Ceritinib formulation

a technology of ceritinib and formulation, which is applied in the field of ceritinib formulation, can solve the problems of affecting the compressibility of tablets, difficult formulation of ceritinib, and general adverse effects of drug load, so as to reduce or alleviate at least one symptom, increase progression-free survival, and overall survival

Inactive Publication Date: 2019-01-24
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]Surprisingly it was found that a high drug load of more than 40 weight percent, preferably more than 45 wt %, more preferably more than 50 wt %, particularly 60 wt % of Ceritinib in a tablet can be achieved by using a specifically adapted wet granulation process, whereby solely the pharmaceutical active ingredient ceritinib is granulated with a binder. Said wet granulation process also leads to high compressibility and much reduced or even no sticking and picking during manufacturing. The latter can be further improved by adding the right amount of a lubricant, such as for example magnesium stearate. The tablet obtained by employing the disclosed process exhibits suitable hardness and reduced friability. Also of importance is the high drug load of pharmaceutical composition that can be reached. For example, the table can comprise for example 70% by weight of the drug substance. The tablet can be thus of an acceptable size that is more convenient for patients to swallow, even if containing doses up to 375 mg or more. Compared to the capsule, the in vitro dissolution profiles predict that the tablet can also behave in vivo comparably to capsule. The compliance of taking the new formulation is expected to be much improved compared to the one of a capsule given the high daily dose that needs to be administered and inconvenient size of a capsule.
[0079]The term “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present disclosure, the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human.

Problems solved by technology

Ceritinib is a difficult compound to formulate.
In addition, physical characteristics of Ceritinib cause sticking and picking during tableting or encapsulation of the drug and make it poorly compressible.
If the dose is to be increased in a respective dosage form, the increase in drug load generally negatively affects the compressibility of a tablet.
Ceritinib's sticky nature causes a high drug load to further negatively influence the manufacturing of tablets due to enhanced sticking / picking.

Method used

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Examples

Experimental program
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Effect test

examples

[0098]The following Examples illustrate the disclosure described above; they are not, however, intended to limit the scope of the disclosure in any way. The beneficial effects of the ceritinib for use in the treatment according to the present disclosure, or methods as disclosed herein can also be determined by other test models known as such to the person skilled in the pertinent art.

[0099]All experiments described hereinafter were performed by using the following laboratory or manufacturing equipment:

Granulator: Top or bottom driven High shear mixer.

Sieve: Manual hand sieve, oscillating and rotating sieve mill

Drying: Fluidized bed dryers

Tableting machine: Compaction simulator / Excentric tableting machine, rotary tableting machine

Roller compactor: Cantilevered roll design and feature a vertical tapered deed screw system

Film coating drum: Perforated drum coater

Dissolution apparatus: USP II Dissolution apparatus

examples 1 to 3a

ulation Technology

[0100]It was determined during the formulation preworks that all formulations tested showed very significant sticking issues during a tableting step. The sticking issue was occurring at all three tested common manufacturing processes for tablets, either direct blending / compression, roller compaction / compression or wet granulation / compression. However, the sticking issue was significantly reduced using wet granulation. In addition, the wet granulation approach allowed loading of the highest amount of drug. Roller compaction and direct compression did not result in an appropriate tablet or an acceptable manufacturing process, leading to the conclusion to that these technologies could not be selected. For direct compression (example 1) all listed excipients except magnesium stearate were blended, then Mg-stearate was added and the mix blended again and compressed.

[0101]Roller compaction approach (dry granulation) shown in example 2 was done by blending LDK378 drug sub...

examples 3b to 6

er

[0103]In an additional development step, the impact of the choice of a binder for a wet granulation phase was determined. Hypromellose and povidone were selected for testing out of several binder types (starch based binders, povidone based binders, copovidone based binders, hypromellose based binders, hydroxypropylcellulose based binders and hydroxyethylcellulose based binders) (cf. examples 4 and 5 in table 2). A binder for wet granulation can be added either in a dry state to the granulation mixture (granule phase) before the wet granulation is conducted with water or the binder can be dissolved in e.g. water to form a granulation liquid, which is then used to conduct the wet granulation of the granulation mixture. The granulation mixture can consist of a drug substance and several excipients (e.g. filler, disintegrant and / or other excipients) which are granulated together with the applied binder (examples 4 and 5). However, a specifically modified approach was taken, by which o...

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Abstract

The present disclosure relates to a new pharmaceutical composition comprising Ceritinib. Particularly it is directed to the tablet that is prepared by wet granulation, wherein povidone is used as a binder. Further feature of the composition is that the drug and the binder form the inner phase, whereas all other excipients are added in a powder form as an outer phase. This way, the sticking of the composition is prevented and sufficient tablet hardness can be reached.

Description

FIELD OF THE DISCLOSURE[0001]The present disclosure relates to a new pharmaceutical composition comprising Ceritinib. It further relates to a tablet comprising Ceritinib and a process of preparing said tablet. In addition, the disclosure also related to a use of the pharmaceutical composition or the tablet.BACKGROUND OF THE INVENTION[0002]WO2008 / 073687 A1 disclosed ceritinib (also named LDK378) as compound 66 in Example 7. Chemical formula of ceritinib is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.[0003]Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor. ALK is a member of the insulin receptor superfamily of receptor tyrosine kinases. Genetic alterations of ALK have been implicated in oncogenesis in hematopoietic and non-hematopoietic tumours. The gene has been found to be rearranged, mutated, or amplified in a series of tumours, including non-small cell lung cancer. Ceritinib has been approved by th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/506A61K9/20A61K9/16
CPCA61K9/2095A61K9/1617A61K9/2013A61K31/506A61K9/2027A61K9/2063A61K9/2059A61K9/2054A61K9/1635A61K9/2077A61K9/1652A61K9/1658A61P35/00A61P35/04A61P43/00
Inventor BREULLES, SEBASTIENENSSLIN, SIMON
Owner NOVARTIS AG
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