Propofol-containing composition with enhanced antibacterial effect

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes sterile anesthetic composition for parenteral administration of propofol emulsified in water for injection. The composition comprise above 3 wt.-% but 6 wt.-% of less of solvent not mixing with water. Propofol is dissolved in indicated solvent. The composition is stabilized with 0.2-1.0 wt.-% of surface-active substance and has pH value level in the range 5.0-7.5. The composition with reduced pH value level allows preventing above 10-fold elevating growth of microorganisms for at least 24 h after random external pollution. Reduced fat content in composition also provides the stable analgetic effect for prolonged time and with reduced risk for the blood fat content exceeding.

EFFECT: improved and valuable properties of composition.

15 cl, 4 dwg, 4 tbl, 3 ex

 

The scope of the invention

The invention concerns an optimized pharmaceutical compositions, known as propofol, which is an anesthetic for intravenous anesthesia with increased inhibition of microbes. In particular, the invention concerns an optimized composition of the emulsion of propofol, which, as shown, is bacteriostatic or fungistatic, and some songs - bactericidal and fungicidal without the use of preservatives or other antimicrobial agents.

The level of technology

Propofol (2,6-diisopropylphenol) is a well-known intravenous anaesthetic agent, which is widely used. For example, in intensive care units (RTO), where treatment can be very long, propofol has the advantage in performance after the introduction or admission with food plus a very short period of Wake - up for a few minutes, instead of hours.

Propofol is a hydrophobic, water-insoluble oil. To overcome the problem of insolubility of his need to connect with solvent substances, surfactants, solvents or emulsion oil-in-water”. There are a number of known compositions of propofol, which was published in the U.S. patents 4065635, 4452817 and 4798846, owned by Glen and James.

There are two Chapter the main problems, associated with the compositions described in the aforementioned patents:

(1) the risk of microbial contamination due to the high content of nutrients and lack antimicrobial preservatives. The study Arduino and others, 1991; Sosis and Braverman, 1973; and PDR, 1995, showed that the emulsion of propofol, which do not include preservatives, will cause the growth of bacteria and to constitute a risk of bacterial contamination;

(2) hyperlipidemia in patients who receive long-term treatment analgesic in Oita, due to the high content of fat. The study Gottardis and others, 1989; DeSoreruer and others, 1990; Lindholm, 1992; and Eddieston and others, 1991, showed that a dose of triglyceride may become a significant problem in long-term care soothing in Oita, if as the basis sedatives use the emulsion, which consists of 1% propofol and 10% soybean oil.

To solve the problem of bacterial contamination of the emulsion of propofol were developed following a patented composition of propofol:

patent noAuthorsPublication date
5637625Duncan H. HaynesJune 10, 1997
5714520Christopher .J. and otherFebruary 3, 1998
6028108 February 22, 2000
6100302Satish K.R. and otherAugust 8, 2000
PCT WO 99/39696Mirejovsky D. and othersAugust 12, 1999
PCT WO 00/24376The magician T. and othersmay 4, 2000

The compositions described in U.S. patent No. 5714520, marketed as DIPRIVAN(R)and their composition is sterile, without pyrogenic preparation, emulsion, containing 1% (m/o mass/volume) of propofol in 10% (m/a) soybean oil. The composition contains 1.2% (m/o) egg lecithin as a surfactant, to 2.25% (m/o) glycerol for isotonic composition, of sodium hydroxide for adjustment of pH and 0.005% (m/o) EDTA (EDTA) as a preservative. This composition prevents no more than a tenfold increase of one gram negative (such as Pseudomonas aeruginosa and Escherichia Li) and positive bacteria (Staphylococcus aureus)and fungi (such as Candida albicans) within a twenty-four hour period. However, EDTA, which is the combined metal ion, removes cations, such ions of calcium, magnesium and zinc. This can be a potential danger for some patients with low calcium or low levels of other cations, and particularly critical for patients Oita.

In U.S. patent No. 6028108 for before the rotation of bacterial contamination composition of propofol as preservative contains 0.0005% (m/o) pentetate. Pentetate is a combined metal ion, similar to EDTA, and therefore is the same potentially dangerous.

The composition described in the application WO No. 99/39696 is nonproprietary (generic) propofol, which is to prevent the growth of microbes as preservative containing 0.25 mg/ml sodium metabisulfite. After 24 hours, the increase was not more than one logarithm (log). Recently R. Langevin, 1999, expressed concern about the fact that generic propofol, which contains 0.25 mg/ml sodium metabisulfite, with its infusion at 50 mg/kg/min leads to the introduction of sulfite in an amount that approaches the toxic level (i.e. approximately LD 50 for Shurov) approximately 25 hours. In particular, the addition of sulfites in this medication raises concerns about the potential impact on children.

The composition described in the application WO No. 00/24376, is a composition that contains an antibacterial substance which is a compound selected from the group comprising benzyl alcohol and ethylenediaminetriacetate (EDTA) sodium chloride benzothia; benzyl alcohol and sodium benzoate. The composition contains EDTA, which is associated with the side effects mentioned above. Benzyl alcohol is associated with negative reactions, which were reported Evens and Lopez-Negse and other Composition cannot be trusted with the introduction, in particular, those patients who need treatment painkiller in the RTO for an extended period.

The composition described in U.S. patent No. 5637625, is surrounded by a phospholipid of microcephaly of propofol containing 6.8% propofol without soybean oil. However, there is a probability that this composition during injection can cause increased pain at the injection site to an unacceptable level.

The composition described in U.S. patent No. 6100302, is an emulsion of propofol, which contains 1-3% soybean oil in order to prevent accidental microbial contamination during prolonged IV infusion due to the increased efficiency of propofol. However, the composition containing 2% soybean oil, can prevent the increase of more than one logarithm E. Li after 48 hours.

In particular, the composition, which contains 3% soybean oil, has a more than ten-fold increase in E. coli after 24 hours, which does not meet the current industry standards to prevent the growth of microbes more than one log after 24 hours. Obviously, this composition with the introduction may also add to the problems associated with pain after injection, due to the higher division of propofol in the aqueous phase. This question was studied M.Eriksson and others, 1997

The above problem has prompted the authors to develop the optimal composition of propofol, which is proposed in this invention. Propofol is a blocked phenol. Phenol shows significant antimicrobial activity in solutions with low pH (Arthur H. Kibbe, 2000). In this invention, it was found that the composition of propofol with a low pH level is more effective in the inhibition of microbial growth, as shown in figure 2 and Figure 3. Composition with low pH also reduces the concentration of anions of propofol. Due to the fact that propofol is a weak acid with a pKa equal to 11, this effect would lead to a reduction in pain after the injection, which was investigated Klement and others, 1991, and J. Babl, 1995.

Egg lecithin is used in pharmaceutical products are mainly as a dispersant, emulsifier and stabilizer. Lecithin is also used as a component enterally and parenterally food compositions, Arthur H. Kibbe, 2000.

It was also found that in this invention the composition of propofol containing a reduced amount of egg lecithin, leads to a significant increase antibacterial ability, as demonstrated in figure 4. Soybean oil is also a food source for microbial growth. As shown in figure 2, econometrie shows the high content of the soybean oil in the composition promotes the growth of bacteria.

Thus, it was established that is free from preservatives optimal composition of propofol proposed in this invention, are directed primarily to the solution of professional problems, and these problems are eliminated or at least greatly reduced.

Description of the invention

This invention provides optimized sterile composition of propofol for parenteral administration, which contains reduced amounts of triglycerides egg lecithin and soybean oil. The composition consists predominantly of emulsion oil-in-water” with a diameter of particles of approximately 200-400 nanometers, in which propofol dissolved in immiscible with water, a solvent such as soybean oil, and stable surface-active agent, such as egg lecithin. The composition of propofol with a low content of lecithin and soybean oil and a pH in the range of 5.0 to 7.5 has a number of advantages:

(1) no preservatives,

(2) providing compositions with excellent manifestation of antibacterial activity compared to compositions with a high content of lecithin and oil soluble emulsion containing preservatives,

(3) reduced the risk of hyperlipidemia in patients and

<> (4) low pH compositions of propofol may reduce caused by propofol pain after the injections, as shown in studies Klement and others, 1991; bl and others, 1995, and Eriksson and others, 1997.

These and other objects and advantages of this invention will become clearer from the subsequent detailed description of the best options embodiments of the invention and appended claims, considered together with the accompanying drawings.

Brief description of the drawings.

Figure 1 is an illustration, which is an emulsion of propofol, covered in egg lecithin.

Figure 2 is a graph which illustrates how the amount of soybean oil and the pH of the composition of propofol affect the growth of C. Albicans after inoculation for 24 and 48 hours. Also shown is the difference in bacterial growth at pH=6 and pH=8.

Figure 3 is a graph that illustrates how the pH of the compositions of propofol affects the growth of Escherichia Coli after inoculation for 24 and 48 hours. Also shown is the difference in bacterial growth when the content of the soybean oil 5%and 10%.

Figure 4 is a graph that illustrates how the content of egg lecithin in the composition of propofol affects the growth of Escherichia Li after inoculation for 24 and 48 hours.

The best way to embodiments of the invention

The invention relates to a sterile pharmaceutical composition for parenteral introduction the tion, consisting of emulsions of oil-in-water”, in which propofol dissolved in a solvent, immiscible with water, predominantly in soy oil, and stable surface-active substance, mainly egg lecithin. In addition, the composition contains a reduced amount of egg lecithin and soybean oil and, in addition, has a low pH in order to inhibit microbial contamination during intravenous infusion over a certain period of time.

I believe that the emulsion oil-in-water” is a clear two-phase system that is in balance and acts as a single unit, and is kinetically stable but thermodynamically unstable system.

Consider that prevent significant growth of microorganisms occurs if the growth of microorganisms mainly by no more than one log after external contamination, which is usually found in the hospital premises, such as intensive care units (RTO), and the like. For this definition, pollution is approximately 50-200 colony forming units/ml at a temperature in the range from 20 to 25°C.

The composition of this invention usually contains from 0.1 to 5% wt. propofol, preferably from 1 to 5% of propofol, more predpochtitel is but if the composition contains 1%, 2% or 5% of propofol.

Water-immiscible solvent is present, respectively, in the number, which is predominantly from 1 to 10% by weight of the composition, better from 3 to 6% by weight of the composition, which contains 1 or 2% propofol, and from 6 to 10% by weight of the composition with 5% of propofol.

Emulsion oil-in-water” can be prepared by dissolving propofol in a water-immiscible solvent and preparing the aqueous phase that contains a surface-active agent and other water-soluble components, and then mixing the oil with the aqueous phase. To get a perfect emulsion, the initial (rough) emulsion is subjected to homogenization under high pressure.

In the compositions of this invention can be used with a wide range of water-immiscible solvents. Usually water-immiscible solvent is a vegetable oil, such as soybean, safflower, cottonseed, corn, sunflower, peanut, castor and olive. Mostly vegetable oil is soybean oil. Alternative water-immiscible solvents are esters of medium to glinotsementnyj fatty acids, such as mono -, di - or triglyceride, or chemically modified or industrial palmitate, glycerol esters or castor oil is, gidrirovannoe polyaxial. Additional alternative water-immiscible solvent may be oil marine industries, such as oil of cod liver oil or other fish oil. Suitable solvents can also be fractionated oil, such as fractionated oil of coconut or modified soybean oil. In addition, the composition of this invention can comprise a mixture of two or more of the above-mentioned water-immiscible solvents.

In order to obtain a stable emulsion, the composition of the present invention is acceptable from a pharmaceutical point of view, surface-active substance. Surface-active substance is present, respectively, in the quantity not exceeding 1% by weight of the composition, which contains from 3 to 6% water-immiscible solvent, or preferably from 0.2 to 1.0% by weight of the composition, more preferably of 0.6% by weight of the composition. For compositions containing from 6 to 10% water-immiscible solvent, a suitable amount of surfactant is not more than 2% by weight of the composition and preferably from 0.6 to 2% by weight of the composition, and more preferably of 1.2% by weight of the composition. Suitable surfactants are non-ionic sintet the ical surfactants, such as ethoxylated simple and complex esiri, polypropylene - polyethylene block copolymers and phosphatides, such existing in nature phosphatides, as egg and soy phosphatides, and modified or synthetically derived phosphatides (e.g., phosphatides obtained by physical fractionation and/or chromatography), or a mixture thereof. The best surface-active substances are egg and soy phosphatides. The best is egg phosphatid.

The composition of the present invention is designed to provide a pH in the range from 4.5 to 9.5, and preferably the composition has a pH in the range of 5.0 to 7.5. The desired pH can be achieved by adding alkali such as sodium hydroxide, or acid, for example hydrochloric acid.

The composition of this invention can be made isotonic with blood by administering the appropriate modifier toychest, such as glycerin.

The composition of this invention contains acceptable from a pharmaceutical point of view, the media. The media is mostly water, not containing pyrogenic drugs, or water for injection U.S.P.

The composition of the present invention is a sterile aqueous composition is prepared by standard manufacturing techniques, using, for example, aseptic processing is whether thermal sterilization in autoclaves.

The compositions of this invention are useful as anesthetics, which have soothing properties, provide and maintain General anesthesia.

In accordance with the second aspect of the invention provides a method of producing anesthesia (including comfort, security and support of General anesthesia) in warm-blooded animals, including humans.

The process of anesthesia is the introduction of parenteral sterile aqueous pharmaceutical composition comprising the emulsion of the “oil in water”, in which propofol in a water-immiscible solvent emulsify water and surface-active substance. Description best songs are presented in the examples below.

Normally, the levels dosing of propofol for producing General anesthesia for adults is approximately 2.0-2.5 mg/kg Dose to maintain anesthesia usually is about 4-12 mg/kg/hour. Sedative effect can be achieved, for example, at a dose of 0.3 to 4.5 mg/kg/hour. Equal doses of propofol, producing General anesthesia induction and maintenance, and receive sedative effect may be based on existing data and literature to be determined by a specialist (doctor) so that they fit a specific patient and respond to the treatment.

Thus, first of all, this picture is giving offers optimal composition, containing a smaller number of egg lecithin, which is reduced from 1.2% wt., provided industry standard, up to 0.6%.

Secondly, this invention provides a composition with a lower content of the soybean oil, which is reduced with prescribed industry standard 10% wt. to 3-6%.

Thirdly, the invention provides a composition with a low pH level, which is changed with the prescribed industry standard 7,0-8,5-5,0-7,5.

In accordance with this invention there have been several benefits to owning no more than a tenfold increase in the growth of microorganisms, such as S.Aureus, .li, .Aeruginosa and .Albicans at least within 24 hours. Another useful feature of this invention consists in the introduction of this composition to a patient with hyperlipidemia, which is low in fat it contains, provides a low risk of triglyceridemia.

EXAMPLE 1

The best composition is the composition below:

Sodium hydroxide
Composition
Componentswt.%.
Propofol1,0
Soybean oil3,0-6,0
Egg lecithin0,2-1,0
Glycerin2,25
q.5
Water for injection100
pH5,0-7,5

The cooking process is carried out in a nitrogen atmosphere, and the weight referred to the weight of the final volume.

Sterile water emulsion oil-in-water” for parenteral administration was prepared in the following sequence:

1. The aqueous phase was prepared by adding lecithin and glycerin in water for injection at approximately 20-60°C, and stirred until then, until he had homogeneous variance.

2. An oil phase was prepared by adding propofol in soybean oil, and stirring at approximately 20-60°to dissolve.

3. The oil phase was added to the aqueous phase, mixed, and the pH was adjusted using sodium hydroxide, and then stirred until the formation of a coarse emulsion.

4. The coarse emulsion was microdispersion to obtain globules of the desired size.

5. The pH of the emulsion, if necessary, regulated. The final emulsion was filtered into a chilled container.

6. Then the final emulsion in an atmosphere of nitrogen was poured into containers and subjected to autoclave.

Emulsion oil-in-water”, which contains 2 or 5% wt. propofol can be prepared in the same way, using the concentrations of the components described in example 2 and example 3.

WHEN IS EP 2

Composition
Componentswt.%.
Propofol2,0
Soybean oil3,0-6,0
Egg lecithin0.2 to 1.0
Glycerin2,25
Sodium hydroxideq.5
Water for injection100
pH5,0-7,5

EXAMPLE 3

Composition
Componentswt.%.
Propofol5,0
Soybean oil6,0-10,0
Egg lecithin1,2
Glycerin2,25
Sodium hydroxideq.5
Water for injection100
pH5,0-7,5

Microbiological activity

The composition of the oil-in-water propofol different compositions were prepared as described above. To test the effectiveness of prevention (conservation) of approximately 50-200 colony forming units (CFU) per 1 ml of the four organisms in accordance with standard U.S. P. S. Aureus (ATCCF 6538), E. Li (ATSS 8739), P. Aeruginosa (ATCC 9027) and C. Albicans (ATCC 1023) was inoculable in each composition and kept at 20-25° C. the Number of viable organisms tested were determined after 24 and 48 hours.

The antimicrobial effect of the composition of propofol with low concentrations of egg lecithin and soybean oil and low pH are illustrated by the data in the following tables 1-4. This action contrasts with the effect of different compositions of propofol, which contain 1.2% egg lecithin, 10% emulsion of soybean oil, and the composition of propofol, which contains 0.005% EDTA and sold under the brand name DIPRIVAN(R). These results show that composition with a low content of egg lecithin and soybean oil and low pH is effective to prevent more than 10-fold increase in growth of microorganisms within 24 hours after microbial contamination.

As shown in the data tables, the compositions of this invention have the advantages of that disclosed in the description and the claims.

Although the invention is described quite in detail and illustrated by the accompanying charts, it should not be limited to these details due to the fact that the invention can be made of changes and modifications which do not affect the essence of the invention and are not beyond the invention. For example, the described compositions and manufacturing processes are common, so uh what about the description encompasses any and all modifications and forms, which may relate to terminology and not beyond the scope of the claims.

Table 1
Comparison of microbial growth S.Aureus
Composition (%)Microbial growth (log CFU/ml)
pH=4,5pH=5,5pH=6.5pH=7,5pH=8,5
PropofolSoybean oilEgg lecithinInoculation No.24h48h24h48h24h48h24h48h24h48h
130,61,6400000,700,70,30,30
140,61,64000,30the 1.441,261,581,261,740,91
150,61,640 00,30,301,751,831,991,651,76
250,61,640000000000
240,61,64  00    0about
131,21,64      0,780,6  
1101,21,64      2,95>5,47  
1101,21,71      3,34>of 3.77   
510-1,21,64      00  
 Diprivan 1,71      00  

0 means that all S.Aureus were killed.

Table 2
Comparison of microbial growth .Aeruginosa
Composition (%)Microbial growth (log CFU/ml)
pH=4,5pH=5,5pH=6.5pH=7,5pH=8,5
PropofolSoybean oilEgg lecithinInoculation No.24h48h24h48h24h48h24h48h24h48h
130,62,09 0000000000
140,62,090000000000
150,62,090About00000000
250,62,090000000000
240,62,09  00    00
131,22,09      00  
110 1,22,09      >5,48>5,48  
1101,21,36      >5,48>5,48  
5101,22,09      00  
 Diprivan 1,36      0,351,36  

0 means that all .Aeruginosa died.

 
Table 3
Comparison of microbial growth E.Coli
Composition (%)Microbial growth (log CFU/ml)
pH=4,5pH=55 pH=6.5pH=7,5pH=8,5
PropofolSoybean oilEgg lecithinInoculation No.24h48h24h48h24h48424h48h24h48h
130,62,3100,300000000
140,62,3100100,910,60,3000
150,62,31000,80,61,230,781,040,30,70
250,62,310000000000
240,6 2,31  00    00
131,22,12      >5,48>5,48  
1101,22,31      >5,683,48  
1101,21,98      >5,48>5,48  
5101,22,31      00  
 Diprivan 1,98     1,231,11  

0 means that all E. coli were killed.

Table 4
Comparison of microbial growth .Albicans
Composition (%)Microbial growth (log CFU/ml)
pH=4,5pH=5,5pH=6.5pH=7,5pH=8,5
PropofolSoybean oilEgg lecithinInoculation No.24h48h24h48h24h48h24h48h24h48h
130,61,660000000000
140,61,660000000000
15 0,61,660000000,81000,51
250,61,660000000000
240,61,66  00    00
131,21,66      00  
1101,21,66      >5,47>5,47  
1101,21,76      >5,38 >5,38  
5101,21,66      00  
 Diprivan 1,76      10  

0 means that all .Albicans died.

1. Sterile an anaesthetic pharmaceutical composition for parenteral administration of propofol in which the above-mentioned propofol dissolved in a quantity greater than 3 but less than or equal to 6 wt.% water-immiscible solvent, is emulsified in water for injection and stable 0.2 to 1.0 wt.% surface-active substances having a pH in the range of 5.0 to 7.5, to prevent more than 10-fold increase in the growth of the microorganisms Pseudomonas Aeruginosa, Escherichia Coli, staphylococcus Aureus and Candida Albicans at least within 24 hours after accidental exposure to contaminants.

2. Sterile an anaesthetic pharmaceutical composition according to p. 1, wherein the water-immiscible solvent is an RA is equipment oil or an ester of a fatty acid.

3. Sterile an anaesthetic pharmaceutical composition according to p. 2, wherein the water-immiscible solvent is a soybean oil.

4. Sterile an anaesthetic pharmaceutical composition under item 1, characterized in that the surfactant is a natural phosphatid.

5. Sterile an anaesthetic pharmaceutical composition according to p. 4, characterized in that the natural phosphatic is a egg lecithin.

6. Sterile an anaesthetic pharmaceutical composition under item 1, characterized in that the surfactant is a synthetic phosphatid.

7. Sterile an anaesthetic pharmaceutical composition under item 1, characterized in that is isotonic with respect to blood.

8. Sterile an anaesthetic pharmaceutical composition according to p. 7, characterized in that is isotonic with respect to blood due to the introduction of glycerin.

9. Sterile an anaesthetic pharmaceutical composition under item 1, characterized in that propofol add in the amount of 1% to 2 wt.%.

10. Sterile an anaesthetic pharmaceutical composition according to p. 9, characterized in that propofol add in the amount of 1 wt.%.

11. Sterile an anaesthetic pharmaceutical composition according to p. 9, characterized in that propofoltoradol in the amount of 2 wt.%.

12. Sterile an anaesthetic pharmaceutical composition of claim 10, characterized in that it contains 0.2 - 1 wt.% egg lecithin.

13. Sterile an anaesthetic pharmaceutical composition according to p. 11, characterized in that it contains 0.2 - 1 wt.% egg lecithin.

14. Sterile an anaesthetic pharmaceutical composition according to p. 10, characterized in that it contains more than 3 but less than or equal to 6 wt.% soybean oil.

15. Sterile an anaesthetic pharmaceutical composition according to p. 11, characterized in that it contains more than 3 but less than or equal to 6 wt.% soybean oil.



 

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