CO-AUTHORITY is the fact of creating a work by two or more a large number of people.
Civil Code of the Russian Federation part four - chapter 70 - regulates relations arising in connection with the creation and use of works of science, literature and art ( Copyright ), phonograms, performances, productions, programs of on-air and cable broadcasting organizations ( rights - related to copyright ).
Related rights protect the interests of performers, producers of phonograms and broadcasting and cable broadcasting organizations.
AP- protects the form of expression of the idea, more precisely, the work in its one specific form.
object AP is an work.
Work is the result creative activity, which does not depend on the purpose and dignity of the work, as well as on the way it is expressed.
That. the legislation does not distinguish between highly artistic and "useless" works.
The work can belong to three large areas: science, literature and art.
“Creativity” is a human activity that generates something qualitatively new and is distinguished by originality, originality and socio-historical uniqueness. (Soviet encyclopedic Dictionary. M. " Soviet Encyclopedia", 1987, p.1314)
For example, the copyright holders of the works of the avant-garde musician John Cage, who composed “4 minutes of silence” (more precisely, 4.33), filed claims against Vanessa May, who also “composed” a composition on her disc, which is a minute of complete silence. Is there creativity here?
Thus, The work must meet only two requirements: be creative and exist in some objective form.
In relations related to the creation, use and disposal of copyright, participates big number entities, which can be both citizens and legal entities.
Author works of science, literature or art are recognized by the citizen, creative work which it was created. The person indicated as the author on the original or copy of the work is considered to be its author, unless otherwise proven.
Citizens who have not made a personal creative contribution to the creation of such a result are not recognized as the authors of the ID result, Art. 1228 of the Civil Code of the Russian Federation), including those that provided the author of such a result with only technical, consulting, organizational or material assistance or assistance, or only contributed to the registration of rights to such a result or its use.
So, for example, the author of such a work as a term paper or diploma work is its creator - a student, and not scientific director. Of course, the student is recognized as the author, provided that his work is not "downloaded" from the Internet and has an independent creative character.
A certain age is required to exercise copyright. If the author of a work is a person under the age of 14, then his copyright is exercised by legal representatives (parents, guardians). Minors between the ages of 14 and 18 have the right to independently, without the consent of their parents, adoptive parents and guardian, exercise the rights of the author.
Art. 1258
Apart from individual works, works can be created in co-authorship, i.e. joint creative work of several persons (Ilf and Petrov, the Strugatsky brothers).
While creating joint work occurs:
At the same time, the right to use such a work belongs to the co-authors jointly. The relationship of co-authors may be determined by agreement between them.
Derivative works- (translations, adaptations, annotations, film adaptations, arrangements, dramatizations, abstracts, summaries, reviews, and other processing of works of science, literature and art);
Derivative works are protected whether or not the works on which they are based are copyrighted.
Subjects of copyright include the authors collections and authors of other composite works(encyclopedias, dictionaries, newspapers, anthologies, periodicals and continuing collections scientific papers, databases) and other composite works, which are creative work by selection or arrangement of materials.
2. The compiler of a collection or other composite work owns the copyright for the selection or arrangement of materials (compilation).
4. The copyright of a translator, compiler or other author of a derivative or composite work shall be protected as rights to independent objects copyright, regardless of the protection of the rights of the authors of the works on which the derivative or composite work is based.
6. Copyright to a translation, collection, other derivative or composite work does not prevent other persons from translating or reworking the same work through a different selection or arrangement of materials.
7. Publisher of composite works and periodicals owns the right to use such publications. The publisher has the right to indicate its name in any use of such publications or require such indication.
The invention relates to the pharmaceutical industry and relates to pharmaceutical compositions for aerosols with two or more active ingredients. The invention lies in the fact that the composition for use by inhalation or nasal route contains a propellant, such as fluorocarbon propellant (FU), which includes a combination of two or more active substances, and at least one active substance is present in dissolved form in in combination with at least one other active substance in the form of suspended particles. The invention provides for the introduction of higher doses. 22 w.p. f-ly.
The present invention relates to new aerosol pharmaceutical compositions containing two or more active substances, which are intended for use by inhalation or nasal administration. BACKGROUND OF THE INVENTION In metered valve inhalers (VDIs) in which evacuation occurs under the action of a propellant, the active ingredients may be in the form of solutions or suspensions. The vast majority of aerosol compositions for DCI are prepared as suspensions, especially if the formulation contains more than one active ingredient. Compositions in the form of solutions are used only to a limited extent. In these cases, the compositions usually contain only one active ingredient. As a rule, the chemical stability of active substances in suspension is much higher than in solution. In addition, the active substance may be present in a suspension at a higher concentration than in solution, whereby the composition in the form of a suspension allows the administration of higher doses. The main disadvantage of suspension formulations is that over time (e.g. during storage) the suspended particles stick together to form larger, more or less stable agglomerates, or form loose flocculent particles, precipitates or floating layers, or in the worst case, growth occurs. particles, which significantly impairs the pharmaceutical quality of the product. The size of the formed particles and the growth rate of the particles depend on the characteristics of the solubility liquid phase. Thus, moisture penetration during storage or the required increase in polarity, which, for example, can be obtained by adding co-solvents, can have a negative impact on the quality of the final medical product, especially if the suspended particles have polar structural elements. The suspension can be physically stabilized by the addition of a surface active substances, by decreasing harmful effects caused by moisture and/or particle growth, whereby the suspended particles can be held in suspension for a longer period of time. As a rule, compositions of the solution type do not have problems associated with the increase in particle size or with the processes of destruction of the mixture, such as sedimentation or flocculation. However, in this case there is a serious risk chemical decomposition. It is also a disadvantage that the limited solubility of the ingredients may preclude the administration of high doses. AT recent times the most preferred solvents are the chlorofluorohydrocarbons (CFCs) TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetrafluoroethane). The solubility of the ingredients can be increased by the addition of co-solvents. In addition, additional measures are usually required to chemically stabilize the dissolved components. So far, CFCs such as TG 11 above, for example, have often been used as propellants. However, since CFCs have been linked to ozone depletion, their production and use is on the verge of being phased out. Attempts are being made to replace them with special fluorocarbons (FCs), which have a less destructive effect on ozone layer, but differ in completely different solubility characteristics. Toxicological profile and physicochemical characteristics, such as, for example, steam pressure, allow you to determine which FUs can be used in the IDM. The most promising representatives at present are TG 134а (1,1,2,2-tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane). Treatment by inhalation may require aerosol formulations with two or more active ingredients. In these cases, the composition of the active substances, taken at the required concentration, is prepared in the form of solutions or suspensions, and there are often problems associated with the chemical stability of the individual substances or with the level of concentration that can be achieved. The main problems arise if one of the active ingredients cannot be suspended or is unstable in a composition of this type in the form of a suspension, or if one of the active substances is chemically unstable or cannot be dissolved in a composition of this type in the form of a solution, especially when FU is used as a propellant. Thus, one of the objects of the present invention is the development of a composition for aerosols with a metering valve, which contains two or more active substances and which is free from the above disadvantages. Description of the invention When creating the invention, it was unexpectedly found that a large number of active substances can be prepared in the form of a solution and suspension, combined in one composition. The invention relates to stable aerosol compositions in which fluorocarbons are used as propellants, primarily TG 134a and/or TG 227, comprising two or more active substances, where at least one active substance is prepared in the form of a solution and at least one active the substance is present in the form of a suspension. The pharmaceutical composition according to the invention is used for treatment by inhalation, in particular for the treatment of diseases of the pharynx and respiratory tract, for example asthmatic diseases and chronic obstructive pulmonary disease (COPD). Detailed description In one embodiment, a combination of two or more active substances suitable for medical purposes is used, including beclomethasone, budesonide, cromoglycic acid, fenoterol, flunisolide, fluticasone, ipratropium bromide, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol (albuterol), salmeterol , terbutaline, N-[methyl]-N-hydroxyacetamide, their esters, salts, solvates. Which of the active ingredients listed above are included in the composition according to the invention as a solution and which as a suspension depends on the specific combinations of active ingredients, and this can be determined fairly quickly using dissolution and suspension experiments. According to a preferred embodiment, one or more of the following active ingredients are suspended: budesonide, cromoglycic acid, nedocromil, reproterol and/or salbutamol (albuterol) or esters, salts and/or solvates of these compounds, and one or more of the following active ingredients is dissolved: beclomethasone, fenoterol, ipratropium bromide, orciprenaline and/or oxytropium bromide, N-methyl]-N-hydroxyacetamide or esters, salts and/or solvates of these compounds. Variants comprising two different active ingredients are preferred. According to a most preferred embodiment, dissolved ipratropium bromide is included in the composition, especially in combination with salbutamol sulfate (albuterol sulfate) as the suspended active ingredient. In all embodiments, the active substances are used in a therapeutic effective amount, i.e. in an amount that can provide successful treatment. The concentration of active substances and the volume released by one press of the spray valve are regulated in such a way that with one or more presses of the spray valve, the amount of active substance required or recommended for medical reasons is released. One embodiment relates to compositions in which the suspended particles are stabilized by the addition of surfactants or other suspension stabilizing agents in order to stabilize the suspended particles against physical changes. The importance of this approach is that the particle size can be maintained at a pharmaceutically acceptable level even for extended periods of time, such as during storage. Preferred particle sizes are up to 20 µm, however, a particularly preferred particle size is in the range of 5 to 15 µm, most preferably does not exceed 10 µm. The advantage of particles of this size is that such particles are small enough to penetrate deeply into the lungs, but not so small that they are exhaled to the outside with exhaled air. Suitable surfactants and suspension stabilizing agents include all pharmacologically acceptable substances which have a lipophilic hydrocarbon group and one or more functional hydrophilic groups, especially C 5 -C 20 fatty alcohols, C 5 -C 20 fatty acids, C fatty esters. 5-C 20 acids, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. 5 -C 20 fatty acids, propylene glycol diesters and/or triglycerides and/or C 5 -C 20 fatty acid sorbitans are preferred, with oleic acid and sorbitan mono-, di- and trioleates being particularly preferred. AT alternative toxicologically and pharmacologically acceptable polymers and block copolymers can be used as suspension stabilizing agents. The surfactants used may be either non-fluorinated or partially fluorinated or perfluorinated, where "fluorinated" refers to the replacement of carbon bonded hydrogen radicals with fluorine radicals. The amount of surfactant may be in a ratio of up to 1:1, based on the weight of suspended active ingredients; preferably in a ratio of 0.0001:1 to 0.5:1, particularly preferably in a ratio of 0.0001:1 to 0.25:1. Another advantage of the above surfactants is that they can be used to lubricate the valve. Thus, according to one embodiment, the invention relates to compositions in which surfactants are added to lubricate the valve. According to another embodiment, the solubility of at least one active substance to be dissolved can be increased by adding one or more co-solvents. The advantage of this option is that the active(s) substance or substances to be(s) dissolved, can(may) be included(s) in the composition at higher concentrations. The addition of a co-solvent must not exceed the critical threshold of liquid phase polarity at which one of the adverse factors described above begins to act on the suspended particles of the active substance. Suitable co-solvents are pharmacologically acceptable alcohols such as ethanol, esters, or water, or mixtures thereof; ethanol is preferred. Co-solvent concentration relative to total mass composition is from 0.0001 to 50 wt.%, preferably from 0.0001 to 25 wt. %. According to another embodiment, a concentration of 0.0001 to 10% by weight is preferred, with particularly preferred embodiments being those in which an amount of alcohol is added that is necessary to dissolve the active ingredient to be dissolved. In yet another embodiment, other conventional propellants are added to the FU propellants. These additional propellants, among other FCs, may be hydrocarbons such as propane, butane, isobutane or pentane, provided that the mixture is pharmacologically acceptable. And according to another embodiment, stabilizers are added to the composition, important property which is the impact on the pharmaceutical stability of the active substances, even over extended periods of time, for example during storage. In the context of the present description, the term "stabilizers" refers to those substances that prolong the persistence and shelf life of a pharmaceutical composition by preventing or slowing down chemical changes individual ingredients, especially active substances, for example, those caused by subsequent interactions or degradation, or such substances that prevent biological pollution. Stabilizers preferred for this purpose are substances which influence the pH value of the liquid phase, such as acids and/or their salts, especially suitable substances are hydrochloric acid, sulfuric acid, Nitric acid, phosphoric acid, ascorbic acid, citric acid and their salts. In addition, bactericides, fungicides, etc. such as benzalkonium chloride or ethylenediaminetetraacetate are also preferred. The most preferred stabilizer is citric acid. The concentration of stabilizers can reach 1000 frequent. /million, preferably up to 100 ppm and most preferably between 20 and 40 ppm. One most preferred embodiment comprises suspended salbutamol sulfate (albuterol sulfate), dissolved ipratropium bromide, ethanol as co-solvent, and citric acid as a stabilizer. EXAMPLES Example 1 In a solution containing 89.96 g (1 mol, 89.71 wt%) of liquefied TG 134a and 10.03 g (218 mmol, 10.00 wt%) of ethanol, 37 mg (0.09 mmol, 0.037 wt.%) ipratropium bromide and suspended 4 mg (20 μmoles, 0.004 wt.%) citric acid and 210.5 mg (0.88 mmol, 0.21 wt.%) salbutamol sulfate (albuterol sulfate) together with 0.05 wt.% surfactant (for example, 50 mg (177 mmol) oleic acid). Example 2 Similar to example 1, but TG 227 is used instead of TG 134a as a gaseous propellant. Example 3 Disodium chromoglycate is suspended in liquefied P134 (TG 134a) and small amounts of ethanol and fenoterol hydrobromide are dissolved in it. Example 4 Similar to example 3, but TG 227 is used instead of TG 134a as the gaseous propellant.
Claim
1. Pharmaceutical composition for an inhaler with a metered valve, in which evacuation occurs under the action of a propellant, with a hydrofluorocarbon as a propellant, and the drug contains a combination of two or more active compounds, characterized in that at least one active compound, which is selected from ipratropium bromide , fenoterol and their salts, is present in dissolved form using a co-solvent, in admixture with at least another active compound in the form of suspended particles, which is selected from salbutamol (albuterol), cromoglycic acid and their salts. Pharmaceutical composition according to claim 1, characterized in that it consists of a combination of active substances, consisting of two active substances. Pharmaceutical composition according to claim 1, characterized in that it is a combination of two active substances - ipratropium bromide and salbutamol sulfate. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that TG 134a and/or TG 227.5 is used as a propellant. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the co-solvent is present in a concentration of from 0.0001 to 50 wt.% in terms of liquefied propellant. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the co-solvent is present in a concentration of up to 25 wt.% in terms of the liquefied propellant. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the co-solvent is present in a concentration of up to 10% by weight, based on the liquefied propellant. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the co-solvent is selected from the group of pharmacologically acceptable alcohols, pharmacologically acceptable esters, water or mixtures thereof. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that ethanol is used as a co-solvent. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that it is stabilized by the addition of a stabilizer. Pharmaceutical composition according to claim 10, characterized in that the stabilizer contains one or more acids and/or their salts. Pharmaceutical composition according to claim 10, characterized in that the stabilizer is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride and/or ethylenediaminetetraacetic acid and/or their salts. Pharmaceutical composition according to claim 10, characterized in that citric acid is used as a stabilizer. 14. Pharmaceutical composition according to any one of claims 10-13, characterized in that the stabilizer is present in an amount of up to 100 ppm. Pharmaceutical composition according to any one of claims 10-13, characterized in that the stabilizer is present in an amount of up to 40 ppm. Pharmaceutical composition according to any one of claims 1 to 15, characterized in that it contains a surfactant or suspension stabilizing agent. Pharmaceutical composition according to claim 16, characterized in that the surfactant is selected from the group consisting of (C 5 -C 20) fatty alcohols, (C 5 -C 20) fatty acids, esters (C 5 -C 20) fatty acids, lecithin, glycerides, propylene glycol esters, polyoxyethanes, polysorbates, sorbitan esters and/or carbohydrates. Pharmaceutical composition according to claim 16, characterized in that the surfactant is selected from the group of (C 5 -C 20) fatty acids and/or their esters. Pharmaceutical composition according to claim 16, characterized in that the surfactant is selected from the group consisting of oleic acid and/or sorbitan mono-, -di- or -trioleate. Pharmaceutical composition according to claim 16, characterized in that the surfactant contains oleic acid. Pharmaceutical composition according to claim 16, characterized in that the surfactant or suspension stabilizing agent comprises a toxicologically acceptable polymer and/or block polymer. Pharmaceutical composition according to any one of claims 1 to 21, characterized in that it includes ipratropium bromide, salbutamol sulfate, ethanol, citric acid and TG 227.23. Pharmaceutical composition according to any one of claims 1 to 21, characterized in that it includes ipratropium bromide, salbutamol sulfate, ethanol, citric acid and TG 134a.
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The invention relates to medicine, namely the controlled release of therapeutic compounds from drug delivery systems
A multiple pregnancy is a pregnancy with two or more fetuses. In the presence of pregnancy with two fetuses, they talk about twins, three - about triplets, etc. Each of the fetuses in a multiple pregnancy is called a twin. Twin births occur once in 87 births, triplets - once in 872 (6400) twins, quadruplets - once in 873 (51200) triplets, etc. (according to the Gallin formula).
The causes of multiple pregnancy are not well understood. It has been proven that two or more follicles can mature in one ovary. In addition, ovulation can occur simultaneously in both ovaries. In favor of these possibilities, the facts of detection during an operation for a tubal pregnancy in the same ovary of two flowering yellow bodies or in each of the ovaries, one flowering yellow body speak. In addition, there can be two or more eggs in one follicle. The cause of multiple pregnancy can be fertilization with sperm from different partners, fertilization against the background of an existing pregnancy, induced pregnancy. Twins, formed from the fertilization of two eggs, are called dizygotic, identical twins result from atypical crushing of the egg. Where the separation of the egg occurs completely, two identical twins are formed. Such twins are called identical. Identical twins are much less common than fraternal twins (1:10). If, with complete separation of the eggs, both rudiments are located in the uterus at a sufficient distance from each other, then the embryos developing from them form a separate amnion each for themselves and remain separate - biamniotic twins. If both amniotic sacs are enclosed in one common chorion for both twins, and the septum between them consists of two shells (two amnions), then such twins are called monochorionic. They share a common placenta. If both rudiments lie side by side, this leads to the formation of one amniotic cavity common to both (monoamniotic twins). Identical twins are always of the same sex - either both boys or both girls, they are similar to each other, their blood type is always the same.
Course and management of multiple pregnancy
With multiple pregnancies, due to the heavy load on the body, women note early fatigue, shortness of breath, impaired urination, and constipation. Frequent and early complications of pregnancy are premature birth (50% of cases), toxicosis and gestosis, varicose disease, polyhydramnios, low weight and immaturity of fruits, death of one of the fruits. In some cases, polyhydramnios in one cavity may be accompanied by oligohydramnios in another.
Recognition of multiple pregnancy in the first months is quite difficult and becomes easier in the second half of pregnancy. Pay attention to the discrepancy between the size of the uterus and the gestational age. On palpation, many small parts are determined, two heads, two backs. During auscultation - two or more points for determining the fetal heartbeat and a zone of silence between them. The height of the uterine fundus is greater than in a singleton pregnancy at the same time. When measuring the length of the fetus with a tazomer - a large length of the fetus with a small head. The most reliable diagnostic method is an ultrasound.
In the vast majority of twins (88.0%), both fetuses are in a longitudinal position and occupy one right, the other - left half uterus. Most often, both fetuses are presented with a head (45.0%). There are other options for the location of the fetus in the uterus. One fetus may be in cephalic presentation, the second in breech presentation (43.0%). Both fetuses are in breech presentation (6.0%). One fruit is in the longitudinal position, the other is in the transverse position (5.5%), or both fruits are in the transverse position (0.5%). Medical supervision of pregnant women with multiple pregnancies is carried out taking into account possible complications, highlighting them as a risk group for the development of perinatal pathology.
The course and management of childbirth
The prognosis of pregnancy and childbirth with multiple pregnancy is less favorable than with one fetus. At the slightest deviation from the normal course of pregnancy, mandatory hospitalization is indicated. Re-hospitalization in the antenatal department is carried out 2-3 weeks before the due date, the purpose of which is to examine the pregnant woman and determine the time and method of delivery.
Multiple pregnancy is accompanied by frequent complications of the birth act. Most births occur prematurely, the weight of newborns is less than 2500 g, possibly pelvic and transverse positions of the second fetus. Frequent untimely discharge of amniotic fluid may be accompanied by prolapse of small parts of the fetus and umbilical cord, which is facilitated by the pelvic and transverse positions and the small size of the fetus.
During the period of disclosure, functional insufficiency of the overstretched, thinned muscles of the uterus manifests itself, weakness of the birth forces develops, premature discharge of amniotic fluid occurs, so the period of disclosure is delayed.
The period of exile may also be delayed due to the development of anomalies in labor activity. Prolonged labor is dangerous for the mother (bleeding, infection) and the fetus (hypoxia).
Placental abruption before the birth of the second fetus leads to its intrauterine death. There may be a transverse position of the second fetus, twin collision (adhesion of two large parts of the body), bleeding in the third stage of labor, in the early postpartum period, delayed uterine involution and infectious diseases.
Conducting childbirth with multiple pregnancies requires great attention, a clear orientation in the obstetric situation and highly qualified, allowing you to perform any operation. In the period of disclosure, it is necessary to carefully monitor the condition of the woman in labor and the fetus. If there is polyhydramnios, an opening of the fetal bladder is shown when the cervix is 4 cm open and the water is slowly removed (within 1-2 hours).
In order to reduce the complications of childbirth with multiple pregnancies and perinatal mortality of the second fetus, it is currently recommended to open the fetal bladder of the second fetus immediately after the birth of the first fetus, and immediately begin intravenous drip administration of 5 units. oxytocin in a 5% glucose solution in order to accelerate the second stage of labor until the placenta separates. With bleeding, the development of hypoxia of the second fetus or its transverse position, for the purpose of rapid delivery, a classic external-internal obstetric rotation of the fetus on the leg is shown, followed by its extraction by the pelvic end
Particularly dangerous are the III stage of labor and the early postpartum period by the development of bleeding. After the birth of the placenta, a thorough examination is carried out to determine the integrity of the lobules and membranes and the type of twins (one- or two-egg).
In the postpartum period, careful monitoring of the puerperal, prevention of subinvolution of the uterus is necessary.
Perinatal mortality in multiple pregnancies is 2 times more common than in single births. Therefore, in modern obstetrics there is a tendency to expand the indications for abdominal delivery in the interests of the fetus. Indications for cesarean section associated with polyhydramnios include triplets, the transverse position of both or one of the fetuses, breech presentation of both fetuses or the first of them, and not associated with multiple pregnancy - fetal hypoxia, anomalies in labor, prolapse of the umbilical cord, extragenital pathology of the mother, severe preeclampsia, previa and placental abruption.
Prevention of complications in multiple pregnancy is the prevention of complications during pregnancy.
See all
Pharmaceutical composition for aerosols with two or bilateral number of active substances (71) Applicant Boeringer Ingelheim Pharmacetikalz, Inc. (73) Patent holder Boeringer Ingelheim Pharmaceticus, Inc. (57) 1. Pharmaceutical composition for an inhaler with a dosing valve in which the evacuation occurs under the action of propellant containing a hydrofluorocarbon as a propellant and a combination of two or more active compounds, characterized in that at least one active compound selected from the group consisting of ipratropium bromide, fenoterol and their salts is present in a dissolved form obtained using a co-solvent, and at least one other active compound selected from the group consisting of salbutamol (albuterol), cromoglycic acid and salts thereof, is present in the form of suspended particles. 2. Pharmaceutical composition according to claim 1, characterized in that it contains a combination of two active compounds. 3. Pharmaceutical composition according to paragraphs. 1 or 2, characterized in that it contains a combination of two active compounds - ipratropium bromide and salbutamol sulfate. 4. Pharmaceutical composition according to any one of paragraphs. 1-3, characterized in that it contains 134 a and/or 227 as a propellant. 5. Pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains a co-solvent in an amount of from 0.0001 to 50 wt. in terms of liquefied propellant. 6. Pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains a co-solvent in an amount of from 0.0001 to 25 wt. in terms of liquefied propellant. 7. Pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains a co-solvent in an amount of from 0.0001 to 10 wt. in terms of liquefied propellant. 8. Pharmaceutical composition according to any one of paragraphs. 1-7, characterized in that it contains a co-solvent selected from the group including pharmacologically acceptable alcohols, pharmacologically acceptable esters, water and mixtures thereof. 8208 1 2006.06.30 9. Pharmaceutical composition according to any one of paragraphs. 1-7, characterized in that it contains ethanol as a co-solvent. 10. Pharmaceutical composition according to any one of paragraphs. 1-9, characterized in that it additionally contains a composition stabilizer. 11. A pharmaceutical composition according to claim 10, characterized in that it contains one or more acids and/or their salts as a stabilizer. 12. The pharmaceutical composition according to claim 10, characterized in that it contains a stabilizer selected from the group including hydrochloric, sulfuric, nitric, phosphoric, ascorbic and citric acids, benzalkonium chloride, ethylenediaminetetraacetic acid and their salts. 13. Pharmaceutical composition according to claim 10, characterized in that it contains citric acid as a stabilizer. 14. Pharmaceutical composition according to any one of paragraphs. 10-13, characterized in that it contains a stabilizer in an amount of up to 100 ppm. 15. Pharmaceutical composition according to any one of paragraphs. 10-13, characterized in that it contains a stabilizer in an amount of up to 40 ppm. 16. Pharmaceutical composition according to any one of paragraphs. 1-15, characterized in that it additionally contains a surfactant or suspension stabilizing agent. 17. The pharmaceutical composition according to claim 16, characterized in that it contains a surfactant selected from the group consisting of (5-20)-fatty alcohols, (5-20)-fatty acids, esters (5-20)- fatty acids, lecithin, glycerides, propylene glycol esters, polyoxyethanes, polysorbates, sorbitan esters and carbohydrates. 18. Pharmaceutical composition according to claim 16, characterized in that it contains (5-20)-fatty acids and/or their esters as a surfactant. 19. The pharmaceutical composition according to claim 16, characterized in that it contains oleic acid and/or sorbitan mono-, -diyl-trioleate as a surfactant. 20. Pharmaceutical composition according to claim 16, characterized in that it contains oleic acid as a surfactant. 21. Pharmaceutical composition according to claim 16, characterized in that the surfactant or suspension stabilizing agent contains a toxicologically acceptable polymer and/or block polymer. 22. Pharmaceutical composition according to any one of paragraphs. 1-21, characterized in that it contains ipratropium bromide, salbutamol sulfate, ethanol, citric acid and 227. 23. Pharmaceutical composition according to any one of paragraphs. 1-21, characterized in that it contains ipratropium bromide, salbutamol sulfate, ethanol, citric acid and 134 a. The present invention relates to new aerosol pharmaceutical compositions containing two or more active substances, which are intended for use by inhalation or nasal administration. In metered valve inhalers (VDIs), in which evacuation occurs under the action of a propellant, the active substances may be in the form of solutions or suspensions. The vast majority of aerosol compositions for DCI are prepared in the form of suspensions, especially if the preparation contains more than one active ingredient. Compositions in the form of solutions are used only to a limited extent. In these cases, the compositions usually contain only one active ingredient. 2 8208 1 2006.06.30 As a rule, the chemical stability of active substances in suspension is much higher than in solution. In addition, the active substance may be present in a suspension at a higher concentration than in solution, whereby the composition in the form of a suspension allows the administration of higher doses. The main disadvantage of compositions in the form of a suspension is that over time (for example, during storage) the suspended particles stick together to form larger, more or less stable agglomerates or form loose flocculent particles, precipitates or floating layers, or in the worst case, growth occurs. particles, which significantly impairs the pharmaceutical quality of the product. The size of the formed particles and the growth rate of particles depend on the characteristics of the solubility of the liquid phase. Thus, moisture penetration during storage or the required increase in polarity, which, for example, can be obtained by adding co-solvents, can have a negative impact on the quality of the final medical product, especially if the suspended particles have polar structural elements. The suspension can be physically stabilized by the addition of surfactants by reducing the detrimental effects caused by moisture and/or particle growth, whereby the suspended particles can be held in suspension for a longer period of time. As a rule, compositions of the solution type do not have problems associated with the increase in particle size or with the processes of destruction of the mixture, such as sedimentation or flocculation. However, in this case there is a serious risk of chemical decomposition. It is also a disadvantage that the limited solubility of the ingredients may preclude the administration of high doses. Recently, chlorofluorohydrocarbons (CFCs)11 (trichlorofluoromethane),12 (dichlorodifluoromethane) and 114 (dichlorotetrafluoroethane) have been proposed as the most preferred solvents. The solubility of the ingredients can be increased by the addition of co-solvents. In addition, additional measures are usually required to chemically stabilize the dissolved components. So far, CFCs such as the above 11, for example, have often been used as propellants. However, since CFCs have been linked to ozone depletion, their production and use is on the verge of being phased out. Attempts are being made to replace them with special fluorohydrocarbons (FCs), which are less damaging to the ozone layer but have completely different solubility characteristics. The toxicological profile and physicochemical properties, such as, for example, vapor pressure, make it possible to determine which FUs can be used in an ICD. The most promising representatives at present are 134 a (1,1,2,2-tetrafluoroethane) and 227 (1,1,1,2,3,3,3-heptafluoropropane). Treatment by inhalation may require aerosol formulations with two or more active ingredients. In these cases, the composition of the active substances, taken at the required concentration, is prepared in the form of solutions or suspensions, and there are often problems associated with the chemical stability of the individual substances or with the level of concentration that can be achieved. The main problems arise if one of the active ingredients cannot be suspended or is unstable in this type of suspension formulation, or if one of the active ingredients is chemically unstable or cannot be dissolved in this type of solution formulation, especially when FU is used as the propellant. Thus, one of the objectives of the present invention is to provide a metering valve aerosol composition which contains two or more active ingredients and which avoids the disadvantages mentioned above. 3 8208 1 2006.06.30 During the development of the invention, it has surprisingly been found that a large number of active substances can be prepared in the form of a solution and suspension, combined in one composition. The pharmaceutical composition for an inhaler with a metered valve, in which evacuation occurs under the action of a propellant, according to the invention contains a hydrofluorocarbon as a propellant and a combination of two or more active compounds, wherein at least one active compound is selected from the group including ipratropium bromide, fenoterol and their salts, is present in a dissolved form obtained using a co-solvent, and at least one other active compound selected from the group consisting of salbutamol (albuterol), cromoglycine acid and their salts, is present in the form of suspended particles. In a preferred embodiment, the pharmaceutical composition according to the invention contains a combination of two active compounds - ipratropium bromide and salbutamol sulfate, contains 134 a and / or 22 7 as a propellant, and also contains a co-solvent selected from the group including pharmacologically acceptable alcohols, pharmacologically acceptable esters, water and mixtures thereof, ethanol, in an amount of from 0.0001 to 50 wt. , preferably from 0.0001 to 25 wt. , more preferably from 0.0001 to 10 wt. , in terms of liquefied propellant. Preferably, the pharmaceutical composition according to the invention additionally contains a composition stabilizer selected from the group consisting of hydrochloric, sulfuric, nitric, phosphoric, ascorbic and citric acids, benzalkonium chloride, ethylenediaminetetraacetic acid and/or their salts in an amount up to 100 ppm, preferably up to 40 ppm. million Preferably, the pharmaceutical composition according to the invention further comprises a surfactant or suspension stabilizing agent selected from the group consisting of (C 5-C 20)-fatty alcohols, (C 5-C 20)-fatty acids and/or their esters, lecithin, glycerides, propylene glycol esters, polyoxyethanes, polysorbates, sorbitan esters and carbohydrates, oleic acid and/or sorbitan mono-, -di- or -trioleate, wherein the surfactant or suspension stabilizing agent contains a toxicologically acceptable polymer and /or block polymer. Preferably the pharmaceutical composition according to the invention contains ipratropium bromide, salbutamol sulfate, ethanol, citric acid and 227 or 134 a. The pharmaceutical composition according to the invention is used for treatment by inhalation, in particular for the treatment of diseases of the pharynx and respiratory tract such as asthma and chronic obstructive pulmonary disease (COPD). According to one embodiment, a combination of two or more active substances suitable for medical purposes is used, including beclomethasone, budesonide, cromoglycic acid, fenoterol, flunisolide, fluticasone, ipratropium bromide, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol (albuterol), salmeterol, terbutaline, 2,2-dimethyl-4-(2-oxo-2Hpyridin-1-yl)-6-trifluoromethyl-2H-1-benzopyran-3-ylmethylhydroxyacetamide, their esters, salts, solvates. Which of the active ingredients listed above are included in the composition according to the invention as a solution and which as a suspension depends on the specific combinations of active ingredients, and this can be determined fairly quickly using dissolution and suspension experiments. According to a preferred embodiment, one or more of the following active ingredients budesonide, cromoglycic acid, nedocromil, reproterol and/or salbutamol (albuterol) or esters, salts and/or solvates of these compounds are suspended, and one or more of the following active ingredients beclomethasone is dissolved, fenoterol, ipratropium bromide, orciprenaline and/or 4 8208 1 2006.06.30 oxytropium bromide, 3-ylmethylhydroxyacetamide or esters, salts and/or solvates of these compounds. Variants comprising two different active ingredients are preferred. In a most preferred embodiment, dissolved ipratropium bromide is included in the composition, especially in combination with salbutamol sulfate (albuterol sulfate) as the suspended active ingredient. In all embodiments, the active ingredients are used in a therapeutically effective amount, i. in an amount that can provide successful treatment. The concentration of active substances and the volume released by one press of the spray valve are regulated in such a way that with one or more presses of the spray valve, the amount of active substance required or recommended for medical reasons is released. One embodiment relates to compositions in which the suspended particles are stabilized by the addition of surfactants or other suspension stabilizing agents in order to stabilize the suspended particles against physical changes. The importance of this approach lies in the fact that the particle size can be maintained at a pharmaceutically acceptable level even for extended periods of time, for example, during storage. Preferred particle sizes are up to 20 µm, however, a particularly preferred particle size is in the range of 5 to 15 µm, most preferably does not exceed 10 µm. The advantage of particles of this size is that such particles are small enough to penetrate deeply into the lungs, but not so small that they are exhaled to the outside with exhaled air. Suitable surfactants and suspension stabilizing agents include all pharmacologically acceptable substances which have a lipophilic hydrocarbon group and one or more functionally active hydrophilic groups, especially 5-C 20 fatty alcohols, C 5-C 20 fatty acids, C 5 fatty esters. -C 20 acids, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. C 5 -C 20 fatty acids, propylene glycol diesters and/or triglycerides and/or C 5 -C 20 fatty acid sorbitans are preferred, with oleic acid and sorbitan mono-, di- and trioleates being particularly preferred. Alternatively, toxicologically and pharmacologically acceptable polymers and block copolymers can be used as suspension stabilizing agents. The surfactants used may be either non-fluorinated or partially fluorinated or perfluorinated, where fluorinated refers to the replacement of carbon-bonded hydrogen radicals with fluorine radicals. The amount of surfactant can be in a ratio of up to 11, based on the weight of suspended active ingredients, preferably in a ratio of 0.00011 to 0.51, particularly preferably in a ratio of 0.00011 to 0.251. Another advantage of the above surfactants is that they can be used to lubricate the valve. Thus, according to one embodiment, the invention relates to compositions in which surfactants are added to lubricate the valve. According to another embodiment, the solubility of at least one active substance to be dissolved can be increased by adding one or more co-solvents. The advantage of this option is that the active substance(s) or substances to be dissolved can (may) be included in the composition at higher concentrations. The addition of a co-solvent must not exceed the critical threshold of liquid phase polarity at which one of the adverse factors described above begins to act on the suspended particles of the active substance. Suitable co-solvents are pharmacologically acceptable alcohols such as ethanol, esters or water, or mixtures thereof, ethanol is preferred. The concentration of the co-solvent in relation to the total weight of the composition is from 0.0001 to 50 wt. , preferably from 0.0001 to 25 wt. . According to another embodiment, the preferred concentration is from 0.0001 to 10 wt. , moreover, particularly preferred embodiments are those according to which an amount of alcohol is added that is necessary to dissolve the active substance to be dissolved. In yet another embodiment, other conventional propellants are added to the FU propellants. These additional propellants, in addition to other FCs, may be hydrocarbons such as propane, butane, isobutane or pentane, provided that the mixture is pharmacologically acceptable. And according to another embodiment, stabilizers are added to the composition, an important property of which is to affect the pharmaceutical stability of the active substances even over extended periods of time, for example during storage. In the context of the present description, the term stabilizers refers to those substances that prolong the stability and shelf life of a pharmaceutical composition by preventing or slowing down chemical changes in individual ingredients, especially active substances, for example, caused by subsequent interactions or degradation, or those substances that prevent biological contamination. Stabilizers preferred for this purpose are substances which influence the pH value of the liquid phase, such as acids and/or their salts, particularly suitable substances are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid and their salts. . In addition, bactericides, fungicides, etc. such as benzalkonium chloride or ethylenediaminetetraacetate are also preferred. The most preferred stabilizer is citric acid. The concentration of stabilizers can be up to 1000 ppm, preferably up to 100 ppm, and most preferably between 20 and 40 ppm. /mln. One most preferred embodiment includes suspended salbutamol sulfate (albuterol sulfate), dissolved ipratropium bromide, ethanol as a co-solvent, and citric acid as a stabilizer. Example 1 In a solution containing 89.96 g (1 mol, 89.71 wt.) of liquefied 134 a and 10.03 g (0.88 mmol, 0.21 wt.) of salbutamol sulfate (albuterol sulfate) together with 0, 05 wt. surfactant (for example, 50 mg (177 mmol) oleic acid. Example 2. Similar to example 1, but 227 instead of 134 a is used as gaseous propellant. Example 3. Disodium chromoglycate is suspended in liquefied P 134 (134 a) and small amounts of ethanol and fenoterol hydrobromide are dissolved in it.Example 4 Similar to example 3, but 227 instead of 134 u are used as gaseous propellant. national center intellectual property. 220034, Minsk, st. Kozlova, 20. 6
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Pharmaceutical composition for aerosols with two or more active ingredients
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Groups of words, consisting of two or more words, between which there can be very different relationships, in many cases can be treated as one word. Sometimes it is even difficult to say whether we are dealing with one or two words; cf.
Page 103. To-day was once two words, but there is now an increasing tendency to write it without a hyphen (today); in addition, the ability to say from today indicates that to no longer has its original meaning. Tomorrow "tomorrow" is also now a whole word, since one can even say I look forward to tomorrow. However, for us in this chapter it does not matter whether these combinations and other doubtful cases are taken for one or two separate words; a group of words (just like a single word) can be both primary, and adjunct, and subjunct.
Word groups various types in the function of primary words: Sunday afternoon was fine "Sunday was fine"; I spent Sunday afternoon at home We met the kind old archbishop of York cf. further English. It had taken him ever since to get used to the idea; You have until ten to-night. From infancy to manhood is rather a tedious period (Cowper); French jusqu' au roi l'a cru; Nous avons assez pour jusqu' à samed; Spanish Hasta los malvados creen en el (Galdos).
Groups of words in the function of adjuncts: a Sunday afternoon concert "Sunday afternoon concert"; the Archbishop of York "archbishop of York", the party in power "ruling party"; the kind old Archbishop of York's daughter "daughter of the good old Archbishop of York"; cf. also a Saturday to Monday excursion; the time between two and four; his after dinner pipe.
Groups of words in the function of subjuncts (tertiary words): Didn't sleep all Sunday afternoon „He slept all Sunday afternoon“. He didn't smokes after dinner He didn't smoke after dinner He didn't go to all the principal cities of Europe He traveled to all the principal cities of Europe Don't lives next door to Captain Strong; The canal ran north and south; He used to laugh a good deal; five feet high; He wants things his own way; Things shall go man-of-war fashion.
He ran upstairs three steps at a time; cf. "absolute construction" in chapter "Nexus" (IX).
As can already be seen from the examples given, a group that performs the function of primary, secondary or tertiary may itself contain components that are in the relationship indicated by these three terms. The rank of the group itself is one thing, but the rank within the group is another. As a result, quite complex relationships can arise; however, they are always easy to analyze from the point of view developed in this chapter. This can be illustrated with examples: We met the kind old Archbishop of York "We met the kind old Archbishop of York": the last six words form one primary group - the addition to met, but the group itself consists of the primary word Archbishop and four adjuncts - the, kind , old, of York; or rather, it should be said that the Archbishop of York, consisting of the primal word Archbishop and the adjunct of York, is a primary group defined by the three adjuncts the, kind, and old. But the adjunct of York, in turn, consists of the particle (preposition) of and its complement, the primary word York. Further, this entire group can be made into an adjunct by being used in the form genitive: We met the kind old Archbishop of York's daughter
Doesn't live on this side the river here the whole group, consisting of the last five words, is tertiary in relation to lives "lives"; on this side, consisting of the particle (preposition) on and the complement this (adjunct) side ( primary word), is itself a group preposition and takes as a complement the group(adjunct) river (primary word). But in The sentence buildings on this side the river are ancient The same five-word group is an adjunct to buildings. In this way, a natural and consistent analysis of even the most complex combinations occurring in the language can be achieved.
More on the topic of GROUPS OF WORDS:
- c) Committing a crime as part of a group of persons, a group of persons by prior agreement, an organized group or a criminal community (criminal organization)
