Source: http://russianpatents.com/patent/242/2423130.html
Timestamp: 2017-11-21 09:52:25
Document Index: 398143186

Matched Legal Cases: ['art 100', 'art 100', 'art 100', 'art 100', 'art 100', 'art 100', 'art 0', 'art 0', 'art 0', 'art 0', 'art 0', 'art 0', 'art 0', 'art 10', 'art 10', 'art 10', 'art 9', 'art 10', '§ 42', '§ 42', '§ 42']

Epoprostenol-containing composition and method of its obtaining
A61K31/5585 -
This application claims the priority of Provisional applications U.S. patent No. 60/764,769, filed February 3, 006; No. 60/772,563, filed February 13, 2006; and No. 60/783,6429, filed March 20, 2006; which are fully incorporated into this description by reference.
This invention relates to a stable containing epoprostenol compositions, which can be combined with commercially available intravenous fluids for parenteral use in environments with approximately 15-30°C for more than 24 hours.
Cardiovascular disorders and diseases and their associated complications are a major cause of disability and death in patients in the United States and Western Europe. For example, in recent years, more than 500,000 deaths per year in the United States alone occur as a result of coronary artery disease, and in addition, 700000 patients hospitalized with myocardial infarction.
There is a continuous search for effective long-term treatment of disorders and diseases of the heart and arteries, such as atherosclerosis, arteriosclerosis, congestive heart failure, angina and other disorders and diseases associated with the cardiovascular systemoutprintln methods of treating such disorders and diseases include, for example, the use of vasodilators, plastic vessels and bypass operations. Such methods of treatment were disapproved because of the level of risk compared to the benefits gained in a variety of treatment methods. In addition, these treatment methods have serious shortcomings regarding the effectiveness with prolonged use. The use of vasodilator drugs and mechanical interventions for acute and chronic occlusive vascular diseases of the heart, Central and peripheral cardiovascular system to date is ineffective to obtain a favorable long-term results. Currently used treatments minimally affect the outcome of the disease, because treatment is directed more at what is happening at disease processes than on the original molecular cause of the disease or disorder.
For example, a reasonable explanation for the actions of vasoactive medicinal compositions is a decrease in blood pressure by direct or indirect effects on vascular smooth muscle and/or heart, thereby reducing the resistance of blood vessels and blood flow disorder. These drugs do not treat the original cause of high blood pressure and impaired blood flow. Rather, they try to mind is isit the impact of the disease or disorder. These drugs activate the sympathetic nervous system through baroreceptor reflex, which increases heart rate and force of myocardial contractions, which is not always necessary to achieve positive impacts. Other side effects of these medications include headache, palpitations, anxiety, mild depression, dry mouth, unpleasant taste in the mouth, nausea, vomiting, angina, myocardial infarction, congestive heart failure, low cardiac output, fluid retention, fatigue, weakness and others. Pharmacological treatment of most diseases is not very specific in its action on the initial molecular cause of the disease, and treated very limited range of effects for diseases that are multifactorial.
As an additional example of such an improved outcome when atherosclerosis occurs when cholesterol level decline and medicinal treatment of diseases associated with lipid. However, these treatments do not treat blood clotting disorders associated with these diseases, which are known to be proximal phenomena that cause heart attack and stroke. They do not prevent the cellular or molecular reactions related to thrombocy the am, macrophages, neutrophils, lymphocytes, smooth muscle cells, and other cell types, which are known to be involved in atherosclerosis and complications of this disease.
Similarly thrombolytic therapy, plastic vessels and bypass surgery have minimal success in the long term. The currently used mechanical and pharmacological methods of treatment are focused on the particular case of partial or complete occlusion or occluded vessel in a particular place or eliminate clogging or vessel continuum by connecting vessels. These methods of treatment may not be directed at physiological disorders in normal homeostatic systems that enable occlusive processes to begin and develop. This way they cannot be directed at a multicentre nature of the homeostatic disorders. These deficiencies often lead to recurrent occlusion in the initially cured vessel and to microemboli due to incomplete dissolution of thrombus in the treatment at the site of occlusion. There is no cure for places, presumably correctly occluded or strategyrunner, which is supposed to yield currently available coarse technologies.
There is a huge need in the treatment procedure, which prevents the failure of normal homeostatic control and which restores the control at the beginning of the development of disorders.
Return internal regulatory systems and cellular domains to a healthy state could prevent stenosis, occlusion, thrombosis and thromboembolic processes that take place due to data breaches. Permanent and episodic regaining control in normal molecular processes that ultimately regulate homeostasis, can prevent atherosclerosis, its variants, hypertension, congestive heart failure, macro - and microthrombus and embolism and complications of these diseases, including (but not organizovalisj them) myocardial infarction, stroke, and related diseases of the kidney and related diseases of the Central and peripheral nervous system and associated disorders of other systems of cells. Additionally, the rapid restoration of homeostatic control during acceleration and accumulation of damaging processes can minimize both the extent and duration of effects on the atomic and molecular levels, levels, membranes, cells, and organ.
Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a natural prostaglandin, have the s potential vasodilatory action, as well as inhibiting action regarding the aggregation of platelets. Epoprostenol is a (5Z,9(alpha),11(alpha),13TH,15S)-6,9-epoxy-of 11.15-dihydroxypregna-5,13-Dien-1-oevuyu acid. Epoprostenol sodium has a molecular mass of 374,45 and the molecular formula C20H31NaO5and was approved by the food and drug U.S. FDA) as Flolan (sold by GlaxoSmithKline) September 20, 1995 for the treatment of patients with cardio-vascular obstructive pulmonary disease.
Flolan for injection is a sterile sodium salt of epoprostenol prepared for intravenous (IV) injection. Each ampoule liofilizirovannogo Flolan contains epoprostenol sodium in an amount equivalent to 0.5 mg or 1.5 mg of epoprostenol, 3,76 mg glycine, 2,93 mg of sodium chloride and 50 mg mannitol. Can also be added to the sodium hydroxide for adjustment of pH.
Flolan is a white or yellowish powder that must be reconstituted with sterile diluent for Flolan. Sterile diluent for Flolan comes in glass ampoules containing 94 mg glycine, is 73.5 mg of sodium chloride, sodium hydroxide (added to regulate pH) in 50 ml of water for injection, USP. The recovered solution Flolan has a pH of 10.2 to 10.8 and is more volatile than lower pH.
Epoprostenol (Formula I), ekzoticeski vinyl is rostau ether, rapidly hydrolyzed under defined pH dependence, up to 6-keto-PGF (Formula II). Formula I and formula II below:
The chemical nature of epoprostenol, especially potential hydrolytic instability, makes very difficult the development of its containing a stable composition. Vinylester derived PGI2-Na is better stabilized in solution by using buffer solution under alkaline environment (>pH 8.8). The half-life of epoprostenol sodium in water, i.e. the time during which lost 50% of its efficiency in dependence on pH are presented below in table 1:
Stability epoprostenol in solution at a pH of from 7.2 to 9.3
Temperature (C) PH Half-time
0 8,9 21,0
23 8,9 4,4
23 9,3 10,33
23 7,2 0,033
As shown in table 1,50% epoprostenol decomposes in about 10 hours at a pH of 9.3 at 23°C. to manufacture sterile dosage form, the connection should not lose efficiency at least 12 hours, preferably at ambient conditions. If this is unattainable, the connection must be stable at 4°C for approximately 12 hours for use in cooling conditions.
Flolan is supplied in lyophilized form in the vial with the vial, which contains 50 ml of sterile diluent buffered glycine and made isotonic with sodium chloride. pH isotonic is regulated in the range from 10.2 to 10.8 with sodium hydroxide. Ampoule with liofilizirovannam content restore using a special diluent and used for patients suffering from cardiovascular diseases.
Flolan should only restore data sterile diluent for Flolan. The recovered solutions of Flolan should not be diluted or used with other parenteral solutions or medications. The recovered solutions of Flolan should be protected from light and stored in the refrigerator at 2-8°C (36-46°F), if they are not used immediately. Located in Jolo is ilnicki solution however, can only be stored for two days, after the expiration of this period should be discarded. In addition, the recovered solution will not freeze if the solution was frozen, it should be discarded.
Thus, there remains a need for containing epoprostenol compositions that can be recovered using commercially available intravenous fluids and that after the restoration to their application does not need to be stored in the refrigerator.
The author of this invention unexpectedly found that the solution epoprostenol in the presence of an alkalizing remedies at high pH (>11) compared with Flolan is very stable. Accordingly, one of the objectives of the present invention is to provide pharmaceutical compositions containing epoprostenol or its salt, and at least one alkalizing treatment with pH>11. The composition is characterized by increased stability after recovery using commercially available intravenous (IV) fluids. When restoring and/or dilution by using a commercially available intravenous fluids stability of this composition is characterized by at least 90% of the stability of the original epoprostenol, persisting after 24-48 hours at 15-30°C.
The other is OI the present invention is to provide methods of obtaining freeze-dried pharmaceutical compositions containing epoprostenol and alkalizing agent. Such lyophilized composition during recovery has a pH>11.
Another objective of the present invention is to provide methods of administration restored lyophilized pharmaceutical compositions containing epoprostenol and alkalizing product with a high pH. The recovered solution is preferably used for the treatment of cardiovascular diseases such as atherosclerosis, arteriosclerosis, congestive heart failure, angina, cardiovascular obstructive pulmonary disease and hypertension.
The main advantages of the present invention include hemocompatibility and self-preservation (the ability to pass the test on the effectiveness of the preservation of the United States Pharmacopeia (USP) without the presence of preservatives) restored and/or a dilute solution. Typically, when a chemical substance is injected, it must be compatible with blood and should not cause the destruction of blood cells. Typically, the compositions with high pH and/or hypotonic solutions with the introduction of causing the destruction of red blood cells. Because of the presence of epoprostenol composition is injected at high pH (>11), one should expect the damage to blood cells. However, the author was surprised to find that the destruction of blood cells is not h is observed and that the solution epoprostenol, according to the present invention, has the same hemocompatibility as isotonic in these studies. Additionally, restored and/or a diluted solution has a high resistance to microorganisms and can be tested for the effectiveness of the preservation of the United States Pharmacopeia (USP).
The composition according to the present invention contains epoprostenol or its salt and an alkalizing agent. Used in the description of the term "epoprostenol" applies or the free acid or salt epoprostenol. The mass ratio of epoprostenol:alkalizing the tool is preferably from about 1:25 to 1:200, more preferably from about 1:25 to 1:100, most preferably 1:33,3. The most preferred compositions contain or 0.5 mg epoprostenol and 50 mg of arginine, or 1.5 mg epoprostenol and 50 mg of arginine in a vial. The composition preferably also contains enough reason to restored and/or a diluted solution had a pH>11.
Used in the description of the term "alkalizing agent" means a facility that provides an alkaline environment (pH>7)when epoprostenol dissolved in water together with an alkalizing agent. Additionally, while alkalizing the tool provides an alkaline environment, it is not the soda the inhabitants of the basic hydroxyl groups, but may contain at least one functional group, which accepts a proton from water, when dissolved in water or a mixture of water/organic solvents. Alkalizing the tool should have at least one PKandmore to 9.0. Preferably, the alkalizing remedy is in the solid phase and soluble in an aqueous environment. Alkalizing remedies can represent, but not limited to, arginine, lysine, meglumine, N-methylglucamine, any other amino acid with PKand9,0 or greater, alkaline phosphates, such as trinatriyfosfat, inorganic carbonates such as sodium carbonate, sodium salts of carboxylic acids, such as tetranitro-EDTA, or combinations thereof. The most preferred alkalizing remedies are arginine and sodium carbonate.
In some embodiments of alkalizing agent can be a well-known buffers, including but not limited to, various saline, acidic and basic forms of the following anions: citrate, phosphate, tartrate, succinate, adipate, maleate, lactate, acetate, bicarbonate, pyruvate, and carbonate. Typical salts of these buffers, which can be used are the sodium and potassium forms up until the salt and its quantity are physiologically compatible in composities injection. Can also be used a mixture of data buffers.
High pH (>11) composition (recovery) preferably reach by adding inorganic bases. Used in the description, the term "inorganic base" is defined as a chemical substance containing free hydroxide, which can inadvertently accept a proton from water and used to adjust the pH of the mass of the fluid to the desired level. Preferred inorganic bases are sodium hydroxide, potassium hydroxide, other alkali hydroxides, ferrous hydroxides such as magnesium hydroxide and volatile hydroxide, such as ammonium hydroxide. Can also be used organic bases such as primary, secondary and tertiary amines, aromatic amines such as aniline and aromatic alcohol (such as phenol). The combination of organic and inorganic bases is also suitable for the present invention. Preferably, the base is added so that the pH of the mass of the solution was more than 11, preferably more than 12, and most preferably more than 13. The preferred base for use in this invention is sodium hydroxide.
The composition is preferably lyophilic obtained by subl the awareness drying (lyophilization) the main mass of the solution, containing epoprostenol or its salt and arginine. the pH of the mass of the solution is preferably adjust to the level of approximately 12.5 to 13.5, most preferably 13 by adding sodium hydroxide.
The term "liofilizirovanny" in relation to these pharmaceutical compositions means of freeze-drying under reduced pressure many vials, each of which contains the standard dose containing epoprostenol compositions according to the present invention. Freeze drying, by means of which perform the above-described lyophilization, are commercially available and are easily accessible to a person skilled in the art. The preferred method of freeze-drying consists of three cycles: the cycle of freezing, primary drying cycle and a secondary drying cycle. The freezing cycle includes the following stages:
1. Cooling on the shelf to approximately -30°C. or below at a rate of about 0.5 to 0.7°C/min and keeping shelves at this temperature for about 30-40 minutes or until until the temperature of the composition reaches about -25°C. or below.
2. Lowering the temperature of the shelves to approximately -45°C±2°C or below until such time as the temperature of the composition reaches about -38°C±2°C or below.
3. Keeping the product at this temperature for about six hours is in or longer.
4. Apply vacuum until such time as the pressure in the chamber reaches from 50 millitorr or less.
5. Maintaining the temperature of the shelf is approximately -45°C±2°C for approximately 45 minutes or more, even after applying the vacuum.
After a cycle of freezing the dried composition in the primary drying cycle, which includes the following stages:
1. Raising the shelf temperature to approximately 0°C±2°C with a heating rate of approximately 20±2°C/hour in vacuum and continue drying until then, until the temperature of the composition reaches about -3±2°C or higher.
2. Raising the shelf temperature to about 25±2°C and the cycle continued drying in vacuum, continue drying until then, until the temperature of the composition reaches about 20±2°C or higher.
After primary drying cycle composition further dried in a vacuum in the secondary drying cycle by increasing the shelf temperature to approximately 45±2°C at a rate of about 3±2°C/hour and continue drying until then, until the composition reaches 38±2°C or above. Here is preferably set at a very slow rate of drying so that the time during which achieved approximately 40±2°C 25±2°C was approximately 5 hours.
The composition may also be applied to other pharmaceutically priemel the appropriate fillers. These fillers may include (not limited to) the preservatives present in amount of about 0.1 to 0.5%), media (present in amounts of about 1-5%), tools, modifying toychest (in a quantity sufficient to make the solution isotonic), fillers (present in amounts of about 1-10%) and other conventional components used for the preparation of pharmaceutical compositions. Preferably, these fillers do not affect the basic characteristics of the composition.
Specific preservatives, intended for use, may include benzyl alcohol, parabens, phenol and derivatives of phenol, benzalkonium chloride, and mixtures thereof. Depending on which particular preservative is used, the amount of preservative may vary. Preferably, the preservative is present in the amount of approximately 0.1 to 0.5%, more preferably 0.2 percent.
Typical examples of means, modifying toychest include sodium chloride, lures, dextrose, glucose, lactose and sucrose. Amount, modifying toychest, should be sufficient to bring the solution to the isotonic condition. This number varies depending on the solution type and the means of modifying toychest. However, the person skilled in the art technician who should be able to determine the amount of funds modifying toychest sufficient to cause the solution to the isotonic condition.
Typical examples of fillers include, but are not limited to, gidroxiatilkrahmal (HES); sugars such as sorbitol, lactose, dextran, maltose, mannose, ribose, sucrose, mannitol, trehalose, cyclodextrin; other mono - or polysaccharides; glycine; polyvinylpyrrolidone (PVP); or combinations thereof. The filler may be present in amounts of about 1-10%, preferably 1-5%, most preferably 5%.
In a preferred embodiment, the implementation of a stable freeze-dried composition contains epoprostenol (or its salt, such as epoprostenol sodium), mannitol and arginine. The ratio of epoprostenol:arginine is approximately from 1:25 to 1:200, more preferably from about 1:25 to 1:100, most preferably about 1:33,3. The ratio of arginine:mannitol is from about 5:1 to 1:5, preferably from about 3:1 to 1:3. Preferred compositions contain or 0.5 mg epoprostenol and 50 mg of arginine and mannitol, or 1.5 mg epoprostenol and 50 mg of arginine and mannitol on the ampoule. The bulk of the solution for lyophilization or contains 0.5 mg of epoprostenol and 50 mg mannitol, and arginine, or 1.5 mg epoprostenol and 50 mg of arginine and mannitol in ml. pH of the mass of the solution is adjusted to the match > 11 using sodium hydroxide before lyophilization.
In another embodiment, the implementation of the present composition contains epoprostenol (or its salt, such as epoprostenol sodium and arginine. The composition can also include a base, which may be an inorganic base such as sodium hydroxide, or an organic base, or a combination of organic and inorganic bases. The base is added so that the pH of the mass of the solution was more than 11, preferably more than 12, and most preferably 13 or higher.
In another implementation of the present invention developed a stable lyophilized composition containing epoprostenol (or its salt, such as epoprostenol sodium), mannitol and the base, preferably in a ratio from about 1:25 to 1:200 (epoprostenol:mannitol), more preferably 1:100, most preferably 1:33,3. Preferably, the compositions contain or 0.5 mg epoprostenol and 50 mg mannitol, or 1.5 mg epoprostenol and 50 mg mannitol per ampoule. The bulk of the solution for lyophilization or contains 0.5 mg of epoprostenol and 50 mg mannitol, or 1.5 mg epoprostenol and 50 mg mannitol in ml. pH of the mass of the solution is adjusted to the level 13,0 with the help of the Foundation.
Freeze-dried composition can be restored using the existing p is adage intravenous fluids. These solutions include, but are not limited to, water for injection (WFI), including bacteriostatic and sterile WFI WFI, a 0.9 percent solution of sodium chloride (isotonic); ringer's solution with lactate; ringer's solution; solution of sodium carbonate; bicarbonate solution; the solution of amino acids; and similar readily available pharmaceutical diluents. The preferred diluent is an isotonic solution or ringer's solution with lactate. After recovery and/or dilution pH of the recovered solution is more than 11, preferably more than 11.3, more preferably more than about to 11.5, and most preferably more than approximately 11,8.
The pharmaceutical composition according to the present invention prepared in the form of a standard dose or multinational shape and may be in the form of injections or infusions, such as solution, suspension or emulsion. Preferably, it is derived as a dry lyophilized powder, which can be reconstructed to form a liquid solution, suspension or emulsion before use by any of various methods, involving intravenous administration. Preferably, for the introduction of freeze-dried composition to restore 100-10 mg/ml, preferably 10 μg/ml of the Diluted solution is with ailnoth 90% (retains 90% original epoprostenol) at 15-30°C after 24-48 hours.
Without further description it is assumed that an ordinary specialist in the art can, using the preceding description and the following illustrative examples, to obtain and apply the compounds according to the present invention, as well as to apply the claimed methods. The following examples are given to illustrate the present invention. It should be understood that this invention is not limited by specific conditions or details described in these examples.
Example 1. Stability Flolan for injection
In order to determine the stability currently available for sale option epoprostenol (Flolan), the authors of the invention have been lyophilized ampoules of epoprostenol and diluent according to the composition given in the Table reference of the doctor (Physician''s Desk Reference (PDR)). Flolan for injection is a sterile sodium salt formulated for intravenous (IV) injection. Each vial of lyophilized Flolan contains the number of epoprostenol sodium equivalent to 0.5 mg or 1.5 mg of epoprostenol, 3,76 mg glycine, 2,93 mg of sodium chloride and 50 mg mannitol. For regulating the pH can also be added to the sodium hydroxide. The authors of the present invention has been modeling Flolan compounds of the formula.
Flolan can be restored using sterile diluent, made specifically for Flolan. Sterile diluent for Flolan are supplied in glass ampoules containing 94 mg glycine, is 73.5 mg of sodium chloride, sodium hydroxide (added to regulate pH) in 50 ml of water for injection, USP. The range of pH of the diluent contained in the PDR, is from 10.2 to 10.8, consequently, the inventors have received a diluent, according to the above, and adjusted the pH of the diluent to the level of 10.5. Ampoules with modeling composition was restored with the help of a diluent according to the instructions given in the PDR, and watched the stability of the diluent at 5±1°C. stability Data are collected in table 2 below. In the PDR also described that the diluted solution should be applied to <25°C. Because the drug is administered continuously by infusion pump, bag of solution is usually kept in the bladder with ice, which should be changed every 8 hours.
The stability of the composition Flolan in solution at 5°C, pH of 10.5
TIME (HOURS) Analysis of epoprostenol area, in % Square, 6-keto-PGF and leave impurities in %
start 100,0 2,5 99,7 0,31
5,0 99,3 0,39
7,5 the 98.9 0,44
10,0 98,5 0,55
12,5 98,0 0,61
15,0 97,5 0,71
18,0 to 97.1 0,80
39,0 86,7 4,49
53,0 80,3 6,59
77,0 61,6 12,9
As shown in table 2, the composition being destroyed at a rate of about 0.5 to 1% for every three hours during the first 39 hours; therefore, within 24 hours he will be destroyed approximately 4-8%. In the subsequent time there is an even greater rate of destruction.
The authors also studied the stability of the composition Flolan at 29±1°C. the Composition of Flolan the ruin which was more than 4% for 1 hour (presented in table 3), whereas the composition according to the present invention, lost more than 2% of the drug within 24 hours (presented in table 7).
The stability of the composition Flolan in the solution, pH of 10.5, at 29±1°C
start 100,0 0,08
1 for 95.2 1,48
2 91,2 2,54
3 87,1 3,54
4 of 83.4 to 4.41
5 80,4 5,39
Example 2. Stability epoprostenol with arginine
Got the solution epoprostenol containing 50 mg/ml arginine, and determined its stability at 5°C. the data Obtained are presented in Table 4:
Stability epoprostenol in solution in the presence of 50 mg/ml arginine, pH 11,9, at 5±1°C
start 100,0 0,15
2 99,9 0,19
4 99,8 0,19
6 99,7 0,21
8 99,6 0,22
10 99,6 0,23
12,5 99,6 0,25
14,5 99,5 0,26
39 98,6 0,63
53 of 92.7 1,15
77 92,5 2,05
100 92,5 2,10
124 2,25
As shown in table 4, the content of active substance in the composition is reduced only by 1.4% for 53 hours, while the composition of Flolan (table 2) is reduced to approximately 20% active ingredient content within a given time. These data suggest that the solution epoprostenol can continuously use for about 5 days without changing the solution in the tank, allowing a large amount and guaranteed sterility. This is a significant improvement compared with Flolan, because the solution of Flolan in tank pump should be replaced every 12 hours.
The stability of the same composition was also investigated at pH of 11.2; data are given in table 5 below:
Stability epoprostenol in solution in the presence of 50 mg/ml arginine, pH of 11.2, at 5±1°C
tr> start 100,0 -
4,0 99,5 0,28
7,0 99,0 0,39
10,0 98,6 0,53
11,5 98,3 0,57
of 17.5 97,3 0,80
The data show that even at pH of 11.2 stability of the composition according to the invention is higher than that of the composition Flolan (table 2).
Example 3. Stability restored lyophilisate
In the next series of experiments the pH of the solution containing epoprostenol and arginine, adjusted to the level 13,0 with sodium hydroxide, after which the solution liofilizirovanny. After recovery of freeze-dried using 1 ml of water for injection recovered solution contained 50 mg/ml arginine and 0.5 mg/ml epoprostenol. the pH of the solution was 13,0. Data on the stability at 5°C are presented below in table 6, at 29°C table 7:
Stability epoprostenol in solution in the presence of 50 mg/ml arginine, at 5±1°C, pH of 13.0
start 100,0 0,16
14,5 99,8 0,20
53 98,8 0,29
124 98,0 0,40
148 97,6 0,45
192 97,3 0,47
240 96,9 0,61
480 96,6 0,70
Thus, in the present invention it is shown that the loss occurs only 3.4% of the active substance for 480 hours, or, on average, to 0.007%/h at a constant temperature of 5°C.
Additionally, an advantage of the present invention is that the composition does not require any special time is of avatele. The lyophilized composition can be restored using water for injection to a concentration of reaching 5 ng/ml, while the pH of the solution is still supported above 11,0 due to the buffering capacity of arginine with the main PKand=13,2 and 10.8, as well as additional base is added to regulate the pH.
Stability epoprostenol in solution in the presence of 50 mg/ml arginine, pH of 13.0, at 29±1°C
start 100,0 0,072
1 100,0 0,087
5 99,8 0,18
7 99,3 0,21
8 99,2 0,25
9 of 99.1 0,29
0 98,8 0,28
11 98,6 0,29
12 98,5 0,30
13 98,1 0,38
14 98,0 0,37
15 of 97.8 0,39
24 97,5 0,39
36 97,5 0,45
Finally, as was observed only 1.5% destruction for 12 hours at 29°C., this composition can be obtained in the device for injecting without cooling the mass of the solution to 5°C. It would be impossible for the present to sell the stock, because the pH of the mass of the solution is 10.5, and the composition could be obtained at 5°C for 12 hours, otherwise there is a significant destruction.
Example 4. Comparison with different containing epoprostenol songs
In the next stage of development, the inventors have selected a few lyophilize avannah compositions with a pH mainstream solution for lyophilization, adjusted level from 10.5 to 13.0 in the presence of various fillers. The composition of the studied compositions detailed in table 8, stability data are shown in table 9 below.
The stability of some songs-prototypes containing epoprostenol
The series number Amount (mg) of filler used in the composition
SWU Trehalose Arginine Lures HES NaCl Glycine Na2CO3 LV est. wt. Rast.
SWU-7 0,5 50 13
SWU-8 0,5 50 3 3,75 10,5
SWU-10 0,5 50 50 13
SWU-12 0,5 100 13
SWU-13 0,5 50 50 13
SWU-14 0,5 50 13
SWU-19 0,5 50 12
SWU-20 0,5 50 13
SWU-23 0,5 50 50 13
SWU-24 0,5 50 50 11
SWU-25 0,5 50 50 12
SWU-26 0,5 50 50 13
SWU-27 0,5 50 12
SWU-30 0,5 100 97,76 11
SWU-31 0,5 100 97,76 1
SWU-32 0,5 50 97,76 11
SWU-33 0,5 50 12
SWU-38 0,5 50 13
SWU: epoprostenol; HES: gidroxiatilkrahmal; pH, inorg. masrat.: the pH of the mass of the solution.
Stability of compositions-prototypes containing epoprostenol
The series number Stability (% from the beginning) when stored at 40°C
SWU-7 99 97 NP NP
SWU-8 40 0 NP NP
SWU-10 99 99 99 100
SWU-12 76 NP NP NP
SWU-13 99 98 99 97
SWU-14 100 96 97 83
SWU-19 (25%)* 87 NP NP NP
29 NP NP NP
SWU-23 94 96
SWU-24 0
SWU-25 60 35 24
SWU-26 (11%) 100 101 100
SWU-27 60
SWU-30 88 96
SWU-31 90 74
SWU-32 76 100
SWU-33 95
SWU-38 (13%) 94
* numbers in parentheses indicate the water content of the lyophilisate. NP: not performed.
During lyophilization several parties were lyophilized together, which led to different moisture contents. It was also measured the moisture content in selected samples (SWU-19, 20, 26 and 38). As shown in table 8 above, the stability of epoprostenol more at pH 13, compared to samples with lower pH. Compositions containing mannitol/HES, or mannitol/arginine, or HES/sodium carbonate showed excellent stability.
In the next stage for lyophilization were selected compositions containing arginine/mannitol, pH main mass of the solution is adjusted to 13. As the moisture content varies from batch to batch, the lyophilization cycle was optimized so that uniformly to give a moisture content less than 12% by providing three cycles of way lyophilization, which was discussed above. Using Opti is yserowanego way lyophilization was obtained following songs:
1. Three parties of the composition containing per ampoule epoprostenol (0.5 mg)/arginine (50 mg)/mannitol (50 mg)/pH 13.
2. One part of the song that contains each vial of epoprostenol (0.5 mg)/arginine (50 mg)/mannitol (50 mg)/pH 12.
3. Two batches of the composition containing per ampoule epoprostenol (0.5 mg)/arginine (50 mg)/trehalose (50 mg)/pH 13.
4. One part of the song that contains each vial of epoprostenol (0.5 mg)/arginine (50 mg)/trehalose (50 mg)/pH 12.
5. One batch of each of the compositions Flolan with pH adjusted to 12 and 13.
The moisture content for each of these parties were in the range of 7-10%.
Data on the stability in the solid state when stored for three months for the selected compositions are presented in tables 10-18 below:
Party No. of EX-01: SWU/mannitol/arginine/pH::0,5/50/50/13*
Storage temperature The analysis time SWU, mg/ampoule SWU,% 6-PGF, mg/ampoule 6-PGF,% Additional peaks
The area, in%
40°C start 0,49 100 null null No data
15 days 0,49 100 null null No data
1 month 0,50 102 null null 0,2
2 months 0,48 98 0,003 0,65 0,72
3 months 0,48 98 0,002 0,49 0,78
25°C 3 months 0,48 98 0,00034 0,07 0,12
* SWU/mannitol/arginine/pH:: 0,5/50/50/13=0.5 mg/vial epoprostenol, 50 mg/vial mannitol, 50 mg/vial arginine, and pH 13.
Party No. of EX-02: SWU/mannitol/arginine/pH::0,5/50/50/13
The area, in %
1 month 0,50 12 null null 0,2
2 months 0,48 98 0,003 0,64 0,73
3 months 0,49 100 0,0041 0,84 0,87
25°C 3 months 0,49 100 0,0004 0,08 0,12
Party No. of EX-03: EPP/mannitol/arginine/pH::0,5/50/50/13
2 months 0,50 102 0,0021 0,41 0,66
3 months 0,48 98 0,0041 0,84 1,07
25°C 3 months 0,49 100 0,00044 0,09 0,12
Party No. of EX-07: SWU/mannitol/arginine/pH::0,5/50/50/12
40°C start 0,47 100 0,002 0,36 0,08
15 days 0,013 2,8 0,07 14,8 0,76
1 month 0,008 1,7 0,072 15,4 0,66
Lot no EX-04: EPP/trehalose/arginine/pH::0,5/50/50/13
40°C start 0,52 100 0,0006 0,11 0,08
15 days 0,52 100 0,0007 0,13 0,08
1 month 0,52 100 null null 0,12
2 months 0,49 94 0,007 1,4 0,38
3 months 0,49 94 0,0114 2,2 0,80
25°C 3 months 0,52 100 0,0006 0,12 0,17
Lot no EX-06: SWU/arginine/trehalose/pH::0,5/50/50/13
40°C start 0,52 100 0,0006 0,12 0,08
15 days 0,52 100 0,0006 0,12 0,08
1 month 0,50 96 null null 0,11
2 months 0,48 92 0,011 2,08 0,31
3 months 0,49 94 0,012 2,3 0,87
25°C 3 months 0,51 98 0,0001 0,02 0,17
Lot no EX-05: EPP/trehalose/arginine/pH::0,5/50/50/12
40°C start 0,51 100,0 null null 0,15
15 days 0,51 100,0 0,003 0,57 0,2
1 month 0,40 78 0,003 0,74 0,45
2 months 0,32 63 0,004 0,82 1,33
Parthi is no EX-08: Composition, modeling Flolan*: pH 12
40°C start 0,50 100,0 0,0014 0,28 0,11
15 days 0,03 6,0 0,072 14.4V 1,56
1 month 0,011 2,2 to 0.032 6,4 0,78
* The term "Composition, modeling Flolan"refers to a composition that is identical to the commercially available Flolan, sold by GlaxoSmithKline, except that the pH is adjusted to a specified pH level.
Party No. of EX-09: Composition, modeling Flolan*: pH 13
40°C start 0,50 100 0,001 0,2 0,12
15 days 0,50 100 0,0012 0,24 0,12
2 months 0,44 88 0,003 0,6 0,82
3 months 0,45 90 0,0083 1,7 0,3
25°C 3 months 0,48 96 0,00074 0,15 null
As you can see from the above data, epoprostenol the most stable compositions containing mannitol/arginine, in which the pH of the mass of the solution is adjusted to 13. For these compositions follow compositions containing arginine/trehalose in which the bulk of the solution for lyophilization adjusted to pH 13. Compositions containing together with arginine or trehalose or mannitol in conditions of lower pH, are less stable at 40°C, compared to compositions in which the pH of 13. Composition simulating Flolan, almost completely destroyed within one month at 40°C and pH 12. At pH 13 she had the best stability, but not so good as composition containing mannitol/arginine with a pH of 13.
Example 5. The stability of various restored compositions of epoprostenol, diluted to 10 μg/ml
Also studies have been conducted dilution in order to determine suitable if the compositions according to the present invention for intravenous injection at room temperature. Research is of stability was carried out at a temperature from 25°C to 30°C, in order to simulate the temperature of the introduction for more than 24 hours with a large amount of solutions for parenteral injection.
To this end, the lyophilisate of epoprostenol recovered and diluted to 10 μg/ml of isotonic, and determined the stability within 48 hours at 25°C and 30°C. Stability upon dilution for all three parties primary compositions were determined upon dilution with isotonic solution at 25°C and 30°C. in Addition to these studies for one randomly selected party primary composition were conducted stability studies at 25°C and 30°C when diluted with 5% dextrose (D5W), WFI (own production) and ringer's solution with lactate.
For studies under the dilution of the contents of each ampoule was restored 5 ml of diluent. The clear solution was placed in a 50 ml volumetric flask. The ampoule was three times washed in 5 ml of diluent, and used for washing the portion of the diluent was placed in the flask. Then the contents of the flask were diluted with diluent and diluent brought to the mark. the pH of the diluted solution was measured and recorded. The contents of the flask stood at temperatures that were identified, and the analysis was performed within the specied time intervals. Data on the stability upon dilution with various diluents present the Lena river below in tables 19-30.
Research dilution isotonic
Stability upon dilution of epoprostenol saline, lot no EX-01 25°C, pH 11,58
The analysis time SWU (µg/ml) % of baseline 6-PGF* (µg/ml) % SWU (source) Additional peaks
Start 10,10 100,0 Null Null Null
6 hours 10,06 99,6 Null Null Null
12 hours 10,02 99,2 Null Null Null
18 hours 9,95 98,5 Null Null Null
24 hours 9,81 to 97.1 0,12 1,19 Null
30 PM 9,71 96,1 0,32 3,17 Null
36 hours 9,62 for 95.2 0,40 3,96 Null
42 hours 9,52 94,3 0,48 4,75 Null
48 hours 9,46 93,7 0,52 5,14 Null
* 6-PGF - 6-keto-PGF.
Stability upon dilution of epoprostenol saline, lot no EX-01 at 30 the
6 hours of 10.05 99,5 Null Null Null
12 hours 9,92 of 98.2 Null Null Null
18 hours 9,79 96,9 0,37 3.65 Null
24 hours 9,62 for 95.3 0,59 of 5.89 Null
30 PM 9,37 92,8 0,76 7,52 Null
36 hours of 9.21 91,2 0,83 by 8.22 Null
42 hours 9,02 89,3 1,30 12,87 Null
48 hours 8,94 88,5 of 1.34 of 13.27 Null
Stability upon dilution of epoprostenol saline, lot no EX-02 25°C, pH 11,58
Start 10,30 100,0 Null Null Null
6 hours 10,24 99,4 Null Null Null
12 hours 10,20 99,0 Null Null Null
18 hours 10,00 to 97.1 Null Null Null
24 hours 9,96 96,7 0,07 0,68 Null
30 PM 9,85 95,6 0,27 2,62 Null
36 hours 9,76 94,8 0,34 3,30 td align="center"> Null
42 hours 9,68 94,0 0,44 4,27 Null
48 hours 9,58 93,0 0,48 of 4.66 Null
Stability upon dilution of epoprostenol saline, lot no EX-02 at 30°C
Start 10,20 100,0 Null Null Null
6 hours 10,13 99,3 Null Well the ü Null
12 hours there is a 10.03 98,3 Null Null Null
18 hours 9,82 96,3 0,32 3,14 Null
24 hours 9,70 95,1 0,52 5,10 Null
30 PM for 9.47 92,8 0,70 6,90 Null
36 hours 9,29 to 91.1 0,79 7,74 Null
42 hours 9,10 89,2 1,21 up 11,86 Null
48 hours 9,02 88,4 1,27 12,45 Null
Stability upon dilution of epoprostenol saline, lot no EX-03 25°C, pH of 11.6
6 hours 10,20 99,0 Null Null Null
24 hours 9,94 96,5 0,09 0,87 Null
30 PM 9,82 for 95.3 0,29 2,81 Null
36 hours 9,71 94,3 0,37 3,59 Null
42 hours being 9.61 93,3 0,46 4,47 Null
48 hours at 9.53 92,5 0,51 4,95 Null
Stability upon dilution of epoprostenol saline, lot no EX-03 at 30°C
6 hours 10,10 99,0 Null Null Null
12 hours 9,96 97,6 Null Null Null
18 hours 9,77 95,8 0,33 3,24 Null
24 hours being 9.61 a 94.2 0,58 5,69 Null
30 PM 9,44 92,5 td align="center"> 0,75 7,35 Null
36 hours of 9.30 91,2 0,83 8,14 Null
42 hours 9,10 89,2 1,30 was 12.75 Null
48 hours 8,96 of 87.8 1,33 13,04 Null
As shown in tables 19-24, diluted solutions of epoprostenol were quite stable at 25°C and 30°C, while maintaining more than 90% of the active substance over a period of time of at least 24 hours. All investigated parties had minimum oscillation stability from batch to batch at both temperatures. The only observed product degradation was a 6-keto-PGF.
Research dilution D5W:
Stability upon dilution of epoprostenol D5W, lot no EX-03 25°C, pH of 10.9
2 hours 9,83 96,4 Null Null Null
4 hours 9,40 92,2 0,03 0,29 Null
6 hours the remaining 9.08 89,0 0,04 0,39 Null
8 hours 8,81 86,4 0,07 0,69 Null
Stability upon dilution of epoprostenol D5W, lot no EX-03 at 30°C
2 hours 9,76 95,7 Null Null Null
4 hours 9,40 92,2 0,04 0,39 Null
6 hours 9,04 88,6 0,04 0,39 Null
8 hours 8,60 84,3 0,08 0,80 Null
Epoprostenol in 5% dextrose (D5W) was destroyed stronger than in saline solution. Levels of 6-keto-PGF were very low, other peaks were not observed. In this case, approximately 84% of the drug degraded for 8 hours, but no other peaks, indicating the product degradation was not found.
Instability in D5W may be partly associated with a significant fall in pH, because the pH drop was more than expected. In the event of such a fall in pH D5W cannot be used to restore/dilution, according to the present invention.
Study of stability of epoprostenol when diluted with water for injection
Stability upon dilution of epoprostenol WFI, lot no EX-03 25°C, pH 11,55
The area is %
Start 9,04 100,0 Null Null Null
6 hours 8,97 99,2 Null Null Null
12 hours 8,86 98,0 Null Null Null
18 hours 8,77 97,0 Null Null Null
24 hours 8,68 96,0 0,11 1,20 Null
30 PM 8,60 95,1 0,12 1,30 Null
36 hours 8,60 95,0 0,41 4,54 Null
42 hours 8,43 93,3 0,46 5,10 Null
48 hours to 8.41 93,0 0,80 8,90 Null
Stability upon dilution of epoprostenol WFI, lot no EX-03 at 30°C
6 hours 8,93 98,8 0,06 0,7 Null
12 hours 8,78 to 97.1 0,09 1,04 Null
18 hours 8,25 for 91.3 0,21 2,30 Null
24 hours 7,27 80,4 0,48 5,32 Null
30 PM of 5.75 64,0 0,78 8,60 Null
36 hours 3,37 37,3 1,76 19,5 Null
42 hours 1,64 18,1 3,20 35,0 21,1
48 hours 0,79 8,73 4,30 to 47.2 26,2
Interestingly, the stability of epoprostenol in water and isotonic solution at 25°C was close. However, in water at 30°C epoprostenol destroyed faster than isotonic. However, for more than 18 hours was maintained the level of the active substance over 90%. Degradation was accelerated after the passage of time 24 hours.
Study of stability when diluted with ringer's solution with lactate
Also studies have been conducted stability when diluted with ringer's solution with lactate, and data are presented below in tables 29-30:
Stability upon dilution of epoprostenol ringer's solution with lactate, lot no EX-03 25°C, pH 11,63
Start 10,50 100,0 Null Null Null
6 hours 10,43 99,3 0,17 1,6 Null
12 hours 10,20 to 97.1 0,24 2,3 0,9
18 hours 10,08 96,0 0,25 2,4 2,0
24 hours 9,98 95,1 0,17 1,6 3,6
30 PM 9,94 94,7 0,19 1,8 3,5
36 hours 9,82 93,5 0,19 1,8 3,4
42 hours 9,74 92,8 0,18 1,7 3,2
48 hours being 9.61 91,5 0,35 3,3 3,1
Stability upon dilution of epoprostenol ringer's solution with lactate, lot no EX-03 at 30°C
6 hours 10,34 98,5 0,09 0,83 2,59
12 hours 10,31 of 98.2 0,13 1,22 3,85
18 hours 10,20 to 97.1 0,09 0,87 6,04
24 hours 9,82 93,5 0,11 1,00 6,00
30 PM 9,62 to 91.6 0,15 1,40 5,76
42 PM 9,26 88,2 0,18 1,72 6,24
Stability epoprostenol in ringer's solution with lactate compare the and stability in isotonic solution at both investigated temperatures.
Although some preferred implementations of the present invention described herein particularly, to a specialist in the field of engineering that applies the present invention, it is obvious that variations and modifications of the various implementation options presented and described herein may be made without deviating from the essence and scope of the present invention. Accordingly, the invention is limited only by the framework of the attached claims and applicable law.
1. A method of obtaining a composition containing epoprostenol, which includes stages:
(a) obtaining a solution epoprostenol containing (i) epoprostenol or its salt, and (ii) arginine; and
(b) bringing the pH of the solution to more than 12;
where stage (b) is performed by adding an inorganic base selected from the group consisting of sodium hydroxide and potassium hydroxide.
2. The method according to claim 1, further comprising the stage of:
(c) lyophilization of the solution.
3. The method according to claim 2, in which stage (s) includes a cycle of freezing and subsequent primary cycle of drying and secondary drying cycle.
4. The method according to claim 3, in which the freezing cycle includes:
(i) placing the solution on the shelf in the chamber of the freeze-drying;
(ii) cooling the shelves to -30°C or below at a rate of 0.5-0.7°C/min;
(iii) keeping at -30°C or below approximately 30 km minili until until the solution temperature reaches -25°C or below;
(iv) lowering the temperature of the shelves to -45°C±2°C until the solution temperature reaches approximately -38°C±2°C;
(v) maintaining the solution at -38°C±2°C for six hours or longer;
(vi) applying a vacuum to until the chamber pressure reaches about 50 mtorr or less; and
(vii) maintaining the shelf temperature of -45°C±2°C for 45 min or more after applying the vacuum.
5. The method according to claim 3, in which the primary drying cycle includes:
(i) increasing the shelf temperature to 0°C±2°C with heating rate (20±2)°C/h and continued drying in vacuum until the temperature of the composition reaches -3°C±2°C or above; and
(ii) increasing the shelf temperature to (25±2)°C and the continuation of the drying cycle as long as the temperature of the composition reaches 20°C or higher.
6. The method according to claim 3, where the secondary drying cycle includes:
(i) increasing the shelf temperature to (45±2)°C with a speed of (3±2)°C/h and continue drying until then, until the temperature of the composition reaches (38±2)°C or above;
(ii) disconnecting the vacuum and the pressure increase in the chamber with nitrogen; and
(iii) when the pressure in the chamber reaches atmospheric pressure, the cessation of the flow of nitrogen and the sealing composition in an atmosphere of nitrogen.
7. The method according to claim 1, in which the ratio of EP is prosteel or its salt to the arginine is from 1:25 to 1:200.
8. The method according to claim 1, wherein the solution additionally contains a filler.
9. The method of claim 8 in which the filler is selected from the group consisting of hydroxyethylamine (HES), sorbitol, lactose, dextran, maltose, mannose, ribose, sucrose, mannitol, trehalose, cyclodextrin, glycine and polyvinylpyrrolidone (PVP).
10. The method of claim 8 in which the filler is selected from the group consisting of dextran, sucrose and mannitol.
11. The method of claim 8 in which the filler is sucrose.
12. The method of claim 8 in which the filler is mannitol.
13. The method of claim 8 in which the filler is present in an amount of from 1 to 10%.
14. The method according to claim 1, where the salt is epoprostenol sodium.
15. The method according to claim 1, where stage (b) is completed by adding sodium hydroxide.
16. The method according to claim 1, where the pH of the solution was adjusted to 13 or higher.
17. Pharmaceutical composition for treatment of cardiovascular diseases, containing (a) epoprostenol or its salt, and (b) arginine, and (C) a base pH which after the restoration is more than 12, and in which the base is a base selected from the group consisting of sodium hydroxide and potassium hydroxide.
18. The composition according to 17, where the ratio of epoprostenol to arginine is approximately from 1:25 to 1:200.
19. The pharmaceutical composition according to 17, further content is Asa filler.
20. The composition according to claim 19, where the filler is chosen from the group consisting of hydroxyethylamine (HES), sorbitol, lactose, dextran, maltose, mannose, ribose, sucrose, mannitol, trehalose, cyclodextrin, glycine and polyvinylpyrrolidone (PVP).
21. The composition according to claim 19, in which the filler is selected from the group consisting of dextran, sucrose and mannitol.
22. The composition according to claim 19, in which the filler is sucrose.
23. The composition according to claim 19, in which the filler is mannitol.
24. The composition according to claim 19, in which the filler is present in an amount of from 1 to 10%.
25. The composition according to 17, where salt is epoprostenol sodium.
26. The composition according to 17, where the base is a hydroxide of sodium.
27. The composition according to 17, which is liofilizirovannoe composition.
28. The composition according to 17, which is composed in the form of a standard dose or multinational form.
29. The composition according to 17, in which the pH of the recovered solution of 13 or higher.
30. A stable solution for the treatment of cardiovascular diseases, containing (a) epoprostenol or its salt, (b) arginine, (C) water and (d) a base having a pH of more than 12, and in which the base is an inorganic base selected from the group consisting of sodium hydroxide and potassium hydroxide.
31. The solution according to item 30, where the ratio of epoprostenol is to arginine is from 1:25 to 1:200.
32. The solution according to item 30, optionally containing a filler.
33. The solution p, where the filler is chosen from the group consisting of hydroxyethylamine (HES), sorbitol, lactose, dextran, maltose, mannose, ribose, sucrose, mannitol, trehalose, cyclodextrin, glycine and polyvinylpyrrolidone (PVP).
34. The solution p, in which the filler is selected from the group consisting of dextran, sucrose and mannitol.
35. The solution p, in which the filler is sucrose.
36. The solution p, in which the filler is mannitol.
37. The solution p, in which the filler is present in an amount of from 1 to 10%.
38. The solution according to item 30, where salt is epoprostenol sodium.
39. The solution according to item 30, where the base is a hydroxide of sodium.
40. The solution according to item 30, having a pH of 13 or higher.
41. The method of treatment of a patient suffering from a disease selected from the group consisting of atherosclerosis, arteriosclerosis, congestive heart failure, angina and hypertension, including the stage of the introduction to the patient an effective amount of the composition of 17.
42. The method according to paragraph 41, further comprising recovering the composition from the first diluent, before the stage of introduction to obtain the recovered solution.
43. The method according to § 42, where the first solvent is a water in which ECCI, 0,9%sodium chloride solution, ringer's solution with lactate, ringer's solution, a solution of sodium carbonate or bicarbonate solution.
44. The method according to § 42, further comprising a stage of dilution of the recovered solution with a second solvent with the formation of a dilute solution.
45. The method according to item 44, where the diluted solution is gemosovmestimost.
46. The method according to § 42, where the recovered solution is stable.
Method of correcting functions of vascular walls in patients with arterial hypertension of i-ii degree with metabolic syndrome after thrombosis of eye vessels // 2423126
SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with correction of functions of vascular walls in patients with arterial hypertension of I-II degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose indices of anti-aggregate, anti-coagulant and fibrinolytic activity of vascular wall are determined. On the basis of said indices calculated is total anti-thrombotic potential of vessels and if its value is 0.069 and lower, complex treatment, including application of individually selected hypocaloric diet, dosed physical load, pioglitazone 30 mg 1 time per day and valsartan 160 mg 1 time per day in the morning during 4 months, is administered.
EFFECT: complex of drug and non-drug therapy in combination with empirically selected duration of treatment ensures correction of functions of vascular wall and, thus, reduction, of risk of thrombotic complications in said group of patients due to potentiation of therapeutic effect of separate components of therapeutic complex.
Method of evening-out dysfunctions of vascular wall in patients with arterial hypertension of iii degree with metabolic syndrome, after thrombosis of eye vessels // 2423125
SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with correction of functions of vascular walls in patients with arterial hypertension of III degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose indices of anti-aggregate, anti-coagulant and fibrinolytic activity of vascular wall are determined. On the basis of said indices calculated is total anti-thrombotic potential of vessels and if its value is 0.069 and lower, complex treatment, including application of individually selected hypocaloric diet, dosed physical load, pioglitazone 30 mg 1 time per day and valsartan 80 mg 1 time per day in the morning and amlodipine 10 mg 1 time per day during 4 months, is administered.
Method of treating acute left ventricular insufficiency of i-iii class in patients with diabetes mellitus // 2423115
SUBSTANCE: invention relates to medicine, in particular to cardiology, and deals with treatment of acute left ventricular insufficiency (LVI) of I-III class in patients with diabetes mellitus. For this purpose complex treatment, which includes oxygen-therapy 6-8 litres per minute, lifted bed head, introduction of morphine hydrochloride intermittently 1% - to 1 ml intravenously, nitrates, diuretics, inotropes, metoprolol in dose 6.25 mg 2 times per day and ivabradine. If AP is not higher than 100 mm Hg and HR is 100-110 per minute, ivabradine is introduced in day dose 10 mg in two steps, if HR is 120-125, ivabradine is introduced in day dose 15 mg in two steps under control of heart rhythm and conductivity and with AP measurement every 6 hours.
EFFECT: method makes it possible to efficiently reduce sinus tachycardia, which disrupts pathologic vicious circle, connected with shortening of heart diastole and improves heart blood supply and left ventricular contractility, which, in its turn, ensures more efficient relief of I-III class LVI symptoms, reduction of treatment terms and reduction of lethal outcomes in said group of patients.
Pharmaceutical compounds // 2422449
SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting PI3 kinase inhibitor activity. In the formula (I), A represents a thiophen ring; n=1; R1 represents , where m=1; R30 represents H; R4 And R5 together with N atom whereto attached form a 5- or 6-members N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O which is unsubstituted or substituted by one or more substitutes selected from C1-6alkyl, C1-6alkoxy, -N(R"')-alk-OR, -alk-OR, -O-alk-OR, -alk-C(O)NR2, -C(O)NR2, -alk-Het, -N(R)-Het, -O-Het, -N(R)-C(O)- alk-OR, -NR-S(O)2R, -N(R)-alk-S(O)2R, -N(R)-alk-OR, -alk-NR'R", -N(R"')-S(O)2R, S(O)2R"', -S(O)2-alk-ORf 5- or 6-members N-containing heterocyclic group, 5- or 6-members N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, oxo(=O), -SO2NR2, -SO2-alk-NR2 where alk means a C1-6alkylene chain; Het means a 5- or 6-members N-containing heteroaryl group or furan optionally substituted by C1-6alkyl; R means H or C1-6alkyl, or when 2 groups R are bound with N, they together with N atom form a saturated 5- or 6-members N-containing heterocyclic group; each R' and R" means independently H, C1-6alkyl or C1-6alkoxy; R'" represents C1-6alkyl, a 5- or 6-merous saturated N-containing heterocyclic group, or a 5- or 6-merous N-containing heteroaryl group; R2 means where R6 and R7 together with N atom whereto attached form a morpholine group; R3 represents an indazole group.
EFFECT: development of the effective method of preparing the compounds of formula (I), and their application for preparing a drug, a pharmaceutical composition, and a method of inhibition.
Pharmaceutical compounds // 2422448
SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.
EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.
Antiarrhythmic compound precursors, synthesis processes and methods of application // 2422447
SUBSTANCE: invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R1 independently represents H or halogen; R2 represents H or --R10-NR11R12 where R10 represents C1-C6 alkylene; R11 and R12 independently represent H, C1-C4 alkyl; and R3 independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.
EFFECT: new compounds which can find application for preparing the compounds applicable for treatment or prevention of cardiac arrhythmia.
Method of normalisation of functional activity of vessel wall in patients with arterial hypertension of i-ii degree with metabolic syndrome, after thrombosis of eye vessels // 2422141
SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with normalisation of functional activity of vessel wall in patients with arterial hypertension of I-II degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose, indices of anti-aggregation, anti-coagulation and fibrinolytic activity of vascular wall are determined. On the basis of said indices general anti-thrombotic potential of vessels is calculated and if its value is 0.069 and lower, administered is complex treatment, including application of individually selected hupocaloric diet, dosed physical load, introduction of pioglitazone in dose 30 mg 1 time per day and lisinopril in dose 20 mg 1 time per day for 4 months.
EFFECT: complex of drug and non-drug therapy in combination with empirically selected treatment duration ensures complete normalisation of functional activity of vascular wall and, thus, reduction of risk of thrombotic complications in said group of patients due to potentiation of therapeutic effect of separate components of medicinal complex.
Method of complex immunomodulating treatment of patients with chronic heart failure with reduced left ventricular ejection fraction // 2422136
SUBSTANCE: invention relates to medicine, namely to cardiology, and deals with complex immunomodulating treatment of patients with chronic heart failure with reduced left ventricular heart ejection fraction. For this purpose in commonly accepted complex of drug therapy, which includes β-adrenoblockers, ACE inhibitors, diuretics, cardiomagnyl, additionally introduced is recombinant human interleukin 2 (IL-2). IL-2 is introduced in dose 500 IU/ml, in 200 ml of physiological solution, which containf for stabilisation 10 ml of 5% albumin solution, intravenously drop-by-drop daily 1 time for 10 days; treatment course is repeated 1 time per 3 months during 12 months.
EFFECT: complex treatment ensures suppression of chronic immune inflammation due to ability of IL-2 in elaborated mode of introduction to reduce level of endogenic cytokins and activate T- and B- lymphocytes efficiently in said group of patients.
Method of treating and early (urgent) and planned prophylaxis of meteopathic responses in patients with ischemic heart disease, hypertention of i-ii stage with disadaptation syndrome, with application of method of transcranial mesodiencephalic modulation // 2422128
SUBSTANCE: invention relates to medicine, namely to cardiology and balneophysiotherapy. Method includes balneotherapy, walks in the park, physiotherapy. Balneotherapy is performed by carrying out carbonate mineral baths with concentration of carbon dioxide 0.8-1.1 g/l. Course includes 10 baths. Walks in the park are carried out on therapeutic routes of health path with length in both directions 6800 metres. Physiotherapy is performed by impact of continuous and pulsed electric current of low frequency, current intensity 0.1 mA from apparatus "МДМК"-4. Impact is performed in contact way by application of cathode in region of forehead, anode - in region of occiput. Impact is realised by pulses of rectangular shape with 4 ms duration, with ratio by amplitude of continuous and pulse current 1:1 or 0.5:1; frequency from 70 to 90 Hz, changing cyclically for 1 minute. Time of impact is from 8 to 16 minutes, with increase of exposure by 2 minutes every 2 days. Course includes daily performed 6-10 procedures. Additionally drinking mineral waters of Kislovodsk Narzan of medium mineralisation are taken in.
EFFECT: method increases treatment efficiency due to increase of adaptive abilities of hypothalamic stem regulatory centres, produces inhibitory effect on cerebral cortex (CC) and underlying structures of brain stemm reduces frequency of stenocardia recurrences, improves physical exercise tolerance, increases patients' life quality.
2 ex, 12 tbl
Compositions which contain epothilone, and method of their obtaining // 2416407
SUBSTANCE: invention relates to composition for treatment of malignant neoplasm in patient, which contains epothilone - (1S, 3S, 7S, 10R, 11S, 12S, 16K)-7,11-dihydroxy-3-(2-methyl-benzotiasol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion, hydroxypropyl-β-cyclodextrine or simple sulphobutyl ether of β-cyclodextrine and fillers, selected from mannitol and trometamol. Invention also relates to method of claimed composition obtaining, which includes dissolving epothilone in alcohol, dissolving hydroxypropyl-β-cyclodextrine or simple sulphobuthyl ether of β-cyclodextrine in water solution together with mannitol and trometamol, bringing pH of water solution to value 5-9 by means of hydrochloric acid and mixing obtained solutions.
EFFECT: invention also relates to method of malignant neoplasm treatment in patient, which includes intravenous infusion of claimed composition during period of approximately 30 minutes in dose from 10 mg/m2 to 35 mg/m2.
17 cl, 11 ex, 2 dwg
Chemically specified stabiliser // 2409350
SUBSTANCE: present invention refers to pharmacology. Composition of vaccine stabiliser contains at least one amino acid in amount from 0.025 to 100 g/l, at least one sugar in amount from 2.5 to 50 g/l and at least one polyamine in amount from 0.025 to 25 g/l, where all compounds are chemically specified, thus, being free of serum, protein, animal compounds, polymer, in which only average molecular weight or average length of lateral chains are available, from protein lysate, extract of hydrolysate or peptide mixture, characterised by the fact that polyamine represents at least one selected from group made of ethylene diamine, cadaverine, putrescine, spermidine and spermine. Invention also relates to composition of vaccine containing specified composition of stabiliser and biological molecule and/or microorganism; to method for making of pharmaceutical composition providing for mixing of specified composition of stabiliser with biological molecule and/or microorganism; to application of specified composition of stabiliser and vaccines prepared by this method.
EFFECT: improved stabilising properties of stabiliser and stability of vaccine.
30 cl, 13 tbl, 1 ex
Medicinal agents with controlled release based on block-copolymers // 2409348
SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.
EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.
31 cl, 8 ex, 2 dwg
Immunogenic composition // 2405568
SUBSTANCE: invention relates to field of medicine and deals with immunogenic composition. Essence of invention consists in development of immunogenic composition, obtained by culturing transformant of avirulent dividing yeasts-hosts Schizosaccharomyces pombe, in which transformant carries gen, which codes introduced into it antigen protein, representing capsid protein of L1 virus of human papilloma of 16 (HPV-16) type and accumulates in itself expressed antigen protein, for oral application.
EFFECT: development of immunogenic composition for oral application.
3 cl, 5 ex, 2 tbl, 5 dwg
Thermoset neutralised chitosan composition forming hydrogel, its lyophilisate and methods for making // 2385710
SUBSTANCE: group of inventions concerns medicine and pharmacology. There is offered an aqueous thermoset neutralised chitosan composition forming phosphate-free hydrogel at temperature 5°C and higher which contains at total weight of the composition, 0.1-5.0% of reacetylated chitosan with molecular weight not less than 100 kDa and deacetylation degree 40 to 70% neutralised with a hydroxylated base, and 1-30% of a complex-making substance chosen from poliosis and originated polyols. There is offered lyophilisate prepared by lyophilisation of the aqueous thermoset neutralised chitosan composition. There is offered the method for preparing the aqueous thermoset neutralised chitosan composition. There is offered the method for preparing lyophilizate that involves lyophilisation of the aqueous thermoset neutralised chitosan composition. There is offered application of the aqueous thermoset neutralised chitosan composition and lyophilisate for making a drug delivery system, for making an injected dosage form.
EFFECT: invention provides preparing the aqueous thermoset neutralised chitosan composition forming phosphate-free hydrogel with improved properties and acceptable to biomedical application which is easily stored and maintains after-storage thermosetting properties.
20 cl, 9 ex, 8 dwg
Compositions containing resveratrol particles; and method for making thereof (versions) // 2373926
SUBSTANCE: invention refers to pharmaceutical industry, particularly to method for making resveratrol containing particles. The method for making thereof involves dispersion of resveratrol in organic copolymer of lactic and glycolic acids dissolved in methylene chloride, dispersion of prepared suspension in the external phase containing a surface-active substance, removals of the organic solvent, purification of the suspension by centrifugation or filtration, then lyophilisation of the prepared resveratrol particles. The method for making resveratrol containing particles involves addition of resveratrol and lecithin spirit in certain ratio to dissolved chitosan, removal of the organic solvent, and centrifugation of the suspension. Then supernatant containing particles is lyophilised. The composition containing resveratrol particles is made by any of specified methods and a pharmaceutically acceptable diluent or a filling compound.
EFFECT: making particles with prolonged release of resveratrol.
11 cl, 4 dwg, 5 ex
Pharmaceutical composition for parenteral delivery in form of lyophilizate and method of its obtaining // 2370258
SUBSTANCE: invention relates to novel pharmaceutical composition in form of lyophilizate. Lyophilizate is obtained by lyophilic drying of emulsion of "oil in water" type based of lecithin. Emulsion contains badly soluble in water or in oil active substance, effective quantity of antioxidant, emulsion stabiliser, dimethylsulphoxide, copolymer of lactide and glycolide and additive, which prevents enlargement of emulsion particles during freezing. Lyophilizate is characterised by high stability when dissolved by infusion liquids.
EFFECT: reconstructing of emulsion is realised during not more than 15 minutes and without application of additional equipment, restored emulsion containing not less than 80% of particles with size less than 200 nm.
19 cl, 3 dwg, 3 tbl, 8 ex
Therapeutic compositions // 2358729
SUBSTANCE: there is described oral pharmaceutical composition containing 9,10-dehydroepothilone combined with a pharmaceutically acceptable carrier. According to the second version, the oral pharmaceutical composition contains trans-9,10-degihydroepothilone D and a pharmaceutically acceptable carrier containing hydroxypropyl-β-cyclodextrine, ethanol and propylene glycol. The concentrate for injection contains 9,10-degihydroepothilone D in the pharmaceutically acceptable carrier.
EFFECT: good bioavailability of epothilone D.
Lyophilised compositions cci-779 // 2345772
SUBSTANCE: lyophilised preparation forms and solutions CCI-779 are available for production of lyophilised preparation forms CCI-779. The specified solutions consist of CCI-779 and solvent chosen from dimethylsulfoxide, acetonitrile, ethanol, isopropanol, tert-butyl alcohol and their mixtures. Besides, methods of lyophilised preparation forms CCI-779 preparation and restoration are offered.
EFFECT: improved storage stability and preservation of initial activity.
Polylactide nanoparticles // 2423104
SUBSTANCE: invention relates to field of pharmaceutical industry, in particular to method of obtaining system of targeted drug delivery for introduction of pharmaceutically active substance into central nervous system of mammals through hematoencephalic barrier. System contains poly(DL-lactide) and/or poly(DL-lactide-soglycolide)-based nanoparticles, pharmacologically active substance, absorbed, adsorbed and/or included into nanoparticles, and contains TPGS or has coating from surface-active substance pluronic 188, which is precipitated on drug-filled nanoparticles. Described are methods of obtaining system of targeted drug delivery and application of system of targeted drug delivery for treatment of CNS disease or disorder.
EFFECT: elaboration of efficient method of obtaining system of targeted drug delivery for introduction of pharmacologically active substance into central nervous system of mammals through hematoencephalic barrier.
20 cl, 14 ex, 2 dwg