Pharmaceutical compositions for peroral intake of pharmacological active substances

FIELD: pharmaceutics.

SUBSTANCE: a solid pharmaceutical composition contains therapeutically efficient quantity of peptide as a pharmacological active substance, crospovidone or povidone, and an agent that favors peptide's introduction. A peptide is being calcitonin, salmon's calcitonin preferably. The above-mentioned agent is being 5-CNAC (N-(5-chlorsalicyloyl)-8-aminocaprylic acid), preferably, disodium salt 5-CNAC. The composition suggested provides high biological availability of peptides, such, for example, as calcitonin.

EFFECT: higher efficiency of application.

9 cl, 5 ex, 4 tbl

 

Background of invention

The technical field to which the invention relates.

The present invention relates to oral compositions for the introduction of pharmacological active substances, methods for increasing the bioavailability of the input oral pharmacological active substances, and to methods of treatment and/or prevention of diseases in mammals, including humans by oral administration of pharmacological active substance according to the invention.

Description of the prior art

Oral route of administration of pharmacological active substances is the most commonly used route of administration due to its convenience, its relative simplicity and full of pain-free, which helps to observe patients and treatment regimens compared with other routes of administration. However, the biological, chemical and physical barriers, such as different pH values in the gastrointestinal tract, the action of digestive enzymes and poor penetration of the active substance through the membrane of the gastrointestinal tract, makes it difficult to use for mammalian oral route of administration of some pharmacological active substances, for example, demonstrated that oral administration of calcitonin, which are polypep the derivative hormones with long-chain, secreted parafollicular cells of the thyroid gland of mammals and ultimobranchial gland of birds and fish, is difficult, at least partially, due to the insufficient stability of calcitonin in the gastrointestinal tract, but also because of the absence of calcitonin ability to easily be transported through the intestinal wall into the bloodstream.

In U.S. patent No. 5773647 and 5866536 described composition for oral administration of active substances, such as heparin and calcitonin, using modified amino acids, such as N - (5-chlorosalicylic)-8-aminocaproic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]mindcanvas acid (SNAD), and N-(8-[2-hydroxybenzoyl]amino)Caprylic acid (SNAC). In addition, in WO 00/059863 described disodium salt of formula I

where R1, R2, R3and R4independently of one another denote hydrogen, -OH, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy;

R5denotes a substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With1-C16albaniles, substituted or unsubstituted C1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen);

R6and R7independently of one another denote hydrogen, oxygen or With1- 4alkyl;

and their hydrate and solvate, as compounds which provide effective oral administration of active substances, such as calcitonin, cyclosporin and heparin.

The present invention describes pharmaceutical compositions, which provide an even higher bioavailability of oral input by pharmacological active substances, such as peptides, such as calcitonin.

Summary of the invention

Thus, the present invention relates to pharmaceutical compositions, which, quite unexpectedly, significantly enhances the bioavailability of oral input by active substances, in particular peptides. More specifically the invention relates to solid pharmaceutical compositions suitable for oral administration of pharmacological active substances, which contain:

1) a therapeutically effective amount of the pharmacological active substance,

2) crosspovidone or povidone,

3) the agent promoting the introduction of this pharmacological active substance.

The following embodiment of the present invention is a solid pharmaceutical composition suitable for oral administration of calcitonin, which contain:

1) terapeutiche the key effective amount of calcitonin,

2) crosspovidone or povidone.

The following embodiment of the invention is a method of increasing the bioavailability upon oral administration of a pharmacological active substance, consisting in the introduction to the patient who needs the introduction of a specified pharmaceutical active ingredient, an effective amount of the pharmaceutical composition according to the invention.

And yet another embodiment of the invention is a method of treating bone diseases and related calcium disorders, consisting in the introduction to a patient in need of such treatment, a therapeutically effective amount of the composition according to the invention, where the pharmacological active ingredient is a calcitonin.

Other features and advantages of the invention shall become apparent from the following detailed description of the invention.

Detailed description of the invention

Pharmacological active substances which can be used according to the invention include both therapeutic and prophylactic agents, and above all agents, which themselves do not penetrate or penetrate only a small number from the input dose through the mucous membrane of the gastrointestinal tract and/or are sensitive to cleavage by acids and enzymes as docno-intestinal tract. Pharmacological active substances include, but are not limited to, proteins; polypeptides; hormones; polysaccharides, including a mixture of mucopolysaccharides; carbohydrates; lipids, and combinations thereof.

Specific examples of pharmacological active substances include, but are not limited to) the following substances, including those obtained by synthetic, natural or recombinant sources: growth hormone, including human growth hormones (human growth hormone, STH), recombinant human growth hormones (rstg), bovine growth hormones, and porcine growth hormones; hormone-releasing factors, growth hormones; interferons, including α-, β- and γ-interferon; interleukin-1; interleukin-2; insulin, including porcine, bovine, human, and human recombinant insulin, optional with counterions such as sodium, zinc, calcium and ammonium; insulinogenic growth factor, including IGF-1; heparin, including nefrackzionirovannam heparin, heparinoid, dermatan, chondroitin, heparins, low, very low and ultra-low molecular weight; calcitonin, including calcitonin salmon, pig, eel, chicken and human; erythropoietin; atrial naturethese factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors; adrenocorticotropin, gonadotropin-releasing hormone; kitazin; luteinizing hormone releasing factor; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins; cyclosporine; vasopressin; nutrigrain (sodium or disodium salt of chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone (PTH), including its fragments; antimicrobial agents, including agents; vitamins; analogs, fragments, mimetics or modified polyethylene glycol (PEG) derivatives of these compounds, or any combination of them.

Preferred pharmacologically active ingredient is a pharmacologically active peptide, in particular calcitonin. Calcitonin which represents a class of pharmacological active substances, find many uses in the pharmaceutical industry and are typically used to treat, for example, Paget's disease, hypercalcemia and postmenopausal osteoporosis. Various calcitonin, including calcitonin derived from salmon, pigs and eel, go on sale and, as a rule, used, for example, for the treatment of Paget's disease, malignant hypercalcemia, and osteoporosis. Calcitonin may be any calcitonin, including natural, synthetic or derived from recombinant sources, and calcitonin derivative, such as 1,7-Asu-calcitonin in the OC. The composition may contain one kind of calcitonin or any combination of two or more of calcitonin. The preferred calcitonin is a synthetic calcitonin salmon.

Calcitonin are commercially available or can be synthesized by the known methods.

A number of pharmacological active substance, as a rule, represents a quantity effective to solve the task, for example, a therapeutically effective amount. However, this number may be less than this amount, when administered several compositions, i.e. the total effective number can be entered in the form of cumulative doses. The amount of active substance can also exceed the effective amount when the composition provides a continuous release of the pharmacologically active substance. The total number of the active substance, subject to the introduction, can be determined using techniques known to experts in this field. However, that compositions can be entered active ingredient more effectively than when using known from prototype compositions, the patient can enter smaller amounts of active ingredient than that used in known from prototype dosage forms or systems introduction, achieving similar levels to the JVI and/or therapeutic action.

When pharmacological active substance is a calcitonin salmon, appropriate dose, of course, must depend, for example, from the owner and the nature and severity of the condition to be treated. However, as a rule, satisfactory results can be obtained systematically using daily doses of from about 0.5 to about 10 μg/kg body weight of the animal, preferably from 1 to about 6 μg/kg body weight.

The share of pharmacological active substance, as a rule, varies from 0.05 to 70 wt.% in terms of the total weight of the pharmaceutical composition, preferably from 0.01 to 50 wt.%, more preferably from 0.3 to 30 wt.% in terms of the total weight of the pharmaceutical composition.

Crosspovidone can be any crosspovidone. Crosspovidone is a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone, also known as 1-ethynyl-2-pyrrolidinone, with molecular weight of 1000000 or more. A commercially available crospovidone include Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10 company ISP, Kollidon CL, BASF Corporation. The preferred crosspovidone is Polyplasdone XL.

Povidone is a synthetic polymer composed of linear groups 1-vinyl-2-pyrrolidinone with a molecular weight of from 2500 to 3000000. Marketed povidone include Kollidon K-30, Kollion K-90F BASF Corporation and Plasdone K-30 and Plasdone K-29/32 company ISP.

As mentioned above, crospovidone and povidone are available for sale. In another embodiment, they can be obtained synthetically by known processes.

Crosspovidone, povidone, or a combination, generally present in the compositions in amounts of from 0.5 to 50 wt.% in terms of the total weight of the pharmaceutical composition, preferably in amounts of from 2 to 25%, more preferably from 5 to 20 wt.% in terms of the total weight of the pharmaceutical composition.

Promoting the introduction of agents of the present invention are any agents that contribute to the introduction of specific pharmacological active substance. Suitable promoting the introduction of agents are any of the 123 modified amino acids described in the above US patent No. 5866536, or any of the 193 modified amino acids described in the above US patent No. 5773647, or a combination of both. The content of the above-mentioned US patents No. 5773647 and 5866536 fully incorporated into the present description by reference. In addition, contributing to the introduction of the agent can be a disodium salt of any of the above modified amino acids, as well as their ethanol solvate and hydrate. Suitable compounds include the following compounds of formula I

where R 1, R2, R3and R4independently of one another denote hydrogen, -HE, NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy;

R5denotes a substituted or unsubstituted With1-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted C1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen);

R6and R7independently of one another denote hydrogen, oxygen or With1-C4alkyl;

and their hydrates and alcohol solvate. The compounds of formula I and their disodium salts and alcohol solvate and hydrate described in WO 00/059863, the included methods for their preparation.

Disodium salt can be obtained from ethanol MES by evaporation or drying ethanol MES using methods well known in the field, to obtain the anhydrous disodium salt. The drying is generally carried out at a temperature from about 80 to about 120°C, preferably from about 85 to about 90°and most preferably about 85°C. Stage drying is usually carried out at a pressure of 26" Hg or higher. Anhydrous disodium salt typically contains less than about 5 wt.% ethanol and preferably less than about 2 wt.% ethanol in terms of 10%of the total weight of anhydrous disodium salt.

Disodium salt conducive to the introduction of the agent can also be obtained by preparing a suspension conducive to the introduction of the agent in water and adding two molar equivalents of aqueous sodium hydroxide, sodium alkoxide or other Suitable alkoxides of sodium include (but are not limited to sodium methoxide, ethoxide sodium, and combinations thereof.

Another method of obtaining disodium salt provides interaction contributing to the introduction of the agent with one molar equivalent of sodium hydroxide to obtain disodium salt.

Disodium salt can be isolated in the form of a solid substance by concentrating containing disodium salt solution until a thick paste using vacuum distillation. This paste can be dried in a vacuum oven to obtain disodium salt conducive to the introduction of the agent in the form of a solid substance. The solid can be distinguished by spray drying aqueous solution of disodium salt.

Promoting the introduction of agents can be obtained using methods known in this field, for example, using the above methods, including the methods described in US patents No. 5773647 and 5866536.

Ethanol solvate described in the above WO 00/059863 include (but are not limited to, a molecular or Jonny complex of molecules or ions of the solvent is of canola with molecules or ions disodium salt conducive to the introduction of the agent. Typically, ethanol solvate include approximately one molecule or ion of ethanol per molecule disodium salt conducive to the introduction of the agent.

Ethanol MES disodium salt conducive to the introduction of the agent can be obtained by dissolving conducive to the introduction of the agent in ethanol. Typically, each gram conducive to the introduction of the agent is dissolved in from about 1 to about 50 ml of ethanol, usually from about 2 to about 10 ml of ethanol. Then the solution containing conducive to the introduction of the agent/ethanol, subjected to interaction with a molar excess relative to facilitating the introduction of an agent containing a sodium salt, such as odnonatrieva salt, i.e. where each mol conducive to the introduction of the agent has more than one mole of sodium cations, receiving ethanol MES. Suitable odnonatrieva salts include, but are not limited to, sodium hydroxide; sodium alkoxides such as sodium methoxide and ethoxide sodium; and any combination. Preferably at least about two molar equivalent odnonatrieva salt are added to a solution of ethanol, i.e. for each mol conducive to the introduction of the agent has at least about two moles of sodium cations. Typically, the reaction is carried out at a temperature of reflux distilled mixture or at a lower temperature, n is the sample at ambient temperature. Then ethanol MES restore using methods well known in the field, such as the concentration of the resulting suspension by distillation at atmospheric pressure, cooling the concentrated suspension and filtering the solid. After that, the recovered solid is subjected to vacuum drying, receiving ethanol MES.

The hydrate disodium salts contributing to the introduction of agents can be obtained by drying ethanol MES obtaining anhydrous disodium salt according to the above-described methods and hydration of the anhydrous disodium salt. Preferably receive monohydrate disodium salt. Since the anhydrous disodium salt is very hygroscopic, hydrates obtained by keeping the atmosphere humidity. As a rule, the stage of hydration is carried out at a temperature from about appropriate ambient temperature to about 50°C, preferably from ambient temperature to about 30°C and relative humidity of the environment, which constitutes at least 50%. In another embodiment, the anhydrous disodium salt may be hydrated water vapor.

Preferred conducive to the introduction of agents are N-(5-chlorosalicylic)-8-aminocaproic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino Canova acid (SNAD), and N-(8-[2-hydroxybenzoyl]amino)Caprylic acid (SNAC) and their odnonatrieva and disodium salt, ethanol solvate of their sodium salts and monohydrate their sodium salts and their combinations. The most preferred conducive to the introduction of the agent is the disodium salt of 5-CNAC and its monohydrate.

The pharmaceutical compositions of the present invention typically contain an amount effective to support the introduction of one or more conducive to the introduction of agents, i.e. sufficient for the introduction of the active substance in order to achieve the desired action. Generally conducive to the introduction of the agent is present in amount of from 2.5 to 99.4 wt.%, more preferably from 25 to 50 wt.%.

The pharmaceutical compositions of the present invention may be a capsule, including soft gelatin capsule, tablet, caplette or other solid oral drug, all these forms are obtained using the well-known in the field of methods.

The composition may further comprise additives commonly used in quantities that include (but are not limited to, a pH regulator, a preservative, corrigent, taste masking agent, a fragrance, a humectant, a tonic, a dye, a surfactant, a plasticizer, a lubricant such as magnesium stearate, promoting sliding agent, contributing to the pressing in the society, the solubilizer, excipient, diluent, such as microcrystalline cellulose, such as Avicel PH 102, manufactured by FMC Corporation, and any combination thereof. Other additives may include phosphate buffers, citric acid, glycols, and other dispersing agents.

The composition may also include one or more enzyme inhibitors, such as actionin or ejections and their derivatives; Aprotinin, trasilol and inhibitors of the Bowman-Tag (Bowman-Birk).

In addition, the compositions of the present invention may be an inhibitor of transport, i.e. ρ-glycoprotein, such as Ketoprofen.

Preferably, the solid pharmaceutical composition of the present invention include a diluent, such as Avicel, and a lubricant such as magnesium stearate.

Solid pharmaceutical compositions of the present invention can be obtained using conventional methods, for example by mixing the active substance or active substances, contributing to the introduction of the agent, crosspovidone or povidone and other ingredients, plasticization and filling capsules or, instead of filling capsules, molding and subsequent tabletting or extrusion-molding to obtain tablets. In addition, the solid dispersion can be obtained by the known methods, followed by processing with obtaining t is blacki or capsules.

Preferably the ingredients in the pharmaceutical compositions according to the present invention is mixed until homogeneous or homogeneous with getting hard drugs.

The compositions of the present invention can be used for introduction of the active substance to any needy in this animal, including but not limited to, mammals such as rodents, cows, pigs, dogs, cats and primates, including man.

Below the invention is illustrated in the examples.

Example 1

Produce tablets of the present invention (example a)And a tablet, the method of manufacture of which is described in comparative examples B and C, in which instead of crosspovidone was used Ac-Di-Sol (Ac-Di-Sol is a sewn sodium carboxymethyl cellulose), and in comparative example D, which describes the preparation jointly freeze-dried capsules, all of these forms contain 5-CNAC and calcitonin salmon.

In particular, tablets receive the following method.

Example retrieve And

0,502 g calcitonin salmon, pre-sifted through a sieve with openings 40 mesh, 120 g of disodium salt of 5-CNAC, pre-sifted through a sieve with openings 35 mesh, and 20 g of Polyplasdone XL (crosspovidone, NF (national pharmaceutical form)) are combined in a vessel with a volume of 500 ml and mix with what omashu of the turbula type mixer for 2 min at a speed of 46 rpm Additionally, in a vessel add 125,4 g disodium salt of 5-CNAC, pre-sifted through a sieve with openings 35 mesh, and 32.5 g of Avicel PH 102 and stirred for 8 min at a speed of 46 rpm In a vessel add more of 32.5 g of Avicel and stirred for 5 min at a speed of 46 rpm 4.0 g of magnesium stearate is sifted in a vessel using sieves with openings 35 mesh and stirred for 1 min at a speed of 46 rpm Final mixture is pressed with obtaining tablets with tabletiruemogo press type Manesty B3B. The mass of the tablet is about 400 mg.

Comparative example B

Combine 14 g of disodium salt of 5-CNAC and 0.56 g of CabOSil and sieved through a sieve with openings 40 mesh. 0.3 g of a mixture of disodium salt of 5-CNAC/CabOSil, 0,028 g calcitonin salmon, pre-sifted through a sieve with openings 40 mesh, and 0.56 g of Ac-Di-Sol, pre-sifted through a sieve with openings 30 mesh, merge into a V-shaped mixer with cover. The mixture is stirred for 2 minutes Approximately 14.3 g of a mixture of disodium salt of 5-CNAC/Cab-O-Sil added exponentially in V-shaped mixer with cover and stirred for 2 min after each addition (add consistently about 0.8 and 1.7, 3.2 and 8.6 g). 12,43 g Avicel PH 102 and 0.42 g of magnesium stearate, previously sifted through a sieve with the size of the hole is 45 mesh, make a V-shaped mixer with cover and stirred for 5 minutes the Final mixture is then sieved through a sieve with openings 40 mesh and pressed to obtain tablets with tabletiruemogo press, for example, type Manesty F3. The mass of the tablet is about 400 mg.

Comparative example

0,1224 g calcitonin salmon, pre-sifted through a sieve with openings 40 mesh, 30 g of disodium salt of 5-CNAC, pre-sifted through a sieve with openings 35 mesh, and 4 g of Ac-Di-Sol is placed in a container with a volume of 500 ml glass type Rugen®and mix using the turbula type mixer for 2 min at a speed of 46 rpm Advanced in a vessel add 31,35 g disodium salt of 5-CNAC, pre-sifted through a sieve with openings 35 mesh, and 15 g of Avicel PH 102 and stirred for 8 min at a speed of 46 rpm Combine 2 g CabOSil and 16,15 g Avicel and sieved through a sieve with openings 18 mesh. In a vessel add the mix CabOSil/Avicel and stirred for 5 min at a speed of 46 rpm, 1.5 g of magnesium stearate is sifted into the vessel through a sieve with openings 35 mesh and stirred for 2 min at a speed of 46 rpm Final mixture is pressed with obtaining tablets with tabletiruemogo press type Manesty B3B. The mass of the tablet is about 400 mg.

Comparative example G

18 kg of water for injection and 0.16 kg of sodium hydroxide, NF, contribute to the vessel and stirred until dissolution. In a vessel add 0.800 to kg free acid 5-CNAC and stirred at 400-600 rpm for at least 10 minutes the pH Value of the mixture in the vessel was adjusted to about 8.5 with 10h. of sodium hydroxide. The contents of the vessel are stirred for at least 10 min after each addition 10h. of sodium hydroxide. 10h. a solution of sodium hydroxide receive, adding 40 g of sodium hydroxide, NF to 100 ml of water for injection. The final weight of the multicomponent solution is brought to 20,320 kg, adding water for injection (density 1,016). The contents of the vessel was stirred at 400-600 rpm for at least 30 minutes a Multicomponent solution is filtered into another container using a peristaltic pump, silicone tubing and membrane capsule filter DuraPore MPHL with pore size of 0.45 μm. Prepare a solution of phosphate buffer, adding 13.8 g of monohydrate odnonatrieva salt of phosphoric acid, USP (USP), 900 g of water for injection and bringing the pH to 4.0 with 1,0N. solution of phosphoric acid. The solution of phosphoric acid is prepared by adding 0.96 g of phosphoric acid, NF, 25 ml of water for injection. The final weight of a solution of phosphate buffer adjusted to 1007 g (density of 1,007) with water for injection and stirred for 5 minutes

Buffered solution Kahle is italina salmon is cooked, adding 1.6 g of calcitonin salmon to 660 g of a solution of phosphate buffer. The final weight of the solution is brought to 806,4 g (density 1,008) with a solution of phosphate buffer and stirred for at least 5 min at a rotation speed of 250 rpm or less.

0.800 to kg buffered solution of calcitonin salmon is added dropwise in 20 kg of a solution of 5-CNAC with constant stirring at a speed of 250 rpm or less for at least 5 minutes

Approximately 0.75 l solution of calcitonin salmon/5-CNAC filter tray lyophilization stainless steel (30.5×30.5 cm) to obtain a final layer of mortar depth 0,8-0,9 see For filtering a 21.75 l solution of calcitonin salmon/5-CNAC use about 29 pallets. The pallets are placed in a freeze dryer Edwards and lyophilizers using the following process:

1. After loading pallets and sealing the freeze dryer shelf is cooled at a rate of 1°C/min

2. After reaching the temperature on the shelf -45°To keep the temperature on the shelf at the level of -45°With at least 120 minutes

3. Cool the condenser to a temperature of -50°With or below.

4. Pump out the air from the chamber and then, while maintaining the vacuum at the level of 300 μm, increase the temperature on the shelf to -30°at the rate of 1°C/min

5. Keep the temperature on the shelf on level -30�B0; With over 180 minutes

6. Reduce the pressure in the chamber to 200 μm, and then, while maintaining the vacuum of 200 microns, the overall temperature on the shelf to -20°at the rate of 1°C/min

7. Keep the temperature on the shelf on level -20°C for 200 minutes

8. Increase the temperature on the shelf to -10°at the rate of 1°C/min

9. Keep the temperature on the shelf on level -10°C for 360 minutes

10. Increase the temperature on the shelf to 0°at the rate of 1°C/min

11. Keep the temperature on the shelf at level 0°C for 720 minutes

12. Reduce the pressure in the chamber to 100 μm, and then, while maintaining the vacuum at 100 μm, increase the temperature on the shelf to +10°at the rate of 1°C/min

13. Keep the temperature on the shelf on level +10°With over 540 minutes

14. Increase the temperature on the shelf to +25°at the rate of 1°C/min

15. Keep the temperature on the shelf at +25°With over 440 minutes

16. Relieve the vacuum and unload pallets.

Subjected joint lyophilization solution calcitonin salmon/5-CNAC remove from trays and store in refrigerator in plastic and sealed with foil boxes. For the application of each capsule (size AA) fill about 400 mg joint subjected lyophilization of the product.

Example 2

Introduction primates

Tablets or capsules, th is prepared according to example 1, enter makaka RH as follows: for each option processing using the group consisting of 4-6 monkeys, which is administered either 1 capsule or 2 tablets obtained according to example 1, using the following method:

Rhesus monkeys are secured on the chairs, the night before the processing, and they are fully conscious during the whole experiment. Capsules or tablets administered via gastric tube, after which the lead 10 ml of water.

Blood samples are collected through 0,25, 0,5, 0,75, 1, 1,5, 2, 3, 4, 5 and 6 h after treatment. The level of plasma calcitonin salmon assessed using radioimmunoassay. The levels of calcitonin salmon (LKT) plasma primates obtained for each group of monkeys, average and calculate the maximum average concentration of calcitonin in plasma and area under the curve (AUC), the results are shown in table 1.

Table 1
TrackWithpoppyLKT (PG/ml)AUC LKT
Comparative example G415792.4 M.
Comparative example B457992,5
Comparative example329797
Example a24204400

As can be seen from table 1, d is I calcitonin salmon values poppyand AUC significantly higher for the composition of the present invention, which contains crosspovidone (example A)than for the compositions of comparative examples without crosspovidone, which leads to a significant increase in bioavailability of the compositions according to the invention by oral administration.

Example 3

Express assessment of stability

Tablets containing 0,065, 0,400, and 2,500 mg LKT receive according to the comparative example and example And accordingly, the content of LKT and Avicel adjusted so as to obtain the required concentration. Tablets are placed in a vessel made of HDPE (high density polyethylene) with desiccant, and then seal and close the lid. Experiments on accelerated stability evaluation carried out by placing the samples, the stability of which was examining the camera with the conditions relevant to the environment, i.e. on 25°C and 60%relative humidity (RH). Samples are removed from the camera at certain points in time, i.e. after 3, 4 and 6 weeks and analyze the content of LKT using GHUR. The results are presented in table 2.

Table 2
Analysis LKTTablet weight 0,065 mgTablet weight 0,400 mgThe tablet m is soy 2,500 mg
25°C/60% 0VComparative exampleExample aComparative exampleExample aComparative exampleExample a
At the beginning of the experiment93,5%100,9%94,3%103,0%100,3%98,0%
3 weeks-97,4%-98,8%--
4 weeks84,2%-88,8%-91,5%100,2%
6 weeks-95,2%-to 96.9%--

Comparison of the stability of the composition obtained according to the comparative example, after 4 weeks (reduced concentration LKT about 10%) and compositions of the present invention, obtained according to example A, after 6 weeks (reduced concentration LKT about 5%) during storage of both compositions at room temperature suggests that the composition of the present invention has improved stability of tablets prepared according to the method according to the invention.

Example 4

The disintegration of the tablets prepared from solid compositions, evaluate, making that the notches according to the method described in example 1, which contain 60% of the disodium salt of 5-CNAC, 29% Avicel, 1% of magnesium stearate, but without LKT. The disintegration of the tablets evaluated according to the test USP Disintegration Test <701>, and the hardness of the tablets was determined by using a calibrated instrument for determining the hardness of tablets of type Vector/Schleuniger 6D. The results are presented in table 3.

Table 3
ExcipientContent (%)Hardness (kPa)*Disintegration (min)Hardness (kPa)Disintegration (min)
Ac-Di-Sol10the 5.71.1 to 1.4the 10.15,6-6,5
Explotab106,92,6-3,310,36,5-7,5
Polyplasdone XL107,30,6-0,810,52,4-2,7
Ac-Di-Sol(Cab-O-Sil)106,34,3-5,310,3of 7.3 to 8.0
* kilopascals

The results presented in table 3, indicate that the use of Polyplasdone XL (crosspovidone) in combination with 5-CNAC leads to more rapid disintegration of tablets in comparison with the tablets obtained with the use of 5-CNAC in combination with one the mi excipients, that demonstrates improved release profile of pharmacological active substance from the solid compositions of the present invention.

Example 5

Chemical stability

Samples for experiments on the assessment of stability under extreme stress preparing, placing tablets (obtained analogously to example 1 above, using the ratio of ingredients specified in table 4) in a closed vessel amber color. Experiments on accelerated stability evaluation carried out by placing the samples in a calibrated oven with a temperature of 60°C. the Content of LKT in the samples is assessed through GHUR in the initial time and after 3 or 4 days. The results are presented in table 4.

Table 4
Excipients (0.4 mg LKT/200 mg disodium salt of 5-CNAC)60°The content of LKT in early experienceContent LKT after keeping under stressChange, %
Ac-Di-Sol, Cab-0-Sil, Avicel, Mg-stearate (comparative example)3 days94,0%12,3%-81,7%
10% Polyplasdone XL-10, Avicel, Mg-stearate (example A)4 days98,3%86,5%-11,8%

As can be seen from table 4, the chemical article is mobility LKT during curing under conditions of extreme stress was higher when using the compositions of the present invention (example E), containing crosspovidone (Polyplasdone XL-10), compared with nesteriak crosspovidone compositions obtained according to comparative examples.

From the above description it is evident that the compositions of the present invention have a significantly improved bioavailability by oral administration of the active substance, in particular calcitonin compared with other compositions for oral administration, a higher decay rate and very good stability.

The above embodiments of the invention are given only to illustrate the invention and are not intended to limit its scope. Professionals in this field should be obvious many other ways to exercise and variations which fall within the scope of invention.

1. Solid pharmaceutical composition for oral administration of pharmacologically active ingredient containing (a) a peptide as a therapeutically effective amount of a pharmacologically active substance; b) crosspovidone or povidone; C) an agent that promotes the introduction of this pharmacologically active substance, representing a compound of formula (I)

where R1, R2, R3and R4independently of one another Ref who are hydrogen, -IT, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy;

R5denotes a substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted With1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen);

R6and R7independently of one another denote hydrogen, oxygen or With1-C4alkyl;

their hydrates and alcohol solvate and the disodium salt.

2. The composition according to claim 1, where the peptide is calcitonin.

3. The composition according to claim 2, where calcitonin is a calcitonin salmon.

4. The composition according to claim 1, containing crosspovidone.

5. The composition according to claim 1, where contributing to the introduction of an agent is a 5-CNAC (N-(5-chlorosalicylic)-8-aminocaproyl acid).

6. The composition according to claim 1, where contributing to the introduction of an agent is a disodium salt of 5-CNAC.

7. The composition according to claim 1, which further comprises a diluent.

8. The composition according to claim 7, where the diluent is a microcrystalline cellulose.

9. The composition according to claim 1, which further comprises a lubricant.

10. The composition according to claim 9, where the lubricant is a stearate.



 

Same patents:

FIELD: biotechnology.

SUBSTANCE: invention relates to inhibitor of matrix metalloproteinases representing extract from fungus Canoderma atrum obtained by using of water and/or lower alcohols as extractant. Also disclosed are pharmaceutical agent for inhibition of tumor metastasis containing of 0.03-10 wt.% of abovementioned extract and foodstuff containing claimed extract.

EFFECT: improved inhibitor of matrix proteinases.

3 cl, 18 ex, 4 tbl

FIELD: medicine, medicinal biochemistry, pharmaceutical technology.

SUBSTANCE: invention proposes the composite that comprises complex of vitamins D3, B6, C, K and calcium salts, citric acid, lactose and sorbitol as the special supplement, and lubricating agent and correcting agent for taste and/or odor. The method for preparing the composite involves mixing the above said components and if necessary the following tableting process of the prepared mixture. The new composite shows stability of quality indices in the store process being among them index "the content of vitamin D3" that provides the fitness time above 2 years and absence of by-side adverse toxic effect that is typical for destruction products of active components.

EFFECT: improved preparing method, improved and valuable properties of composite.

7 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine, orthopedics.

SUBSTANCE: the present innovation deals with treating osseous diseases caused by calcium exchange disorders. For this purpose certain calcium preparations should be reduced up to amorphous state to be perorally applied per 0.5-1.0 g, 2-4 times daily, at courses of not less than 10 d. The innovation provides efficient treatment due to high biodigestibility of amorphous calcium and its active accumulation in bony tissue.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine; medical engineering.

SUBSTANCE: biotransplant has genetically unmodified mesenchyma stem cell culture as active component obtained from fetal donor autologous material. The tissue is subjected to disaggregation and the produced cell suspension is resuspended and cultivated on growth medium containing transferrin, insulin, fibroblast growth factor and heparin to accumulate mature stroma in cell culture. Method involves intravenously dropping mesenchyma stem cell culture in the amount of 50 to 500 mln in 50-100 ml of physiologic saline.

EFFECT: accelerated recovery of bone tissue; positive biochemical factors dynamics; improved patient locomotor activity.

6 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.

EFFECT: valuable medicinal properties of pharmaceutical composition.

16 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying biphosphonate for treating osteonecrosis and/or osteonecrosis dissecans. This medicinal preparation could be additionally applied for preventing the development of osteonecrosis and/or osteonecrosis dissecans and any complications associated with both diseases. Biphosphonate acts for the decrease or prevention of severe degree of deformation and/or destruction of a bone or a cartilage and provides the chance to form new bony tissue in a patient.

EFFECT: higher efficiency of therapy.

38 cl, 7 dwg, 1 tbl

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, traumatology.

SUBSTANCE: osseous defect after filling with collapan and usage of metallofixative should be covered with absorbable collagen film that provides orientation of osseous regenerate's organization.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

The invention relates to the field of medicine and relates to a treatment for abnormal bone metabolism

The invention relates to medicine, namely to traumatology and orthopedics, and can be used for the treatment of fistulous forms of chronic osteomyelitis with the presence of small sequestrum
The invention relates to medicine, surgery and can be used for the treatment of osteomyelitis

The invention relates to new thiazole derivative of the formula (I) in which R1denotes a group of formula (a)-(d), where R2denotes a group of formula (II), R3denotes hydrogen, alkyl, cycloalkyl, and so on; R4denotes alkyl, phenyl, heteroaryl; R5and R6each independently of one another denote hydrogen, heteroaryl; R7and R8each independently of one another denotes hydrogen, or R7and R8together with the N atoms to which they are linked, form a 5-6-membered heterocycle; R9denotes hydrogen, alkyl, cycloalkyl; R10denotes phenyl, benzyl, and so on; And denotes a carbonyl or sulfonyl; In denotes hydrogen; and m each represents zero or a positive number from zero to 2, but not equal to zero when R1denotes-NH2; b denotes a number from zero to 4; C, d, f, g, k, l and m each independently of one another denotes zero or 1, so that each of the C, f and g cannot simultaneously denote zero and thus m does not denote zero when f or g represents 1; q represents zero or 1, and each k and l also denotes zero, when i denotes zero; e denotes a number from zero to 3; h represents a number from zero to 5; j denotes a number from zero to 2; and the sum is

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with mixing dry St. John's wort extract with additional substances followed by compressing, sieving, treating compact extract with additional substances including titanium dioxide and talc with subsequent tableting, moreover, compressing should be carried out with highly dispersed silicon dioxide only, at a certain portion of silicon dioxide supplemented before compression, one should apply the particles of compact extract at certain distribution according to the size of particles to achieve certain bulk density of particles of compact extract and density after compression; the particles of compact extract should be additionally covered with combination of aerators chosen out of sodium-crosscarmelose, sodium-carboxymethyl starch. The above-mentioned method enables to obtain tablets at high portion of extract, high characteristics of decomposition and releasing of biologically active substances.

EFFECT: higher efficiency.

5 cl

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