Voclosporin

• Molecular FormulaC₆₃H₁₁₁N₁₁O₁₂
• Average mass1214.622 Da

VOCLOSPORIN

Aurinia Pharmaceuticals  (following its merger with  Isotechnika ), in collaboration with licensee  Paladin Labs  (a subsidiary of Endo International plc ),  3SBio ,and  ILJIN , is developing a capsule formulation of the immunosuppressant calcineurin inhibitor peptide voclosporin for the treatment of psoriasis, the prevention of organ rejection after transplantation, autoimmune disease including systemic lupus erythematosus and lupus nephritis, and nephrotic syndrome including focal segmental glomerulosclerosis;

Voclosporin is an experimental immunosuppressant drug being developed by Aurinia Pharmaceuticals. It is being studied as a potential treatment for lupus nephritis (LN) and uveitis.^[1] It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.^[2] Voclosporin was discovered by Robert T. Foster and his team at Isotechnika in the mid 1990s.^[3] Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013.

Initially, voclosporin was a mixture of equal proporations of cis and trans geometric isomers of amino acid-1 modified cyclosporin. Later, in collaboration with Roche in Basel, Switzerland, voclosporin’s manufacturing was changed to yield the predominantly trans isomer which possesses most of the beneficial effect of the drug (immunosuppression) in the treatment of organ transplantation and autoimmune diseases.

Patent

WO-2020082061

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020082061&_cid=P12-K9MDK8-59382-1

Novel crystalline forms of voclosporin  which is a structural analog of cyclosporine A as calcineurin signal-transduction pathway inhibitor useful for treating lupus nephritis.

Voclosporin is a structural analog of cyclosporine A, with an additional single carbon extension that has a double-bond on one side chain. Voclosporin has the chemical name (3S,6S,9S,l2R,l5S,l8S,2lS,24S,30S,33S)-30-Ethyl-33-[(lR,2R,4E)-l-hydroxy-2-methyl-4,6-heptadien-l-yl]-6,9,l8,24-tetraisobutyl-3,2l-diisopropyl-l,4,7,l0,l2,l5,l9,25,28-nonamethyl-l,4,7,l0,l3,l6,l9,22,25,28,3 l-undecaazacyclotritriacontane-2,5,8,l l,l4,l7,20,23,26,29,32-undecone and the following chemical structure:

Voclosporin is reported to be a semisynthetic structural analogue of cyclosporine that exerts its immunosuppressant effects by inhibition of the calcineurin signal-transduction pathway and is in Phase 3 Clinical Development for Lupus Nephritis.

[0003] Voclosporin and process for preparation thereof are known from International Patent Application No. WO 1999/18120.

[0004] Certain mixtures of cis and trans-isomers of cyclosporin A analogs referred to as

ISA_TX247 in different ratios are known from U.S. Patent No. 6,998,385, U.S. Patent No. 7,332,472 and U.S. Patent No. 9,765,119.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Voclosporin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (¹³C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active

pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0008] For at least these reasons, there is a need for solid state forms (including solvated forms) of Voclosporin and salts thereof.

HPLC method:

Method description

Column: Zorbax SB C18, 1.8 pm, 100×2.1 mm

Mobile phase: A: 38 ACN : 7 TBME : 55 voda : 0.02 H₃P0₄ (V/V/V/V)

B: 70 ACN : 7 TBME : 23 voda : 0.02 H P0₄ (V/V/V/V)

Flow rate: 0.5 mL/min

Gradient

Analysis time: 26 minutes + 3 minutes equilibration

Injection volume: 3.0 pL

Column temperature: 90 °C

Diluent: Ethanol

Detection: UV, 210 nm

EXAMPLES

[0095] The starting material Voclosporin crude may be obtained according to ET.S. Patent No. 6,998,385 ETnless otherwise indicated, the purity is determined by HPLC (area percent). The crude product contained according to HPLC analysis 42.6 % trans-Voclosporin (further only Voclosporin), 40.2 % cis-Voclosporin and 2.9 % Cyclosporin A. The crude Voclosporin was purified by column chromatography on silica gel using a mixture of toluene and acetone 82 : 18 (v/v) as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated, obtaining purified Voclosporin as a white foam. According to HPLC analysis it contained 85.7 % Voclosporin, 3.6 % cis-Voclosporin and 2.6 % Cyclosporin A (further only purified Voclosporin).

[0096] The Voclosporin crude (containing about 42.6 % of Voclosporin) was used for further optimization of the chromatographic separation of cis-Voclosporin and Voclosporin and the effort resulted in improved process for chromatographic separation which includes purification by column chromatography on silica gel using a mixture of toluene and methylisobutylketone 38 : 62 as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated to a dry residue, weighing 31.0 grams. This residue was not analyzed. The material was dissolved in 25 ml of acetone and then 50 ml of water was added and the solution was let to crystallize for 2 hours in the refrigerator. Then the crystalline product was separated by filtration and dried in vacuum dryer (40 °C, 50 mbar, 12 hours), obtaining 29.6 g of dry product containing 90.6 % of Voclosporin, 0.4 % cis-Voclosporin and 3.7 % Cyclosporin A (further mentioned as final Voclosporin).

Example 1: Preparation of Voclosporin Form A

4.1 grams of Purified Voclosporin was dissolved in acetone and the solution was evaporated to 8.0 grams and the concentrate was diluted by 6 ml of water. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and water 1 : 1 (v/v) and dried on open air obtaining 2.6 grams of crystalline product Form A. Voclosporin form A was confirmed by PXRD as presented in Figure 1.

Example 2: Preparation of Voclosporin Form B

[0097] 1.0 gram of Purified Voclosporin was dissolved in a mixture of 1.5 ml acetone and 3.0 ml n-hexane. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and hexane 1 : 2 (v/v) and dried on open air obtaining 0.5 grams of crystalline product Form B. Voclosporin form B was confirmed by PXRD as presented in Figure 2.

Example 3: Preparation of Amorphous Voclosporin

[0098] 2.0 grams of Purified Voclosporin was dissolved in 40 ml of hot cyclohexane and the solution was stirred for 12 hours at room temperature. Then the crystalline product was filtered off and washed with 5 ml of cyclohexane and dried on open air, obtaining 1.3 grams of amorphous powder. Amorphous Voclosporin was confirmed by PXRD as presented in Figure 3

Example 4: Preparation of Voclosporin Form C

[0099] Final Voclosporin (2 grams) was dissolved in acetonitrile (20 ml) at 50 °C, water (6 ml) was added with stirring, and the clear solution was allowed to crystallize 5 days at 20 °C. Colorless needle crystals were directly mounted to the goniometer head in order to define the crystal structure. Voclosporin form C was confirmed by X-ray crystal structure determination.

References

External links

• Voclosporin, ClinicalTrials.gov

Voclosporin

Names
IUPAC name (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4,6-heptadien-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
Other names VCS, ISA247, Luveniq
Identifiers
CAS Number	515814-01-4
3D model (JSmol)	Interactive image
ChemSpider	5293683
PubChem CID	6918486
InChI[show]
SMILES[show]
Properties
Chemical formula	C63H111N11O12
Molar mass	1214.646 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

REFERENCES

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//////////VOCLOSPORIN, Voclosporin, ISA247, ISAtx 247, ISAtx-247, ISAtx247, Luveniq, LX211,

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