Oral suspension containing a high dose of mofetil of mycophenolate

 

(57) Abstract:

Water oral suspension and anhydrous granular composition with a high dose of mofetil of mycophenolate or mycophenolate acids contain the specified substance 7.5 to 30% (wt./vol.), suspendisse and/or increase the viscosity of the agent, sweeteners, flavouring, buffer (up to pH 5.0 - 7.0) and optionally a wetting agent, intensifier of taste and flavor or substance, damper bitterness, an antimicrobial agent and a dye. The compositions of the present invention is suitable for use mofetil of mycophenolate or mycophenolate acid as immunosuppressive agents, anti-inflammatory agents, antineoplastic agents, antiproliferative agents, antiviral agents, and protivopsoriaticescoe agents. 6 C. and 25 C.p. f-crystals.

The technical field to which the invention relates

The present invention relates to movetile of mycophenolate and mycophenolic acid, in particular to improved compositions, and more specifically the present invention relates to oral suspension compositions with a high dose of these substances. The invention also relates to methods of producing these compositions.

the>was originally described as an antibiotic with low activity found in the fermentative broth Penicillium brevicompactum. Later it was found that the IFC and some related compounds, such as mofetil of mycophenolate (morpholinoethyl ether IFC), having the following structure:

< / BR>
have, in particular, is a useful therapeutic properties, for example, as immunosuppressing drugs. See, for example, the U.S. patents 3880995, 4727069, 4753935 and 4786637, which is incorporated into this description by reference.

IFC and mofetil of mycophenolate despite improved oral bioprosthetic last require daily doses of the order of from 2.0 to 3.5 or even 4.0 g per day (or even 5.0 g / day in the case of the IFC, as described, for example, in U.S. patent 3880995), depending on the subject to treat the patient and condition of the disease. When applying the composition with the usual dosage containing 250 mg capsule standard size 1 (volume of 0.48 cm3), patients receiving a daily dose of 3.0 g, is required to take twelve capsules daily, which increases the anxiety of the patient about adherence and convenience.

Coarse dispersions, such as oral suspensions contain finely es (15th edition, chapters 22 and 83, 1975) and for certain products in the Physicians' Desk Reference (46th edition, Medical Economics Date, 1992). As you know, oral suspensions suitable for use, for example, for children or the elderly, and they are typically not used for the purpose of obtaining compositions with a high dose. Some "ready to use" fillers for suspension, such as Ora-PlusTMin conjunction with Ora-SweetTM(both are supplied Paddock Laboratories Inc. Minneapolis, MN), suitable for the preparation of drugs on the individual recipe, however, their suitability for any particular active agent must be installed in each specific case. Moreover, such fillers are contra-indications in relation to the preservation of long-term stability and, therefore, are intended only for short-term use.

Oral suspension mofetil of mycophenolate have been described, for example, in U.S. patent 4753935 (see example 7), but for relatively low doses containing 1 g of active substance in 100 ml. Despite the fact that such suspensions are functional, they are for the patient the same concern about adherence and convenience, as mentioned above compositions in the form of capsules with a low dose.

Brief description of the invention

The present invention relates to oral suspensions containing a high dose of mofetil of mycophenolate or mycophenolate acid, and to methods for their preparation.

One subject of the invention relates to oral suspensions with a high dose, having the following composition:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate or mycophenolate acid - 7,5-30,0

Suspendisse/increase the viscosity agent is 0.1 to 3.0

Wetting agent - 0-0,5

Sweeteners - 30,0-70,0

Flavor - 0,1-2,0

An intensifier of taste and aroma/substance, damper bitterness - 0-1,0

The buffer to a pH of 5.0-7.0 - 0.5 to 1.5

Antimicrobial agent - 0-10,0

Dye - 0-0,01

Distilled water - D. K. 100

According to a preferred variant of execution of the present invention relates to oral suspensions with a high dose of mofetil of mycophenolate having the following composition:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20,0

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorb is>/BR>Aspartame - 0-0,5

Lecithin - 0-0,1

Citric acid - 0,02-0,25

Secondary acidic sodium phosphate - 0,19-0,67

Methylparaben - 0-0,18

Propylparaben - 0-0,02

Flavouring (selected from the vine, (optional with anise), cherry, strawberry or mint) - 0,3-1,0

Magnasweet- 0-1

The dye (s) selected from red 28, red 40, blue 1, blue 2 green or 3) - 0,005

Distilled water - D. K. 100

According to another preferred variant of execution of the present invention relates to oral suspensions with a high dose of mofetil of mycophenolate having the following composition:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20,0

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 30-50

Lycasin(multicopy syrup) - 10-30

Sucrose - 0-10

Fructose - 0-10

Aspartame - 0-0,5

Lecithin - 0-0,5

Citric acid - 0,02-0,25

Secondary acidic sodium phosphate - 0,19-0,8

Methylparaben - 0-0,18

Propylparaben - 0-0,02

Flavouring (selected from the vine, (optional with anise), cherry, strawberry, mint, orange, berry or mixed fruit) - 0,1-is any of 1, blue 2 green or 3) - 0,005

Distilled water - D. K. 100

Another subject of the invention relates to anhydrous granular composition mofetil of mycophenolate intended for receipt by combining with water oral suspension with a high dose, having the following composition:

Ingredient mg/ml*:

Mofetil of mycophenolate or mycophenolate acid - 75-300

Suspendisse/increase the viscosity of the agent - 1-30

Wetting agent - 0-10

Sweeteners - 1-1200

The flavor of 0.1 - 100

An intensifier of taste and aroma/substance, damper bitterness - 0-50

Antimicrobial agent - 0-10

Dye - 0-2

(*concentration after contact with water)

According to a preferred variant of execution of the present invention relates to anhydrous granular composition mofetil of mycophenolate intended for receipt by combining with water oral suspension with a high dose, having the following composition:

Ingredient mg/ml*:

Mofetil of mycophenolate - 200

Xanthan gum - 1-1,5

Colloidal silicon dioxide is 5-10

Sorbitol - 0-550

Aspartame - 0-3

Soy lecithin - 1-2

Methylparaben sodium - 0-1 orange, berry or mixed fruit) - 0,1-3,0

Dye (red, blue and/or yellow that matches the flavor) - 0,01-0,1

(*concentration after contact with water)

Detailed description of the invention

Definitions and General options

The following definitions are provided to illustrate and clarify the meaning and scope of various terms used to describe the invention.

About active agent, "mofetil of mycofenolate" used in the compositions of the present invention, it is understood that it includes and its pharmaceutically acceptable salts.

The term "effective amount" means a dosage sufficient to provide treatment status of the disease treated. It will vary depending on the patient, the disease and provide treatment.

The term "% (mass/vol.)" or as a percentage of the mass to the volume" refers to the number of excipient and/or medicinal substance, measured in units of mass (grams), which is contained in the final volume (ml) of suspension. The number of excipient and/or medicinal substance is expressed as the percentage of the total, the final volume of liquid product.

Unless otherwise noted, the described processes are at atmospheric pressure in the temperature range of 5oC to 100oC (preferably from 10oC to 50oC, most preferably at "room" temperature, or the temperature "environment", i.e., at 20oC).

If not specified, it is assumed that the percentage of trains, the time periods and conditions are approximate, for example, to add about 10% (weight/vol. ) at approximately atmospheric pressure in the temperature range from approximately 5oC to about 100oC (preferably from about 10oC to approximately the 50oC; most preferably at about 20oC) during the period of time from about 1 to about 10 hours (preferably for about 5 hours). Assume that the parameters specified in the examples are specific, but not rough.

Materials

Mofetil of mycophenolate can be obtained according to the description of U.S. patent 4753935, previously included in the present description by reference. Now the Scripture as a reference. Mycophenolate acid is commercially available, for example, supplied by the company Sigma Chemical Company, St. Louis, MO. The sources of various excipients described below, for example, in those cases, if the material is not publicly available or if the preferred product from a particular supplier.

Suspendresume and/or increase the viscosity of the agents used in the compositions according to the invention, include, for example: hypromellose (preferably according to United States Pharmacopeia (USP): hypromellose 2910); xanthan gum (preferably according to the pharmacological Handbook National Formulary (NF): xanthan gum, and most preferably KeltrolCR supplied by Kelco, San Diego, CA); microcrystalline cellulose (which is a colloidal suspendium agent, preferably according to NF: microcrystalline cellulose, and most preferably AvicelRC-591, supplied by FMC Corporation, Philadelphia, PA); sodium carboxymethyl cellulose (preferably according to USP: sodium carboxymethyl cellulose, or according to the British Pharmacopoeia (BP): nutricology or sodium carboxymethyl cellulose); and colloidal silicon dioxide (preferably according to NF: kolloidn the>/P>Wetting agents used in the compositions according to the invention, include, for example: lecithin (relevant or not relevant pharmacopoeial standards soy lecithin), poloxamer (supplied by BASF Wyandotte Corporation, Parsippany, NJ, under the trade mark Pluronic F68).

Sweeteners used in the compositions according to the invention, include, for example, 70% solution of sorbitol (preferably according to USP: the solution of sorbitol); multicopy syrup (preferably according to USP or NF, most preferably Lycasinsupplied by Roquette Corporation, Gurnee, IL), sucrose (preferably according to NF or BP/EP (European Pharmacopoeia)); fructose (preferably according to USP); aspartame (preferably according to NF); xylitol (preferably with a degree of purity of the relevant pharmacopoeial standards); mannitol (preferably according to USP or BP); sorbitol powder (preferably according to NF or BP); ▫ maltitol, crystalline (not relevant pharmacopoeial standards or preferably MaltisorbSF supplied by Roquette Corporation, Gurnee, IL). In cases where there is a choice of physical form, for use in suspended compositions preferred liquid sweetening the society (except aspartame) can also function as agents, increasing the viscosity and/or antimicrobial preservatives.

The flavors used in the compositions according to the invention, include, for example: mint, strawberry, cherry, orange, berry, mixed fruit and grape (optional mixed with anise). They are delivered by the company Tastmaker, Cincinnatti, HE; Crompton &Knowles Corporation, Mahwah, NJ; and International Flavors & Fragrances Inc., Camden, NJ.

Intensifiers of taste and aroma (or substances, damper bitterness) used in the compositions of the present invention, include, for example: Magnasweet(supplied by MacAndrews & Forbes Company, Camden, NJ).

The buffers used in the compositions according to the invention include as components, for example, citric acid (preferably according to USP) and the secondary acid sodium phosphate (preferably according to USP).

Antimicrobial agents used in the compositions according to the invention, include, for example: sodium benzoate; methyl paraben sodium (preferably according to NF: methylparaben sodium); methylparaben (preferably according to NF: methylparaben, or according to BP: methylhydroxybenzoate, or according to EP: methyl parahydroxybenzoate); propylparaben (preferably according to NF: propylparaben, or according to B who?), used in the compositions according to the invention, include, for example: FD&C red 28, FD&C red 40, FD&C red 3, FD&C blue 1, FD&C blue 2, FD&C yellow 6 and FD&C green 3.

Oral suspension with a high dose

The composition of

Oral suspensions of the present invention with a high dose have the following General structure:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate or mycophenolate acid - 7,5-30,0

Suspendisse/increase the viscosity agent is 0.1 to 3.0

Wetting agent - 0-0,5

Sweeteners - 30,0-70,0

Flavor - 0,1-2,0

An intensifier of taste and aroma/substance, damper bitterness - 0-1,0

Buffer - to 0.5-1.5

Antimicrobial agent - 0-10,0

Dye - 0-0,01

Distilled water - D. K. 100

In particular, if the active agent is IFC, the pH must be maintained at a level lower than 7.0 in order to avoid dilution.

Preferred oral suspension according to the present invention have the following composition:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 30-50

L - 0-0,1

Citric acid - 0,02-0,25

Secondary acidic sodium phosphate - 0,19-0,67

Methylparaben - 0-0,18

Propylparaben - 0-0,02

Flavor - 0,3-1,0

Magnasweet- 0-1

Dye - 0,005

Distilled water - D. K. 100

The most preferred oral suspension according to the present invention has the following composition:

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

Microcrystalline cellulose - 0,2

Xanthan gum - a 0.1

Sorbitol 70% solution - 30-50

Lycasin(multicopy syrup) - 10-30

Sucrose - 0-10

Fructose - 0-10

Aspartame - 0-0,5

Lecithin - 0-0,5

Citric acid - 0,02-0,25

Secondary acidic sodium phosphate - 0,19-0,8

Methylparaben - 0-0,18

Propylparaben - 0-0,02

Flavor - 0,1-1,0

Magnasweet- 0-1

Dye - 0,005

Distilled water - D. K. 100

The method of obtaining

1. The hot water (up to approximately 70oC) was added antimicrobial agent and dispersively, then added suspendresume and/or increase the viscosity agents (preferably microcrystalline cellulose, and then xanthan gum).

2. Was dissolved by mixing the buffer(s) (n is e substance(a), wetting agent(s), dye(s), aromatic amplifier(s) and flavouring(s).

3. To the mixture obtained in stage 2, was added to the active substance (mofetil of mycophenolate or mikofenolna acid); the liquid is thoroughly mixed before the formation of the suspension.

Anhydrous granulated composition

The composition of

Anhydrous granular compositions of the present invention have the following General structure:

Ingredient mg/ml*:

Mofetil of mycophenolate or mycophenolate acid - 75-300

Suspendisse/increase the viscosity of the agent - 10-30

Wetting agent - 3-10

Sweeteners - 200-1200

Flavor - 3-100

An intensifier of taste and aroma/substance, damper bitterness - 0-50

Antimicrobial agent - 0-10

Dye - 0-2

(*concentration after contact with water)

The preferred anhydrous granular composition has the following composition:

Ingredient mg/ml*:

Mofetil of mycophenolate - 200

The sodium carboxymethyl cellulose - 20

Sucrose - 0-700

Fructose - 0-700

Xylitol - 0-700

Mannitol - 0-1200

Sorbitol - 0-1080

▫ Maltitol - 0-740

Pluronic F68 - 4-8

Flavor - 10

Potassium sorbate is izvozna granulated composition has the following composition:

Ingredient mg/ml*:

Mofetil of mycophenolate - 200

Xanthan gum - 1-1,5

Colloidal silicon dioxide is 5-10

Sucrose - 0-700

Fructose - 0-700

Xylitol - 0-700

Mannitol - 0-1200

Sorbitol - 0-1080

▫ Maltitol - 0-740

Soy lecithin - 1-2

Flavor - 1-10

Methylparaben sodium - 0-10

Dye - 0-1

(*concentration after contact with water)

The method of obtaining

1. Mofetil of mycophenolate, sweetener(s), wetting agent(s) and suspendisse and/or increase the viscosity of the agent(s) were weighed and combined in the mixer.

2. The dye(s) and buffer(s) dissolved in the water.

3. The solution obtained in stage 2, was added to the tank of the mixer to the mixture obtained in stage 1, up until not received pellets of the desired size.

4. The granules were dried and then grinded to reduce the size of the particles.

5. Using the stirrer, was added suspendisse and/or increase the viscosity of the agent(s), flavor(s) and antimicrobial agent(s).

When used as a pharmaceutical composition for use, for example, mofetil of mycophenolate or mycophenolate acid, anhydrous granular component is Holocene suspension and apply oral way.

In another embodiment, the granules are placed in the container, such that after connecting to the appropriate volume of water to provide a supply of a drug in suspension for an extended period of time (for example, 90 g of mofetil of mycophenolate placed in the vessel with the label, to which it must be filled with distilled water to obtain a final volume of 450 ml, provide a 30-day supply of a drug).

Preferred compositions

Preferred the following composition.

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

The solution of sorbitol - 50

Sucrose - 10

Lycasin- 10

Lecithin - 0,1

Methylparaben - being 0.036

Propylparaben - 0,004

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Citric acid - 0,0542

Secondary acidic sodium phosphate - 0,673

Distilled water - D. K. 100

The pH of the composition is brought to 7, as a liquid suspension it is suitable for oral administration.

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

BR>
Lycasin(multicopy syrup) - 10

Soy lecithin - 0,1

Methylparaben - 0,04-0,1

Flavor mixed-fruit - <0,3
Citric acid - 0,06

Secondary acidic sodium phosphate - 0,7

Distilled water - D. K. 100

The pH of the composition is brought to 7, as a liquid suspension it is suitable for oral administration.

Ingredient, mg:

Mofetil of mycophenolate - 90000

The sodium carboxymethyl cellulose - 9000

Mannitol - 180000

Aspartame - 1575

Pluronic F68 - 1800

Potassium sorbate - 225

The cherry flavor - 4500

Dye (red 40 blue 1, 90:10) to 4.5

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Ingredient, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 450

Colloidal silicon dioxide - 2250

Soy lecithin - 450

Sorbitol - 247500

Aspartame - 225

Methylparaben sodium - 900

The berry flavor - 1350

Lake, FD&C red N3 - 13,5

Lake, FD&C blue No. 1 - 2,7

This composition is stored in a container with a label, up to the

Ingredient, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 450

Colloidal silicon dioxide - 2250

Soy lecithin - 450

Sorbitol - 135000

Aspartame - 450

Citric acid - 225

Sodium citrate - 4500

Methylparaben sodium - 900

The berry flavor - 1350

Lake, FD&C red N3 - 13,5

Lake, FD&C blue No. 1 - 2,7

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Ingredient, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 675

Colloidal silicon dioxide - 4500

Soy lecithin - 900

Aspartame - 900

Methylparaben sodium - 1035

Flavor mixed-fruit - 900

Lake, FD&C red N3 - 3,6

Lake, FD&C yellow N6 - 0,9

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Ingredient, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 450

Colloidal silicon dioxide - 2250

Soy lecithin - 450

Sorbitol - 247500

Aspartame - 225

Citric acid-Khabibullina, FD&C red N3 - 2,79

Lake, FD&C yellow N6 - 0,675

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Ingredient, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 675

Colloidal silicon dioxide - 4500

Soy lecithin - 900

Aspartame - 900

Citric acid - 225

Sodium citrate - 4500

Methylparaben sodium - 450

The flavor of orange - 450

Dye (FD&C yellow N6) - 45

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Testing, purpose and application

Testing

To assess the suitability of the compositions obtained in accordance with the present invention conducted the following tests. Test techniques known to experts in this field of technology.

1. Time education (anhydrous granules).

2. Ease of resuspendable solid material(s).

3. Appearance.

4. The amount of the drug dissolved in the continuous aqueous phase.

5. Chemical stability (the camping product(s) decomposition (e.g., mycophenolic acid from the suspension mofetil of mycophenolate).

7. The viscosity.

8. The density.

9. Freezing/melting (aggregation).

10. The deposition rate.

11. The amount of sludge.

12. The homogeneity of the medicinal substance.

13. The particle size.

14. Antimicrobial effectiveness test (according to USP/BP).

15. Gravity and vibration voltage (simulation conditions of carriage).

Assessing the acceptability of the compositions obtained in accordance with the present invention, conduct the following test. Test techniques known to experts in this field of technology.

1. Ease of resuspendable solid material(s).

2. Appearance.

3. Chemical stability (percentage of the drug concentration specified on the label).

4. The percentage of the product(s) decomposition, formed over time.

5. The viscosity.

6. The density.

7. The homogeneity of the medicinal substance.

8. The particle size.

9. Antimicrobial effectiveness test (according to USP/BP).

Eligibility criteria include any of the following minimum shaking the precipitate was redispersible and restored the original suspension. From a practical point of view, any residue should registerroutes for 10 seconds with a minimum of manual shaking.

Appearance: in a freshly prepared suspension of all solid materials should be evenly and homogeneous dispersed in the liquid phase. Over time, you may receive the precipitate; and in the ideal case, the amount of sediment should include the entire volume of the suspension. In that case, if the volume of sediment is less than the volume of the suspension, the resulting supernatant layer should be transparent (showing that the system is flaky).

Chemical stability: number of medicinal substances must be maintained at a level of 90-110% of the concentration specified on the label.

The percentage of the product(s) decomposition, formed over time: it is considered acceptable education not more than 5% of the product(s) decomposition over a period of time equal to 2 years.

Viscosity: the viscosity must be high enough to prevent rapid sedimentation. However, too high a viscosity is not acceptable from the point of view of the consumer. Acceptable range of approximately 200-1000 CP, and the preferred range is 250-dispersively solid particles (drug substance); match the density of the filler and medicines should prevent the deposition. Acceptable ranges for the compositions of the present invention is 1,10-1,25 g/ml

Homogeneity: after a minimum of manual shaking of the package containing the suspension, the amount of drug found in the upper, middle and lower parts of the packaged suspension, shall not vary more than 10%.

Particle size: over time the average particle size of the suspension shall not vary by more than 20% from the average particle size of freshly prepared suspension.

Antimicrobial effectiveness: the suspension should be tested for antimicrobial efficacy using methods adopted in USP and BP. In order to be acceptable, the suspension must pass these tests in accordance with the relevant specifications.

The composition of the invention showed satisfactory results when they were subjected to the above tests. Specialists in the art should be obvious from this description that the choice of specific ingredients and their relative concentrations will alter the characteristic balances received etTMhowever , the characteristic balance of the obtained composition is unacceptably viscous and it can be expected that the presence of too many drugs dissolved in the continuous aqueous phase, contributes to the enhanced formation of decomposition products and the loss of chemical stability (pH value inherent in these fillers, ie 5.0 is the lowest acceptable pH for mofetil of mycophenolate in these compositions).

The purpose

The compositions of the present invention suitable for oral administration under any regime oral treatment with mofetil of mycophenolate or mycophenolate acid. Although the dose levels for humans has yet to be clarified, the usual daily dose of mofetil of mycophenolate or mycophenolate acid is from 2.0 to 5.0 g, preferably approximately from 2.0 to 3.5, the Amount of applied active compounds must, of course, depend on the subject to the patient's treatment and condition of the disease, severity of disease, the method and schedule of application and the decision of the attending physician. For example, the mode of treatment, including the use of 3.0 g of mofetil of mycofenolate a day, which previously included the acquisition of 12 capsules (250 mg) (for example, six easy dose (for example, full teaspoon) twice a day. The compositions of the present invention, in particular, suitable for use by gastric lavage.

Application

The compositions of the present invention is suitable for use mofetil of mycophenolate or mycophenolate acid ("compound") as immunosuppressive agents, anti-inflammatory agents, antineoplastic agents, antiproliferative agents, antiviral agents, and protivopsoriaticescoe agents (as described in more detail below) for mammals, including domesticated animals (cattle, pigs, sheep, goats, horses), Pets (cats, dogs), and preferably humans. These compounds are inhibitors of insertunorderedlist (IMPDH) and, thus, inhibit de novo purine synthesis; they possess antiproliferative action (for example, in the cells of smooth muscles and as B-and T-lymphocytes) and inhibit the formation of antibodies and the glycosylation of molecules, causing adhesion of cells in lymphocytes and endothelial cells.

As immunosuppressive agents compound suitable for the treatment of autoimmune disorders, for example: Insa the public colitis); system wolf eritematoso; chronic active hepatitis; multiple sclerosis; grave's disease; Hashimoto thyroiditis; syndrome behceta; heavy pseudoparallelism gravis, Sjogren syndrome; pernicious anemia; idiopathic adrenal insufficiency; and pluriglandular autoimmune syndrome types I and II.

Compounds according to the invention is also suitable as a therapeutic immunosuppressive agents in the treatment of asthma, immunohemolytic anemia, glomerulonephritis and hepatitis. Prophylactic use of compounds as immunosuppressive agents includes treatment of rejection of allografts, for example, heart, lung, pancreatic, kidney, liver, skin and corneal allografts, and prevention of graft versus host.

Compounds suitable for inhibiting proliferation reactions to damage blood vessels, such as stenosis of the blood vessel walls, resulting stroke restenosis after plastic surgery on the blood vessels and restenosis after heart surgery using cardiopulmonary bypass.

Compounds according to the invention is suitable as PRA and uveitis.

As anticancer agents compound suitable for the treatment of solid tumors and malignant tumors lymphoreticular origin. For example, solid tumors, for which treatment is suitable compounds include: head and neck cancer, including squamous cell carcinoma; lung cancer including small cell and both the lung carcinoma; tumors of the mediastinum; esophageal cancer, including squamous cell carcinoma and adenocarcinoma; pancreatic cancer; cancer of the system of the liver and gallbladder, including hepatocellular carcinoma, cholangiocellular carcinoma, carcinoma of the gallbladder and carcinoma of the biliary tract; carcinoma of the small intestine, including adenocarcinoma, sarcoma, lymphoma and carcinoid tumors; cancer of the colorectal system, including cancer of the colon and rectum cancer; metastatic carcinoma; cancer of the urinary tract, including ovarian cancer, sarcoma of the uterus and renal carcinoma cells, ureters, bladder, prostate, urethra, penis, ovaries, vulva, vagina, cervix, endometrium and fallopian tubes; breast cancer; cancer of the endocrine system; soft tissue sarcoma; malignant mesothelioma; skin cancer, including locatiestudies tumor of the bone; and a neoplasm of plasma cells.

As antitumor agents for the treatment of malignant diseases lymphoreticular origin compound suitable for treatment, such as lymphomas and leukemias, including malignant diseases B-, T - and promonocytic cell lines, mushroom mycoses, non-Hodgkin's lymphoma, malignant cell lymphoma Bernita and other EBV-transformed B-lymphocytes, lymphomas resulting from viral infection of Epstein-Barr recipients of allografts, chronic lymphocytic leukemia, acute lymphocytic leukemia and volostockletocny leukemia.

As antiviral agents the compounds according to the invention is suitable for treatment, such as retroviruses, including virus T-cell lymphoma human types I and II (HTLV-1 and HTLV-2), the human immunodeficiency viruses types I and II (HIV-1, HIV-2) virus and carcinoma of the nasopharynx person (NPCV) and for the treatment of herpes viruses, including EBV-infected B-lymphocytes, cytomegaly virus, herpes virus type 6, herpes simplex viruses types 1 and 2 (HSV-1, HSV-2) and herpes zoster.

As protivopolozhnyh agents compound suitable for the treatment, for example, progo, to enable specialists in the art to more clearly understand and implement the present invention. They should not be construed as limiting the scope of invention, but only as illustrating and describing it.

Examples 1-24

These examples illustrate receiving oral suspension compositions with a high dose. In each example the composition received in one of the following different ways:

A. 1. To hot water was added hypromellose and dispersively.

2. To the dispersion obtained in stage 1, were added microcrystalline cellulose and dispersively.

3. To the mixture obtained in stage 2, was added xanthan gum and dispersively.

4. To the mixture obtained in stage 3, were added separately with stirring, sweeteners, flavorings, colorants and lecithin.

5. In a small aliquot quantities of water separately dissolved citric acid and secondary acidic sodium phosphate and then added to the mixture obtained in stage 4, bringing the pH to the specified level.

6. In a small aliquot quantities of water (heated to 80oC) separately rastolchennoy on stage 6, added mofetil of mycophenolate and thoroughly mixed prior to the formation of a suspension suitable for oral administration.

B. 1. In hot water (70-75oC) was dissolved under stirring methylparaben sodium.

2. To the dispersion obtained in stage 1, were added microcrystalline cellulose and dispersively.

3. To the dispersion obtained in stage 2, with stirring, was added a solution of sorbitol. To the mixture was added xanthan gum and dispersively. After that, when the stirring solution was added to maldita.

4. In a separate vessel containing distilled water, was added and dissolved citric acid, and then was added and dissolved anhydrous secondary acidic sodium phosphate. After this was dissolved sucrose was added and dispersively soy lecithin. Then added and dispersively mofetil of mycophenolate.

5. The dispersion obtained at stages 3 and 4 were combined and stirred.

6. Preparing the mother solution of the dye. To the dispersion obtained in stage 5, was added with stirring, a dye and flavoring.

7. The dispersion obtained in stage 6, if necessary, brought with distilled water to the desired volume.
Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Lecithin - 0,1

Methylparaben - being 0.036

Propylparaben - 0,004

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,241

Secondary acidic sodium phosphate - 0,547, pH 6

Distilled water - D. K. 100

Example 2

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Lecithin - 0,1

Methylparaben - being 0.036

Propylparaben - 0,004

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28: blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,0542

Secondary acidic sodium phosphate - 0,673, pH 7

Distilled water - D. K. 100

Example 3

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystallin>(multicopy syrup) - 10

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,0542

Secondary acidic sodium phosphate - 0,673, pH 7

Distilled water - D. K. 100

Example 4

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,2

Microcrystalline cellulose - 0,2

Xanthan gum - 0,075

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Lecithin - 0,1

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,0962

Secondary acidic sodium phosphate - 0,219, pH 6

Distilled water - D. K. 100

Example 5

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Lecithin - 0,1

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 7

Distilled water - D. K. 100

Example 6

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,35

Microcrystalline cellulose - 0,3

Xanthan gum - 0,125

Sorbitol 70% solution - 30

Sucrose - 10

Lycasin(multicopy syrup) - 30

The grape flavor - 0,75

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,0217

Secondary acidic sodium phosphate - 0,269, pH 7

Distilled water - D. K. 100

Example 7

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 30

Sucrose - 10

Lycasin(multicopy syrup) - 30

Lecithin - 0,1

The grape flavor - 1,0

The anise flavor - 0,01

Magnasweet- 0,2

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,142

Secondary acidic sodium phosphate - 0,438, pH 6

Distilled water - D. K. 100

Example 8

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - ü - 0,1

Sorbitol 70% solution - 30

Lycasin(multicopy syrup) - 10

Aspartame - 0,5

Lecithin - 0,1

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,0217

Secondary acidic sodium phosphate - 0,269, pH 7

Distilled water - D. K. 100

Example 9

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 30

Sucrose - 10

Lycasin(multicopy syrup) - 30

Lecithin - 0,1

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90:10) - 0,005

Buffer:

Citric acid - 0,136

Secondary acidic sodium phosphate - 0,192, pH 5

Distilled water - D. K. 100

Example 10

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

The hypromellose - 1

Microcrystalline cellulose - 0,25

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Lecithin - 0,1

The grape flavor - 1,0
R>Buffer:

Citric acid - 0,0217

Secondary acidic sodium phosphate - 0,192, pH 7

Distilled water - D. K. 100

Example 11

Ingredient, % (mass/vol.):

Mofetil of mycophenolate - 20

Microcrystalline cellulose - 0,2

Xanthan gum - a 0.1

Sorbitol 70% solution - 50

Sucrose - 10

Lycasin(multicopy syrup) - 10

Soy lecithin - 0,1

Citric acid - 0,06

Secondary acidic sodium phosphate (pH 7) - 0,7

Methylparaben - 0,04-0,1

Flavor - <0,3
Distilled water - D. K. 100

Example 12

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient, mg:

Mofetil of mycophenolate - 3000

The sodium carboxymethyl cellulose - 300

Sorbitol powder - 3000

Xylitol - 2000

▫ Maltitol - 2000

Pluronic F68 - 60

Flavor mint - 150

FD&C green 3 - 0,1

The above ingredients are combined and stirred to obtain a homogeneous mixture, adding an adequate amount of distilled water to obtain the desired granule size. The mixture granularit and then dried, obtaining anhydrous granules, suitable for Idaho shaking before the formation of the suspension, containing 3.0 g of mofetil of mycophenolate in 15 ml.

Example 13

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient, mg:

Mofetil of mycophenolate - 2000

The sodium carboxymethyl cellulose - 200

Mannitol - 4000

Aspartame - 35

Pluronic F68 - 40

The cherry flavor - 100

FD&C red 40 - 0,1

FD&C blue 1 - 0,01

Example 14

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient, mg:

Mofetil of mycophenolate - 2000

The sodium carboxymethyl cellulose - 200

Sorbitol powder - 10000

Pluronic F68 - 40

The cherry flavor - 100

FD&C red 40 - 0,1

FD&C blue 1 - 0,01

Example 15

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient, mg:

Mofetil of mycophenolate - 2000

The sodium carboxymethyl cellulose - 200

Mannitol - 4000

Aspartame - 35

Potassium sorbate - 5

Pluronic F68 - 40

The cherry flavor - 100

FD&C red 40 - 0,1

FD&C blue 1 - 0,01

Example 16

This example presents the composition of anhydrous granular compositions according to the invention.


Soy lecithin - 15

Sorbitol - 8250

Aspartame - 7,5

Methylparaben sodium - 30

The berry flavor - 45

Lake, FD&C red N3 - 0,45

Lake, FD&C blue No. 1 - 0,09

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 15 ml.

Example 17

Ingredient, mg:

Mofetil of mycophenolate - 3000

Xanthan gum - 15

Colloidal silicon dioxide - 75

Soy lecithin - 15

Sorbitol - 4500

Aspartame - 15

Citric acid is 67.5

Sodium citrate - 150

Methylparaben sodium - 30

The berry flavor - 45

Lake, FD&C red N3 - 0,45

Lake, FD&C blue No. 1 - 0,09

This composition is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 15 ml.

Example 18

Ingredient, mg:

Mofetil of mycophenolate - 3000

Xanthan gum - 15

Colloidal silicon dioxide - 75

Soy lecithin - 15

Sorbitol - 8250

Aspartame - 7,5

Citric acid is 7.5

Sodium citrate - 150

Methylparaben sodium - 34,5

Flavor mixed-fro in the container with the label, to which it should be filled with distilled water to obtain the given final volume of 15 ml.

Example 19

Ingredient, mg:

Mofetil of mycophenolate - 2000

The sodium carboxymethyl cellulose - 200

Mannitol - 4000

Aspartame - 35

Potassium sorbate - 5

Pluronic F68 - 40

The cherry flavor - 100

FD&C red 40 - 0,1

FD&C blue 1 - 0,01

Example 20

This example presents anhydrous granular composition according to the invention is stored in the container with the label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

Ingredient, mg:

Mofetil of mycophenolate - 90000

The sodium carboxymethyl cellulose - 9000

Mannitol - 180000

Aspartame - 1575

Pluronic F68 - 1800

Potassium sorbate - 225

The cherry flavor - 4500

Dye (red 40 blue 1, 90:10) to 4.5

Example 21

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient mg/ml*:

Mofetil of mycophenolate - 200,0

Xanthan gum - 1,0

Colloidal silicon dioxide - 5,0

Soy lecithin - 1,0

Sorbitol - 300,0

Aspartame - 1,0

Lemon kislota red N3 - 0,034

Lake, FD&C blue No. 1 - 0,006

(*concentration after contact with water)

To obtain anhydrous granular composition mofetil of mycophenolate, sorbitol, aspartame, soy lecithin and xanthan gum were mixed in the mixer for 5 minutes. The dye was dissolved with sodium citrate and citric acid in distilled water at a temperature of approximately 45-55oC. Then the solution was cooled to room temperature. This solution containing the dye/buffer, was added with stirring to a mixture of mofetil of mycophenolate in a chilled tank mixer with a speed approximately equal to 60 ml/min When the temperature of the particle size distribution exceeded the 30oC, the stirring was stopped and granulometric composition was allowed to cool to 20 to 24oC. once the temperature of the particle size distribution was achieved 20-24oC, it was additionally stirred for 2 to 8 minutes and then dried. If necessary, granulometric composition was ground to reduce the particle size. Then using a stir bar was added colloidal silicon dioxide, flavor and methylparaben sodium.

Example 22

This example presents SOS is mycophenolate - 200,0

Xanthan gum - 1,5

Colloidal silicon dioxide - 10,0

Soy lecithin - 2,0

Aspartame - 2,0

Citric acid - 0.5

Sodium citrate - 10,0

Methylparaben sodium - 1,0

The flavor of orange - 1,0

Dye (FD&C yellow N6) - 0,1

(*concentration after contact with water)

Example 23

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient mg/ml*:

Mofetil of mycophenolate - 200,0

Xanthan gum - 1,0

Colloidal silicon dioxide - 5,0

Soy lecithin - 1,0

Sorbitol - 550,0

Aspartame - 0,5

Methylparaben sodium - 2,0

The berry flavor - 3,0

Lake, FD&C red N6 - 0,034

Lake, FD&C blue No. 1 - 0,006

(*concentration after contact with water)

Example 24

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient mg/ml*:

Mofetil of mycophenolate - 200,0

Xanthan gum - 1,5

Colloidal silicon dioxide - 10,0

Soy lecithin - 2,0

Aspartame - 2,0

Methylparaben sodium - 2,3

Flavor mixed-fruit - 2,0

Lake, FD&C crasr 25

This example presents the composition of anhydrous granular compositions according to the invention.

Ingredient mg/ml*:

Mofetil of mycophenolate - 200,0

Xanthan gum - 1,0

Colloidal silicon dioxide - 5,0

Soy lecithin - 1,0

Sorbitol - 550,0

Aspartame - 0,5

Citric acid - 0.5

Sodium citrate - 10,0

Methylparaben sodium - 2,3

Flavor mixed-fruit - 2,0

Lake, FD&C red N3 - 0,0062

Lake, FD&C yellow N6 - 0,0015

(*concentration after contact with water)

Examples 26-50

In accordance with the methods described in examples 1-25, and replacing mofetil of mycophenolate mycophenolic acid, get the appropriate suspension and anhydrous granules.

Although the present invention has been described with reference to specific examples of its implementation, to a person skilled in the art it is obvious that can be done various changes and replaced by equivalents without deviating from the scope of the present invention. In addition, can be made numerous modifications to adapt a particular situation, material, composition of matter, process, stage or stages of the process to the object and the amount of NaF claims. All the above patents and publications is incorporated into this description by reference.

1. Pharmaceutical composition in the form of liquid suspensions suitable for oral administration, comprising mofetil of mycophenolate or mikofenolna acid, characterized in that it further comprises suspendisse and/or increase the viscosity of the agent, sweetening agents, flavouring, buffered to pH 5.0 - 7.0 and distilled water in the following ratio of components, % (wt./about):

Mofetil of mycophenolate or mycophenolate or mycophenolate acid - 7,5 - 30,0

Suspendisse and/or increase the viscosity of the agent - 0,1 - 3,0

Sweeteners - 30,0 - 70,0

Flavor - 0,1 - 2,0

The buffer to pH 5.0 - 7.0 - 0.5 to 1.5

Distilled water Up to 100

2. The pharmaceutical composition under item 1, characterized in that the fact that it additionally contains a wetting agent in an amount of not more than 0.5% (wt./about).

3. The pharmaceutical composition under item 1 or 2, characterized in that it further comprises an intensifier of taste and flavor or substance, damper bitterness, in the amount of not more than 1.0% (wt./vol.).

4. The pharmaceutical composition according to paragraphs.1 to 3, characterized in that it DOPOLNITEL on PP.1 - 4, characterized in that it further contains a colorant in an amount of not more than 0.01% (wt./vol.).

6. The pharmaceutical composition under item 1, characterized in that it has the following composition, % (wt./vol.):

Mofetil of mycophenolate - 20,0

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

Sorbitol 70% solution - 30 - 50

Lycasin(multicopy syrup) - 10 - 30

Sucrose - 0 - 10

Fructose - 0 - 10

Aspartame - 0 - 0,5

Lecithin - 0 - 0,1

Citric acid - 0,02 - 0,25

Secondary acidic sodium phosphate - 0,19 - 0,67

Methylparaben - 0 - 0,18

Propylparaben - 0 - 0,02

Flavor - 0,3 - 1,0

Magnasweet(monomineralic glycerin) - 0 - 1

Dye - 0,005

Distilled water Up to 100

7. The pharmaceutical composition under item 1, characterized in that it contains 20% (wt./about) mofetil of mycophenolate.

8. The pharmaceutical composition under item 1, characterized in that it has the following composition, % (wt./vol.):

Mofetil of mycophenolate - 20,0

Microcrystalline cellulose - 0,2

Xanthan gum - a 0.1

Sorbitol 70% solution - 30 - 50

Lycasin(multicopy syrup) - 10 - 30

Saha is origny acid phosphate sodium 0,19 - 0,8

Methylparaben sodium - 0 - 0,18

Propylparaben - 0 - 0,02

Flavor - 0,1 - 1,0

Magnasweet(monomineralic glycerin) - 0 - 1

Dye - 0,005

Distilled water Up to 100

9. The pharmaceutical composition according to p. 8, characterized in that it has the following composition, % (wt./vol.):

Mofetil of mycophenolate - 20,0

Microcrystalline cellulose - 0,2

Xanthan gum - a 0.1

Sorbitol 70% solution - 50

Lycasin(multicopy syrup) - 10

Sucrose - 10

Soy lecithin - 0,1

Citric acid - 0,06

Secondary acidic sodium phosphate - 0,7

Methylparaben sodium - 0.04

Flavor - <0,3
Distilled water Up to 100

10. Anhydrous granulated pharmaceutical composition, characterized in that it contains the ingredients in the following weight ratio:

Mofetil of mycophenolate or mycophenolate acid - 75 - 300

Suspendisse/increase the viscosity of the agent is 1 - 30

Sweeteners - 1 - 1200

The flavor of 0.1 - 100

and after adding water suitable for suspension for oral administration.

11. The pharmaceutical composition according to p. 10, characterized in that it zizia under item 10 or 11, characterized in that it further comprises an intensifier of taste and flavor or substance, damper bitterness, in an amount not more than 50 weight. h

13. The pharmaceutical composition according to paragraphs.10 to 12, characterized in that it further comprises an antimicrobial agent in an amount of not more than 10 weight. h

14. The pharmaceutical composition according to paragraphs.10 to 13, characterized in that it further contains a colorant in an amount of not more than 3 weight. h

15. The pharmaceutical composition according to paragraphs.10 to 14, characterized in that it further comprises a buffer.

16. The pharmaceutical composition according to p. 10, characterized in that it contains 200 mg/ml mofetil of mycophenolate.

17. The pharmaceutical composition according to paragraphs.10 to 13, characterized in that it contains the ingredients in the following weight ratio:

Mofetil of mycophenolate - 200

The sodium carboxymethyl cellulose - 20

Mannitol - 400

Aspartame - 3,5

Pluronic F68 - 4

Potassium sorbate - 0,5

The cherry flavor - 10

Dye (red 40 blue 1, 90 : 10) - 0,01

18. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that it contains the ingredients in the following weight ratio:

Mofetil of mycophenolate - 200

Xantana aritin - 1 - 2

Methylparaben sodium - 0,5 - 2,5

Flavouring - 1 - 3

Dye (corresponding to the flavor) - 1 - 3

19. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that it has the following composition under the following component content (mg):

Mofetil of mycophenolate - 90000

The sodium carboxymethyl cellulose - 9000

Mannitol - 180000

Aspartame - 1575

Pluronic F68 - 1800

Potassium sorbate - 225

The cherry flavor - 4500

Dye (red 28 : blue 1, 90 : 10) to 4.5

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

20. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that it has the following composition, with the following content of components, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 450

Colloidal silicon dioxide - 2250

Soy lecithin - 450

Sorbitol - 247500

Aspartame - 225

Methylparaben sodium - 900

The berry flavor - 1350

Lake, FD&C red N3 - 13,5

Lake, FD&C blue No. 1 - 2,7

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 is blowing component, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 450

Colloidal silicon dioxide - 2250

Soy lecithin - 450

Sorbitol - 135000

Aspartame - 450

Citric acid - 225

Sodium citrate - 4500

Methylparaben sodium - 900

The berry flavor - 1350

Lake, FD&C red N3 - 13,5

Lake, FD&C blue No. 1 - 2,7

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

22. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that it has the following composition, with the following content of components, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 675

Colloidal silicon dioxide - 4500

Soy lecithin - 900

Aspartame - 900

Methylparaben sodium - 1035

Flavor mixed-fruit - 900

Lake, FD&C red N3 - 3,6

Lake, FD&C blue N6 - 0,9

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

23. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that it has the following composition in the following compound is R> Soy lecithin - 450

Sorbitol - 247500

Aspartame - 225

Citric acid - 225

Sodium citrate - 4500

Methylparaben sodium - 1035

Flavor mixed-fruit - 900

Lake, FD&C red N3 - 2,79

Lake, FD&C yellow N6 - 0,675

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

24. The pharmaceutical composition according to paragraphs.10 to 16, characterized in that having the following composition in the following ratio of components, mg:

Mofetil of mycophenolate - 90000

Xanthan gum - 675

Colloidal silicon dioxide - 4500

Soy lecithin - 900

Aspartame - 900

Citric acid - 225

Sodium citrate - 4500

Methylparaben sodium - 450

The flavor of orange - 450

Lake, FD&C yellow N6 - 45

and stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume of 450 ml

25. The pharmaceutical composition according to p. 10, characterized in that it is stored in a container with a label, to which it should be filled with distilled water to obtain the given final volume.

26. Paraphenalia, characterized in that it has the following composition, % (wt./about):

Mofetil of mycophenolate - 20

The hypromellose - 0,25

Microcrystalline cellulose - 0,25

Xanthan gum - a 0.1

The solution of sorbitol - 50

Sucrose - 10

Lycasin- 10

Lecithin - 0,1

Methylparaben - being 0.036

Propylparaben - 0,004

The grape flavor - 1,0

The anise flavor - 0,01

Dye (red 28 : blue 1, 90 : 10) - 0,005

Citric acid - 0,0542

Secondary acidic sodium phosphate - 0,673

Distilled water up to 100

and is brought to a pH of 7.

27. Pharmaceutical composition in the form of liquid suspensions suitable for oral administration, comprising mofetil of mycophenolate, characterized in that it has the following composition, % (wt./vol.):

Mofetil of mycophenolate - 20

Microcrystalline cellulose - 0,2

Xanthan gum - a 0.1

The solution of sorbitol - 50

Lycasin- 10

Sucrose - 10

Lecithin - 0,1

Citric acid - 0,06

Secondary acidic sodium phosphate - 0,7

Methylparaben sodium - 0.04

Flavor - <0,3
Distilled water Up to 100
oC) then adding suspendida and/or increase the viscosity agents (preferably microcrystalline cellulose, and then xanthan gum); (b) dissolving under stirring buffer(a)s (preferably citric acid, and then the secondary acid phosphate) followed by the addition, sweeteners(in), flavoring, optional wetting agent, intensifier of taste and fragrance and/or dye; and (C) adding the active substance (mofetil of mycophenolate or mycophenolate acid) to the mixture obtained in stage (b), with subsequent mixing of the fluid to the formation of the suspension.

29. The method of obtaining anhydrous granular composition according to PP.10 - 15, including: a) mixing mofetil of mycophenolate, sweeteners (b) suspending and/or increase the viscosity agent and optionally a wetting agent(s) in the mixer; b) dissolving the dye or buffer(s) if any, in the water;

C) the mixture obtained in stage (b) solution obtained in stage (a) the contents of the tank mixer and mixing to obtain the desired granule size; d) drying Gran is youseo and/or increase the viscosity of the agent, flavoring or antimicrobial agent to the granules obtained in stage (d).

30. The pharmaceutical composition under item 1, characterized in that it has an immunosuppressive, anti-inflammatory, antitumor, antiviral, protivopolozhnym protivoprotosanam action.

31. Pharmaceutical composition in the form of anhydrous granular composition according to p. 10, characterized in that it has an immunosuppressive, anti-inflammatory, antitumor, antiviral, protectorates, protivoprolezhnevyy action.

 

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The invention relates to medicine, in particular to the emulsion on the basis of propolis
Propolis emulsion // 2145844
The invention relates to medicine, in particular to the emulsion on the basis of propolis

The invention relates to medicine and biotechnology and relates to a new method of obtaining spherical particles based on one or more active principles
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