NOVEL AMORPHOUS ACTIVE PHARMACEUTICAL INGREDIENTS

Abstract

The present invention is directed to a solid and substantially amorphous active pharmaceutical ingredient, to an oral pharmaceutical formulation comprising said substantially amorphous active pharmaceutical ingredient, as well as to a method for the manufacture of the same. The invention is also directed to the use of a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) to stabilize an active pharmaceutical ingredient (API).

Claims

1.-19. (canceled)

20. A solid substantially amorphous active pharmaceutical ingredient, comprising an API in an amount of at least 20% by weight, in admixture with a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), wherein said admixture of MMC and API (MMC-API admixture) has: (i) pores with a peak pore width in the range of 2 nm to 10 nm; (ii) an average BET surface area in the range of 150-600 m.sup.2/g; (iii) an average pore volume in the range of 0.1-1.2 cm.sup.3/g; and (iv) an average particle size distribution exhibiting a d.sub.10 value of 70-430 m; and wherein the API is idelalisib.

21. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has pores with a peak pore width in the range of 3 nm to 9 nm.

22. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average BET surface area in the range of 150-500 m.sup.2/g.

23. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average pore volume in the range of 0.1-0.9 cm.sup.3/g.

24. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average particle size distribution exhibiting a d.sub.10 value of 70-350 m.

25. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average particle size distribution exhibiting a d.sub.50 value of 75-500 m.

26. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average particle size distribution exhibiting a d.sub.50 value of 75-400 m.

27. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average particle size distribution exhibiting a d.sub.90 value of 170-500 m.

28. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average particle size distribution exhibiting a d.sub.90 value of 220-500 m.

29.-30. (canceled)

31. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, having a compressibility index of 15 or less.

32.-33. (canceled)

34. A solid substantially amorphous active pharmaceutical ingredient according to claim 20, having a Hausner ratio of 1.18 or less.

35. (canceled)

36. An oral pharmaceutical formulation, comprising a solid substantially amorphous active pharmaceutical ingredient according to claim 20, in admixture with a pharmaceutically and pharmacologically acceptable excipient, carrier, and/or diluent.

37. An oral pharmaceutical formulation which is bioequivalent to a pharmaceutical formulation according to claim 36.

38. (canceled)

39. A method for treatment of cancer whereby a solid substantially amorphous active pharmaceutical ingredient according to claim 20 is administered to a subject in need of such treatment.

40.-41. (canceled)

42. A method for treatment according to claim 39, wherein the cancer is leukemia.

43. A method for treatment according to claim 42, wherein the leukemia is Chronic Lymphocytic Leukemia (CLL).

44. A solid substantially amorphous active pharmaceutical ingredient according to claim 21, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has pores with a peak pore width in the range of 3 nm to 8 nm.

45. A solid substantially amorphous active pharmaceutical ingredient according to claim 21, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has pores with a peak pore width in the range of 3 nm to 7 nm.

46. A solid substantially amorphous active pharmaceutical ingredient according to claim 22, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average BET surface area in the range of or 60-430 m.sup.2/g.

47. A solid substantially amorphous active pharmaceutical ingredient according to claim 23, wherein said solid substantially amorphous active pharmaceutical ingredient (MMC-API admixture) has an average pore volume in the range of or 0.1-0.8 cm.sup.3/g.

Description

DESCRIPTION OF THE FIGURES

[0208] FIG. 1 illustrates the peak pore width of MMC Batch 2 compared to the API idelalisib loaded into MMC Batch 2 (referred to as MMC-idelalisib).

[0209] FIG. 2a and FIG. 2b shows thermograms recorded by using DSC for crystalline APIs (dotted shown only for A-batches for clarity), corresponding intermediates (lines) and stability samples (dashed), at T1 (dashed) (i.e. after storage for 1 month at 75% relative humidity and room temperature), T6 (dash-dotted), and T8 or T12 (dash-dot-dotted). None of MMC-APIs or stability samples exhibit endothermic signals indicating presence of crystalline API. The relative heat-flow thermograms are separated for clarity.

[0210] FIG. 3 shows an X-ray powder diffractogram (XRPD) for MMC-APIs, at TO (i.e. after API loading).

[0211] FIG. 4 shows an X-ray powder diffractogram (XRPD) for MMC-APIs, after storage for 1 month (T1) at 75% relative humidity and room temperature.

[0212] FIG. 5 shows an X-ray powder diffractogram (XRPD) for MMC-APIs, after storage for 6 months (T6) and 8 Months (T8), or 12 months (T12) at 75% relative humidity and room temperature.

GENERAL METHODS FOR PREPARATION

I. General Method for the Preparation of Particulate Anhydrous Mesoporous Magnesium Carbonate (MMC)

[0213] A particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as disclosed and claimed herein, may be prepared by a process comprising the steps of: [0214] (i) stirring magnesium oxide (MgO) and methanol under a CO.sub.2 pressure of 0.5-8 bar, and at a temperature of 15-60 C. for 12 hours-1 week in a pressure reactor, providing a reaction mixture; [0215] (ii) heating the reaction mixture under a pressure of 100 mbar-1013 mbar, and at a temperature of 10-70 C. providing a gel; [0216] (iii) drying the gel of step (ii) at 70-120 C., providing particles; [0217] (iv) finally heat-treating the particles obtained in step (iii) at a temperature of up to 300 C.; and [0218] (v) optionally milling and fractionating the particles obtained in step (iv) with regard to size.

[0219] The stirring in step (i) may be performed at a rotation speed of 10-500 rpm, and the ratio MgO [g]/Methanol [ml] may be 1:12.5, i.e. 1.0 g MgO/12.5 ml methanol.

[0220] The final optional heat-treatment (iv) of the particles may be performed by using a furnace with normal atmosphere. The temperature may be ramped from room temperature and up to 300 C. for 5-15 hours, and the temperature may thereafter be fixed at the elevated temperature for up to 24 hours.

[0221] The obtained material is a solid material or a cake which is then crushed into a particulate material. This may be done by grinding or milling (e.g. jet milling). Particles of the desired size are then size fractionized in order to provide a particle size distribution exhibiting a d.sub.10 value of 70-430 m.

[0222] The fractionation step (v) with regard to size, may be performed by dry sieving or by wet sieving. The particle size may also be controlled during the synthesis by using different types of reactors, raw material, or different methods for heat treatment.

Material Characterization

[0223] Pore size is determined using nitrogen gas adsorption. Measurements are made on a Gemini VII 2390 or a Tristar II Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, GA, USA) operated at 77.3 K, providing data to be used for determining pore size, pore volume and BET surface area of MMC and MMC loaded with API (MMC-API), respectively). Prior to analysis, 100-200 mg sample is added to a sample tube and degassed without or under vacuum for at least 12 hours at 105 C. Pore size distributions are obtained using density functional theory (DFT) applied to the adsorption branch of nitrogen sorption isotherms. The surface area is determined by using well-recognized BET equation, and hence calculated from the nitrogen sorption isotherms (Brunauer et al, JACS, 60, 1938, 309-319).

[0224] It is to be noted that the BET surface area, measured by nitrogen adsorption analysis as herein described, may be higher if measured on an MMC which has not undergone heat treatment as herein described. Heat treating the MMC, i.e. exposing the MMC to elevated temperatures for a prolonged time, such as above 200 C. for over 10 hours in an oven, reduces the residual methanol content to typically below 4% by weight. Residual methanol is mostly dispersed inside the pores of the MMC which, depending on the amount by weight, may impact measurements of BET surface area by nitrogen adsorption analysis. The BET surface area of MMC which has not been heat treated may thus vary from 400-900 m.sup.2/g (such as 450-900 m.sup.2/g or 500-850 m.sup.2/g). The BET surface area as measured in accordance with the present invention, is measured on heat treated MMC.

[0225] Powder XRPD patterns may be obtained on a Bruker D8 Advance Twin-Twin diffractometer (Bruker UK Ltd., Coventry, UK) with CuK.sub.a radiation (=1.54 ), generating XRPD patterns through elastic X-ray scattering. Prior to the analysis, samples are ground, dispersed with ethanol and applied as a thin layer upon a zero-background silicon sample holder, or as a dry powder. Any residual solvent is evaporated under a heat lamp prior to analysis. The analysis setup may be in the 20 range 20-80 degrees, 5-80 degrees or 5-65 degrees.

[0226] Presence or non-presence of crystals as detected by DSC is determined by equilibrating a weighed sample in a DSC (Differential Scanning Calorimetry) sample holder at a suitable temperature. The temperature is ramped at 10 C./min to a suitable temperature at which the sample is kept isothermally for 5 minutes before ramping the temperature down to the equilibration temperature. Finally, the temperature is ramped to well above the melting point of the sample. The equilibration temperature may be 35 C. and the isothermal temperature may be 80 C.

[0227] The particle size distributions are measured using laser diffraction with the Malvern Mastersizer 3000, using a dry method. The light scattering data, converted to particle size distribution are analyzed using Mie-scattering model, using the non-spherical particle type and MMC (MgCO.sub.3) as material (i.e. MgCO.sub.3 settings for the refractive index, adsorption index and density). Prior to adding the sample to the instrument, the sample container is mixed well in order to ensure good sampling. A few grams of powder is added to instrument for the measurement, the measurement time is set to 10-30 seconds. The lower obstruction limit is set to 0.5% and the upper limit to 5%, the air pressure is set to 1.5 barg. During the measurement the feed rate is constantly adjusted so that the obstruction is kept between 0.5% and 5%. All measurements are run in at least triplicate, from which an average result is calculated.

[0228] The particle size distribution of an MMC-API, or MMC, may also be measured using a wet method by laser diffraction with the Malvern Mastersizer 3000 with a Hydro MV accessory. The light scattering data, converted to particle size distribution are analyzed using Mie-scattering model, using the non-spherical particle type. The refractive index was set to 1.72 and absorption 0.01. In the software the dispersant is set as water with a refractive index of 1.33 and a level sensor threshold of 100. Maximum pump speed (3500 rpm) is used to prevent sedimentation of dispersed MMC-API, or MMC. All of the measurements including MMC-API, or MMC, are done in 10 mM NaOH. A background is taken with the cell filled with 10 mM NaOH and 3500 rpm pumping. A typical analysis includes 20 mg of MMC-API, or MMC, dispersed in 2.5 ml 10 mM sodium hydroxide in a 5 ml glass vial by 2 minutes of bath sonication. After sonication the MMC-API, or MMC, the sample is transferred to the measurement cell. The vial is rinsed several times to make sure all of the particular material has been transferred. Measurement duration is 10 seconds background and 10 seconds sample. Six sub runs are made, upon which an average result is calculated.

Investigation of Powder Flowability

Tapped Density and Bulk Density Measurement

[0229] A mechanically tapping device (Pharma Test PT-TD, Hainburg, Germany) is used to evaluate the powder's propensity to dense packing. A glass cylinder with a diameter of 12 mm (n=3) is filled with 10 ml of powder and weighed to obtain the initial bulk density, Bulk. Thereafter, the cylinder is mechanically tapped with a constant velocity until the most stable arrangement is achieved and the volume does no longer decrease. A comparison between the Bulk, and the final bulk density, tapped, is made. By measuring the untapped apparent volume, V.sub.0, and the final tapped apparent volume, V.sub.f, the compressibility index and Hausner ratio is calculated using equation 1 and 2. They are used as a measurement of the powder's flowability (European Pharmacopeia 9.0).

Compressibility Index (%)=100(V.sub.0V.sub.f/V.sub.0)Equation 1

Hausner ratio=V.sub.0/V.sub.fEquation 2

II. Preparation of a Solid Substantially Amorphous API (MMC-API)

[0230] A solid substantially amorphous active pharmaceutical ingredient, comprising an API in admixture with particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC), may be prepared by [0231] a. dissolving an API in a solvent such as an organic solvent; [0232] b. adding a particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as herein disclosed and claimed, to the API solution of step (a); [0233] c. evaporating the solvent; and [0234] d. optionally drying the final product.

[0235] The API starting materials apremilast, binimetinib, cabozantinib, eliglustat, enzalutamide, etravirine, idelalisib, tofacitinib and vandetanib were all purchased from Chemtronica AB, Sollentuna, Sweden.

[0236] The ratio API [g]/anhydrous and particulate substantially amorphous mesoporous magnesium carbonate (MMC) [g] depends on the target API load: e.g. 2/8 for 20 wt % API load, or 3/7 for 30 wt % API load.

[0237] Examples of solvents useful in dissolving the API in step a) are lower alcohols such as methanol or ethanol, and acetone or mixtures thereof. Also 1-butanol, 2-butanol, acidified ethanol (0.1% 1M HCl), butyl acetate, tert-butylmethyl ether, dichloromethane, dimethyl sulfoxide, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine may be useful in dissolving an API.

[0238] Evaporation of the solvent in step c) may be performed at a reduced pressure, and at a temperature of room temperature and up to 70 C., such as 50-70 C.

[0239] The optional drying in step d) may be performed at a temperature of 70-100 C.

[0240] A high API load may be useful to reduce the amount of mesoporous material and in order to reduce the size of a capsule or tablet when formulating the amorphous API into a drug product, but the amount of API cannot be too high due to the risk of crystallization.

[0241] To obtain the substantially amorphous active pharmaceutical ingredient according to the present invention (MMC-API), the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) obtained after sieving, is mixed with a solution of an API in a container, such as an evaporation flask or round flask, or in a reactor, such as a glass/glass lined/stainless steel/Hastelloy reactor. The loading step is dependent on the properties of the active pharmaceutically ingredient.

[0242] API is added to a container whereupon an adequate amount of a suitable organic solvent is added in order to dissolve the API. The API-solvent mixture is sonicated at a temperature in the range from room temperature to 50 C., or as applicable, until the API is completely dissolved (typically 0-30 minutes).

[0243] Thereafter, MMC particles (particulate anhydrous and substantially amorphous mesoporous magnesium carbonate) prepared as described in the General Method I above (General Method for the preparation of particulate anhydrous Mesoporous Magnesium Carbonate (MMC)), is added to the API solution. The target API load is 20-30% by weight. The mesoporous particles (MMC) are mixed with the API solution at room temperature (20-25 C.) by swirling the flask by hand for 10 seconds whereupon the container is attached to a rotary evaporator (Rotavapor R-300 with Heating Bath B-305, Heating Bath B-300 Base, Vacuum pump V-300 and Interface I-300 or Interface I-300 Pro, Bchi, Flawil, Switzerland). Solvent is evaporated from the mixture at a pressure in the range from 100-650 mbar at a temperature in the range from room temperature to 65 C. and a rotation speed of 100 rpm. The solid substantially amorphous active pharmaceutical ingredient, herein called an MMC-API, obtained from solvent evaporation is thereafter placed in an oven for final drying typically at 80 C. for 20-24 hours. The dried MMC-API is transferred from the container and analyzed by nitrogen gas adsorption to determine pore size, pore volume and BET surface area, as well as XRPD and DSC to determine whether the API is present in its amorphous state.

[0244] Nitrogen gas adsorption is performed on a Tristar II Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, GA, USA) operated at 77.3 K. 100-200 mg MMC-API is added to a sample tube and degassed under vacuum for at least 12 hours at 105 C. prior to analysis.

[0245] XRPD is measured using a Bruker D8 TwinTwin X-ray Diffractometer (Bruker UK Ltd., Coventry, UK) with Cu-K.sub. radiation (=1.54 ). Prior to the analysis, MMC-APIs are ground using a mortar and a pestle, and the powder poured onto a silicon zero background sample holder with a cavity. The analysis set-up is in the 2 range 5-65 degrees.

[0246] DSC analysis is performed using a DSC Q2000 (TA Instruments, Newcastle, DE, USA). 2-6 mg of MMC-API is applied onto an aluminum pan, onto which an aluminum lid is placed and firmly closed using a crimper. To allow moisture from the sample to evaporate during the analysis, a pinhole is made in the middle of the pan using a needle.

[0247] The DSC analysis was run accordingly:

Cycle 1:

[0248] Equilibration at 35 C.

Cycle 2:

[0249] Ramp 10 C./min to 80.00 C. [0250] Isothermal for 5 minutes. [0251] Ramp 10 C./min to 35 C.

Cycle 3:

[0252] Ramp 10 C./min to well above melting temperature of each respective API.

[0253] Solid substantially amorphous active pharmaceutical ingredients (MMC-APIs) are stored at room temperature in a desiccator containing a saturated NaCl solution, providing for a 75% relative humidity atmosphere. After 1 month of storage the MMC-APIs are analyzed with XRPD and DSC, as described above, to determine whether they are still amorphous or if they have crystallized.

[0254] The solid substantially amorphous active pharmaceutical ingredient (MMC-API) according to the present invention, may also be obtained by first preparing a solution of the API in a suitable solvent followed by wet impregnation onto the MMC, by spray-drying the dissolved API together with the dispersed MMC particles, by spraying the API onto MMC material suspended by a gas-stream (fluid-bed setup), by low- or high-shear wet granulation whereby the dissolved API may be applied by spraying, or by any other pharmaceutical process method.

[0255] If the admixture of MMC and API (i.e. the substantially amorphous active pharmaceutical ingredient according to the present invention, the MMC-API) is prepared on MMC which has not been heat treated, i.e. an MMC having a residual methanol content typically above 7 wt %, it is to be noted that the BET surface area may be higher on such MMC-API. The BET surface area of an MMC-API prepared on an MMC that has not been heat treated may in such case thus vary from 300-600 m.sup.2/g (such as 310-550 m.sup.2/g or 320-500 m.sup.2/g). The BET surface area as described and claimed in accordance with the present invention, is measured on MMC-API which has been prepared on MMC that was heat treated prior to API loading into the MMC material.

Stability Testing

[0256] A solid substantially amorphous active pharmaceutical ingredient as disclosed and claimed herein (MMC-API), is stored at room temperature in a desiccator containing a saturated NaCl mixture so that the relative humidity is substantially 75%. The stability of the amorphous form is measured using XRPD and DSC at different time points such as 1 month, 1 year or longer.

[0257] Powder XRPD patterns are obtained on a Bruker D8 Advance Twin-Twin diffractometer (Bruker UK Ltd., Coventry, UK) with CuK.sub.a radiation (=1.54 ), generating XRPD patterns through elastic X-ray scattering. Prior to the analysis, samples may be ground, dispersed with ethanol and applied as a thin layer upon a zero-background silicon sample holder, or as a dry powder. Any remaining solvent is evaporated, such as under a heat lamp or infrared light, prior to the analysis. The analysis setup may be in the 20 range 20-80 degrees, 5-80 degrees or 5-65 degrees.

[0258] DSC analysis is determined by equilibrating a weighed sample in a DSC (Differential Scanning Calorimetry) sample holder at a suitable temperature. The temperature is ramped at 10 C./min to a suitable temperature at which the sample is kept isothermally for 5 minutes before ramping the temperature down to the equilibration temperature. Finally, the temperature is ramped to a temperature well above the melting point of the API. The equilibration temperature may be 35 C. and the isothermal temperature may be 80 C.

[0259] To assess the chemical integrity of the APIs and excipients, in case excipients are used, a High Performance Liquid Chromatography (HPLC) system, with the appropriate software and equipped with suitable pump, auto-sampler, column, column oven and UV-VIS detector may be used. The analytical column used for the separation is selected considering the type of system that is used and the chemical entity that is analyzed. A typical analysis is performed, but not limited to, under constant column temperature of 252 C. and the separation is typically, but not limited to, carried out in isocratic mode with mobile phase constituting acetonitrile. Prior to use, the mobile phase may be filtered using millipore 0.45 m filter and degassed on an ultrasonic bath. After optimization, the ideal flow rate is identified and samples of suitable volume and concentration is injected in to the HPLC system to initiate the analysis. The analytical goal is to identify the parent chemical entity and/or the absence or presence of any chemical degradation products.

Pharmaceutical Formulations

[0260] A solid substantially amorphous active pharmaceutical ingredient as herein described and claimed (MMC-API), may be formulated as an oral pharmaceutical formulation in admixture with a pharmaceutically and pharmacologically acceptable excipient, carrier and/or diluent. Examples of a useful oral pharmaceutical formulation (a drug product) may be selected from any one of a tablet, a powder, a capsule, with solid substantially amorphous API, a granule or a cachet, each containing a predetermined amount of an amorphous API as herein described and claimed.

[0261] Examples of pharmaceutically acceptable excipients, carriers and/or diluents useful when formulating a solid substantially amorphous active pharmaceutical ingredient as herein described and claimed (MMC-API), are thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, carrier substances, lubricants or binders. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g. lactose, glucose, sucrose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g. magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g. starch, and sodium starch glycolate); wetting agents; diluents; coloring agents; emulsifying agents; pH buffering agents; preservatives; and mixtures thereof.

[0262] A substantially amorphous active pharmaceutical ingredient as disclosed and claimed herein (MMC-API), may be formulated into tablets, powder, capsules or cachet, using any suitable formulation technique known to a skilled person. Alternatively, the substantially amorphous active pharmaceutical ingredient (MMC-API) may be filled into a capsule, such as a hard gelatin capsule or a soft gelatin capsule.

Medical Use

[0263] One aspect of the present invention is the use of a solid substantially amorphous active pharmaceutical ingredient (MMC-API), as herein disclosed and claimed, in therapy.

[0264] Yet an aspect of the invention is a solid substantially amorphous active pharmaceutical ingredient as herein disclosed and claimed (MMC-API), for the treatment of any medical condition selected from psoriasis such as psoriatic arthritis or plaque psoriasis; cancer such as melanoma including unresectable or metastatic melanoma; or NSCLC; cell carcinoma such as advanced renal cell carcinoma (RCC); Gaucher 4 disease type 1 (GD1); prostate cancer such as metastatic castration-resistant prostate cancer; Human Immunodeficiency Virus infections (HIV) such as HIV Type 1 (HIV 1); diabetes; pulmonary arterial hypertension (PA-1); coronavirus disease 2019 (COVID-19);

[0265] Leukemia such as Chronic Lymphocytic Leukemia (CLL); Follicular B-Cell non-Hodgkin Lymphoma (FL); Small Lymphocytic Lymphoma (SLL); Rheumatoid Arthritis; and thyroid cancer such as symptomatic or progressive medullary thyroid cancer.

[0266] Yet an aspect of the invention, is the use of a solid substantially amorphous active pharmaceutical ingredient as herein disclosed and claimed (MMC-API), for the manufacture of a medicament for the treatment of any medical condition selected from psoriasis such as psoriatic arthritis or plaque psoriasis; cancer such as melanoma including unresectable or metastatic melanoma; or NSCLC; cell carcinoma such as advanced renal cell carcinoma (RCC); Gaucher 4 disease type 1 (GD1); prostate cancer such as metastatic castration-resistant prostate cancer; Human Immunodeficiency Virus infections (HIV) such as HIV Type 1 (HIV 1); diabetes; pulmonary arterial hypertension (PAI); coronavirus disease 2019 (COVID-19); Leukemia such as Chronic Lymphocytic Leukemia (CLL); Follicular B-Cell non-Hodgkin Lymphoma (FL); Small Lymphocytic Lymphoma (SLL); Rheumatoid Arthritis; and thyroid cancer such as symptomatic or progressive medullary thyroid cancer.

[0267] Yet an aspect of the invention, is a method for the treatment of any medical condition selected from psoriasis such as psoriatic arthritis or plaque psoriasis; cancer such as melanoma including unresectable or metastatic melanoma; or NSCLC; cell carcinoma such as advanced renal cell carcinoma (RCC); Gaucher 4 disease type 1 (GD1); prostate cancer such as metastatic castration-resistant prostate cancer; Human Immunodeficiency Virus infections (HIV) such as HIV Type 1 (HIV 1); diabetes; pulmonary arterial hypertension (PAH); coronavirus disease 2019 (COVID-19); Leukemia such as Chronic Lymphocytic Leukemia (CLL); Follicular B-Cell non-Hodgkin Lymphoma (FL); Small Lymphocytic Lymphoma (SLL); Rheumatoid Arthritis; and thyroid cancer such as symptomatic or progressive medullary thyroid cancer; whereby a solid substantially amorphous active pharmaceutical ingredient as herein disclosed and claimed (MMC-API), is administered to a subject in need of such treatment.

[0268] The use or treatment of the medical indications disclosed herein, may be monotherapy, or combination therapy with for example a drug used as standard of care therapy.

EXAMPLES

Example 1Preparation and Flowability of Particulate Anhydrous and Substantially Amorphous Mesoporous Magnesium Carbonate (MMC)

[0269] Particulate anhydrous and substantially amorphous mesoporous magnesium carbonate Batch 1 was prepared by: [0270] (i) stirring 2000 g magnesium oxide (MgO) (PharMagnesia MO Type B150 purchased from Lehmann & Voss & Co. KG, Hamburg) and 25 L of methanol (purchased from Solveco AB, Rosersberg, Sweden) in a conical dryer; [0271] (ii) applying 4 bar CO.sub.2 pressure and stirring (25 rpm) the solution from (i) at room temperature for 3 days; [0272] (iii) releasing the pressure of the reaction liquid formed in (ii); [0273] (iv) heating the reaction liquid from room temperature to 50 C. for 9 hours at 20 rpm. The temperature was hold at 50 C. for 7.5 hours, providing a gel; [0274] (v) drying the gel at 50-160 C. for 7 hours at 950 mbar and 20 rpm. The temperature was hold at 160 C. for 16 hours, forming particles; [0275] (vi) finally heat treating the particles of step (v) at a temperature of 250 C. in normal atmosphere using a furnace. The temperature was ramped from room temperature to 250 C. during 10 hours and hold at 250 C. for 10 more hours; [0276] (vii) the obtained anhydrous and substantially amorphous mesoporous particulate magnesium carbonate was ground with a mortar and pestle and sieved (dry) (30 minutes, amplitude 100%) using a Vibratory Sieve Shaker AS 200 basic (Retsch GmbH, Haan, Germany) and sieves to mesh size 150 m and 250 m.

[0277] Particulate anhydrous and substantially amorphous mesoporous magnesium carbonate Batch 2 was prepared by: [0278] (i) stirring 160 g magnesium oxide (MgO) (PharMagnesia MO Type B150 purchased from Lehmann & Voss & Co. KG, Hamburg) and 2 L of methanol (purchased from Solveco AB, Rosersberg, Sweden) in a stainless steel pressure reactor; [0279] (ii) applying 4 bar CO.sub.2 pressure and stirring (400 rpm) the solution from (i) at room temperature for 7 days; [0280] (iii) transferring the reaction liquid formed in (ii) to two evaporation flasks (a and b) connected to a rotary evaporator; [0281] (iv) heating the reaction liquids at 60 C. and at 60 rpm using the rotary evaporator for 6 hours, providing a gel; [0282] (v) [0283] a. drying the gel at 70 C. for 1 hour, 80 C. for 30 minutes and 100 C. for 1 hour the rotary evaporator, [0284] b. drying the gel at 100 C. using the rotary evaporator for 3 hours, forming particles; [0285] (vi) finally heat treating the particles of step (v) at a temperature of 250 C. in normal atmosphere using a furnace. The temperature was ramped from room temperature to 250 C. during 10 hours and hold at 250 C. for 10 more hours; [0286] (vii) the obtained anhydrous and substantially amorphous mesoporous particulate magnesium carbonate was ground with a mortar and pestle and sieved (dry) (30 minutes, amplitude 100%) using a Vibratory Sieve Shaker AS 200 basic (Retsch GmbH, Haan, Germany) and sieves with mesh sizes: 1 mm, 710 m, 500 m, 250 m and 150 m.

[0287] Nitrogen gas adsorption analysis, XRPD, DSC and investigation of powder flowability, including tapped density and bulk density measurement, on the obtained MMC are performed as described elsewhere herein.

[0288] Particulate anhydrous and substantially amorphous mesoporous magnesium carbonate Batch 3 was prepared by repeating the method described for Batch 2 four times, yielding four sub batches, varying the CO.sub.2 pressure between 4 and 4.5 bar and reaction time between 4 and 6 days (i). The reaction liquids were heated to 60 C. for 4.5-5 (iv) and further heated to between 100 C. and 105 C. for between 1 and 3 hours (v) b. After final heat treatment (vi) and sieving (vii) the sub batches were pooled as Batch 3.

Results

Batch 1

[0289] A fraction with a mean particle sizes (D.sub.50) of 192.0 m was obtained. The obtained particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) had a BET surface area of 373 m.sup.2/g and a pore volume of 0.56 cm.sup.3/g with 100% of the pore volume from pores <10 nm in diameter.

Batch 2

[0290] A fraction with a mean particle sizes (D.sub.50) of 209.0 m was obtained. The obtained particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) had a BET surface area of 365 m.sup.2/g and a pore volume of 0.76 cm.sup.3/g with 100% of the pore volume from pores <10 nm in diameter.

Batch 3

[0291] A fraction with a mean particle sizes (D.sub.50) of 211.0 m was obtained. The obtained particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) had a BET surface area of 402 m.sup.2/g and a pore volume of 0.64 cm.sup.3/g with 100% of the pore volume from pores <10 nm in diameter.

[0292] The bulk and tapped density for the fractions are shown in Table 1. By using the obtained values, the Carr index and Hausner ratio were calculated for the fraction and the flow property classified according to European Pharmacopeia 9.0. The fraction was classified to good. The results are summarized in Table 1 below.

TABLE-US-00001 TABLE 1 Flowability properties of the fraction obtained in Example 1 of particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (abbreviated MMC in the table below). Values are given as mean and (s.d). Bulk Tapped D.sub.10 D.sub.50 D.sub.90 density density Carr Hausner Flow MMC [m] [m] [m] [g/ml] [g/ml] index ratio property* Batch 1 96.7 192.0 306.0 0.58 0.64 10.67 1.12 Good Batch 2 84.4 209.0 352.0 0.47 0.525 10 1.11 Good Batch 3 94.0 211.0 356.0 0.53 0.60 10.33 1.12 Good *According to European Pharmacopeia 9.0 (2016), Chapter 2.9.36. Powder Flow

Example 2Preparation and Stability Testing of Solid Substantially Amorphous Idelalisib (i.e. MMC-Idelalisib)

[0293] By following the general procedure described above, the API idelalisib was loaded into MMC particles (particulate anhydrous and substantially amorphous mesoporous magnesium carbonate) prepared according to Example 1 above (MMC Batch 2 was used in this Example). The API was used in its free form.

[0294] 1538.0 mg idelalisib was added to an evaporation flask. 200 ml acetone was added in order to dissolve the idelalisib. The mixture was sonicated for 1 minute at room temperature until the idelalisib was dissolved.

[0295] 3524.2 mg of mesoporous particles (MMC) were added to the idelalisib solution. The target API load of idelalisib was 30 wt %. The mesoporous particles (MMC) were mixed with the idelalisib solution at room temperature (20-25 C.) by swirling the flask by hand for 10 seconds, whereupon the evaporation flask was attached to the rotary evaporator (with Interface I-300 Pro). The solvent was evaporated from the mixture at 600 mbar, a temperature of 55 C. and a rotation speed of 100 rpm. After 2 min the pressure was increased to 650 mbar to minimize the risk of boiling. After 4 minutes the pressure was reduced to 600 mbar whereupon the evaporation continued for an additional 5 minutes. The pressure was further reduced to 500 mbar and the evaporation continued for 4 minutes. Lastly the pressure was reduced to 300 mbar for 1 minute until the acetone had evaporated and a solid, substantially amorphous idelalisib, herein called MMC-idelalisib, was obtained.

[0296] The MMC-idelalisib was put into an oven for final drying at 80 C. for 24 hours. The finally dried MMC-idelalisib was removed from the evaporation flask and analyzed by nitrogen gas adsorption to determine pore size, pore volume and BET surface area, as well as XRPD and DSC to determine whether idelalisib was present in its amorphous state.

[0297] Nitrogen gas adsorption was performed on a Tristar II Plus 3030 surface area and porosity analyzer (Micromeritics, Norcross, GA, USA) operated at 77.3 K. 100-200 mg MMC-idelalisib was added to a sample tube and degassed under vacuum for at least 12 hours at 105 C. prior to analysis.

[0298] XRPD was measured using a Bruker D8 TwinTwin X-ray Diffractometer (Bruker UK Ltd., Coventry, UK) with Cu-K.sub. radiation (=1.54 ). The MMC-idelalisib was ground and the powder poured onto a silicon zero background sample holder with a cavity. The analysis set-up was in the 20 range: 5-65 degrees.

[0299] DSC analysis was performed using a DSC Q2000 (TA Instruments, Newcastle, DE, USA). 3.52 mg of MMC-idelalisib was added to an aluminum pan, onto which an aluminum lid was placed and firmly closed using a crimper. To allow moisture from the sample to evaporate during the analysis, a pinhole was made in the middle of the pan using a needle.

[0300] The DSC analysis was run accordingly:

Cycle 1:

[0301] Equilibration at 35 C.

Cycle 2:

[0302] Ramp 10 C./min to 80.00 C. [0303] Isothermal for 5 minutes. [0304] Ramp 10 C./min to 35 C.

Cycle 3:

[0305] Ramp 10 C./min to 300 C.

[0306] The MMC-idelalisib was stored at room temperature in a desiccator containing a saturated NaCl solution, resulting in a 75% relative humidity atmosphere. After 1 month of storage the MMC-idelalisib was analyzed with XRPD and DSC, according to described methods herein, to determine whether it was still amorphous or if it had crystallized.

[0307] The specific conditions given in this example for the loading of idelalisib into the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate, is summarized in Table 2a and Table 2b.

Example 3Preparation and Stability Testing of Solid Substantially Amorphous APIs (i.e. MMC-API)

[0308] By following the general procedure described above and more specifically by following the specific procedure as described for Example 2 using the specific conditions presented in Table 2a and Table 2b below, the APIs etravirine, vandetanib, binimetinib, cabozantinib, tofacitinib, eliglustat, enzalutamide and apremilast, were each loaded into MMC particles (particulate anhydrous and substantially amorphous mesoporous magnesium carbonate) prepared according to Example 1.

[0309] All APIs were used in its free form.

[0310] All MMC-APIs were analyzed by nitrogen gas adsorption, XRPD and/or DSC as described above. The specific conditions for each API are presented in Table 2a and Table 2b below. All MMC-APIs were analyzed by nitrogen gas adsorption, XRPD and/or DSC as described above.

TABLE-US-00002 TABLE 2a Selected APIs loaded into MMC, amounts and parameters applied to produce the corresponding amorphous MMC-APIs. API in the API Sonication MMC-API MMC load API Solvent [37 Hz] MMC admixture batch [wt %] [mg] [ml] [ C.] [Min] [mg] Apremilast(a) 1 30 297.3 Acetone 150 N/A N/A 699.5 Apremilast(b) 3 30 902.7 Acetone 200 N/A N/A 2106.6 Binimetinib(a) 2 30 310.8 Acetone 500 40 30 701.2 Binimetinib(b) 3 30 908.25 Acetone 1200 40 90 2100.75 Cabozantinib(a) 1 30 297.5 Acetone 400 43-50 10 700.3 Cabozantinib(b) 3 20 401.4 Acetone 200 30-40 14 1592.7 Eliglustat(a) 2 30 296.9 Acetone 100 20 1 699.6 Eliglustat(b) 3 30 908.2 Acetone 150 20 1 2103.2 Enzalutamide(a) 2 30 307.8 Acetone 100 45 2 704.3 Enzalutamide(b) 3 25 502.7 Acetone 100 40 15 1498.97 Etravirine(a) 2 20 209.8 Acetone 250 40 15 802.0 Etravirine(b) 3 20 602.9 Acetone 200 22-36 27 2401.9 Idelalisib(a) 2 30 1538.0 Acetone 200 RT 1 3524.2 Idelalisib(b) 3 30 603.9 Acetone 150 42 15 1402.5 Tofacitinib(a) 2 30 1521.3 Acetone 200 RT 1 3527.0 Tofacitinib(b) 3 25 505.2 Acetone 100 40 15 1501.5 Vandetanib(a) 2 20 401.41 Ethanol 400 40 3 1601.3 Vandetanib(b) 3 20 302.8 Ethanol 250 25 2 1201.7

TABLE-US-00003 TABLE 2b Specific conditions for loading of APIs into MMC through solvent evaporation according to the general loading description, applied to produce the corresponding amorphous MMC-APIs. Solvent evaporation API in the Rotation Temper- Final MMC-API speed ature Pressure Duration drying admixture [rpm] [ C.] [mbar] [min] [hours] Apremilast(a) 100 55 500 2 22 450 2 300 3 200 4 100 2 Apremilast(b) 100 55 520 0.33 24 550 0.5 580 0.33 600 3 550 1.75 500 1.33 450 0.5 400 0.5 350 0.33 300 1 Binimetinib(a) 100 55 550 15 24 500 1 Binimetinib(b) 100 55 550 2 21 500 2 450 2 400 8 350 4 300 3 200 1 Cabozantinib(a) 100 55 600 1 23 500 1 450 2 400 3 300 0.33 350 3 250 2 200 12 100 3 Cabozantinib(b) 100 55 500 3 21 480 2.5 450 0.25 430 0.25 350 2 Eliglustat(a) 100 55 500 2 24 450 5 300 1 Eliglustat(b) 100 55 500 2 21 450 2 400 1 300 1 200 0.5 Enzalutamide(a) 100 55 500 3 24 450 1 400 2 300 1 RT 250 1 Enzalutamide(b) 100 55 500 3 22 450 1.75 300 2 Etravirine(a) 100 55 550 2 24 500 2 450 5 400 10 RT 300 2 Etravirine(b) 100 55 500 3 24 480 1 450 1 400 1 350 0.33 320 0.75 300 1 Idelalisib(a) 100 55 600 2 24 650 4 600 5 550 4 300 1 Idelalisib(b) 100 55 500 2 22 480 0.33 450 1 430 1 400 0.5 380 0.25 350 0.17 300 1 Tofacitinib(a) 100 55 600 1 24 650 5 600 4 550 3 300 1 Tofacitinib(b) 100 55 500 2.17 22 480 1.33 450 0.42 400 0.5 350 0.25 300 1 Vandetanib(a) 100 65 500 1 20 450 1 400 2 350 0.5 300 0.5 250 1 200 1 170 3 150 10 Vandetanib(b) 100 60 550 0.5 24 500 0.5 450 0.5 400 0.5 350 4 250 1 200 3 170 4 150 4 130 1 110 1

Results

[0311] All APIs were loaded into the particulate anhydrous and substantially amorphous mesoporous magnesium carbonate (MMC) as can be seen by the change in pore volume, BET surface area and pore size.

[0312] Results from nitrogen gas adsorption of unloaded mesoporous particulate magnesium carbonate (MMC) (Table 2c) and the material (MMC) after loading (Table 2d) are presented below. The peak pore width of MMC Batch 2 compared to idelalisib loaded into MMC Batch 2 (referred to as MMC-idelalisib) is illustrated in FIG. 1.

TABLE-US-00004 TABLE 2c Pore volume, BET surface area and peak pore width of MMC. Pore Volume BET Surface Peak Pore at p/p.sub.0 0.97 Area Width MMC [cm.sup.3/g] [m.sup.2/g] [nm] Batch 1 0.56 373 4.7 Batch 2 0.76 365 5.6 Batch 3 0.64 402 4.9

TABLE-US-00005 TABLE 2d Pore volume, BET surface area and peak pore width of MMC-API, i.e. after loading of API into MMC. API in the Pore Volume BET Surface Peak Pore MMC-API API at p/p.sub.0 0.97 Area Width admixture load [cm.sup.3/g] [m.sup.2/g] [nm] Apremilast(a) 30 0.48 359 4.5 Apremilast(b) 30 0.35 302 4.2 Binimetinib(a) 30 0.38 255 5.2 Binimetinib(b) 30 0.44 373 4.5 Cabozantinib(a) 30 0.52 401 4.5 Cabozantinib(b) 20 N/A N/A N/A Eliglustat(a) 30 0.30 187 4.8 Eliglustat(b) 30 0.22 198 4.1 Enzalutamide(a) 30 0.35 215 5.0 Enzalutamide(b) 25 N/A N/A N/A Etravirine(a) 20 0.49 302 5.2 Etravirine(b) 20 0.51 333 4.9 Idelalisib(a) 30 0.40 313 4.7 Idelalisib (b) 30 N/A N/A N/A Tofacitinib(a) 30 0.36 243 4.9 Tofacitinib (b) 25 N/A N/A N/A Vandetanib(a) 20 0.61 327 5.4 Vandetanib (b) 20 N/A N/A N/A

[0313] According to results from XRPD and/or DSC, all loaded APIs measured were amorphous, as shown in Table 2e, FIG. 2a, FIG. 2b and FIG. 3.

TABLE-US-00006 TABLE 2e Physical state of API after loading into MMC (i.e. MMC-API). API in the MMC-API XRPD amorphous DSC amorphous admixture API load after loading after loading Apremilast(a) 30 Yes Yes Apremilast (b) 30 Yes Yes Binimetinib(a) 30 Yes Yes Binimetinib (b) 30 Yes Yes Cabozantinib(a) 30 Yes Yes Cabozantinib(b) 20 Yes Yes Eliglustat(a) 30 Yes Yes Eliglustat(b) 30 Yes Yes Enzalutamide(a) 30 Yes Yes Enzalutamide(b) 25 Yes Yes Etravirine(a) 20 Yes Yes Etravirine(b) 20 Yes Yes Idelalisib(a) 30 Yes Yes Idelalisib(b) 30 Yes Yes Tofacitinib(a) 30 Yes Yes Tofacitinib(b) 25 Yes Yes Vandetanib(a) 20 N/A Yes Vandetanib(b) 20 N/A Yes

[0314] After storage for 1, 6 and 8 months, or for 12 months, at 75% relative humidity and room temperature, the MMC-APIs (except for etravirine) were analyzed with XRPD and DSC again. Results from XRPD and DSC are presented in Table 2f and illustrated in FIG. 2a, FIG. 2b, FIG. 3, FIG. 4, and FIG. 5.

TABLE-US-00007 TABLE 2f Physical state of solid substantially amorphous API (i.e. MMC-API) after storage for 1 month and/or 6 months, at room temperature and 75% relative humidity. These results are also presented in FIG. 4 and FIG. 5. XRPD DSC XRPD DSC amor- amor- amor- amor- phous phous phous phous API in the after after after after MMC-API API storage storage storage storage admixture load [1 month] [1 month] [6 months] [6 months] Apremilast(a) 30 Yes Yes N/A N/A Apremilast(b) 30 Yes Yes Yes.sup.(1) Yes.sup.(1) Binimetinib(a) 30 Yes Yes N/A N/A Binimetinib(b) 30 Yes Yes Yes.sup.(1) Yes.sup.(1) Cabozantinib(a) 30 Yes Yes N/A N/A Cabozantinib(b) 20 Yes Yes Yes Yes Eliglustat(a) 30 Yes Yes N/A N/A Eliglustat(b) 30 Yes Yes Yes.sup.(1) Yes.sup.(1) Enzalutamide(a) 30 Yes Yes N/A N/A Enzalutamide(b) 25 Yes Yes Yes Yes Etravirine(a) 20 N/A N/A N/A N/A Etravirine(b) 20 Yes Yes Yes.sup.(1) Yes.sup.(1) Idelalisib(a) 30 Yes Yes Yes.sup.(2) Yes.sup.(2) Idelalisib(b) 30 Yes Yes Yes Yes Tofacitinib(a) 30 Yes Yes N/A N/A Tofacitinib(b) 25 Yes Yes Yes Yes Vandetanib(a) 20 N/A Yes N/A N/A Vandetanib(b) 20 N/A Yes N/A Yes .sup.(1)Also amorphous after storage for 8 months .sup.(2)Also amorphous after storage for 12 months