WO2020101597A2

WO2020101597A2 - Capsule compositions comprising tyrosine-kinase inhibitors

Info

Publication number: WO2020101597A2
Application number: PCT/TR2019/050581
Authority: WO
Inventors: Ali Ihsan SECKIN; Yuksel TOPALOGLU; Irem Yenice
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2018-08-27
Filing date: 2019-07-16
Publication date: 2020-05-22
Also published as: WO2020101597A3

Abstract

The present invention relates to solid oral pharmaceutical compositions comprising at least one tyrosine-kinase inhibitor (TKI), particularly nilotinib, or a pharmaceutically acceptable salt thereof providing high stability, solubility and patient compliance.

Description

CAPSULE COMPOSITIONS COMPRISING TYROSI E-KINASE INHIBITORS

Field of the Invention

Background of the Invention

Tyrosine kinase inhibitors (TKI) are pharmaceutical drugs that inhibit tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia.

They are also called tyrphostins, the short name for“tyrosine phosphorylation inhibitor”, originally coined in a 1988 publication which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor (EGFR). The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor. It was further shown that in spite of the conservation of the tyrosine- kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative FIER2.

Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents. Based on this work imatinib was developed against chronic myelogenous leukemia (CML) and later gefitinib and erlotinib aiming at the EGF receptor. Sunitinib, an inhibitor of the receptors for FGF, PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors.

Adavosertib, also referred to as AZD1775 or MK17750, is a Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors. Flowever, toxicities such as myelosuppression, diarrhea, and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug.

Lapatinib, FDA approved for treatment in conjunction with chemotherapy or hormone therapy, is also currently undergoing clinical trials in the treatment of HER2-overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing. A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea.

Nilotinib is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib- resistant chronic myelogenous leukemia. Structurally related to imatinib, it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. Nilotinib is a selective Bcr-Abl kinase inhibitor that is 10-30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells. Nilotinib was developed by Novartis and is sold under the trade name Tasigna®.

The chemical name of nilotinib is 4-methyl-N-[3-(4-methylimidazol-1 -yl)-5- (trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide and its chemical structure is shown in Formula 1.

Nilotinib, especially its hydrochloride monohydrate salt, has already been used in the formulations in the prior art. For instance, the patent document numbered EP2068839B1 mentions formulations comprising nilotinib or a salt thereof, a surfactant and a lubricant less than 1 % by weight. It is also specified that hydrochloride monohydrate salt of nilotinib is used in the formulation and the surfactant is poloxamer 188. The formulation further comprises lactose monohydrate in a considerably high amount, namely less than 40%, specifically about 20% by weight. Considering all these information, it can be said that stability of the formulation is not a priority for this document since the use of monohydrate salt shall have a negative effect on the moisture content of the formulation. Another point is poloxamers, essentially, are wetting agents and they are mostly used as wetting agents in eye-drop formulations, skin-wound cleansers etc. (Handbook of Pharmaceutical Excipients, R. C. Rowe, P. J. Sheskey and M.E. Quinn, sixth edition, page 507). Wetting agents are known to allow the water to penetrate in the area and promote the chemical degradation. On the other hand, lactose monohydrate also contains water in its chemical structure and it is a highly hygroscopic excipient. Moreover, lactose content is risky for the lactose-intolerant patients, especially because of its high ratio in the formulation. The preparation method is based on wet granulation which is another risky choice to make a stable formulation.

Another patent document numbered WO2012164578A1 discloses a pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the composition is prepared by dry granulation. This document considers the water content in the formulation as the technical problem, since it provokes the risk of crystallization and/or degradation of the formulation, and it claims to handle this problem by using dry granulation. However, the formulation comprises microcrystalline cellulose and poloxamer which are highly hygroscopic. In addition to that, there is no information about a selection of a nilotinib salt and its effect on the stability. Hydrochloride monohydrate salt of nilotinib is also considered to be used in the formulation despite its water content.

Based on the information above, there is a need in the art for solid oral pharmaceutical compositions providing high stability and solubility with patient compliance, comprising convenient forms of nilotinib and combining them with suitable excipients.

Objectives and Brief Description of the Invention

The main object of the present invention is to obtain capsule compositions comprising at least one tyrosine-kinase inhibitor (TKI), which removes all the above-mentioned problems and brings additional advantages to the prior art.

A further object of the present invention is to develop capsule compositions of TKI having reduced moisture content and reduced hygroscopicity. A further object of the present invention is to develop capsule compositions of TKI having improved stability and prolonged shelf life.

A further object of the present invention is to develop capsule compositions of TKI providing enhanced solubility.

Another object of the present invention is to develop capsule compositions comprising TKI and having increased patient compliance.

Another object of the present invention is to develop solid oral pharmaceutical compositions comprising TKI for use in the treatment of chronic myelogenous leukemia.

Another object of the present invention is to develop capsule compositions of nilotinib, especially compositions comprising hydrochloride anhydrous salt of nilotinib providing the above-mentioned properties.

Another object of the present invention is to develop a process for preparing said capsule formulations comprising dry granulation which is performed by slugging with briquette presses.

Detailed Description of the Invention

For the purposes outlined above, detailed features of the present invention are presented herein.

The present invention relates to a capsule composition comprising at least one tyrosine- kinase inhibitor (TKI) or a pharmaceutically acceptable salt thereof.

According to the preferred embodiment, the composition is free of binder.

According to the preferred embodiment of the invention, said tyrosine-kinase inhibitor is selected from the group comprising erlotinib, gefitinib, olmutinib, osimertinib, rociletinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, lestaurtinib, cediranib, lenvatinib, nintedanib, regorafenib, semaxanib, tivozanib, toceranib, vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, dasatinib, lestaurtinib, momelotinib, ruxolitinib, pacritinib, cobimetinib, selumetinib, trametinib, binimetinib, alectinib, brigatinib, ceritinib, crizotinib, ibrutinib. According to the preferred embodiment of the invention, the tyrosine-kinase inhibitor is nilotinib.

According to the most preferred embodiment, the capsule composition comprises nilotinib hydrochloride anhydrous.

A hydrous compound (a hydrate) is a chemical compound with water in its structure. For example, hydrated salts have water within their crystals. Hydrates form naturally when ionic compounds are exposed to air and make bonds with water molecules. Specifically, the bond is formed between the cation of the molecule and the water molecule. The water that remains is usually known as water of hydration or water of crystallization. This water content brings the risk of crystallization and degradation along when said hydrous component is used in a solid dosage formulation.

On the other hand, anhydrous compounds (anhydrates) are compounds with no water in their structure. After water is removed from a hydrate, it becomes an anhydrate. The water molecules are removed by suction or heating the compound to a high temperature. For example, an anhydrous salt has had water driven out from its crystals.

For this invention, it has been observed that the use of an anhydrous salt of nilotinib as the active ingredient increases both stability and solubility.

Nilotinib hydrochloride anhydrous can be in amorphous form, polymorphous form or crystalline form.

In an embodiment, nilotinib hydrochloride anhydrous is in crystalline form. Crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. The crystalline form is more stable than the amorphous form and has a lower energy at the molecular level with stronger bonding (mostly ionic bonds) between molecules that require higher energy to break. Besides, crystalline form also exhibits improved solubility, hygroscopicity, bulk properties and flowability.

According to the preferred embodiment, the amount of nilotinib hydrochloride anhydrous in the total composition is 10-90%, preferably 20-80%, most preferably 40-60% by weight. According to this embodiment, the amount of nilotinib in the composition is between 40 mg and 360 mg, preferably between 80 mg and 320 mg and more preferably between 160 mg and 240 mg. Most preferably, the composition of the invention comprises 200 mg nilotinib.

In one embodiment of the invention, the composition further comprises at least one excipient selected from fillers, disintegrants, lubricants, glidants, surfactants or mixtures thereof.

According to one embodiment of the invention, the composition comprises at least one filler selected from the group comprising microcrystalline cellulose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dibasic calcium phosphate anhydrate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof.

The amount of the filler is in the range of 10-70%, preferably 20-60%, most preferably 30- 50% by weight of the total composition.

In a preferred embodiment of the invention, the composition comprises a filler which is mannitol.

According to a preferred embodiment of the invention, the composition subjected to the invention is free of lactose. Since the filler amount in the formulation is respectively high, lactose is not preferable for the present invention in order to develop a composition which can be safely used in the treatment of lactose-intolerant patients.

According to one embodiment of the invention, the composition comprises at least one disintegrant selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, sodium starch glycollate, polacrilin potassium (amberlite 188), starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof.

Considering the moisture retention properties of the disintegrants; the amount of disintegrant is kept below 10%, more preferably below 5% by weight of the composition, in order to ensure continuity of stability. The formulation of the invention was designed without having to compromise on solubility and bioavailability to achieve high stability, which was linked to the surprisingly coordinated effect of the selection of nilotinib hydrochloride anhydrous as a source of nilotinib and the specified amount of the disintegrant. It has been seen that formulations prepared with other salts of nilotinib have not the same effect. The said surprising effect is further enhanced by using the crystalline form of nilotinib.

In a preferred embodiment of the invention, the composition comprises a single disintegrant which is selected from sodium starch glycollate, polacrilin potassium (amberlite 188), starch (starch 1500).

According to one embodiment of the invention, the composition comprises at least one lubricant and at least one glidant selected from the group comprising magnesium stearate, calcium stearate, colloidal silicon dioxide (colloidal anhydrous silica), sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.

In a preferred embodiment of the invention, the composition comprises magnesium stearate as lubricant. The amount of magnesium stearate is 0.1 -5%, preferably 0.3-2% by weight of the total composition.

In a preferred embodiment of the invention, the composition comprises colloidal anhydrous silica as glidant. The amount of colloidal anhydrous silica is 0.1 -5%, preferably 0.3-2% by weight of the total composition.

In a preferred embodiment of the invention, the ratio of lubricant to glidant is in the range of 0.1 :1 to 5:1 , preferably 0.5:1 to 2:1 in order to ensure the desired flowability which eases the dry granulation process. Most preferably, this ratio is 1 :1.

It has also been found that the ratios of the disintegrant, lubricant and glidant in the composition have also great importance in order to obtain solid oral pharmaceutical compositions providing high solubility and high stability at the same time. In a preferred embodiment of the invention, the weight ratio of the disintegrant to the total amount of lubricant and glidant is in the range of from 50:1 to 0.1 :1 , preferably 10:1 to 1 :1 , more preferably 5:1 to 3:1 . According to one embodiment of the invention, the composition comprises at least one surfactant selected from the group comprising soluplus (a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate), sodium lauryl sulfate, sodium stearyl sulfate, sodium oleyl sulfate, sodium cetyl sulfate, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinates, polyethylene glycols and polysorbates.

In a preferred embodiment of the invention, the composition comprises polysorbate, most preferably sepitrap, as surfactant. In one embodiment; sepitrap 80, which comprises polysorbate 80 in an amount of 45-65% and a carrier in an amount of 35-55% by weight, is used as surfactant. In another embodiment; sepitrap 4000, which comprises polyoxyl 40 hydrogenated castor oil in an amount of 55-75% and a carrier in an amount of 25-45% by weight, is used as surfactant. The amount of surfactant is 0.1 -5%, preferably 0.3-2% by weight of the total composition.

According to a preferred embodiment, the composition is free of poloxamers because of their wetting properties. Poloxamers are wetting agents which allow the water to penetrate and thus promote the chemical degradation of the composition.

In one embodiment of the invention, the total composition comprises the following:

- 10-90% by weight of nilotinib hydrochloride anhydrous

- 10-70% by weight of mannitol

- less than 10% by weight of polacrilin potassium

- 0.1 -5% by weight of magnesium stearate

- 0.1 -5% by weight of colloidal anhydrous silica

- 0.1 -5% by weight of sepitrap 80 which comprises polysorbate 80 in an amount of 45-65% and a carrier in an amount of 35-55% by weight of sepitrap 80

In another embodiment of the invention, the total composition comprises the following:

- 10-90% by weight of nilotinib hydrochloride anhydrous

- 10-70% by weight of mannitol

- less than 10% by weight of sodium starch glycollate

- 0.1 -5% by weight of magnesium stearate

- 0.1 -5% by weight of colloidal anhydrous silica

- 0.1 -5% by weight of sepitrap 4000 which comprises polyoxyl 40 hydrogenated castor oil in an amount of 55-75% and a carrier in an amount of 25-45% by weight by weight of sepitrap 80 In the preferred embodiment of the invention, the compositions disclosed in any of the above embodiments are filled into capsules with high moisture resistance. According to this embodiment, said capsules comprises gelatin. In one embodiment, capsule further comprises titanium dioxide, yellow iron oxide, shellac and red iron oxide.

These analytically selected ratios provide the effective dosages required for the treatment and surprisingly improve stability and the solubility of the composition subjected to the invention at the same time. According to all these embodiments, the following formulation can be used in the capsule dosage form of the invention.

Example 1 : Capsule formulation

Example 2: Capsule formulation

The above-mentioned pharmaceutical formulations are prepared by dry granulation comprising following steps:

-Sieving nilotinib hydrochloride anhydrous, mannitol, polacrilin potassium, colloidal anhydrous silica, sepitrap 80 and half by weight of magnesium stearate and then mixing all together

- Adding the other half by weight of magnesium stearate to this mixture and then mixing to prepare a total mixture

- Compressing the total mixture into briquettes

- Sieving the briquettes through a mesh to prepare granules

- Filling the obtained granules into capsules

Example 3: Capsule formulation

The above-mentioned pharmaceutical formulation is prepared by dry granulation comprising following steps:

-Sieving nilotinib hydrochloride anhydrous, mannitol, sodium starch glycollate, colloidal anhydrous silica, sepitrap 4000 and a part of magnesium stearate and then mixing all together

- Adding the other part of magnesium stearate to this mixture and then mixing to prepare a total mixture

- Compressing the total mixture into briquettes

- Sieving the briquettes through a mesh to prepare granules

- Filling the obtained granules into capsules

In a preferred embodiment, a part of magnesium stearate represents half by weight of magnesium stearate. At dry granulation, granules can be formed without the necessity of a binder by compaction. In this invention for which the moisture control and stability are some of the priorities, dry granulation is the most preferable method to prepare stable compositions. Additionally, it is a rapid and low energy requiring method in which hydrolytic decomposition or other undesirable processes due to heating can be avoided. Preformation of dry granulation needs few tools, small work place, and expensive drying operations are avoidable.

Claims

1. A capsule composition comprising at least one tyrosine-kinase inhibitor or a pharmaceutically acceptable salt thereof, wherein the composition is free of binder.

2. The capsule composition according to claim 1 , wherein said tyrosine-kinase inhibitor is selected from the group comprising erlotinib, gefitinib, olmutinib, osimertinib, rociletinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, lestaurtinib, cediranib, lenvatinib, nintedanib, regorafenib, semaxanib, tivozanib, toceranib, vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, dasatinib, lestaurtinib, momelotinib, ruxolitinib, pacritinib, cobimetinib, selumetinib, trametinib, binimetinib, alectinib, brigatinib, ceritinib, crizotinib, ibrutinib.

3. The capsule composition according to claim 1 , wherein said tyrosine-kinase inhibitor is nilotinib.

4. The capsule composition according to claim 1 , wherein the composition comprises nilotinib hydrochloride anhydrous.

5. The capsule composition according to claim 4, wherein the amount of nilotinib hydrochloride anhydrous in the total composition is 10-90%, preferably 20-80%, most preferably 40-60% by weight.

6. The capsule composition according to any one of the preceding claims, wherein the composition further comprises at least one excipient selected from fillers, disintegrants, lubricants, glidants, surfactants or mixtures thereof.

7. The capsule composition according to claim 6, wherein the composition comprises at least one disintegrant selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, sodium starch glycollate, polacrilin potassium (amberlite 188), starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof.

8. The capsule composition according to claim 7, wherein the amount of the disintegrant is less than 10%, more preferably less than 5% by weight of the composition.

9. The capsule composition according to claim 6, wherein the composition comprises at least one lubricant and at least one glidant selected from the group comprising magnesium stearate, calcium stearate, colloidal silicon dioxide (colloidal anhydrous silica), sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.

10. The capsule composition according to claim 9, wherein the ratio of lubricant to glidant is in the range of 0.1 :1 to 5:1 , preferably 0.5:1 to 2:1 , most preferably this ratio is 1 :1 .

1 1. The capsule composition according to any one of the claims 7 to 10, wherein the weight ratio of disintegrant to the total amount of lubricant and glidant is in the range of 50:1 to 0.1 :1 , preferably 10:1 to 1 :1 , more preferably 5:1 to 3:1.

12. The capsule composition according to any one of the preceding claims, wherein the composition is free of lactose.

13. The capsule composition according to any one of the preceding claims, wherein the composition is free of poloxamers.

14. The capsule composition according to any one of the preceding claims, wherein the composition comprises

- 10-90% by weight of nilotinib hydrochloride anhydrous

- 10-70% by weight of mannitol

- less than 10% by weight of polacrilin potassium

- 0.1 -5% by weight of magnesium stearate

- 0.1 -5% by weight of colloidal anhydrous silica

- 0.1 -5% by weight of sepitrap 80 which comprises polysorbate 80 in an amount of

45-65% and a carrier in an amount of 35-55% by weight of sepitrap 80.

15. The capsule composition according to any one of the claims 1 to 13, wherein the composition comprises

- 10-90% by weight of nilotinib hydrochloride anhydrous

- 10-70% by weight of mannitol

- less than 10% by weight of sodium starch glycollate

- 0.1 -5% by weight of magnesium stearate

- 0.1 -5% by weight of colloidal anhydrous silica

- 0.1 -5% by weight of sepitrap 4000 which comprises polyoxyl 40 hydrogenated castor oil in an amount of 55-75% and a carrier in an amount of 25-45% by weight by weight of sepitrap 80.