PROCESS FOR PRODUCING A PHARMACEUTICAL FORMULATION COMPRISING CRYSTALLINE AND AMORPHOUS FRACTIONS OF AN ACTIVE SUBSTANCE

Abstract

A process for producing a pharmaceutical formulation comprising the steps of: A) providing particles of a polymer, wherein particles of a pharmaceutical active substance are additionally at least partially embedded in the particles of the polymer; B) heating the particles of the polymer to a predetermined temperature for a predetermined time and C) cooling the particles of the polymer after the predetermined time to a temperature of 18° C. to 24° C., wherein the polymer is at least partially soluble in water and the active substance is at least partially soluble in the polymer.

The particulate pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution of ≤1 μm. The predetermined temperature is within a range from 10 K below the glass transition temperature (determined by DSC in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min) of the polymer to the melting temperature of the active substance. The total proportion of the active substance in the polymer is greater than the amount of active substance soluble in the polymer at the predetermined temperature.

The invention further relates to a pharmaceutical formulation comprising a particulate pharmaceutical active substance coated with an at least partially water-soluble polymer, to a process for producing a suspension of a pharmaceutical formulation and to a suspension of a pharmaceutical active substance.

Claims

1. A Process for producing a pharmaceutical formulation in the form of a hybrid system comprising an amorphous solid solution mixed with crystalline nanoparticles, comprising: A) providing particles of a polymer, wherein particles of a pharmaceutical active substance are additionally at least partially embedded in the particles of the polymer; B) heating the particles of the polymer to a predetermined temperature for a predetermined time; C) cooling the particles of the polymer after the predetermined time to a temperature of 18° C. to 24° C. to produce the pharmaceutical formulation in the form of a hybrid system comprising an amorphous solid solution mixed with crystalline nanoparticles, wherein the polymer is at least partially soluble in water and the active substance is at least partially soluble in the polymer, wherein the particulate pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution (volume-based; determined by laser diffraction in accordance with ISO 13320:2009) of ≤1 μm, the predetermined temperature is within a range from 10 K below the glass transition temperature (determined by DSC in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min) of the polymer to the melting temperature of the active substance (determined by DSC in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min), and the total proportion of the active substance in the polymer is greater than the amount of active substance soluble in the polymer at the predetermined temperature.

2. Process according to claim 1, wherein the predetermined temperature is within a range of ±10 K of the glass transition temperature (determined by DSC in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min) of the polymer to no higher than 10 K below the melting temperature of the active substance (determined by DSC in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min).

3. Process according to claim 1, wherein the predetermined time in B) is ≥1 second to 10 hours.

4. Process according to claim 1, wherein the material provided in A) is obtained by milling a suspension comprising particles of the active substance and an aqueous solution of the polymer and then drying.

5. Process according to claim 1, wherein, in B), a suspension comprising particles of the active substance and an aqueous solution of the polymer is atomized from a nozzle of a multi-substance nozzle and a gas having a temperature higher than the predetermined temperature is discharged from another nozzle of the multi-substance nozzle, with the result that the suspension is dried and the dried material is heated to the predetermined temperature.

6. Process according to claim 1, wherein, in B), a suspension comprising particles of the active substance is atomized from a nozzle of a multi-substance nozzle and an aqueous solution of the polymer and of the active substance is atomized from another nozzle of the multi-substance nozzle, with the result that a mixture containing the atomized particle suspension arises, and additionally a gas having a temperature higher than the predetermined temperature is discharged from another nozzle of the multi-substance nozzle, with the result that the mixture is dried and the dried material is heated to the predetermined temperature.

7. Process according to claim 1, wherein the pharmaceutical active substance is selected from: ciclosporin A, ciclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate mofetil, gusperimus; acetylsalicylic acid, ibuprofen, S(+)-ibuprofen, indometacin, diclofenac, piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen, fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumetone; nifedipine, nitrendipine, nimodipine, nisoldipine, isradipine, felodipine, amlodipine, nilvadipine, lacidipine, benidipine, lercanidipine, furnidipine, niguldipine; α-lipoic acid; muramyl dipeptide or tripeptide, romurtide; vitamin A, D, E or F; vincopectin, vincristine, vinblastine, reserpine, codeine; bromocriptine, dihydroergotamine, dihydroergocristine; chlorambucil, etoposide, teniposide, idoxifene, tallimustine, teloxantrone, tirapazamine, carzelesin, dexniguldipine, intoplicine, idarubicin, miltefosine, trofosfamide, melphalan, lomustine, 4,5-bis(4-fluoroanilino)phthalimide; 4,5-dianilinophthalimide; thymoctonan, prezatide-copper acetate; erythromycin, daunorubicin, gramicidin, doxorubicin, amphotericin B, gentamicin, leucomycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin; fluconazole, ketoconazole, itraconazole; famotidine, cimetidine, ranitidine, roxatidine, nizatidine, omeprazole; N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]benzamide, N-benzoylstaurosporine; BOC-PhecPhe-Val-Phe-morpholine or the O-[2-(2-methoxyethoxy)acetoxy] derivative thereof; N-[4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethyl)-3-methoxybenzoyl]-2-vinyloxy]benzenesulfonamide or a mixture thereof.

8. Process according to claim 1, wherein the polymer is selected from methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, carboxyalkyl cellulose esters, starches, sodium carboxymethyl amylopectin, chitosan, alginic acid, alkali metal salts and ammonium salts of alginic acid, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum, polyacrylic acid and salts thereof, polymethacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, N-vinylpyrrolidone-vinyl acetate copolymers or a mixture thereof.

9. Process according to claim 1, wherein the particles of the polymer additionally comprise an ionic surfactant.

10. Process according to claim 1, wherein the active substance and the polymer are present in a relative weight ratio of 1:4 to 9:1.

11. Process according to claim 8, wherein the polymer and the surfactant are present in a relative weight ratio of 10:1 to 300:1.

12. Pharmaceutical formulation comprising a particulate pharmaceutical active substance coated with an at least partially water-soluble polymer, wherein the particulate pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution of ≤1 μm, in the polymer, the same active substance is additionally also dispersed in amorphous form and the total proportion of the active substance in the polymer is greater than the amount of active substance soluble in the polymer at 20° C.

13. Formulation according to claim 12, wherein the polymer additionally comprises an ionic surfactant.

14. Process for producing a suspension of a pharmaceutical formulation comprising suspending a formulation according to claim 12 in a suspension medium.

15. Suspension of a pharmaceutical active substance obtainable by a process according to claim 14.

Description

EXAMPLES

[0045] The present invention is elucidated in detail by the examples and figures that follow, but without being restricted thereto. The abbreviation “wt %” means percent by weight and is based on the total weight of the aqueous suspension. PVP K12 is a polyvinylpyrrolidone having a Fikentscher K value (DIN EN ISO 1628-1) of 12. SDS is sodium dodecyl sulfate. KVA 64 is Kollidon® VA64, a vinylpyrrolidone-vinyl acetate copolymer. Instrumental analyses were by Fourier-transform infrared spectroscopy (FTIR) and X-ray powder diffractometry (XRPD).

[0046] The glass transition temperatures T.sub.g of PVP K12 and KVA 64 were determined by dynamic differential scanning calorimetry (dynamic DSC) in accordance with DIN EN ISO 11357-2 at a heating rate of 10 K/min. T.sub.g is 107° C. for PVP K12 and 101° C. for KVA 64.

Example 1: Indometacin-PVP K12 System

[0047] The nanosuspension was prepared using a planetary ball mill (Fritsch Pulverisette 5). For this, 10 wt % of indometacin was stabilized with 6 wt % of PVP K12 and 0.1 wt % of SDS. The polymer-surfactant solutions were prepared and dissolved separately. The solution was then mixed with indometacin powder and the resulting suspension homogenized on a stirring plate. The milling compartments were filled 60% (by volume) with 0.4-0.6 mm milling beads (SiLibeads, zirconium oxide, yttrium-stabilized) and the remaining volume was filled with suspension, taking care to exclude air bubbles. After milling for 1 h 30 min at 400 rpm, a nanosuspension containing particles having a d.sub.90<500 nm (Malvern, Mastersizer 2000) was present that could be used for drying.

[0048] For freeze-drying, 3 ml vials were filled with 0.7 g of suspension (filling level <1 cm), placed in the freeze-dryer, which was precooled to −40° C., and dried. The resulting powders containing active substance nanoparticles were then used to produce the hybrid systems.

[0049] The powders containing active substance nanoparticles (active substance content ≥60 wt % of active substance, PVP K12, SDS) were then baked at approx. 100° C. for up to 4 h. This afforded amorphous-crystalline hybrid systems consisting of both amorphous solid solution and finely dispersed crystalline phase. The mixed systems were demonstrated by XRPD and FTIR measurements.

[0050] FIG. 1 shows FTIR spectra of amorphous and crystalline indometacin (IMC), of the thermally equilibrated powder containing indometacin nanoparticles (IMC:PVP K12:SDS) and of the powder containing nanoparticles without thermal equilibration. FIG. 2 shows XRP diffraction patterns of thermally equilibrated powder containing indometacin nanoparticles and of the powder containing indometacin nanoparticles without thermal equilibration.

[0051] Examination of the FTIR spectra of the purely amorphous and purely crystalline active substance shows clearly that a peak at 994 cm.sup.−1 is characteristic of amorphous indometacin and a peak at 904 cm.sup.−1 is characteristic of crystalline indometacin.

[0052] If the thermally equilibrated sample is compared with the sample without thermal equilibration, it can be seen from FIG. 1 that both amorphous and crystalline fractions are present after thermal equilibration. Moreover, it can be seen from FIG. 2 that both amorphous and crystalline fractions are present in the thermally equilibrated sample, with the crystalline form being unaffected.

Example 2: Indometacin-KVA 64 System

[0053] The powders containing nanoparticles were prepared in an analogous manner to example 1, except that KVA 64 was used instead of PVP K12.

[0054] The powders containing active substance nanoparticles (active substance content >60 wt % of active substance, KVA 64 (<40 wt %), SDS) were then baked at approx. 100° C. This afforded amorphous-crystalline hybrid systems consisting of both amorphous solid solution and finely dispersed crystalline phase. The mixed systems were demonstrated by XRPD and FTIR measurements.

[0055] FIG. 3 shows FTIR spectra of amorphous and crystalline indometacin (IMC), of the thermally equilibrated powder containing indometacin nanoparticles (IMC:KVA 64:SDS) and of the powder containing nanoparticles without thermal equilibration. FIG. 4 shows XRP diffraction patterns of thermally equilibrated powder containing indometacin nanoparticles and of the powder containing indometacin nanoparticles without thermal equilibration.

[0056] Examination of the FTIR spectra of the purely amorphous and purely crystalline active substance shows clearly that a peak at 994 cm.sup.−1 is characteristic of amorphous indometacin and a peak at 904 cm.sup.−1 is characteristic of crystalline indometacin. If the thermally equilibrated sample is now compared with the sample without thermal equilibration, it can be seen from FIG. 3 that both amorphous and crystalline fractions are present after thermal equilibration. Moreover, it can be seen from FIG. 4 that both amorphous and crystalline fractions are present in the thermally equilibrated sample, with the crystalline form being unaffected.

[0057] FIG. 5 shows a schematic representation of the process according to the invention, in which particles 100 of an at least partially water-soluble polymer such as PVP K12 or KVA 64 are provided, in which the pharmaceutical active substance is present in the form of a plurality of nanocrystalline particles 200. A suitable active substance is in particular indometacin or naproxen.

[0058] An increase in temperature ΔT close to the glass transition temperature T.sub.g of the polymer results in partial dissolution of the active substance in the polymer. This is indicated by the curved arrows on the particles 200 in the middle picture.

[0059] The bottom picture depicts the pharmaceutical formulation of the invention that is obtainable by the process. In addition to the active substance nanoparticles 200, dissolved active substance is present in the polymer 110. This can be characterized as a monomolecular separation of the active substance or “solid dispersion”.

[0060] FIG. 6 is a variation on the representation in FIG. 5, in which only a single active substance nanoparticle is present in the polymer 100, 110. The depictions of this in FIGS. 5 and 6 are not necessarily on the same scale.