Pharmaceutical compositions

Abstract

The present disclosure relates to pharmaceutical compositions and formulations comprising Compound I defined herein, or a pharmaceutically acceptable salt thereof, as the active substance. The pharmaceutical compositions / formulations are for oral use and are suitable for the treatment of medical conditions in which CK2α activity is implicated.

Description

PHARMACEUTICAL COMPOSITIONSFIELD OF THE DISCLOSURE

[0001] The present invention relates to pharmaceutical compositions and formulations comprising a CK2a inhibitor, or a pharmaceutically acceptable salt thereof. The present invention also relates to methods of making the pharmaceutical compositions and formulations defined herein, and to the use of these pharmaceutical compositions and formulations for the treatment of diseases and disorders in which CK2a activity is implicated (e.g. in the treatment of cancer).BACKGROUND OF THE DISCLOSURE

[0002] CK2a is a serine / threonine kinase that is a key regulator of many cellular processes and is involved in cellular proliferation and anti-apoptotic mechanisms (Battistutta & Lolli, Mol. Cell. Biochem. 2011). It mainly exists as a holoenzyme composed of two catalytic (a and / or o’) and a dimer of regulatory (P) subunits, but it can also be found as the isolated subunits (Niefind et al, EM BO J 2001). Unlike most other kinases, it is constitutively active and more than 300 proteins have been identified as putative CK2a substrates, making it one of the most pleiotropic proteins in eukaryotic systems (Meggio & Pinna, FASEB 2003).

[0003] CK2a is a pro-survival kinase that operates across multiple signaling pathways to convey a proliferative and anti-apoptotic phenotype to cells. Consequently, cancer cells are often described as being addicted to CK2a activity and a high-profile genome-wide CRISPR-Cas9 screen highlighted CK2a as a top tier, high priority drug target for Colorectal Cancer (CRC) (Behan et al, Nature 2019). The target is well validated by human data that correlates poor patient survival in numerous tumor types, including CRC, with increased CK2a expression (Lin etal, PLoS ONE 2011). Additionally, data from clinical samples shows CK2a expression is upregulated in numerous tumor types (Ortega et al, PLoS ONE 2014; Di Maira etal, 2019).

[0004] The human genetics of CRC are well characterized and approximately 80% tumors are identified as being wnt pathway mutation driven (e.g. APC, p-catenin) (Zhan et al, Oncogene 2017). The wnt pathway is known to be sensitive to and amplified by CK2a activity and can be inhibited by loss of CK2a function (Gao & Wang, JBC 2006). For example, in animal models, CK2a inhibition prevents tumor growth that is driven by different mutations in the wnt pathway (Dowling et al, ACS 2016).

[0005] CK2a also contributes to the malignant phenotype in cholangiocarinoma (CCA), which is known to be a wnt-dysregulated tumor type (Zhan et al, Oncogene 2017). CK2a is overexpressed in human CCA samples and CCA tumor cell lines (Di Maira et al, Oncogenesis2019); and disruption of CK2a activity in CCA cell models is reported to inhibit tumorigenic properties. (Zakharia etal, Translational Oncology 2019).

[0006] Existing CK2a inhibitors target the highly conserved ATP binding site. This design strategy often leads to a poor selectivity profile for such inhibitors over other kinases.

[0007] WO2022 / 185041 discloses a series of potent and more selective CK2a inhibitors that bind to the catalytic ATP site of CK2a (to drive potent enzyme inhibition) but also interact with other areas of CK2a, such as the aD site (to drive high levels of selectivity over other kinases).

[0008] One particular compound CK2a inhibitor disclosed in WO2022 / 185041 is 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I). The structure of Compound I is shown below:Compound I

[0009] There is a need for suitable formulations for the effective delivery of Compound I in vivo.

[0010] The present disclosure was devised with the foregoing in mind.SUMMARY OF THE DISCLOSURE

[0011] The present inventors discovered that Compound I possesses poor bioavailability when administered orally in solution form. As a consequence, there is a particular need for formulations comprising Compound I that have improved oral bioavailability.

[0012] The present invention therefore relates to novel formulations of Compound I, or a pharmaceutically acceptable salt thereof, that have been developed to provide improved oral bioavailability profiles.

[0013] According to a first aspect of the invention, there is provided a pharmaceutical composition comprising 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I), or a pharmaceutically acceptable salt thereof, dispersed in one or more pharmaceuticallyacceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise one or more permeation enhancers.

[0014] In a further aspect, there is provided a method of manufacturing the pharmaceutical composition described herein comprising the step of mixing as an active substance Compound I, or a pharmaceutically acceptable salt thereof, with one or more permeation enhancers.

[0015] In a further aspect, there is provided a pharmaceutical formulation (e.g. a capsule) for oral use comprising a pharmaceutical composition as defined herein.

[0016] In a particular aspect, the present invention provides a solution or suspension formulation comprising Compound I, or a pharmaceutically acceptable salt thereof, and one or more penetration enhancers dispersed in a pharmaceutically acceptable vehicle.

[0017] In a further aspect, the present invention provides a method of manufacturing a solution or suspension formulation as defined herein comprising the step of mixing Compound I, or a pharmaceutically acceptable salt thereof, with one or more permeation enhancers in a pharmaceutically acceptable vehicle.

[0018] In a further aspect, there is provided a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use as a medicament.

[0019] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in therapy.

[0020] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a disease or condition in which CK2a activity is implicated.

[0021] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of CK2a.

[0022] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm.

[0023] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a cancer.

[0024] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a viral infection.

[0025] In another aspect, the present invention provides the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a disease or condition in which CK2a activity is implicated.

[0026] In another aspect, the present invention provides the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a disease or condition associated with aberrant activity of CK2a.

[0027] In another aspect, the present invention provides the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm.

[0028] In another aspect, the present invention the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a cancer.

[0029] In another aspect, the present invention provides the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a viral infection.

[0030] In another aspect, the present invention provides a method of treating a disease or condition in which CK2a activity is implicated, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0031] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of CK2a, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0032] In another aspect, the present invention provides a method of treating a proliferative disorder (e.g. cancer or benign neoplasms), a viral infection, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / orregulating cardiac rhythm, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0033] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0034] In another aspect, the present invention provides a method of treating a viral infection, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0035] In another aspect, the present invention provides a combination treatment comprising a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, with one or more additional therapeutic agents.

[0036] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.

[0037] Preferred, suitable, and optional features of any one particular aspect of the present disclosure are also preferred, suitable, and optional features of any other aspect.BRIEF DESCRIPTION OF THE DRA WINGS

[0038] For a better understanding of the disclosure, and to show how embodiments of the same are put into effect, reference is now made, by way of example, to the following figures, in which:Figures 1 and 2 show the results for the digestive modelling experiments carried out in Example 2 herein. The Figures show the API (Compound I) concentration versus time for formulations A-E (see example 2) in liquid mix samples (Figure 1) and aqueous samples (Figure 2).Figure 3 shows the plasma concentration versus time for Compound I obtained for formulations A-E in the in vivo dog PK study (see example 2).DETAILED DESCRIPTION OF THE DISCLOSURE

[0039] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0040] The disclosed compositions, formulations, processes of manufacture and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions, formulations, processes of manufacture and methods are not limited to the specific compositions, formulations, processes of manufacture and methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, formulations, processes of manufacture and methods

[0041] Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

[0042] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment.

[0043] The term “about” when used in reference to numerical ranges, cut-offs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term “about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

[0044] It is to be appreciated that certain features of the disclosed compositions, formulations, processes of manufacture and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, formulations processes of manufacture and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0045] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0046] Where a composition is said to comprise a stipulated ingredient, it is to include the composition comprising one type of the stipulated ingredient, or a mixture of types of the stipulated ingredients. For example, said composition may comprise at least one type of the stipulated ingredient, such as at least two types, at least three types, or at least four types. Suitably, the composition comprises one type of the stipulated ingredient, two types of thestipulated ingredients, three types of the stipulated ingredients or four types of the stipulated ingredients.

[0047] Where a composition is said to comprise a stipulated ingredient (optionally in a stipulated amount or concentration), said composition may optionally include additional ingredients other than that stipulated. However, in certain embodiments, a composition might “consist essentially of’ one or more stipulated ingredients, or may “consist of” of just the stipulated ingredients. Herein, where a composition is said to “consist essentially of” a particular ingredient or ingredients, said composition suitably comprises at least 70 wt% of the stipulated ingredient or ingredients, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to “consist essentially of” a particular component consists of the stipulated ingredient or ingredients save for one or more trace impurities. In certain embodiments, if is stated that a composition might “consist of” one or more stipulated ingredients, then it means that said compositions contains only the stipulated ingredient or ingredients, save for one or more trace impurities.

[0048] The term “permeation enhancer” is used to refer to a pharmaceutically acceptable excipient which increases the flux or amount of a drug (Compound I in this case) through the intestinal epithelium of the Gl tract, thereby increasing the absorption and bioavailability of the drug.

[0049] References to a “semi-solid” herein refer to any material which at room temperature is a solid and at a temperature above room temperature is a liquid. Suitably, room temperature is about 15°C to about 25°C, such as about 20°C to about 25°C. Suitably, room temperature is about 20°C. Suitably, room temperature is 15°C to 25°C, such as 20°C to 25°C. Suitably, room temperature is 20°C.

[0050] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0051] As used herein, the phrase “therapeutically effective dose” refers to an amount of thepharmaceutical composition or pharmaceutical formulation comprising the active substance, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and / or regression of the benign or malignant disease or prevention of the development of the benign or malignant disease, as determined by any means suitable in the art.

[0052] As used herein, “subject” includes a vertebrate; mammal, such as primates, humans, dogs, cattle, and horses; or a domestic animal.

[0053] Compound I may be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and / or physically compatible with the other ingredients present in a formulation, and / or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application. A suitable pharmaceutically acceptable salt of Compound I, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of Compound I is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.PHARMACEUTICAL COMPOSITIONS

[0054] The present invention relates to novel compositions of Compound I that provide improved oral bioavailability.

[0055] Compound I possesses some challenging properties from a drug delivery perspective. Firstly, the compound has low solubility at pH values within 3.5 to 8.5 (less than1 microgram / mL) and low solubility in fasted state simulated intestinal fluid (FaSSIF; 2 micrograms / mL at pH 6.5 and 11 micrograms / mL at pH 5). The compound also exhibits low cell permeability in a Caco-2 model. In addition to the low solubility and permeability characteristics, the inventors also discovered that Compound I is a substrate for P-gp mediated efflux.

[0056] In light of these observations, oral formulations comprising Compound I, or a pharmaceutically acceptable salt thereof, and one or more permeation enhancers were developed.

[0057] The present invention provides a pharmaceutical composition comprising 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I), or a pharmaceutically acceptable salt thereof, dispersed in one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise one or more permeation enhancers.

[0058] Compound I may be present as a free base or as a pharmaceutically acceptable salt. In an embodiment, Compound I is in the form of the free base. In another embodiment, compound I is a provided as a pharmaceutically acceptable salt. Compound I may also be present in any solid state form, for example an amorphous or crystalline form. Suitably, compound I is present in a crystalline form.

[0059] Suitably, the pharmaceutical composition comprises a homogenous dispersion of Compound I, or a pharmaceutically acceptable salt thereof, throughout the composition.

[0060] The pharmaceutical composition may be a solid, semi-solid or fluid / liquid at room temperature. In an embodiment, the pharmaceutical composition is a solid at room temperature. In another embodiment, the pharmaceutical composition is a semi-solid at room temperature. In another embodiment, the pharmaceutical composition is a fluid / liquid at room temperature.

[0061] The amount of Compound I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition will vary depending on the dosage of Compound I to be administered. Typically, Compound I, or a pharmaceutically acceptable salt thereof, will be present at any one of the amounts set out in any one of the numbered paragraphs (1) to (19) below:(1) 2 to 25% w / w of the total pharmaceutical composition;(2) 5 to 25% w / w of the total pharmaceutical composition;(3) 8 to 25% w / w of the total pharmaceutical composition;(4) 10 to 25% w / w of the total pharmaceutical composition;(5) 10 to 22% w / w of the total pharmaceutical composition;(6) 10 to 20% w / w of the total pharmaceutical composition;(7) 11 to 20% w / w of the total pharmaceutical composition;(8) 12 to 20% w / w of the total pharmaceutical composition;(9) 13 to 20% w / w of the total pharmaceutical composition;(10) 14 to 20% w / w of the total pharmaceutical composition;(11) 15 to 20% w / w of the total pharmaceutical composition;(12) 10 to 18% w / w of the total pharmaceutical composition;(13) 11 to 18% w / w of the total pharmaceutical composition;(14) 12 to 18% w / w of the total pharmaceutical composition;(15) 13 to 18% w / w of the total pharmaceutical composition;(16) 14 to 18% w / w of the total pharmaceutical composition;(17) 15 to 18% w / w of the total pharmaceutical composition;(18) 16 to 18% w / w of the total pharmaceutical composition; or(19) 16 to 17% w / w of the total pharmaceutical composition.

[0062] In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (1) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (2) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (3) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (4) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (5) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (6) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (7) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (8) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (9) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (10) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (11) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (12) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (13) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (14) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (15) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (16) above. In an embodiment, the pharmaceutical compositioncomprises Compound I in amount specified in paragraph (17) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (18) above. In an embodiment, the pharmaceutical composition comprises Compound I in amount specified in paragraph (19) above.

[0063] In further embodiments, Compound I is present in an amount of about 2% w / w of the total pharmaceutical composition, about 3% w / w of the total pharmaceutical composition, about 4% w / w of the total pharmaceutical composition, about 5% w / w of the total pharmaceutical composition, about 6% w / w of the total pharmaceutical composition, about 7% w / w of the total pharmaceutical composition, about 8% w / w of the total pharmaceutical composition, about 9% w / w of the total pharmaceutical composition, about 10% w / w of the total pharmaceutical composition, about 11% w / w of the total pharmaceutical composition, about 12% w / w of the total pharmaceutical composition, about 13% w / w of the total pharmaceutical composition, about 14% w / w of the total pharmaceutical composition, about 15% w / w of the total pharmaceutical composition, about 16% w / w of the total pharmaceutical composition, about 17% w / w of the total pharmaceutical composition, about 18% w / w of the total pharmaceutical composition, about 19% w / w of the total pharmaceutical composition, about 20% w / w of the total pharmaceutical composition, about 21% w / w of the total pharmaceutical composition, about 22% w / w of the total pharmaceutical composition, about 23% w / w of the total pharmaceutical composition, about 24% w / w of the total pharmaceutical composition, or about 25% w / w of the total pharmaceutical composition.The permeation enhancer

[0064] A permeation enhancer is any pharmaceutically acceptable excipient that is capable of enhancing the flux of Compound I across the intestinal epithelium of the Gl tract. Any suitable permeation enhancer, or combinations of permeation enhancers, may be used in the compositions of the present invention.

[0065] Without wishing to be bound by any particular theory, a “permeation enhancer” may enhance the uptake of the Compound I defined herein by one or more mechanisms, including, for example: (i) enhancing the solubility of the drug concerned in the Gl tract; (ii) enhancing the absorption of the drug through the intestinal epithelium, e.g. by increasing the cell membrane permeability of the intestinal epithelial cells; (iii) interacting with tight junction proteins and modulating the tight junctions to promote paracellular transport; and / or (iv) acting as a P-gp inhibitor that decreases P-gp-mediated efflux of Compound I from the cells of the intestinal epithelium.

[0066] The one or more permeation enhancers may be present in an amount set out in any one of numbered paragraphs (20) to (51) set out below:(20) 25% w / w to 98% w / w of the total pharmaceutical composition;(21 ) 30% w / w to 98% w / w of the total pharmaceutical composition;(22) 40% w / w to 98% w / w of the total pharmaceutical composition;(23) 50% w / w to 98% w / w of the total pharmaceutical composition;(24) 60% w / w to 98% w / w of the total pharmaceutical composition;(25) 70% w / w to 98% w / w of the total pharmaceutical composition;(26) 75% w / w to 98% w / w of the total pharmaceutical composition;(27) 80% w / w to 98% w / w of the total pharmaceutical composition;(28) 25% w / w to 95% w / w of the total pharmaceutical composition;(29) 30% w / w to 95% w / w of the total pharmaceutical composition;(30) 40% w / w to 95% w / w of the total pharmaceutical composition;(31 ) 50% w / w to 95% w / w of the total pharmaceutical composition;(32) 60% w / w to 95% w / w of the total pharmaceutical composition;(33) 70% w / w to 95% w / w of the total pharmaceutical composition;(34) 75% w / w to 95% w / w of the total pharmaceutical composition;(35) 80% w / w to 95% w / w of the total pharmaceutical composition;(36) 25% w / w to 90% w / w of the total pharmaceutical composition;(37) 30% w / w to 90% w / w of the total pharmaceutical composition;(38) 40% w / w to 90% w / w of the total pharmaceutical composition;(39) 50% w / w to 90% w / w of the total pharmaceutical composition;(40) 60% w / w to 90% w / w of the total pharmaceutical composition;(41 ) 70% w / w to 90% w / w of the total pharmaceutical composition;(42) 75% w / w to 90% w / w of the total pharmaceutical composition;(43) 80% w / w to 90% w / w of the total pharmaceutical composition;(44) 25% w / w to 85% w / w of the total pharmaceutical composition;(45) 30% w / w to 85% w / w of the total pharmaceutical composition;(46) 40% w / w to 85% w / w of the total pharmaceutical composition;(47) 50% w / w to 85% w / w of the total pharmaceutical composition;(48) 60% w / w to 85% w / w of the total pharmaceutical composition;(49) 70% w / w to 85% w / w of the total pharmaceutical composition;(50) 75% w / w to 85% w / w of the total pharmaceutical composition; or(51) 80% w / w to 85% w / w of the total pharmaceutical composition.

[0067] In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (20) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (21) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (22) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (23) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (24) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (25) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (26) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (27) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (28) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (29) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (30) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (31) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (32) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (33) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (34) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (35) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (36) above. In an embodiment, the pharmaceutical compositioncomprises one or more permeation enhancers in amount specified in paragraph (37) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (38) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (39) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (40) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (41) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (42) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (43) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (44) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (45) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (46) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (47) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (48) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (49) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (50) above. In an embodiment, the pharmaceutical composition comprises one or more permeation enhancers in amount specified in paragraph (51) above.

[0068] In further embodiments, the pharmaceutical composition comprises one or more permeation enhancers in amount of about 25% w / w of the total pharmaceutical composition, about 30% w / w of the total pharmaceutical composition, about 35% w / w of the total pharmaceutical composition, about 40% w / w of the total pharmaceutical composition, about 45% w / w of the total pharmaceutical composition, about 50% w / w of the total pharmaceutical composition, about 55% w / w of the total pharmaceutical composition, about 60% w / w of the total pharmaceutical composition, about 65% w / w of the total pharmaceutical composition, about 70% w / w of the total pharmaceutical composition, about 75% w / w of the total pharmaceutical composition, about 76% w / w of the total pharmaceutical composition, about 77% w / w of the total pharmaceutical composition, about 78% w / w of the total pharmaceutical composition, about 79% w / w of the total pharmaceutical composition, about 80% w / w of thetotal pharmaceutical composition, about 81% w / w of the total pharmaceutical composition, about 82% w / w of the total pharmaceutical composition, about 83% w / w of the total pharmaceutical composition, about 84% w / w of the total pharmaceutical composition, about 85% w / w of the total pharmaceutical composition, about 86% w / w of the total pharmaceutical composition, about 87% w / w of the total pharmaceutical composition, about 88% w / w of the total pharmaceutical composition, about 89% w / w of the total pharmaceutical composition, about 90% w / w of the total pharmaceutical composition, about 91% w / w of the total pharmaceutical composition, about 92% w / w of the total pharmaceutical composition, about 93% w / w of the total pharmaceutical composition, about 94% w / w of the total pharmaceutical composition, or about 95% w / w of the total pharmaceutical composition.

[0069] In an embodiment, the pharmaceutical composition comprises two or more permeation enhancers. In another embodiment, the pharmaceutical composition comprises two or three permeation enhancers.

[0070] Examples of suitable permeation enhancers are set out in any one of numbered paragraphs (52) to (62) set out below:(52) Surfactants:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate, and derivatives of C8 / C10 acids such as salcaprozate sodium (SNAC) and caprylic / capric triglycerides);polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG-40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS- 15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type i)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT);cetyltrime-thylammonium bromide (CTAB);Polymers:dextrans, agar, gellan gum, gum arabic, gum traganth, guar gum, carrageenan gum, xanthan gum, alginates, chitosan, polyethylene glycol;amphiphilic di-block copolymers (e.g. methoxyPEG-block-polycaprolactone (MePEG-b-PCL), Soluplus);Pluronic block copolymers (e.g. poloxamer407 and 188);Glycerides:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60); monoolein (Peceol™);monostearin;Phospholipids:1.2-dioctanoyl-sn-glycero-3-phosphocholine (8:0 PC);1.2-didecanoyl-sn-glycero-3-phosphocholine (10:0 PC);Cyclodextrins:methylated cyclodextrin;Pharmaceutical agents:e.g. verapamil, cyclosporine, trifluoperazine, quinidine, reserpine, yohimbine, tamoxifen, toremifene, vincristine, dexverapamil, PSC 833 (valspodar), VX-710 (biricodar), GF120918 (elacridar), LY335979 (zosuquidar), XR9576 (tariquidar), R101933 (laniquidar), WK-X-34, and OC144-093 (ontogeny);Natural products such as:Alkaloids - e.g. glaucine, pervilleine, berberine, kopsiflorine, lobeline, cepharanthine, ibogaine, theobromine;Flavonoids - e.g. quercetin, morin, phloretin, rhamnetin, plagiochin E, daidzin, procyanidine, rotenone;Coumarins - e.g. decursinol, bergaptol, galbanic acid, farnesiferol;Terpenoid - e.g. citral, latilagascene, paraliane, pepluanin A, jolkinol B, euphoportlandol lhelioscopinolide, tuckeyanols, euphotuckeyanol, isopimaric acid, totarol;Saponins - e.g. gracillin, tenacissimoside A, karavilagenin C, balsaminol, ginsenoside F1, protopanaxatriol;Peptides - e.g. discodermolide, kendarimide, hapalosin, nocardioazine;Resins - e.g. gambogic acid, orizabin;Miscellaneous natural compounds - e.g. acetoxy cavicolacetate, arctigenin, pheophorbide, porphyrin, cannabinol, gomisin, pregomisin, phenylbutanoid.(53) Surfactants:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate, and derivatives of C8 / C10 acids such as salcaprozate sodium (SNAC) and caprylic / capric triglycerides)polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG-40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS- 15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type i)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT);cetyltrime-thylammonium bromide (CTAB);Polymers:dextrans, agar, gellan gum, gum arabic, gum traganth, guar gum, carrageenan gum, xanthan gum, alginates, chitosan, polyethylene glycol;amphiphilic di-block copolymers (e.g. methoxyPEG-block-polycaprolactone (MePEG-b-PCL), Soluplus);Pluronic block copolymers (e.g. poloxamer407 and 188);Glycerides:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60); monoolein (Peceol™);monostearin.(54) Surfactants:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate, and derivatives of C8 / C10 acids such as salcaprozate sodium (SNAC) and caprylic / capric triglycerides)polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG-40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS- 15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type i)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT);cetyltrime-thylammonium bromide (CTAB);Polymers:polyethylene glycol;Pluronic block copolymers (e.g. poloxamer 407 and 188);Glycerides:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(55) Surfactants:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG-40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS- 15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type i)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];Polymers:polyethylene glycol;Pluronic block copolymers (e.g. poloxamer 407 and 188);Glycerides:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(56) Surfactants:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG-40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS- 15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; and / or PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14)];Glycerides:capric / caprylic triglycerides (e.g. Crodamol GTCC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(57) Surfactants:sodium caproate, sodium caprate or sodium caprylate;Vitamin E TPGS;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; and / or PEG-8 caprylic / capric glycerides - also known as Labrasol;Glycerides:capric / caprylic triglyceride (e.g. Crodamol GTCC);capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(58) sodium caprate or sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride -also known as PEG-32 laurate or Gelucire 44 / 14; and / or capric / caprylic triglyceride (e.g. Crodamol GTCC).(59) sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; and / orcapric / caprylic triglyceride (e.g. Crodamol GTCC).(59) sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; and / orlauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; (60) PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL or Kolliphor EL; and / orcapric / caprylic triglyceride (e.g. Crodamol GTCC).(61) Vitamin E TPGS; and / orPEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15.(62) PEG-8 caprylic / capric glycerides - also known as Labrasol; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).

[0071] In further embodiments of the invention, the one or more permeation enhancers are as defined in any one of paragraphs (63) to (92) below:(63) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;b. a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition;c. a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition;d. a phospholipid as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / ore. a cyclodextrin as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition;(64) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;b. a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / orc. a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition;(65) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 25 to 95% w / w of the total pharmaceutical composition;b. a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 50% w / w of the total pharmaceutical composition; and / orc. a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(66) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein as defined herein in an amount of 30 to 95% w / w of the total pharmaceutical composition;b. a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 50% w / w of the total pharmaceutical composition; and / orc. a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(67) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 30 to 95% w / w of the total pharmaceutical composition; and / orb. a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(68) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 35 to 90% w / w of the total pharmaceutical composition; and / orb. a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(69) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 35 to 85% w / w of the total pharmaceutical composition; and / orb. a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(70) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above wherein the surfactant is selected from one or more of the following: fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. , e.g. sodium caproate, sodium caprate or sodium caprylate, and derivatives of C8 / C10 acids such as salcaprozate sodium (SNAC) and caprylic / capric triglycerides) polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG- 40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate -also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT); cetyltrime-thylammonium bromide (CTAB);and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60); monoolein (Peceol™);monostearin.(71) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above wherein the surfactant is selected from one or more of the following: fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. , e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG-40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxy stearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(72) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG- 40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6caprylic / capric glycerides - aiso known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(73) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG- 40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hyd oxy stearate ~ also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; and / or PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14)];and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC); and / orcapric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(74) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: sodium caproate; sodium caprate; sodium caprylate;Vitamin E TPGS;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; and / orPEG-8 caprylic / capric glycerides - also known as Labrasol;and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(75) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: sodium caprylate;Vitamin E TPGS;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following: capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(76) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is capric / caprylic triglycerides (e.g. Crodamol GTCC).(77) the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following: sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / orb. a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is capric / caprylic triglycerides (e.g. Crodamol GTCC).(78) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(79) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(80) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(81) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 5 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(82) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(83) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 40% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 50% w / w of the total pharmaceutical composition.(84) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 25 to 35% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 40% w / w of the total pharmaceutical composition.(85) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 5 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(86) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(87) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 30% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 30 to 60% w / w of the total pharmaceutical composition.(88) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 30% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 35 to 55% w / w of the total pharmaceutical composition;(89) the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(90) the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 60% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(91) the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 30 to 50% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 50% w / w of the total pharmaceutical composition.(92) the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 35 to 45% w / w of the total pharmaceutical composition.

[0072] In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (52) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (53) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (54) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (55) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (56) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (57) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (58) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (59) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (60) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (61) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (62) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (63) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (64) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (65) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (66) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (67) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (68) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (69) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (70) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (71) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (72) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (73) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (74) above. Inan embodiment, the one or more permeation enhancers are as defined in any one of paragraph (75) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (76) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (77) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (78) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (79) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (80) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (81) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (82) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (83) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (84) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (85) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (86) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (87) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (88) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (89) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (90) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (91) above. In an embodiment, the one or more permeation enhancers are as defined in any one of paragraph (91) above.Additional excipients

[0073] Optionally, the pharmaceutical compositions of the present invention may further comprise one or more additional excipients (in addition to Compound I, or a pharmaceutically acceptable salt thereof, and the one or more permeation enhancers).

[0074] Examples of suitable additional excipients include lubricants, glidants, fillers, carriers, viscosity modifiers, opacifiers, preservatives, flavourings and / or colourants.

[0075] A suitable preservative is an antioxidant, for example, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or alpha tocopherol.

[0076] The one or more additional excipients may be present in an amount ranging from 0.1 to 80% w / w of the total composition. Suitably, the one or more additional excipients may be present in an amount ranging from 0.1 to 70% w / w, 0.1 to 60% w / w, 0.1 to 50% w / w, 0.1to 40% w / w, 0.1 to 30% w / w, 0.1 to 25% w / w, 0.1 to 20% w / w, 0.1 to 15% w / w, 0.1 to 10% w / w, 0.1 to 5% w / w, 0.1 to 4% w / w or 0.5 to 3 w / w of the total composition.

[0077] In an embodiment, the pharmaceutical compositions of the present invention include a lubricant, e.g. fumed silica (such as Aerosil 200), to enhance the flow properties of the composition, prevent caking and / or improve the stability of the composition. The lubricant (e.g. fumed silica I Aerosil 200), is suitably present in an amount of .1 to 5% w / w, 0.1 to 4% w / w or 0.5 to 3 w / w of the total composition.Particular embodiments of the pharmaceutical compositions

[0078] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (1) above, the permeation is enhancer is present in amount defined in paragraph (20) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (52) above.

[0079] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (2) above, the permeation is enhancer is present in amount defined in paragraph (22) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (53) above.

[0080] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (3) above, the permeation is enhancer is present in amount defined in paragraph (24) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (54) above.

[0081] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (4) above, the permeation is enhancer is present in amount defined in paragraph (26) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (55) above.

[0082] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (5) above, the permeation is enhancer is present in amount definedin paragraph (26) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (55) above.

[0083] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (6) above, the permeation is enhancer is present in amount defined in paragraph (28) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (56) above.

[0084] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (7) above, the permeation is enhancer is present in amount defined in paragraph (30) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0085] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (1) above, the permeation is enhancer is present in amount defined in paragraph (20) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0086] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (2) above, the permeation is enhancer is present in amount defined in paragraph (22) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0087] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (3) above, the permeation is enhancer is present in amount defined in paragraph (24) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0088] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (4) above, the permeation is enhancer is present in amount defined in paragraph (26) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0089] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition isas defined in paragraph (5) above, the permeation is enhancer is present in amount defined in paragraph (28) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0090] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (7) above, the permeation is enhancer is present in amount defined in paragraph (32) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0091] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (8) above, the permeation is enhancer is present in amount defined in paragraph (34) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0092] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (9) above, the permeation is enhancer is present in amount defined in paragraph (36) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0093] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (10) above, the permeation is enhancer is present in amount defined in paragraph (38) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0094] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (12) above, the permeation is enhancer is present in amount defined in paragraph (40) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0095] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (14) above, the permeation is enhancer is present in amount defined in paragraph (42) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0096] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (16) above, the permeation is enhancer is present in amount defined in paragraph (44) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0097] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (18) above, the permeation is enhancer is present in amount defined in paragraph (46) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0098] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (19) above, the permeation is enhancer is present in amount defined in paragraph (48) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (57) above.

[0099] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (18) above, the permeation is enhancer is present in amount defined in paragraph (46) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (58) above.

[0100] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (19) above, the permeation is enhancer is present in amount defined in paragraph (48) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (58) above.

[0101] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (18) above, the permeation is enhancer is present in amount defined in paragraph (46) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (59) above.

[0102] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (19) above, the permeation is enhancer is present in amount defined in paragraph (48) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (59) above.

[0103] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (18) above, the permeation is enhancer is present in amount defined in paragraph (46) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (60) above.

[0104] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (19) above, the permeation is enhancer is present in amount defined in paragraph (48) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (60) above.

[0105] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (18) above, the permeation is enhancer is present in amount defined in paragraph (46) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (61) above.

[0106] In a particular embodiment of the invention, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, present in the pharmaceutical composition is as defined in paragraph (19) above, the permeation is enhancer is present in amount defined in paragraph (48) above, and the permeation enhancer is selected from one or more of the options defined in paragraph (62) above.PHARMACEUTICAL FORMULATIONS

[0107] In one aspect, there is provided a pharmaceutical formulation comprising the pharmaceutical composition as defined herein.

[0108] In a further aspect, there is provided a pharmaceutical formulation for oral use comprising the pharmaceutical composition as defined herein. In an embodiment, the formulation is an immediate release formulation.

[0109] The pharmaceutical formulation may be any dosage form suitable for oral use (for example, hard or soft capsules, suspensions, emulsions, syrups or elixirs, sprays).

[0110] In an embodiment, the pharmaceutical formulation is a capsule formulation.

[0111] In an embodiment, the pharmaceutical formulation is an immediate release capsule formulation comprising a capsule shell.

[0112] Suitably, the capsule shell comprises gelatin or HPMC.

[0113] Suitably, the capsule shell comprises gelatin, such as hard gelatin.

[0114] Suitably, the capsules shell is a size 00, 0, 1, 2, 3 or 4 size capsule shell.

[0115] Suitably, the pharmaceutical formulation comprises a capsule shell and the pharmaceutical composition as defined herein is located within the capsule shell.

[0116] Suitably, the pharmaceutical formulation consists of a capsule shell and the pharmaceutical composition as defined herein located within the capsule shell.

[0117] Advantageously, having a good content uniformity ensures each dosage form of the pharmaceutical formulation contains the intended quantity of the active substance. This is critical from a patient safety and efficacy perspective.

[0118] The pharmaceutical formulation for oral use comprising the pharmaceutical composition as defined herein suitably comprises between about 1 mg and about 200 mg of the active substance, such as between about 10 mg and about 150 mg, about 20 mg and about 150 mg, or about 30 mg and about 100 mg.

[0119] The pharmaceutical formulation of the invention may be administered once daily or multiple time per day, for example, once daily, twice daily, three times a day or four times a day.Process of manufacture

[0120] In a further aspect, there is a method of manufacturing the pharmaceutical composition described herein comprising the step of mixing Compound I, or a pharmaceutically acceptable salt thereof, with a permeation enhancer.

[0121] In a further aspect, there is a method of manufacturing the pharmaceutical formulation described herein comprising the steps of:(i) mixing Compound I, or a pharmaceutically acceptable salt thereof, with a permeation enhancer; and(ii) loading the pharmaceutical composition into a capsule.

[0122] Suitably, the permeation enhancer is a liquid in the mixing step.

[0123] Suitably, the step of mixing the active substance into the non-aqueous solvent is performed at room temperature or at an elevated temperature, depending on the permeation enhancer concerned. For semi-solid permeation enhancers that are solid at room temperature and liquid at elevated temperatures, the mixing step is conducted at an elevated temperature above the melting point for the permeation enhancer concerned. For example, the mixingmay be carried out at a temperature of about 15°C to about 80°C, about 18°C to about 80°C, about 20°C to about 80°C.

[0124] The step of mixing Compound I into the permeation enhancer may be performed under an inert atmosphere, e.g. a nitrogen atmosphere.

[0125] Suitably, the pharmaceutical composition comprises a homogenous dispersion of Compound I in the permeation enhancer following the mixing step.

[0126] Once formed, the pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt thereof, and a permeation enhancer may be loaded into a capsule to form a capsule formulation of the present invention. Suitably, the capsules are filled by a liquid fill process, where by a fluid pharmaceutical composition is loaded into the capsules.Solution or suspension formulations for oral delivery

[0127] In a particular aspect, the present invention provides a solution or suspension formulation comprising Compound I, or a pharmaceutically acceptable salt thereof, and one or more penetration enhancers, dispersed in a pharmaceutically acceptable vehicle.

[0128] The amount of Compound I, or a pharmaceutically acceptable salt thereof, present in the solution or suspension formulation will vary depending on the dosage of Compound I to be administered. Typically, Compound I, or a pharmaceutically acceptable salt thereof, will be present at any one of the amounts set out in any one of the numbered paragraphs (93) to (117) below:(93) 0.05 to 30 % w / v of the total formulation;(94) 0.05 to 25 % w / v of the total formulation;(95) 0.05 to 20 % w / v of the total formulation;(96) 0.05 to 15 % w / v of the total formulation;(97) 0.05 to 10 % w / v of the total formulation;(98) 0.1 to 30% w / v of the total formulation;(99) 0.1 to 25% w / v of the total formulation;(100) 0.1 to 20% w / v of the total formulation;(101) 0.1 to 15% w / v of the total formulation;(102) 0.1 to 10% w / v of the total formulation;(103) 0.5 to 30% w / v of the total formulation;(104) 0.5 to 25% w / v of the total formulation;(105) 0.5 to 20% w / v of the total formulation;(106) 0.5 to 15% w / v of the total formulation;(107) 0.5 to 10% w / v of the total formulation;(108) 1 to 30% w / v of the total formulation;(109) 1 to 25% w / v of the total formulation;(110) 1 to 20% w / v of the total formulation;(111) 1 to 15% w / v of the total formulation;(112) 1 to 10% w / v of the total formulation;(113) 2 to 30% w / v of the total formulation;(114) 2 to 25% w / v of the total formulation;(115) 2 to 20% w / v of the total formulation;(116) 2 to 15% w / v of the total formulation; or(117) 2 to 10% w / v of the total formulation.

[0129] Alternatively, Compound I, or a pharmaceutically acceptable salt thereof, will be present at any one of the amounts set out in any one of the numbered paragraphs (118) to (147) below:(118) 0.5 to 300 mg / ml;(119) 0.5 to 250 mg / ml;(120) 0.5 to 200 mg / ml;(121) 0.5 to 150 mg / ml;(122) 0.5 to 100 mg / ml;(123) 0.5 to 50 mg / ml;(124) 1 to 300 mg / ml;(125) 1 to 250 mg / ml;(126) 1 to 200 mg / ml;(127) 1 to 150 mg / ml;(128) 1 to 100 mg / ml;(129) 1 to 50 mg / ml;(130) 5 to 300 mg / ml;(131) 5 to 250 mg / ml;(132) 5 to 200 mg / ml;(133) 5 to 150 mg / ml;(134) 5 to 100 mg / ml;(135) 5 to 50 mg / ml;(136) 10 to 300 mg / ml;(137) 10 to 250 mg / ml;(138) 10 to 200 mg / ml;(139) 10 to 150 mg / ml;(140) 10 to 100 mg / ml;(141) 10 to 50 mg / ml;(142) 20 to 300 mg / ml;(143) 20 to 250 mg / ml;(144) 20 to 200 mg / ml;(145) 20 to 150 mg / ml;(146) 20 to 100 mg / ml; or(147) 20 to 50 mg / ml.

[0130] Any suitable permeation enhancer may be used in the solution or suspension formulations. Examples of suitable penetration enhancers are described herein.

[0131] Particularly suitable penetration enhancers for solutions or suspension formulations of Compound I include Cremophor EL, Cremophor RH40 (Kolliphor RH40), polysorbate 80 (Tween 80), Vitamin E TPGS, Solutol HS-15, gelucire, or labrasol. In a particular embodiment, the penetration enhancer for the solutions or suspension formulations of Compound I is Cremophor EL.

[0132] The amount of penetration enhancer present in the solution or suspension formulation will vary. Typically, the penetration enhancer will be present at any one of the amounts set out in any one of the numbered paragraphs (148) to (167) below:(148) 1 to 70 % w / v of the total formulation;(149) 1 to 60 % w / v of the total formulation;(150) 1 to 50 % w / v of the total formulation;(151) 1 to 40 % w / v of the total formulation;(152) 1 to 30 % w / v of the total formulation;(153) 5 to 70 % w / v of the total formulation;(154) 5 to 60 % w / v of the total formulation;(155) 5 to 50 % w / v of the total formulation;(156) 5 to 40 % w / v of the total formulation;(157) 5 to 30 % w / v of the total formulation;(158) 10 to 70 % w / v of the total formulation;(159) 10 to 60 % w / v of the total formulation;(160) 10 to 50 % w / v of the total formulation;(161) 10 to 40 % w / v of the total formulation;(162) 10 to 30 % w / v of the total formulation;(163) 15 to 70 % w / v of the total formulation;(164) 15 to 60 % w / v of the total formulation;(165) 15 to 50 % w / v of the total formulation;(166) 15 to 40 % w / v of the total formulation; or(167) 15 to 30 % w / v of the total formulation.

[0133] The solution or suspension formulations more optionally comprise one or more additional excipients. Exemplary additional excipients include buffers, preservatives, antioxidants, stabilisers, solubilisers, wetting agents, masking agents, colouring agents, flavouring agents, and / or sweetening agents.

[0134] In a particular embodiment, the solution or suspension formulation comprises a solubliser (e.g. PEG). In certain embodiments, the solubiliser may form the vehicle for the solution or suspension formulation. The solubiliser may be present in, for example, an amount set out in any one of the numbered paragraphs (168) to (185) below:(168) 1 to 70 % w / v of the total formulation;(169) 1 to 60 % w / v of the total formulation;(170) 1 to 50 % w / v of the total formulation;(171) 1 to 40 % w / v of the total formulation;(172) 5 to 70 % w / v of the total formulation;(173) 5 to 60 % w / v of the total formulation;(174) 5 to 50 % w / v of the total formulation;(175) 5 to 40 % w / v of the total formulation;(176) 10 to 70 % w / v of the total formulation;(177) 10 to 60 % w / v of the total formulation;(178) 10 to 50 % w / v of the total formulation;(179) 10 to 40 % w / v of the total formulation;(180) 10 to 30 % w / v of the total formulation;(181) 20 to 70 % w / v of the total formulation;(182) 20 to 60 % w / v of the total formulation;(183) 20 to 50 % w / v of the total formulation;(184) 20 to 40 % w / v of the total formulation; or(185) 20 to 30 % w / v of the total formulation.

[0135] In an embodiment, the vehicle is an aqueous vehicle. The vehicle may be water or a mixture of water and a suitable solubiliser (e.g. PEG).

[0136] In a further aspect, the present invention provides a method of manufacturing a solution or suspension formulation as defined herein comprising the step of mixing Compound I, or a pharmaceutically acceptable salt thereof, with one or more permeation enhancers in a pharmaceutically acceptable vehicle.Therapeutic Uses and Applications

[0137] Compound I is a potent inhibitor of Casein Kinase 2 alpha (CK2a). It is designed to bind to the catalytic ATP site of CK2a (to drive potent enzyme inhibition) and the aD site (to drive high levels of selectivity over other kinases) [Brear etal, Chem Sci 2016],

[0138] Accordingly, Compound I are useful for the treatment and / or prevention of diseases and conditions in which CK2a activity is implicated, such as, for example, but not limited to, the treatment and / or prevention of proliferative disorders (e.g. cancer), viral infections, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration and the regulation of circadian rhythm.

[0139] The present disclosure therefore provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use as a medicament.

[0140] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in therapy.

[0141] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in the treatment of a disease or condition in which CK2a activity is implicated.

[0142] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in the treatment of a disease or condition associated with aberrant activity of CK2a.

[0143] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm.

[0144] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in the treatment of cancer.

[0145] The present disclosure further provides a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein for use in the treatment of a viral infection.

[0146] The present disclosure further provides the use of a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein in the manufacture of a medicament for use in:(i) the treatment of a disease or condition in which CK2a activity is implicated;(ii) the treatment of a disease or condition associated with aberrant activity of CK2a; (iii) the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm; (iv) for use in the treatment of cancer; or(v) the treatment of a viral infection.

[0147] The present disclosure further provides a method of treating:(i) a disease or condition in which CK2a activity is implicated;(ii) a disease or condition associated with aberrant activity of CK2a;(iii) proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm;(iv) cancer; or(v) a viral infection;the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein or a pharmaceutical formulation as defined herein.

[0148] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a proliferative disorder.

[0149] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a proliferative disorder (e.g. cancer or a benign neoplasms).

[0150] In another aspect, the present invention provides a method of treating a proliferative disorder (e.g. cancer or benign neoplasms), said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0151] The terms "proliferative disorder" and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth,whether in vitro or in vivo.

[0152] Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, cancers, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, blood and skin.

[0153] In certain aspects of the present invention, the proliferative disorder is cancer, suitably a cancer selected from lung, colon / colorectal, breast, ovarian, prostate, liver, pancreas, brain, blood, cholangiocarcinoma and skin cancer.

[0154] In a particular aspect of the invention, the proliferative disorder is colon / colorectal, cholangiocarcinoma, ovarian or prostate cancer.

[0155] In a particular aspect of the invention, the proliferative disorder is colorectal cancer.

[0156] In certain aspects of the present invention, the proliferative disorder is hematopoietic tumour, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); and myelofibrosis.

[0157] A benign neoplasm may be, for example, hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas or pituitary adenomas. The benign neoplasm may be endometrial implants or a keratocystic odontogenic tumor.

[0158] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a cancer.

[0159] In another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a cancer.

[0160] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0161] The cancer may be non-metastatic or metastatic and which may be a solid tumour or a haematological (“liquid”) cancer. The cancer may, for example, be selected from:(1) Carcinoma, including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (a malignant neoplasm of the bladder)), bronchogenic carcinoma, colorectal carcinoma (including, but not limited to, colon carcinoma and rectal carcinoma), anal carcinoma, gastric carcinoma, lung carcinoma (including but not limited to small cell carcinoma (SCLC) and non-small cell carcinoma of the lung (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrine tumors), breast carcinoma (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian carcinoma (including, but not limited to, ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord-stromal tumor), liver and bile duct carcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate carcinoma, adenocarcinoma, brain tumours (including, but not limited to glioma, glioblastoma and medulloblastoma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney carcinoma (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilm's tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical carcinoma, uterine carcinoma (including, but not limited to, endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors), testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous carcinoma;(2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective tissue types) and other soft tissue sarcomas;(3) Myeloma and multiple myeloma;(4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.(5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas;(6) Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;(7) Melanoma, uveal melanoma and retinoblastoma; and(8) Mixed Types, including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.

[0162] Suitably, a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, may be for use in the treatment of a cancer selected from cancer selected from colon / colorectal cancer, cholangiocarcinoma, gastric cancer, skin cancer (e.g. basal cell carcinoma), ovarian, prostate, breast cancer, liver cancer, pancreatic cancer, brain cancer, blood cancers (leukaemia’s, myelomas), bladder cancer, bone cancer, head and neck cancer, renal cancer and lung cancer.

[0163] More suitably, the cancer is selected from colon / colorectal cancer, prostate cancer, ovarian cancer, basal cell carcinoma or cholangiocarcinoma.

[0164] In a particular aspect of the present invention, the cancer is basal cell carcinoma.

[0165] In a particular aspect of the present invention, the cancer is colorectal cancer.

[0166] In a particular aspect of the present invention, the cancer is cholangiocarcinoma.

[0167] In a further aspect of the present invention, the cancer is prostate cancer.

[0168] In a further aspect of the present invention, the cancer is ovarian cancer.

[0169] In another aspect of the present invention, the cancer is a hematopoietic tumour.

[0170] It is hypothesised that the pharmaceutical compositions or pharmaceutical formulations defined herein, will be particularly suited to the treatment of wnt pathway driven cancers, e.g. wnt pathway mutated colorectal cancer or cholangiocarcinoma (Di Maira et al, 2019).

[0171] In addition to CK2a having a very well characterized function in wnt pathway activity, it also plays a role in other key cellular pathways known to be upregulated in cancer, such as, but not limited to, the DNA damage response (Ruzzene & Pinna, 2010; Montenarh, Transl. Cancer Res 2016). Thus, the pharmaceutical compositions or pharmaceutical formulations defined herein may have a further use in the treatment of PARP insensitive tumors in prostate / ovarian cancer.

[0172] CK2a has also been identified as a key host protein required for viral replication (e.g. in SARS-CoV2) and as such could represent an antiviral treatment (Gordon et al. Nature 2020).

[0173] Thus, in another aspect, the present invention provides a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, for use in the treatment of a viral infection.

[0174] In another aspect, the present invention provides the use of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein, in the manufacture of a medicament for use in the treatment of a viral infection.

[0175] In another aspect, the present invention provides a method of treating a viral infection, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as defined herein, or a pharmaceutical formulation as defined herein.

[0176] Suitably, the virus is a coronavirus, e.g. SARS-CoV2.

[0177] The amount of the Compound I present in the pharmaceutical composition or the pharmaceutical formulation will necessarily vary depending upon the individual treated. For example, the formulation intended for oral administration to humans will generally contain, for example, from about 10 mg to about 250mg of the active substance.

[0178] The size of the dose for therapeutic or prophylactic purposes of the active substance will naturally vary according to the nature and severity of the conditions, the age and sex ofthe animal or patient and the route of administration, according to well known principles of medicine.

[0179] In one embodiment, between about 10 and about 1000 mg / dose / day of Compound I is administered to the patient, such as between about 30 and about 300 mg / dose / day or about 30 and about 200 mg / dose / day.Combination Therapies

[0180] The pharmaceutical compositions and / or pharmaceutical formulations of the present disclosure are useful for the treatment of conditions in which therapy with a CK2a inhibitor is beneficial. Examples of such conditions are outlined above in the therapeutic use section of the present disclosure.

[0181] The pharmaceutical compositions and pharmaceutical formulations of the present disclosure may be used in combination with one or more additional therapeutic agents for the treatment of the condition concerned.

[0182] An additional therapeutic agent may be included in the pharmaceutical composition or pharmaceutical formulation of the present disclosure with the Compound I, or a pharmaceutically acceptable salt thereof, as defined herein, or, alternatively, it may be administered separately, either at the same time as the pharmaceutical composition or pharmaceutical formulation of the present disclosure or at an earlier or later time.

[0183] Therefore, in a further aspect of the disclosure, there is provided a combination product comprising a pharmaceutical composition and / or pharmaceutical formulation of the present disclosure and a pharmaceutical composition comprising an additional therapeutic agent useful in the treatment or prevention of any one of the therapeutic conditions referred to herein, wherein the pharmaceutical composition and / or pharmaceutical formulation of the present disclosure and the pharmaceutical composition comprising the additional therapeutic agent are administered simultaneously, sequentially or separately.

[0184] According to this aspect of the disclosure there is provided a combination for use in the treatment of disease or condition in which therapy with a CK2a inhibitor is beneficial, comprising a pharmaceutical composition or pharmaceutical formulation of the present disclosure as defined hereinbefore, and one or more additional therapeutic agents.

[0185] The present disclosure also provides a pharmaceutical composition and / or pharmaceutical formulation of the present disclosure and one or more additional therapeutic agents for use in the treatment of cancer, wherein the pharmaceutical composition and / or formulation of the present disclosure and the additional therapeutic agent are administered simultaneously, sequentially or separately.

[0186] In certain embodiments, the pharmaceutical composition and / orpharmaceutical formulation of the present disclosure may be used for the treatment of cancer in patients receiving one or more additional cancer therapies. The one or more additional cancer therapies may include radiotherapy, surgical therapy, chemotherapy, immunotherapy or a combination thereof.

[0187] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0188] As indicated above, the combination therapy of the present disclosure may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination products employ the compositions and formulations of the present disclosure within the dosage range described hereinbefore and one or more further pharmaceutically-active agents, wherein each additional agent is used within its approved dosage range.Particular aspects and embodiments of the present disclosure

[0189] The following numbered statements further define particular aspects and embodiments of the present disclosure.(1) A pharmaceutical composition comprising 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I), or a pharmaceutically acceptable salt thereof, dispersed in one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise one or more permeation enhancers.(2) The pharmaceutical composition according to statement (1) above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 2 to 25% w / w of the total pharmaceutical composition. (3) The pharmaceutical composition according to statement (1) or statement (2) above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 5 to 25% w / w of the total pharmaceutical composition.(4) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 8 to 25% w / w of the total pharmaceutical composition.(5) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 22% w / w of the total pharmaceutical composition.(6) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition.(7) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 11 to 20% w / w of the total pharmaceutical composition.(8) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 12 to 20% w / w of the total pharmaceutical composition.(9) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 13 to 20% w / w of the total pharmaceutical composition.(10) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 14 to 20% w / w of the total pharmaceutical composition.(11) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 20% w / w of the total pharmaceutical composition.(12) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or apharmaceutically acceptable salt thereof, in an amount of 10 to 18% w / w of the total pharmaceutical composition.(13) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 11 to 18% w / w of the total pharmaceutical composition.(14) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 12 to 18% w / w of the total pharmaceutical composition.(15) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 13 to 18% w / w of the total pharmaceutical composition.(16) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 14 to 18% w / w of the total pharmaceutical composition.(17) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition.(18) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 18% w / w of the total pharmaceutical composition.(19) The pharmaceutical composition according to any one of the preceding statements, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition.(20) The pharmaceutical composition according to any preceding paragraph, wherein the pharmaceutical composition comprises one or more permeation enhancers present in an amount selected from any one of the following options:a. 25% w / w to 98% w / w of the total pharmaceutical composition;b. 30% w / w to 98% w / w of the total pharmaceutical composition;c. 40% w / w to 98% w / w of the total pharmaceutical composition;d. 50% w / w to 98% w / w of the total pharmaceutical composition;e. 60% w / w to 98% w / w of the total pharmaceutical composition;f. 70% w / w to 98% w / w of the total pharmaceutical composition;g. 75% w / w to 98% w / w of the total pharmaceutical composition; orh. 80% w / w to 98% w / w of the total pharmaceutical composition.(21) The pharmaceutical composition according to any one of statements (1) to (19) above, wherein the pharmaceutical composition comprises one or more permeation enhancers present in an amount selected from any one of the following options:a. 25% w / w to 95% w / w of the total pharmaceutical composition;b. 30% w / w to 95% w / w of the total pharmaceutical composition;c. 40% w / w to 95% w / w of the total pharmaceutical composition;d. 50% w / w to 95% w / w of the total pharmaceutical composition;e. 60% w / w to 95% w / w of the total pharmaceutical composition;f. 70% w / w to 95% w / w of the total pharmaceutical composition;g. 75% w / w to 95% w / w of the total pharmaceutical composition; orh. 80% w / w to 95% w / w of the total pharmaceutical composition.(22) The pharmaceutical composition according to any one of statements (1) to (19) above, wherein the pharmaceutical composition comprises one or more permeation enhancers present in an amount selected from any one of the following options:a. 25% w / w to 90% w / w of the total pharmaceutical composition;b. 30% w / w to 90% w / w of the total pharmaceutical composition;c. 40% w / w to 90% w / w of the total pharmaceutical composition;d. 50% w / w to 90% w / w of the total pharmaceutical composition;e. 60% w / w to 90% w / w of the total pharmaceutical composition;f. 70% w / w to 90% w / w of the total pharmaceutical composition;g. 75% w / w to 90% w / w of the total pharmaceutical composition; orh. 80% w / w to 90% w / w of the total pharmaceutical composition.(23) The pharmaceutical composition according to any one of statements (1) to (19) above, wherein the pharmaceutical composition comprises one or more permeation enhancers present in an amount selected from any one of the following options:a. 25% w / w to 85% w / w of the total pharmaceutical composition;b. 30% w / w to 85% w / w of the total pharmaceutical composition;c. 40% w / w to 85% w / w of the total pharmaceutical composition;d. 50% w / w to 85% w / w of the total pharmaceutical composition;e. 60% w / w to 85% w / w of the total pharmaceutical composition;f. 70% w / w to 85% w / w of the total pharmaceutical composition;g. 75% w / w to 85% w / w of the total pharmaceutical composition; orh. 80% w / w to 85% w / w of the total pharmaceutical composition.(24) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers are selected from the group consisting of surfactants, polymers, glycerides, phospholipids or cyclodextrins that function to increase the flux across the intestinal epithelium.(25) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers are selected from the group consisting of surfactants, polymers, or glycerides, that function to increase the flux across the intestinal epithelium.(26) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers are selected from the group consisting of surfactants or glycerides, that function to increase the flux across the intestinal epithelium.(27) The pharmaceutical composition according to any one of statements (24) to (26) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:a. a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;b. a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition;c. a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition;d. a phospholipid as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / ore. a cyclodextrin as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(29) The pharmaceutical composition according to statement (25) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or(iii) a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(30) The pharmaceutical composition according to statement (25) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 25 to 95% w / w of the total pharmaceutical composition;(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 50% w / w of the total pharmaceutical composition; and / or(iii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(31) The pharmaceutical composition according to statement (25) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein as defined herein in an amount of 30 to 95% w / w of the total pharmaceutical composition;(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 50% w / w of the total pharmaceutical composition; and / or(iii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(32) The pharmaceutical composition according to statement (26) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 30 to 95% w / w of the total pharmaceutical composition; and / or(ii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(33) The pharmaceutical composition according to statement (26) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant as defined herein in an amount of 35 to 90% w / w of the total pharmaceutical composition; and / or(ii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(34) The pharmaceutical composition according to statement (26) above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 35 to 85% w / w of the total pharmaceutical composition; and / or(ii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition;(35) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition are selected from :(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above wherein the surfactant is selected from one or more of the following:fatty acid salts (e.g. caproic acid and caprylic acid salts, , e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG- 40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxy stearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG pal itate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT); cetyltrime-thylammonium bromide (CTAB);and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60); monoolein (Peceol™);monostearin.(36) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above wherein the surfactant is selected from one or more of the following:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);sucrose esters (e.g. sucrose monolaurate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG- 40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];PEG ethers (e.g. Brij 78);propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(37) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate)polysorbates (e.g. polysorbate 80, 20);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG- 40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxy stearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride -- also known as Gelucire 48 / 16)];propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)];propylene glycol mono or di-caprylate [e.g. Capryol PGMC];and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC);linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(38) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate);tocopheryl esters (e.g. Vitamin E TPGS);PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL); or PEG- 40 castor oil (also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG- hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; and / or PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14)];and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(39) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:sodium caproate; sodium caprate; sodium caprylate;Vitamin E TPGS;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; and / orPEG-8 caprylic / capric glycerides - also known as Labrasol;and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(40) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:sodium caprylate;Vitamin E TPGS;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).(41) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is capric / caprylic triglycerides (e.g. Crodamol GTCC).(42) The pharmaceutical composition according to any one of the preceding paragraphs above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant present in any of the amounts defined in paragraphs (63) to (69) above, wherein the surfactant is selected from one or more of the following:sodium caprylate;PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;PEG-15 hydroxystearate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; PEG-8 caprylic / capric glycerides - also known as Labrasol;and / or(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is capric / caprylic triglycerides (e.g. Crodamol GTCC).(43) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(44) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(45) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(46) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 5 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / orcapric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(47) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(48) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 40% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 50% w / w of the total pharmaceutical composition.(49) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 25 to 35% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 40% w / w of the total pharmaceutical composition.(50) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 5 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 50% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(51) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(52) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 30% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 30 to 60% w / w of the total pharmaceutical composition.(53) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 30% w / w of the total pharmaceutical composition; andlauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 35 to 55% w / w of the total pharmaceutical composition;(54) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 60% w / w of the total pharmaceutical composition;PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition; and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition.(55) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 60% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(56) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 30 to 50% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 50% w / w of the total pharmaceutical composition.(57) The pharmaceutical composition according to any one of the preceding statements above, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:PEG-35 castor oil (Kolliphor EL)present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andcapric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 35 to 45% w / w of the total pharmaceutical composition.(58) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition is selected from one of the following: (i) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 40% w / w of the total pharmaceutical composition;d. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 50% w / w of the total pharmaceutical composition; ande. fumed silica (Aerosil 200) present in an amount of 0.1 to 3% w / w of the total pharmaceutical composition;(ii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 17 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 25 to 35% w / w of the total pharmaceutical composition;d. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 40% w / w of the total pharmaceutical composition; ande. fumed silica (Aerosil 200) present in an amount of 0.5 to 2% w / w of the total pharmaceutical composition;(iii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 18 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 27 to 33% w / w of the total pharmaceutical composition;d. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 40% w / w of the total pharmaceutical composition; ande. fumed silica (Aerosil 200) present in an amount of 0.5 to 2% w / w of the total pharmaceutical composition;(iv) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 18 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 27 to 33% w / w of the total pharmaceutical composition;d. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 33 to 37% w / w of the total pharmaceutical composition; ande. fumed silica (Aerosil 200) present in an amount of 0.5 to 1.5% w / w of the total pharmaceutical composition.(59) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition is selected from one of the following: (i) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; andd. lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 20 to 60% w / w of the total pharmaceutical composition;(ii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 17 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 30% w / w of the total pharmaceutical composition; andd. lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 30 to 60% w / w of the total pharmaceutical composition;(iii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 18 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 25% w / w of the total pharmaceutical composition; andd. lauroyl PEG1500 glyceride (Gelucire 44 / 14) present in an amount of 40 to 50% w / w of the total pharmaceutical composition;(iv) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. sodium caprylate present in an amount of 18 to 20% w / w of the total pharmaceutical composition;c. PEG-35 castor oil (Kolliphor EL)present in an amount of 17 to 23% w / w of the total pharmaceutical composition; andd. lauroyl PEG 500 glyceride (Gelucire 44 / 14) present in an amount of 42 to 48% w / w of the total pharmaceutical composition.(60) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition is selected from one of the following: (i) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition;b. PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 60% w / w of the total pharmaceutical composition; andc. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition; andd. fumed silica (Aerosil 200) present in an amount of 0.1 to 3% w / w of the total pharmaceutical composition;(ii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition;b. PEG-35 castor oil (Kolliphor EL)present in an amount of 30 to 50% w / w of the total pharmaceutical composition; andc. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 30 to 50% w / w of the total pharmaceutical composition; andd. fumed silica (Aerosil 200) present in an amount of 0.5 to 2% w / w of the total pharmaceutical composition;(iii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-35 castor oil (Kolliphor EL)present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andc. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andd. fumed silica (Aerosil 200) present in an amount of 0.5 to 2% w / w of the total pharmaceutical composition;(iv) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-35 castor oil (Kolliphor EL)present in an amount of 38 to 43% w / w of the total pharmaceutical composition; andc. capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 38 to 43% w / w of the total pharmaceutical composition; andd. fumed silica (Aerosil 200) present in an amount of 0.5 to 1.5% w / w of the total pharmaceutical composition.(61) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition is selected from one of the following:(i) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition;b. PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 20 to 70% w / w of the total pharmaceutical composition; andc. Vitamin E TPGS present in an amount of 20 to 60% w / w of the total pharmaceutical composition;(ii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition;b. PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 30 to 70% w / w of the total pharmaceutical composition; andc. Vitamin E TPGS present in an amount of 20 to 50% w / w of the total pharmaceutical composition;(iii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 40 to 60% w / w of the total pharmaceutical composition; andc. Vitamin E TPGS present in an amount of 20 to 40% w / w of the total pharmaceutical composition;(iv) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 45 to 55% w / w of the total pharmaceutical composition; andc. Vitamin E TPGS present in an amount of 30 to 40% w / w of the total pharmaceutical composition.(62) The pharmaceutical composition according to any one of the preceding statements above, wherein the pharmaceutical composition is selected from one of the following: (i) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 10 to 20% w / w of the total pharmaceutical composition;b. PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 20 to 60% w / w of the total pharmaceutical composition; andc. capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 20 to 60% w / w of the total pharmaceutical composition.(ii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 15 to 18% w / w of the total pharmaceutical composition;b. PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 30 to 50% w / w of the total pharmaceutical composition; andc. capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 30 to 50% w / w of the total pharmaceutical composition.(iii) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andc. capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 35 to 45% w / w of the total pharmaceutical composition;(iv) a pharmaceutical composition comprising:a. Compound I, or a pharmaceutically acceptable salt thereof, in an amount of 16 to 17% w / w of the total pharmaceutical composition;b. PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 35 to 45% w / w of the total pharmaceutical composition; andc. capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 35 to 45% w / w of the total pharmaceutical composition.(63) A pharmaceutical formulation for oral use comprising the pharmaceutical composition according to statements (1) to (62).(64) A capsule formulation for oral use comprising the pharmaceutical composition according to statements (1) to (62), optionally a gelatin or HPMC capsule.(65) A pharmaceutical formulation according to statement (63) or a capsule formulation according to statement (64), wherein the formulation is an immediate release formulation. (66) A pharmaceutical formulation according to statement (63) or (65), or a capsule formulation according to statement (64) or (65), wherein formulation comprises between about 10 and about 1000 mg, between about 10 and about 600 mg, or between about 450 and about 150 mg of Compound I, or a pharmaceutically acceptable salt thereof.(67) A pharmaceutical formulation for oral use according to any one of statements (63) to (65) or a pharmaceutical composition according to any one of statements (1) to (62) for use in:(i) therapy;(ii) the treatment of a disease or condition in which CK2a activity is implicated;(iii) the treatment of a disease or condition associated with aberrant activity of CK2a; (iv) the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm; (v) the treatment of a cancer; or(vi) the treatment of a viral infection.(68) The use of a pharmaceutical formulation for oral use according to any one of statements (63) to (65) above or a pharmaceutical composition according to any one of statements (1) to (62) above in the manufacture of a medicament for use in:(i) therapy;(ii) the treatment of a disease or condition in which CK2a activity is implicated;(iii) the treatment of a disease or condition associated with aberrant activity of CK2a; (iv) the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm; (v) the treatment of a cancer; or(vi) the treatment of a viral infection.(69) A method of treating:(vi) a disease or condition in which CK2a activity is implicated;(vii)a disease or condition associated with aberrant activity of CK2a;(viii) proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm;(ix) cancer; or(x) a viral infection;the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to any one of statements (1) to (62) above, or a pharmaceutical formulation according to any one of statements (63) to (65) above.ExamplesPhysicochemical properties of Compound I

[0190] The objective of this study was to investigate the permeability and physicochemical properties of Compound I.AbbreviationsLog D

[0191] The Log D assay is a miniaturized 1-octanol / buffer shake flask method followed by liquid chromatography coupled to tandem mass spectrometry (LC / MS / MS) analysis.1 Compound I (10 mM in dimethyl sulfoxide [DMSO]; 2 pL / well) and QC samples (10 mM in DMSO; 2 pL / well) were transferred in duplicate from storage tubes to the 96-well polypropylene cluster tubes.2 Buffer-saturated 1-octanol (150 pL / well) and 1-octanol saturated buffer (150 pL / well) were added to the well, respectively.3 The tubes were vigorously shaken on their sides for 1 minute and then shaken at a speed of 600 rpm for 1 hour.4 The tubes were centrifuged at 4000 rpm for 10 minutes.5 The buffer-layer sample and 1 -octanol-layer samples were diluted with internal standard solution prior to LC-MS / MS analysis.6 The Log D value for each compound was calculated by the following equation:[Y -fold dilution of compound^.octa^ x Y & [X-fold compound ng)-xpKa1 Ionic Strength Adjusted Water (ISA, 0.15 M KCI) was prepared by weighing KCI (about 1.12 g) and dissolving with 100 mL water. The sample was mixed well.2 Potassium chloride (5.59 g) was dissolved in 100 mL deionized water and made up to 500 mL with analytical grade methanol (MeOH; ionic strength adjusted MeOH solution) to make a cosolvent of 80% v / v MeOH.pKa determinations:

[0192] Ultraviolet (UV) metric method: A 5 pL sample of 10 mmol / L in DMSO stock solution and 25 pLfast UV buffer were pipetted into a sample vial. 1.5 mLof 80% v / v MeOH was added into the sample vial. The sample solution was pre-acidified with 0.5 M hydrochloric acid (HCI), then titrated three times from low to high pH.

[0193] pH metric method: A 1 mg sample of test article was weighed into a sample vial and1.5 mL 80% v / v MeOH was added. The sample solution pre-acidified with 0.5 M HCI, then titrated three times from high to low pH.Kinetic Solubility

[0194] The kinetic solubility assay employs the shake flask method followed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) analysis.1 Test articles were dissolved in 100% DMSO as stock solutions of 10 mM.2 Test compounds and controls (10 mM in DMSO, 10 pL / vial) were added to 50 mM phosphate buffer (490 pL / well) to produce a final concentration of 200 iM Compound I.3 Solubility solution samples were incubated and shaken on an orbital shaker for 24 hours at room temperature (25 ± 2°C).4 Each solubility solution (200 iL) was transferred into a new MultiScreen filter plate (membrane of polycarbonate), filtered by millipore vacuum manifold and the filtrate collected.5 HPLC-UV was used to determine the test compound concentration of the filtrate. 6 Calibration samples at concentrations of 1, 20 and 200 iM were prepared and used to determine the concentrations of the kinetic solubility samples.Thermodynamic solubility

[0195] The thermodynamic solubility assay employs the shake flask method followed by HPLC-UV analysis.1 Appropriate amounts of Compound I and control compounds were weighed into lower chambers of Whatman miniuniprep vials, respectively.2 450 iL of 50 mM phosphate buffer (PB, pH 1.0, 3.5, 4.5, 6.5, 7.4, 9.0 and 10.0), Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF) into lower chambers of the Whatman miniuniprep vials to achieve an over-saturation suspension.3 The samples were vortexed for at least 2 minutes.4 Samples were incubated with shaking at 800 rpm, at room temperature for 24 hours then centrifuged at 4000 rpm for 20 minutes.5 The miniunipreps were compressed to prepare filtrates for injection into HPLC system and the concentration calculated against a standard curve.Caco-2 Studies1 Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96-well Corning Insert plates at 1 x 105cells / cm2and the medium was refreshed every 4-5 days until the 21stto 28thday when confluent cell monolayer formation was established.2 The transport buffer in the study was Hanks' Balanced Salt Solution (HBSS) with 10.0 mM 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES) at pH 7.40 ± 0.05.3 Compound I was tested at 2 .M bi-directionally in duplicate. Digoxin was tested at 10 .M bi-directionally in duplicate, while nadolol and metoprolol were tested at 2 .M in the apical (A) to basolateral (B) direction in duplicate. Final DMSO concentration was adjusted to less than 1%.4 The plate was incubated for 2 hours in a CO2 incubator at 37 ± 1°C, with 5% CO2, at saturated humidity, without shaking.5 After mixing with acetonitrile containing internal standard, all samples were centrifuged at 3200 x g for 10 minutes. For nadolol and metoprolol, 100 .L supernatant solution was diluted with 300 .L ultra-pure water for LC-MS / MS analysis. For digoxin and Compound I, 100 .L supernatant solution was diluted with 100 .L ultra-pure water for LC-MS / MS analysis.6 Concentrations of test and control compounds in starting solution, donor solution, and receiver solution were quantified by LC-MS / MS methodologies, using peak area ratio of analyte / internal standard.7 After the transport assay, a lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.

[0196] The apparent permeability coefficient Papp(cm / s) was calculated using the equation:PaPP= (dCr / dt) x vr / (A x Co)where: dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (pM / s); Vris the solution volume in the receiver chamber (0.075 mL on theapical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm2for the area of the monolayer; Co is the initial concentration in the donor chamber (pM).

[0197] The efflux ratio was calculated using the equation:Efflux Ratio = Papp(B-A) / Papp(A-B)

[0198] Percent recovery was calculated using the equation:% Solution Recovery = 100 x [(Vrx Cr) + (Vd x Cd)] I (Vd x Co) where:Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side);Cd and Crare the final concentrations of transport compound in donor and receiver chambers, respectively.MDR1-MDCKII Cell Studies1 MDR1-MDCKII cells (obtained from Piet Borst at the Netherlands Cancer Institute) were seeded onto PET in 96-well insert systems at 2.5 x 105cells / mL until to 4-7 days for confluent cell monolayer formation.2 Compound I was diluted with the transport buffer (HBSS with 10 mM Hepes, pH 7.4) from DMSO stock solution to a concentration of 2 iM (DMSO <1%) and applied to the apical or basolateral side of the cell monolayer.3 The permeability of Compound I from the A to B direction or B to A direction was determined in duplicate. Digoxin was tested at 10 pM from A to B direction or B to A direction as well, while nadolol and metoprolol were tested at 2 pM in A to B direction in duplicate.4 The plate was incubated for 2.5 hours in CO2 incubator at 37 ± 1°C, with 5% CO2, at saturated humidity, without shaking. In addition, the efflux ratio of each compound was also determined.5 Compound I and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / internal standard (IS).6 After the transport assay, a lucifer yellow rejection assay was applied to determine the cell monolayer integrity.7 Buffers were removed from both apical and basolateral chambers, followed by the addition of 75 .L of 100 iM lucifer yellow in transport buffer and 250 i L transport buffer in apical and basolateral chambers, respectively.8 The plate was incubated for 30 minutes at 37°C with 5% CO2 and saturated humidity, without shaking.9 After a 30 minute incubation, 20 pL of lucifer yellow samples were taken from the apical sides, followed by the addition of 60 pL of Transport Buffer. Lucifer yellow samples (80 jiL) were taken from the basolateral sides.10 The relative fluorescence unit (RFU) of lucifer yellow was measured at 425 / 528 nm (excitation / emission) with an Envision plate reader.

[0199] The apparent permeability coefficient Papp(cm / s) was calculated using the equation:PaPP= (dCr / dt) x vr / (A x Co)where:dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (pM / s);Vris the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side);A is the surface area for the transport, i.e. 0.0804 cm2for the area of the monolayer; Co is the initial concentration in the donor chamber (pM).

[0200] The efflux ratio was calculated using the equation:Efflux Ratio = Papp(B-A) I Papp(A-B)Percent recovery was calculated using the equation:% Solution Recovery = 100 x [(Vrx Cr) + (Vd x Cd)] I (Vd x Co) where:Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side);Cd and Crare the final concentrations of transport compound in donor and receiver chambers, respectively.

[0201] The apparent permeability coefficient Papp(cm / s) was calculated using the equation:where:RFUApicai and RFUBasoiaterai are the relative fluorescence unit values of lucifer yellow in the apical and basolateral wells, respectively;VApical and VBasoiaterai are the volume of apical and basolateral wells (0.075 mL and 0.25 mL), respectively.

[0202] The % Lucifer Yellow should be less than 2.Results

[0203] The physicochemical properties of Compound I are summarized in Table 1.Table 1 - Physicochemical properties of Compound I< < < < < < < < < < < <FaSSIF = Fasted State Simulated Intestinal Fluid; FeSSIF = Fed State Simulated Intestinal Fluid; PB = Phosphate buffer (50 mM).

[0204] In Caco-2 cells, the apparent permeability (Papp) of Compound I in the apical to basolateral (A-B) direction was 0.53-0.76 x 10'6cm / s and in the B-A direction 20.3-23.2 x 10’6cm / s (Table 2). The B-A / A-B efflux ratio (ER) of 26.6-44.2 indicates that Compound I acts as a substrate of efflux transporters in Caco-2 cells.

[0205] The ability of Compound I to act as a substrate of the ABC transporter P-glycoprotein (P-gp) was studied in MDCK-MDR1 cell monolayers (Table 3). Apparent permeability (Papp) in the A-B direction was 3.52-5.02 x 10'6cm / s and in the B-A direction 17.39-22.65 x 10'6cm / s. The ER of 4.5-4.9 indicates that Compound I acts as a substrate of P-gp.Table 2 - Caco-2 permeability of Compound I

[0206] Overall, the permeability of Compound I in vitro is moderate.Example 2 - Capsule Formulation DevelopmentExcipient solubility

[0207] The kinetic solubility of Compound I was measured in 16 excipients (listed in Table 3 below). Excipients were selected to cover a range of chemical and physical properties, including melting point and HLB value.

[0208] Both placebo and active samples were prepared using each excipient. All thermosoftening excipients were melted prior to use, to ensure homogeneity. For placebo samples, 1 g of excipient was transferred into a labelled scintillation vial. Initial active samples were prepared by dispensing 1 g of excipient into a labelled scintillation vial and adding approximately 25 mg of API (Compound I), with weight dispensed recorded in the laboratory notebook. The API / excipient mix was then stirred using a spatula and visually assessed. If no API was visible by eye, then the sample was examined under the microscope, in both nonpolarised and polarised light. The microscope hit stage was used for thermos-softening excipients, at either 50 or 70 °C as detailed in Table 4. The active samples were compared to the corresponding placebo samples and to images of the API crystals in the aqueous suspension. If API crystals were seen in the sample, either by eye or under the microscope, then the sample was subject to up to four 15-minute cycles of sonication using an ultrasonic bath, with the visual assessments repeated after each cycle. Sonication was carried out above the melting point / range for thermos-softening excipients, as detailed in Table 4. Where no API crystals were visible in an active sample under the microscope, it was recorded that Compound I was soluble in the excipient at that concentration.

[0209] As no solubility was observed at 25 mg / g, further active samples were prepared at approximately 5 mg / g and the testing was repeated. For excipients where solubility was not demonstrated at 5 mg / g, the assessment was concluded with the API considered to be insoluble in the selected excipient.Table 3 - excipient details&><< & <<"< < &Table 4<>Results

[0210] The results are shown below in Table 5 below.Table 5 - Kinetic solubility at approximately 5 mg / g Compound I>"<

[0211] Compound I was considered insoluble in all excipients in the study. Based on the results obtained, a suspension formulation was selected to achieve the target drug loading per capsule.

[0212] All excipients were progressed to an excipient compatibility study. Binary mixes were held under accelerated conditions (40 °C / 75 % RH) for eight weeks, with analysis at both T=4 weeks and T=8 weeks. The initial results suggested the stability was high for all excipients.Formulation design

[0213] The following ten prototype formulations shown in Tables 6 and 7 below were prepared (APL-5125 is Compound I):Table 6 - Prototype formulationsTable 7 - Prototype formulations

[0214] The protype formulations were assessed and based on an assessment of the ease of preparation, suspension stability, dispersion assessment, density and viscosity, and the ability to maximise drug loading. The following five formulations were selected as lead candidate formulations:Table 8: Lead candidate formulations for capsule formulations of Compound I

[0215] To further screen these options to define the lead clinical formulation, an assessment of in vitro performance, using digestive modelling, and a physical stability study were carried out.Formulation stability

[0216] Upon preparation, the suspensions were left to stand for 24 hours with regular observations recorded with regard to sedimentation and phase separation. All formulations were deemed acceptable after this study.Digestive modelling

[0217] Digestive modelling (ref. Williams et al. JPS, 101 (9), 2012, 3360-3380) is an in vitro method to determine where the API partitions to (aqueous, lipidic or solid / pellet phase) over time during simulated digestion. Samples were separated into oil, aqueous and pellet phases as appropriate and analysed by HPLC to determine API concentrations in the different fractions. The results help to understand the potential performance of each formulation on digestion in vivo and may be used to screen the lead prototype formulations to help select a formulation to progress.

[0218] A 37ml sample of digestive medium was added to the glass digestive modelling apparatus vessel and equilibrated to 37 °C, with stirrer speed set to 8. Approximately 0.5 g of molten formulation was added and the exact weight was recorded by difference. The autoburette was filled with 0.6M NaOH solution and a 10 minute pre-digestion phase was performed. During the pre-digestion phase, the pH was adjusted manually to 6.5 + / - 0.1 using 0.05M NaOH solution and / or 0.05 M HCI solution.

[0219] After the 10-minute pre-digestion phase was complete, a 1 mL sample was removed and transferred to a pre-weighed Eppendorf tube labelled T = 0. To initiate digestion, a 4 mL portion of pancreatin suspension was then added, and the Metrohm Titrando pH stat was started, to automatically adjust the pH to 6.5 throughout. 1mL samples were removed at T = 5, 15, 30 and 60 minutes and transferred to pre-weighed Eppendorf tubes containing 10 pL digestion inhibitor. All samples removed were centrifuged for 10 minutes at 14800 rpm and 37 °C, using the bench top ultracentrifuge, then the solid and liquid components were separated by transfer of the liquid to a clean Eppendorf tube labelled with the time point. The end weight of the Eppendorf tube containing the solid was recorded and it was labelled ‘pellet’. Further centrifugation (bench top ultracentrifuge, 10 minutes, 14800 rpm, 37 °C) was applied to the liquid components, to separate an aqueous sample. The end weights of the aqueous and liquid mix samples were recorded before analysis.

[0220] Analysis for Compound I by HPLC was carried out using the conditions and gradient detailed in Tables 9 and 10 respectively. The diluent was 50:50 methanol and purified water. Sample preparation was carried out differently for the pellet and liquid samples. To prepare the pellet samples for analysis, the full pellet was transferred to 100 mL volumetric flask, with the Eppendorf tube rinsed into the flask multiple times. Approximately 75 mL diluent was then added to the flask, and the mix was then sonicated and swirled until the solids had fully dissolved. The flask was equilibrated to room temperature and made to volume before the sample for analysis and passed through a 0.45 pm 25 mm nylon syringe filter. To prepare the liquid (aqueous and liquid mix) samples for analysis, 0.2 mL of the liquid was pipetted into thescintillation vial, and 4.8 mL of diluent was added by pipette. The mix was shaken vigorously by hand for 10 seconds before the sample for analysis was passed through a 0.45 pm 25 mm nylon syringe filter.Table 9Table 10Results

[0221] The results are shown in Figures 1 and 2.

[0222] Overall, whilst there was some discrimination between the formulations, the actual amounts of API detected in either the lipidic or aqueous phases was low. However, differentiation was observed between formulations where formulation prototypes B & D demonstrated observably lower drug concentrations relative to prototypes A, C & E.In vivo PK study

[0223] To further support lead formulation selection, a dog PK study was performed with formulations A, C & E filled into size 0 hard gelatin capsules at a drug dose of 100mg.Study Objectives

[0224] To determine the pharmacokinetics of Compound I in plasma following administration of a variety of 100 mg PO capsules of Compound I to male beagle dogs. Materials and MethodsTable 11 - FormulationsTable 12 - Study designDosina Schedule

[0225] Pentagastrin was prepared as outlined in Table 13 and animals were dosed 0.5 hours before test article (capsule) dosing following the schedule in Table 14.Table 13 - Study DesignIM = Intramuscular; PBS = buffered saline.Table 14 - Dosing ScheduleTable 15 - MatricesExperimental proceduresSampling

[0226] In each phase of the study, plasma samples were collected at 0.25, 0.5, 1, 2, 3, 4, 8 and 24-hour timepoints. Each blood collection (0.5 mL per time point) was performed from peripheral vein of each animal into pre-chilled potassium EDTA-K2 (0.85-1.15 mg) and placed on wet ice until centrifugation. Samples were centrifuged (3200 g for 10 minutes at 2 to 8°C) within one hour of collection. The plasma samples were divided into approximate 0.1 ml_x2 aliquots, transferred into labelled polypropylene micro-centrifuge tubes and stored at -60°C or lower until bio-analysis.Plasma preparation

[0227] Protein precipitation (PPT) using 96 well plate:1. An aliquot of 20 pL of either unknown sample, calibration standard, quality control, dilute quality control, single blank and double blank samples were added to a 96-well plate. 2. Each sample (except the double blank) was quenched with 400 pL of internal standard solution (acetonitrile containing 100 ng / mL of labetalol, tolbutamide, verapamil, dexamethasone, glyburide and celecoxib). Double blank samples were quenched with120 pL acetonitrile. The samples were vortex-mixed for 10 minutes at 800 rpm, then centrifuged for 15 minutes at 3220 g (4000 rpm), at 4°C.3. 50 pL supernatant was transferred to another clean 96-well plate and centrifuged for 5 min at 3220 g, 4 °C, prior to direct injection for liquid chromatography coupled to tandem mass spectrometry (LC-MS / MS) analysis.Dilution procedure:1. 10-fold dilution factor: An aliquot of 2 pL of the 0.5 hour to 8 hour timepoint samples were added to 18 pL blank matrix.

[0228] Samples were analyzed against calibration curves of 1-3000 ng / mL of Compound I in male beagle dog plasma (EDTA-K2).Data analysis

[0229] Plasma concentration versus time data was analyzed by non-compartmental approaches (Linear / log trapezoidal method) using the Phoenix WinNonlin 6.3 software program. Related PK parameters were calculated i.e. maximum observed concentration (Cmax) or time to Cmax (Tmax) for extravascular administration, and half-life (T%), area under concentration time curve from time zero to last measurable timepoint (AllCo-t), area under concentration time curve from time zero to infinity (AUCo-inf) for all routes and graphs of plasma concentration versus time profile were reported.Results

[0230] The PO single dose pharmacokinetics of Compound I were assessed in n=3 male beagle dogs per capsule formulation. Coated and uncoated capsules containing 100 mg Compound I in various formulations (A, C and E) were administered in the same dogs, with a 24-hour washout period in between doses.

[0231] Compound I exposures observed with gelatin 100 mg uncoated capsules containing Compound I alone yielded a mean AUCo-iast of 14,511 ng h / mL and a mean Cmax of 5637 ng / mL.

[0232] Exposures were higher for the gelatin 100 mg uncoated capsules containing Compound I in all three formulations tested compared to Compound I in the capsule alone. The mean AUCo-iast for Compound I in the uncoated capsules with formulations A, C and E were determined as 38,622, 48,070 and 42,399 ng h / mL respectively. This represents a foldincrease in total Compound I exposure of 2.7, 3.3 and 2.9-fold for formulations A, C and E respectively compared to Compound I in the capsule alone.

[0233] The Cmaxforthe gelatin 100 mg uncoated capsules containing Compound I in all three formulations was also higher than Compound I in the capsule alone. The mean Cmax for Compound I in the uncoated capsules with formulations A, C and E were determined as 13,400, 12,100 and 12,133 ng / mL respectively. This represents a fold increase in Compound I Cmax of 2.4, 2.1 and 2.2-fold for formulations A, C and E respectively compared to Compound I in the capsule alone.

[0234] Exposures following dosing of coated capsules containing Compound I in both formulations tested (A and E) were lower than capsules containing Compound I alone.

[0235] The rate of absorption of Compound I was similar across all capsules with Tmax values in the range of 1.17-2.67 hours. The half-life of Compound I was longest in gelatin 100 mg uncoated capsules containing formulation C and E with values of 5.27 and 4.98 hours determined, respectively.

[0236] Formulation C (Compound I 17%, Na Caprylrate 19%, Kolliphor EL 29%, Crodamol GTCC 35%) had the highest oral bioavailability in the study.

[0237] Results are summarized in Table 16. Pharmacokinetic profiles of Compound I in plasma following oral administration in dog are shown in Figure 3.Table 16: PK results summary from dog study comparing formulations A / C / EExample 3 - Solution / Suspension Formulation DevelopmentMaterials & MethodsGeneral sample processing procedure:

[0238] Protein precipitation (PPT) using 96-well plate:1. An aliquot of 20 pL of either unknown sample, calibration standard, quality control, dilute quality control, single blank and double blank samples were added to a 96-well plate. 2. Each sample (except the double blank) was quenched with 400 pL of internal standard solution (acetonitrile containing 100 ng / mL of labetalol, tolbutamide,verapamil, dexamethasone, glyburide and celecoxib). Double blank samples were quenched with 400 pL acetonitrile. The samples were vortex-mixed for 10 minutes at 800 rpm, then centrifuged for 15 minutes at 3220 g (4000 rpm), at 4°C.3. 50 pL supernatant was transferred to another clean 96-well plate and centrifuged for 5 min at 3220 g, 4 °C, prior to direct injection for liquid chromatography coupled to tandem mass spectrometry (LC-MS / MS) analysis.Dilution procedures:

[0239] 10-fold dilution factor for plasma samples: An aliquot of 4 pL of the 0.083 hour to 2-hour timepoint samples were added to 36 pL blank matrix.Plasma concentration:

[0240] Plasma concentration versus time data was analysed by non-compartmental approaches (linear / log trapezoidal method) using the Phoenix WinNonlin 6.3 software program. Related PK parameters were calculated according to dosing route, e.g. clearance (Cl), steady state volume of distribution (Vdss), maximum observed concentration (Cmax) or time to Cmax (Tmax) for extravascular administration, and half-life (T%), area under concentration time curve from time zero to last measurable timepoint (AUCo-iast), area under concentration time curve from time zero to infinity (AUCo-inf) for all routes and graphs of plasma concentration versus time profile were reported.Results

[0241] The oral pharmacokinetics of Compound I were further investigated in a formulation study with four groups of three male rats, each administered one of three different formulations at doses of 1 or 10 mg / kg.

[0242] After oral dosing, Compound I was rapidly absorbed with Tmax in all formulations achieved between 0.25 to 0.5 hours. Compound I exposure was 2.8-fold higher in terms of Cmax and 2.7-5.4-fold higher for AUCo-iast following administration in the 30% PEG 400: 20% Cremophor EL: 50% water formulation. Half-life was similar across all formulations investigated.

[0243] The results are summarized in Error! Reference source not found..Table 11: Compound I - Mean Plasma Pharmacokinetics in Male Rats Following Oral Administration Using a Range of FormulationsDose escalation study

[0244] The oral pharmacokinetics of Compound I were assessed in three male and female rats per dose group in a dose escalation study (100, 300 and 1000 mg / kg). Compound I was administered once daily for 5 days at 100 mg / kg and a single dose at 300 and 1000 mg / kg. Although sex differences in exposure were observed in rats at 3 mg / kg, at these higher doses (100, 300 and 1000 mg / kg), the exposure between male and female rats was <2-fold, therefore mean data across both sexes has been calculated.

[0245] After oral dosing, Tmax varied between 0.25 and 8.0 hours. A comparison of Compound I exposure on Day 1 and Day 5 for the 100 mg / kg dose suggests no obvious evidence of accumulation, with Cmax values of 15,172 and 13,600 ng / mL calculated for Day 1and 5, and AUCo-iast values of 122,988 and 185,212 ng h / mL. The variability in half-life values observed and differences between the AUCo-iast and AllCo-mf values suggest that the terminal phase of the pharmacokinetic profile could not be accurately determined in the study.

[0246] Compound I increases in a sub-proportional manner with respect to dose, with 2.7-fold and 4.5-fold increases in Cmax and AUCo-iast across a 10-fold dose range (100-1000 mg / kg).

[0247] The results are summarized in Error! Reference source not found..Table 12: Compound I - Mean Plasma Pharmacokinetics in Male and Female Rats Following Repeat Oral Dose Administration& & & &Example 4 - Solution / Suspension Formulation DevelopmentStudy objectives

[0248] The purpose of this study is to determine the pharmacokinetics of Compound I in plasma, following oral gavage administration of Compound I to male SD rats (Age: 7-10 weeks; Fasted overnight I food returned 4 hours after dosing) solution I suspension formulations with different permeation enhancers.Materials & MethodsStudy design

[0249] Oral formulations of Compound I were prepared by dispersing Compound I (1mg / ml) into formulations comprising:30% PEG 400 (as a solubiliser);20% of a penetration enhancer selected from Tween 80 (Group 01), Vitamin E TPGS (Group 02), Kolliphor HS 15 (Group 03), Kolliphor RH40 / Cremophor RH30 (Group 04), Gelucire 48 / 16 (Group 05), Labrosol (Group 06);and 50% water (adjusted to pH 4).

[0250] The appropriate amount of Compound I was accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or a uniform suspension. Vortexing or sonication in water bath was utilised as necessary. Animals were dosed within four hours after the formulation is prepared.

[0251] Prior to dosing, formulation samples were removed from each of the formulation solutions or suspensions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and the dose Compound I was validated by LC / LIV or LC-MS / MS.Table 19: - Treatment groups and formulation details

[0252] The male SD rats were aged from 7-10 weeks and were fasted overnight prior to dosing. Food was returned 4 hours after dosing.Dosina Schedule and sample collection

[0253] The formulations were administered to test group at time 0 on day 1.Dose Administration:

[0254] For PO dosing, the dose formulation will be administered via oral gavage following facility SOPs. The dose volume will be determined by the animals' body weight collected on the morning of dosing day.Blood collection

[0255] Blood samples (0.3ml per time point) were collected from each animal at 0.25, 0.5, 1, 2, 4, 8 and 24 hours. Samples were placed in pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation.Plasma Processing:

[0256] Blood samples were processed for plasma by centrifugation at approximately 4°C, 3,200 g for 10 min. Plasma was collected respectively and transferred into pre-labeled 96 well plate or polypropylene tubes, quick frozen over dry ice and kept at -60°C or lower until LC-MS / MS analysis. LC-MS / MS analysis was used to quantify the amount of Compound I in each plasma sample.Results

[0257] Related PK parameters will be calculated according to dosing route, e.g. Cl, Vdss and Co for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T%, AUC(o-t), AUC(o-inf), MRT(o-t), MRT(o-inf) for all routes.Table 20: the PK results for each treatment group

Claims

1. CLAIMS1. A pharmaceutical composition comprising 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I), ora pharmaceutically acceptable salt thereof, dispersed in one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise one or more permeation enhancers.

2. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, in an amount of:4.a) 2 to 25% w / w of the total pharmaceutical composition;5.b) 5 to 25% w / w of the total pharmaceutical composition;6.c) 8 to 25% w / w of the total pharmaceutical composition;7.d) 10 to 22% w / w of the total pharmaceutical composition;8.e) 10 to 20% w / w of the total pharmaceutical composition;9.f) 11 to 20% w / w of the total pharmaceutical composition;10.g) 12 to 20% w / w of the total pharmaceutical composition;11.h) 13 to 20% w / w of the total pharmaceutical composition;12.i) 14 to 20% w / w of the total pharmaceutical composition;13.j) 15 to 20% w / w of the total pharmaceutical composition;14.k) 10 to 18% w / w of the total pharmaceutical composition;15.l) 11 to 18% w / w of the total pharmaceutical composition;16.m) 12 to 18% w / w of the total pharmaceutical composition;17.n) 13 to 18% w / w of the total pharmaceutical composition;18.o) 14 to 18% w / w of the total pharmaceutical composition;19.p) 15 to 18% w / w of the total pharmaceutical composition;20.q) 16 to 18% w / w of the total pharmaceutical composition; or21.r) 16 to 17% w / w of the total pharmaceutical composition.

3. A pharmaceutical composition according to any one of the preceding claim 1 or claim 2, wherein the pharmaceutical composition comprises one or more permeation enhancers present in an amount selected from any one of the following options:22.a. 25% w / w to 98% w / w of the total pharmaceutical composition;23.b. 30% w / w to 98% w / w of the total pharmaceutical composition;24.c. 40% w / w to 98% w / w of the total pharmaceutical composition;25.d. 50% w / w to 98% w / w of the total pharmaceutical composition;26.e. 60% w / w to 98% w / w of the total pharmaceutical composition;27.f. 70% w / w to 98% w / w of the total pharmaceutical composition;28.g. 75% w / w to 98% w / w of the total pharmaceutical composition; or29.h. 80% w / w to 98% w / w of the total pharmaceutical composition.

4. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers are selected from the group consisting of surfactants, polymers, glycerides, phospholipids or cyclodextrins.

5. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;32.(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition;33.(iii) a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition;34.(iv) a phospholipid as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or35.(v) a cyclodextrin as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition.

5. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise:(i) a surfactant as defined herein in an amount of 20 to 95% w / w of the total pharmaceutical composition;37.(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or38.(iii) a glyceride as defined herein present in an amount of 0 to 60% w / w of the total pharmaceutical composition.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein as defined herein in an amount of 30 to 95% w / w of the total pharmaceutical composition;40.(ii) a polymer (e.g. PEG and / or Poloxamer) as defined herein in an amount of 0 to 50% w / w of the total pharmaceutical composition; and / or41.(iii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition.

7. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant as defined herein in an amount of 35 to 90% w / w of the total pharmaceutical composition; and / or43.(ii) a glyceride as defined herein present in an amount of 0 to 50% w / w of the total pharmaceutical composition.

8. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant selected from one or more of the following:45.fatty acid salts (e.g. caproic acid and caprylic acid salts, e.g. sodium caproate, sodium caprate or sodium caprylate)46.polysorbates (e.g. polysorbate 80, 20);47.sucrose esters (e.g. sucrose monolaurate); tocopheryl esters (e.g. Vitamin E TPGS);48.PEG esters [e.g. PEG castor oil I polyoxyl castor oil (e.g. PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL; or PEG-40 castor oil - also known as polyoxyl 40 caster oil or Kolliphor RH40); PEG-hydoxystearate / polyoxyl hydroxystearate (e.g. PEG-15 hydroxystearate - also known as Solutol HS-15 / Kolliphor HS-15), PEG caprylic / capric glycerides (e.g. PEG-8 caprylic / capric glycerides - also known as Labrasol; PEG-6 caprylic / capric glycerides - also known as Softigen 767), PEG stearate (e.g. Myrj), PEG laurate (e.g. lauroyl PEG1500 glyceride - also known as PEG- 32 laurate or Gelucire 44 / 14), and / or PEG palmitate / stearate (e.g. palmitic / stearic PEG1500 glyceride - also known as Gelucire 48 / 16)];49.PEG ethers (e.g. Brij 78);50.propylene glycol monolaurate [e.g. Lauroglycol 90 (Type II) or Lauroglycol FCC (Type I)]; propylene glycol mono or di-caprylate [e.g. Capryol PGMC];51.sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT);52.cetyltrime-thylammonium bromide (CTAB);53.and / or54.(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:55.capric / caprylic triglycerides (e.g. Crodamol GTCC);56.linoleic / oleic mono-, di-, and / or tri-glycerides (e.g. Maisine CC); and / or capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60);57.monoolein (Peceol™);58.monostearin.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) a surfactant selected from one or more of the following:60.sodium caproate; sodium caprate; or sodium caprylate;61.Vitamin E TPGS; PEG-35 castor oil - also known as polyoxyl 35 castor oil, cremophor EL, or Kolliphor EL;62.PEG- 15 hydroxy stea rate - also known as Solutol HS-15 or Kolliphor HS-15; lauroyl PEG 1500 glyceride - also known as PEG-32 laurate or Gelucire 44 / 14; and / or PEG-8 caprylic / capric glycerides - also known as Labrasol;63.and / or64.(ii) a glyceride present in any of the amounts defined in paragraphs (63) to (69) above wherein the glyceride is selected from one or more of the following:65.capric / caprylic triglycerides (e.g. Crodamol GTCC); and / or66.capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60).

10. A pharmaceutical composition according to any one of the preceding claims, wherein the one or more permeation enhancers present in the pharmaceutical composition comprise: (i) sodium caprylate present in an amount of 0 to 25% w / w of the total pharmaceutical composition;68.PEG-35 castor oil (Kolliphor EL)present in an amount of 15 to 50% w / w of the total pharmaceutical composition;69.PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;70.lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;71.PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;72.capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or73.capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition:74.(ii) sodium caprylate present in an amount of 5 to 25% w / w of the total pharmaceutical composition; PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 50% w / w of the total pharmaceutical composition;75.PEG-15 hydroxystearate (Kolliphor HS-15) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;76.lauroyl PEG 1500 glyceride (Gelucire 44 / 14) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;77.PEG-8 caprylic / capric glycerides (Labrasol) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;78.capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 0 to 60% w / w of the total pharmaceutical composition; and / or79.capric / caprylic mono-, di- and / or tri-glycerides (e.g. Labrafac MC60) present in an amount of 0 to 60% w / w of the total pharmaceutical composition;80.(iii) sodium caprylate present in an amount of 10 to 25% w / w of the total pharmaceutical composition;81.PEG-35 castor oil (Kolliphor EL)present in an amount of 10 to 40% w / w of the total pharmaceutical composition; and82.capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 60% w / w of the total pharmaceutical composition; or83.(iv) sodium caprylate present in an amount of 15 to 20% w / w of the total pharmaceutical composition;84.PEG-35 castor oil (Kolliphor EL)present in an amount of 20 to 40% w / w of the total pharmaceutical composition; and85.capric / caprylic triglycerides (e.g. Crodamol GTCC) present in an amount of 20 to 50% w / w of the total pharmaceutical composition.

11. A pharmaceutical formulation for oral use comprising the pharmaceutical composition according to any one of claims 1 to 10.

12. A capsule formulation for oral use comprising the pharmaceutical composition according to any one of claims 1 to 10, optionally a gelatin or HPMC capsule.

13. A pharmaceutical formulation according to claim 11 or a capsule formulation according to claim 12, wherein the formulation is an immediate release formulation.

14. A solution or suspension formulation comprising 5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy) benzyl)amino) butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (Compound I), or a pharmaceutically acceptable salt thereof, and one or more penetration enhancers dispersed in a pharmaceutically acceptable vehicle.

15. A pharmaceutical formulation according to claim 11 or claim 13, or a capsule formulation according to claim 12 or claim 13, or a solution or suspension formulation according to claim 14, wherein formulation comprises between about 10 and about 1000 mg, between about 10 and about 600 mg, or between about 150mg and about 450 mg of Compound I, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical formulation for oral use according to claim 11 or claim 13, or a capsule formulation according to claim 12 or claim 13, or a solution or suspension formulation according to claim 14, or a pharmaceutical composition according to any one of claims 1 to 10 for use in:91.(i) therapy;92.(ii) the treatment of a disease or condition in which CK2a activity is implicated; (iii) the treatment of a disease or condition associated with aberrant activity of CK2a;93.(iv) the treatment of proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm;94.(v) the treatment of a cancer; or95.(vi) the treatment of a viral infection.

16. A method of treating:97.(i) a disease or condition in which CK2a activity is implicated; (ii) a disease or condition associated with aberrant activity of CK2a;98.(iii) proliferative disorders (e.g. cancer or benign neoplasms), viral infections, an inflammatory disease or condition, diabetes, vascular and ischemic disorders, neurodegenerative disorders and / or the regulation of circadian rhythm;99.(iv) cancer; or100.(v) a viral infection;101.the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical formulation for oral use according to claim 11 or claim 13, or a capsule formulation according to claim 12 or claim 13, or a solution or suspension formulation according to claim 14, or a pharmaceutical composition according to any one of claims 1 to 10.

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