WO2014118112A1

WO2014118112A1 - Pharmaceutical composition comprising erlotinib hydrochloride

Info

Publication number: WO2014118112A1
Application number: PCT/EP2014/051477
Authority: WO
Inventors: Marta VIVANCOS MARTINEZ
Original assignee: Synthon B.V.
Priority date: 2013-01-29
Filing date: 2014-01-27
Publication date: 2014-08-07

Abstract

The present invention relates to a pharmaceutical composition comprising polymorphic Frm Aof erlotinib hydrochloride and an effective amount of a carbomer.

Description

PHARMACEUTICAL COMPOSITION COMPRISING ERLOTINIB

HYDROCHLORIDE

BACKGROUND OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising erlotinib hydrochloride in its crystalline Form A.

Erlotinib, chemically [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)- amine of formula (I)

is a compound that inhibits the human epidermal growth factor receptor tyrosine kinase, also known as EGFR-TK, that is critical for growth of malignant cells. EGFR overexpression is associated with disease progression, and reduced survival. Erlotinib acts by blocking tyrosine kinase activity of EGFR-TK, resulting in inhibition of the signalling pathway, and decreased growth of malignant tumours. Erlotinib is thus useful for the treatment of proliferative disorders such as cancers in humans. Erlotinib is marketed as its hydrochloride salt under such brand names as Tarceva^® (OSI Pharmaceuticals, Inc.) for the treatment of certain lung cancers and pancreatic cancer.

WO 96/30347 teaches quinazoline derivatives for treating hyperproliferative diseases such as cancers. Example 20 shows the formation of erlotinib free base and the subsequent conversion to the hydrochloride salt. Pharmaceutical compositions are only generically disclosed, there is not one specific example. Neither is there any disclosure about polymorphism of erlotinib hydrochloride.

WO 01/34574 discloses the existence of two polymorphic Forms of erlotinib hydrochloride which were designated as Form A and B. Form B is thermodynamically more stable than Form A. The document describes processes for producing each polymorph in an essentially pure form, and describes the use of the stable polymorph B form for treating hyperproliferative disorders, such as cancer. Pharmaceutical compositions are only generically disclosed.

WO 2010/086441 relates to a pharmaceutical composition comprising erlotinib hydrochloride and discloses pharmaceutical compositions comprising polymorph A of erlotinib hydrochloride and a hydrophihc excipient. According to the description, the addition of this excipient not only stabilises polymorphic form A, but it also increases the dissolution of the active pharmaceutical ingredient. According to the authors of WO 2010/086441, there is thus no requirement of providing the active pharmaceutical ingredient in a nanoparticulate form as was deemed necessary by the authors of WO 2006/110811.

WO 2010/086441 provides on page 6 a long list of suitable hydrophihc excipients, such as for example hydrophihc polymers. The hydrophihc polymer can have a weight average molecular weight in the range of about 1 ,000 g/mol to about 150,000 g/mol, preferably in the range of about 2,000 g/mol to about 90,000 g/mol. Microcrystalhne cellulose is the preferred hydrophilic excipient. The amount of hydrophilic excipient to be used in accordance with WO 2010/086441 is in the range of about 10 wt.% to about 90 wt.%, most preferably in the range of about 50 wt.% to about 70 wt.% (see page 7). In the example on page 12, apart from microcrystalhne cellulose also a surfactant, i.e. sodium lauryl sulphate, was included in the formulation of Form A. While WO 2010/086441 seems to provide a formulation wherein erlotinib hydrochloride Form A is stable, the present invention relates to an alternative pharmaceutical composition comprising erlotinib hydrochloride Form A in a thermodynamically stable form and with suitable release rate, which does not require the use of a surfactant, particularly sodium lauryl sulphate (SLS).

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition suitable for administration of polymorphic Form A of erlotinib hydrochloride, which composition exhibits improved stability upon long-term storage, has a suitable release rate and which does not require the use of a surfactant.

In one aspect, the present invention relates to a pharmaceutical composition comprising polymorphic Form A of erlotinib hydrochloride and an effective amount of a carbomer.

The effective amount of the carbomer is from 0.1 to 2.0 wt.% relative to the weight of erlotinib hydrochloride, preferably from 0.2 to 1.0 wt.%.

The composition is preferably formulated in the form of a dosage form for oral administration. Preferably the composition does not comprise a surfactant.

Preferably the pharmaceutical composition exhibits an in vitro release profile wherein on average from 10 to 30% of the erlotinib hydrochloride is dissolved within 15 minutes after placement of the composition in a dissolution test conducted using USP apparatus II with a spindle rotation speed of 75 rpm and a dissolution medium of 0.1 N HCl and 1% SDS, pH 1.0 at 37°C.

In a second aspect, the invention relates to the use of a carbomer for stabilisation of polymorphic Form A o f erlotinib hydrochloride . In a third aspect, the invention relates to a composition comprising polymorphic Form A of erlotinib hydrochloride and an effective amount of a carbomer for use as a medicament, preferably in the treatment of proliferative disorders, particularly in the treatment of non- small cell lung cancer and pancreatic cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Dissolution profiles of formulations 1 A and IB in acidic media

Figure 2: Flow scheme of dry granulation/direct compression process for the preparation of erlotinib hydrochloride Form A tablets

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising polymorphic form A of erlotinib hydrochloride and an effective amount of a carbomer.

Erlotinib hydrochloride can be synthesised using techniques well known in the art, e.g., as disclosed in WO 96/30347.

Polymorph A of erlotinib hydrochloride and a method for its preparation have been disclosed in WO 01/34574. 2-Theta values of characteristic peaks taken from the X-ray powder diffraction pattern of polymorph A of erlotinib hydrochloride and their relative intensities are summarised in Table 1 below (cf. Table 2 on page 17 of WO 01/34574).

Table 1

Anode: Cu - Wavelength 1 : 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range#l - Coupled: 3.000 to 40.000 StepSize: 0.040 Step Time: 1.00

Smoothing Width: 0.300 Threshold: 1.0 2-Theta I (rel) 2-Theta I (rel) 2-Theta I (rel) 2-Theta I (rel) 2-Theta I (rel)

5.579 100.0 13.340 1.7 19.517 4.8 24.594 8.2 30.673 3.5

6.165 3.9 15.135 2.1 21.152 4.7 25.398 9.3 32.759 3.7

7.522 1.5 15.534 2.3 21.230 4.4 26.173 6.0 34.440 1.8

8.006 1.2 16.193 2.4 22.360 4.7 26.572 5.3 36.154 1.3

8.696 1.4 16.991 3.6 22.703 12.4 27.080 4.2 37.404 2.2

9.841 13.1 18.447 3.5 23.502 24.2 29.240 7.1 38.905 1.7

11.251 7.8 18.862 12.2 24.175 8.8 30.007 3.0

The XRPD pattern of Form A as used or measured in the pharmaceutical compositions of the present invention substantially corresponds to that as disclosed for Form A in WO 01/34574. "Substantially corresponds" is meant to cover variations/differences in the pattern that would he understood by a worker skilled in the art not to represent a difference in the crystal structure, hut rather differences in the technique, equipment, sample preparation, impurities, etc.

The term "pharmaceutical composition" refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition is in a single dosage form, the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell.

It is known from WO 01/34574 and WO 2010/086441 that under conventional conditions polymorph A of erlotinib hydrochloride is thermodynamically unstable and converts into polymorph B.

Contrary to this prior art knowledge, the present invention is based on the surprising finding that polymorph A of erlotinib hydrochloride can be stabilised in a pharmaceutical composition when combined with an effective amount of a carbomer. "Stabilised" in the sense of the present invention means that in the pharmaceutical composition erlotinib hydrochloride maintains its polymorphic Form A even under harsh storage conditions of 75% relative humidity and 40°C for at least 3 months, preferably for at least 12 months.

Maintaining its polymorphic Form A therefore means that polymorph A of erlotinib hydrochloride during storage is not converted into any other polymorph of erlotinib hydrochloride, in particular not into polymorph B.

The thermodynamic stability of polymorph A of erlotinib hydrochloride in the pharmaceutical composition of the present invention is confirmed by the stability data as provided in the examples section. Stability was tested for up to 6 months at 25°C/60% relative humidity and 40°C/75% relative humidity. These data confirm that polymorph A of erlotinib hydrochloride is thermodynamically stable in the pharmaceutical composition of the present invention and in particular that polymorph A is not converted into polymorph B during storage over at least 3 months.

From WO 2010/086441 , it is also known that the addition of hydrophilic excipients to a formulation comprising erlotinib hydrochloride Form A increases the dissolution of the pharmaceutical composition.

Surprisingly, it was found that the addition of a carbomer, which is a hydrophilic excipient, does not only stabilise the polymorphic form of the active pharmaceutical ingredient, but instead of increasing, it rather decreases the dissolution rate of the pharmaceutical composition. In a particular case , it is possible to mimic the dissolution of the Tarceva^® tablets that contain the more stable, hence less soluble erlotinib hydrochloride Form B. Thus, the combination of polymorph A of erlotinib hydrochloride and an effective amount of a carbomer in the pharmaceutical composition of the present invention results in several advantages over the prior art formulations. The first advantage is that polymorph A of erlotinib hydrochloride, which is known to be thermodynamically unstable, is stabilised. A further advantage is that the dissolution of the pharmaceutical composition in acidic media is modified to mimic the dissolution of the Tarceva^® tablets that contain the less soluble erlotinib hydrochloride Form B.

The surprising result of adding an effective amount of a carbomer on the dissolution profile of the pharmaceutical composition containing polymorph A of erlotinib hydrochloride is demonstrated in Figure IB. This figure shows the dissolution profiles of the tablets of Example 1 B according to the present invention containing 1.20 wt.% of Carbopol 971P, in which on average from 10 to 30% of the erlotinib hydrochloride is dissolved within 15 minutes after placement of the composition in a dissolution test conducted using USP apparatus II with a spindle rotation speed of 75 rpm and a dissolution medium of 0.1 N HCl and 1% SDS, pH 1.0 at 37°C, 20 to 40% within 30 minutes, and 30 to 60% within 60 minutes. It is evident that the carbomer in the pharmaceutical composition of the present invention significantly modifies the dissolution when compared to results of the

pharmaceutical composition of Example 1A.

Pn the context of the present invention, with "a carbomer" is meant a synthetic high- molecular-weight polymer of acrylic acid that is crosslmked with either allyl sucrose or allyl ethers of pentaerythritol (Handbook of Pharmaceutical Excipients; Edited by Raymond C Rowe, Paul J Sheskey, Walter G Cook and Marian E Fenton; May 2012). Preferably, the carbomer is a Carbopol® (B.F. Goodrich) polymer, and even more preferably the carbomer is the homopolymer Carbopol 971P.

Carbopol homopolymers are polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol. Carbopol copolymers are polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol. A Carbopol interpolymer is a carbomer homopolymer or copolymer that contains a block copolymer of polyethylene glycol and a long chain alkyl acid ester. Preferably, Carbopol homopolymers are used in accordance with the present invention.

The "effective amount" of carbomer to be used in accordance with the present invention is not specifically limited to any range and can easily be determined by the person skilled in the art. The effective amount of carbomer should be able to stabilise erlotinib hydrochloride Form A and, at the same time, modify the release rate of erlotinib from the pharmaceutical composition to the desired level. Typically, an amount of carbomer of less than 10 wt.%, preferably from 0.1 to 2.0 wt.% relative to the weight of erlotinib

hydrochloride, and more preferably of from 0.2 to 1 .0 wt.%, is used. The amount typically used in accordance with the present invention is significantly lower than the preferred amount of hydrophilic excipient used in accordance with WO 2010/086441 , i.e. 50 to 70 wt.%.

In order to provide a pharmaceutical composition having an optimal dissolution profile, it is preferred that the pharmaceutical composition is essentially free of polymorph B of erlotinib hydrochloride. Being essentially free of polymorph B means that polymorph B is present in the pharmaceutical composition of the present invention in an amount of less than 5 wt.%, preferably in an amount of less than 1 wt.%, each based on the total amount of erlotinib hydrochloride. Most preferably, the pharmaceutical composition of the present invention does not contain any polymorph B of erlotinib hydrochloride. Furthermore, it is preferred that the pharmaceutical composition does not contain any polymorph of erlotinib hydrochloride other than polymorph A. Thus, the pharmaceutical composition of the present invention preferably comprises erlotinib hydrochloride essentially only as polymorph A, i.e., at least 95 wt.% of the total amount of erlotinib hydrochloride in the pharmaceutical composition is present in polymorphic Form A, preferably at least 99 wt.%. Most preferred, erlotinib hydrochloride is present in the pharmaceutical composition only in polymorphic Form A. The particle size of the active pharmaceutical ingredient in the pharmaceutical composition of the present invention is not particularly limited. However, in view of the disadvantages associated with the preparation and handling of nanoparticles, it is preferred that the erlotinib hydrochloride in the pharmaceutical composition of the present invention has a D90 particle size of 5 μπι or larger, preferably from 5 to 100 μηι. D 0 particle size means a particle size distribution where 90 vol.% of the total amount of erlotinib hydrochloride in the pharmaceutical composition has a particle size of 5 μηι or larger, preferably from 5 to 100 μπι, when measured by laser diffraction in wet state (sunflower oil:n-hexane 50:50) with a Malvern Laser Mastersizer 2000.

The pharmaceutical composition of the present invention can additionally comprise one or more further active pharmaceutical ingredients, in particular one or more compounds useful in treating hyperproliferative disorders, such as cancer or other neoplastic diseases, or the pharmaceutical composition of the present invention can be administered in conjunction with such a compound. Examples of suitable other active pharmaceutical ingredients are disclosed, for example, in WO 2006/11081 1 (page 8-9, [0023]; page 18, [0061]).

The dosage of erlotinib hydrochloride can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient, and the mode of administration, and will need to be fit to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1 ,000 mg, especially about 5 mg to about 500 mg, preferably about 25 mg to about 200 mg is applicable. Depending on the severity of the disease and the precise pharmacokinetic profile, the compound can be administered with one or several daily dosage units, e.g. in one to three dosage units.

The pharmaceutical composition of the present invention may further comprise one or more conventional pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients for various different dosage forms are well-known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances such as absorption enhancers, penetration enhancers, surfactants, co-surfactants, and specialized oils. The proper excipient(s) is (are) selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphates, sugars, etc.

Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose; polyvinylpyrrolidones; polyethylenoxides; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; and polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Eudragit^® (Rohm), polycarbophil, and chitosan polymers. Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated polyglycolyzed glycerate. Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate. Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars

(polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches.

The pharmaceutical compositions of the present invention may be formulated into various types of dosage forms, for instance as solutions or suspensions, or as tablets, capsules, granules, pellets or sachets for oral administration. A particularly preferred pharmaceutical composition is in the form of a solid oral dosage form, preferably tablets. The tablet is preferably a swallowable tablet. It may optionally be coated with a film coat comprising, in essence, any suitable inert coating material known in the art. The above lists of excipients and forms are not exhaustive.

Bi one embodiment of the present invention, the pharmaceutical composition does not contain a surfactant, preferably it does not contain sodium lauryl sulphate.

The pharmaceutical composition may contain for example dosage amounts of 25, 50,

100 or 150 mg of erlotinib (27.3, 54.6, 109.3 or 163.9 mg of erlotinib hydrochloride). Thus, the administered amount can be readily varied according to the individual patient's need, tolerance and safety.

The pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art. Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants and the mixture can be compressed into tablets or filled into sachets or capsules of suitable size.

Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients.

Suitable powder or granulate mixtures according to the invention are also obtainable by spray drying, lyophilisation, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method. The so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules. The above mentioned methods known in the art also include grinding and sieving techniques permitting the adjustment of desired particle size distributions.

The effective amount of carbomer can be used for stabilisation of polymorphic form A of erlotinib hydrochloride. The effective amount to be used in accordance with the present invention is not specifically limited to any range and can easily be determined by the person skilled in the art. Typically, an amount of carbomer of less than 10 wt.%, preferably from 0.1 to 2.0 wt.% relative to the weight of erlotinib hydrochloride, and more preferably of from 0.2 to 1.0 wt.%, is used.

Preferably, the carbomer is a Carbopol® (B.F. Goodrich) polymer, and even more preferably the carbomer is the homopolymer Carbopol 971 P.

The composition according to the present invention may be used as medicament. The composition typically may be used in the treatment of proliferative disorders, particularly in the treatment of non-small cell lung cancer and pancreatic cancer.

The invention will be further described with reference to the following non-limiting examples.

EXAMPLES

Tablet composition

1A. Same composition as Tarceva^® formulation IB. Formulation with 1.20 wt.% of Carbopol

971P

mg % mg %

Sodium lauryl sulphate 4.50 1.00 Carbopol 97 IP 5.40 1.20

Magnesium stearate 4.50 1.00 Magnesium stearate 4.50 1.00

Extragranular components Extragranular components

Lactose monohydrate spray 51.89 1 1.53 Lactose monohydrate spray 51.93 11.54 dried (Supertab U SD) dried (Supertab U SD)

SMicrocrystalline cellulose 99.58 22.13 Microcrystalline cellulose 99.56 22.13 (Avicel PH I 02) (Avicel PHI 02)

Sodium starch glycolate 9.00 2.00 Sodium starch glycolate 9.00 2.00 (Glycolis) (Glycolis)

Magnesium stearate 4.50 1.00 Magnesium stearate 4.50 1.00

Uncoated tablet mass 450.0 100.0 Uncoated tablet mass 450.0 100.0

Erlotinib hydrochloride, carbopol or sodium lauryl sulphate, and part of the lactose monohydrate, microcrystalline cellulose and sodium starch glycolate are sieved and mixed for 20 min (blend A). Magnesium stearate is sieved and added to the blend A to be mixed for an additional 3 minutes. Lubricated blend A is compacted in a roller compactor and after that milled to obtain granules. The rest of the lactose monohydrate, microcrystalline cellulose and sodium starch glycolate of the formulation are sieved and mixed with the granules for 15 min. Finally, magnesium stearate is sieved and added to the previous mixture. The lubricated blend is compressed.

A schematic overview of the process for making the tablets of formulation IB is provided in Figure 2. Dissolution profiles

Dissolution profiles were measured using the paddle method (USP app. II) in 1000 ml of acidic media (pH 1.0 (0.1 N HCl and 1% SDS) or 2.0; 75 rpm; 37°C). Figure 1A shows the dissolution profiles for the marketed 150 mg Tarceva^® tablet compared with an uncoated tablet having the same quantitative composition as the Tarceva^® tablet core but comprising erlotinib hydrochloride Form A (Example 1A in the above table). Figure IB shows the dissolution profiles for the marketed 150 mg Tarceva^® tablet compared with an uncoated tablet in accordance with the present invention comprising erlotinib hydrochloride Form A and a carbomer, i.e., Carbopol 971P (Example IB in the above table).

Stability data

New triplex AMI

40°C/75% H 25°C/60%RH 40°C/75%RH 25°C/60%RH

MV.EOB.hcl.tabl50.120502.01.Cl (Formulation with 1.20% of Carbopol)

t=0 Form A Form A Form A Form A t=l months Form A

t=3 months Form A Form A Form A Form A

In the above examples, the XRPD patterns were recorded on a Bruker-AXS D8 (Θ/2Θ geometry, reflection mode, Vantec PSD detector) at the following settings:

Start angle (20): 2.0 °

End angle (20): 35.0 °

Scan step width: 0.02 °

Scan step time: between 0.7-1 1.0 seconds

Radiation type: Cu

Radiation wavelengths: I .54060 A (Και), primary monochromator used

Exit slit: 6.0 mm

Focus slit: 0.2 mm

Divergence slit: Variable (V20)

Antiscatter slit: I I.8 mm

Receiving slit: 20.7 mm

Claims

A pharmaceutical composition comprising polymorphic Form A of erlotinib hydrochloride and an effective amount of a carbomer.

The pharmaceutical composition according to claim 1 , wherein the effective amount of the carbomer is from 0.1 to 2.0 wt.% relative to the weight of erlotinib hydrochloride, preferably from 0.2 to 1.0 wt.%.

The pharmaceutical composition according to claim 1 or 2, wherein the erlotinib hydrochloride has a particle size distribution with a D 0 of 5 μιη or larger, preferably from 5 to 100 μπι.

The pharmaceutical composition according to any one of claims 1 to 3 comprising 25, 50, 100 or 150 mg of erlotinib (27.3, 54.6, 109.3 or 163.9 mg of erlotinib

hydrochloride).

The pharmaceutical composition according to any one of claims 1 to 4, wherein the carbomer is a homopolymer of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol.

The pharmaceutical composition according to any one of claims 1 to 5, comprising 1.20 wt.% of the carbomer.

The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is in the form of an oral dosage form, preferably a tablet.

The pharmaceutical composition according to claim 7, wherein the composition does not contain a surfactant, preferably it does not contain sodium lauryl sulphate.

The pharmaceutical composition according to claim 7 or 8, said composition exhibiting an in vitro release profile wherein on average from 10 to 30% of the erlotinib hydrochloride is dissolved within 15 minutes after placement of the composition in a dissolution test conducted using USP apparatus II with a spindle rotation speed of 75 rpm and a dissolution medium of 0.1 N HC1 and 1% SDS, pH 1.0 at 37°C.

10. The pharmaceutical composition according to claim 9 wherein no more than about from 20 to 40% of the erlotinib hydrochloride dissolves within 30 minutes in said test. 1 1. The pharmaceutical composition according to claim 9 or 10 wherein no more than about from 30 to 60% of the erlotinib hydrochloride dissolves within 60 minutes in said test.

12. Use of an effective amount of a carbomer for stabilisation of polymorphic Form A of erlotinib hydrochloride.

13. Use according to claim 12 , wherein the effective amount of carbomer is from 0.1 to 2.0 wt.% relative to the weight of erlotinib hydrochloride, preferably from 0.2 to 1.0 wt.%.

14. Use according to claim 12 or 13, wherein the carbomer is a homopolymer of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol.

15. The pharmaceutical composition according to any one of claims 1 to 11 for use as a medicament.

16. The pharmaceutical composition according to claim 15 for use in the treatment of proliferative disorders, particularly in the treatment of non-small cell lung cancer and pancreatic cancer.