents, pigments, plasticizers and antiadhesive, etc., Preferably the active ingredient and other additives used in the above in the present description.

The present invention relates to solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active ingredient and filler, baking powder, a lubricant, a substance that improves slip and binder as an additive. Other additives can serve as (but not limited to, stabilizers, diluents, surfactants, film-forming substances which STV, pigments, plasticizers and antiadhesive, etc., Preferably the active ingredient and other additives used in the above in the present description.

The person skilled in the art can select one or more of these additives with specific desired properties of the solid oral dosage form using conventional experiments without any unnecessary effort.

In one variant of the invention, the solid oral dosage form proposed in the present invention contains as an additive filler or diluent, such as confectionery sugar, compressible sugar, dextrine, dextrin, dextrose, lactose, mannitol, starches, such as potato starch, wheat starch, corn starch, hydroxypropylcellulose, hydroxyethylcellulose, hypromellose (HPMC), powdered cellulose, sorbitol, sucrose and talc, preferably microcrystalline cellulose, for example the products marketed under the registered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL. The most preferred filler is microcrystalline cellulose primarily with a density of approximately 0.45 g/cm3for example, AVICEL.

As leavening agents particularly noteworthy calcium salt of carboxyl is icellulse (CMC-CA), sodium carboxymethyl cellulose (CMC-Na), crosslinked PVP (for example, CROSPOVIDON, POLYPLASDONE or KOLLIDON XL), alginic acid, sodium alginate and guar gum, the most preferred are crosslinked PVP (CROSPOVIDON), crosslinked CMC (Ac-Di-Sol), carboximetilkrahmal-Na (PRIMOJEL and EXPLOTAB). The preferred baking powder is CROSPOVIDON.

As of sizing should be emphasized Mg stearate, stearate aluminum (Al) or calcium (Ca), PEG 4000-8000 and talc, hydrogenated castor oil, stearic acid and its salts, complex glycerol esters, Na-fumarate, hydrogenated cottonseed oil, etc. the Most preferred lubricant is magnesium stearate.

As substances that enhance the slide, it should be noted colloidal silica, such as colloidal silicon dioxide, for example, AEROSIL, magnesium trisilicate (Mg), powdered cellulose, starch, talc and rejonowy calcium phosphate, or combinations of fillers or binders, for example silicatization microcrystalline cellulose (PROSOLV). The most preferred substance that improves the slip is colloidal silicon dioxide (e.g., AEROSIL 200).

As the binders used for wet granulation, it should be noted polyvinylpyrrolidone (PVP), such as PVP K 30, HPMC, for example, have their degree of viscosity of 3 or 6 SP, and polyethylene glycol (PEG) such as PEG 4000. The most preferred binder is PVP K 30.

Thus, in one variant of the invention, the solid oral dosage form proposed in the present invention contains as an additive filler, preferably microcrystalline cellulose.

In one variant of the invention, the solid oral dosage form proposed in the present invention contains as an additive in addition to the baking powder filler, preferably it contains microcrystalline cellulose and crosspovidone.

In one variant of the invention, the solid oral dosage form proposed in the present invention contains as an additive in addition to the filler and baking powder lubricant, preferably it contains microcrystalline cellulose, crosspovidone and magnesium stearate.

In one variant of the invention, the solid oral dosage form proposed in the present invention contains as an additive in addition to the filler, baking powder and lubricant a substance that improves the slide, preferably it contains microcrystalline cellulose, crosspovidone, magnesium stearate and colloidal silicon dioxide.

In one embodiment, the implementation and the attainment of a solid oral dosage form, proposed in the present invention contains as an additive in addition to the filler, baking powder, sizing and substances that improve the slip binder, preferably it contains microcrystalline cellulose, crosspovidone, magnesium stearate, colloidal silicon dioxide, and povidone.

In particular, the kernel of mini-tablets, proposed in this invention and represented in the present description, can be obtained by molding a mixture containing the same granules that are contained in marketed formulations form of aliskiren SPP100, and the outer or external phase, preferably an external phase containing more magnesium stearate does not contain superathletes, in contrast to marketed formulation, with which comparison is made (preparative reference form).

The amount of additives used for each type, such as a substance that improves the slip binder, baking powder, filler or diluent and a sizing or coating may vary in the normal area. For example, the number of sizing can vary from 0.2 to 5 wt.%, in particular, the amount of magnesium stearate may be from 1.0 to 3.0 wt.%, for example, from 1.5 to 2.5 wt.%; the number of binders which may vary from about 0 to about 20 wt.%, for example from 2.5 to 4.5 wt.%; the amount of baking powder can vary from about 0 to about 20 wt.%, for example from 3 to 5 wt.%; the amount of filler or diluent may vary from about 0 to about 80 wt.%, for example from 20 to 50 wt.%; while the number of substances that improve slip, can vary from about 0 to about 5 wt.%, for example from 0.4 to 1.0 wt.%, and the amount of film coating can vary from 0 to 5 mg/cm2for example from 0.4 to 0.7 mg/cm2.

Typical proposed in this invention is a solid oral dosage forms is that they may contain only a relatively small number of high content of active substance. This gives you the opportunity to prepare a standard dosage forms, having a small physical size. The share of the total amount of additives in the considered standard dosage form without coating may account for about 65 wt.% or less, calculated on the total weight of the solid oral dosage form, more specifically about 60% or less. Preferably the content of the additives is from about 35 to 58 wt.%, more preferably the content of the additives is from about 50 to about 56 wt.% in terms of the mass of profumata.

Preferred to icesto filler, contained in the core tablet, primarily such as microcrystalline cellulose is from about 30 to 40%, most preferably it is from about 33 to 40% in recalculation on weight of a standard dosage forms.

The preferred amount of binder contained in the core tablet, primarily such as povidone, is from about 2.5 to 4.5%, most preferably it is from about 3 to 4% in recalculation on weight of a standard dosage forms.

The preferred amount of baking powder contained in the core tablet, primarily such as crosspovidone, is from about 3 to 5%, most preferably it is from about 3.5 to 4.5% in recalculation on weight of a standard dosage forms.

The preferred amount of a substance that improves the slip contained in the core tablet, especially such as is from about 0.4 to 1.0%, most preferably it is from about 0.6 to 0.9% in recalculation on weight of a standard dosage forms.

The preferred amount of the lubricant contained in the core tablet, primarily such as magnesium stearate is from about 1.5 to 3%, most preferably it is from about 1.5 to 2.5% in recalculation on weight of a standard dosage forms.

Suppose the equipment the amount of film coating is from about 0.4 to 0.7 mg/cm on a standard dosage form.

The preferred number of aliskiren and additives described in more detail in the examples to illustrate.

The absolute amount of each additive and the relative amount compared to other additives also depend on the desired properties of the solid oral dosage form and the person skilled in the art can select them using the standard experiments without undue effort. For example, you can choose solid oral dosage form, with immediate and/or delayed release of the active substance, thereby providing a quantitative control release of the active substance or do not provide such control.

In a specific embodiment of the invention as a filler/binder used microcrystalline cellulose; as baking powder is used crosspovidone, as filler/binder applied povidone, as the granulation liquid for use ethanol containing 5% isopropanol, which later can be removed during processing, as substances that improve slip, used silica, anhydrous colloidal/colloidal silicon dioxide, and as lubricant applied stearate, preferably in a concentration that is specified in the examples with the whole what Yu illustrations.

In particular, the concentration of magnesium stearate present in the external phase may be from about 1.5 to 3%, preferably from about 1.5 to 2.5% in recalculation on weight of a standard dosage forms.

At the core of the mini-tablets, proposed in this invention and represented in the present description, it is possible to apply coating, which may serve to mask the bitter taste of the drug substance and, therefore, enhance compliance sick mode and a treatment regimen and/or to provide control of the release of the active substance, representing aliskiren, in vitro and in vivo.

Thus, the solid oral dosage form proposed in the present invention can be coated tablets or pills, preferably having a film coating of tablets or pills, in this case, the coating of solid oral dosage forms, as a rule, consists of a polymer, such as HPMC, PVP, or so on, sugar, shellac or other material for film coating, which is widely distributed in this area. You should pay attention to the fact that the coating can be applied by numerous methods known in this field, such as a coating by spraying in a fluidized bed, which is performed by known methods, for example the EP, using devices manufactured by companies Aeromatic, Glatt, Wurster or Htittlin, in a machine for coating with a perforated Chan, which is performed by known methods, for example, using devices manufactured by companies Accela Cota, Glatt, Driam or other companies, or other widely adopted in the field methods. In these methods can be applied additives normally used in the preparation of confectionery products.

In one of the embodiments of the invention on the mini-tablets are coated with taste masking material, such as polyacrylate, preferably EudragitRsuch as EudragitR-E or EudragitR-RD100, or RS/RL (see Handbook of Pharnaceutical Excipients, loc. cit., p. 362 and beyond), especially EudragitR-E.

It is suitable for use in the compositions proposed in the invention, the materials for the coating include polyacrylates, especially polymetylmetacrylate, preferably:

1.(a) a copolymer consisting of monomers selected from methacrylic acid, esters of methacrylic acid, acrylic acid and esters of acrylic acid;

2.b) a copolymer consisting of monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate; or

3.C) a copolymer consisting of monomers selected from acrylate, methylmethacrylat is and chloride trimethylammoniumchloride;

more preferably the products listed in paragraph 2.b), for example, products manufactured by Evonik under the trademark EudragitR.

The most preferred acrylic polymers are:

1.1) copolymers (1:1), which consist of monomers selected from methacrylic acid and (ness.) alilovic esters of methacrylic acid, such as the copolymers (1:1), consisting of methacrylic acid and methyl methacrylate, which are sold under the trademark EudragitRL, for example EudragitRLI00, and the copolymer (1:1) of methacrylic acid and ethyl ester of acrylic acid, which is sold under the trademark EudragitRL100-55;

2.2) copolymer (1:2:1), consisting of butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate, which is sold under the trademark EudragitToE; and

3.3) copolymer (1:2:0,2), consisting of acrylate, methacrylate and chloride trimethylammoniumchloride that sold under the trademark EudragitRRL; or a corresponding copolymer (1:2:0,1), which is sold under the trademark EudragitRRS; or the copolymer (1:2:0,2), consisting of acrylate, methacrylate and chloride trimethylammoniumchloride, which in combination with carboxymethyl cellulose sold under the trademark Eudragit RD;

<> more preferably the products listed in paragraph 2.2).

The above polyacrylates preferably have an average molecular weight component is from about 50,000 to about 500000, for example approximately 150,000.

It was found that the polyacrylates, especially EudragitRE, the most suitable for use as coatings for solid dosage forms containing aliskiren in free base form and in the form of its salts, for example, in the form of profumata of aliskiren, since the coating comprising EudragitRE, does not undergo rapid dissolution at neutral pH in the oral cavity, and is soluble only at pH values below 5, and therefore prevents the dissolution of having a bitter taste of aliskiren before it enters into the stomach.

The above materials for the coating can be applied in mixture with other excipients, which are typically included in the composition of the coatings, such as talc, magnesium stearate or silicon dioxide, for example synthetic amorphous silicic acid of the type SyloidR(company Grace), for example SyloidR244 FP, or colloidal silicon dioxide, such as AerosilRfor example, AerosilR200, or wetting agents, for example sodium dodecyl sulphate or above glycols, or Polysorbate.

According to another object invented the I solid dosage form may have additional coverage, for example, the layer reduces the stickiness of the substance deposited on one of the above coatings, for example, containing the product, which is a colloidal silicon dioxide, such as AerosilRthat can help avoid sticking of solid dosage forms to each other or to the walls of the container, such as capsules.

The most preferred compositions proposed in the invention are particles of aliskiren coated with the coating, such as tablets, such as mini-tablets or pellets, the coating of which consists of (taste masking) polyacrylate, preferably EudragitRE or EudragitRRD100, especially EudragitRE.

In addition, the coating may include additional components such as a plasticizer, such as triacetin, triethylcitrate, diethylsilane, polyethylene glycol 3000, 4000 or 6000, acetyltributyl, acetyltributyl or diethylphthalate, and/or reducing the viscosity of a substance, such as magnesium stearate, colloidal silicon dioxide, synthetic amorphous silicic acid, such as Syloid 244 FP, talc, or glycerol monostearate. In addition, the coating may contain, preferably in the form of aqueous dispersions, one or more thickeners in order to avoid deposition of suspended excipients, for example, HPMC 3 JV or HPMC 6 SP.

In a specific embodiment of the invention as antiadhesive apply stearate, as film-forming substances used basically copolymer butylated methacrylate, as a plasticizer used dibutylsebacate, as a solubilizer used nutriceuticals/lauryl sulfate and purified water as a solvent (a).

If you want to provide a delayed release, it is possible to apply the coating technology for consisting of many particles products, systems based wax matrix tablets based on polymer matrix or polymer coating, or other technologies that are widely used in this field.

Quantitative control release of the active substance can be secured using conventional methods known in this field. Known forms of drugs of this type are oral osmotic system (e.g., OROS), coated tablets, matrix tablets, tablets coated by extrusion coating, multilayer tablets, etc.

In composition with modified release, proposed in the invention can be coated using a component that provides long-term, continuous, gradual and prolonged release action is the pollutant specific representing aliskiren or its pharmaceutically acceptable salt in the body, preferably in the small intestine, for example, modifying the release coating such as a diffusion coating.

Examples of such modifying the release of components of the coating are, for example, derivatives of cellulose, such as ethylcellulose, for example, such a product, as Aquacoat® ECD, manufactured by FMC; Surelease manufactured by use, acrylic copolymers, preferably acrylic and methacrylic copolymers containing Quaternary ammonium group, for example three(C1-C4alkyl)ammoniummolybdate group, for example trimethylammoniumchloride group, for example, acrylic/methacrylic ester with different ratios of the groups of the Quaternary ammonium 20:1 RL/40:1 RS, such as polymers, marketed by the company Rohm Pharma in the form of products under the trademark Eudragit RLR, Eudragit RSRor Eudragit NERor copolymers; and/or mixtures thereof. Most preferred are mixtures of Eudragit RSR:Eudragit RLRin a mass ratio of about 75:25, preferably 90:10, preferably 95:5.

Modifying the release of components of the coating can be in the form of an aqueous dispersion, for example in the form of a 30% aqueous dispersion or organic solution, for example of 1.5% organic solution. For example, modifying the release of components of the coating may be a mixture of Eudragit RLRand Eudragit RSRa 30% aqueous dispersion or 12.5% organic solution.

The number of modifying the release of components of the coating may range from about 30 to about 100 wt.%, more preferably from about 50 to about 100 wt.% in terms of the total weight of the coating.

The share of modifying the release coating, such as diffusion coatings preferably have from 1 to 50 wt.%, more preferably 2-20 wt.%, even more preferably 4-10 wt.% of the total weight of the composition.

The person skilled in the art can optionally choose the nature and amount of polymer included in the modifying the release coating, to control the dissolution profile of component representing aliskiren.

In other specific embodiments of the invention proposed delaying the release coating, in which the plasticizer used dibutylsebacate, as film-forming substances used aqueous dispersion of ethyl cellulose, as other film-forming substances used hypromellose, as substances that improve slip, used silica, anhydrous colloidal/colloidal silicon dioxide and purified in the in the solvent (B).

Modifying the release coating may optionally contain one or more other components or excipients, for example a pore-forming substance, a plasticizer, reducing the stickiness of the substance, wetting agent, for example from among the following substances.

Suitable pore-forming agents can serve not dependent on the pH value of the pore-forming substances, such as HPMC, or a pore-forming substance, the action of which depends on the pH value. Suitable depending on the pH value of the pore-forming substances may be intersolubility pore-forming substances, for example intersolubility the polymers used for coating.

In the context of the present description intersolubility a pore-forming substance is a pore-forming substance, which ensures the release of the drug substance in the environment having a pH value of>5, for example in the intestinal fluid, and prevents the release of the drug substance in an acidic environment, for example in the stomach. Example intersolubility pore-forming substances, which can be used according to the present invention, are HPMC-phthalate (HPMC-f), for example NR, NR, for example, manufactured by ShinEtsu; HPMC-acetylsuccinate (GPMC-AU), for example Aqoat LF or Aqoat MF, for example, produced Phi is my ShinEtsu; the copolymer methylacrylate acid-ethylacrylate acid, for example methacrylic acid copolymer such as Eudragit L, S, L100-55 and/or L30D, manufactured by Rohm Pharma, Acryl-Eze manufactured by use, Kollicoat MAE 30 DP, manufactured by BASF; cellulitecellulite, such as Aquacoat CPD, manufactured by FMC Biopolymer or Polymer, manufactured by Eastman Kodak; and polyvinylacetate, for example Sureteric, use, or any of their mixtures. Preferably HPMC-f and HPMC-AC can be combined with ethylcellulose or acrylic and methacrylic copolymers containing Quaternary ammonium group, for example, three(C1-C4alkyl)ammoniummolybdate groups, such as Eudragit RS in organic solutions for coating, GPMC-AU dispergirovannoyj in the water, you can also combine with the aqueous dispersion of ethyl cellulose, such as Aquacoat ECD, manufactured by FMC.

Phthalates of hydroxypropylmethylcellulose, generally have a molecular weight of from 20,000 to 100,000 Da, such as from about 80,000 to 130,000 Yes, the content hydroxypropyl groups is, for example, from 5 to 10%, the content of methoxypropyl is from 18 to 24%, and the content fallnich groups ranges from 21 to 35%. Examples of suitable phthalates of hydroxypropylmethylcellulose are products having content hydroxypropyl groups from 6 to 10%, the content of methoxypropyl from 20 to 24%, the content of ftaly is lnyh groups from 21 to 27%, molecular weight of about 84000 Yes, which are sold under the trademark NR from the company Shin-Etsu Chemical Co. Ltd., Tokyo, Japan, products having content hydroxypropyl groups, the content of methoxypropyl and content fallnich groups that make up 5-9%, 18-22% 27-35%, respectively, and the molecular weight 78000 Yes, which are sold under the trademark NR from the same supplier.

Examples suitable for use acetylsalicylate hydroxypropylmethylcellulose are, for example, the products marketed under the trademarks of Aqoat LF or Aqoat MF from the company Shin-Etsu Chemical Co. Ltd., Tokyo, Japan.

Modifying the release coating applied to the composition proposed in the invention may contain a pore-forming substance in an amount of 0 to 70 wt.%, more preferably from 5 to 50 wt.% in terms of the total weight of modifying the release coating.

The composition proposed in the invention, may also include a pore-forming substance, for example a substance forming pores by dissolving in water, such as polyethylene glycol, polyvinylpyrrolidone, polyethylene oxide, a derivative of cellulose, such as hydroxyethyl cellulose, hypromellose (HPMC), hydroxypropylcellulose or other derivatives of cellulose, for example, substances that are soluble in KIS the th environment, such as ammonium salt, acrylate or methacrylate esters, such as Eudragit E or Eudragit EPO; polyacrylic acid; substances, swelling in water, such as Eudragit RS, RL, NE 30D, substance, soluble in alkaline medium, i.e. representing intersolubility the polymer used for coating, for example Eudragit L, S, L100-55 or any mixture. GPMC, due to its viscosity in aqueous solution, may also perform the function of the thickener. According to the invention a pore-forming substance can be a hydrophilic agents, such as water-soluble plasticizers, such as PEG, triacetin, triethylcitrate or hydrophilic silica, for example Aerosil 200 or Syloid 244 FP.

Suitable for use according to the invention plasticizers are, for example, triacetin, triethylcitrate, tributyltin, dibutylsebacate, diethylsilane, polyethylene glycol 400, 3000, 4000 or 6000, acetyltributyl, acetyltributyl and diethylphthalate or mixtures thereof. The preferred plasticizer may be triethylcitrate or dibutylsebacate. The plasticizer, as a rule, leads to swelling of part of the coating polymer, which reduces the glass transition temperature of the polymer increases its flexibility and viscosity and changes its permeability. When the plasticizer is the tsya hydrophilic, as, for example, polyethylene glycol, as a rule, the solubility of the coating increases. When the plasticizer is hydrophobic, such as diethylphthalate or dibutylsebacate, as a rule, the solubility of the coating is reduced.

Preferably the plasticizer is present in an amount of 1 to 50 wt.%, preferably from 2 to 35 wt.%, more preferably from 5 to 25 wt.% in terms of the total weight of the coating.

Examples of reducing the stickiness of the substance is silicon dioxide, for example, colloidal silica, synthetic amorphous silicic acid, such as Syloid 244 FP, talc, Aerosil 200 or glycerol monostearate. Preferred reducing stickiness substances are Areosil 200 and Syloid 244 FP. When reducing the stickiness of the substance is hydrophilic, such as Aerosil 200 or Syloid 244 FP, the permeability to water/swelling of the coating (hence, also the release of the drug substance), as a rule, increases. When the plasticizer is hydrophobic, such as talc or glycerol monostearate, the permeability of the coating in water, as a rule, is reduced. Reducing the stickiness of the substance does not necessarily include in the coating composition in order to reduce slidenote cores medicines and ensure good separation.

Preferably reduces the stickiness ve is estvo is present in a quantity comprising from 1 to 50 wt.%, more preferably from 5 to 25 wt.% in terms of the total weight of the coating.

Suitable wetting agents are, for example, sodium lauryl sulfate, cetomacrogol, wax, glycerol monostearate, ester sorbitan, poloxamer. Wetting agents optionally included in the coating composition due to their ability to reduce interfacial tension and to improve the contact sprayable solutions and suspensions with treated surfaces.

Preferably the wetting agent is present in amount of 0.1 to 20 wt.%, more preferably from 1 to 5 wt.% in terms of dry weight of the coating.

In another specific embodiment, the invention proposed floor with slow release, where as substances that improve slip, used silica, anhydrous colloidal/colloidal silicon dioxide, as a plasticizer used triethylcitrate, as a film-forming substance used is a copolymer of ammoniojarosite type And, as other film-forming substance used is a copolymer of ammoniojarosite type B and purified water is used as solvent (C).

With the invention it has been unexpectedly found that for all three variants a, B and bioavailability of aliskiren possible was the support level, almost comparable to the level typical for known solid dosage forms, such as marketed containing aliskiren product or preparative form of a capsule, the bioavailability of which was found in earlier clinical studies, significantly greater than the bioavailability containing aliskiren preparative liquid forms. Thus, with the invention it has been unexpectedly found that new form is proposed in the present invention, provides a higher dissolution rate than the solid form of the medicinal product, it is characterized by a dissolution rate, which is comparable to the rate of dissolution characteristic of liquid preparative forms, but the bioavailability is not getting worse, it is comparable to the bioavailability characteristic of known solid dosage forms, and higher than that of preparative liquid forms.

Solid standard dosage form proposed in the invention and represented in the present description primarily containing aliskiren standard solid dosage form in the form of mini-coated tablets intended for oral administration, has a bioavailability significantly exceeding the biological is dostupnost liquid containing aliskiren preparative forms. In particular, the bioavailability of mini-tablets coated exceeds the biological availability of liquid containing aliskiren preparative forms at least 1.1 times, preferably at least 1.3 times, most preferably at least 1.5 times.

This fact is particularly surprising for standard solid dosage forms corresponding to option a, which has a very quick release of active ingredient after administration, comparable to the release characteristic of liquid preparative forms.

For the preparation of core tablets containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, it is possible to apply a method of wet granulation.

Wet granulation of aliskiren in combination with excipients using water and/or aqueous solution of the binder leads to a change of polymorphism of drug substances, causing it to partially transformed into amorphous state, and reduces chemical stability of the drug product (DP).

However, it was found that the wet granulation of aliskiren using a mixture of organic solvents or organic solution of a binder is the best method of preparing the respective containing aliskiren TBE the development of oral dosage forms, first of all tablets, with the following advantages:

- the specified wet granulation reduces the bulk volume of aliskiren in the granulation process;

- minimized the impact of the resulting change in the quality of the drug substance;

- you can easily achieve a high loading medicines in excess of about 46 wt.% the standard dosage form;

- can be prepared formulation in the form of tablets with sufficient hardness, resistance to raskruchivaniyu, disintegration time, dissolution rate, and so on;

- reduces to a minimum the tendency to caking and improve the fluidity characteristics of the drug substance;

- to provide for sustainable production process DP;

- achieved an increase in scale of production process to ensure reproducible characteristics of the DP; and

- stability is achieved, sufficient to provide the desired retention time.

Excipients may be distributed partially in the internal (granular) phase and partly in the external phase, as in the case of the present invention. Microcrystalline cellulose (filler) and crosspovidone (baking powder) are present partially in the internal phase and partly in the external phase, PVP K 30 (binder) is componentistica internal phase, performing the function of the binder in the granulation process, while colloidal silicon dioxide (a substance that improves the slip) and magnesium stearate (lubricant) are the only components of the external phase.

Present in the internal phase excipients such as filler, binder and baking powder, and drug substance are mixed and granularit together with ethanolic a binder, and an additional portion of ethanol. The granules are dried and sieved. External phase containing, for example, a leavening agent, a filler, a substance that improves the slide, and the sizing, sift together the dried granules and mix. The resulting mixture is pressed to obtain tablets. On kernel optional can be applied film coating.

Granular phase (phase representing granules) is considered as the internal phase is added to the granules excipients regarded as an external phase tablet press mixture.

The invention relates also to a method for preparing a solid oral dosage forms described above in the present description. Such solid oral dosage form can be prepared by processing the above components, taken in appropriate quantities to obtain a standard dosage forms.

Thisway, in the present invention, a method for preparation of solid oral forms of the drug proposed in the present invention, namely, that:

1) mix the active substance and additives and granularit these components together with the liquid for granulation;

2) obtained dried granules, alternating between drying stages with sifting;

3) mixing the dried granules with the excipients constituting the external phase;

4) pressed the mixture to obtain a solid oral dosage forms in the form of a core tablet; and

5) optional coated on the resulting core tablets with obtaining tablets with a film coating.

Preferably in stage (1) an additive selected from a filler, baking powder and binder. and at the stage (3) excipients included in the external phase is selected from a filler, baking powder, sizing and substances that improve the slip.

Liquid for granulation can be an ethanol, a mixture of ethanol and water, a mixture of ethanol, water and isopropanol, or a solution of PVP in the above mixtures. Preferred is a mixture of ethanol and water in a ratio of from about 50/50 to about 99/1 (wt.%), most preferably in a ratio of about 94/6 (wt.%). The preferred mixture of ethanol, water and isopropanol is the tsya mixture in a ratio of from about 45/45/5 to about 98/1/1 (wt.%), most preferably from about 88,5/5,5/6,0 up to about 91,5/4,5/4,0 (wt.%). PVP is preferably present in the above mixtures in a concentration of from about 5 to about 30 wt.%, preferably from about 15 to about 25 wt.%, more preferably from about 16 to about 22 wt.%.

Keep in mind that you can apply numerous known methods of granulation, drying and mixing, known in this field, such as spray granulation in the fluidized bed, wet granulation in a mixer with a high shear effort, melt granulation, drying in a fluidized bed dryer, the mixture in the gravitational smesiteli or in a drum mixer, pressing with reception of tablets using dropwinsonde stamp or rotary tablet press.

Preparation of granules can be performed on standard equipment suitable for the process of granulation of organic products. Preparation of the final mixture and pressing with reception of tablets can also be carried out using standard equipment.

For example, stage (1) can be done using a granulator, high shear effort, for example, the type of demand include Collette Gral; stage (2) can be performed in the fluidized bed dryer; stage (3) can be done using grave is operating mixer (for example, container mixer, drum mixer); and stage (4) can be done by dry pressing, for example, using a rotary tablet press

As described above, then onto the core tablets optional can be applied film coating, resulting in a gain above the tablet with a film coating.

Due to the high hygroscopicity and sensitivity aliskiren to the action of water, the caller changes his polymorphism, preferably should avoid using water to prevent for these reasons, changes polymorphism of drug substances (the transition to the amorphous state, the reduction of the chemical stability). This problem can be solved by applying process of applying a film of an organic coating.

In the claimed invention unexpectedly found that, for containing aliskiren core tablets, you can apply the process of applying a water film coating using standard film coating composition, without causing changes polymorphism.

Film coating may also contain as a polymer HPMC, as dye pigments based on iron oxide, titanium dioxide, as a plasticizer PEG and as antiadhesive talc. Pigments or dyes can the be applied to improve the appearance, and to identify compositions. Other dyes which are generally suitable for use, can serve as carotenoids, chlorophyll and varnishes.

The conditions in which carry out the application of film coatings, must ensure that the core tablets will not absorb significant amounts of moisture, and that the medicinal substance in the tablet will not come into close contact with droplets of water. This is ensured by adjusting the process parameters in such a way as to reduce the amount of moisture falling on the core tablets.

Thus, the production of mini-tablets can be accomplished with the use of pellets, typically used in the manufacture of standard dosage forms, however, it is necessary to take measures to adapt the formulation and manufacturing process.

Mini-tablets are compressed on a standard rotary tablet press equipped with special tooling tooling with multiple heads. Tooling with multiple heads can contain up to 19 heads on one stamp. Such stamps for mini-tablets have a large contact area in the mold compared to a standard tablet stamped. Therefore, the procedures lubrication formulation and/or tooling (for example, lubrication spray) play the most important role in the production process.

While conducting experiments in the development process it was found that the stamp had a lower stiffness, despite the small buoyancy force. To overcome this problem have used different designs of the heads of the stamp and the special Cam on the rotary tablet press. You can also adapt formulation, for example to increase the concentration of sizing.

At the next stage, carry out the alignment of such characteristics of mini-tablets, as the rate of dissolution, the dissolution rate of monocable by modification of release due to application of the film coating.

In a specific embodiment, the present invention proposed three variants, obtained using the same mixture of granules, which are used for preparation of the formulation, marketed under the trademark SPP100, in which the external phase change due to the application of different coatings.

These options are identified as follows:

Option a: pH-sensitive coating Eudragit EPO, the most rapid rate of release of the drug substance (DR)

Option B: the coating consisting of ethyl cellulose+GPMC, average DR

Option b: the coating comprising Eudragit RL/RS, the slowest DR.

In order to overcome mutually of pugable the common challenges, associated large surface area of the mini-tablets and high hygroscopicity of aliskiren, it was necessary to modify conditions of drying in the tub so that to reduce the high water content in the mini-tablet with a film coating. It has become possible to carry out through the use of equipment for coating, providing more suitable conditions for drying, such as a device for coating in the fluidized bed.

As an additional measure, you can also modify the external phase by removing the baking powder, which by its nature is hygroscopic. This is possible because in this case the lack of baking powder can be compensated due to the large surface area characteristic of mini-tablets, which leads to more rapid disintegration even without baking powder. In addition, you can increase the amount of sizing in comparison with the marketed dosage form, as used for the manufacture of mini-tablets tooling with multiple heads has a large area of contact.

Solid oral dosage forms proposed in the present invention can be used in Pediatrics to reduce blood pressure levels in children either systolic or diastolic the definition, or both of them. The conditions for which treatment it is possible to apply the present invention include (but not limited to) hypertension (malignant, primary arterial, renovascular, diabetic, isolated systolic, or hypertension other secondary type), congestive heart failure, angina (stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive disorder (such as Alzheimer's disease) and udar, headache and chronic heart failure.

The present invention relates also to a method of treatment of hypertension (malignant, primary arterial, renovascular, diabetic, isolated systolic, or hypertension other secondary type), congestive heart failure, angina (stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricle hypertrophy, cognitive impairment, such as Alzheimer's, stroke, headache and chronic heart failure, implying that is, bringing children, especially children aged from 0.5 to 17 who are in need of such treatment, a therapeutically effective solid oral dosage form, proposed in this invention.

The present invention relates also to the use of solid oral dosage forms proposed in the present invention, for preparing a medicinal product intended to treat children with hypertension (malignant, primary arterial, renovascular, diabetic, isolated systolic, or hypertension other secondary type), congestive heart failure, angina (stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricle hypertrophy, cognitive impairment, stroke, headache and chronic heart failure.

The present invention relates also to pharmaceutical compositions intended for the treatment of children hypertension (malignant, primary arterial, renovascular, diabetic, isolated systolic, or hypertension other secondary type), congestive heart failure, angina (stable or unstable), myocardial infarction, ATA is osclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricle hypertrophy, cognitive impairment, stroke, headache and chronic heart failure, which is a solid oral dosage form, proposed in this invention.

Final precise dose of the active substance and the specific preparative form intended for administration, must depend on many factors, such as the condition to be treated, the desired duration of treatment and the rate of release of the active substance. For example, the required amount of the active substance and its rate of release can be determined using known methods in vitro or in vivo, based on estimates of how long a particular concentration of the active substance remains in the blood plasma is acceptable to provide a therapeutic action level.

In the above description given a full statement of the invention including preferred variants of its implementation. Modifications and improvements of the embodiments, which are specifically presented in this description, fall under the scope of the following claims. It is understood that the person skilled in the art can the t without undue experimentation to fully implement the present invention. Thus, in the present description, the examples should be considered only as illustrative and in no way limit the present invention.

Examples

Example 1: Preparation of different variants of mini tablets

Prepared three options for pediatric mini-pills (mini-pills, 300 mg, SPP100 (3.125 mg/tablet)) using the same mixture of granules, which are used in marketed formulations form SPP100. Was carried out by modification of the external phase of the core tablets were coated, as a result, were received from the following options:

Option a: pH-sensitive coating comprising Eudragit EPO, the rapid rate of release of drug (DR);

Option B: the coating consisting of ethyl cellulose+GPMC, average DR;

Option b: the coating comprising Eudragit RL/RS, the slowest DR.

Compositions for the above options are presented in tables 1-1, 1-2 and 1-3.

Example 2: a Study on the relative bioavailability (BA)

Conducted a study on the relative BA for evaluation of characteristics of the formulation in the form of options And pediatric mini-pills (mini-pills, 300 mg, SPP100 (3.125 mg/tablet)). The composition of the investigational medicinal product is presented in table 1-1. As the standard of comparison used tablets SPP10, 300 mg, which go on sale in the form of the final intended for implementation (Final Market Image (FMI)).

The evaluation of pharmacokinetic parameters and the taste was conducted with the participation of adult volunteers. The results of these studies, conducted for the variant As presented in tables 2 and 3 and in Fig.1.

Reference example 1: capsules containing aliskiren

Composition [mg] the contents of the capsule (capsule No. 0):

Profumata of aliskiren41,44
EcosimRUB 171.1
Polyplasdone XL26,56
Aerosil 2002,4
Magnesium stearate3,6
Only245,1

The capsule was filled with a dry mixture containing the drug substance and excipients. For a dose of aliskiren, part 75 mg, calculated on the basis of the required two capsules.

Reference example 2: preparative liquid form, containing aliskiren

Medicinal substance in a quantity equivalent to 75 mg of aliskiren in the form of the base (=82,8 mg of profumata) were introduced into a bottle with a capacity of 125ml, without the addition of excipients and then introduced together with 200 ml of tap water, while the drug substance was dissolved in a vial in one part of water, and the remaining water used for washing bottles.

Example 3: Pharmacokinetic characteristics with the introduction of sick children

Held open with multiple dose study of pharmacokinetic and pharmacodynamic characteristics involving 24 patients children aged 6-17 years. For eight consecutive days introduced aliskiren in daily single doses, comprising 2 mg/kg or 6 mg/kg on day 0 and day 8 took blood samples and evaluated the pharmacokinetic characteristics using analysis based on compartmentalism approach.

It was found that the characteristics of the impact of aliskiren for sick children is similar to the characteristics of the effects observed in healthy adults when used in comparable doses. The results are presented in table 5 and Fig.2-13. The average characteristics of the exposure (exposure) of a drug (AUC and Cmaxwhen it is used in a dose of 2 mg/kg and at a dose of 6 mg/kg was similar to the corresponding characteristics observed in healthy adults (Fig.2-5), but they had more variability, which is likely due to the smaller is the size of the sample (children aged 12-17 years: n=19 (the total number of children), n=9 in the group that was administered a dose of 2 mg/kg, and n=10 per group were administered a dose of 6 mg/kg; for children age 6-11 years: n=5 (total number of children), n=3 in the group that was administered a dose of 2 mg/kg, and n=2 in the group that was administered a dose of 6 mg/kg). The median values of Tmax, the average accumulation rate of the medicinal product and the end of time half-life of the medicinal product corresponded to the values characteristic of adults.

In General, the accumulation of drug in patients aged 12-17 years was at the level from low to medium, with average curves exposure obtained at day 8, were comparable with the corresponding curves obtained on day 1. Comparison of average curves exposure obtained at a dose of 6 mg/kg and a dose of 2 mg/kg, revealed a specific increase exposure in response to increasing doses. In the steady state (day 8) in patients aged 12-17 years was observed a 2.5-fold increase in the AUC values and 1.7-fold increase in value Withmaxin response to a threefold increase in the dose. These results are consistent with the pharmacokinetic characteristics of aliskiren observed in adults. The results obtained on patients aged 6-11 years were similar to the results obtained in adults and in children older is atrasta.

Average profiles of the concentration-time in day 1 and day 8, obtained in the group of sick children age 12-17 years who were administered a dose of 2 mg/kg, shown in Fig.6, and in the group of children who were administered a dose of 6 mg/kg, shown in Fig.7.

Average profiles of the concentration-time obtained on day 1 in groups of patients children aged 12-17 years who were administered a dose of 2 mg/kg (n=9) and 6 mg/kg (n=10), shown in Fig.8. Average profiles of the concentration-time obtained on day 1 in groups of patients children aged 12-17 years who were administered a dose of 2 mg/kg (n=9) and 6 mg/kg (n=10), shown in Fig.9.

In Fig.10 presents the average profiles of the concentration-time obtained on day 1 and day 8 in the group of sick children age 6-11 years who were administered a dose of 2 mg/kg (n=3). In Fig.11 presents the average profiles of the concentration-time obtained on day 1 and day 8 in the group of sick children age 6-11 years who were administered a dose of 6 mg/kg (n=3).

In Fig.12 presents the average profiles of the concentration-time obtained on day 1 in groups of sick children age 6-11 years who were administered a dose of 2 mg/kg (n=3) and a dose of 6 mg/kg (n=2). In Fig.13 presents the average profiles of the concentration-time obtained at day 8 in groups of sick children age 6-11 years who were administered a dose of 2 mg/kg (n=3) and a dose of 6 mg/kg (n=2).

Table

The composition containing 3.125 mg SPP100 "mini-pill" with a film coating, where the "mini-pill" has a film coating consisting of a copolymer main methacrylate (option a)
IngredientAmount (mg) of 3.125 mg tablet film-coatedFunction
The core tablets
profumata SPP1003,4531*the active ingredient
cellulose2,613the filler/binder
microcrystalline/microcrystalline cellulosesubstance
crosspovidone0,296baking powder
povidone0,250the filler/binder
ethanol containing 5% isopropanol---**the fluid granulation
ramesam, anhydrous colloidal/colloidal silicon dioxideto 0.060a substance that improves the glide
magnesium stearateto 0.127sizing
The mass of the nucleus tablets6,799
FloorApproximate amount (mg)
magnesium stearate0,09parting agent
basically copolymer butylated methacrylate0,35film-forming substance
dibutylsebacate0,05the plasticizer
nutriceuticals/sodium dodecyl sulfate0,02solubilizers substance
purified water**---**solvent
The total mass of the tablet film-coated7,31
*corresponds to, for example, 3.125 mg SPP100 in the form of base
**removed during processing

Table 1-2
The composition containing 3.125 mg SPP100 "mini-pill" with a film coating, where the "mini-pill" has a film coating consisting of ethyl cellulose and hypromellose (B)
IngredientAmount (mg) of 3.125 mg tablet film-coatedFunction
The core tablets
profumata SPP1003,4531*the active ingredient
microcrystalline cellulose/microcrystalline cellulose2,613the filler/binder
crosspovidone0,296baking powder
povidone0,250 the filler/binder
ethanol containing 5% isopropanol---**the fluid granulation
silica, anhydrous colloidal/colloidal silicon dioxideto 0.060a substance that improves the glide
magnesium stearate0,161sizing
The mass of the nucleus tablets6,833
Floor
dibutylsebacate
Approximate amount (mg)
0,0976
the plasticizer
aqueous dispersion of ethyl cellulose0,208film-forming substance
hypromellose
silica, anhydrous colloidal/colloidal silicon dioxide
0,254
0,040
film-forming substance
a substance that improves the glide
water, purified**... **solvent
The total mass of the tablet p is anonym coating 7,433
* matches 3.125 mg SPP100 in the form of base
** removed during processing

Table 1-3
The composition containing 3.125 mg SPP100 "mini-pill" with a film coating, where the "mini-pill" has a film coating consisting of a copolymer of ammoniojarosite type a and b (C)
IngredientAmount (mg) of 3.125 mg tablet film-coatedFunction
The core tablets
profumata SPP1003,4531*the active ingredient
microcrystalline cellulose/microcrystalline cellulose2,613the filler/binder
crosspovidone0,296baking powder
povidone 0,250the filler/binder
substance
ethanol containing 5%---**the fluid granulation
isopropanol
silica, anhydrous colloidal/colloidal silicon dioxide0,0600a substance that improves the glide
magnesium stearate0,161sizing
The mass of the nucleus tablets6,833
Floorapproximate amount (mg)
silica, anhydrous colloidal/colloidal silicon dioxide0,076a substance that improves the glide
triethylcitrateto 0.060the plasticizer
the copolymer ammoniojarosite type a 0,142film-forming substance
the copolymer ammoniojarosite type0,142film-forming substance
water purified**---**solvent
The total mass of the tablet film-coated7,2531
* matches 3.125 mg SPP100 in the form of base
** removed during processing

Table 2
The average geometric values and coefficients of variation (CV%) Cmaxand AUC SPP for option a
The reference variant of the SPP (N=29)Option a (N=25)
the geometric mean valueCV%the geometric mean valueCV%
Withmax(ng/ml) 1865528944
AUC0-1(ng·h/ml)114940141245
AUC0-inf(ng·h/ml)126240153944

Bioavailability formulation proposed in the present invention, is comparable to the bioavailability marketed tablets containing aliskiren (reference), and preparative forms as capsules, and much more than bioavailability preparative liquid form.

Table 5
Pharmacokinetic characteristics with the introduction of sick children
Age group (age in years)DoseDayWithmax(ng/ml)Tmax+(h) AUCtau(ng·h/ml)AlT1/2 (h)
Average1361,0391----
S. K. O.1133264----
CV%97
2 mg/kg
Average279 1,08462,140
S. K. O.83580,5 3,08041.35,0
CV%128956213
12-17Average4241,81801----
S. K. O.1189of 0.5, 4,0811----
CV % 45
6 mg/kg
Average4862,020891,342
S. K. O.83010,5,3,010030,66,5
CV%62485016
Average 390,5149----
S. K. O.121of 0.5, 0,374----
CV%5349----
2 mg/kg
Average480,52401,54,
S. K. O. 8390,5 1,01830,56,6
CV %81763116
6-11
Average3231,31841----
S. K. O.1551,0, 1,51168----
CV%1763-- --
6 mg/kg
Average2590,89560,536
S. K. O.82740,5, 1,05680.00.7
CV %1065902
* the median value (minimum value, maximum value).

1. Solid standard dosage form intended for oral administration, which is the way the th mini-pill, having a core and outer cover, where
the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, and
the external coating is a coating that contains masking the taste of a material selected from polyacrylate, and/or modifying the release component coating selected from cellulose derivatives and acrylic copolymers, and their mixtures, and
this tablet has a size from 1 mm to 4 mm

2. Solid standard dosage form under item 1, where the specified mini-tablet has a size of 1.5 to 3 mm.

3. Solid standard dosage form under item 1, where the specified mini-tablet has a size of 1.5 to 2.5 mm

4. Solid standard dosage form under item 1, where the specified mini-tablet has a size of 2 mm.

5. Solid standard dosage form under item 1, where the specified mini-tablet contains aliskiren in the amount of about 2 mg/tablet to about 4 mg/tablet.

6. Solid standard dosage form under item 5, where this mini-tablet contains aliskiren in number average of 3.125 mg/tablet.

7. Solid standard dosage form according to any one of paragraphs.1-6, where the polyacrylate is selected from:
(a) a copolymer consisting of monomers selected from methacrylic acid, esters is macrolevel acid, acrylic acid and esters of acrylic acid;
b) a copolymer consisting of monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate; or
b) a copolymer consisting of monomers selected from ethyl acrylate, methyl methacrylate and chloride trimethylammoniumchloride.

8. Solid standard dosage form under item 7, where the polyacrylate is a copolymer consisting of monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate.

9. Solid standard dosage form under item 7, where the film coating contains magnesium stearate, basically copolymer butylated methacrylate, dibutylsebacate and sodium lauryl sulfate.

10. Solid standard dosage form according to any one of paragraphs.1-6, in which the film coating has a pH-dependent release profile.

11. Solid standard dosage form under item 10, in which the film coating provides the dissolution of aliskiren in vitro in the amount of about 30% or less, within 5 min, about 80% or less, within 10 min, and about 95% or less, within 15 min, while the pH value of about 2 to 4.5.

12. Solid standard dosage form under item 11, in which the film coating provides the dissolution of aliskiren in vitro inthe number, approximately 10% or less for 15 min, about 70% or less for 30 min, and about 95% or less within 60 min, while the pH value of about 6 to 7, in particular at pH 6.8.

13. Solid standard dosage form under item 11 or 12, in which the specified film coating contains the basic copolymer butylated methacrylate.

14. Solid standard dosage form according to any one of paragraphs.1-6, in which the specified film coating contains as the film-forming substance to an aqueous dispersion of ethyl cellulose and, optionally, hypromellose.

15. Solid standard dosage form under item 14 in which the film coating contains dibutylsebacate, the aqueous dispersion of ethyl cellulose, hypromellose, and colloidal silicon dioxide.

16. Solid standard dosage form according to any one of paragraphs.1-6, in which the film coating contains a copolymer of ammoniojarosite, in particular a copolymer of ammoniojarosite type a and/or copolymer of ammoniojarosite type Century.

17. Solid standard dosage form under item 16, in which the film coating contains colloidal silicon dioxide, triethylcitrate, a copolymer of ammoniojarosite type a and/or copolymer of ammoniojarosite type Century.

18. Solid standard dosage form under item 1, which is designed for use in Les the drop of a disease or condition in children.

19. Solid oral dosage form under item 1, intended for use in the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is a vaccine, including a peptide, bound to a pharmaceutically acceptable carrier, which is not angiotensin II and has an amino acid sequence of formula (X1)m(X2)n(X3)oX4X5HPX6, where X1 represents G or D, X2 represents A, P, M, G or R; X3 represents G, A, H or V; X4 represents S, A, D or Y; X5 represents A, D, H, S, N or I; X6 represents A, L or F, where m, n and o independently on each other equals 0 or 1 on condition that when o equals 0, both m and n equal 0, and when n equals 0, m equals 0, and where the peptide is not a peptide DRVYIHPF. The application of such a peptide for the vaccine production is also characterised.

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8 cl, 13 dwg, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I: cis-COOR-XCH-(CH2)a-CH=CH-(CH2)b-CH3, wherein (a) and (b) can take any value from 0 to 14, (X) is specified in: OH, NH2, CH3, F, F3C, HS, O-CH3, PO4(CH2-CH3)2 and CH3COO, and (R) represents sodium (Na) applicable for preventing and/or treating obesity, hypertension and/or cancer. Also, the invention refers to using the compounds of formula I for preparing a pharmaceutical and/or nutrient composition, to the pharmaceutical and/or nutrient composition based on the compounds of formula I, to a cosmetic, non-therapeutic method for improving skin manifestations and to a method for preventing and/or treating the diseases in humans and animals with using the compounds of formula I.

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18 cl, 22 dwg, 5 tbl, 9 ex

FIELD: medicine, pharmaceutics.

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32 cl, 111 ex

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SUBSTANCE: invention refers to pharmaceutics, namely to a stable pharmaceutical composition of nanostructured telmisartan for treating hypertension, containing nanostructured telmisartan having an average particle size less than approximately 600 nm, and at least one stabilising agent specified in a group of sodium dodecyl sulphate and polyvinyl pyrrolidone, wherein the composition in prepared in a continuous flow reactor, preferentially in a microfluidics continuous flow reactor, as well as to a method for preparing the composition and using it.

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11 cl, 9 ex, 3 tbl, 14 dwg

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6 cl, 6 dwg, 4 tbl, 8 ex

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11 cl, 2 ex, 1 tbl

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3 ex

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6 dwg, 10 tbl, 3 ex

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16 cl, 10 tbl, 4 ex

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5 tbl, 319 ex

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18 cl, 1 tbl, 27 ex

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3 cl, 4 dwg, 1 ex

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SUBSTANCE: claimed invention is aimed at pharmaceutical compositions and methods of producing such compositions, where compositions include combination of particles with synchronised impulse release (SIR-particles) and particles with fast release (FR-particles). Each SIR-particle includes core, covered with SIR-layer; core includes weakly basic poorly soluble medicinal substance and pharmaceutically acceptable organic acid, which are separated from each other by layer with delayed release. Each FR-particle includes granule, which contains weakly basic poorly soluble medicinal substance, pharmaceutically acceptable binding substance, at least, one auxiliary substance and, at least, one backing powder. As organic acid, fumaric acid is preferably applied. FR-granules are conjoined with SIR-granules in single pharmaceutical formula, for example, in capsule.

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32 cl, 11 dwg, 2 tbl, 8 ex

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EFFECT: therapeutic preparation is storage-stable and complies with the Pharmacopoeia requirements.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology, and concerns solid dosage forms of taurine. The dosage forms are applicable in treating type I and II diabetes mellitus, cardiovascular insufficiency and hepatobilliary systems. The dosage forms of taurine contain pharmaceutically acceptable carriers, excipients and additives differing by the fact that such forms have an external coating; as taurine promotors, they contain potassium chloride and N-vinylpyrrolidone copolymer.

EFFECT: solid dosage forms possess the improved pharmacological properties and improved efficacy in cardiovascular insufficiency, diabetes mellitus and hepatobilliary systems.

5 cl, 6 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a solid oral pharmaceutical formulation containing a hydrolised form of 5-chloro-M-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide in the amount of 1 to 60%. The formulation contains sodium lauryl sulphate as a wetting agent and hydroxypropylmethyl cellulose as a hydrophilic binding agent. The pharmaceutical formulation is presented in the form of a tablet.

EFFECT: formulation according to the invention provides higher biological availability of the active ingredient.

17 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing a medicinal agent containing vardenafil hydrochloride trihydrate in the solid form wherein vardenafil hydrochloride trihydrate is treated with suitable pharmaceutical additives at temperature from approximately 20°C to approximately 45°C. The ambient relative humidity of the procedure makes 30% to 90%. The treated medicinal agent is film-coated at temperature within the range from 40°C to 55°C.

EFFECT: method according to the invention provide the additional stage of repeated hydration for the purpose of preparing the trihydrate form of vardenafil hydrochloride.

20 cl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: per oral pharmaceutical drug form, in composition of which included are at least two medical substances in from of separately preliminarily formed pills. In claimed form medicinal substances from one side are together in hermetically in vivo water-soluble wrapping or coating, and from the other side are separated in such a way, that active agents of combined medicinal substances cannot contact with each other. At least one of medications is selected from the following groups of therapeutic medications: non-steroidal anti-inflammatory preparation (NAIP), inhibitor of proton pump (IPP), beta-blocker, statin, conversion enzyme inhibitor (CEI), biguanide, neuromuscular blocking agent, calcium inhibitor, corticoid, antidepressant, benzodiazepine, inhibitor of intestinal transit of non-atropine-like action, intestinal antibacterial medication, and following therapeutic molecules: spironolactone, propranolol, clarithromycin, amoxicillin, low dose acetylsalicylic acid, potassium, clopidogrel.

EFFECT: pharmaceutical drug form by invention ensures patient with one drug form for several medicinal preparations, which makes it possible to avoid separate introduction of medicinal preparations.

21 cl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention characterises a method for preparing coated tablets by immersing a core containing an active substance into a liquid coating and drying the above coated core to form an outer coating layer on the core. The liquid coating contains at least one type of starch containing amylose making at least approximately 50 wt % of said starch. Preferentially, used starch represents pea starch. The liquid coating for the outer layer may additionally contain at least one type of natural gum and one plasticising agent. What is also described is a coated tablet prepared by the above method.

EFFECT: use of the high-amylose starch compositions containing at least 50 wt % of amylose for coating the tablets and capsules by immersion provides an average glance of approximately 325 that is specific for the gelatine-coated dosage forms, with no disadvantages and limitations specific for gelatine.

20 cl, 3 tbl, 11 ex

FIELD: medicine, pharmaceutics.

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EFFECT: invention provides reducing serious side-effects associated with the administration of bupropion.

9 cl, 54 dwg, 42 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions based on botulinum toxin and is intended for diagnostic or therapeutic introduction to a subject. A lyophilised or dried in vacuum composition contains botulinum toxin, stabilised with a non-protein excipient; a compound, selected from the group, consisting of the first monosaccharide, the first disaccharide, the first trisaccharide and the first alcohol, obtained by the reduction of the first monosaccharide; and a compound, selected from the group, consisting of the second monosaccharide, the second disaccharide, the second trisaccharide, the second alcohol and amino acid. In the other aspect the pharmaceutical composition contains botulinum toxin, stabilised with the non-protein excipient; polyethyleneglycol and a compound, selected from the group, consisting of monosaccharide, disaccharide, trisaccharide and amino acid. The pharmaceutical composition can contain botulinum toxin, stabilised with the non-protein excipient, polyvinylpyrrolidone; and disaccharide. The pharmaceutical composition of botulinum toxin, which does not contain an animal protein, includes botulinum toxin; a compound, selected from the group, consisting of the first monosaccharide, the first disaccharide, the first trisaccharide and amino acid.

EFFECT: application of the group of inventions provides the stable pharmaceutical composition for diagnostic or therapeutic introduction to a subject.

6 cl, 8 tbl, 5 ex

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