Pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns valsartan pill obtained by pressing. A pill contains pharmacologically effective valsartan quantity, filler and fluffer. Weight ratio of valsartan to filler is 2:1 to 0.3:1. Weight ratio of valsartan to fluffer is 2.9:1 to 1:1. The pill includes over 30 mass % of filler. Preferable filler is monocrystallic cellulose. Preferable fluffer is crospovidone. The claimed pill has at least 1.2 times higher biological accessibility in comparison to the known valsartan-containing composition.

EFFECT: increased biological accessibility of valsartan-containing composition.

9 cl, 2 dwg, 4 tbl, 8 ex

 

The invention relates to an oral solid dosage forms containing valsartan.

It is known that valsartan representing receptor antagonist of angiotensin II, is an effective medicine for the treatment of congestive heart failure and reduce blood pressure in patients regardless of their age, gender or race, and also has good tolerability. The combination of valsartan and HCTZ (hydrochlorothiazide) is used for the treatment of hypertension.

In WO 97/49394, the contents of which are incorporated into this description by reference, as the object of the invention (but not limited to the described solid oral dosage forms, obtained, for example, by pressing valsartan, optionally in salt form, optionally in combination with hydrochlorthiazide (HCTZ).

With the invention it has been unexpectedly found that it is possible to prepare solid compositions (below in the present description called "compositions according to the invention)containing valsartan or its pharmaceutically acceptable salt or hydrate (below in the present description called "active ingredient")with higher characteristics bioavailability in comparison with the known composition containing valsartan.

One of the objects of the present invention is the tsya oral solid pharmaceutical composition, for example, in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which has on average at least 1.2 times, for example, 1.2 to 3 times, for example, 1.3-2 times, for example, 1.7 times higher bioavailability than containing valsartan capsule, for example, capsule, marketed under the trademark Diovan®for example, containing 20, 40, 80 or 160 mg of valsartan, or any the corresponding capsule containing the standard dose of 1 to 500 mg of valsartan.

Another object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which has on average at least 1.5 times, for example, up to 3 times, for example, 2.5 times higher bioavailability than containing valsartan capsule, for example a capsule, marketed under the trademark Diovan®for example, containing 20, 40, 80 or 160 mg of valsartan, or any the corresponding capsule containing a standard dose of 1-500 mg of valsartan, which is set when the study is assured bioavailability to humans with the introduction of a single dose of 40 mg

The present invention relates to an oral solid pharmaceutical composition, e.g. in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which has on average at least 1.2 times, for example, up to 2 times, for example, 1.5 times higher bioavailability than containing valsartan capsule, for example, capsule, marketed under the trademark Diovan®for example, containing 20, 40, 80 or 160 mg of valsartan, or any corresponding capsule containing a standard dose of 1-500 mg of valsartan, which is installed in the study of bioavailability for humans with the introduction of a single dose of 320 mg

The next object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which is characterized by an AUC value greater than 4.5 mg/l, for example, up to 8 mg/l, for example, 6 mg/l under the same conditions under which the capsule containing 40 mg of active substance, characterized by the value of the AUC, sostavlyajushie,9 mg/L. If not specified, the value of AUC is determined by the least squares method.

Another object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which is characterized by an AUC value of more than 30 mg/l, for example, up to 40 mg/l, for example, 35 mg/l under the same conditions in which the capsule contains 320 mg of the active substance, characterized by the value of the AUC, part of 29.4 mg/L.

The next object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing a pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which is characterized by a value Cmax of at least about 0,77 mg/l, for example, up to 3.5 mg/l, for example, 1.3 mg/l, which is installed in the study of bioavailability for humans with the introduction of a single dose of 40 mg

Another object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets, the content is based on pharmacologically effective amount of valsartan, or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, which is characterized by the value of Cmax is at least approximately of 4.75 mg/l, for example, up to 15 mg/l, for example, 6 mg/l, which is installed in the study of bioavailability for humans with the introduction of a single dose of 320 mg

The standard dose of the composition according to the invention can contain 1-500 mg, for example, 2-400 mg, for example 5 are 300 mg, for example, 10-200 mg, for example, 20 to 200 mg, for example, 30-100 mg of active substance. Examples are dose containing 10, 20, 40, 80, 160 or 320 mg of the active substance.

Among other benefits, increased bioavailability allows you to prepare oral solid dosage form containing a low dose of the active substance, which are better tolerated by patients. Another object of the present invention are oral solid pharmaceutical composition, e.g. in the form of tablets containing as active substance less than 20 mg, for example, 1-15 mg, such as 1, 5 or 10 mg, or any other intermediate dose of valsartan or pharmaceutically acceptable salt or hydrate. For a given amount of active ingredient specified oral solid dosage forms, e.g. tablets, can have a smaller size than any known composition containing this active substance.

It should be noted that example 2 does not belong to the first group, the composition is. It should also be borne in mind that the example 3 does not belong to the second group of songs.

Another object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing valsartan or its pharmaceutically acceptable salt or hydrate and containing from 10 to 80%, for example, from 20 to 80%, for example, from 25 to 75%, for example, from 30 to 70%, for example, from 35 to 65%, for example, from 40 to 60%, for example, 50% of baking powder, calculated on the total weight of the composition.

The next object of the present invention is an oral solid pharmaceutical composition, e.g. in the form of tablets containing valsartan or its pharmaceutically acceptable salt or hydrate and include the baking powder in a mass ratio of from 10:1 to 0.5:1, for example, a 9.5:1, for example, 8:1, for example from 5:1 to 0.5:1, for example from 5:1 to 1:1, for example, from 2.9:1 to 1:1, for example, from 2.5 to 1:1, for example, from 2 to 1:1, for example, 1.5:1.

In a preferred embodiment, the compositions of the present invention contain more than 30% of filler, for example, microcrystalline cellulose, calculated on the total weight of engine components specified oral solid dosage forms, for example, contain from 31 to 65%, for example, from 40 to 60%, for example, 50%.

Preferably the compositions according to the invention the active substance and the filler are present in a mass ratio of the drop from 4:1 to 0.3:1, for example, from 3:1 to 0.3:1, for example, from 2.5:1 to 0.5:1, for example, from 2:1 to 1:1, for example, 1,4:1.

The composition of the invention can be in the form of tablets, for example, compressed tablets, which can be produced using the following method.

The composition of the invention contain additives which are usually used in the manufacture of the considered dosage forms. You can apply to facilitate tableting excipients commonly used in the manufacture of tablets, it can be noted that there is an extensive literature devoted to this issue, see, first of all, the reference Fiedler "Lexikon der Hilfsstoffe", 4th ed., ECV Aulendorf, 1996, is hereby incorporated into this description by reference. They include (but are not limited to) disintegrating agents, binders, sizing, substances that improve slip, stabilizers, fillers or diluents, surfactants, etc.

As leavening agents that can be used in the compositions of the present invention, is particularly noteworthy

carboxymethylcellulose calcium (CMC-CA)

carboxymethylcellulose sodium (CMC-Na, crosscarmellose sodium), marketed, e.g. under the trademark Ac-Di-Sol®, Primellose®, Pharmacel® XL, Explocel® and Nymcel® ZSX, for example, having a molecular weight of 90000 - 700000,

- custom made watering nipernaadi (PVP), for example crospovidone, such as Polyplasdone® XL and Kollidon® CL, first of all, having a molecular weight of more than 1,000,000, more preferably having a distribution of particle sizes less than 400 μm, or less than 74 microns,

- alginic acid, sodium alginate and guar gum.

Preferably the baking powder may be a crosslinked PVP, crosspovidone, crosslinked CMC and Ac-Di-Sol®. The preferred baking powder is crosspovidone.

As the binders that can be used in the compositions of the present invention, is particularly noteworthy

- starches such as potato starch, wheat starch, corn starch,

- cellulose, such as microcrystalline cellulose, for example, the products sold under the registered trade marks Avicel®, Filtrak®, Heweten® or Pharmacel®, hydroxypropylcellulose, hydroxyethyl cellulose and hypromellose, such as hydroxypropylcellulose having content hydroxypropionic links from 5 to 16 wt.% and a molecular weight of from 80,000 to 1150000, more preferably from 140,000 to 850000.

As substances that enhance a slide that can be used in the compositions of the present invention, is particularly noteworthy

- colloidal silicon dioxide, for example, Aerosil®,

- magnesium trisilicate,

powdered cellulose,

- starch,

- talc and

- rejonowy calcium phosphate.

As fillers or diluents, which can be used according to the invention, can be mentioned

- confectionery sugar, compressible sugar, dextrine, dextrin, dextrose, lactose, mannitol, sorbitol, sucrose

- microcrystalline cellulose, primarily having a density of about 0.45 g/cm, for example, Avicel®or powdered cellulose and

- talc.

The preferred filler is Avicel®.

As oiling agents that can be used in the compositions of the present invention, is particularly noteworthy

- stearate of magnesium, aluminum or calcium,

- polyethylene glycol (PEG)having a molecular weight of from 4000 to 8000 and

- talc.

Specialist in this field on the basis of standard experiments without excessive costs can select one or more of these additives with specific desired properties of oral solid dosage forms.

The amount of additives used for each type, for example, substances that improve slip, binders, baking powder, filler or diluent and sizing may vary in the normal field of technology. For example, the number of substances that improve the slip can vary from 0.1 to 10 wt.%, first of all from 0,to 5 wt.%, for example, from 0.1 to 0.5 wt.%; the amount of binder may vary from about 10 to 65.3 wt.%, for example, from 10 to 45 wt.%, for example, from 20 to 30 wt.%; the amount of baking powder can vary from 5 to 60 wt.%, for example, from 13 to 50 wt.%, for example, from 15 to 40 wt.%, for example, from 20 to 30 wt.%, for example, can be up to 25 wt.%; the amount of filler or diluent can vary from 15 to 65 wt.%, for example, from 20 to 50 wt.%, for example, from 25 to 40 wt.%, for example, it may be 30 wt.%, while the number of sizing can vary from 0.1 to 5.0 wt.%.

A characteristic feature of oral solid dosage forms of the present invention, for example tablets, is that they contain only a relatively small amount of additives for this high content of active substance. This allows you to prepare a standard dosage form having a small size. The total amount of additives in concrete standard dosage form can be about 65 wt.% or less, calculated on the total weight of the oral solid dosage form, more specifically about 50 wt.% or less. Preferably the content of the additives is from about 35 to 55 wt.%, more preferably 45 to 55 wt.%, for example, from 38 to 43 wt.%.

The absolute number of each of the additives and the correlation with other additives also depend on the desired properties of oral solid dosage forms, and the person skilled in the art can also choose them on the basis of standard experiments without excessive costs. For example, you can choose oral solid dosage form, characterized by rapid and/or slow release of the active substance, which allows quantitative monitoring of release of the active substance, or without such control.

So, if you want to ensure rapid release of the active substance, for example the release of approximately 90% within ten minutes, more preferably within five minutes, apply the powder, such as cross-linked polyvinylpyrrolidone, for example the products known under the trademarks Polyplasdone®XL or Kollidon®CL, especially having a molecular weight of more than 1,000,000, more preferably having a particle size of less than 400 microns, or less than 74 microns, or reactive additives (powder mixture), which cause rapid decomposition of the tablet in the presence of water, for example so-called effervescent tablets that contain acid, in solid form, typically citric acid, in which the water interacts with the base containing chemically bound carbon dioxide, for example, bicarbonate or sodium carbonate, and releases carbon dioxide.

The pharmacy is practical composition of the present invention can be applied for known indications, when used contained a specific active substance, including lowering blood pressure, both systolic and diastolic, or both. The condition in which it is possible to apply compositions of the present invention, include (not limited to) hypertension (malignant, essential, renovascular, diabetic, isolated systolic, or other symptomatic type), congestive heart failure, angina (stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, impaired cognitive ability (such as Alzheimer's disease) and "blow".

The exact dose of the active substance and the specific composition to be introduction, depend on many factors, for example, the condition to be treated, the desired duration of treatment, and the speed of release of the active substance. For example, the required amount of the active substance and its rate of release can be installed using known methods in vitro or in vivo, allowing us to determine how long a specific concentration of the active substance remains in the blood plasma at a level sufficient the La provide therapeutic action.

For example, in clinical experiments, it was found that the composition according to the invention have a higher bioavailability than the marketed drug Diovan®.

Preferably the rate of release of active substance from the composition according to the invention is more than 70% for 10 min, more than 80%, such as 90%, for 30 minutes, and more than 95% in 45 min, for example, at pH 4-7,2, for example, at pH 4.5 to 7, for example, at pH 6.8.

For a mammal, for example a person weighing 75 kg, as well as in standard tests using animals as models that can be applied dose of valsartan from 1 to 400 mg In standard animal experiments and in clinical experiments was demonstrated good tolerability of valsartan entered into the composition of these songs.

Another object of the invention is the method of administration of valsartan to a patient in need of treatment with valsartan, providing for the introduction to the patient the composition according to the invention.

The next object of the invention is the use of valsartan as an active substance for the preparation of any of the above compositions.

One of the objects of the invention is a method for preparing an oral solid dosage form, such as described above tablets. Such oral solid dosage form can sentence afliate by processing components according to the method described in WO 97/49394 (incorporated in the present description by reference), for example, taken in the respective above quantities, receiving standard dosing form.

As an example, below is the process of making the above-described composition according to the invention, providing for the implementation of the following stages:

I) grinding the active substance and pharmaceutically acceptable additives,

(II) compacting a mixture of powdered active substance and additives with obtaining comprimate (karimata) (compacted mass),

(III) transformation of comprimate (karimata) in granular form and

IV) compressing the granules with receiving oral solid dosage forms.

The process is carried out in the absence of water, i.e. use a dry pressing method. The process can be done at the temperature and humidity of the environment; to implement the process is not necessary that it goes in dry atmosphere.

The first stage of grinding I) can be accomplished using standard methods of grinding or fine grinding.

The active substance and additives you can grind either individually or together to obtain particles with a size of from about 0.1 micrometer (μm) to about 1500 microns, for example, from 1.0 to 900 μm, for example, from 60 to 600 μm. In these ranges must nah shall be the size of at least 90% of the crystals as the active substance, and additives. Particles of this size can be obtained by standard methods, for example, by milling in vostokstrojj mill with sieve hammer mill, impact mill, fine grinding, ball mill or vibrating mill.

Fine grinding is preferably carried out using known methods using an ultrasonic disintegrator, for example, the type of BRANSON Sonifier, or by stirring the suspension using high-speed stirrers, stirrers type HOMOREX.

At this stage, the crushed particles are optional, you can sift and mix according to known methods.

Pressing with obtaining comprimate (karimata) is the seal of dry powdered components. Sealing can be accomplished using the method of the piston seal or preferably compaction by rolling. Device for compacting by rolling is widespread and consists of two rolls rotating towards each other. Hydraulic piston presses one of the rolls to the other, providing a sealing action on the crushed particles that come in a roller compactor with the worm gear.

You can apply a sealing force from 25 to 65 kN, for example, from 25 to 45 kN. With the invention it has been unexpectedly found that DL is a particular composition within the specified range sealing forces should use the minimum sealing force to obtain oral solid dosage forms, which pellets break down into primary particles at a given speed, for example, oral solid dosage forms are compressed under the action of the minimum sealing force, the disintegration of which is approximately six times faster. Such a high rate of disintegration is unusual for tablets and it is close to the speed of disintegration of the composition in the form of capsules. The specific value of the minimum sealing force depends on the content of active substance in any of the considered composition and therefore also depends on the number and nature of the present additives.

With this information, the person skilled in the art using standard experiments and without excessive costs can easily determine the minimum sealing force for the other compositions.

The speed of rotation of the rolls can be set in the range from 1 to about 20./min, preferably from 9 to about 15./minutes After passing through the rolls densified mass (Kompromat (copymat)) looks like a thin segmentierung tape.

Kompromat (copymat) can sift or grind, getting granules. Screening in its most simple form represents the transmittance of comprimate (karimata)received after passing through the rolls, through a sieve under mechanical pressure. In a more preferred in which the version of Kompromat (copymat) sieved using oscillating or rotary mill, for example, type MGI 624 Frewitt (firm Key International Inc.).

Compressing the granules to obtain core tablets can be accomplished using conventional teletrauma machine, for example eccentric teletrauma machine type EC-0 Korsch or rotary pressing machine, for example, when pressing force greater than 2 kN. Core tablets may have a different shape, for example, they can be round, oval, oblong, cylindrical or may have any other suitable shape, however, they can vary in size depending on the concentration of therapeutic agents. A characteristic feature of the tablets according to the invention is that they are small, given the number contained in the active substance.

In a preferred variant of the invention, the tablets obtained by the method described above pressing, have a slightly rounded shape in transverse and/or longitudinal section. The edges of the tablets can be beveled or rounded.

In the most preferred embodiment of the invention the oral solid dosage form is a compressed tablet oblong shape having a ratio of length: width: height, for example, comprising 2,5-5,0: 0,9-2,0: 1,0, for example, 2,86-3,16: 1,1-1,3: 1,0, for example, has dimensions of 14.0-14.2 mm: 5.5 to 5.7 mm: 4.5-4.9 mm, which preferably ve is HREA and the bottom surface of the tablet independently from each other can be flat or convex curved relative to the longitudinal axis; the side surfaces are flat, the end surface may have any shape, and the edges can be beveled or rounded.

According to especially preferred variant of the invention, the oral solid dosage form prepared by compressing granules with obtaining tablets containing, for example, from 40 to 80 mg of valsartan, which has an almost disc shape with a slightly convex upper and lower surfaces. Preferably, the tablet has a diameter of about 6-6,5 mm and a height of approximately 2.5-3.5 mm, or a diameter of approximately 8-8 .5 mm and a height of approximately 3-4 mm

According to another particularly preferred variant of the invention, the oral solid dosage form prepared by compressing granules with obtaining tablets containing, for example, 160 mg of valsartan, an oblong shape, which has a length of approximately 10.0-15.0 mm, a width of approximately 5.0 to 6.0 mm and a height of approximately 3-6 mm, for example, 3,0-4,0 mm

According to another particularly preferred variant of the invention, the oral solid dosage form prepared by compressing granules with obtaining tablets containing, for example, 80, 160 or 320 mg of valsartan, almond-shaped, which has a length of approximately 9-11 mm, maximum ø the doctrine of approximately 5-6,5 mm and a height of approximately 3-4 mm, or which has a length of approximately 12-14 mm, the maximum width of approximately 7-8 mm and a height of about 4-5 mm, or which has a length of approximately 15-17 mm, the maximum width of approximately 9-10 mm and a height of approximately 5-6,5 mm.

According to the following particularly preferred variant of the invention, the oral solid dosage form prepared by compressing granules with a receipt containing, for example, 160 mg valsartan tablets are almond-shaped, which has a length of approximately 15-17 mm, the maximum width of approximately 9-10 mm and a height of approximately 5-7 mm

According to another preferred variant of the invention, the tablet has an almost disc shape, with upper and lower surfaces are slightly convex. Preferably, the tablet has a diameter of approximately 8-8 .5 mm and a height of approximately 3-3 .5 mm, or a diameter of approximately 16 mm and a height of approximately 6 mm Volume pills can range from approximately 0.1 to approximately 1 cm, for example, from 0.1 to about 0.45 cm, for example, from 0.2 to 0.3 cm, for example, approximately 0.125 or 0.25, see

In addition, tablets may be transparent, colorless or colored and can have a label that gives the product an individual appearance and allows it races Osnat. To improve appearance, and to identify the composition can be applied dyes. Typical dyes used in the pharmaceutical industry, are carotenoids, iron oxides or chlorophyll.

Presented below are the compositions according to the invention are given only for illustrative purposes.

Examples 1-4:

1234
ComponentsComposition on a standard dosage form (mg)Composition on a standard dosage form(mg)Composition on a standard dosage form (mg)Composition on a standard dosage form(mg)
Granulation
drug, diovan20,040,080,0320,0
drug hydrochlorothiazide--
microcrystalline cellulose (national pharmaceutical formulary (NF), European Pharmacopoeia (Ph.Eur.))/ Avicel PH 10262,0124,054,0216,0
crosspovidone (NF, Ph.Eur.)10,020,0 20,080,0
colloidal anhydrous silica (Ph. EIG.)/colloidal silicon dioxide (NF)/Aerosil 2000,51,00,753,0
start magnesium (NF, Ph.Eur.)1,02,02,510,0
Mixing
colloidal anhydrous silica (Ph. Eur.)/colloidal silicon dioxide (NF)/Aerosil 2000,51,00,753,0
magnesium stearate, NF, Ph.Eur.1,02,02,08,0
Weight kernel /mass party95,0/47,5 kg190,0/47,5 kg160,0/48,0 kg640,0/73,5 kg

Example 5:

Table 1.

(see figure 1) Generalizing the analysis of mean-square values of pharmacokinetic parameters of valsartan (for all patients completed the full cycle of studies to which the results of both types of processing parameters, measurable)
Tablet weight of 40 mg (treatment A) RMSand(N)Capsule weighing 40 mg (processing is mean square) value of and(N)Attitude

RMSb
90%confidence interval for ratio of RMS valuesc
AUCall6,732 (60)3,922 (60)1,72(1,49, 1,97)
AUCinf6,859 (60)4,037 (60)1,70(1,48, 1,95)
Cmax1,245 (60)0,681 (60)1,83(1,57, 2,13)
N denotes the number of experiments, including experiments with repeated dosing.

andThe RMS values are expressed in the original (antilogarithmic) scale.

bThe ratio of the RMS values in the original scale are presented in the form of the antilogarithm of the difference between the RMS in logarithmic scale.

cConfidence interval relations data obtained for tablets and capsules, in the original scale will get antilogarithms confidence limits of the difference between the RMS values of the results of different treatments in logarithmic scale.

Features marketed capsules containing 40 mg Diovan®:

Inner phase: valsartan 40,0 mg; microcrystalline cellulose/Avicel PH 102: 12,55 mg; polyvinylpyrrolidone K: 6,25 is g; sodium lauryl sulfate: 0.3 mg;

External phase: crosspovidone: 6,5 mg; magnesium stearate: 0.65 mg

Total weight: 66,25 mg; capsule size: 3

Example 6:

Table 2.

(see figure 2) Generalizing the analysis of mean-square values of pharmacokinetic parameters of valsartan (for all patients completed the full cycle of studies to which the results of both types of processing parameters, measurable)
Tablet weight of 320 mg (treatment A) RMSa(N)Two capsules 160 mg (treatment C) RMSa(N)The ratio of the RMS valuesb90%confidence interval for ratio of RMS valuesc
AUCall36,53 (60)29,39 (60)1,24(1,14, 1,35)
AUCinf37,32 (60)30,17 (60)1,24(1,14, 1,35)
Cmax6,23 (60)4,88 (60)1,28(1,15, 1,41)
N denotes the number of experiments, including experiments with repeated dosing.

aThe RMS values are expressed in the original (antilogia the economic) scale.

bThe ratio of the RMS values in the original scale are presented in the form of the antilogarithm of the difference between the RMS in logarithmic scale.

cConfidence interval relations data obtained for tablets and capsules, in the original scale will get antilogarithms confidence limits of the difference between the RMS values of the results of different treatments in logarithmic scale.

Characteristics of the marketed capsule contains 160 mg Diovan®:

Inner phase: valsartan 160,0 mg; microcrystalline cellulose/Avicel PH 102: 50.2 mg; polyvinylpyrrolidone K: 125,0 mg; sodium lauryl sulfate: 1.2 mg;

External phase: crosspovidone: 26,0 mg; magnesium stearate: 2.6 mg

Total weight: 265,0 mg; capsule size: 1

Example 7:

The geometric mean
Table 3.

Pharmacokinetic parameters of the composition in the form of tablets containing 40 mg of active ingredient, and the composition in the form of capsules containing 40 mg of active substance (marketed)
TrackStatistical dataTmax(h)Cmax(mg/l)AUClast(h·mg/l)AUCall(h·mg/l)AUC0-8(h·mg/l)
TabletN1)=61
Average2,321,4257,5147,7197,836
SKO0,750,5782,9602.9923,024
The minimum value1,500,1520,8060.9221,104
Average2,001.2847,1317,3467,502
The maximum value4,033,36315,63715,89316,192
CV%32,240,539,438,838,6
The geometric meanof 2.211,3016,8617,0737,202
The upper limit of the 95%confidence interval2,12amounted to -1,2776,7566,9527,062
Track Tmax(h)Cmax(mg/l)AUClast(h·mg/l)AUCall(h·mg/l)AUC0-8(h·mg/l)
The lower limit of the 95%confidence intervalof 2.511,5738,2728,4858,611
CapsuleN=60
Average3,320,7604,1904,3474,461
SKO0,990,3862,1322,1902,227
The minimum value1,500,0720,4720.4720,472
Average4,00of 0.7414,0764,2444,351
The maximum value6,031,8639,78510,01810,140
CV%29,850,850,950,4to 49.9
3,170,6533,5883,7333,843
The lower limit of the 95%confidence intervalof 3.070,6603,6393,7813,885
The upper limit of the 95%confidence intervalto 3.580,8604,7414,9135,036

Example 8:

Table 4.

Comparison of pharmacokinetic parameters of the composition in the form of tablets containing 320 mg of the active substance, and two capsules containing 160 mg of the active substance (marketed)
TrackStatistical dataTmax(h)Cmax(mg/l)AUClast(h·mg/l)AUCall (h·mg/l)AUC0-8(h·mg/l)
TabletN=60
Average2,866,50937,7738,2439,18
SKO 0,922,673the 14.9014,8615,29
The minimum value1,002,4115,0815,0816,21
Average3,006,0735,6535,6537,32
The maximum value4,1714,0983,8883,8886,84
CV%32,341,139,438,939,0
The geometric mean2,706,03235,1035,6036,45
The lower limit of the 95%confidence interval2,625,81933,93of 34.4035,22
The upper limit of the 95%confidence interval3,107,20041,6242,0843,13
CapsuleN=60
Average 3,285,53432,2932,7433,51
SKO0,992,54514,0914,0514,20
The minimum value1,002,0511,2911,5911,73
Average3,014,7329,4530,0530,9
The maximum value6,0011,8173,8173,8175,26
CV%30,346,043,642,942,4
The geometric mean3,124,99829,48of 29.9830,72
The lower limit of the 95%confidence interval3,024,87628,6529,1129,84
The upper limit of the 95%confidence interval3,546,19135,9336,3737,18

1. Compressed tablet containing farmacologiche the key effective amount of valsartan, filling and baking powder in which valsartan and filler are present in a weight ratio of from 2:1 to 0.3:1, and valsartan and baking powder are present in a weight ratio of 2.9:1 to 1:1.

2. The tablet according to claim 1, which contains more than 30 wt.% filler, calculated on the total weight of the components of the tablets.

3. The tablet according to claims 1 or 2, which contains from 31 to 65 wt.% filler, calculated on the total weight of the components of the tablets.

4. The tablet according to one of claims 1 to 3, in which the filler is microcrystalline cellulose.

5. The tablet according to claim 1, in which the powder is chosen from the group comprising calcixerollic (CMC-CA), sodium carboxymethyl cellulose (CMC-Na, nitrocresols) with molecular weight 90000-700000; Poperechnaya polyvinylpyrrolidone (PVP), alginic acid, sodium alginate and guar gum.

6. The tablet according to claim 5, in which the powder is chosen from the group comprising Poperechnaya PVP, crosspovidone and Poperechnaya CMC.

7. The tablet according to any one of claim 5 or 6, in which the baking powder is crosspovidone.

8. The tablet according to any one of claims 1 to 7, which includes a single dose of valsartan in number from 2 to 400 mg

9. The tablet according to any one of claims 1 to 8, optionally containing excipient selected from the group consisting of binders, slip agent and lubricant.



 

Same patents:

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention proposes a lipid compound with formula (I): , where PHG is a polar head group, obtained from one of the following: phospholipid, lysophospholipid, ceramides, monoacylglycerine, diacylglycerine and triacylglycerine, or -W-Linker-HG, p is a number from 1 to 3, X is independently chosen from C6-24alkenyl, containing one or more double bonds and, possibly, one or more triple bonds, or C6-24alkyl, which are can be substituted with at least one of the following: F, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C2-C5acyloxy and C1-C4alkyl; Y chosen from at least one of S, Se, SO2, SO, O and CH2; and Z is a C1-C10alkyl residue, where each of the X, Y and Z groups is chosen independently, when p is 2 or 3, under the condition that, at least one Y does not represent CH2. Description is also given of the use of formula (I) compound or its pharmaceutical salt in the production of medicinal preparations for curing and/prevention of different conditions, pharmaceutical composition, containing formula (I) compound and the method of obtaining a lipid compound with formula (I).

EFFECT: obtaining sulphur containing phospholipid compounds, with useful biological properties.

58 cl, 8 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to processing of reindeer products, specifically to method of biologically active product making of antler reindeer tails. Method implies that raw material is milled to make particles 150-400 mcm, extracted with followed filtration of end product, at that distilled water is used as extracting agent; extraction is performed at temperature 120-126°C during 1.5-2.5 hours at ratio water - raw material 5:1-6:1.

EFFECT: production of aqueous extract having high biological activity and applicable for patients with contraindication to alcohol-containing medicinal agents.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry pharmacy.

SUBSTANCE: invention relates to using the known 2-phenyl-substituted imidazotriazinone of the formula (I): (vardenafil) possessing improved properties as compared with other known inhibitors of phosphodiesterase-5 (PDE-5), such as sildenafil and tadalafil. Proposed compound is used for preparing drugs used in treatment of cardiac insufficiency.

EFFECT: valuable medicinal and biochemical properties of compound.

1 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4]pyrazole dihydrochloride of the formula (I): . This compound is synthesized by interaction of 1-(2-piperazinoethyl)-5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-3-pyrrolin-2-one dihydrochloride with hydrazine hydrate. Synthesized compound can be used in medicine as agent decreasing arterial blood pressure and blood coagulation. Invention provides synthesis of a novel compound not described early that possesses hypotensive and anti-coagulant effect simultaneously.

EFFECT: valuable medicinal properties of compound.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions containing inhibitor of cholesterol esters-transporting protein (CETP) and a water-insoluble additive increasing its concentration. As CETP inhibitor invention uses S-{2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl}-2-methylpropanethioate or a prodrug that forms in vivo S-{2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl}-thiol. A water-insoluble additive increasing the concentration of CETP inhibitor represents crospovidon. Indicated compositions show improved bioavailability in medium wherein they are used that allows using in methods for treatment of cardiovascular disorders.

EFFECT: improved and valuable pharmaceutical properties of compositions.

13 cl, 11 tbl, 5 dwg, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a hypotensive medicinal agent as tablet that comprises captopril, mixture of lactose of particles size above 0.2 mm and microcrystalline cellulose in the ratio from 73:1 to 49:25, respectively, and lubricating agent. Agent is made as a tablet of mass from 0.1 to 0.3 g with the content of captopril 25 or 50 mg. Invention provides making captopril tablets decomposing for 15 min and satisfying Pharmacopoeia requirements by all indices and showing stability in production and storage for 5 years.

EFFECT: improved and valuable pharmaceutical properties of agent.

3 cl, 1 dwg, 4 tbl, 6 ex

FIELD: pharmaceutical industry and technology, pharmacy, medicine, phytotherapy.

SUBSTANCE: method involves three-times extraction of milled coriander herb with 40% ethyl alcohol taken in the ratio raw : extractant = 1:5 for 1 h in each extraction step. Extracts are combined, filtered, ethyl alcohol is removed and prepared aqueous residue is kept at temperature +10°C, not above, for 5 h, not less. Deposit is separated, aqueous extract is dried and the end product is prepared. Invention provides realizing the indicated designation.

EFFECT: improved preparing method.

5 tbl, 2 dwg, 1 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents of prolonged effect used in treatment of arterial hypertension. Medicinal agent of prolonged effect used in treatment of arterial hypertension comprises indapamide, accessory substance represented by interpolymeric complex of polymethacrylic acid with polyethylene glycol or polypropylene glycol. The claimed invention provides preparing a stable and easily dosed medicinal formulation of prolonged effect.

EFFECT: improved and valuable medicinal properties of agent.

1 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising enalapril maleate, lactose, potato starch, polyvinylpyrrolidone and magnesium stearate wherein a medium-molecular polyvinylpyrrolidone aqueous solution is used as polyvinylpyrrolidone, and the pharmaceutical composition comprises indapamide and aerosil additionally. The pharmaceutical composition is made as an enveloped-covered core in the following ratio of the core components, wt.-%: enalapril maleate is taken in the therapeutically effective dose; indapamide, 1.1-2.6; aerosil, 0.2-0.4; potato starch, 20.0-40.0; medium-molecular polyvinylpyrrolidone aqueous solution with the concentration 12%, 1.7-2.3; magnesium stearate, 0.8-1.0, and lactose, the balance. The claimed composition provides enhancing the hypotensive effect based on design of the composition comprising enalapril maleate and indapamide. The selected qualitative and quantitative composition excludes sticking tablet mass on equipment in tablets making process, loss of active substance and change of the ratio mass of components in ready tablets as compared to the measured one. Invention provides high strength and stability of tablets in storage.

EFFECT: improved and valuable properties of pharmaceutical composition, improved preparing method.

2 tbl

FIELD: medicine.

SUBSTANCE: ultrasonic cardiography with intravenous injection of Dopamine is conducted, intravenous injection of Dopamine being combined with transesophageal cardiac stimulation. Dopamine is injected in the amount of 10 mkg/kg/min continuously during the whole examination. Transesophageal cardiac stimulation is performed within the range of 120 to 160 heartbeats per minute, and is commenced with systolic blood pressure being increased by, at least, 20 millimeters of mercury compared to initial.

EFFECT: conducting more permissive examination without complications.

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: suggested use of 2-ethyl-6-methyl-3-oxypiridin succinate as treatment in combination with traditional therapy for faster physical rehabilitation of patients with chronic heart failure.

EFFECT: improved diastolic function of the left myocardial ventricle; higher tolerance to physical stress in patients with chronic cardiac failure of any origin.

2 cl, 2 tbl, 2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry pharmacy.

SUBSTANCE: invention relates to using the known 2-phenyl-substituted imidazotriazinone of the formula (I): (vardenafil) possessing improved properties as compared with other known inhibitors of phosphodiesterase-5 (PDE-5), such as sildenafil and tadalafil. Proposed compound is used for preparing drugs used in treatment of cardiac insufficiency.

EFFECT: valuable medicinal and biochemical properties of compound.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing single dose of local anesthetic and Phentanyl solution at the L2-L3 level for carrying out spinal anesthesia in the amount sufficient for achieving skin analgesia according to pin prick test at the C8-Th1 level in upper abdominal operations and C3-C4 in intrathoracic operations. When reducing systolic arterial blood pressure to 100-80 mm of mercury column and heart beat rate of 60-50 strokes per 1 min, Mezaton and Dobutamine solutions are intravenously infused for regulating hemodynamic parameters at the level close to physiologic values during the whole operation time. Given anesthesia level is supported with epidural introduction of local anesthetics and Phentanyl.

EFFECT: enhanced effectiveness of hemodynamic regulation during surgical intervention.

3 dwg, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes an agent comprising the following components, mg: 2-ethyl-6-methyl-oxypyridine succinate, 25-1500; nicotinamide adenine dinucleotide, 0.5-100, and inositol, 100-1200. Agent can comprise additionally L-carnitine in the amount 10-100 mg. Also, agent can comprise additionally choline alphoscerate in the amount 50-1000 mg. Agent can be prepared in injection or tabletted medicinal formulation or as suppository. Agent provides effective delaying apoptosis and arresting transformation of apoptotic alterations to necrotic alterations in pathological processes of different etiology.

EFFECT: valuable properties and enhanced effectiveness of agent.

4 cl, 2 dwg, 2 tbl, 9 ex

FIELD: medicine, medicine of catastrophes, toxicology, resuscitation.

SUBSTANCE: it is necessary to puncture any available artery, then centripetally under the pressure in flow mode one should introduce oxygenated blood substitute of gas-transport function - perfluorane at the dosage of about 10-30 ml/kg. Immediately after introducing perfluorane it is important to inject adrenaline intra-arterially. Then it is necessary to fulfill indirect cardiac massage, defibrillation, artificial pulmonary ventilation at oxygen supply and intravenous injection of infusion solutions. The innovation enables to reconstruct cardiac function in short terms and, thus, correspondingly, improve cerebral circulation due to providing direct supply of oxygenated blood substitute into the system of cerebral and coronary vessels and, also, maintain the functions reconstructed during the period of transporting a patient into medical center.

EFFECT: higher efficiency of reconstruction.

5 dwg, 1 ex

FIELD: biopharmacology, medicine.

SUBSTANCE: the suggested biotransplant contains mesenchymal stem cells, myoblasts, endothelial precursor cells. The sources for obtaining the cultures being the constituents of biotransplant should be obtained both out of fetal and donor material including the obtaining of autologous cultures; as for biotransplant's variant, it contains myoblasts out of human skeletal fetuses and a biotransplant that contains endothelial precursors; the innovation refers to the method for obtaining biotransplant out of skeletal muscles tissue, and the method for treating chronic cardiac failure. Cellular therapy at different cardiovascular diseases should be usefully applied in a monovariant and in combination with conventional surgical therapeutic methods. The innovation increases the efficiency of impact upon human myocardium.

EFFECT: higher efficiency.

12 cl, 1 ex

FIELD: pharmacology, medicine.

SUBSTANCE: invention relates to new mercaptoacetylamide derivatives, which represents angiotensine converting enzyme and neutral endopeptidase inhibitors and useful in treatment of cardiovascular condition. More particularly invention relates to derivatives of formula I , wherein R1 represents hydrogen or acyl; wherein R2 represents hydrogen or biphenylmethyl; { represents -(CH2)n (n = 1, integer); B1 and B2 are independently hydrogen; or pharmaceutically acceptable salts or stereomers thereof. Method for production of compounds of formula I and formula II, pharmaceutical composition on the base of formula I, method for production thereof and method for treatment of cardiovascular condition.

EFFECT: new derivatives having value biological properties.

14 cl, 3 tbl, 4 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention describes pharmaceutical atorvastatin composition granulated by humid method with at least ca. 5% (mass) addition of alkali-earth metal salt containing: (a) atorvastatin, where atorvastatin is at least partly disordered form or mix of crystal and disordered atorvastatin forms, or its pharmaceutically acceptable salt; and (b) fluffer or combination of fluffers selected out of a group including sodium starch glycolate, starch, corn starch, preliminarily gelatinised starch, sodium alginate, cellulose powder, hydroxypropyl cellulose, magnesium aluminosilicate and potassium polacrylin, where the claimed atorvastatin composition granulated by humid method contains not more than ca. 3% of atorvastatin lactone, on the basis of ratio of lactone peak to the combined peak areas of total formulation, defined by high-efficiency liquid chromatography. Also the invention describes method of obtaining the claimed composition and assays of the composition content.

EFFECT: high purity grade; stable formulation of atorvastatin and good decomposition and bioavailability rate.

23 cl, 4 tbl, 16 ex

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