Amiphostin in powder form for injections and method for its obtaining

FIELD: pharmaceutics.

SUBSTANCE: the suggested powder consists of crystals of one component amiphostin, the length of crystalline granule corresponds to 300-700 mcm at the content of 1-3 molecule of crystalline water. In method for obtaining amiphostin powder for injections one should apply the process of vacuum drying. The innovation provides resistance of the product obtained, the crystals obtained have got moderate length and acceptable mobility without any reduction.

EFFECT: higher efficiency of application.

6 cl, 5 dwg, 13 ex, 3 tbl

 

PREREQUISITES FOR CREATING INVENTIONS

The technical field to which the invention relates.

This invention relates to amifostine in the form of a sterile powder for injection and how to obtain it; mainly the invention relates to amifostine in the form reliabilitybased powder for injection with a high resistance and the method of its production.

The level of technology

Amifostine (S-2-(3-aminopropylene)ethyldihydromorphinone) is an agent, providing a protective effect on cells with a broad spectrum of action. It was used as a radiation means in the military field, and now are usually used as a protective agent in radiation therapy and chemotherapy. Amifostine has a remarkable ability to reduce the negative effects of anti-cancer pharmaceutical drugs, such as cyclophosphamide, diaminedichloroplatinum, adriamycin and anti-HIV drugs, for example, 3-azido-3-deoxythymidine, and does not affect the effectiveness of anticancer pharmaceuticals and anti-HIV drugs.

Currently, US Bioscience Inc produces only commercial product amifostine under the trade name ETHYOL. This product is a lyophilized powder for injection. It is reported that the non-crystalline form obtained freeze suck the th under reduced pressure, is thermally unstable. Thus, this dried product should be stored at a temperature of about -20°and transported at temperatures of from about -70 to -20°to prevent decomposition of the resulting product. It is not only inconvenient, but, in addition, require special packaging and increases the cost of transportation.

In Chinese patent application CN-93117436.8 disclosed a method of obtaining amifostine. The applicant US Bioscience Inc reports that "there are many serious practical problems associated with the methods of "dry fill" or "fill powder in the case reliabilitybased powder amifostine for injection during packaging of bulk solid amifostine. Such problems include difficulties in working with the powder manually, the need to grind the powder to an acceptable particle size and acceptable mobility; it is difficult to keep sterile and dust free conditions, and it is difficult to provide exact dosage solid amifostine in each bottle. In other words, on the basis of the prior art suggest that amifostine as reliabilitybased powder for injection, which consists of crystals of a single component, can not be obtained and used in practice.

A BRIEF DESCRIPTION of the INVENTION

One of the purposes of this invention sostoi the sustainable sterile reliabilitybased powder amifostine for injection, consisting of crystals of one component of amifostine.

The second purpose of this invention is the provision of a method of obtaining sustainable sterile reliabilitybased powder amifostine for injection, which consists of crystals of one component of amifostine.

The third objective of this invention is to provide an industrial method of producing a stable, sterile reliabilitybased powder amifostine for injection, the obtained crystal has a moderate length and acceptable mobility without grinding and can be precision are packaged in bottles.

These and other objectives of the present invention will be described and explained by the following examples.

DETAILED description of the INVENTION

In this invention the above powder amifostine for injection is deliverydiovan powder for injection, which consists of crystals of a single component of amifostine with the length of the crystal from 300 to 700 microns.

In addition, the crystal amifostine in powder amifostine for injection according to this invention contains 1-3 molecules of water of crystallization, preferably 3 molecules of water of crystallization. Water for injection include physiological salt solution, distilled water and glucose, etc.

The method of obtaining powder amifostine for injection according to this invention includes a process which begins source amifostine in water for injection at a mass ratio of 1:2-10. After mixing a basic solution is used to bring the solution pH to 6.6 to 7.4, and then add 75-98% ethanol, the mass ratio of amifostine and ethanol 1:1-5, considering the source amifostine. After freezing appears crystalline precipitate of amifostine length granules 300-700 microns.

Preferably, the method of obtaining powder amifostine for injection according to this invention involves the dissolution of the original amifostine in water for injection, the mass ratio of amifostine and water 1:3-8. After mixing, bring the solution pH to 7.0 to 7.2 using the main solution, and then add 75% ethanol at a ratio of masses of amifostine and ethanol 1:1.5 to 3, considering the source amifostine. After freezing falls crystalline precipitate of amifostine length of pellets from 300 to 700 microns.

The basic solution used in the method of producing powder of amifostine for injection according to this invention may be an aqueous solution of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate. One of these fundamental solutions can be used alone or optionally you can use a combination of two or three of these solutions. Temperature above freezing for crystallization is from -16 to -23°C, freezing time is 5-10 h, the optimum freezing time is 6-8 hours After the death the survival and crystallization carry out the filtration under reduced pressure and drying in vacuum. After analyzing the water content of the crystals sieved through a sieve of 20 to 50 mesh, preferably through a 30 mesh sieve, and then the product is Packed in bottles.

When amifostine is used, its amount is determined, considering the anhydrous form. Intravenous injection of amifostine doing for 30 min prior to the introduction of a chemotherapeutic drug or preparation for radiation therapy, and dose of amifostine is 800 mg/m2for chemotherapy or 200 mg/m2for radiation therapy, considering the surface area of the body. In each case you should follow the advice of a doctor.

The advantages of this invention consist in the increased stability of the drug and the ability to store the drug at room temperature for two years without refrigeration.

In the method of producing powder of amifostine for injection according to this invention does not apply excipient and instead of freeze drying use drying in vacuum, thus eliminating the instability of the drug, possible due to repeated freezing and thawing (i.e. heating and cooling). Crystals of appropriate size can be obtained by regulating the pH, temperature and time of crystallization in the production process. And the length of the pellets crystal amifostine is 300-700 μm. Crystals of this size can sift through the 30 mesh and packaged in vials. Thus, to solve problems associated with the difficulties of working with the powder manually, and there is no need to pulverize the powder to obtain particles of the appropriate size and acceptable mobility; in addition, the task of maintaining a sterile and dust free conditions and observance of precise dosages solid amifostine for each bottle.

The crystal structure of amifostine after vacuum drying

Crystal amifostine looks like a colorless transparent piece. The size of the investigated crystal 0,8×0,6-0,8 mm Crystal belongs to the orthorhombic system, and its space group P212121. The unit cell parameters: a=21,486 (2), b=8,433 (3), c=6,742 (2) ÅZ (molecular number of the unit cell) =4 and V (volume of cell) =1221,6(6) Å3. Corresponding to the molecular formula C5H15N2O3PS·3H2O. the Calculated density of the crystal is DX=1,462 g/cm3.

Data on the intensity of the diffraction get chetyrehrogaja diffractometer Nomus CAD-4 c graphite monochromator, Mo-Kα-radiation, θ/2θ-scan and 2θmax=50,0°. The amount received independent reflections 1211, and the number of observed reflections (|F1>3,0σF|) 1129.

To determine the crystal structure used direct method (SHELXS-86). They are situated is 13 atoms can be determined directly from the E-chart, and then use differential Fourier's method to establish the location of all 15 non-hydrogen atoms and to determine what type of atoms includes, for example, carbon, nitrogen, oxygen, phosphorus and sulfur. Values of atomic coordinates and isotropic thermal vibrational parameters specify the method of least squares. The location of all the hydrogen atoms is determined using the method of geometric calculations and alternative, differential combined Fourier method. Finally, the structural parameters specify full-fabric by the method of least squares. The reliability factor R=0,041, RW=0,044, (Δ/σ)max=0,87, (Δρ)min=-0,290e/A3, ((Δρ)min=0,520e/A3.

The molecular structure is shown below.

Figure 1 shows the projection of the spatial structure, and figure 2 shows a drawing of the packaging unit cell.

These results show that the molecular structure of amifostine is the same as the structure previously described, and molecular spatial structure depicted in figure 1. The crystal contains three molecules of water, and because of the existence of water molecules between the molecules in the crystalline state formed hydrogen bonds. 04...06: 2,851 Å, 05...N2: 2,744 Å, 04...01 (1-x, a 0.5-y, 0.5 to z): 2,83 Å, 04...06 (1-x, 0.5-y, 1,5-z): 2,882 Å, 05...01 (x, y, 1-z: 2,700 Å , 05...02 (of 0.5-x, -y, 0.5 to z): 2,862 Å, 06...03 (x, y, 1-z). You can see in figure 2 that the water molecules stabilize the crystal lattice and, thus, cause the molecules in the crystalline state to build a sustainable manner. Figure 3 shows images of the packaging unit cell, corresponding to previously published data. A comparison of figures 2 and 3 shows that the crystal structure of amifostine identical to the structure described in the literature, i.e. both of these structures are identical to the crystal C5H15N2O3PS 3H2O.

The products of this invention are stored at room temperature and remain active for 1, 3, 5, 12, 18 and 24 months, respectively. Each item in the planned study yielded a satisfactory result. Thus, the validity of the products is at least two years.

All materials and additives (adjuvants) for the implementation of the present invention can be purchased. If you need to get the source amifostine as links can be used by certain well-known documents. These documents are included in this description as a reference. The preferred method of obtaining the source of amifostine described in article Zengslou Tong, et al. (ACTA Pharmaceutica Sinica, 1981, 16(4), 302).

A brief description of the drawing the nd:

Figure 1. The projection of the spatial structure.

Figure 2. The scheme of the packaging unit cell.

Figure 3. The scheme of the packaging unit cell, the corresponding literature data.

Figure 4. Table of atomic coordinates and thermal vibrational parameters.

Figure 5. Table of values of bond lengths and valence angles.

The invention is additionally illustrated by several variants of its implementation. But these embodiments of the invention are used for illustration only and in no way limit the scope of the present invention.

Unless otherwise specified, all parts or measurements expressed in units of mass per total mass.

Example 1

The efficiency of the products according to this invention was compared with the efficiency of amifostine domestic production and efficiency imported amifostine for injection (lyophilized powder for injection). The results obtained prove that the products of this invention have the efficiency, in General, equivalent to the effectiveness of the product imported into the present, as shown in table 1.

Notes: (1) Z denotes amifostine for injection; CY represents a chemotherapy drug cyclophosphamide; F denotes import amifostine for injection (Ethyol); and what about the comparison with group CY *P< 0,05; **P<0,01.

(2) the Group Z200+CY represents the effect of 200 mg/kg of amifostine produced Zhenzhong, Nanjing.

(3) the Group Z100+CY represents the effect of 100 mg/kg of amifostine produced Zhenzhong, Nanjing.

(4) the Group Z50+CY represents the effect of 50 mg/kg of amifostine produced Zhenzhong, Nanjing.

(5) the Group E200+CY represents the effect of 200 mg/kg imported amifostine.

(6) the Group CY demonstrates the effect without using amifostine.

(7) the Control group shows normal values.

Example 2

The products of this invention (which hereinafter will be referred to as "deliverydiovan powder of amifostine for injection from Zhenzhong, Nanjing" compared with conventional liofilizirovannam powder and amifostine received by the claims of a U.S. patent to verify their stability. The results show that the products according to this invention for stability superior to other drugs of amifostine.

Table 2 presents the results of tests on the stability of the products of this invention within 0-90 days at a temperature of 40°C and a relative humidity of 75%.

TABLE 2
Comparison of stability of conventional lyophilized form of amifostine, the product obtained according to the formula of the invention paten is and the USA, and reliabilitybased powder amifostine for injection from Zhenzhong, Nanjing."
The content of amifostine (%) Time (days) (40°C and RH 75%)Conventional dried product (a mixture of crystalline and non-crystalline forms)The product obtained according to patent the formula USA, (crystal granules)Deliverydiovan powder for injection from Zhenzhong, Nanjing(crystal granules)
1212123
098,3199,5599,4599,6698,6101,0100,6
1080,2097,9399,2698,9799,8102,1101,3
3058,4350,5792,1093,3798,8101,9101,0
6023,21of 8.4722,5546,3498,498,898,6
90----94,696,5to 91.1

Example 3

In the table the e 3 presents the results of tests on the long-term sustainability of the products of amifostine at room temperature.

TABLE 3
The test results on persistence (sustainability) of amifostine at room temperature.
(Conditions packaging: retail packaging of a medicinal product)
The batch numberStorage conditionsStorage time (months)Data
Appearance and colorThe test substanceContent (%)
TLCHPLC
No. 1Natural conditions, room temperature0White or almost whiteSpot impurities <1,5%The peak impurity <1,5%99,9
1White or almost whiteSpot impurities <1,5%The peak impurity <1,5%99,0
3White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,0
6White or almost whiteSpot impurities <1,5%The peak impurity <1,5%98,8
12Ely or almost white Spot impurities <1,5%The peak impurity <1,5%98,5
18White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,8
24White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,6
36White or almost whiteSpot impurities <1,5%The peak impurity <1,5%96,55
No. 2Natural conditions, room temperature0White or almost whiteSpot impurities <1,5%The peak impurity <1,5%99,9
1White or almost whiteSpot impurities <1,5%The peak impurity <1,5%99,0
3White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,0
6White or almost whiteSpot impurities <1,5%The peak impurity <1,5%98,8
12White or almost whiteSpot impurities <1,5%The peak impurity <1,5%98,5
&x0200A; 18White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,8
24White or almost whiteSpot impurities <1,5%The peak impurity <1,5%100,6
36White or almost whiteSpot impurities <1,5%The peak impurity <1,5%for 95.3

Example 4: the Preferred method of testing resistance of amifostine, dried in vacuum

(1) Method of determining an analyte - amifostine: Thin layer chromatography (TLC)

TLC conditions:

Stationary phase: silica gel H or silica gel GF254 (Qingdao Ocean Chemical Plant).

Manifesting substance (eluent: mixture of chloroform-methanol-concentrated chlorine water (1:2:2) (all substances are analytically pure products, the same applies to the substances described below).

Coloring manifesting agent: vapours of iodine.

Volume of sample: 5 ál

Get sample for test and control sample

Take a portion of amifostine and dissolved in a mixture of water and methanol (7:3) to obtain a solution containing 10 mg/ml of amifostine, for use as a test sample. And the appropriate number p is target was accurately measured and diluted with a mixture of water and methanol (7:3) to obtain a solution, containing 0.15 mg/ml of amifostine for use as a control sample.

Methods of work

On the same plate for thin-layer chromatography put samples of the test sample and the control sample. After moving the sample eluent on the plate in a chromatographic vessel plate is dried in the air. And the manifestation of the color produced in the vessel saturated with iodine. If the stain of the specimen is spot impurities, tone spots impurities compared to shade spot control sample.

Result

If the tone spots, impurities in the stain test sample is lighter than the color stains the control sample, then we can determine that the content of impurities in the sample to be tested is less than 1.5%. And if the stain impurities in the stain test sample is darker than the color stains the control sample, then we can determine that the content of impurities in the sample to be tested above 1.5%.

Test results

Five batches of amifostine obtained in accordance with example 1, analyze the content of amifostine and the obtained results are compared with data on the purity of the obtained HPLC.

SampleThe purity determined by HPLC Comparison of spot colors impurities and control spotConclusion
199,21%Spot the admixture is lower than the control spotImpurity <1,5%
299,12%Spot the admixture is lower than the control spotImpurity <1,5%
399,50%Spot the admixture is lower than the control spotImpurity <1,5%
499,18%Spot the admixture is lower than the control spotImpurity <1,5%
599,05%Spot the admixture is lower than the control spotImpurity <1,5%

The above results show that the maximum content of impurities in the samples of all five parties, determined in accordance with this example by TLC, it is consistent with the results obtained by HPLC. Thus, confirms the accuracy of the determination of the maximum impurity content by this method.

(2) the Method of determining the content of amifostine by HPLC

The chromatography conditions:

Chromatographic column: kronacil C-18 5 μm 4,6×250 mm (Tena Science Instrument Ltd., Tianjing).

Mobile phase: 0.1% aqueous solution octisalate sodium - is ethanol (50:50) (phosphoric acid to bring the pH to 3)

The wavelength of detection: 210 nm

Flow rate: 1.0 ml/min

Volume of sample: 20 ál

Temperature: room temperature

The relative standard deviation (RSD) at five sampling <2,0%

theoretical number of plates: >1000

The coefficient "blur" peak: <2

Obtaining a test sample and control sample

Obtaining a control sample: an accurately weighed sample of substance-standard (about 50.0 mg) is placed in a volumetric flask of 25 ml in the flask add 12.5 ml of water to dissolve the sample and slowly added dropwise methanol to the mark for dilution.

Obtaining a test sample: an accurately weighed sample sample amifostine (about 50 mg) was placed in a volumetric flask of 25 ml in the flask add 12.5 ml of water to dissolve the sample and slowly added dropwise methanol to the mark for dilution.

The method

Inject 20 µl of sample and control sample respectively. Record the peak areas of the main components of the control sample and the sample and calculate the content of these components by the method of external standard.

Calculations: determination obtained amifostine

where mr is the mass of the anhydrous substance-standard

Ar is the peak area of the control sample,

mx is the mass of the anhydrous sample,

Ax is the peak area of the sample under study.

The definition of amifostine for injection

where Ax is the peak area of the sample under study,

mx is the mass of the sample,

Ar is the peak area of the control sample,

mx is the mass of the sample (counting on anhydrous substance),

1,252 - ratio transformation With5H15N2O3PS, turned into a5H15N2O3PS 3H2O.

Example 5

Source amifostine receive according to the method described Zengshou Tong, et al. (Acta Pharmaceutica Sinica, 1981, 16(4), 302). Under sterile conditions, 50 g source amifostine dissolved in 250 ml of water under stirring at room temperature 18-22°C. a Few drops of saturated sodium bicarbonate solution is added dropwise to dissolve. Determine the pH (between 7.0 and 7.2) and slowly added 125 ml of 98% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23°C)) for 6-8 h to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve of 30 mesh) and filled into vials.

Example 6

In sterile at the given 100 g source amifostine, obtained as in example 1, is dissolved in 500 ml of water at room temperature of 18-22°C. Add a few drops of a saturated solution of sodium bicarbonate. Bring the pH to 6.8-7.0 and add 250 ml of anhydrous ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23°C)) for 6-8 h to obtain a precipitate of white crystalline powder. The length of the crystal granules were 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum desiccator with pjatiokisi phosphorus and determine the water content. The product is then sieved through a sieve of 30 mesh) and filled into vials.

Example 7

Under sterile conditions, 50 g source amifostine containing one molecule of water of crystallization, obtained as in example 1, is dissolved in 250 ml of water at room temperature of 18-22°C. are Added dropwise 1 M sodium carbonate solution and stirred until dissolved. Bring the pH to 7.1-7.3 and slowly added 125 ml of ethanol. The solution is gently mixed and then stored in the refrigerator (-16°-(-23°C)) for 6-8 h to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve of 30 mesh) and rapasov who live in the bottles.

Example 8

Under sterile conditions 100 g source amifostine containing two molecules of water of crystallization, is dissolved in 500 ml of water at room temperature, above. Added dropwise a 0.5 M solution of sodium hydroxide. Adjusting the pH to 6.7-6.9 and slowly add 250 ml of ethanol. The solution is gently mixed and then stored in a refrigerator (at a temperature of above) for 6-8 h to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve of 30 mesh) and filled into vials.

Example 9

Source amifostine receive according to the method described Zengshou Tong, et al. (Acta Pharmaceutica Sinica, 1981, 16(4), 302). Under sterile conditions, 80 g of the obtained source amifostine dissolved in 180 ml of water for injection with stirring at room temperature 18-22°C. Add a few drops of saturated solution of potassium hydroxide for complete dissolution. Determine the pH value (between the 6.6 and 6.7) and slowly added 80 ml of 98% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23° (C) for 5-6 h to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration when s is low pressure are drying in vacuum and determine the water content. The product is then sieved through a sieve of 30 mesh) and filled into vials.

Example 10

Source amifostine receive according to the method described Zengshou Tong, et al. (Acta Pharmaceutica Sinica, 1981, 16(4), 302). Under sterile conditions, 100 g of the obtained source amifostine dissolved in 500 ml of distilled water for injection with stirring at room temperature 18-22°C. Added dropwise a mixture of saturated solutions of sodium hydroxide and sodium bicarbonate for complete dissolution. Determine the pH value (between the 6.8 and 6.9) and slowly added to 200 ml of 98% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23°C)) for 7-8 h to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve (20 mesh) and filled into vials.

Example 11

Under sterile conditions 120g source amifostine dissolved in 1000 ml of distilled water for injection with stirring at room temperature 18-22°C. Add dropwise a saturated solution of sodium bicarbonate for complete dissolution. Determine the pH value (between 6.9 and 7.0) and slowly added 360 ml of 75% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23°C)) for 8-9 hours for the floor is to be placed precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve (20 mesh) and filled into vials.

Example 12

Under sterile conditions 60 g source amifostine dissolved in 600 ml of distilled water for injection with stirring at room temperature 18-22°C. Add dropwise a saturated solution of sodium carbonate to dissolve. Determine the pH value (between a 7.1 and 7.2) and slowly added to 180 ml of 95% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23°C)) for 9-10 hours to obtain a precipitate of white crystalline powder. The length of the crystal granules is 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve (20 mesh) and filled into vials.

Example 13

Under sterile conditions, 50 g of commercial amifostine dissolved in 150 ml of distilled water for injection with stirring at room temperature 18-22°C. Add dropwise a saturated solution of sodium carbonate to dissolve. Determine the pH value (between 7.3 and 7.4) and slowly added 120 ml of 75% ethanol. After mixing, the solution was stored in a refrigerator (-16°-(-23° (C) during the 6-8 hours to obtain a precipitate of white crystalline powder. The length of the crystal granules 300-700 μm. After filtration under reduced pressure carry out the drying in a vacuum and determine the water content. The product is then sieved through a sieve of 30 mesh) and filled into vials.

1. The powder amifostine for injection, which consists of crystals of a single component of amifostine, characterized in that it is deliverydiovan powder of amifostine for injection, the length of the granules of crystals is 300-700 μm and crystals of amifostine contain 1-3 molecules of water of crystallization.

2. The powder amifostine for injection according to claim 1, characterized in that the crystals of amifostine contain 3 molecules of water of crystallization.

3. The method of obtaining powder amifostine for injection according to claims 1 and 2, characterized in that the source amifostine is dissolved in water for injection, the mass ratio of amifostine and water 1:2-10, the basic solution was adjusted value of pH to 6.6 to 7.4 after mixing, add 75-98%ethanol at a mass ratio of 1:1-5, considering the source amifostine followed by freezing and crystallization at a temperature of -16 to -23°C for 5-10 hours

4. The method of obtaining powder amifostine for injection according to claims 1 and 2, characterized in that the source amifostine is dissolved in water for injection, the mass ratio of amifostine and water 1:3-8, the basic solution was adjusted value is their pH to 7.0 to 7.2 after mixing, add 75%ethanol at a mass ratio of 1:1.5 to 3, considering the source amifostine followed by freezing and crystallization at a temperature of -16 to -23°C for 5-10 hours

5. The method of obtaining powder amifostine for injection BP and 4, characterized in that the above basic solution may be a solution of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate, and each of them can be used alone or optionally you can use a combination of two or three of them.

6. The method of obtaining powder amifostine for injection BP and 4, characterized in that after freezing and crystallization spend filtration under reduced pressure and drying in vacuum with subsequent analysis on the water content and sift the powder through a sieve 20-50 mesh and then Packed it in bottles.



 

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5 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to preparations reducing blood cholesterol level. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and their derivatives and analogs known as inhibitors of HMG-CoA-reductase are used as anti-hypercholesterolemic agents. Above mentioned active substances can be destabilized as result of effect of environment and their destruction can be accelerated in interaction with other pharmaceutical agents, such as excipients, binding agents, lubricating agents, substances promoting to slipping and disintegrating agents. Therefore, pharmaceutical components and a method for preparing a pharmaceutical preparation must be taken thoroughly to avoid above said undesirable interactions and reactions. Invention relates to inhibitor of HMG-CoA-reductase that stabilized by formation of a homogenous composition with buffer substance or an alkalinizing substance. This homogenous composition is used as an active substance in pharmaceutical preparation used for treatment of hypercholesterolemia and hyperlipidemia. Invention enhances the enhancement of stability and homogeneity of the preparation.

EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

FIELD: medicine, gastroenterology.

SUBSTANCE: one should apply food additives as tablets of oats, corn and cabbage by "Biophyt" company; moreover, to decrease motor system of biliary ducts one should apply tablets of oats, to increase motor system - tablets of corn and for total normalization of kinetics - tablets of cabbage. Treatment lasts for 10 d at the dosage of 1-2 tablets twice daily 30 min meals. The present innovation enables to normalize functional activity of biliary ducts at the background of shortened therapeutic terms.

EFFECT: higher efficiency of therapy.

4 ex

The invention relates to bistrotdepierrerue solid dosage form that dissolves in the mouth within sixty (60), more preferably thirty (30), most preferably ten (10) seconds

FIELD: neurological diseases.

SUBSTANCE: composition contains therapeutically effective amount of anticonvulsant agent dissolved or dispersed in aqueous carrier containing 10-80 vol % aliphatic alcohol, 10-80 vol % ethylene glycol, and 0.1-5 vol % bile acid salt or lecithin. Indicated carrier ensures increased access of anticonvulsant agent (such as benzodiazepin, in particular diazepam, clonazepam, phoenitoin, mephoenitoin, ethotoin, phenobarbital, carbamazepin, ethosuccinamide, valproic acid, gabapentine, trimethadion, lamotrigin) into blood and rapid pharmacological response when using nasal administration.

EFFECT: accelerated anticonvulsant effect.

11 cl, 9 dwg, 10 tbl, 13 ex

FIELD: medicine, pharmacy.

SUBSTANCE: pharmaceutical composition possesses an anti-estrogenic effect. The composition comprises fulvestrant in ricinoleate vehicle, a pharmaceutically acceptable anhydrous ester solvent and pharmaceutically acceptable alcohol. The composition is adopted for intramuscular administration and maintains the therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. The composition for intramuscular injection provides satisfied releasing fulvestrant for prolonged time.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

32 cl, 4 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation comprising propolis, dimethylsulfoxide and accessory substances as active substance and it comprises novocaine, anaesthesin as additional active components, and glycerol and 70% ethyl alcohol as accessory substances. The preparation can comprise 1% aqueous solution of ionized silver. The proposed treatment method is realized by applying the indicated preparation, once per 24 h, for 30 min, treatment course involves 7-10 procedures. Invention provides reducing treatment period of patients with diseases of locomotor system, peripheral nervous system and skin integuments and enhancing effectiveness of the preparation also.

EFFECT: improved treatment method, enhanced and valuable properties of preparation.

5 cl, 7 ex

FIELD: medicine, dermatology.

SUBSTANCE: invention proposes an anti-infectious preparation comprising the combination of active substances with topical and systemic antifungal agents and a water-insoluble film-forming agent. The systemic antifungal agent is taken among the group including intraconazole, terbinafine and fluconazole or their salts. The topical antifungal agent is taken among the group including ciclopirox, 6-(2,4,4-trimethylpentyl)-1-hydroxy-4-methyl-2(1H)-pyridone, amorolfine and butenafine or their salts. The preparation is used as lacquer for nails in therapy of onychomycosis. The lacquer preparation provides high concentration of systemic antifungal agents in nails after its topical applying. The significant advantage of the preparation involves short time in treatment of anychomycosis.

EFFECT: enhanced effectiveness and valuable medicinal properties of preparation.

6 cl, 6 ex

FIELD: medicine; medical engineering.

SUBSTANCE: method involves locally administering 30-50% hypertonic solution of xymedon hydrochloride, combined smoothly corrugated draining device, introducing gauze drain into upper part of wound cavity and intra-drain ultrasonic cavitation.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications.

5 cl, 4 dwg

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in stomatology in the topical anesthesia. The pharmaceutical composition comprising articaine hydrochloride and epinephrine hydrochloride and accessory substances, such as sodium metabisulfite, sodium chloride and water for injection involves additionally glycine and pH-regulating substance taken in the definite ratio of components. Invention provides preparing the preparation that is stable, non-toxic and doesn't cause allergic response reactions and elicits highly expressed infiltration and conducting anesthetic activity, good tissue tolerance and activity promoting to accelerated wound-healing in the post-operative period.

EFFECT: improved and valuable medicinal properties of composition.

3 cl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to an aqueous composition consisting of moxifloxacin hydrochloride and sodium chloride and comprising from 0.04% to 0.4% (mas/vol) (as measured for the amount of moxifloxacin) of moxifloxacin hydrochloride and from 0.4% to 0.9% (mas/vol) of sodium chloride. Also, invention relates to applying this composition with the aim for preparing a medicinal agent used for prophylaxis or treatment of bacterial infections in humans or animals. Invention provides stability of the prepared moxifloxacin solution as moxifloxacin hydrochloride in the presence of iron ions.

EFFECT: improved properties of compositions.

6 cl.

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new pharmaceutical composition comprising benzamide derivative and one or some additives taken among the following substances: 1) mixture of polyethylene glycol and surface-active substance; 2) amino acid or inorganic acid salt, and 3) propylene carbonate. The composition comprises benzamide derivative taken in the amount from 0.001 to 1000 mg per a single dosing formulation. The composition shows the enhanced solubility and absorption capacity in oral route of administration.

EFFECT: improved medicinal and pharmaceutical properties of composition.

9 cl, 4 tbl, 1 dwg, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to manufacturing medicinal preparations with wound-healing effect, in particular, to preparation with wound-healing effect comprising an agent stimulating epithelization. The wound-healing agent comprises vitamin E in concentrations 0.01-5.0 wt.-% in chitosan gel. Preferable variant represents applying chitosan gel formed by fractionated low-molecular chitosan of molecular mass from 10 to 20 kDa, or from 20 to 50 kDa, or from 50 to 300 kDa taken in the concentration from 1.0 to 10.0 wt.-%. Except for, it is possible additional applying antibacterial agent in wound-healing agent taken among the following order: chloramfenicol, lyncomycin, metronidazol, ciprofloxacin, benzalkonium chloride, additional using an antibacterial agent and lidocaine in agent, additional using an antibacterial agent and adrenaline in agent, and additional using hydrocortisone in the concentration 0.5 wt.-% in agent. Invention provides preparing wound-healing effect that occurs early essentially in epithelization and without formation of colloidal scars and reduces time for appearance of tissue regeneration markers.

EFFECT: valuable properties of agent.

8 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the propofol anesthetic composition suitable for parenteral administration. The composition comprises propofol in the concentration from 1 mg/ml to 20 mg/ml, d-alpha-tocopheryl polyethylene glycol-1000 succinate (TPGS) in the concentration from 10 mg/ml to 200 mg/ml, and water. The mass ratio of propofol to TPGS is at least 1:10. The composition is sterilized by final sterilization in autoclave. The present composition overcomes shortcomings of the ready preparative formulation in the emulsion form, namely, it provides the stable clear product in storage under regulated temperature conditions, i. e . in cooling.

EFFECT: improved and valuable pharmaceutical properties of composition.

11 cl, 7 ex

FIELD: medicine.

SUBSTANCE: method involves incubating flasks containing 70-80 ml of blood and 40 ml of preservative agent for 20 min at 37°C together with chemotherapeutical preparations. Next to it, treatment with alternating magnetic field of 50 mTesla units intensity and frequency of 50 Hz is applied at continuous rotation about its axis at 20 rpm speed. 30 mg/m2 of Doxorubicin is added to the first flask contents. 500 mg/m2 of cyclophosphane are added to the second flask and 20 mg/m2 of methotrexate are added to the third flask. Incubation and treatment with alternating magnetic field is started with the first flask at the first and the eighth day. Total chemopreparations quantity is equal to 60-80 mg, cyclophosphan is applied in the amount of 1200-1600 mg, methotrexate - 40 mg.

EFFECT: enhanced effectiveness of treatment.

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