Pharmaceutical compositions of ivacaftor

Abstract

The present invention relates to stable pharmaceutical compositions comprising ivacaftor as active ingredient, crospovidone as disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression method.

Description

[0001] DESCRIPTION

[0002] PHARMACEUTICAL COMPOSITIONS OF IVACAFTOR

[0003] Field of Invention

[0004] The present invention relates to stable pharmaceutical compositions comprising ivacaftor as active ingredient, crospovidone as disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression method.

[0005] State of the Art

[0006] Cystic Fibrosis (CF) is a severe, inherited genetic disorder that predominantly affects the lungs, pancreas, digestive system, and other vital organs, leading to serious, life-threatening complications. It is caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which encodes a protein responsible for regulating the movement of salt and water in cells. When the CFTR protein malfunctions, chloride transport is disrupted, leading to the buildup of thick mucus, particularly in the lungs. This mucus accumulation causes chronic respiratory problems, recurrent infections, and progressive lung damage. Thus, this life-shortening disease requires multiple daily medications aimed at improving quality of life and managing symptoms. However, until recently, none of these treatments addressed the underlying genetic defect that causes CF.

[0007] Ivacaftor, also known as VX-770, is a groundbreaking therapy for CF that targets the root genetic cause of the disease by addressing the dysfunctional CFTR protein. This orally bioavailable small molecule offers a novel approach to treating the underlying pathophysiology of cystic fibrosis. It works by improving the function of the dysfunctional CFTR protein, which is responsible for the disrupted chloride transport in CF patients. This targeted approach offers hope for better outcomes by addressing the genetic defect rather than merely managing symptoms.

[0008] The chemical name of ivacaftor is methyl N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3 - carboxamide. The molecular formula is C24H28N2O3and the compound has a molecular weight of 392.5 g / mol.

[0009] The structural formula of ivacaftor is shown in Formula I.

[0010]

[0011] Formula I

[0012] Ivacaftor is a white to off-white crystalline solid. It is freely soluble in a methylethyl ketone / water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone, and ethanol, but practically insoluble in water and buffers with a pH range of 1.0 to 7.0.

[0013] Ivacaftor and its pharmaceutically acceptable salts thereof were first described in the EP1773816 patent document by Vertex Pharmaceuticals Incorporated for treatment of cystic fibrosis.

[0014] Ivacaftor was first commercially authorized by the U. S. Food Drug Administration in January 2012. The medicinal product of has been launched in the white to off-white granules and film-coated tablet dosage form under the name ofKALYDECO® in the strengths of 5.8, 13.4, 25, 50 and 75 mg, and 150 mg, respectively.

[0015] In the state of the art, many patents / patent applications are summarized below.

[0016] EP2464337 relates to a pharmaceutical composition comprising about 4.1% w / w of a solid dispersion, with ivacaftor in an amorphous or substantially amorphous form (80% w / w of the dispersion), combined with HPMCAS (19.5% w / w of the dispersion) to enhance solubility, and 0.5% w / w of SLS. Additionally, the composition contains microcrystalline cellulose (30.5% w / w), lactose (30.4% w / w), sodium croscarmellose (3% w / w), SLS (0.5% w / w), colloidal silicon dioxide (0.5% w / w), and magnesium stearate (1% w / w). Moreover, this formulation is made into a tablet and is intended for treating or reducing the severity of cystic fibrosis in patients with the ΔF508 mutation, and it can be administered either concurrently with, before, or after other therapeutic treatments.

[0017] EP1993360 relates to a solid stable dispersion comprising amorphous ivacaftor.EP3219705 relates to a pharmaceutical composition comprising amorphous ivacaftor having less than 30% crystalline.

[0018] EP3708564 relates to a crystalline form of ivacaftor, characterized by an X-ray powder diffraction pattern with peaks at certain 20 angles (6.2±0.2, 7.6±0.2, 12.3±0.2, and 18.0±0.2 degrees), obtaining using Cu K alpha radiation. In this document, ivacaftor form B is disclosed, providing a distinct crystalline structure.

[0019] EP2819670 relates to a pharmaceutical composition in unit dose form that contains granules, pellets, particles, or mini-tablets. The composition includes 30-50% of a solid dispersion by¬ weight, which contains about 80% amorphous or substantially amorphous ivacaftor, 19.5% HPMCAS, and 0.5% SLS. It also includes a binary filler made of mannitol and lactose in a 1:3 ratio, a sweetener (sucralose), a disintegrant, a glidant, and a lubricant, with the option of adding a wetting agent. The amorphous ivacaftor has less than 15% crystallinity, and the dose ranges from 1 mg to 250 mg.

[0020] EP2328618 relates to a pharmaceutical composition in tablet form. The composition consists of 34.1% of a solid dispersion containing 80% of substantially amorphous ivacaftor, 19.5% HPMCAS, and 0.5% SLS. Additionally, it includes 30.5% microcrystalline cellulose, 30.4% lactose, 3% sodium croscarmellose, 0.5% SLS, 0.5% colloidal silicon dioxide, and 1% magnesium stearate.

[0021] EP3345625 relates to a pharmaceutical composition comprising a solid dispersion containing 80% of amorphous or substantially amorphous ivacaftor, with less than 15% crystalline content. Additionally, the dispersion includes 19.5% of either hydroxypropyl methylcellulose acetate succinate (HPMCAS) or vinylpyrrolidone / vinyl acetate copolymer (PVP / VA), and 0.5% sodium lauryl sulfate (SLS), all by weight of the dispersion.

[0022] EP3842037 relates to a pharmaceutical composition comprising 5% to 50% of a solid dispersion. The dispersion contains 70% to 90% of amorphous or substantially amorphous ivacaftor with less than 15% crystallinity, and 30% to 10% of a polymer, either hydroxypropyl methylcellulose acetate succinate (HPMCAS) or vinylpyrrolidone / vinyl acetate copolymer (PVA / VA). The composition also includes 25% to 50% of a filler, 1% to 10% of a disintegrant, 0.3% to 2% of a surfactant, 5% to 50% of a binder, 0.05% to 2% of a glidant, and 0.1% to 2% of a lubricant.WO2024039333 describes a pharmaceutical composition comprising a solid dispersion of ivacaftor prepared by hot-melt extrusion. In this composition, ivacaftor is dispersed within a matrix that contains at least two polymers wherein the polymers are hydroxypropyl methyl cellulose acetate succinate and graft copolymer of polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol.

[0023] WO2016199085 relates to stable nanoparticulate compositions comprising ivacaftor nanoparticles. These nanoparticles exhibit good stability and have an average particle size of less than about 2000 nm, improving the solubility and bioavailability of ivacaftor for pharmaceutical use.

[0024] Ivacaftor pharmacokinetics are similar between healthy adults and CF patients. After a single 150 mg oral dose in a fed state, Tmax occurs at approximately 4 hours, with AUC of 10600 ng*hr / mL and Cmax of 768 ng / mL. Steady-state concentrations are reached by days 3-5 with an accumulation ratio of 2.2-2.9. Moreover, ivacaftor exposure increases 2.5- to 4-fold with fat¬ containing food, so KALYDECO® should be taken with fatty foods like eggs, butter, or dairy. Ivacaftor is a BCS Class II drug and accordingly has low solubility and high permeability. As a basic molecule (pKa values between 9.43 and 11.60), ivacaftor exhibits high solubility in acidic media but poor solubility in water.

[0025] Besides its solubility challenge, ivacaftor is also considered as a high-dose drug, with 75 mg and 150 mg doses in KALYDECO®, which is presented as a film-coated tablet. To address its solubility challenges, advanced formulation techniques like spray-dried dispersion (SDD) are used, where the active substance is converted into an amorphous form through the use of excipients, improving dissolution and absorption.

[0026] However, there is a need for stable pharmaceutical compositions comprising ivacaftor as active ingredient manufactured by using direct compression method with improved in-vitro release and impurity profile characteristics.

[0027] Summary of the Invention

[0028] The object of this invention is to develop stable pharmaceutical compositions comprising ivacaftor or pharmaceutically acceptable salt in a premix form, combined with at least one excipient to be used in the treatment of CFTR-mediated diseases such as cystic fibrosis.The invention provides a pharmaceutical composition where ivacaftor constitutes 75 wt% of the premix matrix. The premix matrix comprises 75 wt% ivacaftor along with 24.5% a water-soluble polymer and pharmaceutically acceptable excipient.

[0029] The invention provides a pharmaceutical composition comprising 75 wt% ivacaftor along with 24.5% a water-soluble polymer and 0.5% surfactant to overcome the disadvantageous properties of BCS Class II regarding solubility and its on dissolution profile.

[0030] Thus, the polymorphic form of ivacaftor in the premix is amorphous form.

[0031] Amorphous forms generally present enhanced solubility properties. In spite of improved solubility nature, amorphous forms are known to be most unstable forms, which can cause degradation and lead to many problems related to impurity.

[0032] The invention provides stable pharmaceutical compositions comprising a specific weight ratio pf premix composed of 75.0 wt% ivacaftor along with 24.5% a water-soluble polymer and 0.5% surfactant and at least one pharmaceutically acceptable excipient, particularly crospovidone as disintegrant. The present invention is manufactured by using direct compression method and indicates improved dissolution and nitrosamine impurity profiles.

[0033] Detailed Description of the Invention

[0034] The present invention provides a pharmaceutical composition comprising ivacaftor, or a pharmaceutically acceptable salt thereof, in premix form for the treatment of CFTR-mediated diseases, such as cystic fibrosis, in an immediate-release dosage form.

[0035] The term "premix" refers to a system where an active substance is dispersed within a polymer matrix. Premixes typically consist of an active compound distributed in a suitable carrier medium. In one embodiment, the carrier comprises a polymer, preferably a water-soluble polymer, and may include optional excipients based on active substance’s physicochemical and chemical properties.

[0036] In certain embodiments of stable pharmaceutical compositions comprises, active substance ivacaftor is present premix form maximum 75.0% by weight of the premix.

[0037] In certain embodiments of stable pharmaceutical compositions comprises the polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), is present in the premix form maximum 24.5% by weight of the premix.HPMCAS is a polymer which presents dual functions to assist low-soluble drugs. One is to promote rapid dissolution and second one is to prevent the precipitation of the drug by maintaining sustainable concentration in metabolism.

[0038] In certain embodiments of stable pharmaceutical compositions comprises, sodium lauryl sulfate (SLS) as the additional pharmaceutically acceptable excipient to be employed in surfactant function, is present in the premix form maximum approximately 0.5% by weight of the premix. SLS is surfactant that reduces the surface tension and assist low-soluble drugs to be wetted rapidly in a solvent and dissolve to maintain therapeutically effective concentrations.

[0039] The most critical development of the invention is to design the qualitative formula of the composition, because enhancing the solubility of low-soluble drugs depends on the equilibrium of the concentrations of these three materials in weight ratio by the total composition.

[0040] This formulation enhances the absorption and therapeutic efficacy of ivacaftor by addressing its poor water solubility, which is sparingly soluble in water (< 0.05 pg / ml). Thus, upon the solubility limitations, the polymorphic form of ivacaftor has the critical role.

[0041] Thus, the qualitative and quantitative identifications of the disintegrant in the total composition is essential considering the composition is in immeadiate-release dosage form.

[0042] The present invention is a high-drug load pharmaceutical composition comprising 30-35% ivacaftor by weight of the composition.

[0043] Improvements in physicochemical properties can be achieved by altering the physical forms of a given compound such as polymorphs. The physicochemical properties can be altered by choosing different polymorphs. The most important properties during drug discovery and development include solubility, dissolution, and phy si cal / chemi cal stability.

[0044] The amorphous form is one of the most promising approaches to address the low solubility of active substances, the latter being an increasing challenge in the development of pharmaceutical compositions includes them. The amorphous forms are high-energy solids and always ace the tendency to convert crystalline forms. Hence, beside solubility enhancing support, stability is critical to design stable pharmaceutical compositions.

[0045] The polymorphic conversion is affected with various manufacturing activities such as temperature expose during drying, oxidative condition expose during granulation with thesolvent and also the pressure performed during multiple steps based on applied manufacturing processes.

[0046] Thus, the selection of proper polymorph of drug substance for therapeutic use is very important to obtain the appropriate drug product with bioavailability and bioequivalence.

[0047] Therefore, the disintegrant was investigated as per the requirements of the proposed formulations comprising ivacaftor as active ingredient. In addition to above-mentioned problems sourced from ivacaftor itself such as low soluble drug in high amount. Hence, the disintegrant is selected from the group comprising superdisintegrants.

[0048] Superdisintegrants classified as synthetic, semi -synthetic, natural, and co-processed blends have been used to overcome the solubility limitations of solid dosage forms. Disintegrants indicate the advantages in solid formulations with enhanced effect of drug dissolution rate, improved efficacy.

[0049] Further, the present invention was designed along with pharmaceutically acceptable excipients and a superdisintegrant to obtain an improved ivacaftor dissolution release rate and impurity profile.

[0050] On the other hand, stable formulation designs investigated with pharmaceutically acceptable excipients by providing carefully designed quantitative and qualitative formulations with a specific manufacturing method.

[0051] The manufacturing method of the present invention is direct compression regarding to avoid any deviation from internationally acceptable quality attributes by controlling lessen adverse effects of process activities on impurity profile during manufacturing.

[0052] Direct compression is a manufacturing method preferred for low dose drugs and for drugs that inherently possess good compression characteristics. Actually, it is not a type of manufacturing process that can be expected to be applicable in the present invention because ivacaftor is a low soluble drug employed in high amount in the formulation.

[0053] Crospovidone is one the superdisintegrants to be used in low-soluble drug formulations that is applicable easily in direct compression process activites.Despite these challenges, the present invention was successfully formulated as a pharmaceutical composition using direct compression method by selecting excipients, including binders, disintegrant, glidant, lubricant and surfactant.

[0054] In another embodiment, the diluent is selected from dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose, mannitol, primarily calcium salts, and mixtures thereof. The preferred diluent is a combination of lactose anhydrous and microcrystalline cellulose. The preferred weight ratio is between 55.0%-66.0% by total weight of the composition.

[0055] In another embodiment, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof, with crospovidone is preferred. The preferred weight ratio is between 2%-5% by total weight of the composition.

[0056] In another embodiment, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, stearic acid, and mixtures thereof, with magnesium stearate being preferred. The preferred weight ratio is between 1.0%-2.0% by total weight of the composition.

[0057] In a preferred embodiment, the pharmaceutical composition comprises glidant, selected from the group consisting of colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof. Preferably, the glidant is colloidal silicon dioxide. The preferred weight ratio is between 1.0%-2.0% by total weight of the composition.

[0058] In another embodiment, the surfactant is selected from sodium stearate, sodium lauryl sulfate, docusate sodium, polysorbates, poloxamer, and mixtures thereof, with sodium lauryl sulfate being preferred to be added to the composition besides the amount in premix form.

[0059] In one embodiment, the pharmaceutical composition comprising ivacaftor in a premix along with HPMCAS and SLS, and pharmaceutically acceptable above-mentioned excipients is manufactured using direct compression. The embodiments are applicable to be generated based on dose proportional approach to get multiple strengths. Thus final tablet weight ranges from 100 mg to 600 mg.

[0060] In the embodiments of the present invention the amount of premix is between 30-35% by weight of the total composition.The inventors surprisingly achieved to provide stable pharmaceutical composition comprising ivacaftor in premix form manufactured by using direct compression method, presents proper dissolution profiles and impurity profiles.

[0061] Table 1: Quantitative compositions of Example 1 and Example 2

[0062] Weight ratio, (%)

[0063] Raw material

[0064] Example 1 Example 2

[0065] Ivacaftor premix* 30.0 35.0

[0066] Lactose monohydrate

[0067] 66.0 55.0

[0068] Cellulose, Microcrystalline

[0069] Crospovidone 2.0 5.0

[0070] Sodium lauril sulfate** 0 0.6

[0071] Silica, colloidal anhydrous 1.0 2.0

[0072] Magnesium stearate 1.0 2.0

[0073] Core tablet 100 100

[0074]

[0075] *Premix is composed of Ivacaftor active substance, HPMCAS and SLS qualitatively.

[0076] ** In the composition of Example 2, SLS is added to the formulation as extra beside the amount in premix to obtain the total weight of 0.8% by the total composition.

[0077] Table 2: Quantitative formulation of premixes employed in Example 1 and Example 2

[0078] Weight ratio, (%)

[0079] Raw material

[0080] Example 1 Example 2

[0081] Ivacaftor active substance 22.5 26.25

[0082] HPMCAS 7.35 8.575

[0083] SLS 0.15 0.175

[0084]

[0085] Further in Example- 1 and Example-2, the process for the preparation of a pharmaceutical composition manufactured by using direct compression, including the steps of:

[0086] a) Premix comprising specificed amounts of ivacaftor, HPMCAS and SLS in Table 2, and microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidalsilicon dioxide, SLS (if added as extra) and magnesium stearate were screened through a proper sieve and stirred.

[0087] b) The powder blend in step a, was mixed.

[0088] c) Tablet compression was performed with powder blend in step b.

[0089] d) Optionally, the tablets were film coated.

[0090] Although, no technical document recommends or leads the technical person to use direct compression method for stable pharmaceutical compositions comprising high-drug load amorphous ivacaftor in premix form, the inventors are accomplished and provide the present invention with proper polymorphic stability and dissolution profile.

Claims

CLAIMS1. A stable pharmaceutical composition comprising ivacaftor in a premix form wherein the composition comprises;a premix comprising ivacaftor, hydroxypropyl methylcellulose acetate succinate and sodium lauryl sulfate, wherein the weight ratio of premix is between 30.0%– 35.0% by total weight of the composition,crospovidone in weight ratio between 2.0% – 5.0% by total weight of the composition.

2. A stable pharmaceutical composition according to claim 1, wherein weight ratio of ivacaftor in premix form is 75.0%.

3. A stable pharmaceutical composition according to claim 1, wherein weight ratio of hydroxypropyl methylcellulose acetate succinate in premix form is 24.5%.

4. A stable pharmaceutical composition according to claim 1, wherein weight ratio of sodium lauryl sulfate in premix form is 0.5%.

5. A stable pharmaceutical composition according to claim 1, wherein ivacaftor is in amorphous form.

6. A stable pharmaceutical composition according to any one of the preceeding claims, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from the group comprising diluent, disintegrant, surfactant, lubricant and glidant.

7. A stable pharmaceutical composition according to claim 6, wherein the diluent is a mixture of lactose monohydrate and microcrystalline cellulose.

8. A stable pharmaceutical composition according to claim 6, wherein the disintegrant is crospovidone.

9. A stable pharmaceutical composition according to claim 6, wherein the surfactant is sodium lauryl sulfate.

10. A stable pharmaceutical composition according to claim 1, wherein weight ratio of sodium lauryl sulfate in the composition is 0.8% by total weight of the composition.

11. A stable pharmaceutical composition according to claim 6, wherein the lubricant is magnesium stearate.

12. A stable pharmaceutical composition according to claim 6, wherein the glidant is colloidal silicon dioxide.

13. A direct compression method for the preparation of a pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of; a) Premix comprising specificed amounts of ivacaftor, HPMCAS and SLS, and microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, SLS (if added as extra) and magnesium stearate were screened through a proper sieve and stirred.b) The powder blend in step a, was mixed.c) Tablet compression was performed with powder blend in step b.d) Optionally, the tablets were film coated.

Images