Vismodegib formulation

Abstract

Presented invention relates to a pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 µm and 190 µm, preferably between 160 µm and 180 µm and to a process for preparation thereof.

Description

[0001] P1827PC00

[0002] VISMODEGIB FORMULATION

[0003] The invention relates to a pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm. The presented invention further relates to a process for preparation of the pharmaceutical composition.

[0004] BACKGROUND OF THE PRESENT INVENTION

[0005] The invention relates to a pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm. The presented invention further relates to a process for preparation of the composition.

[0006] Vismodegib, compound of formula (1):

[0007]

[0008] (1 )

[0009] chemically 2-Chl oro-N-[4-chloro-3-(pyri din-2 -yl)phenyl]-4-(methanesulfonyl)benzamide, is a small molecule systemic hedgehog antagonist. Vismodegib is marketed under the trade name Erivedge® for the treatment of patients with advanced basal cell carcinoma for whom surgery is considered inappropriate.

[0010] Vismodegib was disclosed in W02006028958 application. An article published as Org. Process Res. Dev. 2016, 20, 1509-1519 described a process for preparation of Vismodegib and a solid Form B thereof.Vismodegib is expressing low solubility and high permeability. It is therefore challenging to develop a pharmaceutical composition showing similar dissolution profile as marketed product Erivedge®. We have surprisingly found that when polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm, is used for preparation of a pharmaceutical composition, similar dissolution profile as marketed product Erivedge® is obtained. We have also surprisingly found that when polymorphic Form B of Vismodegib having particle size distribution D(90) bigger or lower than between 150 pm and 190 pm were used for preparation of a pharmaceutical composition, the dissolution profiles were different from dissolution profiles of the marketed product and therefore bioequivalence cannot not be reached.

[0011] BRIEF DESCRIPTION OF THE INVENTION

[0012] The invention relates to a pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm. The presented invention further relates to a process for the preparation of the composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm.

[0013] The present invention also relates to Vismodegib in polymorphic Form B having D(90) particle size between 150 pm and 190 pm, preferably between 160 pm and 180 pm and to a process for preparation thereof.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form B of Vismodegib prepared according to Example 2.DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm.

[0017] The pharmaceutical composition is preferably oral composition, more preferably it is a capsule or a tablet.

[0018] D(90) value is defined such that 90% by volume of the particles have a particle size smaller than D(90) value and 10% by volume of the particles have a particle size greater than D(90) value.

[0019] The pharmaceutical composition according to presented invention comprises by weight based on the total weight of the composition between 40 % and 50 % of polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm

[0020] The pharmaceutical composition can further comprising:

[0021] a. One or more fillers;

[0022] b. One or more surfactants;

[0023] c. One or more disintegrants;

[0024] d. One or more binders;

[0025] e. One or more lubricants.

[0026] Fillers are used to increase the bulk volume of a tablet or capsule. By combining a filler with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. The composition according to the present invention comprises by weight based on the total weight of the composition between 30% and 60%, preferably between 40% and 50% of one or more fillers.Suitable examples of fillers to be used in accordance with the present invention include microcrystalline cellulose or lactose, such as lactose monohydrate, starch or pregelatinized starch or calcium phosphate are used. Preferably microcrystalline cellulose or lactose monohydrate and combination thereof are used.

[0027] Binders hold the excipients that are present in granules, a capsule or a tablet together. Binders ensure that capsules, tablets and granules can be formed having the desired or required mechanical strength. Binders which are suitable for use in accordance with the present invention include povidone or hydroxypropyl methylcellulose or dihydroxy propyl cellulose or sodium carboxyl methylcellulose. Preferably povidone is used. The composition of the present invention comprises by weight based on the total weight of the composition from 1% to 5% of one or more binders.

[0028] Surfactants are amphipathic substances with lyophobic and lyophilic groups.

[0029] Surfactants have several uses in pharmaceuticals:

[0030] i) For solubilisation of hydrophobic drugs in aqueous media;

[0031] ii) As components of emulsions;

[0032] iii) Surfactant self-assembly vehicles for oral and transdermal drug delivery; iv) As plasticizers in semisolid delivery systems; and

[0033] v) As agents to improve drug absorption and penetration.

[0034] Suitable examples of surfactant to be used in accordance with the presented invention include sodium lauryl sulfate or sodium laureth sulfate or dioctyl sodium sulfosuccinate or lecithin or Span such as Span 8 or Span 20 or Span 40, or Tween such as Tween 20 or Tween 40 or Tween 60 or Polysorbate 20 or Polysorbate 80 or Pol oxamer 188 or Polyoxyethylene stearate(s). Preferably sodium lauryl sulfate is used. The pharmaceutical composition of the present invention comprises by weight based on the total weight of the composition from between 1% and 5% of one or more surfactants.Disintegrants are added to a tablet composition to promote the breakup of the capsule blend or tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient. Suitable examples of disintegrants to be used in accordance with the present invention include sodium starch glycolate, preferably sodium starch glycolate - type A, or croscarmellose sodium or crospovidone or mixtures of any of the foregoing. Preferably sodium starch glycolate - type A is used. The pharmaceutical composition of the present invention comprises by weight based on the total weight of the composition from between 2% and 8% of one or more disintegrants.

[0035] The pharmaceutical composition of the invention may also contain a lubricant.

[0036] Lubricants are generally used in order to reduce sliding friction. Suitable lubricants to be used in accordance with the present invention include talc or magnesium stearate or sodium stearyl fumarate or calcium stearate or stearic acid or glyceryl behenate or hydrogenated vegetable oil or glycerine fumarate. The pharmaceutical composition of the present invention comprises by weight based on the total weight of the composition from between 0.5% and 5% of one or more lubricants.

[0037] The pharmaceutical composition according to presented invention therefore comprises by weight based on the total weight of the composition:

[0038] a. Between 40% and 50 % of polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm;

[0039] b. Between 30% and 60%, preferably between 40% and 50%, of one or more fillers, preferably selected from microcrystalline cellulose or lactose or a combination thereof;

[0040] c. Between 1% and 5% of one or more surfactants, preferably sodium lauryl sulfate;d. Between 2% and 8% of one or more disintegrants, preferably sodium starch glycolate;

[0041] e. Between 1% and 5% of one or more binders, preferably povidone;

[0042] f. Between 0.5 % and 5% of one or more lubricants, preferably selected from talc or magnesium stearate or combination thereof.

[0043] The pharmaceutical composition according to the present invention can be prepared by a process comprising:

[0044] a. Preparing the granulate by mixing polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm with one or more fillers, the surfactant, the disintegrant, the binder and wetting agent;

[0045] b. Drying and milling the granulate obtained in step a;

[0046] c. Preparing the final blend by blending the granulate with the disintegrant and the lubricant;

[0047] d. Filling the blend into capsules or compressing the blend into tablets.

[0048] The present invention further relates to polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm. The solid form Form B of Vismodegib is described in Org. Process Res. Dev. 2016, 20, 1509-1519.

[0049] The polymorphic Form B of Vismodegib having D(90) particle size between 150 pm and 190 pm, preferably between 160 pm and 180 pm can be prepared by a process comprising:

[0050] a. Dissolving Vismodegib in a mixture of methyl isobutyl ketone and water, wherein the volume ratio between methyl isobutyl ketone and water is between 200:1 and 210:1;b. Cooling the solution to a temperature between 70°C and 80°C in a course of between 45 and 90 minutes;

[0051] c. Cooling the mixture to a temperature between -10°C and 10°C in the course of between 70 and 120 minutes to obtain a suspension;

[0052] d. Wett milling of the suspension at between 10000 and 13800 RPM (revolutions per minute) at a temperature between -10°C and 10°C;

[0053] e. Repeating step d. at least 2 times;

[0054] f. Isolating the solid form of Vismodegib at a temperature between -10°C and 10°C. Vismodegib used in the process can be prepared for example by a process described in W02006028958 application or Org. Process Res. Dev. 2016, 20, 1509-1519 article.

[0055] The concentration of Vismodegib in the mixture of water and methyl isobutyl ketone in step a. can be between 0.07 g / g and 0.12 g / g. Dissolving of Vismodegib in the mixture can be done at a temperature between 90°C and 100°C. After dissolving obtained solution is cooled to a temperature between 70°C and 80°C in a course of between 45 and 120 minutes and subsequently cooled to a temperature between -10°C and 10°C to obtain a suspension. The suspension is wet milled at the temperature between -10°C and 10°C at between 10000 and 13800 RMP (revolutions per minute). The milled step is repeated at least 2 times, preferably 2 times or 3 times or 4 times or 5 times or 6 times or 7 times or 10 times to obtain solid form of Vismodegib having D(90) particle size between 150 pm and 190 pm, preferably between 160 pm and 180 pm. The Vismodegib particles in polymorph Form B wherein the particles have D(90) particle size between 150 pm and 190 pm, preferably between 160 pm and 180 pm are separated by any isolation method for example filtration or by use of centrifuge at the temperature between -10°C and 10°C.

[0056] Polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm or the pharmaceuticalcomposition of the presented invention can be used for treatment of conditions that are treatable by Vismodegib, for example advanced basal cell carcinoma, keratocystic odontogenic tumor, colorectal cancer, myelofibrosis, idiopathic pulmonary disease, meningioma, pontine glioma, medulloblastoma, prostate cancer, recurrent or metastatic pancreatic cancer, sarcoma, multiple myeloma, triple negative breast cancer, gastric adenocarcinoma, small cell lung cancer or chronic graft-versus-host disease.

[0057] The invention will be further described with reference to the following examples.

[0058] EXAMPLES

[0059] The particle size of the particles and particle volume ratio between the particles populations were measured by laser diffraction. For example by using the Mastersizer 3000 software from Malvern Instruments which operates in size range from 0.01pm to 3500pm.

[0060] 10 g of the sample was used for preparation of representative sample using quartering method. The dispersion unit was filed with the dispersant and degassed. The obscuration was set to 4% - 20% by adding the sample into dispersion unit and the measurement immediately run using following method parameters.

[0061] Particle Type

[0062] Non-spherical particle mode Yes

[0063] Is Fraunhofer type No

[0064] Material properties

[0065] Refractive index 1.670

[0066] Absorption index 0.01

[0067] Dispersant properties

[0068] Dispersant name 2,2,4-trimethyl pentane

[0069]

[0070] Measurement duration

[0071] Background measurement duration (red) 10.00 s Sample measurement duration (red) 10.00 s Perform blue light measurement Yes Background measurement duration (blue) 10.00 s Sample measurement duration (blue) 10.00 s Measurement sequence

[0072] Aliquots 1

[0073] Number of measurements 3

[0074] Delay between measurements 0.00 s

[0075] Pre-measurement delay 120.00 s Accessory control settings

[0076] Accessory name Hydro MV Stirrer speed 3200 rpm Ultrasound percentage 40 % Ultrasound mode Pre-Measurement Ultrasonication duration 60.00 s Analysis settings

[0077] Analysis model General Purpose Fine powder mode Yes Analysis sensitivity Normal

[0078]

[0079] XRPD spectrum of Vismodegib particles was obtained using the following measurement conditions:

[0080] Panalytical Empyrean diffractometer with 0 / 20 geometry (transmition mode), equipped with a PixCell 3D detector

[0081] Start angle (20): 2.0°

[0082] End angle (20): 35.0°

[0083] Step size: 0.026°

[0084] Scan speed: 0.0955 “ / seconds

[0085] Radiation type: Cu

[0086] Radiation wavelengths: 1.5406 A (Kai)

[0087] Divergence slit: 1 / 2°

[0088] Antiscatter slit: 1 / 2°

[0089] Seller slit: 0.02 rad

[0090] Detector slit: 7.5 mm

[0091] Rotation speed: 30 rpm

[0092]

[0093] Example 1: Vismodegib formulation

[0094] Vismodegib capsules were prepared in a conventional way as described further herein below and have the following compositions:

[0095] Ingredient Amount / dosage unit mg % Intragranular phase

[0096] Vismodegib in Form B having particle size 150 43.0 between 150 pm and 190 pm

[0097] Microcrystalline cellulose 87.3 25.0

[0098] Lactose monohydrate 71.5 20.5

[0099] Sodium lauryl sulfate 7.0 2.0

[0100] Sodium starch glycolate, type A 8.8 2.5

[0101] Povidone 10.5 3.0

[0102] Water q.s.

[0103] Extragranular phase

[0104] Sodium starch glycolate, type A 8.8 2.5

[0105] Talc 3.5 1.0

[0106] Magnesium stearate 1.7 0.5

[0107] Capsule shell

[0108] Gelatine capsules size 1 76.0

[0109]

[0110] Vismodegib, microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate and sodium lauryl glycolate were blended. The povidone was dissolved in required amount of water and the prepared solution was added over the previous blend to granulate it. Obtained wet granulates were dried and milled. The milled granulate was blended with sodium starch glycolate and talc and thereafter with the magnesium stearate. The blend was filled into hard capsules.

[0111] The dissolution profiles of the prepared capsule composition and Originator's product Erivedge® were compared by use of following method: USP II (paddles); 75 rpm; 900 ml;

[0112]

[0113]

[0114] Example 2: Preparation of Vismodegib particles in polymorph Form B wherein the particle size of Vismodegib particles is between 150 and 190 pm

[0115] 16 kg of Vismodegib were mixed with 164 kg of methyl isobutyl ketone, and 0.8 kg of water. The mixture was then stirred at 80 RPM and temperature is gradually increased to 95 °C. Obtained solution was then cooled to 75 °C in the course of 60 minutes and further cooled down to 0 °C in the course of 90 minutes. Obtained slurry is stirred at 0 °C for additional 60 minutes.

[0116] The slurry is wet milled at 0°C at the rotor speed of 13800 RPM for a total time of 25 minutes. The wet milling step is repeated two more times to provide polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm, preferably between 160 pm and 180 pm.

[0117] XRPD pattern of obtained Vismodegib particles corresponds to XRPD pattern depicted in Figure 1.

Claims

CLAIMS1. A pharmaceutical composition comprising polymorphic Form B of Vismodegib having particle size distribution D(90) between 150 pm and 190 pm.

2. The pharmaceutical composition according to claim 1 wherein the particle size distribution D(90) is between 160 pm and 180 pm.

3. The pharmaceutical composition according to claim 1 or 2 further comprising:a. One or more fillers;b. One or more surfactants;c. One or more disintegrants;d. One or more binders;e. One or more lubricants.

4. The pharmaceutical composition according to claim 3 wherein the composition comprises by weight based on the total weight of the composition:a. Between 40% and 50% of Vismodegib;b. Between 30% and 60% of one or more fillers;c. Between 1% and 5% of one or more surfactants;d. Between 2% and 8 % of one or more disintegrants;e. Between 1% and 5% of one or more binders;f. Between 0.5% and 5% of one or more lubricants.

5. The pharmaceutical composition according to claims 3 or 4 wherein the composition comprises:a. One or more fillers selected from microcrystalline cellulose or lactose or a combination thereof;b. A surfactant beeing sodium lauryl sulfate;c. A disintegrant beeing sodium starch glycolate;d. A binder being povidone;e. One or more lubricants selected from talc or magnesium stearate or combination thereof.

6. The pharmaceutical composition according to any one of claims 1 to 5 wherein the composition is oral composition.

7. The composition according to claim 6 wherein the composition is in the form of a capsule or in the form of a tablet.

8. The composition according to claim 7 wherein the composition is in the form of a capsule.

9. A process for preparation of the composition according to any one of claims 1 to 8 comprising:a. Preparing the granulate by mixing Vismodegib with one or more fillers, the surfactant, the disintegrant, the binder and wetting agent;b. Drying and milling the granulate obtained in step a;c. Preparing the final blend by blending the granulate with the disintegrant and the lubricant;d. Filling the blend into capsules or compressing the blend into tablets.

10. The composition according to any one of claims 1 to 8 for use in the treatment of advanced basal cell carcinoma, keratocystic odontogenic tumor, colorectal cancer, myelofibrosis, idiopathic pulmonary disease, meningioma, pontine glioma, medulloblastoma, prostate cancer, recurrent or metastatic pancreatic cancer, sarcoma, multiple myeloma, triple negative breast cancer, gastric adenocarcinoma, small cell lung cancer or chronic graft-versus-host disease.

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