Pharmaceutical composition for reduction of primary radiation response and early transient incapability

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition for the reduction of a primary radiation response and an early transient incapacity containing ondansetron and gastrozepin in mass ratio 1-12:2-15; the composition is used as an injectable dosage form.

EFFECT: what is developed is the new composition.

3 cl, 3 tbl, 2 dwg

 

The present invention relates to a new combination pharmaceutical composition which may find application as a means of protection from ionizing radiation, in particular for the relief of the primary reaction to radiation (BMD) and an early transient incapacitation.

On the territory of the Russian Federation in organizations using sources of ionizing radiation, are more than 222 thousand personnel categories "A" and "B" [Onishchenko GG Results and prospects of radiation safety of the population of the Russian Federation, Onishchenko // Radiation hygiene. - 2008. 1, spec. release. - P.4-10.]. Only in the last decade in our country on radiation-dangerous objects recorded 36 emergency situations, involving more than 80 people, of whom 48 had received acute radiation and combined lesions [Kotenko C.V. Radiation accident of the third Millennium Russia (2000-2007) with the development of acute radiation injuries / C.V. Kotenko, A. Bushmanov // Herald of the Russian military-medical Academy. - 2008. - №3 (23). - Pril. - page 39-43].

Despite an international agreement to limit the use of nuclear weapons remains the possibility of its application in modern wars and local conflicts, and the threat of nuclear terrorism in recent years has been steadily age is t [Kutsenko S.A. Promising directions of improvement of medical devices radiation and chemical protection / S. Kutsenko, A. Grebenyuk // Medical aspects of radiation and chemical safety: Materials Grew. scient. proc. - SPb., 2001. - p.24-26;

Organization of sanitary-hygienic and medical-preventive measures in case of radiation accidents: Manual / edited by L.A. Ilyin. - M.: vzmc Protection, 2005. - 522 pages

Cirincione J. Deadly arsenals: tracking weapons of mass distraction / J. Cirincione, J.B. Wolfsthal, M. Rajkumar // Modern dangerous. - Washington: Carnegie Endowment for International Peace, 2002. - p.175-186].

All this suggests that currently there is an urgent need for effective medical tools, radiation protection, and further improvement in the light of the requirements of the Federal law "On radiation safety of population" [On radiation safety of population: the Federal law from 09.01.96 No. 3 - FZ. / SOBR. legislation of the Russian Federation. - 1996. No. 7. - str-1616], is one of the priority tasks on national security.

Known application of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it or its hydrate or its salts as a means of acute emetic response caused by the use of drugs or other means of chemotherapy and/or rent is norditropin tumors or radiation. Most often this purpose hydrochloride dehydrate 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it (ondansetron, Letran) (I) (a Patent of great Britain No. 2153821, 2290963; European patent No. 191562, 219929; the patent of Russia №1528319, 2041876, 2159614 and other Order of the chief of gumu MO of the Russian Federation No. 224 from 01.06.1996 "Of acceptance for the supply of medical services of the Armed forces of the Russian Federation tablets latrine 0,004 covered shell").

Known applications for the prevention of primary reaction to radiation and the early transient incapacitation of several compositions of physiologically active substances on the basis of ondansetron.

One such drug is a combination of ondansetron and benzamide or its derivatives (Patent RF №2229882). The disadvantage of this tool is the poor efficiency in protecting against diarrhea.

C6H5CN

Benzamid

Renowned pharmaceutical composition comprising ondansetron and metacin (iodine-methylate 2-dimethylaminoethanol ether benzyl acid) (II) (Patent RF №2185825), which has improved animationtime properties and a significant reduction in diarrhoeal syndrome (closest equivalent).

Described pharmaceutical composition containing ondansetron, metacin and benzamid (P is the tent of the Russian Federation No. 2234315), with improved antiemetic activity, especially at high doses of ionizing radiation.

Known combo drug consisting of ondansetron or its salts (I) and metacin (II), which added caffeine (III) if the ratio of ingredients in a 4:1:20÷300 (RF Patent No. 2363463)with improved properties improve efficiency.

The disadvantage of the above medicines and pharmaceutical compositions is that they are all solid dosage (potentially) tools that can not only be used for prevention, but not heavily ABOUT when developed vomiting and diarrhea.

The objective of the invention is to provide pharmaceutical compositions for edema and ABOUT early transient incapacitation, which is possible only in injectable dosage forms. The task is dictated by the modern methods of warfare, especially the ability to use in combat so-called tactical nuclear weapons. In terms of warfare and, in particular, in the use of nuclear (including neutron) weapons especially important is the use of such funds in the form of a single injection, which can be done in the manner of self - or mutual.

Was necessary, it seemed easy solution: to prepare a pharmaceutical composition, comprising ondansetron and metacin, similarly tableted dosage form according to the patent of Russian Federation №2185825. You have made numerous attempts at creating such a composition, but they all failed. The best performance with the use of a solubilizer Solutol HS-15, salubrizare Kollidon 12 PF and varying amounts of propylene glycol or polyethylene oxide 400, which was laid on the study of preservation, has withstood the "accelerated" aging in terms of room temperature, a few more years, then dropped a small amount, which according to thin-layer chromatography was hydroiodic ondansetron.

Were investigated, some used in medical practice M-cholinolytics, for example, Tropicamide, cyclomed, gastrotsepin.

The problem is solved by the creation of a pharmaceutical composition on the basis of ondansetron gastrochaena.

Gastrotsepin [INN - Pirenzepine (Pirenzepine)] synonyms Gastrozepin, Pyrene-Sapin, Gastrosil, Gastrozepin, Castroman, Getropin, Gastric, Pyrene, Abrinac, Bisvanil, Duogestral, Gasteril, Gastrol, Gastropin, Gastropiren, Gastrozepin, Leblon, Pirezam, Pirigast, Ulcepin, Ulcin, Ulcopir, Ulcosan, Ulcozepin.

5,11-Dihydro-11-[4-methyl-1-(piperazinil)acetyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-7-he Digi rochloride

Gastrotsepin - blocker M1-acetylcholine receptors. Does not penetrate the BBB and has no effect on the Central nervous system; chronotropic action expressed little. In therapeutic doses does not significantly affect the motility of the gallbladder and bladder. Inhibits the secretion of gastric juice, reduce the secretion of gastrin, reduces the production of hydrochloric acid and pepsin. After stimulation with histamine blocking the secretion of hydrochloric acid 25%; after eating - 53%; after the introduction of insulin by 58%. At 1 h after ingestion of pirenzepine reduces the secretion of hydrochloric acid by 48% and 30% for 2 hours pepsin Secretion stimulated by insulin, reduced by 49%, histamine - 34%. Inhibits the secretion of bicarbonate from the epithelium into the cavity of the stomach in patients with erosive lesions of the antrum and strengthens the protection of the gastric mucosa; increases blood flow into the submucosal layer of the stomach and intestines, improves microcirculation.

Gastrotsepin not completely absorbed in the digestive tract. The maximum concentration in plasma is determined after 2-3 h after administration. After oral administration, the average bioavailability of 10%to 20%. Simultaneous administration with food decreases the value of AUC by 30%. Only 12% pirenzepine bound to plasma proteins [Carmine A., Brogden R.N., Pirenzepine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in peptic ulcer disease and other allied diseases, Drgs, v.30, No.2, p.85-126, 1985]. Poorly crosses the placental barrier and the blood. Once inside almost completely excreted in the feces, parenteral equally in urine and feces. Total plasma clearance is approximately 250 ml/min Renal clearance is about half the size, which is approximately equivalent to the level of glomerular filtration. The drug is characterized by a long half-life (10-12 h), which explains its long-lasting therapeutic effect. The pharmacokinetics of the drug in renal or hepatic insufficiency does not change significantly. The apparent volume of distribution averaged 14 l, which corresponds to the approximate volume of the extracellular space of the person.

Gastrotsepin used in gastric ulcer and 12 duodenal ulcer (treatment and prevention); erosive-ulcerative lesions of the gastrointestinal tract, including those caused by anti-rheumatic and anti-inflammatory drugs; stress ulcers of the gastrointestinal tract [93]; chronic hyperacid reflux esophagitis; syndrome Zollinger-Ellison; bleeding from erosions and ulcerations in the upper GI tract.

Gastrotsepin easily soluble in water, poorly in methanol, very bad in ethanol and methylene chloride.

Thus, based on literature data it was difficult to assume a high opticianry activity is of gastrochaena.

According to the present invention features a pharmaceutical composition for the relief of the primary reaction to radiation (PRO), containing in its composition ondansetron and astrocamp in injectable dosage form.

In the proposed pharmaceutical composition ondansetron use in the form of the hydrochloride dihydrate, and gastrotsepin as dichlorhydrate.

The pharmaceutical composition contains ondansetron and gastrotsepin mass ratio 1-12:2-15.

To create a dosage form used in the pharmaceutical composition of composition:

Pharmaceutical substanceThe ratio in weight./vol.%
Ondansetron (Letran)0.1 to 1.2 percent by weight
Gastrotsepin0,2-1,5% weight
Water for injectionto 100 ml

Mainly use the following ratio of components in weight percent: ondansetron: gastrotsepin 2-10:4-10.

Lower settings pharmaceutical compositions are determined by the efficiency legform when knocking ABOUT. Upper limits associated with the solubility of substances in the dosage form.

To omnitele, the compositions may include bactericides, such as methyl or propyl parabens.

The compositions may contain a polar organic solvents such as propylene glycol (see example 2), the polyethylene glycol-400, dimethyl sulfoxide in the amounts allowed in the State Pharmacopoeia of the Russian Federation.

The proposed composition for the first time allows for not only prevention, but also to pain ABOUT.

The following examples illustrate but do not limit the claims of the applicant.

Experimental examples

Example 1

300 ml ampoule solution gastrochaena dissolved 2.4 g of dichlorhydrate hydrate ondansetron, was filtered through a filter 0,22 µm, poured sterile for ampoules and vials. Be aware that drug in the form of gastrochaena contains almost 40% propylene glycol, but since this dosage form is intended for intravenous or intramuscular injection, we left for the beginning used a ready lectora of gastrochaena. Although injectable dosage form used in the Russian Federation, it contains a greater quantity of propylene glycol than is allowed by the State Pharmacopoeia of the Russian Federation. Studied in this example, the composition is not suitable for use for people in Russia, but it is useful to assess the effectiveness of the animal (composition 1).

Determining the content of the acting is x substances carried out by HPLC method.

1 ml of the composition of ondansetron hydrochloride dihydrate and gastrochaena dissolved in 19 ml of hexane (mark "OFS"), add 200 ál of methanol (solution A). Solution A was placed in an ultrasonic bath for 3 minutes and then subjected to solid phase extraction.

Solid-phase extraction: Chuck, Deepak P (1 ml) condition 4 ml of hexane (mark "OFS"), through the cartridge miss 2 ml of solution A at a rate of 0.5 ml/min, then the cartridge was washed with 4 ml of hexane (mark "OFS"). The cartridge dry air 20 minutes the Analytes desorbed from the cartridge eluent to a final volume of 4 ml of the eluate Obtained solution chromatographic three to five times, using high-performance liquid chromatograph. Conditions chromatographic analysis: column stainless steel of 3.9×300 mm, filled with octadecylsilane (C18) with a particle size of 10 μm (e.g. Bondapak C18); mobile phase acetonitrile - phosphate buffer pH=4,6 (20:80); spectrophotometric detector. Solid-phase extraction solution And is conducted in three rounds of Deepak P.

Parallel conduct solid-phase extraction (three rounds of Deepak P) with subsequent chromatographic analysis of the solution of standard samples of ondansetron hydrochloride and gastrochaena. Calculation of the content of active substances carried out by standard methods.

Example 2

In 470 ml of water for injects the th dissolved 4.0 g of dichlorhydrate hydrate ondansetron and 2.5 g of dichlorhydrate of gastrochaena, bring water to a 500 ml. Filtered through a filter 0,22 µm, poured into sterile for ampoules and vials (composition 1).

Chromatographic analysis was performed by standard methods using standard samples of ondansetron and gastrochaena.

The samples were laid on storage under accelerated aging composition latrine and gastrochaena withstand storage at temperatures of 50 and 60°C is equivalent to 2.5 years of storage pari normal conditions.

Experimental biological examples

General characteristics of the experimental material and irradiation conditions

In the initial examination of experimental animals paid attention to their General condition, physical activity, condition of coat and visible mucous membranes. Patients and substandard animals penalized. Selected for the experiments the animals were kept in a vivarium conditions on a standard diet with free access to water. Prior to the present study, animals were placed in quarantine, they were within 10-15 days. All experimental and control groups were formed with a uniform distribution of animals by number, gender, body weight, etc. Before irradiation the animals were not fed, but not limited to access to water. All experiments were performed in the first half of the day.

For experimental is modelirovaniya the PPR animals were subjected to General relatively uniform (non-uniform distribution of the absorbed dose in the body segments - 10%) one-time irradiation of gamma-quanta in the installation IGUR-1 (dose - 1,017 Gy/min). For irradiation, the dog was placed in an aluminum container. After irradiation the animals were observed for 5 h in vivarium conditions.

Research on the efficiency of antiemetics

Antiemetic and antidiarrheal activity of the preparations was studied in experiments on dogs irradiated at doses of 20 Gy. Were evaluated by the following indicators anticipations (antiemetic and antidiarrheal activity, according to the requirements of "guidelines for experimental and clinical study of therapies of radiation injuries and medical and biological requirements for these tools:

- the presence of salivation after irradiation;

the number of retching and vomiting;

- the number of acts of vomiting;

the percentage of animals that had a gag reaction.

the time of occurrence of emetic reactions;

- duration of emetic reactions;

the number of urge for defecation;

- the number of acts of defecation;

the percentage of animals which have been recorded acts of defecation;

the time of occurrence of acts of defecation.

The results of experimental studies

The results of the experiments showed that with the introduction of compositions No. 1 and No. 2 visually recorded violations in the General condition and behavior of the dogs was not bluedale. Injection was accompanied by almost no pain. During the first 2 h of observation of experimental animals locomotor activity of dogs kept at a sufficiently high level. Animals were actively moving within the zone of observation. Changes in the reactions of animals to the experimenter and his actions were not observed. In further observed reduced behavioral activity of animals. So, after 4-5 h after drug injection in the behavior of the dogs was significantly dominated by periods of immobility, turning into a short sleep. This caused locomotor activity remained at a relatively high level. When approaching the experimenter dog stood up on his feet and came toward him.

Antiemetic effect of the compositions

General relatively uniform gamma-irradiation dogs at a dose of 20 Gy resulted in the development of animals marked symptoms ABOUT. So, are given in table 1 data show that in all animals of the control group after 25-30 min after irradiation at a dose of 20 Gy was observed the occurrence of vomiting. The number of emetic acts ranging from 5 to 8, with a gag reaction lasted for 80-140 min Development acrophase emetic response falls between 40-60 min after irradiation.

The introduction of complex products has led to significant changes is in the nature of the flow emetic response. So, after the introduction of combination No. 1 in one dog of six postradiation vomiting was not observed. In animals with emetic response latent period last increased 4.5 times, and the number of emetic acts and duration decreased 5.6 and 5.5 times, respectively, compared with the same indicators in the placebo group. Somewhat different pattern was observed with the introduction of irradiated animals combination No. 2. So, of the six dogs, postradiation vomiting was noted in only four. Introduction immediately after irradiation combination No. 2 was increased latent period of 4.0 times, and the number of emetic acts and duration of emetic reactions decreased 9.5 and 7.3 times.

Antiemetic efficacy of combinations (dogs, irradiation at a dose of 20 Gy, n=6 in each group)

Experimental groupThe index value (N±mM)
The number of animals with vomitingThe number of emetic acts absedThe latent period, minThe duration of emetic reactions, min
Placebo66,7±1,527,5±4,6 110±31,8
Composition No. 151,2±0,2*124,3±10,2*20,0±3,2*
Composition No. 24*0,7±0,3*112,5±7,5*15,0±0,1*
* - differences significant (p<0.05) as compared with group "Placebo"

Antidiarrheal activity of the compositions of the Other main syndrome PRO - diarrhea, also visible when exposed to dogs at a dose of 20 Gy. As can be seen from the data given in the table, in the "Placebo" the four animals of the six 10-30 min after irradiation was observed the development of severe diarrhea. Diarrhoea is one - time defecation liquid mass with admixture of mucus. Introduction to the study of complex products completely prevents the development of diarrhea in irradiated animals.

Antidiarrheal efficacy of complex medications (dogs, irradiation at a dose of 20 Gy, n=6 in each group)

Experimental groupThe metric value (M±mM)
The number of stomach what's with diarrhea the latent period, min
Placebo420±9
Composition No. 10*0*
Composition No. 20*0*
* - differences significant (p<0.05) as compared with group "Placebo"

Impact on early post-radiation physical inactivity

Manifestations of early post-radiation inactivity became noticeable after 15-30 min after irradiation, when expressed in the face of diarrheal illness level of spontaneous and evoked motor activity of irradiated animals began to decline (figures 1 and 2). The animals ceased to move within the zone of observation, were a long time in a horizontal position. In the early post-radiation period (1-3 h after irradiation), the level of spontaneous motor activity in irradiated animals ranged greatly from motor "anxiety" (in the period immediately preceding the emetic response or diarrhea) to immobile lying on the side (in the period after the implementation of emetic reactions). Expressed oppression behavioral activity observed spusta hours or more on the background of decreasing the intensity of dyspeptic disorders.

The proposed pharmaceutical compositions can increase the magnitude of spontaneous and induced locomotor activity in irradiated animals 2.5-3.6 times compared with a group of "Placebo". As shown in figure 1 and 2 both compositions affect the behavioral activity of irradiated dogs is almost the same. Spontaneous and evoked locomotor activity of the animals of the experimental group gradually decreases, but remains at a sufficiently high level. Most of the time dog walking or standing, actively respond to external stimuli and commands received from the experimenter.

1. Pharmaceutical composition for relief of the primary reaction to radiation (BMD) and an early transient incapacitation, characterized in that it contains in its composition ondansetron and gastrotsepin mass ratio 1-12:2-15 and is used in injectable dosage forms.

2. The pharmaceutical composition according to claim 1, characterized in that it contains in its composition of ondansetron as the hydrochloride dihydrate, and gastrotsepin as dichlorhydrate.

3. The pharmaceutical composition according to claim 1, characterized in that it contains ondansetron hydrochloride dehydrate, gastrotsepin dichlorhydrate and water in the ratio of wt.%/about.: 0,1-1,2:0,2-1,5 water to 100 ml.

4. The pharmaceutical composition according to claim 1, characterized in that the content is it the ondansetron hydrochloride dehydrate, gastrotsepin dichlorhydrate ratio: 2-10:4-10.



 

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17 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to method of obtaining optically pure antiemetic medication, R-(+)-ondansetron, which includes the following stages: a) processing of ondansetron hydrochloride with base, which is selected from group, containing metal hydroxide and carbonate or bicarbonate; b) processing of free ondansetron base with R/S-(+)-n-toluyl tartrate acid in mixture of dimethylforamide and water obtaining salt of 3-R/S-ondansetron-n-toluene tartrate acid; c) fractional recrystallisation of salt of 3-R/S- ondansetron-n-di-toluene tartrate acid from mixture of dimethylformamide and water, if necessary, in presence of primer obtaining salt of 3-R-(+)- ondansetron-n-di-toluene tartrate acid of required enantiomer purity; and processing by base with obtaining free base of 3-R-(+)- ondansetron, and at first ondansetron salt is dissolved in water at room temperatute, after which dimethylformamide is added to solution, with further heating of mixture to 80-85°C, cooling to 60°C and filtration at that temperature, ratio of water and dimethylformamide volume in mixture constituting 2:1; d) processing of free base of R-(+)-ondansetron with hydrochloric acid in presence of alcohol as solvent obtaining 3-R-(+)-ondansetron hydrochloride.

EFFECT: claimed method is less time-consuming and ensures higher product purity in comparison with known methods-analogues.

4 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a biologically active substance showing 5-HT3-serotonin receptor antagonist properties, 1-piperidinopropyl-2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole of formula I. The compound has been known as a local anaesthetic. There are shown evident 5-HT3-antagonist properties of the compound in the macromolar concentration equal to the reference preparation ondansetron with the compound of formula I being safer.

EFFECT: new properties of the compound can be used for creating the effective agents exhibiting antiemetic, anxiolytic and analgesic activities.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, and can be used for prevention of post-operation nausea and vomiting in children in otolayngologic (ENT) surgery. Premedication is performed. Dexametazone is introduced in dose 0.2 mg/kg i/v, 8 mg maximum. Propofol is introduced in dose 2-3 mg/kg i/v, fentanyl 4-5 mcg/kg i/v with anesthesia induction. Anesthesia is performed with nitrous oxide - oxygen mixture N2O+O2 with ratio 2:1. Propofol 2.5-3.5 mg/kg/hour i/v, fentanyl 3-4 mcg/kg/hour in micro-jet manner in basis-anesthesia. When operation is over, metoclopromide is introduced in dose 0.2 mg/kg i/v not more than 10 mg. After extubation oxygenation with oxygen through facial mask in dose 3-4 l/min is carried out for 3-5 minutes.

EFFECT: method makes it possible to prevent syndrome of post-operation nausea and vomiting in children in ENT surgery.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly coloproctology, and may be used for treating chronic anal fissure. The method involves an anal fissurectomy with a graduated sphincterotomy and a drug-induced therapy. A patient's preoperative psychoemotional status is assessed by questionnaire survey according to the Hospital Anxiety and Depression Scale (HADS). If the disorders have been shown by the questionnaire survey, namely 8-10 points "subclinical anxiety/depression" or 11 points and more "clinical anxiety/depression", a psychopharmaceutical therapy with Grandaxin or Tianeptine. The preparations are administered in common doses for 4 weeks.

EFFECT: method provides the effective treatment of the disease with comorbid psychoemotional disorders, exposure on the additional mechanisms of the anal fissure pathogenesis in this case.

3 ex

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