MXPA00006161A

MXPA00006161A - Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant

Info

Publication number: MXPA00006161A
Application number: MXPA/A/2000/006161A
Authority: MX
Inventors: Gabrielle Sjoquist
Original assignee: Astra Ab
Priority date: 1997-12-22
Filing date: 2000-06-21
Publication date: 2002-02-26

Abstract

The present invention relates to a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant. The invention further relates to a process for the preparation of the pharmaceutical composition and use of the pharmaceutical composition for the manufacture of a medicament for treating allergic and/or inflammatory diseases in the respiratory tract or for treating intestinal diseases and methods for treatment of the diseases in a mammal, including man.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING MICELLES COMPRISING A LIPOFILIC GLUCOCORTICOSTEROID AND ONLY ONE SURFACTANT The present invention relates to a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant. The invention further relates to a process for the preparation of the pharmaceutical composition and the use of the pharmaceutical composition for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases in the respiratory tract or for the treatment of intestinal diseases and methods for the treatment of diseases in a mammal, including man.

BACKGROUND OF THE INVENTION Rhinitis and asthma are currently effectively treated by the use of glucocorticosteroids such as, for example, mometasone furoate, budesonide, and fluticasone propionate. Patent applications that REF .: 121016 may be mentioned in this context are WO 92/13873 and WO 96/19199 both from Astra AB of Sweden.

Well-known methods for the administration of glucocorticosteroids are by oral and nasal inhalation. The glucocorticosteroid compositions are used in the form of powders in dry powder inhalers, such as suspensions or suspensions in metered dose pressurized inhalers. (pMDIs). A suspension in water is a user-friendly form of administration for the user because the solution is easily accepted by the mucosa. However, in a suspension in water the glucocorticosteroid crystals are in contact with the water which can affect the stability of the glucocorticosteroid. A glucocorticosteroid can be chemically degraded, for example, by hydrolysis when such a compound is used. In addition, compositions in the form of suspensions may be less stable than solutions for example due to sedimentation or precipitation. It is also easier to administer a solution with precision compared to a suspension.

The North American Patent 4,994,439 of California Biotechnology discloses aqueous compositions for administration by the transmucosal membrane of protein or peptide drugs wherein the compositions comprise the drug in mixtures with at least one bile salt or fusidata or one of its derivatives and at least one nonionic detergent of the formula RO ( CHR 'CH20) nR, where R is H and the other R represents the radical of a saturated or unsaturated cyclic or unsaturated acyclic alcohol of 6-40 carbons. The use of a mixture of carrier components results in the formation of mixed micelles, which exhibit efficiencies in transport through mucous membranes comparable or better than those achieved by the use of only bile salts / fusidates. Detergents by themselves are weak absorption promoters.

European Patent EP 0179583 Al of Merck & Co. Inc. describes a system for improving the rate of dissolution in water and the solubility of weakly soluble drugs. The compositions of EP 0179583 A1 involve the combination of weakly water soluble drugs with the surfactant in appropriate ratios and by an appropriate means which results in the formation of an anhydrous product. The examples are directed to anhydrous compositions of the antiparasitic agents inverctin or abarmectin and a surfactant.

It is an object of the present invention to provide a stable aqueous solution of a lipophilic glucocorticosteroid for use as a medicament, especially for the treatment of allergic and / or inflammatory diseases in the respiratory tract and also for the treatment of intestinal diseases such as inflammatory diseases. of the intestine (IBD), ulcerative colitis and Crohn's disease.

A further object of the invention is to provide a process for the preparation of such a stable solution.BRIEF DESCRIPTION OF THE INVENTION According to the invention there is provided a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.

According to a preferred embodiment, the composition comprises one and only one nonionic surfactant.

According to another preferred embodiment, the composition is used for the treatment of allergic and / or inflammatory diseases in the respiratory tract.

According to yet another preferred embodiment, the composition is used for the treatment of intestinal diseases.

According to a further aspect of the invention, it comprises a process for the preparation of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant, the process comprising the steps of: a) dissolution of the glucocorticosteroid in the surfactant; b) addition of an aqueous medium to the solution of step a) and stirring of the solution.

According to yet another aspect of the invention, the use of a composition comprising micelles in an aqueous medium is obtained, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of allergic and inflammatory diseases in the respiratory tract.

According to a further aspect of the invention the use of a composition comprising micelles in an aqueous medium is obtained, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of intestinal diseases.

Another aspect of the invention is a method for the treatment of allergic and / or inflammatory diseases in the respiratory tract of a mammal, including man. The method is characterized by administration to the mammal in need of such treatment of a therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.

A final aspect of the invention is a method for the treatment of intestinal diseases in a mammal including man. The method is characterized by administration to the mammal in need of such treatment of a therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention it was found that lipophilic glucocorticosteroids and their esters can be incorporated into micelles formed by a surfactant, especially a non-ionic surfactant, in an aqueous medium. According to "Pharmaceutical Dosage Forms: Disperse Systems (Pharmaceutical Dosage Forms: Dispersed Systems", vol.1, p.315 ff (1998) edited by HA Lieberman et al., Micelles are molecular aggregates formed in the solution of a surfactant Surfactants in a dilute aqueous solution exist mainly as monomers, but at higher concentrations numerous surfactant molecules are aggregated for micellar forms.Thus, a stable formulation is obtained in which the lipophilic glucocorticosteroid / glucocorticosteroid ester is protected and possible that is absorbed.

The micelles will act as non-aqueous storages for the lipophilic glucocorticosteroid and possibly affect the pharmacokinetics and deposition of the glucocorticosteroid molecule. The glucocorticosteroid will be easier to dose accurately as will precise administration to the patient. For additional information on the expression "lipophilic" reference can be made to the aforementioned reference where on page 155 states that "lipophilic drugs can be moistened with semi-polar oils and liquids".

The problems with the preparation of compositions comprising the lipophilic glucocorticosteroids used in the invention in an aqueous medium is that they are very difficult to dissolve in water and therefore obtain a stable composition. It has been found in the present invention that by dissolving the lipophilic glucocorticosteroid in a surfactant, preferably a nonionic surfactant, stable compositions can be obtained with the glucocorticosteroid in micellar form.

The inventor of the present invention has further found that the use of stable compositions comprising rhopalponide palmitate incorporated into micelles formed by a surfactant, causes less irritation in the lung after oral inhalation by human patients, than what experienced after oral inhalation of the same surfactant by itself.

The present compositions comprise one and only one surfactant. The surfactant used in the present compositions may be zwitterionic, anionic or cationic nonionics. However, the use of a nonionic surfactant is preferred, since this normally reduces the risk of side effects after administration. Examples of nonionic, zwitterionic, anionic or cationic surfactants that can be used in the present invention can be found in the Handbook of Pharmaceutical Excipients by Wade and Weller, 1994 of The Pharmaceutical Press, London.

The nonionic surfactants used in accordance with the present invention are conveniently selected from the poloxamers, for example, poloxamer 188; polyoxyethylene alkyl ethers, for example, stearyl ether poloxyl 10, stearyl ether poloxyl 20; polyoxyethylenates stearates, for example, polyoxyl 8 stearate, polyoxyl stearate 12; polyoxyethylene glycol hydroxystearates, for example, polyoxyethylene glycol 12-hydroxystearates, fatty acid esters of polyoxyethylene sorbitan. A preferred group of nonionic surfactants is that of the fatty acid esters of polyoxyethylene sorbitan, for example, monolaurate, monopalmitate, monostearate or sorbitan polyoxyethylene monooleate, also known as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80, respectively. Examples of suitable commercial polysorbates with Tween ™ 20, Tween ™ 40, Tween ™ 60 and Tween ™ 80. A further preferred group of nonionic surfactants is that of polyoxyethylene glycol 12-hydroxystearate and an especially preferred compound is 12-hydroxystearate polyoxyethylene glycol 660.

In the present invention, lipophilic glucocorticosteroids are related to lipophilic glucocorticosteroids per se, as well as to their pharmaceutically acceptable solvates, esters, acetals and salts, and solvates of any of these.

Examples of glucocorticosteroids that can be used in the present invention include betamethasone, fluticasone (eg, as propionate), budesonide, tipredane, dexamethasone, beclomethasone (eg, as dipropionate), prednisolone, fluocinolone (eg, as acetonide), ometasone (for example, as furoate), rofleponide (for example, as palmitate), flumethasone, flunisolide, cyclosonide, deflazacort, cortivazole, 16a, 17a-butylidenedioxy-6a, 9a-difluoro-11β, 21-dihydroxy-pregna-1, -diene-3, 20-dione; 6a, 9a-difluoro-l, l-hydroxy-l6a, 17a-butylidenedioxy-17β-methylthio-androsta-l, 4-en-3-one; S-methyl ester of 16a, 17a-butylidenedioxy-6a, 9a-difluoro-11β-hydroxy-3-oxo-androsta-1, 4-diene-17β-carbocationic acid ester; 9a-Chloro-6a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17a-methyl carboxylate; S- (2-oxo-tetrahydrofuran-3-yl) ester of 6a, 9a-difluoro-lys-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-l, 4-diene-17β-carbocationic acid; optionally in their pure isomeric forms (where such forms exist) and / or in the form of their solvates, esters, acetals or pharmaceutically acceptable salts, or where they apply solvates of any of these. Conveniently, use is made of ometasone furoate, beclomethasone dipropionate or fluticasone propionate or glucocorticosteroids with an asymmetric acetal structure, for example, comprising the 16a, 17a-butylidenedioxy group, such as budesonide or rofleponide or solvates, esters, acetals or salts pharmaceutically acceptable, or where applicable, their solvates. The most preferred lipophilic glucocorticosteroid ester is rofleponide palmitate.

The amount of surfactant used in the composition should be less than 5% (w / w) of the total weight of the composition. Preferably, the amount of surfactant is less than 3% (weight / weight) and more preferably less than 1% (weight / weight) of the weight of the total composition. The concentration of the surfactant must, however, be higher than the critical micelle concentration (CMC), the lower concentration at which the micelles are formed in an aqueous medium. The value of the CMC depends mainly on the temperature and the concentration of the possible additives. It is the competence of the experienced person to determine the CMC for each individual composition and therefore prepare appropriate micelles according to the present invention.

The amount of glucocorticosteroid used depends on the area of utility. If the glucocorticosteroid is used for the treatment of diseases in the respiratory tract by inhaling an appropriate daily dose of 10 to 2400 μg, preferably 10 to 1600 μg. If the glucocorticosteroid is used for the treatment of intestinal diseases, the appropriate daily dose is 400 to 4000 μg, preferably 800 to 3000 μg.

The composition according to the invention may also contain one or more pharmaceutically acceptable additives such as buffer solutions and other pH modifiers, antioxidants, coupling agents to further increase stability, viscosity regulating agents and isotonicity modifying agents. Compounds used as such agents are compounds generally used in drug formulations, for example, EDTA for complexing and carboxymethyl cellulose (CMC) to regulate viscosity. As substances for adjusting isotonicity, glucose, mannitol, salts, glycerol and propylene glycol may be mentioned.

Preferably buffer solutions are used in such a way that the pH of the composition is from 4 to 7. However, it is preferred to use one or more antioxidants, which may be soluble in water to a lesser or greater degree. Examples of such antioxidants include, without limitation, tocopherols, especially α-tocopherol, and preferably racemic α-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ascorbic acid.

In order to prepare the aqueous composition according to the present invention the glucocorticosteroid drug has to be dissolved in a first stage. It has been found in the present invention that a stable glucocorticosteroid composition is obtained if the glucocorticosteroid is dissolved in the surfactant. Subsequently, the aqueous medium is added to the glucocorticosteroid surfactant solution and the mixture is stirred, preferably vigorously stirred, to obtain a stable and homogeneous solution. Preferably the aqueous medium has the same temperature as the surfactant solution of the glucocorticosteroid before it is added to the solution. If other pharmaceutically acceptable additives are used they are conveniently added to the aqueous medium before mixing with the surfactant solution of the glucocorticosteroid if they are soluble in water. Otherwise, they are added to the surfactant solution. In a preferred embodiment of the process, glucose is dissolved in the aqueous medium in an isotonic amount.

The surfactant used may be a solid compound at room temperature or a more or less fluid compound. If a solid surfactant is used it must be heated in order to melt it in a first stage of the process. Subsequently, the glucocorticosteroid is dissolved in the molten surfactant. This is a preferred embodiment of the invention.

If the surfactant is sufficiently fluid the glucocorticosteroid can be dissolved directly in the surfactant at room temperature or it may be appropriate to increase the temperature of the surfactant to dissolve the glucocorticosteroid more easily. After add water.

An additional possibility is to dissolve the surfactant in a conventional organic solvent, for example, ethanol, and subsequently dissolve the glucocorticosteroid in this solution or vice versa. Then the organic solvent has to be evaporated before the aqueous medium is added. It is important that the organic solvent is removed from the composition otherwise the composition will have an itchy effect on the nose of the patient if the composition is used for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases in the tract respiratory.

Optionally the composition according to the invention can be made sterile in a convenient manner, for example, by the use of steam or irradiation dry heat.

The composition according to the invention is used for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases in the respiratory tract. The composition can be administered via the upper or lower respiratory tract, including nasal or oral inhalation. The composition according to the invention can be used in common devices for aqueous solutions for nasal or oral inhalation, for example, in a spray pump or in a nebulizer. For administration by nebulization reference is made to "Medication Nebulizer Performance (Medication Nebulizer Performance)", Chest 110 (2),. { 1996), pp.498-505. The composition according to the invention is also used for the manufacture of a medicament for the treatment of intestinal diseases such as inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease. The compositions can then be administered by rectal administration.

The invention also relates to a method for the treatment of allergic and / or inflammatory diseases in the respiratory tract of a mammal, including man. The composition according to the invention is administered in a therapeutically effective amount to the mammal in need of such treatment, preferably by nasal or oral inhalation.

The invention also relates to a method for the treatment of intestinal diseases in a mammal, including man. The composition according to the invention is administered in a therapeutically effective amount to the mammal in need of such treatment, preferably by rectal administration.

The invention will now be illustrated by the following non-limiting example: EXAMPLE Preparation of rofleponide palmitate in micellar solution. 5 g of Solutol® HS15 (polyethylene glycol 12-hydroxystearate 660) prepared by BASF of Germany at 35 ° C-40 ° C are melted in a beaker. 100 mg rofleponide palmitate is added and dissolved in the casting.

An isotonic solution of 25 g of glucose is heated to -40 ° C and are added to the casting using intense agitation. A clear solution containing 0.2 mg rofleponide palmitate / ml is obtained.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims

A pharmaceutical composition comprising micelles in an aqueous medium, characterized in that the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.
The composition according to claim 1, characterized in that the surfactant is a non-ionic surfactant.
The composition according to claim 2, characterized in that said nonionic surfactant is selected from the group consisting of poloxamers, alkyl polyoxyethylene esters, polyoxyethylene stearates, polyoxyethylene glycol hydroxystearate and fatty acid esters of polyoxyethylene sorbitan.
The composition according to claim 3, characterized in that the nonionic surfactant is a polyoxyethylene glycol 12-hydroxystearate.
The composition according to claim 4, characterized in that the nonionic surfactant is polyoxyethylene glycol 6-hydroxystearate 660.
The composition according to claim 3, characterized in that the nonionic surfactant is polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.
The composition according to any of the preceding claims, characterized in that the glucocorticosteroid is selected from the group consisting of ometasone furoate, beclomethasone propionate, fluticasone propionate, glucocorticosteroids with an asymmetric acetal structure involving a 16a, 17a-butylidenedioxy group, and solvates, esters, acetals and pharmaceutically acceptable salts of any of these.
The composition according to claim 7, characterized in that the glucocorticosteroid is rofleponide palmitate.
A composition according to any of the preceding claims, characterized in that the amount of surfactant is less than 5% (w / w) of the weight of the total composition, preferably less than 3% (weight / weight), more preferably less than 1% (weight / weight) of the weight of the total composition.
10. A composition according to any one of the preceding claims, characterized in that it additionally comprises one or more pharmaceutically acceptable additives selected from the group consisting of antioxidants, isotonicity modifying agents, pH modifiers, prior ready agents and viscosity regulating agents.
11. A composition according to claim 10, characterized in that the isotonicity modifying agent is glucose.
12. A composition according to claim 10, characterized in that the antioxidant is selected from the group consisting of tocopherols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ascorbic acid.
13. A process for the preparation of a pharmaceutical composition comprising micelles in an aqueous medium, characterized in that the micelles comprise a lipophilic glucocorticosteroid and one and only one Pharmaceutically acceptable surfactant, the process comprising the steps of: a) dissolving the glucocorticosteroid in the surfactant; and b) adding the aqueous medium to the solution of step a) and stirring the solution.
14. The process according to claim 13, characterized in that said surfactant is a nonionic surfactant.
15. The process according to claim 14, characterized in that said nonionic surfactant is selected from the group consisting of poloxamers, alkyl polyoxyethylene ethers, polyoxyethylene stearates, polyoxyethylene glycol hydroxystearate and fatty acid esters of polyoxyethylene sorbitan.
16. The process according to claim 15, characterized in that the nonionic surfactant is a polyoxyethylene glycol 12-hydroxystearate.
17. The process according to claim 16, characterized in that the nonionic surfactant is polyoxyethylene glycol 6-hydroxystearate 660.
18. The process according to claim 15, characterized in that the polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.
19. The process according to any of claims 13-18, characterized in that the glucocorticosteroid is selected from the group consisting of mometasone furoate, beclomethasone dipropionate, fluticasone propionate, glucocorticosteroids with an asymmetric acetal structure involving a group 16a, 17a- butylidenedioxy, and solvates, esters, acetals and pharmaceutically acceptable salts, and solvates of any of these.
20. The process according to claim 19, characterized in that the glucocorticosteroid is rofleponide palmitate.
21. The process according to any of claims 13-20, characterized in that the amount of the surfactant is less than 5% (w / w) of the weight of the total composition, preferably less than 3% (w / w), more preferably less than 1% (weight / weight) of the weight of the total composition.
22. The process according to any of claims 13-21, characterized in that the composition additionally comprises one or more pharmaceutically acceptable additives selected from the group consisting of antioxidants, isotonicity modifying agents, pH modifiers, pre-filled agents and viscosity regulating agents. .
23. The process according to claim 22, characterized in that it comprises the dissolution of glucose in an isotonic amount in the aqueous medium before adding the aqueous medium to the solution of stage a).
24. The use of a pharmaceutical composition comprising micelles in an aqueous medium, characterized in that the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases in the tract respiratory.
25. The use according to claim 24, characterized in that the daily dose of the glucocorticosteroid falls within the range of 10 to 2400 μg, preferably 10 to 1600 μg.
26. The use of a pharmaceutical composition comprising micelles in an aqueous medium, characterized in that the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of intestinal diseases.
27. The use according to claim 26, characterized in that the daily dose of the glucocorticosteroid falls within the range of 400 to 4000 μg, preferably 800 to 3000 μg.
28. The use according to any of claims 24 to 27, characterized in that the composition is as defined in any of claims 2-12.
29. A method for the treatment of allergic and / or inflammatory diseases in the respiratory tract of a mammal, characterized in that it comprises administration to the mammal in need of such treatment of a therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, in wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant. A method for the treatment of intestinal diseases in a mammal, characterized in that it comprises administration to the mammal in need of such treatment of a therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only a pharmaceutically acceptable surfactant. A method for treatment according to claim 29 or 30, characterized in that the composition is as defined in any of claims 2-12.