WO2013129970A2 - Composition pharmaceutique pour injections possédant une activité vasocontrictive, anticongestive, anti-inflammatoire (et variantes) - Google Patents

Composition pharmaceutique pour injections possédant une activité vasocontrictive, anticongestive, anti-inflammatoire (et variantes) Download PDF

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Publication number
WO2013129970A2
WO2013129970A2 PCT/RU2013/000135 RU2013000135W WO2013129970A2 WO 2013129970 A2 WO2013129970 A2 WO 2013129970A2 RU 2013000135 W RU2013000135 W RU 2013000135W WO 2013129970 A2 WO2013129970 A2 WO 2013129970A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
naphazoline
isotopes
carbon
pharmaceutical
Prior art date
Application number
PCT/RU2013/000135
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English (en)
Russian (ru)
Other versions
WO2013129970A3 (fr
Inventor
Владимир Павлович ЛОБКО
Анастасия Геннадьевна ЧЕЛЯЕВА
Original Assignee
Lobko Vladimir Pavlovich
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lobko Vladimir Pavlovich filed Critical Lobko Vladimir Pavlovich
Publication of WO2013129970A2 publication Critical patent/WO2013129970A2/fr
Publication of WO2013129970A3 publication Critical patent/WO2013129970A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

Definitions

  • composition with vasoconstrictor, anti-congestive, anti-inflammatory effect is provided.
  • adrenoreactive systems causes constriction of peripheral blood vessels (nafazolin, instructions for use published on the Internet at: http://it-apharm.ru/nafazolin.html).
  • sanorin is an emulsion that has a milder effect, longer
  • the prototype of the three variants of the invention can be a pharmaceutical composition containing naphazoline (Instructions for the medical use of the drug naphthyzine, published on the Internet at:
  • the disadvantages of the prototype are the relatively large time of the onset of the therapeutic effect, low stability during the shelf life and the possibility of increasing the therapeutic effect, only by increasing the concentration
  • Acute rhinitis is a runny nose due to acute inflammation of the lining of the nasal cavity, accompanied by a disorder of its functions — breathing, smell, tear conduction, etc.
  • Congestion is a rush of blood to a specific part of the body.
  • the pharmaceutical composition has a vasoconstrictor
  • nC N , C / NC
  • Biologically active additives are also known, which, when introduced together with the active principle, increase the pharmacological activity of therapeutic drugs by optimizing the rate of assimilation of the active principle. So in an antitumor agent (USSR author's certificate N 1683190, published 04/20/1995) is additionally introduced
  • polyvinylpyrrolidone and sorbic acid These components increase the antitumor activity of the active principle.
  • the invention achieves an increase in the rate of onset of the therapeutic effect (as well as other technical results) while maintaining
  • Trace elements iron, copper, manganese, zinc, cobalt, iodine, fluorine, chromium, molybdenum, vanadium, nickel, strontium, silicon, selenium are recognized as essential for human and animal life.
  • Minerals, metal salts have an antimicrobial effect, inactivating the enzymes necessary for the life of microorganisms. Enzyme inactivation occurs through the interaction of metal ions with sulfhydryl groups of enzymes.
  • Metals have a pronounced local effect on the mucous membranes. At the concentrations of mineral substances considered in the application, the local action of these substances may be astringent or irritating.
  • Figure 1 presents the chromatogram of the claimed pharmaceutical composition on a column with sorbent C 18. Detection at 220nm.
  • Figure 2 presents the chromatogram of the pharmaceutical composition on a column with a sorbent With 18 using a mass selective detector.
  • Fig. 3 shows a chromatogram of the pharmaceutical composition on a C 18 sorbent column using a mass selective detector.
  • Figure 4 presents the HPLC of the pharmaceutical composition on a column with a chiral sorbent. Detection at 220nm.
  • Figure 6 presents MS MS molecular ion 237.
  • Fig and 9 shows respectively the right and left part of the 1H-NMR spectrum of the pharmaceutical composition.
  • Figure 10 shows the 13C-NMR spectrum of the pharmaceutical composition.
  • Figure 1 1, 12 and 13 shows two-dimensional NMR spectra of the pharmaceutical composition.
  • FIG. 1 presents a diagram of a cavitation reactor for isotopic enrichment of various mixtures.
  • Example 1 a method of introducing minerals into water for injection.
  • Example 2 - a method of obtaining pharmaceutical compositions.
  • Examples 4-9 illustrate the effectiveness of the claimed pharmaceutical compositions in comparison with the prototype.
  • Example 1 The introduction of minerals into the solution (into water for injection) was carried out according to the methodology / Guidelines on methods for monitoring the quality and safety of biologically active food additives. - M .: Federal Center for State Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004, - 240 s /.
  • Solutions were prepared from pure metals using pharmaceutically acceptable solvents to ensure storage stability of the solutions.
  • the concentration of minerals in pharmaceutical formulations was provided in the following ranges, mg / l: potassium - from 0.01 to 55.0;
  • chrome - from 0.001 to 12.0;
  • molybdenum - from 0.001 to 12.0;
  • compositions in particular, magnetic resonance studies, chromatographic studies on columns with various sorbents, etc.
  • composition based on naphazoline and all of the above minerals.
  • concentration of mineral substances in the composition were as follows, mg / l:
  • Figure 1 shows the chromatogram of the pharmaceutical composition on a column with sorbent C 18. The absorption of the eluate was measured at a wavelength of 220 nm.
  • Tables 14-16 The increase in hypoxia from the use of pharmaceutical formulations based on naphazoline and minerals is shown in Tables 14-16.
  • Tables 15 and 16 show data on the effect of 13 C isotopes on enhanced hypoxia.
  • Example 5 the assessment of vasoconstrictor action
  • Brain ischemia was reproduced by ligation of both common carotid arteries. Animals after surgery were observed for 7 days.
  • compositions based on naphazoline and minerals (as well as formulations with 13 C carbon isotopes) and the naphthyzine preparation were administered intraperitoneally during observation days. On the first day, drugs were administered twice: immediately after surgery and 3 hours after surgery. On the second day, the third, etc. - drugs were administered once a day.
  • vasoconstrictor effects of naphthyzine (2 ml with a concentration of naphazoline 1 g / l), pharmaceutical formulations based on naphazoline with minerals, and pharmaceutical formulations with 13 C isotopes on the survival of mice with cerebral ischemia were compared.
  • mice In the area indicated by 36, the survival curves of mice are obtained using pharmaceutical formulations N2N2 9 - 13.
  • survival curves of mice are obtained using pharmaceutical formulations of ⁇ ° ⁇ ° 30 - 34.
  • survival curves of mice are obtained when pharmaceutical formulations ⁇ 2 ⁇ 2 51 - 55 are used.
  • mice In the area indicated by 36, the survival curves of mice also pass with the use of pharmaceutical compositions based only on naphazoline with 0.5%, 1% content of 13 C carbon isotopes in the composition.
  • mice using a pharmaceutical composition based only on naphazoline with 75% carbon C isotopes in the composition there is a survival curve for mice using a pharmaceutical composition based only on naphazoline with 75% carbon C isotopes in the composition.
  • compositions with 0.5 - 75% content of carbon C isotopes in the composition.
  • Example 6 The developed pharmaceutical compositions for meringue of naphazoline and mineral substances N ° N ° 8-14 were used in the treatment of inflammatory processes of the maxillary sinus cavities (sinusitis) as prescribed in 42 patients aged 27 to 60 years.
  • the drug naphthyzin (with a concentration of 1 g / l) was used in the treatment of sinusitis as prescribed in 6 patients of the same age.
  • the developed pharmaceutical compositions on meringue only of naphazoline (with a concentration of 1 g / l) and 0.5%, 1% and 75% of the carbon content of 13 C in the composition were used in the treatment of inflammatory processes of the maxillary sinus cavities as prescribed in 18 patients of the same age .
  • the developed pharmaceutical formulations were well tolerated by patients.
  • the course of treatment for all patients took 10 days according to the scheme of 5 days of treatment, 3 days break, 5 days of treatment.
  • the method of application of all formulations is in accordance with the instructions for use of the drug naphthyzine.
  • the treatment results showed the following.
  • compositions N ° N ° 8, 9, 29, 30 are similar in action to naphthyzine.
  • their vasoconstrictor With an increase in the amount of minerals in formulations with naphazoline (formulations with N2N2 10, 11, 12, 13, 31, 32, 33, 34), their vasoconstrictor the effect is enhanced, which leads to an increase in the treatment of sinusitis.
  • the more minerals with the composition the more pronounced the effect of the treatment.
  • the effect of the treatment was a longer vasoconstrictor and therapeutic effect.
  • the time of action (compared with the time of action of the drug naphthyzin) increased by 5 - 25%.
  • the time of the onset of the therapeutic effect was reduced (controlled at the time the pupils began to expand) by about 5-10%.
  • compositions N ° N ° 29 - 35, 50 - 56, 71 - 77 have a longer duration of action, not only in comparison with the time the effects of naphthyzine (by 5-30%), but also compared with the time of action of pharmaceutical formulations based on naphazoline and minerals (by percent).
  • Example 7 Comparative studies of the developed pharmaceutical formulations with naphthyzine were also carried out in acute rhinitis and nasal
  • the concentration of naphazoline from 0.1 to 10 g / l significantly - at times - increases the therapeutic effect of pharmaceutical formulations. Additionally, the therapeutic effect was increased by the minerals used in the composition, as well as the substitution of carbon C isotopes for carbon isotopes C. Moreover, it is advisable to apply mineral concentrations close to maximum values
  • Example 8 When developing an application for an invention, comparative studies of developed pharmaceutical compositions based on naphazoline and minerals with naphthyzine in the treatment of conjunctivitis were carried out.
  • the concentration of naphazoline is 0.1 - 0.5 g / l and naphthyzine with a concentration of 0.5 g / l.
  • the time of onset of the therapeutic effect of the action of the compared drugs was evaluated at the time of removing the redness of the eyes.
  • the onset of the therapeutic effect (compared with the onset of the therapeutic effect of the use of naphthyzine) decreased by 5-10%.
  • compositions based on mineral substances retain their pharmaceutical properties for 3.5 years.
  • the stability is also enhanced by the substitution of carbon isotopes of 12 C for carbon isotopes of 13 C.
  • composition of mineral substances in the pharmaceutical compositions described above was limited by the list of mineral substances (macroelements and
  • the Guide describes a method for introducing mineral substances into a solution, as well as methods for precisely controlling the amount of mineral substances in solutions.
  • ranges of weight values (in mg / l) of the components of the compositions are given, which, compared with the prototype, give an effect (according to technical results) of 5% or more.
  • any may be added or any of the following (with the exception of those already mentioned in the composition of mineral substances) may be added, mg / l:
  • the first composition can be performed as follows:
  • the pharmaceutical composition contains naphazoline, and minerals in the following ratio of components in mg / l:
  • composition can be performed as follows:
  • the pharmaceutical composition contains naphazoline, and minerals in the following ratio of components in mg / l:
  • 13 C carbon isotopes in the World are widely used in biochemistry and medicine for diagnostics.
  • the application presents the results of our own research on the effect of 13 C carbon isotopes on the stability and effectiveness of the action of drug formulations based on naphazoline.
  • Carbon isotopes 13 C are not toxic. The experiments show that feeding mice and rats with foods enriched with 75% 13 C carbon does not lead to side effects and poor health.
  • compositions have a vasoconstrictor, anti-congestive, anti-inflammatory effect.
  • the cavitation reactor 1 (see Fig. 14) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.
  • Fig presents a cross section of a cavitation reactor.
  • the reactor channel in the area of cavitation bodies is divided into several channels.
  • cavitation bodies 5 and 6 divide the channel into smaller channels 13, 14 and 15. Outside, the channel is limited by walls 16 and 17, as well as two covers 1 1 and 12. 13 000135
  • channels 24 and 25 are made for supplying carbon dioxide and nitrogen to the cavitation zones.
  • the gas-vapor mixture obtained in the reactor together with the liquid reagent enters the tank 28.
  • the gas-vapor mixture is passed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with 13 C and 12 C are separated.
  • the reactor worked from several hours to several days.
  • a direct dependence of the degree of enrichment of the vapor-gas mixture and the reagent with 13 C isotopes on the operating time of the cavitation reactor is established.
  • the amount of 13 C carbon isotopes was controlled by high resolution mass spectroscopy.
  • the reagent was enriched with carbon isotopes , 3 ° C , to 75%.
  • the gas-vapor mixture obtained in the reactor together with the reagent enters the tank 28.
  • the gas-vapor mixture is passed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with ⁇ 4 ⁇ and 5 N are separated.
  • naphazoline and configured so that it contains nitrogen isotopes 15 N and the ratio:
  • nN (N , 5 N / ⁇ ) 100%
  • ⁇ is the ratio of the amount of nitrogen isotopes 15 ⁇ to the total amount of nitrogen in the pharmaceutical composition
  • the values of the ⁇ indicator took values from the range from 0.01% to 1.375%.
  • the pharmaceutical composition enriched with nitrogen isotopes 5 ⁇ has an increased vasoconstrictor, anti-congestive, anti-inflammatory effect, compared with the pharmaceutical composition, in which there are no nitrogen isotopes ⁇ 5 ⁇ .
  • composition containing naphazoline characterized in that it is made in such a way that it contains carbon isotopes C, and the ratio:
  • nC N 13 C / NC
  • the pharmaceutical composition contains isotopes of nitrogen 15 N and, in addition, the pharmaceutical composition contains isotopes of nitrogen 15 N and
  • nN (N 15 N / NN) 100%
  • nN is the ratio of the number of nitrogen isotopes 15 N to the total amount of nitrogen in the pharmaceutical composition
  • N 15 N the amount of nitrogen isotopes N in the pharmaceutical composition
  • NN is the total number of nitrogen isotopes in the pharmaceutical composition
  • the pharmaceutical composition has a vasoconstrictor
  • the pharmaceutical composition comprises a nitrogen isotopes ⁇ 5 ⁇ and, in addition, the pharmaceutical composition comprises a nitrogen isotopes ⁇ 5 ⁇ and
  • nN (N 15 N / NN) 100%
  • ⁇ is the ratio of the amount of nitrogen isotopes 15 ⁇ to the total amount of nitrogen in the pharmaceutical composition
  • the pharmaceutical composition has a vasoconstrictor

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne les domaines de l'industrie pharmaceutique et de la médecine et peut s'utiliser pour créer et appliquer des compositions pharmaceutiques possédant une activité vasocontrictive, anticongestive, anti-inflammatoire lors de rhinites aigues, de processus inflammatoires des antres maxillaires du nez, de saignements du nez et de conjonctivite. L'invention vise une préparation pharmaceutique à base de naphazoline grâce à l'inclusion dans la composition pharmaceutique de substances minérales, de remplacement dans la composition pharmaceutique des isotopes de carbone 12С pharmaceutique par des isotopes de carbone 13С.
PCT/RU2013/000135 2012-02-29 2013-02-20 Composition pharmaceutique pour injections possédant une activité vasocontrictive, anticongestive, anti-inflammatoire (et variantes) WO2013129970A2 (fr)

Applications Claiming Priority (2)

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EA201200211 2012-02-29
EA201200211A EA021295B1 (ru) 2012-02-29 2012-02-29 Фармацевтический состав, обладающий сосудосуживающим, антиконгестивным, противовоспалительным действием (варианты)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2156087C1 (ru) * 1999-11-25 2000-09-20 Товарищество с ограниченной ответственностью Фирма "Электронная медицина" Биологически активная добавка
RU2251417C2 (ru) * 2003-04-11 2005-05-10 Аникеев Сергей Владимирович Средство для лечения гайморита "антигайморит"
RU2281086C1 (ru) * 2005-01-18 2006-08-10 Сергей Николаевич Анисимов Глазные антигистаминные капли
RU2412188C2 (ru) * 2006-09-21 2011-02-20 Раквалиа Фарма Инк. Производные бензимидазола в качестве селективных ингибиторов кислотной помпы

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3470131B2 (ja) * 1994-03-16 2003-11-25 大正製薬株式会社 持効性点鼻剤
US20050080043A1 (en) * 2000-09-20 2005-04-14 Lee Shahinian Self-preserved antibacterial nasal, inhalable, and topical ophthalmic preparations and medications

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2156087C1 (ru) * 1999-11-25 2000-09-20 Товарищество с ограниченной ответственностью Фирма "Электронная медицина" Биологически активная добавка
RU2251417C2 (ru) * 2003-04-11 2005-05-10 Аникеев Сергей Владимирович Средство для лечения гайморита "антигайморит"
RU2281086C1 (ru) * 2005-01-18 2006-08-10 Сергей Николаевич Анисимов Глазные антигистаминные капли
RU2412188C2 (ru) * 2006-09-21 2011-02-20 Раквалиа Фарма Инк. Производные бензимидазола в качестве селективных ингибиторов кислотной помпы

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
'Registr lekarstvennykh sredstv Rossii.' RLS-APTEKAR. GI. RED. G.L. VYSHKOVSKY VYPUSK vol. 5, 2003, pages 702 - 703 *
'Tekhnologia lekarstvennykh form.' POD RED. T.S. KONDRATEVOI, TOM 1, M., ''MEDITSINA 1991, page 364 *

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EA021295B1 (ru) 2015-05-29
WO2013129970A3 (fr) 2013-11-14
EA201200211A1 (ru) 2013-07-30

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