Medicament with prolonged anti-calcium activity in the form of 1/10% intravenous solution

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention, in particular, relates to prolonged therapeutical form of domestic slow calcium channel blocker, namely ankardin-retard-AZIn (active principle 7,7-ethylenedioxybenzopyran-2,2-dione) in the form of 0.1% solution administered in dose 1 ml in the form of complex with poly(ethylene oxide) 400. Pre-clinical investigations indicated that Ankardin-retard-AZIn was a sufficiently active calcium ion antagonist and, after clinical investigations, it could be applied in medical practice for prevention and treatment of cardiovascular diseases.

EFFECT: extended choice of drugs.

6 tbl, 4 ex

 

The invention relates to medicine and pharmacy, namely to pharmacotherapy of disorders of the cardiovascular system, and the development of new anti-ischemic tool ankerdine-retard AZIn in the form of a 0.1% solution for intravenous possessing prolonged anticalcium action.

In medical practice a number of anti-ischemic drugs with short and prolonged anticalcium activity: phenoptin, nifedipine, diltiazem, senzit, difril (Mashkovsky PPM Medicines. - 2000. 1. - s-415), as well as the newly developed drugs are short-range diamancel-forte (Abishev AS, Agayev AM, Borisenko O.V. Patent of Russia 2187303 C1) and ankerdine-retard AZT (Abishev AS, Agayev AM Patent of Russia 2219927 C1).

However, the above calcium antagonists have a high incidence of side effects, such as phenoptin to 10%, and nifedipine 30%, manifested in the form of swelling of the legs, hypotension, changes in heart rate, hyperglycemia, headache, dizziness, fatigue, flushing of the skin (Mashkovsky PPM Medicines. - 2000. 1. - s, 301, 185). In addition, in recent years, noted that the use of short acting dihydropyridines, especially nifedipine, may increase the risk of developing a malignant tumor is, myocardial infarction and death in patients with arterial hypertension (Kuleshov EV calcium Antagonists and their role in the treatment of diseases of the cardiovascular system. - 2002. - part 1 and 2; Furberg .D., Psaty B.M, Meyer J.V. Circulation. - 1995. - V.92. - R-1331; Psaty V. M., Heckbert S.R., T.D. Koepsell et al. JAMA. - 1995. - V.274. - P.620-625; Pahor m, Psaty B.M., M.H. Alderman et al. Lancet. - 2000. - Dec.9. - 356 (9246):1970-4). In animal experiments has also been established embryotoxicity of diltiazem and most of the calcium antagonists 1,4-dihydropyridine. When long-term therapy with diltiazem, nifedipine and felodipina in the early stages of pregnancy are documented cases of intrauterine fetal death and abnormalities of skeletal development in infants. Therefore, diltiazem and all of 1,4-dihydropyridine derivatives of the first and second generation contraindicated in any pregnancy (Svensson A. Clin. Exp. Hypertension. - 1993. - V.15. - R-1361; Lowe S.A., RubinP. C.J. Hypertension. - 1992. - V.10. - P.201-207).

As for new antagonists of calcium diamancel-forte and ankerdine-retard-AZT, although they are the most active, than their counterparts, and do not have the above-mentioned side effects, but the first is virtually insoluble in aqueous media and therefore slowly permeates through the membrane (within 2 hours) and circulates in the blood line not more than 8 hours, while the second exhibits a consistent prolonged action for 26 hours and the maximum concentration in PLA is IU the blood is only 1.5 hours.

In connection with the above, the development of a new calcium antagonist in the form of a solution for intravenous administration in emergency cases and with prolonged action is urgent because, despite the small number, the list of indications for their use is expanding: arterial hypertension, chronic coronary insufficiency, cardiac arrhythmias, neurological, psychiatric practice and other

The closest to the physico-chemical and pharmacological properties of the claimed product is of ankerdine-retard AZT (Abishev AS, Agayev AM Patent of Russia 2219927 C1).

Therefore, the aim of the present invention is to develop a new drug is an antagonist of calcium ions (ankerdine-retard-AZIn) in the form of a 0.1% solution for intravenous administration in emergency cases, in which the active ingredient is the same 7,7’-ethylenediaminetetra-2,2’-dione.

This goal is achieved by the synthesis of a new combined connection ankerdine-retard-AZIn, representing a complex of 7,7’-ethylenediaminetetra-2,2’-dione with polyethylene oxide with average molecular weight of 400 (REO-400), widely used in pharmaceutical practice, to obtain water-soluble hydrophobic drugs.

To astasia time to declare connection technology for producing the dosage form in the form of a 0.1% solution of 1 ml (ankerdine-retard-AZIn), in which, as described above, as the active component contains 0.001 g substance diamancel. For the specified dosage forms studied technological and pharmacological parameters.

The invention is illustrated by the following specific examples of pre-clinical and technological research:

Example 1. The technology of obtaining injectable form ankerdine-retard-AZIn.

In a glass reactor with a capacity of 3 l is placed a portion pulverized powder substance diamancel and the required number of REO-400. The mixture with constant stirring warm for 3 hours at a temperature of 100°C. Then, with constant stirring, add the required amount of injection water with a temperature close to 100°C. Then, the solution cooled to room temperature under aseptic conditions and filtered through a paper filter.

The resulting solution was poured into ampoules of 1 ml, sealed, check on their tightness, sterilized for 1 hour at a temperature of 105°With control on the mechanical inclusion, labeled and Packed into containers.

For this technology is received and tested 5 batches of product that meets the requirements of the global Fund XI publications (see table 1).

Example 2. The trial of antiarrhythmic activity of various dosage forms of diamancel on chloralkali model arrhythmia.

the La setting antiarrhythmic actions of various forms of diamancel study preventive activity on the model of ventricular fibrillation, caused by the method Malinow et al. (Malinow, M., F. Battle, Malamud Century Nervous mechanisms in ventricular arrhythmias by calcium chloride in rats. Circulat. Res., 1953. - Vol.I. - N-6. - p.554-559).

For this group of laboratory animals (rats 8 individuals) administered study drugs (diamancel-forte, ankerdine-retard-AZT and ankerdine-retard-AZIn of 0.1% at 1 ml) in a dose of 1 mg/kg For testing tablets two groups of rats (8 animals each) enter suspension of diamancel-forte and ankerdine-retard-AZT prepared in 0.9% sodium chloride solution with the addition of Tween-80), as well as ankerdine-retard-AZIn in the same dose. Rats control series injected solvent, animal group comparison - suspension substance diamancel prepared in 0.9% sodium chloride solution with the addition of Tween-80, at the same dose. After exposure (see. table 2) all animals injected intravenously 10% solution of calcium chloride at a dose of 300 mg/kg and spend the ECG recording in the second standard lead. See the development of ventricular fibrillation. Take into account the frequency of implementation of arrhythmias, the frequency of sinus rhythm, the duration of the arrhythmia, the frequency of death. Parameters duration of arrhythmias assessed by student's criterion, the frequency of implementation of arrhythmia, sinus rhythm, and death by Chi - square. The results of the experiments are shown in table 2.

As follows from table 2, diamancel significantly reduces the frequency of death alive is different from adults, in this case, the implementation of arrhythmia reliably manifests the property of the drug to restore sinus rhythm. The differences between the different dosage forms domuncula and substance of all of the parameters are statistically insignificant, however, significantly (p<0,05) different from the control series at exposure of 2.5 hours between the introduction, in particular diamancel-forte, ankerdine-retard (AZT and AZIn) and aritmogeni (frequency vosstanavlivaya normal rhythm and the ability to prevent the death of animals). This shows comparable activity of these dosage forms domuncula and its substance. If you increase the exposure up to 26 hours of the dosage forms listed only ankerdine-retard (AZT and AZIn) retains its effect to the same extent, whereas substance and diamancel-fbrte not active. Therefore, ankerdine-retard (AZT and AZIn) comparable activity with the substance and dimensiom-forte, but significantly exceeds their duration of action, the latter of ankerdine-retard-AZIn comes almost immediately after the introduction (within 5-10 min), which is also evident from the data on comparative pharmacokinetic studies of various dosage forms of nifedipine and domuncula (see tables 3 and 4). Thus, it can be noted that the objective has been achieved.

Example 3. Test protivojishemical the activity of various medicinal forms of diamancel on the model of occlusion of a coronary artery.

To establish anti-ischemic effect of different dosage forms domuncula studied preventive activity in a model of acute coronary occlusion caused by ligation of the anterior branch of the left coronary artery in the middle third method Nversatio (Marrucina NV On the experimental reproduction in rabbits myocardial infarction and arrhythmias (Cardiology. - 1972. No. 12. - S-111).

For this group of laboratory animals (rats 8 individuals) administered the test drugs (diamancel-forte, ankerdine-retard-AZT and ankerdine-retard-AZIn 0.1% solution 1 ml) in a dose of 1 mg/kg For testing tablets two groups of rats (8 animals each) enter suspension of diamancel-forte and ankerdine-retard-AZT prepared in 0.9% sodium chloride solution with the addition of Tween-80, and ankerdine-retard-AZIn in the same dose. Rats control series injected solvent, animal group comparison - suspension substance diamancel prepared in 0.9% sodium chloride solution with the addition of Tween-80, at the same dose. After exposure (see table 5) in all animals cause occlusion of the coronary artery and spend the ECG recording in the second standard lead. See the development of signs of myocardial ischemia: decreased R-wave voltage, expressed recovery interval ST (cat's hump”). Take into account the severity of signs of ischemia in % (R-wave - to the original level, the interval ST - UB is Nude). The parameters of the severity of ischemia assessed by student's criterion. The results of the experiments are given in table 5.

As follows from table 5, when the exposure 2.5 h all legform diamancel, and after 20 h only ankerdine-retard (AZT and AZIn) significantly (p<0,05) compared to the control prevents the decrease of the voltage of the R-wave (11-16%) and the rise of the ST segment (16-22%), indicating that the anti-ischemic effect of the study drug. Differences between sectorname diamancel at exposure of 2.5 h, and between the effects ankerdine-retard (AZT and AZIn) when both exposures are statistically insignificant, this allows to conclude about the comparable activity of all legform diamancel at exposure of 2.5 h, and ankerdine-retard (AZT and AZIn) (2.5 and 20 h). With increasing exposure to 20 h the severity of ischemia on the background of substance and diamancel-forte becomes indistinguishable from that in the control series, whereas ankerdine-retard (AZT and AZIn) exerts anti-ischemic properties in the same way as and when the exposure of 2.5 hours This indicates significantly longer compared to the rest of sectorname diamancel anti-ischemic effect ankerdine-retard (AZT and AZIn). Therefore, ankerdine-retard (AZT and AZIn) and diamancel-forte comparable activity with the substance of diamancel, however ankerdine-retard (AZT and AZIn) significantly exceeds that of other dosage forms and the substantive is in duration of action.

Example 4. Test deprimating activity of various dosage forms of diamancel in the test potentiation subthreshold dose of sodium thiopental.

To establish the duration of action of various dosage forms of diamancel study potentiation of drug action subthreshold dose (12 mg/kg, I/V) sodium thiopental (Rajewski HP Pharmacology of neuroleptics. - M, - 1976., 271 (C).

For this group of laboratory animals (rats 8 individuals) to introduce the study drug (diamancel-forte, ankerdine-retard-AZT and ankerdine-retard-AZIn 0.1% solution 1 ml) in a dose of 1 mg/kg For testing tablets two groups of rats (8 animals each) enter suspension of diamancel-forte and ankerdine-retard AZT, prepared in 0.9% sodium chloride solution with the addition of Tween-80), as well as ankerdine-retard-AZIn in the same dose. Rats control series injected solvent, animal group comparison - suspension substance diamancel prepared in 0.9% sodium chloride solution with the addition of Tween-80, at the same dose. After exposure (see table. 6) all animals in the/type in a freshly prepared solution of sodium thiopental (12 mg/kg). See the development of the lateral position of the animal. The frequency of occurrence of lateral position estimate by Chi-square. The results of the experiments are shown in table 6.

As follows from table 6, all forms of diamancel demonstrate the ability in order to potentiate narcotic effect of sodium thiopental at exposure of 2 hours between administration of the drug and the test agent. The drug entered all lekforma, shows comparable activity, a statistically significant relative to control, but not distinguished between the different dosage forms of the drug. When exposure 18 h between the introduction of diamancel and sodium thiopental activity diamancel-forte, ankerdine-retard and substance did not differ from control. However ankerdine-retard-AZT retained its activity at the level of the other forms on exposure 2 hours.

Thus, diamancel-forte, ankerdine-retard-AZT and substance of diamancel comparable in activity, however, ankerdine-retard-AZT compared to other sectorname and substance has a greater duration. However, if you consider that the content of the active component in ankerdine-retard-AZIn significantly less (20 times)than in ankerdine-retard-AZT and on all tests of its validity is almost at the level of the latter, the prospects of applying ankerdine-retard-AZIn in emergency cases, the treatment of arterial hypertension and ischemic heart disease as antianginal means more preferable. In addition, as can be seen from the pharmacokinetic data presented in tables 3 and 4, the maximum concentration ankerdine-retard-AZT in plasma is reached in 1.5 hours after taking the drug, whereas a similar concentration at ankerdine-retard-AZIn is istihaada almost immediately after the introduction within 5-10 minutes

As a result of preclinical pharmacodynamic (see tables 2, 5 and 6) and pharmacokinetic (see tables 3 and 4) studies have shown that ankerdine-retard (AZT and AZIn) has prolonged high activity and good bioavailability.

4.
Table 2.

Comparative activity of different dosage forms of diamancel influence on model chloralkali arrhythmia.
№ p/pSubstanceExposure time, hFrequency implementation arrhythmia %The frequency of sinus rhythm, %The duration of the arrhythmiaThe frequency of mortality, %
1.Diamancel-forte2,587,542,9*48,7±5,050,0*
2.Diamancel-forte26100,00.046,8±4,2100,0
3.Ankerdine-retard AZT2,587,542,9*50,1±5,050,0*
Ankerdine-retard AZT2675,050,0*47,7±4,137,5*
5.Ankerdine-retard AZIn2,575,033,344,5±4,650,0*
6The substance of diamancel26100,00,042,2±4,3100,0
7Solvent2,5100,00,043,2±4,4100,0
8.Solvent26100,00,050,1±5,2100,0
* p< 0.05 compared with the control series
Table 3

The main pharmacokinetic characteristics retarding forms of nifedipine (“C”) and Dimanche (“AZT”).
DrugsCmaxng/mlTmaxhourAUC ng/ml * hX/And %
“C”40,03,0423,3116,5
“AZT”65,51,5530,8145,6
X/A is the relative bioavailability compared to the drug “S”

Table 4

The parameters characterizing the prolonged action retarding dosage forms of nifedipine (“b” and “C”) and Dimanche (“AZT” and “AZIn”).
DrugsMRT, hHV, ng/mlHVD, h
“B”7,116,06,6
“C”9,120,57,2
“AZT”16,045,028,5
“AZIn”20.062.520.0

The data presented in tables 3 and 4, which were obtained by graphical and mathematical modeling. The maximum concentration of the drugmaxthe relative time of occurrence of Tmaxand the area under the curve of concentration-time (AUC), as in the case of nifedipine (U.S. Patent 4,880,623) were calculated for the FCP is full of curves

Table 5.

Comparative activity of different dosage forms of diamancel influence on the model of coronary occlusion.
№ p/pSubstanceExposure time, hThe voltage of the R-wave (% of initial level)The degree of ST elevation (% to control)
1.Diamancel-forte2,558,2*of 83.4*
2.Diamancel-forte2042,2102,1
3.Ankerdine-retard AZT2,560,0*80,4*
4.Ankerdine-retard AZT2058,3*83,1*
5.Ankerdine-retard AZIn2,562,1*78,0*
6.The substance of diamancel2,557,0*82,2*
7.The substance of diamancel2045,999,0
8.Solvent2,546,2100,0
9.Solvent2044,0100,0
* p<0.05 compared with the control series

Table 6.

Comparative activity of different dosage forms of diamancel influence on narcotic effect of sodium thiopental.
№ p/pSubstanceExposure time, hThe frequency of occurrence of lateral position, %
1.Diamancel-forte2-62,5*
2.Diamancel-forte1812,5
3.Ankerdine-retard AZT2B2,5*
4.Ankerdine-retard AZT1875,0*
5.Ankerdine-retard AZIn275,0*
6.Ankerdine-retard AZIn180,0
7.The substance of diamancel262,5*
8.The substance of diamancel1812,5
9.Solvent20,0
10.Solvent180,0
* p<0.05 compared with the control series

The tool prolonged anticarcinoma steps, characterized in that a represents a 0.1% solution of 1 ml for intravenous administration containing as an active ingredient 0.001 g of 7,7-ethylenediaminetetra-2,2-dione in the form of a complex with polyethylene oxide of molecular weight 400.



 

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10 cl, 3 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with cryoprotective preparations that contain recombinant interferon-α2. The suggested cryoprotective preparation contains recombinant interferon-α2, polyethylene glycol 3000-6000, polyglucin, buffered 0.02%-Trilon B solution at pH being 5.5-7.0 and glycerol at certain ratio of components per 1.0 g preparation. The suggested cryoprotective preparation can additionally contain glycine, 3,7-bis(dimethylamino)phenothiazonium chloride, dry immunoglobulin preparation or dry immunoglobulin preparation for enteral intake. The present innovation provides maximal keeping the activity of recombinant interferon-α2 in cryoprotective preparation at multiple alteration of positive and negative environmental temperature and during storing this cryoprotective preparation under these conditions.

EFFECT: higher efficiency of application.

4 cl, 8 ex

FIELD: veterinary science.

SUBSTANCE: the suggested preparation is being the solution of either avermectines or their derivatives in organic solvents or their mixtures at concentration of 1-35 g/100 ml; as organic solvents the preparation contains benzyl alcohol, ethanol, triethylene glycol, dimethylsulfoxide or their mixtures. This preparation provides in case of needle-free injection the development of "depot" of active substance. Moreover, the latter practically does not enter milk, so the preparation could be applied for treating lactating cows.

EFFECT: higher efficiency of needle-free injection technique.

1 cl, 2 dwg, 3 tbl

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I

as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.

EFFECT: higher efficiency.

10 cl, 15 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.

EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

FIELD: pharmacology, fluorinated quinolone-based drug, in particular ofloxacine for injections.

SUBSTANCE: claimed composition contains therapeutically acceptable amount of ofloxacine and trilon-B, sodium chloride, water for injections as additives.

EFFECT: high therapeutic effectiveness; non-crystallized active agent for a long-time storage.

1 ex

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