PROCESS FOR PRODUCING A PHARMACEUTICAL FORMULATION COMPRISING ACTIVE SUBSTANCE, POLYMER AND SURFACTANT

Abstract

A process for producing a pharmaceutical formulation comprises the steps of: A) suspending a pharmaceutical active substance in an aqueous solution of a polymer; B) drying the mixture obtained in step A); wherein in step A) the pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution of ≤1 μm and before step B) the pharmaceutical active substance is further contacted with an ionic surfactant.

Claims

1. A process for producing a pharmaceutical formulation comprising A) suspending a pharmaceutical active substance in an aqueous solution of a polymer; B) drying the mixture obtained in A); wherein in A) the pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution of ≤1 μm and wherein before B) the pharmaceutical active substance is further contacted with an ionic surfactant and wherein the active substance and the polymer are present in a relative weight ratio of ≥1:2 to ≤5:1.

2. A process according to claim 1, wherein the particles of the active substance are not contacted with a sugar or sugar alcohol.

3. The process according to claim 1, wherein the polymer and the surfactant are present in a relative weight ratio of 10:1 to ≤300:1.

4. A process according to claim 1, wherein the ionic surfactant is selected from: acylamino acids (and salts thereof), carboxylic acids and derivatives, sulfonic acids and sulfonate salts, sulfuric esters, alkylamines, alkylimidazoles, ethoxylated amines, quaternary surfactants, esterquats, amphoteric surfactants or a mixture thereof

5. The process according to claim 1, wherein the active substance is obtained in the form of particles by milling.

6. A process according to claim 5, wherein a preferred milling time (t-preferred) is employed, and said milling time is at least 1.5 times t0, optionally at least 2 times t0 and optionally at least 4 times t0.

7. The process according to claim 1, wherein the active substance is obtained in the form of particles by of precipitation.

8. The process according to claim 1, wherein the drying in B) is effected by freeze-drying.

9. The process according to claim 1, wherein the drying in B) is effected by means of contact drying or by a process based on spraying of the active substance suspension.

10. The process according to claim 9, wherein the outlet temperature (T_out) is lower than the glass transition temperature (Tg) of the polymer present in the suspension (T_out<Tg).

11. The process according to claim 10, wherein the outlet temperature (T_out) is more than 20K below the glass transition temperature (Tg) of the polymer present in the suspension (T_out<Tg−20K).

12. The process according to claim 10, wherein the outlet temperature (T_out) is more than 40K below the glass transition temperature (Tg) of the polymer present in the suspension (T_out<Tg−40K).

13. The process according to claim 1, wherein the dried mixture obtained in B) is then suspended in a suspension medium.

14. A pharmaceutical formulation comprising a pharmaceutical active substance coated with an at least partially water-soluble polymer, wherein the pharmaceutical active substance is present in the form of particles having a d.sub.90 value in the particle size distribution of ≤1 μm and wherein the polymer additionally comprises an ionic surfactant.

Description

EXAMPLES

[0057] 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.

Example 1: Freeze-Drying of Indometacin-PVP K12-SDS Nanosuspensions

[0058] 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.

[0059] For freeze-drying, 3 ml vials were filled with 0.7 g of suspension (filling level <1 cm) and placed in the freeze-dryer, which was precooled to −40° C. The “solid cakes” obtained after drying were crushed into powder with a spatula and wetted with water. The resulting suspension was then measured by static light scattering (Malvern, Mastersizer 2000) and compared with the particle size distribution of the original suspension after milling (FIG. 1). The suspensions, which contained 0.1 wt % of SDS and 6 wt % of PVP K12, showed almost complete redispersibility (10 wt % of indometacin). The resulting active substance content of the redispersible powders containing active substance nanoparticles was over 60 wt %.

[0060] FIG. 1 shows the particle size distribution before drying (after milling) and after redispersion (X=1.120).

[0061] The powders containing nanoparticles were additionally examined by Fourier transform infrared spectroscopy (FTIR, FIG. 2) and X-ray powder diffractometry (XRPD, FIG. 3). It can be seen that the crystalline state of the indometacin particles was maintained.

Example 2: Freeze-Drying of Indometacin-KVA 64-SDS Nanosuspensions

[0062] The nanosuspension was prepared in analogous manner to example 1, except that the polymer KVA 64 was used instead of PVP K12 (10:6:0.1 wt % active substance:polymer: SDS). For freeze-drying, 3 ml vials were filled with 0.7 g of suspension (filling level <1 cm) and placed in the freeze-dryer, which was precooled to −40° C. The “solid cakes” obtained after drying were crushed into powder with a spatula and wetted with water. The resulting suspension was then measured by static light scattering (Malvern, Mastersizer 2000) and compared with the particle size distribution of the original suspension after milling (FIG. 4). The suspensions, which contained 0.1 wt % of SDS and 6 wt % of KVA 64, showed almost complete redispersibility (10 wt % of indometacin). The resulting active substance content of the redispersible powders containing active substance nanoparticles was over 60 wt %.

[0063] FIG. 4 shows the particle size distribution before drying (after milling) and after redispersion (X=1.022).

[0064] The powders containing nanoparticles were additionally examined by Fourier transform infrared spectroscopy (FTIR, FIG. 5) and X-ray powder diffractometry (XRPD, FIG. 6). It can be seen that the crystalline state of the indometacin particles was maintained.

Example 3: Freeze-Drying of Vericiguat-PVP K12-SDS Nanosuspensions

[0065] The nanosuspension was prepared in analogous manner to example 1, except that vericiguat was used instead of indometacin and different concentration ratios were present (10:5.8:0.2 wt % active substance:polymer:SDS). For freeze-drying, 3 ml vials were filled with 0.7 g of suspension (filling level <1 cm) and placed in the freeze-dryer, which was precooled to −40° C. The “solid cakes” obtained after drying were crushed into powder with a spatula and wetted with water. The resulting suspension was then measured by static light scattering (Malvern, Mastersizer 2000) and compared with the particle size distribution of the original suspension after milling (FIG. 7). The suspensions, which contained 0.2 wt % of SDS and 5.8 wt % of PVP K12, showed almost complete redispersibility (10 wt % of vericiguat). The resulting active substance content of the redispersible powders containing active substance nanoparticles was over 60 wt %.

[0066] FIG. 7 shows the particle size distribution before drying (after milling) and after redispersion.

Comparative Example: Freeze-Drying of Indometacin-PVP K12 Nanosuspensions without Surfactant

[0067] The nanosuspension was prepared in analogous manner to example 1, except that the surfactant was omitted altogether. This had no great effect on the outcome of milling, consequently stable production of particles <500 nm was possible here too. For freeze-drying, 3 ml vials were filled with 0.7 g of suspension (filling level <1 cm) and placed in the freeze-dryer, which was precooled to −40° C. The “solid cakes” obtained after drying were crushed into powder with a spatula and wetted with water. The resulting suspension was then measured by static light scattering (Malvern, Mastersizer 2000) and compared with the particle size distribution of the original suspension after milling (FIG. 8). These suspensions did not show adequate redispersibility irrespective of the polymer content (10 wt % of active substance). FIG. 8 shows the particle size distribution before drying (after milling) and after redispersion (X=242.823).

Example 4—Longer Milling Times Result in Improved Redispersibility

[0068] The nanosuspension was prepared using a planetary ball mill (Fritsch Pulverisette 5). For this, 9 wt % of indometacin was stabilized with 9 wt % of PVP K12 and 0.2 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 times of 40 min, 90 min and 720 min at 400 rpm, suspensions having similar d(90) values were present (cf. FIG. 9). The three suspensions were dried by spray-drying (4M8-Trix ProCept) The inlet temperature was 110° C. A two-substance nozzle having a diameter of 1.2 mm was used.

[0069] The resulting powders were dispersed with the same amount of water that was present in the suspension before drying, which meant that the suspensions obtained had concentration ratios identical to those after milling. The particle size distribution of the suspensions after drying and redispersion was compared with that of the suspensions before drying. It can be seen clearly that a longer milling time results in powders having better redispersibility (FIGS. 10-12). Thus, after drying and redispersion, the particle size distribution (PSD) of the suspension milled for 40 min (tc=40 min) shows clear differences from the PSD of the original suspension (cf. FIG. 12). After tc=90, an improvement in redispersibility can already be seen (FIG. 11). By contrast, after drying and redispersion the suspension milled for 720 min (tc=720 min) shows no differences in PSD from the PSD of the original suspension and thus matches the latter completely (cf. FIG. 10).

Example 5—Low Drying Temperatures During Spray-Drying Result in Improved Redispersibility

[0070] The nanosuspension was prepared using a planetary ball mill (Fritsch Pulverisette 5). For this, 9 wt % of indometacin was stabilized with 9 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 90 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. The suspension was dried with the spray-dryer (from ProCepT, model 4M8-TriX) at temperatures from 70° C. to 135° C. The temperatures stated are the gas-outlet temperatures of the spray-dryer and therefore correspond also to the highest possible product temperatures. The volume flow of the suspension was 4.48 ml/min and the volume flow of the dry gas was 0.35 m.sup.3/min. The suspension was atomized at a nozzle pressure of 1 bar. FIG. 13 shows the particle size distributions of the respective suspensions after drying at various temperatures and subsequent redispersion. The temperatures stated correspond to the resulting gas-outlet temperatures. It can be seen clearly that complete redispersibility of the dried powder is achieved up to a temperature of 98° C. This is evident from the fact that the particle size distribution (PSD) of the redispersed powder corresponds to the PSD of the suspension before drying and that is characterized by “milling”. At a temperature of 107° C., the redispersibility is still almost unchanged. However, at temperatures of 115° C. and above there is a tendency to increased agglomerate formation, which adversely affects the redispersibility of the dried powder and is reflected in the PSD as a consequence of the presence of larger particles. The glass transition temperature of the polymer is approx. 112° C. A drying temperature below the glass transition temperature of the polymer is thus shown to be beneficial to the complete redispersibility of powders obtained when drying by means of spray-drying.