Pharmaceutical composition possessing antimicrobial action, and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, namely to a pharmaceutical composition of levofloxacin. The technical result is ensured by using Klucel and a combination of desintegrants, including sodium starch glycolate and sodium croscarmellose in the composition, with the first desintegrant being introduced before wet granulation, and the second one - after dry granulation together with an antifriction agent that is magnesium stearate.

EFFECT: composition possesses a better combination of bioavailability and appearance of tablets, including in storage; as additives, the composition contains microcrystalline cellulose (MCC), sodium starch glycolate, sodium croscarmellose, calcium carbonate, hydroxypropyl cellulose and stearic acids and/or salts thereof.

10 cl, 8 ex, 4 tbl

 

1. The technical field to which the invention relates.

The invention relates to medicine, in particular to the pharmacy, and relates to a pharmaceutical composition having antimicrobial activity and containing as active substance (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (levofloxacin).

2. The level of technology

Respiratory tract infections by frequency of occurrence occupy the first place among the infectious diseases of man. Although the doctor a large number of antibacterial drugs of different classes, in recent years there has been a clear trend to increased mortality from pneumonia in the developed world. The reason may be related primarily to increased resistance to major pathogens of community-acquired respiratory tract infections to many antibiotics. This explains the interest of clinicians to new antibacterial agents, which marks the lower level of bacterial resistance.

Streptococcus pneumoniae is the most frequent causative agent of community-acquired pneumonia in persons of all age groups (30-50%). Most acutely at the present time the problem of distribution among pneumococci penicillinresistant strains. In some countries customerloyalty pneumococci to penicillin can reach 60%. Extensive studies of the distribution of pneumococcal resistance to penicillin in our country was not conducted. According to local studies in Moscow, the frequency of resistant strains of 2%, strains with intermediate sensitivity is about 20%. The resistance of pneumococci to penicillin is not connected with the production of β-lactamases, and modification of the target of the antibiotic in the microbial cell - penitsillinsvyazyvayuschy proteins, therefore, the inhibitor - protected penicillins against these pneumococci are also inactive. The resistance of pneumococci to penicillin is usually associated with resistance to cephalosporins I and II generations, macrolides, tetracyclines, cotrimoxazole. The lowest degree of resistance is established for a drug group fluoroquinolones.

Fluoroquinolones have a broad spectrum of antimicrobial activity. The first drug from the class of quinolones was nalidixic acid (blacks)used since 1962 Nalidixic acid and subsequent quinolones have limited scope and is indicated for the treatment of urinary tract infections and certain intestinal infections (bacterial enterocolitis, dysentery), they quickly develop bacterial resistance. For the treatment of generalized forms of infectious processes and infectious-inflammatory diseases of different localization of these the courthouse square are not applied.

New compounds were obtained by the introduction of a fluorine atom at the 6th position of the quinolone molecules. The presence of fluorine atom (one or more) in the molecule and different substituents at different positions determines the characteristics of antibacterial activity and pharmacokinetic properties of the drugs. Depending on the number of fluorine atoms emit monitorowanie, diflorasone and triptoreline connection.

The first drugs of fluoroquinolones have been proposed for clinical practice in 1978-1980 currently fluoroquinolones occupy one of leading places among the antimicrobial agents for the treatment of various infectious diseases and inflammatory processes in non-communicable clinic. Intensive development of fluoroquinolone (introduced into clinical practice more than 15 drugs) due to their characteristics: a broad spectrum of activity covering gram-negative and gram-positive aerobic and anaerobic microorganisms, including atypical, high antimicrobial activity, bactericidal activity, unusual mechanism of antimicrobial action, optimal pharmacokinetic properties, good tolerability with long-term use. All this determines the high efficacy of fluoroquinolones in the treatment of severe forms of infections of different Loka is Itachi. Currently, the fluoroquinolones are considered as a serious alternative to highly active intravenous broad-spectrum antibiotics.

The totality of the facts makes the actual creation of solid dosage forms levofloxacin pharmaceutical composition, ensuring the effectiveness of antimicrobial action by providing a high degree of bioavailability and rate of absorption, quickly causing a therapeutically effective concentration of drug in systemic blood.

Known dosage form having an antibacterial effect, which is a tablet containing two or more layers, the composition of which is as active substances levofloxacin and as auxiliary substances in various combinations of magnesium stearate, sodium laurylsulfate, polyvinylpyrrolidone, microcrystalline cellulose and other agents, and a shell containing hypromellose (see EN 2234915, published. 27.08.2004).

The way to obtain this dosage form provides for the mixing part of levofloxacin with microcrystalline cellulose, followed by moistening the mixture with water and granulation of the obtained hydrated mixture. Another part of the levofloxacin is mixed with lactose, HC is Hainaut and granularit. The granulate is dried and pressed in a two-layer tablet, a suspension containing hydroxypropylcellulose, put the shell.

The disadvantages described dosage form, and method of its manufacture is that due to the slow release of the active substance the drug has a low antibacterial effects on pathogenic strains of microorganisms. Because of the lower bioavailability of the need to increase therapeutic dose, which negatively affects the microflora of the human body, irritant effect on the mucous membrane of the gastrointestinal tract (GIT).

The closest technical solution (prototype) is a dosage form having an antibacterial effect, which is a tablet dosage form consisting of a nucleus, containing as active substance levofloxacin, as auxiliary substances, magnesium stearate, sodium laurylsulfate, polyvinylpyrrolidone and microcrystalline cellulose, and a shell containing hypromellose, which contains the kernel optional crosspovidone (see EN 2281773, published. 03.06.2005).

The way to obtain this dosage form provides a mixture of levofloxacin with microcrystalline cellulose, wetting the mixture with an aqueous solution polivi is elparoladon, wet granulation, drying, dry granulating, the powder mixture of crosspovidone, magnesium stearate and sodium lauryl sulphate and tableting.

Then from aqueous suspensions of titanium dioxide in aqueous solution of oxypropylation and hydroxypropylcellulose with polyethylene glycol, iron oxide yellow and iron oxide red on the pill cause a shell.

Known dosage form has a high rate of disintegration, but the tablet during storage have a tendency to appearance on their surface numerous swellings and bumps.

Thus, the objective of this invention is to provide pharmaceutical compositions with antimicrobial action on the basis of levofloxacin, satisfying all the requirements of operating in the Russian Federation the State Pharmacopoeia XII publications, including the appearance of a tablet dosage form, and has a high bioavailability.

3. Disclosure of inventions

The problem is solved by the creation of a pharmaceutical composition having antimicrobial activity comprising as active ingredient a therapeutically effective amount of levofloxacin, specially selected additives target (leavening agents, binders). The composition may include components of the shell which covers the core tablets.

As accessories the x chemical composition comprises microcrystalline cellulose (MCC), starch sodium glycolate, croscarmellose sodium, calcium carbonate, hydroxypropylcellulose and stearic acid and/or its salts in the following ratio, wt.%:

Levofloxacin30,0-85,0
Microcrystalline cellulose1,0-10,0
Calcium carbonate1,0-10,0
Hydroxypropylcellulose0,1-5,0
Starch sodium glycolate1,0-15,0
Croscarmellose sodium1,0-15,0
Stearic acid and/or its salts0,5-1,3

Antimicrobial pharmaceutical composition is made in solid form, mainly in the form of tablets, preferably coated. As the shell can be selected any water-soluble shell.

All indicators received levofloxacin tablets comply with pharmacopoeial requirements (Tables 3 and 4).

It is also proposed a method of obtaining a pharmaceutical composition, which comprises wet granulating a mixture of levofloxacin with whom microcrystalline cellulose, with starch sodium glycolate, calcium carbonate and hydroxypropylcellulose, subsequent drying of the granules, dusting croscarmellose sodium salt of stearic acid, and tableting the resulting mass.

Preferably, the method includes the additional step in which the obtained pelletized form in addition put the shell.

Wet granulation is preferably carried out in the fluidized bed, and drying of the granulate is carried out to a residual moisture content of 3.0-4.0 wt.%.

The preferred method is to conduct after drying operations additional granulation.

It is established that a negative impact on the appearance of the tablets of the prototype has been used as disintegrant - povidone, regardless of the method of its introduction.

It was established that to achieve the required performance of bioavailability and improved physico-chemical parameters tableted dosage form of levofloxacin as excipients (binders), you must use Cluzel (hydroxypropylcellulose), contributing to the rapid penetration of water into its mass.

For the manifestation of more severe loosening effect it is advisable to use a synergistically effective mixture of closely and disintegrants of exploses causing swelling frequent the C due to absorption of water, and explores/Solutab with high absorption capacity. The best results were obtained by a combination of disintegrants of exploses (starch sodium glycolate) and explores/Solutab (croscarmellose sodium), and explosion is introduced to wet granulation, which enhances the disintegration of the granules, and Explorer - after dry granulation together with the antifriction agent - magnesium stearate.

4. The implementation of the invention

The following examples illustrate variants of the pharmaceutical composition. Example 1. The technological characteristics of the substance of levofloxacin given in Table 1. Mix pre-sifted powder of the active substance 51,27 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin) (82,7 wt.%), 2.85 g of microcrystalline cellulose (4.6 wt.%), 1.86 g of sodium starch glycolate (3.0 wt.%), only 2.91 g of calcium carbonate (4.7 wt.%), 0,62 g hydroxypropylcellulose (1.0 wt.%) and thoroughly stirred for 30 minutes. Moisten the mixture with purified water, then the wetted mass granularit and dried to a residual moisture content of 3-4%. The dried granules are milled in a ball mill. The dusting of dry granules is carried out by mixing them with 1.86 g croscarmellose sodium (3.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%) The technological characteristics of the granulated pharmaceutical compositions on the basis of levofloxacin are shown in Table 2. Get tablets containing 0.5 g of active substance. The tablets covered with a shell.

Table 1
The technological characteristics of the substance levofloxacin
IndexThe value of the index
Flowability, g/s0
Bulk density, g/cm30,392±0,045
The compressibility, N.52,01±3,48
Density, g/cm1,24±0,3

Table 2
The technological characteristics of the granular pharmaceutical composition based on levofloxacin
IndexThe value of the index
Flowability, g/s10,2±0,6
Bulk density, g/cm3mean HDI of 0.531±0,07
The compressibility, N.28,3±1,2
/p>

Example 2. Getting the tablets carried out as in example 1 on the basis of 48,30 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin) (77,9 wt.%), only 2.91 g of microcrystalline cellulose (4.7 wt.%), 1.86 g of sodium starch glycolate (3.0 wt.%), of 5.83 g of calcium carbonate (to 9.4 wt.%), 0,62 g hydroxypropylcellulose (1.0 wt.%). The dusting of dry granules is carried out by mixing them with 1.86 g croscarmellose sodium (3.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Get a tablet with a content of 0.48 g of active substance. The tablets covered with a shell.

Example 3. Getting the tablets carried out as in example 1 from 27,28 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin) (to 44.0 wt.%), 6.20 g microcrystalline cellulose (10.0 wt%), of 9.30 g of sodium starch glycolate (15.0 wt.%), 6.20 g of calcium carbonate (10.0 wt%), 3,10 g hydroxypropylcellulose (5.0 wt.%). The dusting of dry granules is carried out by mixing from 9.30 g croscarmellose sodium (15.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Get tablets containing 0.27 g of the active substance. The tablets covered with a shell.

Example 4. Getting the tablets carried out as in example 1 on the basis of 37,20 g (-)-(3S)-2,3-dihydro-3-methyl-1-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid, the hemihydrate (substance levofloxacin) (60,0 wt.%), 1.24 g of microcrystalline cellulose (2.0 wt.%), of 9.30 g of sodium starch glycolate (15.0 wt.%), 1.24 g of calcium carbonate (2.0 wt.%), 3,10 hydroxypropylcellulose (5.0 wt.%). The dusting of dry granules is carried out by mixing from 9.30 g croscarmellose sodium (15.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Get a tablet with a content of 0.37 g of active substance. The tablets covered with a shell.

Example 5. Getting the tablets carried out as in example 1 on the basis of 43,40 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin) (70,0 wt.%), 6.20 g microcrystalline cellulose (10.0 wt%), of 0.62 g of sodium starch glycolate (1 wt.%), 6.20 g of calcium carbonate (10.0 wt%), 0.31 g of hydroxypropylcellulose (0.5%). The dusting of dry granules is carried out by mixing them with the 4.65 g croscarmellose sodium (7.5 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Get a tablet with a content of 0.43 g of active substance. The tablets covered with a shell.

Example 6. Getting the tablets carried out as in example 1 on the basis of 45,07 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin) (72,7%by weight), 4.71 g microcrystalline cellulose (7.6 wt.%), ,86 g of sodium starch glycolate (3.0 wt.%), only 2.91 g of calcium carbonate (4.7 wt.%), 0,62 g hydroxypropylcellulose (1.0 wt.%). The dusting implement 6.20 g croscarmellose sodium (10.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Receive capsules or tablets containing 0.45 g of the active substance. The tablets covered with a shell.

Example 7. Getting the tablets carried out as in example 1 on the basis of 45,07 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin), (72,7%by weight), of 1.80 g of microcrystalline cellulose (2.9 wt.%), 6.20 g of sodium starch glycolate (10.0 wt%), of 5.83 g of calcium carbonate (to 9.4 wt.%), 0,62 g hydroxypropylcellulose (1.0 wt.%). The dusting of dry granules is carried out by mixing them with 1.86 g croscarmellose sodium (3.0 wt.%) and 0.62 g of magnesium stearate (1.0 wt.%). Get a tablet with a content of 0.48 g of active substance. The tablets covered with a shell.

Get tablets with satisfactory processing characteristics (table 3) and meets all the requirements of the State Pharmacopoeia XII publications (table 4).

Example 8. Getting the tablets carried out as in example 1 on the basis of 548,25 g (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid hemihydrate (substance levofloxacin), (85,0 wt.%), 64,50 g microcrystalline CE is lulose (10.0 wt%), 6,45 g of sodium starch glycolate (1.0 wt%), 6,45 g of calcium carbonate (1.0 wt%), 3,22 g hydroxypropylcellulose (0.5%). The dusting of dry granules is carried out by mixing them with 9,68 g croscarmellose sodium (1.5 wt.%) and of 6.45 g of magnesium stearate (1.0 wt.%). Get a tablet, containing 0.55 g of the active substance. The tablets covered with a shell.

Table 3
Characteristics of the finished tablets levofloxacin obtained by wet granulation
IndexThe value of the index
Raspadaemost, min8
Compressive strength, N27,61±1,77
Abrasion, %98,5±0,6

1. Pharmaceutical composition having antimicrobial activity comprising as active ingredient a therapeutically effective amount of (-)-(3S)-2,3-dihydro-3-methyl-10-(4-methylpiperazine-1)-7-oxo-9-fluoro-7H-pyrido[1,2,3-d,e][1,4]benzo-oxazin-6-carboxylic acid hemihydrate (levofloxacin), as auxiliary substances microcrystalline cellulose is (MCC), starch sodium glycolate, croscarmellose sodium, calcium carbonate, hydroxypropylcellulose and stearic acid and/or its salts in the following ratio, wt.%:

levofloxacin30,0-85,0
microcrystalline cellulose1,0-10,0
calcium carbonate1,0-10,0
hydroxypropylcellulose0,1-5,0
starch sodium glycolate1,0-15,0
croscarmellose sodium1,0-15,0
stearic acid and/or its salts0,5-1,3

2. The pharmaceutical composition according to claim 1, characterized by the fact that is made in the form of a solid dosage form coated.

3. The pharmaceutical composition according to claim 1, characterized in that a represents a single dosage form.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized by the fact that made in the form of tablets.

5. The pharmaceutical composition according to claim 1, containing as starch sodium glycolate appropriate alcohol what you potato, and/or corn starch and/or modified starch.

6. A method of obtaining a composition, characterized according to claim 1, comprising the following processes: wet granulating a mixture of levofloxacin with microcrystalline cellulose, starch sodium glycolate, calcium carbonate and hydroxypropylcellulose, drying the granules, dusting croscarmellose sodium salt of stearic acid and tableting the resulting mass.

7. The method according to claim 6, in which the obtained pelletized form in addition put the shell.

8. The method according to claim 6, in which the wet granulation is carried out in the fluidized bed.

9. The method according to claim 6, in which the drying of the granulate is carried out to a residual moisture content of 3.0-4.0 wt.%.

10. The method according to claim 6, in which, after drying spend additional granulation.



 

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5 cl, 7 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treatment of hyperphosphatemia, which includes iron oxyhydroxide in quantity from 10 to 80% by weight, with respect to total weight of composition, which is present in quantity over 300 mg per medical form. Composition is produced in form of medical forms, adapted for decay in oral cavity or in small quantity of liquid before swallowing. Invention also relates to method of production of pills, which contain claimed pharmaceutical composition, by direct pressing or dry granulation, as well as to pill for treatment of hyperphosphatemia, which is obtained by claimed method.

EFFECT: invention relates to application of pharmaceutical composition for production of medicine for treatment of hyperphosphatemia and patients with chronic renal insufficiency.

33 cl, 10 tbl, 9 ex

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

EFFECT: drug form by invention is stable to rupture and stable against abuse.

16 cl, 21 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical tablet for oral administration containing ulipristal acetate 3-18 wt %; a diluent 60 - 95 wt % specified in lactose monohydrate, microcrystalline cellulose, cellulose, mannitol and combinations thereof; a binding agent 0 - 10 wt % specified in hydroxypropyl methyl cellulose, povidone and combinations thereof; sodium croscarmellose 1 - 10 wt % and magnesium stearate 0.5 - 4 wt %.The invention also refers to a method for preparing the above tablet which involves mixing the ingredients and forming the tablet by wet granulation or direct compression.

EFFECT: invention provides the new formulation of the tablet with improved disintegration.

13 cl, 2 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to medicine and describes solid peroral drug form in form of pill, which includes: a) therapeutically effective quantity of aliskiren or its pharmaceutically acceptable salt, b) therapeutically effective quantity of hydrochlorothiazide (HCTA), and c) hydrophilic filler, which represents mixture of wheat starch and lactose. Method of obtaining solid pharmaceutical composition as well as its application are described.

EFFECT: invention ensures considerable solidity and short time of disintegration of peroral form.

28 cl, 7 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, particularly to solid pharmaceutical compositions for the immune system suppression and multiple sclerosis treatment. The pharmaceutical composition exhibiting improved flowability contains a S1P receptor modulator representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, lactulose, polyethylene glycol-6000 and polyvinylpyrrolidone. What is also described is a drug preparation containing 2- amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, in the form of a tablet or capsule, placed in pharmaceutically acceptable package, and a method for preparing the drug preparation for oral administration.

EFFECT: invention provides a uniform distribution of the active ingredient in the solid composition, high stability and improved flowability of the solid pharmaceutical composition; the improved flowability of the composition presented in the invention enables using the same on automated equipment.

15 cl, 1 tbl, 4 ex

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