METHOD FOR PRODUCING NANOPARTICLES

Abstract

The present invention describes a method for producing nanoparticles, wherein the nanoparticles contain or consist of hydroxypropyl methylcellulose acetate succinate (HPMCAS), and wherein i) HPMCAS is dissolved in an organic solvent in order to obtain an organic solution and ii) the organic solution is mixed with water to precipitate the nanoparticles in order to obtain precipitated nanoparticles and a mixed liquid phase as well as nanoparticles obtained by that method.

Claims

1. A method for producing nanoparticles comprising an active ingredient and hydroxypropyl methylcellulose acetate succinate (HPMCAS), the method comprising the steps of: a) providing an organic solution of the active ingredient and the HPMCAS in an organic solvent; b) providing an aqueous solution having a pH of 3 to 9; and c) mixing the organic solution with the aqueous solution such as to precipitate the nanoparticles.

2. The method according to claim 1, wherein the aqueous solution is a buffered aqueous solution.

3. The method according to claim 1 or 2, wherein the organic solution is provided in the form of a first fluid stream; the aqueous solution is provided in the form of a second fluid stream; and wherein the mixing includes directing the first and the second fluid stream to contact one another.

4. The method according to claim 3, wherein each of the first and the second fluid stream is ejected from a nozzle, and wherein the fluid streams are directed such as to impinge on one another.

5. The method according to claim 3 or 4, wherein the mixing is performed in a fluidics or microfluidics device.

6. The method according to any one of the preceding claims, wherein the nanoparticles comprise a solid dispersion of the active ingredient in the HPMCAS.

7. The method according to any one of the preceding claims, wherein the active ingredient comprised in the nanoparticles is at least partially amorphous.

8. The method according to any one of the preceding claims, wherein the nanoparticles essentially consist of the active ingredient and the HPMCAS.

9. The method according to any one of the preceding claims, wherein the active ingredient is not more soluble in water than sparingly soluble, and is preferably slightly soluble, very slightly soluble, practically insoluble, or a class 2 or class 4 compound according to the Biopharmaceutical Classification System (BCS) or to the Biopharmaceutical Drug Disposition Classification System (BDDCS).

10. The method according to any one of the preceding claims, wherein the active ingredient is selected from amiodarone, atorvastatin, azithromycin, carbamazepine, carvedilol, chlorpromazine, cisapride, ciprofloxacin, cyclosporine, danazol, dapsone, diclofenac, diflunisal, digoxin, erythromycin, flurbiprofen, glipizide, glyburide, griseofulvin, ibuprofen, indinavir, indomethacin, itraconazole, ketoconazole, lansoprazole, lovastatin, mebendazole, naproxen, nelfinavir, ofloxacin, oxaprozin, phenazopyridine, phenytoin, piroxicam, raloxifene, ritonavir, saquinavir, sirolimus, spironolactone, tacrolimus, talinolol, tamoxifen, terfenadine, warfarin, amphotericin B, chlorthalidone, chlorothiazide, colistin, ciprofloxacin, furosemide, hydrochlorothiazide, mebendazole, methothrexate, neomycin, and enzalutamide.

11. The method according to any one of the preceding claims, wherein the concentration of the active ingredient in the organic solution is at least 20% of its corresponding saturation concentration at normal temperature and pressure.

12. The method according to any one of the preceding claims, wherein the concentration of the active ingredient in the organic solution is not higher than the concentration of the HPMCAS in the organic solution, wherein the concentrations are expressed as weight per volume.

13. The method according to any one of the preceding claims, wherein the organic solvent is selected from acetone, tetrahydrofuran, ethanol, methanol, dichloromethane, and mixtures thereof.

14. The method according to any one of the preceding claims, wherein the buffered aqueous solution comprises acetate buffer.

15. The method according to any one of the preceding claims, wherein the buffered aqueous solution has a pH of 5 to 8, or 5 to 7.

16. The method according to any one of the preceding claims, wherein the buffered aqueous solution and/or the organic solution further comprises a surfactant.

17. The method according to claim 16, wherein the surfactant is selected from pharmaceutically acceptable ionic or nonionic surfactants, wherein the ionic surfactants include, without limitation, phospholipids and sodium dodecyl sulfate, and wherein the nonionic surfactants include, without limitation, polysorbates and poloxamers.

18. The method according to any one of the preceding claims, wherein in step c) the ratio of the volume of the buffered aqueous solution to the volume of the organic solution is at least 1, and preferably from 2 to 20, or from 3 to 10, respectively.

19. The method according to any one of the preceding claims, further comprising a step of d) isolating and/or drying the nanoparticles.

20. Nanoparticles obtainable by the method according to any one of the preceding claims.

21. A pharmaceutical composition comprising the nanoparticles according to any one of claims 20 or 30 to 34 for use as a medicament.

22. A method for producing nanoparticles, wherein the nanoparticles contain or consist of hydroxypropyl methylcellulose acetate succinate (HPMCAS), characterized in that i) HPMCAS is dissolved in an organic solvent in order to obtain an organic solution, ii) the organic solution is mixed with water to precipitate the nanoparticles in order to obtain precipitated nanoparticles and a mixed liquid phase.

23. A method according to claim 22, characterized in that the organic solvent is or comprises acetone.

24. A method according to claim 22 or 23, characterized in that the method is a method for producing nanoparticles for oral application in a human being and wherein the method preferably comprises iii) spray drying or granulating the precipitated nanoparticles and the mixed liquid phase and preparing a tablet, capsule, or powder for oral administration.

25. A method according to one of claims 22 to 24, characterized in that at least one active ingredient is dissolved in the organic solvent respectively organic solution prior to ii), wherein the precipitated nanoparticles contain the at least one active ingredient, and wherein the nanoparticles contain or consist of HPMCAS and the at least one active ingredient.

26. A method according to one of claims 22 to 25, characterized in that the concentration of HPMCAS in the organic solution is 1 to 100 mg/mL, preferably, 5 to 30 mg/mL, and optionally the concentration of the at least one active ingredient in the organic solution is 1 to 30 mg/mL, preferably 2 to 15 mg/mL.

27. A method according to one of claims 22 to 26, characterized in that the water comprises a carboxylic acid and/or conjugated base, preferably acetic acid and/or acetate, preferably in a total concentration of carboxylic acid and conjugated base of 5 to 1000 mM, more preferably of 20 to 500 mM.

28. A method according to one of claims 22 to 27, characterized in that a) the pH value of the water is between 5 and 8, preferably between 6 and 7, and/or b) no active ingredient is dissolved in the organic solvent and the pH value of the water is between 5 and 8, preferably between 6 and 7, or c) at least one active ingredient is dissolved in the organic solvent prior to ii) and the pH value of the water is between 6 and 8, preferably between 6 and 7.

29. A method according to one of claims 22 to 28, characterized in that the ratio by volume of the organic solution to water in ii) is from 1 to between 2 and 10, preferably from 1 to between 3 and 7.

30. Nanoparticles for oral application in a human being obtainable by the method of one of claims 22 to 29.

31. Nanoparticles for oral application in a human being, wherein the nanoparticles contain or consist of hydroxypropyl methylcellulose acetate succinate (HPMCAS), characterized in that the nanoparticles have a particle size of 100 to 900 nm, preferably of 150 to 750 nm, more preferably of 200 to 600 nm, measured by Dynamic Light Scattering.

32. Nanoparticles according to claim 30 or 31, characterized in that the nanoparticles have a polydispersity index of 0.1 to 0.8, preferably of 0.15 to 0.7 or 0.6, measured by Dynamic Light Scattering.

33. Nanoparticles according to one of claims 30 to 32, characterized in that the nanoparticles are amorphous and/or have a spongy structure.

34. Nanoparticles according to one of claims 30 to 33, characterized in that the nanoparticles contain at least one active ingredient, preferably consist of HPMCAS and at least one active ingredient, and more preferably consist of HPMCAS and one active ingredient.

35. Use of the nanoparticles according to one of claims 20 or 30 to 34 for a) a pharmaceutical composition with immediate release in the gastrointestinal tract, more preferably the intestine, and/or b) the oral application of an active ingredient, preferably in a human being, and/or c) increasing bioavailability of an active ingredient in a pharmaceutical composition for oral application and/or d) optionally coupling to an active ingredient.

Description

EXAMPLES

Examples 1 to 8

[0091] These Examples were conducted in line with these method steps:

[0092] i) HPMCAS (AFFINISOL HPMCAS 912G from Dow chemicals) was dissolved in acetone in order to obtain an organic solution and

[0093] ii) the organic solution was quickly mixed under intensive stirring with water to precipitate the nanoparticles in order to obtain precipitated nanoparticles and a mixed liquid phase. The concentration of HPMCAS in the organic solution was 15 mg/mL. The ratio by volume of the organic solution to water was 1 to 5.

[0094] In Examples 1 to 5, no active ingredient was dissolved in the acetone respectively organic solution.

[0095] In Examples 6 to 8, the active ingredient enzalutamide was dissolved in the acetone respectively organic solution prior to ii). The concentration of the active ingredient in the organic solution was 5 mg/mL.

[0096] In Examples 2 to 8, the water comprised 50 mM of acetic acid and/or acetate (50 mM of total carboxylic acid plus conjugated base).

[0097] Further parameters, such as the pH value of the water, the z-average particle size, the polydispersity index is depicted in Table 2:

TABLE-US-00002 TABLE 2 Acetic acid and/or Active acetate in water Particle size Example Ingredient (mM) pH (nm) PDI 1 No — 7 — — 2 No 50 4 — — 3 No 50 5 209 0.189 4 No 50 6 384 0.308 5 No 50 7 347 0.384 6 Yes 50 5 — — 7 Yes 50 6 423 0.244 8 Yes 50 7 582 0.557

[0098] In Examples 1, 2, and 6, formation of one plastic mass was observed. No nanoparticles or no precipitate of nanoparticles could be obtained.

[0099] In Examples 3 to 5 and 7 to 8, nanoparticles were precipitated. The nanoparticles were amorphous and had a spongy structure.

[0100] In Examples 3 to 5, the nanoparticles consist of HPMCAS only.

[0101] In Examples 6 to 8, the nanoparticles consist of HPMCAS and the active ingredient.

Examples 9 to 13

[0102] In this series of examples, a MicroJet Reactor (MAC®) was used to prepare nanoparticles comprising HMPCAS (Aqoat AS-MG, Shin-Etsu Chemical) and either itraconazole (ITZ), aprepitant (APT), or furosemide (FRS) as active ingredient.

[0103] For each experiment, the organic solution was prepared by dissolving the respective active ingredient (5 mg/mL) and the HPMCAS (15 mg/mL) in acetone such as to yield the specified concentrations and a weight ratio of active ingredient to HPMCAS of 3. The aqueous solution consisted of aqueous acetate buffer adjusted to pH 5.

[0104] The organic solutions and the buffered aqueous solutions were provided as fluid streams and mixed by impingement using a Microjet Reactor having nozzles with pinhole diameters of 100 μm for the organic solution and 200 μm for the aqueous solution, respectively. The maximum pressure of the fluid streams were set to either 7 bar or 14 bar, and the volume ratio of the aqueous solution to that of the organic solution was set to either 4 or 5.

[0105] Subsequently, the nanoparticle suspensions obtained upon mixing were characterized with respect to their particle sizes (expressed as z-average) and polydispersity indices (PDI) using a Malvern Zetasizer. For the particle size measurements, the nanoparticle suspensions were diluted 1:10 with acetate buffer solution pH 5. For examples 11 to 13, these measurements were repeated after 24 h of storage at 5° C. in order to evaluate the stability of the nanoparticles.

[0106] The results are shown in Table 3:

TABLE-US-00003 TABLE 3 Ratio aqueous Max. z-average PDI to organic pressure z-average after 24 h after Ex. API phase [bar] [nm] PDI [nm] 24 h 9 ITZ 4 7 288.4 0.111 n/d n/d 10 ITZ 4 14 516.5 0.111 n/d n/d 11 ITZ 5 7 193.8 0.114 192.0 0.097 12 APT 5 7 198.3 0.254 556.7 0.438 13 FRS 5 7 207.0 0.252 244.9 0.238