Bronchodilatory and method thereof

 

The invention relates to medicine and pharmaceutical technology and relates to a bronchodilator, and method of its production. The invention consists in that the composition contains medicines different mechanism of action (theophylline and salbutamol), and as excipients, providing high efficiency and prolonged effect of interpolymer complex polymethacrylic acid and polyethylene glycol. The invention provides a long lasting effect of weight reduction pills and reduce side effects. 3 S. and 3 C.p. f-crystals, 7 tab., 3 Il.

The invention relates to medicine and pharmaceutical technology, in particular to bronchodilators tool used in all forms of bronchial obstruction: bronchial asthma, chronic obstructive bronchitis, pulmonary emphysema and other diseases.

Currently, for the treatment of COPD, in addition to hormonal therapy, the most widely used derivatives xantina (theophylline-1,3-dimethylxanthine) and preparations of a group of simpatomimetikov (salbutamol-2-tert-butylamino-1-(4-hydroxy-3-oxymethylphenyl)-ethanol), which often use the powders for inhalation).

For the convenience of taking the drugs we developed a drug that contains a combination of theophylline and salbutamol sulphate. The drug is available under the name Coastlin CF (India) and contains 300 mg of theophylline, 4 mg of salbutamol sulphate, 296 mg of auxiliary substances [1]. The drug is a two-layer tablet, produced by special technology and is the closest analogue to the technical nature of the claimed invention.

Disadvantages Coastline are a large proportion of excipients in the tablet, which leads to a large mass legform. In addition, the technology of obtaining Coastline quite complicated.

The objective of the invention is the preservation of therapeutic efficacy if the dose of theophylline, the reduction of weight of auxiliary substances, providing the effect duration, weight of the tablet, providing ease of use and reducing side effects.

This object is achieved in that the pharmaceutical composition on the basis of theophylline contains interpolymer complex polymethacrylic acid and polyethylene glycol (IPC) and salbutamol or its salt with the following ratio of ingredients, wt.%: Teofilia are using IPC as prolonging substances, salbutamol or its salts at a given ratio of components: prolongator, theophylline and salbutamol or its salts.

Used interpolymer complex is a product of intermolecular interaction of poly (methacrylic acid) and poly (ethylene glycol) and is a structure with a linear sequence of cooperative hydrogen bonds. Significant role in stabilizing the CRP belongs to hydrophobic interactions. This complex is insoluble in the acidic environment and breaks down into water-soluble components in a neutral environment.

FDI as prolonging substances used in pharmaceutical compositions, containing one active substance (Theopack, Hinipek), however, in the combined pharmaceutical compositions, its use is unknown.

In the inventive solution, the combination of the combination of theophylline and salbutamol or its salts using CRP as prolonging substances provides not only the expected therapeutic effect, but also can reduce the dose of theophylline, the number of auxiliary substances, mass legform, as well as to reduce side effects.

Observe therapeutic effect at lower doses and red eye reduction is sibutrim release of both substances and increase the bioavailability of theophylline in the claimed composition.

As can be seen from comparison of Fig. 1, 2 and 3 the nature of the curves of dissolution of drugs from tablets prototype and tablets claimed composition differs sharply. For the prototype during the observation time released almost all of theophylline and only about half of salbutamol. For the claimed composition during the observation time released 100% of both substances when simbata the nature of the change speed of release of substances. This type of release is achieved by using as prolongator IPK.

The test release is a criterion for prolonging the action of the tablets.

Study of the release of theophylline and salbutamol of the composition was carried out on the device type "Rotary basket" in conditions simulating the gastrointestinal tract: at pH of 1.16 (model of the stomach) and pH 7.5 and ionic strength 0.15 m/l (model intestines). The concentration of theophylline and salbutamol solution was judged according to the peaks obtained by high performance liquid chromatography using pre-constructed calibration curves.

Data on the release of theophylline and salbutamol tablets with different content of the interpolymer complex (from 0 to 39%) indicate that Roemer, if 3 hours tablet (in the absence of IPC) release up to 95% of theophylline and salbutamol of hemisuccinate, tablets, containing 16, 24, 39% of interpolymer complex release of theophylline 66, 60, 40.5 percent; salbutamol of hemisuccinate 63, 60, and 41%, respectively. Further increase in the content of prolonging the excipient is impractical because it leads to an increase in the average weight of the tablet, which makes it difficult to receive patients, and also impair the technological characteristics of the granulated mass. The reduction in the content of FDI in the pharmaceutical composition leads to a decrease prolonging effect, i.e. the increase in the rate of release of the drug. The increase in the content of drug substances over 80% theophylline and 4% for salbutamol and its salts will privada to increase the number of patients for adverse effects and cost of medication; a reduction in the content of medicinal substances below 60% and 1%, respectively, reduces the effectiveness of the drug.

As salts of salbutamol can be used hemisuccinate, sulfate, hydrochloride, benzoate and other salts.

The following examples illustrate the invention.

Example 1.

A pharmaceutical composition comprising (g): Theo is onenow, granulation, drying and tabletting the mixture. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the first line.

Example 2.

A pharmaceutical composition comprising (g): Theophylline - 0,200 (80 wt.%)
Salbutamol benzoate 0.01 to 4 wt.%)
IPC - 0,04 (16 wt.%)
was prepared by mixing the components, pelletizing, grinding bricks and tabletting the obtained granulate. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the second line.

Example 3.

A pharmaceutical composition comprising (g):
Theophylline - 0,200 (60 wt.%)
Salbutamol sulfate 0,003 (1 wt.%)
PCI - to 0.127 (39 wt.%)
was prepared by mixing the components and direct compression of the mixture. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the third line.

Example 4. A pharmaceutical composition comprising (g):
Theophylline - 0,300 (75 wt.%)
Salbutamol hydrochloride - 0.01 (3 wt.%)
IPK - 0,09 (22 wt.%)
was prepared according to example 2. Kinetic data release of substances in percent is a significant composition, contains (g):
Theophylline - 0,300 (75 wt.%)
Salbutamol - 0,004 (1 wt.%)
IPK - 0,096 (24 wt.%)
was prepared according to example 1. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the fifth string.

Example 6.

A pharmaceutical composition comprising (g):
Theophylline - 0,200 (71 wt.%)
Salbutamol - 0,008 (3 wt.%)
IPK - 0,072 (26 wt.%)
was prepared according to example 3. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the sixth string.

Example 7.

A pharmaceutical composition comprising (g):
Theophylline - 0,200 (80 wt.%)
Salbutamol - 0,008 (3.2 wt.%)
IPK - 0,042 (16,8 wt.%)
was prepared according to example 2. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the seventh string.

Example 8.

A pharmaceutical composition comprising (g):
Theophylline - 0,200 (67 wt.%)
Salbutamol hemisuccinate - 0,006 (2 wt.%)
IPK - 0,094 (31 wt.%)
was prepared according to example 1. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the eighth string.

IPK - 0,050 (19 wt.%)
was prepared according to example 2. Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the ninth line.

Example 10 (the prototype).

Medicinal composition [1], which contains (g):
Theophylline - 0,300 (50 wt.%)
Salbutamol sulfate 0,004 (1 wt.%)
Excipients - 0,296 (49 wt.%)
Kinetic data release of substances in percent, averaged over the results of six experiments are shown in table 1, the tenth line.

Were conducted medico-biological tests, including the study of acute toxicity of the claimed composition in mice, rats. For biomedical tests were used, the composition of example 1.

Study of acute toxicity of the inventive compositions on the basis of salbutamol hemisuccinate held on nonlinear white rats and nonlinear white mice. Acute toxicity was determined by the method of probit analysis according to Litchfield and Wilcoxon signed with the calculation of the toxic dose - LD. Calculated on the basis of experimental data toxic dose-LD for the composition and mixture of drugs after intragastric application are presented in table.2.

As can be seen from the table data for rats and for mice (79% and 52%, respectively). This fact shows that the polymeric carrier IPC entered into the drug for prolonged release of drugs, leads, in addition, to reduce their toxic action on the organism.

A study was conducted pharmacokinetics of the claimed composition in comparison with known drug toastin.

A comparative study of the main pharmacokinetic parameters of drugs on patients: 2 patients (men aged 21-42 g weight 70-68 kg) were taken in the morning on an empty stomach 1 tablet of the claimed pharmaceutical compositions and 2 patients (men aged 25-45 years, 74-90 kg) were taken in the morning on an empty stomach 2 tablets coastline. Sampling the blood of patients underwent elbow through the catheter to the drug and after 1, 3, 6, 9, 12 and 24 hours after administration. Calculation of pharmacokinetic parameters was performed according to the program "Farm", which uses the method of least squares, statistical processing according to the program "Stat".

The pharmacokinetic parameters of theophylline and salbutamol when receiving the claimed composition and coastline presented in table. 3,4.

Based on the study of the basic pharmacokinetic parameters of drugs has been shown that the absorption of theophylline claimed composition is characterized by a longer elimination of theophylline compared with coastlines. In accordance with this, the average retention time of theophylline after administration of the inventive compositions more, and ranges from 19 to 31.1 hours compared with coastlines of 14.5. Somewhat higher and the amount of clearance (half-life of drugs by the kidneys) of theophylline after taking coastline compared with the claimed composition.

Relative biodostupnostthew the claimed composition according to theophylline was calculated by the equation [2]

where f is the relative bioavailability;
AUC - area under the pharmacokinetic curve;
S - standard drug;
R - investigational drug.

According to calculations, theophylline relative bioavailability of the tablets of the claimed composition is 180,3% (n=2) in relation to tablets coastline.

When comparing the pharmacokinetic parameters found considerable similarity in the values of the key parameters characterizing the absorption and excretion of salbutamol. For coastline is characterized by a somewhat slower excretion of salbutamol. The relative bioavailability of the claimed composition on salbutamol is 105,4% (n=2) in relation to coastline.

Comparison farmakokineticheskie allows you to decrease the dose.

A study of the pharmacodynamics of the claimed composition during the course of treatment - effect on the function of external respiration (respiratory function).

The study included 90 patients with bronchial asthma at the age of 17-77 years. A mild case of asthma among 6 people, moderate in 6 people, severe 78 people. Patients were under constant aggravation. Treatment was started in the hospital, after dose selection and evaluation of the effectiveness of the drug further continued outpatient treatment. The duration of treatment from 1 month to 3 years. For comparison, 24 people took coastline within 1 month.

All patients had conducted a study of respiratory function respiratory complex firms Erich Jaeger specially developed programs. In the study of curves flow - volume forced inspiratory and expiratory indices of airway resistance and structure of the reserve volume of the lungs was determined bodyplethysmography method. The reliability of the obtained data was evaluated by student's criterion.

From the data given in table.5, shows a significant reduction in airway resistance compared with baseline (R), a statistically significant increase in the cu is the preliminary study of the effect of combination drugs - declare and coastline on the function of external respiration (table.6) revealed a significant increase of performance curves flow-volume and decrease airway resistance in patients receiving both drugs. Domestic drug is not inferior to their foreign counterpart, and for some indicators (coefficient of bronchodilatory FEV1) even surpasses it.

Analysis of the side effects found when using both drugs (table. 7) showed that the claimed composition is less likely to cause tachycardia, arrhythmia, tremor of hands and skin allergic reactions.

During the follow up period there was no single case of serious complications from taking the combined long-acting drugs.

Studies have shown that the claimed composition is highly effective bronchodilator drug in patients with bronchial asthma, have few side effects and can be recommended for wide clinical application in patients with obstructive lung diseases.

Captions to drawings.

Fig. 1. Release (Q) of theophylline and salbutamol sulphate tablets "Coastlin CF" in conditions simulating the gastrointestinal tract (within 2 hours in the tion (Q) of theophylline and salbutamol of hemisuccinate of the tablets of the claimed composition, containing theophylline 0.2 g of salbutamol hemisuccinate 0,006 g and CRP 0,094 g (example 8) in conditions simulating the gastrointestinal tract (within 2 hours in an environment with a pH of 1.2, then - in an environment with pH 7.5). Curve 1 - salbutamol hemisuccinate; 2 - theophylline.

Fig. 3. Release (Q) of theophylline and salbutamol of hemisuccinate tablets claimed composition containing theophylline 0.2 g of salbutamol hemisuccinate 0.01 g and CRP 0.05 g (example 9) in conditions simulating the gastrointestinal tract (within 2 hours in an environment with a pH of 1.2, then - in an environment with pH 7.5). Curve 1 - salbutamol hemisuccinate; 2 - theophylline.

LITERATURE
1. Brochure of the firm Cipla (India).

2. Soloviev, C. N., Firsov, A. A., Filov Century A. Pharmacokinetics. - M.: Medicine, 1980.


Claims

1. Bronchodilators composition on the basis of theophylline and salbutamol, including excipients, characterized in that the composition includes interpolymer complex polymethacrylic acid and polyethylene glycol, salbutamol is used in the form of a base or salt.

2. Bronchodilatory containing theophylline, salbutamol or its salt, a polymeric carrier and auxiliary substances, differing poliatilenglikola and as auxiliary substances it contains calcium stearate in the following ratio of components, wt. %:
Theophylline - 60-80
Salbutamol or its salts - 1-4
Interpolymer complex - 16-39
Calcium stearate - 0,05-1,0
3. Bronchodilator medication in the form of tablets containing theophylline, salbutamol or its salt, a polymeric carrier and an excipient, wherein as the polymer carrier it contains interpolymer complex polymethacrylic acid and polyethylene glycol as an excipient, it contains calcium stearate in the following ratio, wt.%:
Theophylline - 60-80
Salbutamol or its salts - 1-4
Interpolymer complex - 16-39
Calcium stearate - 0,05-1,0
4. A method of obtaining a bronchodilator drug under item 3, characterized in that it is prepared by mixing the components, granulation, drying and tabletting the mixture.

5. A method of obtaining a bronchodilator drug under item 3, characterized in that it is prepared by mixing the components, pelletizing, grinding bricks and tabletting the obtained granulate.

6. A method of obtaining a bronchodilator drug under item 3, characterized in that it is prepared by mixing the components and direct compression of the mixture.

 

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