Self emulsifiable composition for lipophilic compounds

 

The invention relates to medicine, namely to pharmaceutical compositions based on oil phase, which comprises a pharmaceutically active agent connection pianola, which is the inhibitor of retroviral protease, a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 (diglyceride:monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of 16-22 carbon atoms, one or more pharmaceutically acceptable solvents and one or more pharmaceutically acceptable surfactants. This composition is in the form of a self emulsifiable composition, which provides a high concentration and high oral availability for lipophilic compounds piranha. 4 C. and 31 C.p. f-crystals, 3 tables.

The invention relates to new pharmaceutical compositions in the form of savemarriage compositions that provide a high concentration and a high oral bioavailability of the compounds of piranha, which are inhibitors of retroviral protease.

Recently it was discovered that some of the infected with the human immunodeficiency virus (HIV), which leads to acquired immunodeficiency syndrome (AIDS). In particular, it was found that the combination of piranha formula I is particularly effective as retroviral protease inhibitor.

However, like many other HIV protease inhibitors, these compounds are typically lipophilic and, therefore, poorly soluble in water. For example, the compound of formula I has a solubility of approximately 1 μg/ml in a buffer with a pH of 6.5 (close to the pH of the intestine), which is considered extremely low solubility in water and, as you would expect, gives a very low oral bioavailability in the form of the free acid. It is well known that the active drug ingredient or therapeutic component, the input in any way, must have some solubility for the system suction and therapeutic response. Poorly water-soluble compounds are often incomplete or unstable absorption and, consequently, produce a minimal response at the desired dose.

Efforts were made to identify the salts of the compounds of piranha in solid form, which could improve soluble and in salt form are prone to the deposition source of the free acid in the gastrointestinal tract and, therefore, incapable of providing the dose to the desired high concentration to create easy to use and at the same time meet the required criteria in terms of bioavailability.

Recognizing these problems, this invention is directed to pharmaceutical compositions in the form of a self emulsifiable compositions that provide a high concentration and a high oral bioavailability of the compounds of piranha. In particular, it was found that the compositions of the present invention allows to prepare self emulsifiable compositions containing personaly inhibitor of retroviral protease in very high concentrations up to approximately 400 mg/g, in order to allow oral administration, obespechiva at the same time achieving improved bioavailability that is at least twice higher than the bioavailability of a water suspension of the free acid.

In International publication WO 95/30670 described connection of piranha applicable for the treatment of retroviral infections.

In International publication WO 96/39142 described compositions that increase the bioavailability of protease inhibitors.

In a Patent application in the UK the DMA microemulsions.

In the Patent application great Britain GB 2228198 As described pharmaceutical compositions containing cyclosporin as an active ingredient, triglyceride fatty acids, partial esters of glycerin and fatty acids or the full or partial ester of propylene glycol or sorbitol, and a surfactant having L (hydrophilic-lipophilic balance) of at least 10.

In the United Kingdom Patent GB 2257359 In the described pharmaceutical compositions suitable for oral administration, containing cyclosporine, 1,2-propylene glycol, mixed mono-, di - and triglyceride and hydrophilic surfactant.

In U.S. Patent 4230702 described are readily absorbed in the small intestine pharmaceutical composition of pharmacologically active agents, which per se are poorly absorbed in the small intestine.

One purpose of this invention is to provide pharmaceutical compositions containing a compound of piranha formulas I, II, III or IV, which has a high oral bioavailability.

Another purpose of this invention is to provide pharmaceutical compositions containing high drug load connection piranha formulas I, II, III and IV for convenient the s exhibit adequate physical and chemical stability in self emulsifiable compositions.

Another purpose of this invention is to provide a liquid composition for soft elastic capsules.

The objectives of this invention have been achieved due to the fact that this invention provides pharmaceutical compositions in the form of a self emulsifiable compositions which provide high load connections of pyranone (up to approximately 400 mg/g) while maintaining the good oral bioavailability.

This invention specifically provides a pharmaceutical composition based on the application of certain oil phase containing: (a) connection of piranha formula I, II, III or IV, (b) a mixture of diglyceride and monoglyceride in the ratio from about 9:1 to about 6: 4 by weight (diglyceride:monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of sixteen to twenty-two carbon atoms; (c) one or more pharmaceutically acceptable solvent and (a) one or more pharmaceutically acceptable surfactants.

In accordance with this invention describes pharmaceutical compositions containing the compound of pyranone as pharmaceutically active is Nona" refers to the compounds of formula IIwhere R1denotes H; R2stands With3-C5-alkyl, phenyl-(CH2)2-, het-SO2NH-(CH2), cyclopropyl-(CH2)2- F-phenyl-(CH2)2-, het-SO2NH-phenyl or F3C-(CH2)2-; or R1and R2taken together, signify a double bond; R3denotes the R4-(CH2)n-CH(R5), H3C-[O (CH2)2]2-CH2- With3-C5-alkyl, phenyl-(CH2)2-, het-SO2NH-(CH2)2-, (HOCH2)3C-NH-C(O)-NH-(CH2)3-, (HO2C)(H2N)CH-(CH2)2-C (O)-NH- (CH2)3- piperazine-1-yl-C (O)-NH-(CH2)3BUT3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-(CH2)3- cyclopropyl-(CH2)2- F-phenyl-(CH2)2-, het-SO2NH-phenyl or F3C-(CH2)2-; n = 0, 1, or 2; R4denotes phenyl, het, cyclopropyl, N3C-[O(CH2)2]2-, het-SO2NH-, Br-, N3or BUT3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-; R5denotes CH2-CH3or-CH2-cyclopropyl; R6denotes cyclopropyl, CH3-CH2- or tert-butyl; R7b>2is phenyl, optionally substituted by R9or-CH2-SO2-het; R8denotes-H or-CH3; R9represents-CN, -F, -HE or-NO2; where het denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle, optionally substituted-CH3, -CN, -OH, -S(O)OS2H5, -CF3, -NH2or-C(O)-NH2or their pharmaceutically acceptable salt. The preferred compound of formula II is a compound of formula I.

The term "compounds of piranha" relates also to compounds of formula III and formula IV

where R10denotes N, CH3O - or CH3O-[ (CH2)2Oh]3-; R11denotes cyclopropyl or-CH2-CH(CHC)2; R12refers to-NR14SO2is phenyl, optionally substituted by R15, -NRl4SO2-het, -CH2-SO2is phenyl, optionally substituted by R15or-CH2-SO2 14 denotes-H or-CH3; R15represents-CN, -F, -CH3, -COOH or-HE; het denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and includes any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle, optionally substituted with one or two-CH3, -CN, -C(O)-OC2H5or is HE; or their pharmaceutically acceptable salts.

These compounds inhibit retroviral protease and, consequently, inhibit viral replication. They are applicable for the treatment of patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or the virus T-cell human leukemia (HTLV-I or HTLV-II), which causes acquired immunodeficiency syndrome (AIDS) and/or related diseases. Compounds of formulas I, II, III or IV described and claimed in the International application PCT/US 95/05219, incorporated herein by reference, and can be obtained in accordance with the procedures described in International publication WO 95/30670. In particular, it was found that the combination of palaemonidae composition", in the application here, relates to concentrated compositions, capable of generating emulsion or microemulsion when mixed with a sufficient quantity of the water environment.

Emulsions or micro-emulsions obtained according to this invention, are common solutions containing hydrophilic phase and a lipophilic phase. Microemulsions are characterized by their thermodynamic stability, optical transparency and low average size of the droplets, typically less than about 0.15 microns.

The term "media self emulsifiable composition" refers to compositions containing a mixture of diglyceride and monoglyceride in the ratio from about 9:1 to about 6: 4 by weight (diglyceride:monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of sixteen to twenty two carbon atoms, one or more pharmaceutically acceptable solvents and one or more pharmaceutically acceptable surfactants. Optionally, the media self emulsifiable compositions can optionally contain a primary amine.

Diglycerin the present invention refers to an ester of fatty acid and glycerol, with the article is), where R denotes a monounsaturated or dimensional alkyl group having fifteen to twenty-one carbon atom. The preferred diglycerides is diolein (R is monounsaturated alkyl group with seventeen carbon atoms), dionaea (R is dimensional alkyl group with seventeen carbon atoms), or a mixture of diolein and delineat. The most preferred diglycerides is diolein.

A monoglyceride of this invention is the ester of fatty acid and glycerol having the structural formula of NON2-CH(OH)-CH2(O2CR) or HOCH2-CH(O2CR)-CH2HE, where R denotes a monounsaturated or dimensional alkyl group having fifteen to twenty-one carbon atom. The preferred monoglyceride is monooleyl (R is monounsaturated alkyl group with seventeen carbon atoms), monolinoleate (R is dimensional alkyl group with seventeen carbon atoms), or a mixture of monoline and monolinoleate. The most preferred monoglyceride is monooleyl.

A mixture of diglyceride and monoglyceride can be prepared by mixing the individual diglyceride and monoglyceride s, the diglycerides with glycerin.

All of the glycerides of the present invention are known and can be obtained by conventional methods.

The amount of active ingredient in the composition may vary or be adjusted depending on the intended route of administration, the activity of the specific active ingredient, the severity of retroviral infection and required concentration. However, if desirable, the connection of pyranone as retroviral protease inhibitor may be present in the media self emulsifiable compositions of this invention in an amount up to about 400 mg/g with excellent despergiruemaya and high oral availability in vivo, usually reaching 70-84% for rats.

Compositions of the present invention with high oral availability (84% in rats) show almost transparent or translucent solution when diluted with water, which indicates that the formed microemulsion.

Compositions of the present invention with a moderately high bioavailability (60-70% for rats) usually detect visually fine-grained white emulsion without deposition of the drug on dilution with water, which indicates that the emulsion is formed. on the use of a particular oil phase, which includes:
(a) connection of piranha formulas I, II, III or IV as a pharmaceutically active agent,
(b) a mixture of diglyceride and monoglyceride in the ratio from about 9:1 to about 6:4 by weight (diglyceride:monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of sixteen to twenty two carbon atom,
(c) one or more pharmaceutically acceptable solvents and
(d) one or more pharmaceutically acceptable surfactants.

In addition, the composition may further comprise pharmaceutically acceptable primary amine.

The term "pharmaceutically acceptable" as applied here refers to those properties that are biologically compatible with the treated subjects with pharmacological and Toxicological point of view.

The solvents of this invention include propylene glycol, polypropyleneglycol, polyethylene glycol (such as PAGOO, 400, 600 and so on), glycerin, ethanol, triacetin, dimetridazole, glycoluril, propylenecarbonate, water, dimethylacetamide or a mixture thereof.

The preferred solvent is propylene glycol or a mixture, with ical is in the amount from about 50% to about 95%.

Surfactants of this invention referred to as nonionic surfactants, including hydrogenated castor oil Polyoxyl 40, sold under the trade name, among others, Cremophor RH40; castor oil Polyoxyl 35, sold under the trade name, among others, Cremophor EL or Cremophor EL-P; Polysorbate; Solutol HS-15; Tagat TO; Pallikal 6-oleate; polyoxyethylene, saturated poliglecaprone glycerides or poloxamer; all of them are commercially available. Preferred surface-active substance is Cremophor RH40 go Creinophor EL.

Saturated poliglecaprone glycerides in use here include Gelucir 44/14 or Gelucire 50/13.

Polyoxyethylenated in use here include Polyoxyl 6-stearate, Polyoxyl 8-stearate, Polyoxyl 12-stearate and Polyoxyl 20-stearate.

Poloxamer, in the application here, include Poloxamer 124 Poloxamer 188.

Polysorbate in use here include Polysorbate 20, Polysorbate 40, Polysorbate 60 and Polysorbate 80.

The term "primary amine", in the application here, indicates the lowest bonds alkylamines, such as, for example, ethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, Tris(hydroxymethyl)aminomethan, for example, arginine, lysine, or guanidine. Preferred lower Alluminum is dimethylaminoethanol or Tris(hydroxymethyl)aminomethan.

A typical composition of this invention contains:
(a) connection of piranha formulas I, II, III or IV in an amount of from about 1% to about 40% by weight of the total composition,
(b) a mixture of diglyceride and monoglyceride in the ratio from about 9:1 to about 6:4 by weight (diglyceride:monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of sixteen to twenty two carbon atoms in an amount of from about 5% to about 35% by weight of the total composition,
(c) one or more pharmaceutically acceptable solvents in an amount of from about 10% to about 30% by weight of the total composition, and
(d) a pharmaceutically acceptable surfactant in an amount of from about 10% to about 50% by weight of the total composition.

Optional above-mentioned composition further comprises a primary amine in an amount of from about 0.1% to 10% by weight of the total composition.

The preferred composition of this invention contains:
(a) connection of piranha formulas I, II, III or IV in an amount of from about 20% to about 30% by weight of the total cat about 5% to about 20% by weight of the total composition,
(c) a solvent containing propylene glycol or a mixture of propylene glycol and ethanol in an amount of from about 15% to about 25% by weight of the total composition, and
(d) a surfactant containing Cremophor RH40 or remophor EL in the amount from about 30% to about 45% by weight of the total composition.

Another preferred composition of this invention contains:
(a) connection of piranha formulas I, II, III or IV in an amount of from about 20% to about 30% by weight of the total composition,
(b) a mixture of diolein and monoline a ratio of about 8: 2 by weight (diolein: monaleen) in an amount of from about 5% to about 20% by weight of the total composition,
(c) a solvent containing propylene glycol or a mixture of propylene glycol and ethanol in an amount of from about 15% to about 25% by weight of the total composition, and
(d) a surfactant containing Cremophor RH40 or Cremophor EL in the amount from about 30% to about 45% by weight of the total composition.

Optional preferred composition may further contain a basic amine in an amount of from about 0.1% to about 7% by weight of the total composition.

In the preferred compositions of this invention even more preferred composition contains a compound of piranha formula I in an amount of from about 20% to the eye of the I and ethanol is in the ratio of about 1:1.

In the preferred compositions of this invention even more preferred composition comprises Tris(hydroxymethyl)aminomethan or dimethylaminoethanol in the amount of from about 0.1% to 7% by weight of the total composition.

In the preferred compositions of this invention even more preferred composition comprises a mixture of diolein and monoline a ratio of about 8:2 by weight.

In particular, the most preferred composition of this invention contains a compound of piranha formula I.

The composition of this invention may be in the form of a liquid to a soft elastic capsules or hard gelatin capsules for oral administration. The composition may also be in the form of a liquid solution for oral, parenteral, rectal or topical application. The preferred dosage form is a liquid to a soft elastic capsules.

If desirable, the compositions of this invention may further contain conventional pharmaceutical additives, such as agents, co-surfactant (e.g. sodium dodecyl sulfate), coloring agents, improves the taste and odor agents, fragrances, preserving agents, Stabi in a conventional manner, for example, by dissolving the active agent in the solvent, then adding the oil phase, surfactant and optionally a primary amine. Then the resulting solution is prepared in the form of the desired dosage form such as, for example, soft elastic capsules or hard gelatin capsules using known techniques of cooking.

The pharmaceutical compositions of the present invention will be better understood in connection with the following examples, which are intended to illustrate and not to limit the scope of the present invention. Without additional development, the inventors believe that the person skilled in the art can, using the preceding description and the information provided below in the examples to practice the invention in its most complete form.

A. General procedure for preparation of compositions of this invention
The drug is placed in the container. Add solvent containing propylene glycol, or a mixture of solvents selected from ethanol (95%) and propylene glycol (1:1 by weight), and tighten the cover. The container is placed in a water bath at approximately 60oWith and shake gently to dissolve dobavlaut appropriate amount of the mixture of diglyceride (such as diolein) and monoglyceride (such as monaleen), surfactants (such as Cremophor RH40 or Cremophor EL) and optionally a primary amine, such as ethanolamine or diethanolamine). The container is sealed and placed in a water bath at approximately 60oWith and shake gently until a clear solution is formed. The container is usually left in ambient conditions until further use. Examples of compositions are given in the end of the description.

C. Test oral bioavailability
(i) Male rats Sprague-Dawley chose to study oral availability in vivo. Each rat was preparing hirurgicheskoi implantation of a permanent catheter in the upper Vena cava. Each rat weight in the range of 300-400 g, were subjected to fasting overnight prior to dosing. Each composition is administered orally to a group of rats (n=3) at a dose of 20 mg/kg of the Composition with a high concentration of the compounds of formula I (usually 200-300 mg/ml) was diluted 100 times with water and injected directly into the stomach of rats using oral gastric tube. Serial blood samples of 0.25 ml were taken from the permanent catheter through 0,25, 0,5, 1, 2, 4, 6, 8, 12 and 24 h after dosing. These blood samples were analyzed using WAS the rats were put on a schedule depending on the time after injection drugs intravenous (i.v.) or through the mouth and AUC (area under the curve plasma concentration against time) was integrated using the trapezoid rule to calculate absolute bioavailability, shown in the table.1.


(ii) Male Beagle dogs were also chosen for the study oral bioavailability in vivo. Each dog, weighing in the range of 13.5-17.5 kg were subjected to starvation before dosed. Each composition is administered orally to a group of dogs (n=4) at a dose of 20 mg/kg of the Composition of the high concentration of the compounds of formula I (300 mg/d) was encapsulated in gelatin capsules and introduced. Serial blood samples of 2 ml were taken from the jugular vein in 20, 40 min and 1, 2, 4, 6, 8, 12 and 24 h after dosing. These blood samples were analyzed using HPLC analysis, specific compounds of formula I. the concentration of the compounds of formula I in the blood of the tested dogs were put on a schedule based on time and received AUC for calculation of absolute bioavailability. The results are shown in table.2.

(iii) Ten healthy volunteers were administered orally eightfold 150 mg (single dose 1200 mg), disodium salt of compounds of formula I, encapsulating in hard gelatin capsules in the background. Weeks later, the same group oral was administered four times 300 mg (single dose 1,200 mg) of the compounds of formula I in the composition shown in Example 15. Serial blood samples of dobrovolcev took over 30 mdla the compounds of formula I. The concentration of the compounds of formula I in the blood was put on the schedule based on time and received AUC for the calculation of relative bioavailability. The results are shown in table.3.

Relative bioavailability = (AUC)test/(AUC)von100%
This invention provides the desired results, as shown increased absolute or relative oral bioavailability in table.1, 2 and 3.


Claims

1. Pharmaceutical composition comprising (a) compound of piranha formula II

as a pharmaceutically active agent, (b) a mixture of diglyceride and monoglyceride in the ratio from about 9: 1 to about 6: 4 by weight (diglyceride: monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of 16-22 carbon atoms, (c) one or more pharmaceutically acceptable solvents, and (d) one or more pharmaceutically acceptable surfactants,
where R 'N';
R2- C3-C5-alkyl, phenyl-(CH2)2-, het-SO2NH-(CH2)2- cyclopropyl-(CH2)2- F-phenyl-(CH2)2R3- R4-(CH2)n-CH(R5), H3C-[O(CH2)2]2-CH2- With3-C5-alkyl, phenyl-(CH2)2-, het-SO2NH-(CH2)2-, (NON2)3C-NH-C(O)-NH-(CH2)3- BUT2(C)(H2N)CH-(CH2)2-C(O)-NH-(CH2)3- piperazine-1-yl-C(O)-NH-(CH2)3BUT3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-(CH2)3- cyclopropyl-(CH2)2- F-phenyl-(CH2)2-,
het-SO2NH-phenyl or F3C-(CH2)2-;
n = 0, 1, or 2;
R4- phenyl, het, cyclopropyl, H3C-[O(CH2)2]2-, het-SO2NH -, Br-, N3or BUT3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-;
R5- CH2-CH3or-CH2-cyclopropyl;
R6- cyclopropyl, CH3-CH2- or tert-butyl;
R7- -NR8-SO2-het, -NR8SO2is phenyl, optionally substituted by R9or-CH2-SO2is phenyl, optionally substituted by R9or-CH2-SO2-het;
R8Is-h or-CH3;
R9- -CN, -F, -HE or-NO2;
where het denotes a 5-, 6 - or 7-membered saturated or unsaturated ring, the Isla any bicyclic group, in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle, optionally substituted-CH3, -CN, -OH, -C(O)OS2H5, -CF3, -NH2or-C(O)-NH2-;
or its pharmaceutically acceptable salt.

2. The pharmaceutical composition under item 1, where the connection of piranha formula Il is a compound of formula I

3. Pharmaceutical composition comprising (a) compound of piranha formula III

or formula IV

as a pharmaceutically active agent,
(b) a mixture of diglyceride and monoglyceride in the ratio from about 9: 1 to about 6: 4 by weight (diglyceride: monoglyceride), where diglyceride and monoglyceride are esters of mono - or dimensioned fatty acids and glycerol having a chain length of 16-22 carbon atoms, (c) one or more pharmaceutically acceptable solvents, and (d) one or more pharmaceutically acceptable surfactants,
where R10- N-, CH3O - or-CH3O-[(CH2)2Oh]3-;
R11- cyclopropyl or-CH2-CH(CH3)2;
R12- -NR is obazatelno substituted R15or-CH2-SO2-het;
R13Is-h, - (CH2)2-CH3, -CH2-cyclopropyl or-CH2is phenyl;
R14- or-CH3;
R15- -CN, -F, -CH3, -COOH or-HE;
het denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle, optionally substituted with one or two-CH3, -CN, -C(O)-OS2H5or is IT,
or their pharmaceutically acceptable salt.

4. The pharmaceutical composition under item 1 or 3, in which the compound of formula II, III or IV is a number from about 1% to about 40% by weight of the total composition.

5. The pharmaceutical composition according to p. 2, in which the compound of formula I is in the amount from about 20% to about 30% by weight of the total composition.

6. The pharmaceutical composition under item 1 or 3, in which the above-mentioned diglyceride is diolein, delineat or their mixture.

7. The pharmaceutical composition under item 1 or 3, which enter the above monoglyceride is monooleyl, monolinoleate or their mixture.

9. The pharmaceutical composition under item 1 or 3, in which the above-mentioned monoglyceride is monooleyl.

10. The pharmaceutical composition under item 1 or 3, in which a mixture of diglyceride and monoglyceride is in an amount of from about 5% to about 35% by weight of the total composition.

11. The pharmaceutical composition under item 1 or 3, in which a mixture of diglyceride and monoglyceride is in an amount of from about 5% to about 20% by weight of the total composition.

12. The pharmaceutical composition under item 1 or 3, in which a mixture of diglyceride and monoglyceride is in a ratio of about 8: 2 by weight (diglyceride: monoglyceride) and in the amount of from about 5% to about 35% by weight of the total composition.

13. The pharmaceutical composition under item 1 or 3, in which a mixture of diglyceride and monoglyceride is in a ratio of about 8: 2 by weight (diglyceride: monoglyceride) and in the amount of from about 5% to about 20% by weight of the total composition.

14. The pharmaceutical composition under item 1 or 3, in which a mixture of diglyceride and monoglyceride is in a ratio of about 9: 1 by weight (diglyceride: monoglyceride) and from the 3, where the pharmaceutically acceptable solvent is a propylene glycol, polypropyleneglycol, polyethylene glycol, glycerin, ethanol, triacetin, dimetridazole, glycoluril, propylene carbonate, water, dimethylacetamide or a mixture thereof.

16. The pharmaceutical composition under item 1 or 3, where the pharmaceutically acceptable solvent is a propylene glycol.

17. The pharmaceutical composition under item 1 or 3, where the pharmaceutically acceptable solvent is a mixture containing propylene glycol and 95% (V/V) ethanol in a 1: 1 ratio.

18. The pharmaceutical composition under item 1 or 3, where the pharmaceutically acceptable solvent is in an amount of from about 10% to about 30% by weight of the total composition.

19. The pharmaceutical composition under item 1 or 3, where the pharmaceutically acceptable solvent is in an amount of from about 15% to about 25% by weight of the total composition.

20. The pharmaceutical composition under item 1 or 3, where the pharmaceutically acceptable surfactant is a hydrogenated castor oil Polyoxyl 40, castor oil Polyoxyl 35, Solutol HS-15, Tagat TO, Pallikal 6-oleate, polyoxyethylene, poloxamer and 3, where the pharmaceutically acceptable surfactant is a hydrogenated castor oil Polyoxyl 40 or castor oil Polyoxyl 35.

22. The pharmaceutical composition according to p. 21, where it is hydrogenated castor oil Polyoxyl 40 is a Cremophor RH40.

23. The pharmaceutical composition according to p. 21, where it is hydrogenated castor oil Polyoxyl 35 is a Cremoophor EL or Cfemophor EL-p

24. The pharmaceutical composition under item 1 or 3, where the surfactant is in an amount of from about 10% to about 50% by weight of the total composition.

25. The pharmaceutical composition under item 1 or 3, where the surfactant is in an amount of from about 30% to about 45% by weight of the total composition.

26. The pharmaceutical composition under item 1 or 3, where the composition further comprises a primary amine.

27. Pharmaceutical composition for p. 26 where the primary amine is a lower alkylamine, basic amino acid or kolingerova.

28. The pharmaceutical composition according to p. 21, where the lowest alkylamine is an ethanolamine, diethanolamine, triethanolamine, Ethylenediamine, dimethylaminoethanol or Tris(HYDR is Oh arginine, lysine or guanidine.

30. Pharmaceutical composition for p. 26 where the primary amine is from about 0.1% to about 10% by weight of the total composition.

31. Pharmaceutical composition comprising (a) compound of piranha formula I in an amount of from about 20% to about 30% by weight of the total composition, (b) a mixture of diolein and monoline in a ratio of about 9: 1 by weight (diolein: monaleen) in an amount of from about 5% to about 20% by weight of the total composition; (c) a solvent containing propylene glycol or a mixture of propylene glycol and 95% (V/V) ethanol in a ratio of about 1: 1 and in an amount of from about 15% to about 25% by weight of the total composition, and (d) a surfactant containing remophor RH40 or Crmophor EL in the amount from about 30% to about 45% by weight of the total composition.

32. Pharmaceutical composition comprising (a) compound of piranha formula I in an amount of from about 20% to about 30% by weight of the total composition, (b) a mixture of diolein and monoline, in a ratio of about 8: 2 by weight (diolein: monaleen) in an amount of from about 5% to about 20% by weight of the total composition; (c) rastvoritele 1: 1 and in an amount of from about 15% to about 25% by weight of the total composition, and (d) a surfactant containing Cremophor RH40 or Cremophor EL in the amount from about 30% to about 45% by weight of the total composition.

33. The pharmaceutical composition under item 31 or 32, which further comprises dimethylaminoethanol or Tris(hydroxymethyl)aminomethan in the amount of from about 0.1 to 7% by weight of the total composition.

34. The pharmaceutical composition according to paragraphs. 1, 3, 31, or 32, which is a self emulsifiable composition, capable of forming the emulsion or microemulsion when mixed with a sufficient quantity of the water environment.

35. The pharmaceutical composition according to paragraphs. 1, 3, 32, or 33, which is in the form of a liquid to a soft elastic capsules.

 

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The invention relates to the field of pharmacology and concerns microdrops and pharmaceutical composition for injection

The invention relates to new pharmaceutical compositions comprising one or more local anesthetics in oil form, one or more surfactants, water and optional additives agents, taste masking, and also to a method of pain relief and to a method for producing pharmaceutical compositions

The invention relates to a composition for topical application in the form of an emulsion for the treatment of inflammatory and hyperproliferative diseases of the skin and cutaneous manifestations of immunologically mediated diseases

The invention relates to medicine, in particular to the microemulsion preconcentrate, including soluble active agent and a carrier, comprising: 1) a hydrophilic phase, which includes dimetridazole and/or lower alkylalkoxy ether, 2) a lipophilic phase, and 3) surfactant

The invention relates to medicine, in particular to drugs on the basis of finasteride, which is an inhibitor of 5-reductase

The invention relates to the preparation, for example, in the form of capsules, soft coated, containing as active ingredient cyclosporine
The invention relates to containing cyclosporine A liquid dosage forms for oral administration

The invention relates to an anti-inflammatory drug for external use, comprising as active ingredient nimesulide
The invention relates to medicine, in particular to pharmaceutical compositions for intramuscular injection
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