Pharmaceutical compositions comprising ivacaftor

Abstract

The present invention relates to compositions comprising ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, and at least one pharmaceutically acceptable excipient.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING IVACAFTOR Field of the Invention

[0002] The present invention relates to compositions comprising ivacaftor, which is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, and at least one pharmaceutically acceptable excipient.

[0003] Background of the Invention

[0004] Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, that is, in vitro ivacaftor increases CFTR channel gating to enhance chloride transport in certain gating mutations that have a reduced channel open probability compared to normal CFTR. Ivacaftor is used to treat cystic fibrosis in people who have one of several specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

[0005] The chemical name of ivacaftor is N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3 -carboxamide. The structure is as follows:

[0006]

[0007] Formula 1: Ivacaftor

[0008] Ivacaftor was approved by the U.S. Food and Drug Administration (FDA) in 2012 and was developed by VERTEX® Pharmaceuticals for the treatment of cystic fibrosis under the trade name Kalydeco, in the form of a solid dispersion tablet. Kalydeco is marketed in tablet form at strengths of 75 mg and 150 mg, and as oral granules (mini-tablets) in sachets at strengths of 25 mg, 50 mg, and 75 mg per pack. It is indicated for the treatment of cystic fibrosis in patients aged 6 years and older who have the G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.

[0009] Ivacaftor is a drug classified as BCS Class II or IV (low solubility, high permeability or low solubility, low permeability) according to the Biopharmaceutical Classification System (BCS). Itexhibits challenging conditions in terms of bioavailability and bioabsorption. In addition, ivacaftor is a molecule that may exhibit poor flow properties. Due to all these characteristics, it is a difficult and costly drug to develop.

[0010] W02007079139 patent discloses the spray drying method applied to a solution containing ivacaftor in crystalline form and pyrrolidone polymers such as HPMC, HPMCAS and PVP / PV to obtain an amorphous solid dispersion by utilizing the higher solubility of amorphous forms compared to crystalline forms in order to increase the solubility and bioavailability of ivacaftor.

[0011] W02010019239 and WO2011019413 patents disclose a tablet form formulated with various excipients to improve the stability and solubility of the ivacaftor in an amorphous solid dispersion state. In these patents, ivacaftor was also converted into an amorphous solid dispersion through a spray drying process using polymers.

[0012] WO2013130669 patent discloses an oral granule formulation containing ivacaftor, developed in an amorphous solid dispersion form using polymers, suitable for use in pediatric patients. It has been disclosed that amorphous ivacaftor obtained by spray drying method used extra excipients to improve stability, solubility and bioavailability despite the solid dispersion. In the patent, sucralose was preferred as a sweetener for taste masking; however, the reason for this preference was not explained.

[0013] W02022013360 patent discloses a tablet formulation developed with amorphous ivacaftor and a pH-dependent polymer. In the patent, the formulation was not developed as a solid dispersion. However, pH-dependent polymers such as hypromellose acetate succinate (HPMCAS) and methacrylic acid-ethyl acrylate copolymer (1 : 1) were used to maintain the stability of amorphous ivacaftor.

[0014] Regarding KALYDECO®, the European Public Assessment Report explained that to increase the solubility of ivacaftor for both tablets and oral granules, a spray-drying process with a water-soluble polymer was added as an intermediate step to the production process, resulting in amorphous ivacaftor, the products were developed as solid dispersions.

[0015] The general purpose of using solid dispersions in pharmaceutical delivery systems is to increase the solubility of poorly water-soluble active ingredients and to stabilize the amorphous form of the drug substance when it is molecularly dispersed within a polymer matrix. There are various methods for producing solid dispersions. Hot melt extrusion (HME) and spray drying are the most commonly used technologies for obtaining such delivery systems.Hot melt extrusion is a production process in which polymeric materials are heated above their glass transition temperature and mechanically mixed with active pharmaceutical ingredients to molecularly disperse the drug within the polymeric network. However, in this method, the chemical structure of the active ingredient may change during the process under high temperatures, which may lead to a decrease in efficacy or the formation of toxic products. The requirement for high temperature and pressure increases energy costs, which may create an economic disadvantage in large-scale production. HME equipment is generally expensive. Extruders, cooling systems and other auxiliary equipment require a high initial cost. The polymers used in HME are limited. The selection of polymers that have high melting points and are pharmaceutically acceptable is limited. Controlling the particle size of HME-produced particles can be challenging. This situation may cause problems, particularly in achieving the desired release profile. HME requires optimization of multiple parameters (e.g., temperature, pressure, screw speed). This may lead to process variations during scale-up. Some formulations may not flow properly through the extruder, which can cause blockages during processing.

[0016] The spray drying process consists of two main steps: complete solution of the active ingredient and the diluent material (e.g., a polymer) in a solvent or a mixture of solvents, followed by drying of the prepared solution using the spray drying method. The spray drying process requires high energy consumption and equipment costs. This may impose an economic burden in large-scale production. The high temperature requirement poses a problem, particularly for thermally unstable components. For this reason, integrated approaches using low-temperature equipment or alternative drying technologies should be considered. Achieving precise control over particle size, morphology, and density is challenging. This may affect the performance of the formulation. The fine particles produced may cause dust formation and potential occupational health risks in the environment if an appropriate collection system is not available. If organic solvents are used, additional equipment may be required for solvent recovery due to environmental concerns and costs. As a result, the economic, technical, and environmental requirements of the method should be evaluated through a comprehensive feasibility study. Especially in the pharmaceutical field, maximizing the potential of the technology requires continuous process improvements and innovative equipment design.

[0017] pH-dependent polymers are generally hygroscopic in nature. They may exhibit swelling or structural changes under high humidity conditions. Although such polymers are used to ensure the stability of the active ingredient, this situation may adversely affect the physical stability of the drug and impair the controlled release properties of the polymer. The chemical structure of somepH-dependent polymers may degraded at high temperatures, which can negatively affect the release profile and the shelflife of the drug.

[0018] The mechanical properties of pH-dependent polymers, such as brittleness and elasticity, may change over time or when exposed to improper storage conditions. The resistance of the polymer to pH variations in the gastrointestinal tract is a critical factor in terms of stability. Some polymers may partially dissolve in gastric acid before providing release at the target site, which can lead to a loss of efficacy.

[0019] In the prior art, since the active ingredient in the amorphous form has better solubility, it has been observed that it is converted into an amorphous state by the spray drying method together with excipients and formulated in this way. It is obvious that the application of spray drying process to a solution containing ivacaftor and a polymer, resulting in an amorphous form of ivacaftor, is widely used to increase solubility. The amorphous ivacaftor obtained by removing the solvent is processed by granulation techniques to obtain the final product. As can be seen, the process applied to obtain the final product involves numerous challenging steps and methods. In another prior art, amorphous ivacaftor was used in the tablet form without preparing a solid dispersion, and pH-dependent polymers that could cause numerous problems were used to maintain the stability of the amorphous ivacaftor. There is a need in the art to develop alternative ivacaftor compositions that are simplified in process, involve fewer steps, are obtained by a cost-effective, highly efficient and effective production method, have a high dissolution rate and bioavailability, and can provide the desired stability data.

[0020] Brief Description of the Drawings

[0021] Figure 1: Comparative dissolution rate profile of Kalydeco® film-coated tablet, Formulation A, and Formulation B in pH 6.8 sodium phosphate buffer (50 mM)+0.7% SLS

[0022] Figure 2. Comparative dissolution rate profile of Kalydeco® oral granules and Formulation X in pH 6.8 sodium phosphate buffer (50 mM)+ 0.7% SLS

[0023] Detailed Description of the Invention

[0024] The objective of the present invention is to obtain an ivacaftor composition developed through an effective, simple, high-yield, low-cost, and industrially applicable production method involving fewer steps.Another objective of the present invention is to provide ivacaftor pharmaceutical formulations suitable for oral use, with clinically appropriate dissolution and bioavailability, improved flow properties, and providing the desired stability data.

[0025] Every step of the pharmaceutical production process for obtaining the final product carries both qualitative and quantitative risks. The excess of production process steps causes both the loss of active ingredient and undesirable results such as increased impurity. Increases in impurities, chemical or biological contamination, moisture gain or loss; factors affecting the determination of quantity, such as adhesion of the active substance to materials such as devices, granulators, sieves, dust, flying reduce the desired efficiency and lead to time loss. Moreover, this condition causes a considerable increase for an expensive active ingredient such as ivacaftor.

[0026] In the present invention, to overcome this problem, amorphous ivacaftor as the active ingredient was used directly without any processing (such as spray drying, dissolving, or micronization). Thus, compared to the prior art the number of manufacturing steps has been reduced, and a simple, time- and cost-saving, high-yield, and industrially applicable production method has been achieved.

[0027] Since ivacaftor is a poorly water-soluble molecule, it causes problems in terms of dissolution profile and bioavailability. In addition, since the amorphous ivacaftor composition does not exhibit the desired dispersion behavior in the gastrointestinal system, the pharmacological activity of the drug decreases. These problems have been overcome by the pharmaceutical formulation and production method applied in the present invention. The final product exhibits a clinically acceptable dissolution profile, suitable bioavailability, and the desired dispersion characteristics.

[0028] The present invention relates to solid dosage forms comprising ivacaftor as the active ingredient. The solid dosage forms referred to herein are tablets and oral granules (mini tablets). In the formulations of both dosage forms, the active ingredient ivacaftor was used directly in amorphous form without being subjected to any amorphization process.

[0029] In a preferred embodiment of the invention, the formulation developed with amorphous ivacaftor is in the form of a tablet, preferably a film-coated tablet. Without being limited thereto, among the excipients that can be used for the tablet form, at least one filler and / or at least one disintegrant and / or at least one surfactant, and / or at least one binder and / or at least one glidant and / or at least one lubricant can be listed.The fillers suitable for the tablet formulation of the present invention are selected from a group comprising lactose, sorbitol, celluloses, calcium phosphate, starches, sugars (e.g., mannitol, sucrose, or the like), or any combination thereof.

[0030] The disintegrants suitable for the tablet formulation of the present invention are selected from a group comprising croscarmellose sodium, sodium starch glycolate, or a combination thereof.

[0031] The surfactants suitable for the tablet formulation of the present invention are selected from a group comprising sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS), dioctyl sodium sulfosuccinate (Docusate), sodium deoxycholate (DOSS), sorbitan monostearate, sorbitan tristearate, hexadecyltrimethylammonium bromide (HTAB), or mixtures thereof.

[0032] The binders suitable for the tablet formulation of the present invention are selected from a group comprising hydroxypropyl cellulose (HPC), polyethylene glycol, microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyvinyl alcohol, pregelatinized starch, glucose, natural gums, sucrose, sodium alginate, carboxymethyl cellulose, methyl cellulose, or a combination thereof.

[0033] The glidants suitable for the tablet formulation of the present invention are selected from a group comprising colloidal silicon dioxide, talc, or a combination thereof.

[0034] The lubricants suitable for the tablet formulation of the present invention are selected from a group comprising magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or a combination thereof.

[0035] According to a preferred embodiment of the present invention, the tablet formulation comprises microcrystalline cellulose and / or lactose monohydrate as a filler, hydroxypropyl cellulose as a binder, croscarmellose sodium as a disintegrant, sodium lauryl sulfate as a surfactant, colloidal silicon dioxide as a glidant, and magnesium stearate as a lubricant. This composition is defined as Formulation B.

[0036] Raw Material Name Function

[0037] Amorphous Ivacaftor Active Ingredient

[0038]

[0039] Microcrystalline Filler

[0040] Cellulose

[0041] Lactose Monohydrate Filler

[0042] Hydroxypropyl Cellulose Binder

[0043] Croscarmellose Sodium Disintegrant

[0044] Sodium Lauryl Sulfate Surfactant

[0045] Colloidal Silicon Dioxide Glidant

[0046] Magnesium Stearate Lubricant

[0047]

[0048] Table 1. Composition of Formulation B

[0049] In the present invention, trials were performed using HPMCAS (Formulation A) and hydroxypropyl cellulose (Formulation B), provided that the remaining content of the formula was the same. Trials have shown that, unlike pH-dependent polymers, the binding function of hydroxypropyl cellulose is not limited. The use of hydroxypropyl cellulose improved the mechanical strength of the tablets and enhanced the ease of processing during manufacturing. As seen in Table 2, the use of hydroxypropyl cellulose improved the hardness, disintegration and friability properties of the tablet compared to a pH-dependent polymer such as HPMCAS. At the same time, as seen in Table 3, no significant difference in solubility was observed between the separate formulation trials conducted with HPMCAS and hydroxypropyl cellulose. Owing to its pH-independent solubility, hydroxypropyl cellulose ensured a homogeneous distribution of the active ingredient within the tablet, and a stable tablet form was obtained even without the use of a pH-dependent polymer. Consequently, although an active ingredient in amorphous form was used, the production processes were simplified by using hydroxypropyl cellulose as a binder in the invention and a stable formulation that provides quality characteristics was achieved. Owing to the fact that hydroxypropyl cellulose is less expensive than pH-dependent polymers, it has also contributed to the development of a cost-effective tablet. Thus, according to the preferred embodiment of the invention, hydroxypropyl cellulose is used as a binder in the tablet form.Batch no

[0050] Formulation A (HPMCAS) Formulation B (HPC) Parameter

[0051] Hardness 6 kp 10 kp

[0052] Disintegration 2 min 3.5 min

[0053] Friability 0.5 % 0.1 %

[0054]

[0055] Table 2. Comparison of Hardness, Disintegration, and Friability of Formulations A and B

[0056] Batch no

[0057] Kalydeco® Film- Formulation A Formulation B Coated Tablet (HPMCAS) (HPC)

[0058] Time (min)

[0059] 5 51.4 72.2 50.8

[0060] 10 81.1 91.2 78.8

[0061] 15 94.0 97.1 92.3

[0062] 20 98.6 99.9 95.1

[0063] 30 100.2 100.1 97.6

[0064] 45 100.4 100.2 99.1

[0065] 60 100.5 100.4 99.7

[0066] f2 * *

[0067]

[0068] Table 3. Comparison of Dissolution Profiles of Kalydeco® Film-Coated Tablet, Formulation A, and Formulation B

[0069] * Since more than 85% dissolution was achieved within 15 minutes, the dissolution profiles are considered similar without the need for mathematical calculation.

[0070] According to the preferred embodiment of the present invention, the tablet form comprises a production process that includes slug compression and does not involve prior processing of the amorphous ivacaftor active ingredient (such as spray drying, dissolution, or micronization). The production method comprises the following steps:

[0071] i. Amorphous ivacaftor, suitable filler, suitable binder, suitable disintegrant, suitable surfactant and suitable glidant(s) are sieved, mixed and suitable lubricant is added to the blend.

[0072] ii. The obtained powder blend is compressed at the target tablet weight using appropriately sized punches and the compressed blend is sieved through a suitable mesh size at the appropriate speed.iii. The powder blend obtained by process (ii) is sieved at an appropriate speed and through a sieve of suitable mesh size, and the final blend is obtained by adding a suitable lubricant to the blend.

[0073] iv. For the ivacaftor film-coated tablet, the powder blend is compressed at the target weight using appropriately sized punches.

[0074] v. The tablets obtained by process (iv) are film-coated in the film-coating machine until the target weight is reached.

[0075] The slug compression method was selected as the production process to improve the flowability of powders with poor flow properties. The slug compression method is a pre-compression procedure used to prevent the formation of tablets with variable weights due to the poor flow of drug powder and the resulting tablets (slugs) are milled into granules and then re-compressed to produce the final tablets. The resulting tablets are milled into granules, then re-compressed to produce the final tablets. The advantages of the slug compression method are that it requires fewer unit operations than other production methods, making it less costly. Thus, less equipment, lower power consumption, reduced space, time, and labor requirements are achieved. Furthermore, the inadequate flow properties of the active ingredient and the prevention of improper filling of the powder into the die and possible variations in tablet weights, the homogeneous distribution of the active ingredient within the powder, and obtaining high yield by preventing losses during production have proven the accuracy of proceeding with the slug compression method.

[0076] In another preferred embodiment of the invention, the formulation developed with amorphous ivacaftor is in the form of oral granules. Without being limited thereto, among the excipients that can be used for the oral granul form, at least one filler, and / or at least one disintegrant, and / or at least one surfactant, and / or at least one sweetener, and / or at least one glidant, and / or at least one lubricant can be listed.

[0077] The fillers suitable for the oral granule formulation of the present invention are selected from a group comprising lactose, sorbitol, celluloses, calcium phosphate, starches, sugars (e.g., mannitol, sucrose, or the like), or any combination thereof.

[0078] The disintegrants suitable for the oral granule formulation of the present invention are selected from a group comprising croscarmellose sodium, sodium starch glycolate, or any combination thereof.The surfactants suitable for the oral granule formulation of the present invention are selected from a group comprising sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS), dioctyl sodium sulfosuccinate (Docusate), sodium deoxycholate (DOSS), sorbitan monostearate, sorbitan tristearate, hexadecyltrimethylammonium bromide (HTAB), or any combination thereof.

[0079] The sweeteners suitable for the oral granule formulation of the present invention are selected from a group comprising sodium saccharin, sorbitol, aspartame, dextrose, or any combination thereof.

[0080] The glidants suitable for the oral granule formulation of the present invention are selected from a group comprising colloidal silicon dioxide, talc, or any combination thereof.

[0081] The lubricants suitable for the oral granule formulation of the present invention are selected from a group comprising magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0082] According to a preferred embodiment of the present invention, the oral granule formulation comprises microcrystalline cellulose and / or lactose monohydrate as fillers, croscarmellose sodium as a disintegrant, sodium lauryl sulfate as a surfactant, colloidal silicon dioxide as a glidant, sodium saccharin as a sweetener, and magnesium stearate as a lubricant. This composition is defined as Formulation X.

[0083] Raw Material Name Function

[0084] Amorphous Ivacaftor Active Ingredient

[0085] Lactose Monohydrate Filler

[0086] Croscarmellose Sodium Disintegrant

[0087] Sodium Lauryl Sulfate Surfactant

[0088] Sodium Saccharin Sweetener

[0089] Colloidal Silicon Dioxide Glidant

[0090]

[0091] Magnesium Stearate Lubricant

[0092]

[0093] Table 4. Composition of Formulation X

[0094] In the preferred embodiment of the present invention, the selection of sodium saccharin as a sweetener provided a more stable oral granule formulation. In the trials conducted with sucralose in the prior art, it was observed that the samples changed color over time and therefore their stability was impaired. In the samples where sodium saccharine was used, it was observed that the stability of the product did not deteriorate and there was no color change despite all the stress conditions. Thus, a more stable and cost-effective form was obtained.

[0095] The configuration related to the oral granule formulation is a composition comprising ivacaftor and at least one excipient, characterized in that the ivacaftor in said composition is used directly in amorphous form without being subjected to any prior processing step.

[0096] The oral granule formulation preferably comprises sodium saccharin as a sweetener.

[0097] The oral granule formulation preferably comprises amorphous ivacaftor, lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, sodium saccharin, colloidal silicon dioxide, and magnesium stearate.

[0098] According to the preferred embodiment of the present invention, the oral granule form comprises a production process that includes slug compression and does not involve prior processing of the amorphous ivacaftor active ingredient (such as spray drying, dissolution, or micronization). The production method comprises the following steps:

[0099] i. Amorphous ivacaftor, suitable filler, disintegrant, surfactant, glidant and sweetener(s) are sieved and mixed, and a suitable lubricant is then added to the blend.

[0100] ii. The obtained powder blend is compressed, preferably at the target tablet weight, using appropriately sized punches and the compressed blend is sieved through a suitable mesh size at the appropriate speed.

[0101] iii. The powder blend obtained by process (ii) is sieved at an appropriate speed and through a sieve of suitable mesh size, and the final blend is obtained by adding a suitable lubricant to the blend.iv. For Ivacaftor oral granules, the powder blend is compressed using appropriately sized punches, preferably at the target weight, and packaged in the sachet filling machine.

[0102] In the present invention, the use of the slug compression method for the production of oral granules, as in the tablet form, has enabled the improvement of the flow properties of powders with poor flowability and ensured the homogeneous distribution of the active ingredient within the powder. In addition, the use of slug compression has resulted in fewer unit operation requirements and higher yield, providing savings in both time and cost.

[0103] With the present invention, oral granule and tablet forms have been provided comprising amorphous ivacaftor, which has not been subj ected to any prior processing, and suitable excipients, the formulations being highly effective, simple, involving fewer steps, high-yielding, and cost-effective, having clinically appropriate dissolution rate and bioavailability, improved flow properties, and capable of providing the desired stability data.

Claims

1. CLAIMS1. An oral granule composition comprising ivacaftor and at least one excipient, wherein the ivacaftor is used directly in an amorphous form without being subjected to any prior processing.

2. The composition according to claim 1, wherein the composition comprises sodium saccharin as a sweetener.

3. The composition according to claim 1 or 2, wherein the composition comprises -amorphous ivacaftor,-lactose monohydrate,-croscarmellose sodium,-sodium lauryl sulfate,- sodium saccharin,-colloidal silicon dioxide,-magnesium stearate4. The composition according to any of the preceding claims, wherein the oral granules are produced by a slug compression method.

5. The composition according to claim 4, wherein the slug compression method comprises the following steps:i. Amorphous ivacaftor, suitable filler, disintegrant, surfactant, glidant and sweetener(s) are sieved and mixed, and a suitable lubricant is then added to the blend.ii. The obtained powder blend is compressed by using appropriately sized punches and the compressed blend is sieved through a suitable mesh size at the appropriate speed. iii. The powder blend obtained by process (ii) is sieved at an appropriate speed and through a sieve of suitable mesh size, and the final blend is obtained by adding a suitable lubricant to the blend.iv. For Ivacaftor oral granules, the powder blend is compressed using appropriately sized punches and packaged in the sachet filling machine.

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