Patent Application
20240261225
The invention discloses a method for preparation of spray dried solid dispersions, SDD, comprising an active agent, AA, such as an active pharmaceutical ingredient, API, and a dispersion polymer, DISPPOL, wherein the spray drying is done with a solution of AA and of DISPPOL in a solvent comprising C1-3 alkanol and formic acid, and optionally water.
Spray dried solid dispersions, SDD, comprising an active pharmaceutical ingredient, API, and a dispersion polymer, DISPPOL, are typically produced by dissolving the dispersion polymer and the API in a volatile solvent, such as methanol or acetone, or in a mixture of solvents, followed by spray drying. In cases where the API has limited solubility, e.g. <4 wt % at room temperature, in the spray drying solvent, an API suspension can be heated to a temperature either below or above the solvent's ambient pressure boiling point, this is known as “hot spray drying process”, resulting in a higher dissolved concentration of API. In some cases, even the higher temperatures do not give adequate API concentrations that are economical for a spray drying process, or cause other problems such as chemical degradation of the API, or bear the risk of incomplete API dissolution in the heat exchanger. Alternate, non-preferred volatile solvents can provide increased solubility of the API, but these solvents have other disadvantages that make them less desirable, e.g. high cost, toxicity, poor equipment compatibility, poor commercial availability, high disposal costs, challenges removing to sufficiently low levels, higher viscosity.
WO 2019/220282 A1 discloses in Example 1 spray drying of a solution of erlotinib and a dispersion polymer (PMMAMA or hydroxypropyl methylcellulose acetate succinate H grade) in methanol to provide a spray dried dispersion.
WO 2017/108605 A1 discloses in table 1 of the examples spray-drying of a mixture containing dasatinib, polyvinylpyrrolidone (PVP) and a solvent containing ethanol:aqueous HCl (3M):and water 60:5:35.
US 2014/343073 A1 discloses in example 25 spray-drying of a mixture containing dasatinib, HPMC-AS, citric acid hydrate and a solvent containing ethanol and water.
WO 2014/081581 A2 discloses in example 1 spray-drying of a solution containing efavirenz, a polymer such as HPMCAS, acetone and methanol.
WO 2011/082426 A1 discloses in example 6 the preparation of beads by spraying of a solution of meclizine/Kollidon VA 64/formic acid at a ratio of 1:2:I onto 25-30 mesh sugar spheres.
There was a need for a method for preparing spray dried solid dispersion of an active agent, AA, which is a weak organic base in its free base form, and dispersion polymers, which allows for dissolving the APIs in easily processable spray drying solvents such as C1-3 alkanols at modest temperature, i.e. a temperature below the ambient pressure boiling point, at sufficiently high concentrations to enable economical throughput of SDDs. By the method the free base should be obtained as a SDD. The amorphous solid dispersion should be stable over a longer period of time.
It was found that formic acid may be used as processing aid in such spray drying method. The solubility of the AA is increased, which allows for higher concentration of AA in the spray solution than in absence of formic acid. Increased AA solubility gives higher manufacturing throughput, and potentially better spray dried particle characteristics than what is achievable with lower solids content spray solutions. When formic acid is used not only as a processing aid, but as the only solvent then viscosities tend to be high.
Subject of the invention is a method SPRAYDRY for preparing a spray dried solid dispersion, SDD, of an active agent, AA, which is an organic Bronstedt base, comprising:
SDD is a spray dried solid dispersion of AA in DISPPOL. AA and DISPPOL are preferably homogeneously mixed in SDD.
In a solid dispersion of AA in DISPPOL, AA may be homogeneously and preferably also molecularly dispersed in DISPPOL. AA and DISPPOL may form a solid solution in SDD.
AA may be amorphous or substantially amorphous in SDD; substantially means that at least 80 wt %, preferably at least 90 wt %, more preferably at least 95 wt %, even more preferably at least 98 wt %, especially at least 99% wt %, of AA is amorphous; the wt % being based on the total weight of AA in SDD. SDD therefore may be an amorphous SDD. The amorphous nature of AA may be evidenced by a lack of sharp Bragg diffraction peaks in the x-ray pattern when SDD is analyzed by a powder X-Ray Diffraction, PXRD. Possible parameters and settings for a x-ray diffractometer are equipment with a Cu-Kalpha source, setting in modified parallel beam geometry between 3 and 40° 2Theta and a scan rate of 2°/min with a 0.0° step size. Another evidence for the amorphous nature of AA in the SDD may be a single glass transition temperature, Tg. A single Tg is also evidence of a homogeneous mixture of amorphous AA and polymer. Samples as such without any further sample preparation may be used for the determination of the Tg, the determination may run for example in modulated mode at a scan rate of 2.5° C./min, modulation of +1.5° C./min, and a scan range from 0 to 180° C. Amorphous nature of AA shows a Tg which is equal to the Tg of neat DSISPPOL or which is between the Tg of the polymer and the Tg of the AA. The Tg of the SDD is often similar to the weighted average of the Tg of AA and the Tg of DISPPOL. SDD is amorphous or substantially, SDD can also be called amorphous solid dispersion, ASD.
SPRAYSOL is a stable solution of AA in SOLV and formic acid.
SPRAYSOL has only one liquid phase.
SPRAYSOL does not contain AA in solid form.
Preferably, SPRAYSOL does not contain HCl.
Preferably, SPRAYSOL does not contain citric acid.
More preferably, SPRAYSOL does not contain HCl and does not contain citric acid.
Even more preferably, SPRAYSOL does not contain any other acid besides the formic acid.
Especially, SPRAYSOL consists of AA, DISPPOL, formic acid and SOLV, with AA, DISPPOL, formic acid and SOLV as defined herein, also with their embodiments.
The amount of AA with respect to SOLV is above the solubility of AA in SOLV in absence of formic acid.
Possible amount of AA in SPRAYSOL may be at least 0.5 wt %, preferably at least 1 wt %, more preferably at least 3 wt %, with the wt % being based on the weight of SPRAYSOL.
Possible amount of AA may be up to 10 wt %, preferably up to 7.5 wt %, more preferably up to 5 wt %.
Any of the lower limits may be combined with any of the upper limits of AA in SPRAYSOL.
For example, possible amounts of AA in SPRAYSOL may be from 0.5 wt % to 10 wt %, preferably from 1 wt % to 10 wt %, more preferably from 2 wt % to 10 wt %, with the wt % being based on the weight of SPRAYSOL.
The amount of formic acid is sufficient to solubilize AA in SOLV.
The amount of formic acid may be from 1 to 50 eq, preferably from 1 to 40 eq, more preferably from 1 to 30 eq, even more preferably from 1 to 25 eq, especially from 1 to 20 eq, more especially from 1 to 15 eq, even more especially from 1 to 10 eq, in particular from 1 to 5 eq, more in particular from 2 to 5 eq, even more in particular from 3 to 5 eq, based on the molar amount of AA.
In a particular embodiment, the amount of formic acid is from 3.5 to 4.5 eq based on the molar amount of AA, with 4 eq being a possible specific value.
In another particular embodiment, the amount of formic acid is from 3 to 11 eq based on the molar amount of AA.
The amount of formic acid may be up to 50 wt %, preferably up to 40 wt %, more preferably up to 30 wt %, even more preferably up to 25 wt %, especially up to 15 wt %, more especially up to 10 wt %, even more especially up to 7.5, in particular up to 5 wt %, more in particular up to 2 wt %, the wt % being based on the weight of SOLV.
The amount of formic acid may be from 0.05 to 50 wt %, preferably from 0.05 to 40 wt %, more preferably from 0.05 to 30 wt %, even more preferably from 0.05 to 25 wt %, especially from 0.05 to 15 wt %, more especially from 0.1 to 10 wt %, even more especially from 0.1 to 7.5, in particular from 0.1 to 5 wt %, more in particular from 0.1 to 2 wt %, even more in particular from 0.3 to 2 wt %, the wt % being based on the weight of SOLV.
The C1-3 alkanol of SOLV may be methanol, ethanol or isopropanol, preferably methanol or ethanol, more preferably methanol.
The amount of the C1-3 alkanol in SOLV may be at least 60 wt %, or at least 65 wt %, or at least 67.5 wt %, or at least 70 wt %, or at least 75 wt %, or at least 80 wt %, or at least 85 wt %, or at least 90 wt %, or at least 95 wt %; with the wt % being based on the weight of SOLV.
In another embodiment, SOLV may further comprise water.
When SOLV comprises water, then SOLV comprises not more than 40 wt %, preferably not more than 35 wt %, more preferably not more than 32.5 wt %, even more preferably not more than 30 wt %, especially not more than 27.5 wt %, more especially not more than 25 wt %, even more especially not more than 22.5 wt %, in particular not more than 20 wt %, of water;
When the SOLV comprises water, then SOLV may comprise at least 0.5 wt %, preferably at least 1 wt %, more preferably at least 2 wt %; even more preferably at least 5 wt %, of water, with the wt % being based on the combined weights of C1-3 alkanol and water, in another embodiment with the wt % being based on the weight of SOLV.
When SOLV comprises water, then the weight ratio C1-3 alkanol:water in SOLV may be from 99:1 to 60:40, preferably from 99:1 to 65:35, more preferably from 99:1 to 67.5:32.5, even more preferably from 99:1 to 70:30, especially from 99:1 to 75:25, more especially from 99:1 to 80:20, even more especially from 95:5 to 80:20, in particular from 90:10 to 80:20;
When SOLV comprises water, then the combined amount of the C1-3 alkanol and water in SOLV may be at least 60 wt %, or at least 65 wt %, or at least 67.5 wt %, or at least 70 wt %, or at least 75 wt %, or at least 80 wt %, or at least 85 wt %, or at least 90 wt %, or at least 95 wt %; with the wt % being based on the weight of SOLV.
In one embodiment, SOLV consists of C1-3 alkanol and water; preferably, the C1-3 alkanol is MeOH.
In one embodiment, SOLV consists of C1-3 alkanol; preferably, the C1-3 alkanol is MeOH.
In a possible particular embodiment SOLV may be consist of C1-3 alkanol and water with a weight ratio C1-3 alkanol:water from 95:5 to 75:25;
In another possible particular embodiment SOLV may be consist of MeOH and water with a weight ratio C1-3 alkanol:water from 95:5 to 75:25;
AA is in its free base form when combined with the formic acid and SOLV to form SPRAYSOL.
AA may be present in SPRAYSOL in its free base form or in its protonated form.
The SDD may comprise from 1 to 99 wt %, preferably from 10 to 95 wt %, more preferably from 10 to 80 wt %, even more preferably from 20 to 60 wt %, especially from 20 to 40 wt %, more especially from 20 to 30 wt %, of AA, the wt % being based on the weight of the SDD.
The SDD may comprise from 1 to 99 wt %, preferably from 20 to 90 wt %, more preferably from 40 to 80 wt %, even more preferably from 60 to 80 wt %, especially from 70 to 80 wt %, of DISPPOL, the wt % being based on the weight of the SDD.
Preferably, the combined content of AA and DISPPOL in SDD is from 65 to 100 wt %, more preferably from 67.5 to 100 wt %, even more preferably from 80 to 100 wt %; especially from 90 to 100 wt %; more especially from 95 to 100 wt %;
Relative amounts (w/w) of AA to DISPPOL in SDD may be from 50:1 to 1:50, preferably from 25:1 to 1:25, more preferably from 10:1 to 1:10, even more preferably from 1:1 to 1:10, especially from 1:1 to 1:5.
Amounts of DISPPOL and of AA in SPRAYSOL are chosen such that a predefined amount of DISPPOL and of AA in SDD provided.
DISPPOL is present in SPRAYSOL in a dissolved state, the amounts of DISPPOL and SOLV are chosen respectively.
For example amounts of DISPPOL in SPRAYSOL may be from 0.5 wt % to 25 wt %, preferably from 1 wt % to 20 wt %, more preferably from 2.5 wt % to 15 wt %, even more preferably from 3 wt % to 10 wt %, especially from 5 wt % to 10 wt %, with the wt % being based on the weight of SPRAYSOL.
Preferably, AA may have a solubility of 30 mg/mL or less, more preferably of 20 mg/mL or less, even more preferably of 10 mg/mL or less, in SOLV.
AA is an organic Bronstedt base.
AA may be a biologically active compound. The biologically active compound may be desired to be administered to a patient in need of AA.
AA may be a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, agrochemical, fertilizer, pesticide, herbicide, nutrient, or an active pharmaceutical ingredient, API; preferably an API.
AA may be a “small molecule,” generally having a molecular weight of 2000 Daltons or less.
An API, that is AA, may be dasatinib or gefitinib.
AA may be one or more AAs; SDD may contain one or more AAs.
Preferably, AA has a low solubility in SOLV, especially in methanol, e.g. a low solubility of less than 3 wt %, or even less than 2 wt %, or even less than 1 wt %, or even less than 0.5 wt %, or even less than 0.25 wt %.
Preferably the solubility of AA in a mixture of SOLV and formic acid, which has a composition of SOLV and formic acid as is present in SPRAYSOL, is at least 1.1 fold, more preferably at least 1.25 fold, even more preferably at least 1.5 fold, even more preferably at least 1.75 fold, even more preferably at least 2 fold, especially at least 3 fold, more especially at least 4 fold, higher than the solubility of AA in SOLV alone without formic acid.
Preferably the solubility of said AA in SPRAYSOL is at least 1.1 fold, more preferably at least 1.25 fold, even more preferably at least 1.5 fold, even more preferably at least 1.75 fold, even more preferably at least 2 fold, especially at least 3 fold, more especially at least 4 fold, higher than the solubility of AA in SOLV alone without formic acid.
Preferably the concentration of AA dissolved in a mixture of SOLV and formic acid, which has a composition of SOLV and formic acid as is present in SPRAYSOL, is at least 1.1 fold, more preferably at least 1.25 fold, even more preferably at least 1.5 fold, even more preferably at least 1.75 fold, even more preferably at least 2 fold, especially at least 3 fold, more especially at least 4 fold, higher than the solubility of AA in SOLV alone without formic acid.
Preferably the concentration of said AA dissolved in SPRAYSOL is at least 1.1 fold, more preferably at least 1.25 fold, even more preferably at least 1.5 fold, even more preferably at least 1.75 fold, even more preferably at least 2 fold, especially at least 3 fold, more especially at least 4 fold, higher than the solubility of AA in SOLV alone without formic acid.
In SPRAYDRY both SOLV and the formic acid are evaporated.
SPRAYDRY recovers and provides AA in its free base form, so essentially all of AA is obtained and is present in the SDD in its free base form, this means that the basic site of AA which has said basic pKa of 3 or greater is essentially present in deprotonated state in the SDD.
Preferably, AA has a basic pKa of 4 or greater, more preferably of 5 or greater, even more preferably of 6 or greater.
DISPPOL may comprise one or more dispersion polymers, preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, even more preferably 1 or 2 dispersion polymers.
DISPPOL may be a pharmaceutically acceptable dispersion polymer.
Suitable DISPPOL include, but are not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), carboxymethyl ethyl cellulose (CMEC), polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA), poly(methacrylic acid-co-methyl methacrylate) (PMMAMA), poly(methacrylic acid-co-ethyl acrylate), or any combination thereof.
Suitable PMMAMA polymers include, but are not limited to, poly(methacrylic acid-co-methyl methacrylate) 1:1 (for example Eudragit® L100), and poly(methacrylic acid-co-methyl methacrylate) 1:2 (for example Eudragit® S100). Eudragit® are polymer products of Evonik Industries AG, 45128 Essen, Germany.
The poly(methacrylic acid-co-ethyl acrylate) may be poly(methacrylic acid-co-ethyl acrylate) 1:1.
In an embodiment, DISPPOL is hydroxypropyl methyl cellulose, PVP, PVP-VA, HPMCAS or poly(methacrylic acid-co-methyl methacrylate).
In an embodiment, DISPPOL is HPMCAS or PMMAMA.
In another embodiment, DISPPOL is hydroxypropyl methyl cellulose;
Preferred embodiments of HPMCAS are
The dispersion polymer and the mixed solvent are chosen such that the dispersion polymer dissolves in the mixed solvent.
When DISPPOL is hydroxypropyl methyl cellulose then preferably SOLV comprises water, with the amount of water and all its embodiments as stated herein, for example from 10 to 30 wt %, or from 15 to 30 wt %, or from 20 to 30 wt %, with the wt % being based on the weight of SOLV.
The combining of AA, DISPPOL, formic acid, and SOLV, to form SPRAYSOL may be done in any sequence, such as in a first step combining formic acid with SOLV for provide a mixture of formic acid with SOLV, thereafter in a second step adding AA to said mixture to provide a solution of AA in said mixture, thereafter in a third step adding DISPPOL to said solution; or
SPRAYSOL may be fed into the spray dryer with a temperature of SPRAYSOL up to the boiling point of SPRAYSOL at ambient pressure; preferably with a temperature of from 4° C. to the boiling point of SPRAYSOL at ambient pressure, preferably from 4° C. to a temperature below the boiling point of SPRAYSOL at ambient pressure, more preferably from room temperature to 60° C. In the context of this invention the term “SPRAYSOL may be fed into the spray dryer with a temperature of SPRAYSOL” means that “SPRAYSOL is spray dried with a temperature of SPRAYSOL”.
The spray drying may be done with an inlet temperature of from 60 to 165° C., preferably from 80 to 140° C.
The spray drying may be done with an outlet temperature equal to or less than the boiling point of SOLV, such as with an outlet temperature from 20° C. to a temperature of 10° C. below the boiling point of SOLV.
The spray drying may be done with any inert gas commonly used for spray drying, such as nitrogen.
SPRAYSOL may further comprises a dissolved surfactant SURF.
SURF may be mixed with SPRAYSOL.
SURF may be for example a fatty acid and alkyl sulfonate, docusate sodium (for example available from Mallinckrodt Spec. Chern., St. Louis, Mo.), polyoxyethylene sorbitan fatty acid esters (for example Tween®, available from ICI Americas Inc, Wilmington, Del., or Liposorb® P-20, available from Lipochem Inc, Patterson, N.J., or Capmul® POE-0, available from Abitec Corp., Janesville, Wis.), natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, other phospholipids and mono- and diglycerides, vitamin E TPGS, PEO-PPO-PEO triblock copolymers (for example known under the tradename pluronics), or PEO (PEO are also called PEG, polyethyleneglycols (PEG)).
The amount of SURF may be up to 10 wt %, the wt % being based on the weight of SDD.
SPRAYSOL may further comprises pharmaceutically acceptable excipients, such as fillers, disintegrating agents, pigments, binders, lubricants, flavorants, and so forth which can be used for customary purposes and in typical amounts known to the person skilled on the art.
The SDD may comprise residual formic acid, preferably in low amounts; the content of residual formic acid in SDD may be 5'000 ppm or less, preferably 500 ppm or less, more preferably of 100 ppm or less, the ppm being based on the weight of SDD.
Also after the spraying any content of residual formic acid in SDD may be lowered to a predefined content of residual formic acid, this may be done with an additional drying step after spray drying.
The SDD may comprise residual SOLV, the content of residual SOLV in SDD may be 5'000 ppm or less, preferably 3'000 ppm or less, more preferably 500 ppm or less, even more preferably of 100 ppm or less, the ppm being based on the weight of SDD.
Also after the spraying any content of residual SOLV in SDD may be lowered to a predefined content of residual SOLV in SD.
Any residual content of formic acid or of SOLV in SDD may be reduced to the desired predefined and final content by submitting SDD after the spray drying to a second drying. Secondary drying may be done using a tray dryer or any agitated dryer known to the skilled person for drying solids.
Further subject of the invention is a spray dried solid dispersion, SDD, wherein the SDD is obtainable by the method SPRAYDRY;
Dasatinib free base was recrystallized from methanol and dried. Crystalline dasatinib was added in excess to methanol to form a saturated solution at 25° C. The solution was analyzed by TGA and found to contain 3.1 mg/mL dasatinib.
200 mg of crystalline dasatinib was slurried in 10 mL of methanol at 24° C. Upon adding 100 microliter (6.4 eq based on the molar amount of dasatinib) of 98% formic acid the mixture became a clear solution. The concentration of dissolved dasatinib was approximately 19.8 mg/mL and ca. 6 fold higher than the solubility in methanol without formic acid.
Crystalline gefitinib was added in excess to methanol and methanol:water mixtures to form saturated solutions at 20° C. After 24 hour of stirring, 1 mL aliquots were centrifuged at 10'000 RCF for 3 min. The supernatant was then analyzed for gefitinib concentration by HPLC. Solubilities in MeOH:water mixtures are given in Table 1.
The solubility of gefitinib in solvent mixtures with 98% formic acid were obtained by suspending at RT 300 mg of crystalline gefitinib in 5 mL of solvent containing 100 microliters of formic acid at 21° C. (4.0 eq of formic acid). Both solutions were visually clear solutions at 60 mg/mL.
5 ml of a mixture of 4.9 ml of 90:10 methanol/water w/w with 0.1 ml HCOOH weigh 4.122 g based on the densities at RT as stated below.
5 ml of a mixture of 4.9 ml 80:20 methanol:water w/w with 0.1 ml HCOOH weigh 4.212 g based on the densities at RT as stated below.
The solution in the mixture of 4.9 ml of 90:10 MeOH:H2O w/w with 0.1 ml HCOOH was a visually clear solution at 72.8 mg/g based on the densities at RT as stated below.
The solution in the mixture of 4.9 ml of 80:20 MeOH:H2O w/w with 0.1 ml HCOOH was a visually clear solution at 71.2 mg/g based on the densities at RT as stated below.
Table 1 shows the gefitinib solubility enhancement in solvent mixtures using 4.0 eq of formic acid; the solubility enhancement is expressed in Table 1 in form of an Solubility Enhancement Factor which is the ratio of
[Solubility with formic acid]/[Solubility without formic acid]
The solubilities in Table 1 in mg/mL or mg/g are mg gefitinib per mL or per mg solvent, if not explicitly stated otherwise.
In analogy to Example 4 the solubilities of nilotinib at 25° C. were determined.
Table 2 shows the respective nilotinib solubility enhancement in solvent mixtures using 4.0 eq of formic acid; the solubility enhancement is expressed in Table 2 in form of an Solubility Enhancement Factor which is the ratio of
The solubilities in Table 1 in mg/mL are mg nilotinib per mL solvent, if not explicitly stated otherwise.
Addition of formic acid with and without the presence of water results in an increase of solubility of nilotinib over the solubility in MeOH.
37.6 g of methanol as SOLV, 4.4 g water, and 0.4 g formic acid (8.696 mmol, 3.9 eq) were added to a flask to make a solvent blend 88.7/10.4/0.9 (w/w) methanol/water/formic acid.
1.0088 g (2.257 mmol) of gefitinib was added to the flask and stirred with a magnetic stir bar at room temperature (20° C.). Once the drug dissolved and the solution was clear, 3.0086 g of HPMCAS-MG was added to the same flask and stirred until dissolved providing a spray solution SPRAYSOL with 2.2 wt % of gefitinib and 6.5 wt % of HPMCAS-MG based on the weight of SPRAYSOL.
SPRAYSOL did not contain gefitinib in solid form, instead it contained the gefitinib in a completely dissolved state, and it had only one liquid phase.
The calculated volume of the solvent was 47 ml+4.4 ml+0.33 ml=51.73 ml based on the assumed densities stated in Example 4.
The calculated concentration of gefitinib was:
The solution was spray dried using a custom built spray dryer. The solution was pumped into a lab-scale 0.3 m diameter stainless steel spray drying chamber using a peristaltic pump to feed the solution to the nozzle at a flowrate of 15 g/min. A two-fluid nozzle ¼ J series with a 1650 liquid body and a 64 air cap made by Spraying Systems Company, Glendale Heights, IL 60187-7901, United States. Nitrogen gas as sheath gas was used to atomize the solution at a pressure of 20 psi. Heated nitrogen gas (140° C. inlet, 50 to 52° C. outlet, 500 g/min) was used to dry the particles. The resulting SDD was collected using a cyclone to separate the solids from the gas stream.
The collected SDD was placed in a vacuum tray dryer at 40° C. for secondary drying with 3.5 slpm nitrogen sweep for 24 hours at a pressure of 0.2 atm.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21182426.3 | Jun 2021 | EP | regional |
| 22150583.7 | Jan 2022 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/065249 | 6/3/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63196761 | Jun 2021 | US |
