SK9532000A3 - Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant - Google Patents

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

A pharmaceutical composition comprising micelles in an aqueous medium, a process for its preparation and its use

Technical field

I

The present invention relates to a pharmaceutical composition comprising micelles in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant. The invention further relates to a process for the preparation of such a pharmaceutical composition and to the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of allergic or inflammatory airway diseases, or for the treatment of intestinal diseases, and methods for treating such diseases in mammals, including humans.

BACKGROUND OF THE INVENTION

Today, rhinitis and asthma are steroids such as a fluticasone-propionate. In this patent publication WO 92/13873 and WO effectively treated with glucocorticomometasone furoate, budesonide context can be cited 96/19199 (both Astra

AB, Sweden).

Well-known methods of administering glucocorticosteroids are oral or nasal inhalations. Glucocorticosteroid compositions are used in the form of powders in powder inhalers or as solutions or suspensions in pressurized metered dose inhalers (PMDI). A suspension in water is a very suitable form of application since it is readily absorbed by the mucosa. However, in an aqueous suspension, glucocorticosteroid crystals are in contact with water which may affect its stability. If a glucocorticosteroid ester is used, it may be chemically degraded, for example by hydrolysis. Furthermore, suspensions may be less stable than solutions, for example due to sedimentation or precipitation. It is also easier to accurately administer the solution than the suspension.

U.S. Patent No. 4,994,439 (California Biotechnology) discloses aqueous compositions for administering protein or peptide drugs via the mucosa, the compositions comprising the drug in admixture with at least one bile salt or fusidate or derivative thereof, and at least one nonionic surfactant of formula RO ( CHR'CH ₂ O) _n R / wherein R is H and the other R is a saturated or unsaturated cyclic or acyclic organic alcohol containing 6 to 40 carbon atoms. The use of a mixture of carrier components produces mixed micelles whose mucosal transportability is comparable or better than when bile acid salts or fusidates are used alone. Surfactants are known as weak absorption promoters.

EP 0179583 A1 (Merck & Co. Inc.) discloses a system for increasing the dissolution rate and solubility of poorly water soluble drugs. In the compositions described in EP 0179583 A1, the poorly water-soluble drug is mixed in a suitable manner and in appropriate proportions with the surfactant to prepare the anhydrous product. Anhydrous compositions comprising ivermectin or abamectin and a surfactant are described in the examples of said patent specification.

The present invention relates to the preparation of a stable aqueous solution of a lipophilic glucocorticosteroid for use as a medicament, in particular for the treatment of allergic or inflammatory airway diseases, as well as for the treatment of intestinal diseases such as inflammatory bowel disease (IBD), ulcerative colitis and Chrohn's disease.

The invention further relates to a process for the preparation of such a stable solution.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant.

According to a preferred variant of the invention, the composition comprises one single nonionic surfactant.

According to another preferred variant of the invention, the composition is used for the treatment of allergic and / or inflammatory airway diseases.

According to another preferred variant of the invention, the composition is used for the treatment of intestinal diseases.

Another variant of the invention relates to a process for the preparation of a pharmaceutical composition comprising micelles in an aqueous medium, the micelles comprising a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant, the process comprising the steps of:

(a) dissolution of the glucocorticosteroid in the surfactant;

b) adding the aqueous medium to the solution prepared in step a) and stirring the solution.

According to yet another aspect of the invention, a composition comprising micelles in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant, is used for the manufacture of a medicament for the treatment of allergic and inflammatory airway diseases.

According to another aspect of the present invention, a composition comprising micelles in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant, is used for the manufacture of a medicament for the treatment of intestinal diseases.

Another aspect of the invention relates to a method of treating allergic and / or inflammatory airway diseases in mammals, including humans. The method is characterized in that a mammal in need of such treatment is administered a therapeutically effective amount of a micelle-containing pharmaceutical composition in an aqueous environment, said micelles comprising a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant.

The last aspect of the invention relates to a method of treating intestinal diseases in mammals, including humans. The method is characterized in that a mammal in need of such treatment is administered a therapeutically effective amount of a micelle-containing pharmaceutical composition in an aqueous environment, said micelles comprising a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant.

According to the present invention, it has been found that lipophilic glucocorticosteroids and their esters can be incorporated into micelles formed by aqueous surfactants, especially nonionic surfactants. According to the book "Pharmaceutical Dosage Forms; Disperse Systems (edited by H. A. Lieberman et al., Vol. 1, p. 315 et al. (1988)) are micelle molecular aggregates that are formed in surfactant solutions. In dilute aqueous solutions, surfactants exist primarily as monomers, but at higher concentrations a large number of their molecules aggregate to form micelles. This provides a stable environment in which the lipophilic glucocorticosteroid or glucocorticosteroid ester is protected and can be absorbed.

Micelles act as non-aqueous reservoirs of lipophilic glucocorticosteroid and will positively affect its pharmacokinetics and deposition of its molecule. The glucocorticosteroid will also be easier to accurately dose and thus accurately administer to the patient. With regard to the term "lipophilic, refer to the above-cited publication where p. 155, it is written that "lipophilic drugs may be wetted with oils and semi-polar fluids.

The problem with the preparation of the lipophilic glucocorticosteroid compositions used in the invention in an aqueous environment is that they are very difficult to dissolve in water and it is very difficult to obtain a stable composition. Submitting! The present invention has found that by dissolving a lipophilic glucocorticosteroid in a surfactant, preferably a nonionic surfactant, stable compositions can be obtained in which the glucocorticosteroid is in micellar form.

Submitting! of the present invention further found that the use of stable formulations containing, for example, rofleponide epalmitate contained in surfactant micelles in human patients irritates the lungs after oral inhalation less than oral inhalation of the same surfactant itself.

The compositions of the invention contain one single surfactant. The surfactant used may be nonionic, zwitterionic, anionic or cationic. However, it is preferred to use a nonionic surfactant, as this generally 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 Wade and Weller: Handbook of Pharmaceutical Excipients, 1994, The Pharmaceutical Press, London.

The nonionic surfactants of the present invention may preferably be poloxamers, for example poloxamer 188; polyoxyethylene alkyl ethers, for example (polyoxyl 10) stearyl ether, (polyoxyl

20) stearyl ether; polyoxyethylene stearates, for example (polyoxyl 8) stearate, (polyoxyl 12) stearate; polyoxyethylene glycol hydroxy stearates, for example polyoxyethylene glycol-12-hydroxystearates, and polyoxyethylene sorbitan fatty acid esters. A preferred class of nonionic surfactants are polyoxyethylene sorbitan fatty acid esters, for example, monolaurate, monopalmitate, monostearate or polyoxyethylene (20) sorbitan monooleate, also known under the names polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. As examples of suitable polysorbate 80. mention may be made of Tween ™ 20, Tween ™ 40, Tween ™ 60 and Tween ™ 80. Another preferred class of nonionic surfactants are polyoxyethylene glycol-12-hydroxystearates, and particularly preferred is (polyoxyethylene glycol 660) -12-hydroxystearate.

In the present invention, lipophilic glucocorticosteroids are lipophilic glucocorticosteroids alone, but also pharmaceutically acceptable solvates, esters, acetals and salts thereof, as well as solvates of any of these.

Examples of glucocorticosteroids that may be used in the present invention include betamethasone, fluticasone (e.g. as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g. as dipropionate), prednisolone, fluocinolone (e.g. as acetonide), triamcinolone (e.g. , mometasone (e.g. as furoate), rofleponide (e.g. as palmitate), flumethasone, flunisolide, ciclesonide, deflazacort, cortivazole, 16α, 17α-butylidenedioxy-6α, 9α-difluoro-β, 21-dihydroxy-pregna-1,4-diene -3,20-dione, 6α, 9α-difluoro-1H-hydroxy-16α, 17α-butylidenedioxy-17β-methylthioandrosta-4-en-3-one; 16α, 17α-butyldenedioxy-6α, 9α-difluoro-lip-hydroxy-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid S-methyl ester; 9α-chloro-6α-fluoro-1 H -hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17α-carboxylic acid methyl ester; 6α, 9α-Difluoro-1H-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-thiocarboxylic acid S- (2-oxotetrahydrofuran-3-yl) ester; optionally in their pure isomeric forms (if such forms exist) or in the form of their pharmaceutically acceptable solvates, esters, acetals or salts, or solvates of these compounds (if applicable). Preferably, it can be used

Omet mometasoneefuroate beclomethasone dipropionate or fluticasonepropionate, or glucocorticosteroids with an asymmetric acetal structure, containing, for example, 16α, 17α-butylidenedioxy, such as budesonide or rofleponide, or pharmaceutically acceptable solvates, esters, acetals or salts thereof, or solvates thereof. The most preferred lipophilic glucocorticosteroid ester is rofleponide epalmitate.

The amount of surfactant used in the composition of the invention should be less than 5% by weight based on the total weight of the composition.

It is preferred that the amount of surfactant is less than 3% by weight, especially when less than 1% by weight, based on the total weight of the composition. However, the surfactant concentration must be higher than the critical micellar concentration (CMC), the lowest concentration at which micelles are formed in an aqueous environment. The CMC value depends primarily on the temperature and the concentration of any additives. One of ordinary skill in the art can determine the CMC for each individual composition and can thus prepare suitable micelles according to the present invention.

The amount of glucocorticosteroid used depends on the target for which it is used. When the glucocorticosteroid is used to treat respiratory diseases by inhalation, a suitable daily dose is from 10 to 2400 pg, preferably from 10 to 1600 pg. When the glucocorticosteroid is used to treat intestinal diseases, a suitable daily dose is from 400 to 4000 pg, preferably from 800 to 3000 pg.

The composition of the invention may also contain one or more pharmaceutically acceptable excipients such as buffers and other pH adjusting agents, antioxidants, complexing agents for enhancing stability, and viscosity and isotonicity adjusting agents. As such agents, compounds commonly used in the preparation of medicaments such as EDTA for complexation and carboxymethylcellulose (CMC) for viscosity adjustment can be used. Isotonicity agents include glucose, mannitol, salts, glycerol and propylene glycol. As buffers, preferably alkaline buffers are used so that the pH of the composition is from 4 to 7. However, it is preferred to use one or more antioxidants, which may be less or more soluble in water. Such antioxidants include, for example, tocopherols, especially α-tocopherol, and especially racemic α-tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), and ascorbic acid (without being limited to these compounds).

In order to prepare the aqueous composition of the invention, the glucocorticosteroid must first be dissolved in the first step. Submitting! The present invention has found that a stable composition is obtained when the glucocorticosteroid is dissolved in a surfactant. Then, an aqueous medium is added to the solution of the glucocorticosteroid in the surfactant and the mixture is stirred, preferably vigorously, to obtain a stable and homogeneous solution. When added, the aqueous medium preferably has the same temperature as the solution of the glucocorticosteroid in the surfactant. If other pharmaceutically acceptable additives are used, it is advisable to add them to the aqueous medium before mixing with the glucocorticosteroid solution in the surfactant, if they are water-soluble. If they are not soluble in water, they are added to the solution in the surfactant. In a preferred variant of the invention, the glucose is dissolved in an aqueous medium in isotonic amounts.

The surfactant used may be solid or more or less liquid at room temperature. If a solid surfactant is used, it should be heated in a first step to melt. The glucocorticosteroid is then dissolved in the melt. This procedure represents a preferred embodiment of the invention.

If the surfactant is sufficiently fluid, it may dissolve the glucocorticosteroid directly at room temperature, or it may be appropriate to raise the temperature of the surfactant to dissolve the glucocorticosteroid more readily. Water is then added.

Another possibility is to dissolve the surfactant in a conventional organic solvent, for example ethanol, and then dissolve the glucocorticosteroid or vice versa. The organic solvent must then be evaporated before the aqueous medium is added. It is important that the organic solvent be removed from the composition, otherwise the composition would burn the patient's nose if used to treat allergic or inflammatory airway diseases.

Optionally, the composition of the invention may be sterilized by conventional means, such as by dry heat, steam or radiation.

The composition of the invention is used for the manufacture of a medicament for the treatment of allergic or inflammatory airway diseases. The composition may be administered by the upper or lower airways, including nasal or oral inhalation. The composition of the invention may be used in conventional devices used for aqueous solutions for nasal or oral inhalation, for example in a spray pump or nebulizer. For applications using a nebulizer, see "Medication Nebulizer Performance, Chest 110 (2)," p. 498-505 (1996). The composition of the invention is also used in the manufacture of a medicament for the treatment of intestinal diseases such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Thereafter, the composition may be administered rectally.

The invention also relates to a method of treating allergic or inflammatory airway diseases in a mammal, including a human. The composition of the invention is administered in a therapeutically effective amount to a mammal in need of such treatment, preferably by nasal or oral inhalation.

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

The invention is illustrated by the following non-limiting example.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of rofleponide epalmitate

5 g Solutol® HS15 (polyethylene glycol 660-hydroxystearate 660; BASF, Germany) is melted in a beaker at 35-40 ° C. 100 mg of rofleponide epalmitate is dissolved in the melt. An isotonic solution of 25 g of glucose in 495 g of water is heated to 35-40 ° C and added to the melt with vigorous stirring. This gave a clear solution containing 0.2 mg of rofleponide epalmitate per ml.

Claims (29)

A pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant. Second means by claim 1 mark the task s a t ý wherein the surfactant is nonionic surface active material. Third means by claim 2 confesses c and s a wherein the nonionic surfactant is selected from the group consisting of poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyoxyethylene glycol hydroxy stearates and polyoxyethylene sorbitan fatty acid esters. The composition of claim 3, wherein the nonionic surfactant is polyoxyethylene glycol-12-hydroxystearate. The composition of claim 4, wherein the nonionic surfactant is (polyoxyethylene glycol 660) -12-hydroxystearate. The composition of claim 3, wherein the nonionic surfactant is polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. A composition according to any preceding claim; characterized in that the glucocorticosteroid is selected from the group consisting of mometasoneefuroate, beclomethasone dipropionate, fluticasoneepropionate, glucocorticosteroids with an asymmetric acetal structure comprising a 16α, 17α-butylidenedioxy group, and pharmaceutically acceptable solvates thereof, esters, acetates, solvates thereof. The composition of claim 7, wherein the glucocorticosteroid is rofleponide epalmitate. Composition according to any one of the preceding claims, characterized in that the amount of surfactant is less than 5% by weight, based on the total weight of the composition, preferably less than 3% by weight, and even more preferably less than 1% by weight, based on the total. weight of the composition. The composition of any preceding claim, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of antioxidants, isotonicity agents, pH adjusting agents, complexing agents, and viscosity adjusting agents. The composition of claim 10, wherein the isotonicity agent is glucose. Composition according to claim 10, characterized in that the antioxidant is selected from the group consisting of tocopherols, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) and ascorbic acid. A process for the preparation of a pharmaceutical composition comprising micelles in an aqueous medium, the micelles comprising a lipophilic glucocorticosteroid and one single surfactant, comprising the steps of: (a) the glucocorticosteroid is dissolved in the surfactant; and b) an aqueous medium is added to the solution of step a) and the solution is stirred. The method of claim 13, wherein the surfactant is a nonionic surfactant. 15. The method of claim 14 wherein said nonionic surfactant is selected from the group consisting of poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyoxyethylene glycol hydroxy stearates, and polyoxyethylene sorbitan fatty acid esters. A process according to claim 15 wherein the nonionic surfactant is polyoxyethylene glycol-12-hydroxystearate. A process according to claim 16, wherein the nonionic surfactant is (polyoxyethylene glycol 660) -12-hydroxystearate. 18. The process of claim 15 wherein the polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. A process according to any one of claims 13 to 18, wherein the glucocorticosteroid is selected from the group consisting of mometasoneephuroate, beclomethasone dipropionate, fluticasoneepropionate, glucocorticosteroids with an asymmetric acetal structure comprising 16α, 17α-butylidene dioxy esters, and solvates thereof, and solvates thereof, and their solvates. acetals and salts and solvates of any of these compounds. The method of claim 19, wherein the glucocorticosteroid is rofleponide epalmitate. Preparation process according to any one of claims 13 to 20, characterized in that the amount of surfactant is less than 5% by weight, based on the total weight of the composition, preferably less than 3% by weight, and even more preferably less than 1% by weight, based on the total weight of the composition. A process according to any one of claims 13 to 21, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of antioxidants, isotonicity agents, pH adjusting agents, complexing agents and viscosity adjusting agents. A process according to claim 22, characterized in that an isotonic amount of glucose is dissolved in the aqueous medium before the aqueous medium is added to the solution prepared in step a). Use of a pharmaceutical composition comprising micelles in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of allergic and / or inflammatory airway diseases. Use according to claim 24, characterized in that the daily dose of glucocorticosteroid ranges from 10 to 2400 pg, preferably from 10 to 1600 pg. Use of a pharmaceutical composition comprising micelles in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant, for the manufacture of a medicament for the treatment of intestinal diseases. Use according to claim 26, characterized in that the daily dose of glucocorticosteroid ranges from 400 to 4000 pg, preferably from 800 to 3000 gg. Use according to any one of claims 24 to 27, characterized in that the composition is defined in any one of claims 2 to 12. 29. A method of treating allergic and / or inflammatory airway disease in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective dose of a micelle-containing pharmaceutical composition in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant. 30. A method of treating intestinal diseases in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective dose of a micelle-containing pharmaceutical composition in an aqueous environment, wherein the micelles comprise a lipophilic glucocorticosteroid and one single pharmaceutically acceptable surfactant. 31. A method of treatment according to claim 29 or 30, wherein the composition is as defined in any one of claims 2 to 12.