WO2020027665A1

WO2020027665A1 - Novel pharmaceutical compositions for cancer therapy

Info

Publication number: WO2020027665A1
Application number: PCT/NZ2019/050087
Authority: WO
Inventors: Peter SURMAN; Talyn STANTON; Paul Davis; Tinte Itinteang; Swee Tan
Original assignee: Gillies Mcindoe Research Institute
Priority date: 2018-07-30
Filing date: 2019-07-29
Publication date: 2020-02-06

Abstract

The present invention relates to novel therapeutic regimes which are useful in targeting cancer stem cell populations present in cancerous and non-cancerous tumours. Certain drug combinations targeting components of the renin-angiotensin system are particularly useful. In certain examples, the present invention provides pharmaceutical compositions for oral dosing comprising a combination, or "polypill", of (e.g.) propranolol, metformin and celecoxib, or (e.g.) aliskiren and cilazapril, or (e.g.) aliskiren and celecoxib, or (e.g.) metformin, propranolol and cilazapril, or (e.g.) propranolol and quinapril, or (e.g.) metformin and celecoxib, in fixed dose amounts for administration to a cancer patient requiring treatment.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS FOR CANCER THERAPY

TECHNICAL FIELD

The present invention relates to novel therapeutic regimes including, for example, pharmaceutical compositions, articles of manufacture and methods useful for preventing, treating, and/or managing cancer, all of which are useful in targeting unique cancer stem cell populations present in cancerous and non-cancerous tumours.

BACKGROUND OF THE INVENTION

The following includes information that may be useful in understanding the present invention. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein is prior art, or essential, to the presently described or claimed inventions. All publications and patents mentioned herein are hereby incorporated herein by reference in their entirety.

Cancer stem cells (CSCs), the proposed origin of cancer, have been identified in many types of cancer including oral cavity squamous cell carcinoma (OCSCC)¹, malignant melanoma (MM)² and glioblastoma multiforme (GBM)³. These CSCs resist radiotherapy and chemotherapy and they go into a slow cycle state during these treatments⁴. This could explain the observation that cancers that have gone into remission following such treatments return many years later.

Applicants' research has identified CSCs in 12 different types of cancer⁵ including tongue SCC⁶, buccal mucosal SCC⁷, malignant melanoma and GBM⁸.

The Renin Angiotensin System (RAS) is classically associated with blood pressure regulation. Physiologically, the RAS consists of Angiotensinogen which is converted to Angiotensin I (ATI), by renin. ATI is then converted to angiotensin II (ATII), by Angiotensin Converting Enzyme (ACE). ATII, the active peptide, acts on its receptors, Angiotensin II Receptor 1 (ATIIR1) and Angiotensin II Receptor 2 (ATIIR2). Renin is formed by the cleavage of its inactive precursor, pro-renin, by a number of enzymes including Cathepsin⁹, to active renin, as well as by binding to the Pro-Renin Receptor (PRR)¹⁰. Cyclo-oxygenase-2 (COX2) causes the upregulation of PRR¹¹. b-blockers reduce the production of Pro-Renin¹². Furthermore, Insulin Growth Factor (IGF) which acts on Insulin Growth Factor Receptor-1 (IGFR-1) promotes the conversion of Pro-Renin to active Renin¹³, as well as being implicated in cancer metastasis¹⁴. Metformin is a known inhibitor of the IGFR-1 pathway¹⁵. The action of ATII on ATIIR1 and ATIIR2 can be blocked by Angiotensin Receptor Blockers (ATRBs) (Figure 1).

The peptides derived from the RAS have been implicated in tumour progression¹⁶ and the expression of PRR has been associated with a poorer prognosis in cancer patients¹⁷. Applicants have demonstrated the expression of components of the RAS, namely the PRR, ACE, ATIIR1 and ATIIR2 in the CSC population in 12 types of cancer⁵ including tongue SCC¹⁸, buccal mucosal SCC¹⁹, skin SCC, MM and GBM²⁰. This coupled with the understanding of the regulation of the RAS including the expression and function of cathepsin²¹ and IGFR-1 pathway¹⁴ led Applicants to propose CSCs as a novel therapeutic target for cancer by modulation of the RAS using various cocktails of existing drugs that are commonly used for other medical conditions^{18 20}.

The present invention is directed to novel pharmaceutical compositions as well as kits and articles of manufacture comprising the same, and to the use of the pharmaceutical compositions, kits and articles of manufacture in novel treatment regimes for (e.g.) the treatment or management of cancer.

SUMMARY OF THE INVENTION

The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this Summary of the Invention. It is not intended to be all-inclusive and the inventions described and claimed herein are not limited to or by the features of or examples identified in this Summary of the Invention, which is included for purposes of illustration only and not restriction.

Applicants have surprisingly identified that certain drug combinations and pharmaceutical compositions are particularly useful in treating or managing cancer and non- cancerous tumours in a patient.

In an aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib, aliskiren, cilazapril and a pharmaceutically effective excipient.

In another aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib, aliskiren and a pharmaceutically effective excipient.

In another aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib, cilazapril and a pharmaceutically effective excipient.

In another aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, aliskiren, cilazapril and a pharmaceutically effective excipient.

In another aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib, aliskiren, cilazapril and a pharmaceutically effective excipient. In another aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib, aliskiren, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, aliskiren and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib, aliskiren and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, aliskiren, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib, aliskiren and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, aliskiren, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising celecoxib, aliskiren, cilazapril and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising propranolol, aliskiren and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising propranolol, cilazapril and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising metformin, aliskiren and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising metformin, cilazapril and a pharmaceutically effective excipient. In yet another aspect the present invention provides a pharmaceutical composition comprising celecoxib, aliskiren and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising celecoxib, cilazapril and a pharmaceutically effective excipient.

In yet another aspect the present invention provides a pharmaceutical composition comprising aliskiren, cilazapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, celecoxib, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, metformin, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, celecoxib, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, celecoxib, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising celecoxib, aliskiren, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising metformin, quinapril and a pharmaceutically effective excipient. In a further aspect the present invention provides a pharmaceutical composition comprising celecoxib, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising aliskiren, quinapril and a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of between about 40 mg and about 80 mg, (ii) metformin in a dose amount of between about 400 mg and about 600 mg and (iii) celecoxib in a dose amount of between about 75 mg and about 125 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of about 60 mg, (ii) metformin in a dose amount of about 500 mg and (iii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of between about 60 mg and about 90 mg and (ii) cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of about 75 mg and (ii) cilazapril in a dose amount of about 1.25 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising (i) metformin in a dose amount of between about 400 mg and about 600 mg, (ii) propranolol in a dose amount of between about 40 mg and about 80 mg and (iii) cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) metformin in a dose amount of about 500 mg, (ii) propranolol in a dose amount of about 60 mg and (iii) cilazapril in a dose amount of about 1.25 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising (i) aliskiren in a dose amount of between about 60 mg and about 90 mg and (ii) celecoxib in a dose amount of between about 75 mg and about 125 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of about 75 mg and (ii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising (i) propanolol in a dose amount of between about 40 mg and about 80 mg and (ii) quinapril in a dose amount of between about 4 mg and about 6 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of about 60 mg and (ii) quinapril in a dose amount of about 5 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising (i) metformin in a dose amount of between about 400 mg and about 600 mg and (ii) celecoxib in a dose amount of between about 75 mg and about 125 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) metformin in a dose amount of about 500 mg and (ii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising aliskiren in a dose amount of between about 60 mg and about 90 mg, together with a pharmaceutically effective excipient.

In yet a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising aliskiren in a dose amount of about 75 mg, together with a pharmaceutically effective excipient.

In a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

In other aspects, the present invention provides a method for treating and/or managing cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising :

(i) propanolol in a dose amount of between about 40 mg and about 80 mg, metformin in a dose amount of between about 400 mg and about 600 mg celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient; (ii) propanolol in a dose amount of about 60 mg, metformin in a dose amount of 500 mg, celecoxib in a dose amount of about 100 mg, and a pharmaceutically effective excipient;

(iii) aliskiren in a dose amount of between about 60 mg and about 90 mg, cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, and a pharmaceutically effective excipient;

(iv) aliskiren in a dose amount of about 75 mg, cilazapril in a dose amount of about 1.25 mg, and a pharmaceutically effective excipient;

(v) metformin in a dose amount of between about 400 mg and about 600 mg, propranolol in a dose amount of between about 40 mg and about 80 mg, cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, and a pharmaceutically effective excipient;

(vi) metformin in a dose amount of about 500 mg, propranolol in a dose amount of about 60 mg, cilazapril in a dose amount of about 1.25 mg, and a pharmaceutically effective excipient;

(vii) aliskiren in a dose amount of between about 60 mg and about 90 mg, celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient;

(viii) aliskiren in a dose amount of about 75 mg, celecoxib in a dose amount of about 100 mg, and a pharmaceutically effective excipient;

(ix) propanolol in a dose amount of between about 40 mg and about 80 mg, quinapril in a dose amount of between about 4 mg and about 6 mg, and a pharmaceutically effective excipient;

(x) propanolol in a dose amount of about 60 mg, quinapril in a dose amount of about 5 mg, and a pharmaceutically effective excipient;

(xi) metformin in a dose amount of between about 400 mg and about 600 mg, celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient;

(xii) metformin in a dose amount of about 500 mg, celecoxib in a dose amount of about 100 mg, and a pharmaceutically effective excipient;

(xiii) aliskiren in a dose amount of between about 60 mg and about 90 mg, and a pharmaceutically effective excipient; and/or

(xiv) aliskiren in a dose amount of about 75 mg, and a pharmaceutically effective excipient

and wherein the pharmaceutical compostion is formulated for oral administration to the patient.

In a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof comprising : (i) for an initial time interval of about two weeks, administering a pharmaceutical composition comprising about 60 mg of propranolol, about 500 mg of metformin, about 100 mg of celecoxib and a pharmaceutically effective excipient to the patient once daily;

(ii) for a further time interval of about another two weeks, administering the

pharmaceutical composition defined in (i) to the patient twice daily;

(iii) for yet a further time interval of about another two weeks, administering : a. the pharmaceutical composition defined in (i) to the patient twice daily; and

b. a pharmaceutical composition comprising about 75 mg of aliskiren, about 1.25 mg of cilazapril and a pharmaceutically effective excipient to the patient once daily; and

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i) and the pharmaceutical composition defined in (iii)b. to the patient twice daily.

In yet a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof comprising :

(i) for an initial time interval of about two weeks, administering a pharmaceutical composition comprising about 60 mg of propranolol, about 500 mg of metformin, about 100 mg of celecoxib and a pharmaceutically effective excipient to the patient once daily;

(ii) for a further time interval of about another two weeks, administering the

pharmaceutical composition defined in (i) and a pharmaceutical composition comprising about 75 mg of aliskiren, about 1.25 mg of cilazapril and a pharmaceutically effective excipient to the patient once daily;

(iii) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i) to the patient twice daily and a pharmaceutical composition defined in (ii) to the patient once daily; and

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i) and the pharmaceutical composition defined in (ii) to the patient twice daily.

(i) for an initial time interval of about two weeks, administering a pharmaceutical composition comprising about 75 mg of aliskiren, about 100 mg of celecoxib, and a pharmaceutically effective excipient to the patient once daily;

(ii) for a further time interval of about another two weeks, administering the

pharmaceutical composition defined in (i) and a pharmaceutical composition comprising about 500 mg of metformin, about 60 mg of propranolol, about 1.25 mg cilazapril and a pharmaceutically effective excipient to the patient once daily;

(ii) for a further time interval of about two weeks, administering a

pharmaceutical composition defined in (i) to the patient twice daily;

(iii) for a further time interval of about another two weeks, administering:

a. the pharmaceutical composition defined in (i) to the patient twice daily; and

b. a pharmaceutical composition comprising about 500 mg of metformin, about 60 mg of propranolol, about 1.25 mg cilazapril and a pharmaceutically effective excipient to the patient once daily;

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i) and the pharmaceutical composition defined in (iii)b to the patient twice daily.

(i) for an initial time interval of about two weeks, administering :

a. a pharmaceutical composition comprising about 60 mg of propranolol, about 5 mg of quinapril, and a pharmaceutically effective excipient to the patient once daily; and

b. a pharmaceutical composition comprising about 500 mg of metformin, about 100 mg of celecoxib, and a pharmaceutically effective excipient to the patient once daily;

(ii) for a further time interval of about two weeks, administering :

a. the pharmaceutical composition defined in (i)a. to the patient once daily; b. the pharmaceutical composition defined in (i)b. to the patient twice daily; and c. a pharmaceutical composition comprising 75 mg of aliskiren to the patient once daily;

(iii) for a further time interval of about another two weeks, administering :

a. the pharmaceutical compositions defined in (i)a. and (i)b. to the patient twice daily; and

b. the pharmaceutical composition defined in (ii)c. to the patient twice daily; and

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i)a., the pharmaceutical composition defined in (i)b. and the pharmaceutical composition defined in (iii)c. to the patient twice daily.

(i) for an initial time interval of about two weeks, administering :

(ii) for a further time interval of about two weeks, administering the

pharmaceutical compositions defined in (i)a. and (i)b. to the patient twice daily;

(iii) for a further time interval of about another two weeks, administering :

b. a pharmaceutical composition comprising 75 mg aliskiren to the patient once daily;

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical compositions defined in (i)a., (i)b. and (iii)b. to the patient twice daily.

In a further aspect the present invention provides a pharmaceutical composition as described herein for use in a method of treating and/or managing cancer in a patient in need thereof.

In other aspects, the present invention provides a pharmaceutical composition for use in a method of treating or managing cancer in a patient in need thereof, wherein the pharmaceutical composition comprises: (i) propanolol in a dose amount of between about 40 mg and about 80 mg, metformin in a dose amount of between about 400 mg and about 600 mg celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient;

(ii) propanolol in a dose amount of about 60 mg, metformin in a dose amount of 500 mg, celecoxib in a dose amount of about 100 mg, and a pharmaceutically effective excipient;

(xiv) aliskiren in a dose amount of about 75 mg, and a pharmaceutically effective excipient and wherein the pharmaceutical compostion is formulated for oral administration to the patient.

In yet a further aspect the present invention provides a use of a pharmaceutical composition as described herein in a method of treating and/or managing cancer in a patient in need thereof.

In yet another aspect the present invention provides a use of a pharmaceutical composition as described herein for treating and/or managing cancer in a patient in need thereof by administering a therapeutically effective amount of the pharmaceutical compositon to the patient.

In yet another aspect the present invention provides a use of a pharmaceutical composition as described herein in the manufacture of a medicament for treating and/or managing cancer in a patient in need thereof.

in a further aspect the present invention provides an article of manufacture comprising one or more of the pharmaceutical compositions described herein.

In another aspect the present invention provides an article of manufacture comprising one or more of the pharmaceutical compositions described herein, together with instructions for how to administer the at least one pharmaceutical composition to a patient in need thereof.

In an example according to this aspect of the present invention, the article of manufacture comprises at least one pharmaceutical composition comprising :

(i) propranolol, metformin, celecoxib, aliskiren, cilazapril;

(ii) propanolol, metformin, celecoxib, aliskiren;

(iii) propanolol, metformin, celecoxib, aliskiren;

(iv) propanolol, metformin, celecoxib, cilazapril;

(v) propanolol, metformin, aliskiren, cilazapril;

(vi) metformin, celecoxib, aliskiren, cilazapril;

(vii) propanolol, metformin, celecoxib;

(viii) propanolol, metformin, aliskiren;

(ix) propanolol, metformin, cilazapril;

(x) propanolol, celecoxib, aliskiren;

(xi) propanolol, celecoxib, cilazapril;

(xii) propanolol, aliskiren, cilazapril;

(xiii) metformin, celecoxib, aliskiren;

(xiv) 4metformin, aliskiren, cilazapril;

(xv) celecoxib, aliskiren, cilazapril;

(xvi) propanolol, metformin;

(xvii) propanolol, celecoxib;

(xviii) propanolol, aliskiren;

(xix) propanolol, cilazapril; (xx) metformin, celecoxib;

(xxi) metformin, aliskiren;

(xxii) metformin, cilazapril;

(xxiii) celecoxib, aliskiren;

(xxiv) celecoxib, cilazapril;

(xxv) aliskiren, cilazapril

(xxvi) propranolol, metformin, celecoxib, aliskiren, quinapril;

(xxvii) propanolol, metformin, celecoxib, quinapril;

(xxviii) propanolol, metformin, aliskiren, quinapril;

(xxix) metformin, celecoxib, aliskiren, quinapril;

(xxx) propanolol, metformin, quinapril;

(xxxi) propanolol, celecoxib, quinapril;

(xxxii) propanolol, aliskiren, quinapril;

(xxxiii) metformin, celecoxib, quinapril;

(xxxiv) metformin, aliskiren, quinapril;

(xxxv) celecoxib, aliskiren, quinapril;

(xxxvi) propanolol, quinapril;

(xxxvii) metformin, quinapril;

(xxxviii) celecoxib, quinapril; and/or

(xxxix) aliskiren, quinapril

and optionally, instructions for how to administer the at least one pharmaceutical composition to a patient requiring treatment.

In a further aspect the present invention provides an article of manufacture comprising :

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising propanolol in an amount of about 60 mg, metformin in an amount of about 500 mg and celecoxib in an amount of about 100 mg; and

(ii) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg and cilazapril in an amount of about 1.25 mg; and

(iii) instructions for daily or twice daily dosing by administration of the pharmaceutical compositions to a patient in need of treatment.

In yet a further aspect the present invention provides an article of manufacture comprising :

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising metformin in an amount of about 500 mg, propranolol in an amount of about 60 mg and cilazapril in an amount of about 1.25 mg; and

(ii) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg and celecoxib in an amount of about 100 mg; and

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising propranolol in an amount of about 60 mg and quinapril in an amount of about 5 mg; and

(ii) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising metformin in an amount of about 500 mg and celecoxib in an amount of about 100 mg; and

(iii) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg; and

(iv) instructions for daily or twice daily dosing by administration of the pharmaceutical compositions to a patient in need of treatment.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the main pathways associated with the Renin-Angiotensin System. ACE: Angiotensin Converting Enzyme; ACEi: Angiotensin Converting Enzyme inhibitors; Cox2i: COX-2 inhibitors; b-blockers: beta-Blockers; ATIIR2: Angiotensin II Receptor 2; ATIIR1 : Angiotensin II Receptor 1; PRR: Pro-Renin Receptor [also referred to herein as Renin Receptor (RR)]; ATRB: angiotensin receptor blocker; IGF/IGFR-1 : Insulin Growth Factor Receptor-1 Pathway; X: major blockades; + : major promoting steps.

SELECTED DEFINITIONS

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the inventions belong. Although any assays, methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, various assays, methods, devices and materials are now described. It is intended that reference to a range of numbers disclosed herein (for example 1 to 10) also incorporates reference to all related numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

As used in this specification, the terms "comprises", "comprising", and similar words, are not to be interpreted in an exclusive or exhaustive sense. In other words, they are intended to mean "including, but not limited to".

As used in this specification, the term "Aspirin" includes acetylsalicylic acid, a known analgesic used to treat pain, inflammation and fever.

As used in this specification, the term "Celecoxib" includes 4-[5-(4-methylphenyl)-3- (trifluoromethyl)pyrazol-l-yl]benzenesulfonamide, a known COX-2 inhibitor.

As used in this specification, the term "Propranolol" includes (RS)-l-(l- methylethylamino)-3-(l-naphthyloxy)propan-2-ol, a type of beta-blocker known to reduce the production of pro-renin (refer to Figure 1).

As used in this specification, the term "Metformin" includes N,N- dimethylimidodicarbonimidic diamide, a known inhibitor of the IGFR-1 pathway implicated in the conversion of pro-renin to renin (refer to Figure 1).

As used in this specification, the term "Curcumin" includes (lE,6E)-l,7-Bis(4-hydroxy- 3-methoxyphenyl)hepta-l,6-diene-3,5-dione, a natural phenol and known inhibitor of cathepsin (refer to Figure 1).

As used in this specification, the term "Cilazapril" includes (4S,7S)-7-[[(2S)-l-Ethoxy- l-oxo-4-phenylbutan-2-yl]amino]-6-oxo-l,2,3,4,7,8,9,10-octahydropyridazino[l,2- a]diazepine-4-carboxylic acid, a known angiotensin converting enzyme inhibitor (refer to Figure 1).

As used in this specification, the term "Aliskiren" includes (2S,4S,5S,7S)-5-amino-/V- (2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3- methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide, a known renin inhibitor (refer to Figure 1).

As used in this specification, the term "Piperine" includes l-[5-(l,3-Benzodioxol-5-yl)- l-oxo-2,4-pentadienyl]piperidine, which increases the bioavailability of Curcumin.

As used in this specification, the term "Omeprazole" includes 5-methoxy-2-[(4- methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-l/-/-benzimidazole, which decreases the likelihood of peptide ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs) including (e.g.,) Aspirin. As used in this specification, the term "Losartan" includes 2-butyl-4-chloro-l-{[2'-(l/-/- tetrazol-5-yl)biphenyl-4-yl]methyl}-l/-/-imidazol-5-yl)methanol.

As used in this specification, the terms "Quinapril" and "Accupril" may be used interchangeably and includes [3S-[2[R*(R)],3R*]]-2-[2-[[l-Ethoxycarbonyl)-3- phenylpropyl]amino]-l-oxopropyl]-l,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid monohydrochloride.

As used in this specification, the term "polypill" means a single dosage form comprising more than one pharmaceutical active, which in the context of the present invention includes (e.g.) drugs which target the Renin Angiotensin System, in a fixed dose combination.

As used herein, the term "effective amount", "prophylactically effective amount" and "therapeutically effective amount" refers to the amount of a therapy that is sufficient to result in the prevention of the development, recurrence, or onset of a disease or condition and one or more symptoms thereof, to enhance or improve the prophylactic effect(s) of another therapy, reduce the severity, the duration of disease, ameliorate one or more symptoms of the disease or condition, prevent the advancement of the disease or condition, cause regression of the disease or condition, and/or enhance or improve the therapeutic effect(s) of another therapy.

As used herein, the terms "manage", "managing", and "management" in the context of the administration of a therapy to a subject refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent) or a combination of therapies, while not resulting in a cure of the disease or condition. In certain examples, a subject is administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to "manage" the disease or condition so as to prevent the progression or worsening of the disease or condition.

As used herein, the terms "prevent", "preventing" and "prevention" in the context of the administration of a therapy to a subject refers to the prevention or inhibition of the recurrence, onset, and/or development of a disease or condition or a symptom thereof in a subject resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), or a combination of therapies (e.g., a combination of prophylactic or therapeutic agents).

As used herein, the term "marker" or "biomarker" in the context of a tissue means any antigen, molecule or other chemical or biological entity that is specifically found in or on a tissue that it is desired to be identified or identified in or on a particular tissue affected by a disease or disorder, for example cancer. In specific examples, the marker is a cell surface antigen that is differentially or preferentially expressed by specific cell types. In specific examples, the marker is a nuclear antigen that is differentially or preferentially expressed by specific cell types. In specific examples the marker is an intracellular antigen that is differentially or preferentially expressed by specific cell types. As used herein, the term "therapeutic agent" refers to any molecule, compound, and/or substance that is used for the purpose of treating and/or managing a disease or disorder. Examples of therapeutic agents include, but are not limited to, proteins, immunoglobulins (e.g., multi-specific Igs, single chain Igs, Ig fragments, polyclonal antibodies and their fragments, monoclonal antibodies and their fragments), peptides (e.g., peptide receptors, selectins), binding proteins, biologies, proliferation-based therapy agents, hormonal agents, radioimmunotherapies, targeted agents, epigenetic therapies, differentiation therapies, biological agents, and small molecule drugs.

As used herein, the terms "therapies" and "therapy" can refer to any method(s), composition(s), and/or agent(s) that can be used in the prevention, treatment and/or management of cancer or one or more symptoms thereof.

As used herein, the terms "treat", "treatment" and "treating" in the context of the administration of a therapy to a subject refers to the reduction or inhibition of the progression and/or duration of cancer, the reduction or amelioration of the severity of cancer, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.

The term "sample" or "biological sample" as used herein means any sample taken or derived from a subject. Such a sample may be obtained from a subject, or may be obtained from biological materials intended to be provided to the subject. For example, a sample may be obtained from blood being assessed, for example, to investigate cancer in a subject. Included are samples taken or derived from any subjects such as from normal healthy subjects and/or healthy subjects for whom it is useful to understand their cancer status. Preferred samples are biological fluid samples. The term "biological fluid sample" as used herein refers to a sample of bodily fluid obtained for the purpose of, for example, diagnosis, prognosis, classification or evaluation of a subject of interest, such as a patient. The sample may be any sample known in the art in which embryonic stem cells may be detected. Included are any body fluids such as a whole blood sample, plasma, serum, ovarian follicular fluid sample, seminal fluid sample, cerebrospinal fluid, saliva, sputum, urine, pleural effusions, interstitial fluid, synovial fluid, lymph, tears, for example, although whole blood sample, plasma and serum are particularly suited for use in this invention. In addition, one of skill in the art would realise that certain body fluid samples would be more readily analysed following a fractionation or purification procedure, for example, separation of whole blood into serum or plasma components.

The term "patient" and "subject" as used herein is preferably a mammal and includes human, and non-human mammals such as cats, dogs, horses, cows, sheep, deer, mice, rats, primates (including gorillas, rhesus monkeys and chimpanzees), possums and other domestic farm or zoo animals. Thus, the assays, methods and kits described herein have application to both human and non-human animals, in particular, and without limitation, humans, primates, farm animals including cattle, sheep, goats, pigs, deer, alpacas, llamas, buffalo, companion and/or pure bred animals including cats, dogs and horses. Preferred subjects are humans, and most preferably "patients" who as used herein refer to living humans who may receive or are receiving medical care or assessment for a disease or condition. Further, while a subject is preferably a living organism, the invention described herein may be used in post- mortem analyses as well.

As used herein, the term "Renin-Angiotensin System (RAS)" or "Renin-Angiotensin- Aldosterone System (RAAS)" is a hormone system that regulates blood pressure and fluid balance. The wider pathway associated with RAS also includes the Pro/Renin Receptor System (PRRS) and the associated bypass pathways. By way of example, refer to Figure 1. There are a number of known drugs which target the RAS including PRRS, as described in more detail below.

DETAILED DESCRIPTION

The present invention is based on the discovery that non-obvious drug combinations are surprisingly useful for treating and/or preventing cancer including the recurrence of cancer. The drug combinations including pharmaceutical compositions and formulations according to the present invention target components of the renin-angiotensin system (RAS) for which the Applicants have previously demonstrated is expressed by cancer stem cell populations associated with diverse tumour types. These cancer stem cells therefore represent a novel therapeutic target (refer to W02016024870, which is incorporated herein by reference) for which the pharmaceutical compositions and formulations described herein are useful.

In certain examples according to the pharmaceutical compositions described herein, quinapril is substituted for cilazapril.

In a further aspect the present invention provides a pharmaceutical composition comprising propranolol, quinapril and a pharmaceutically effective excipient. In a further aspect the present invention provides a pharmaceutical composition comprising metformin, quinapril and a pharmaceutically effective excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising celecoxib, quinapril and a pharmaceutically effective excipient.

A person skilled in the art will appreciate that pharmaceutically active ingredients comprised within the pharmaceutical compositions described herein may be 'switched' with (e.g.) one or more drugs possessing equivalent activity from the same drug class.

By way of illustration only, propranolol, a known beta-blocker (also referred to as a "b-blocker" or "p-blockers"), may be switched with one or more other beta-blockers including, but not limited to, Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol (Betoptic), Bisoprolol (Cardicor, Emcor, Zebeta), Carteolol (Teoptic), Carvedilol (Coreg, Eucardic), Celiprolol (Celectol), Labetalol (Trandate), Levobunolol (Betagan), Metipranolol (Metipranolol Minims), Metoprolol (Betaloc, Lopresor, Lopressor, Toprol XL), Nadolol (Corgard), Nebivolol (Bystolic, Nebilet), Oxprenolol (Trasicor), Pindolol (Visken), Propranolol (Inderal LA), Sotalol (Beta- Cardone, Sotacor), and Timolol (Betim, Nyogel, Timoptol).

By way of further illustration, metformin, a known insulin-like growth factor receptor inhibitor (also referred to as a "IGFR inhibitor"), may be switched with one or more other IGFR1 inhibitors including, but not limited to, tyrphostins such as AG538 and AG1024, pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541 and Figitumumab (also called CP- 751871).

By way of further illustration, celecoxib, a known COX-2 inhibitor, may be switched with one or more other COX-2 inhibitors including, but not limited to, Nepafenac, Ibuprofen (Dolgesic), Indomethacin, Sulindac, Xanthohumol, Meclofenamate Sodium, Meloxicam, Rofecoxib, Bromfenac Sodium, Ibuprofen Lysine, Ketorolac (Ketorolac tromethamine), Diclofenac Sodium, Etodolac, Ketoprofen, Naproxen Sodium, Piroxicam, Acemetacin, Phenacetin, Tolfenamic Acid, Nimesulide, Flunixin Meglumin, Aspirin, Bufexamac, Niflumic acid, Licofelone, Oxaprozin, Lornoxicam, Lumiracoxib, Zaltoprofen, Ampiroxicam, Valdecoxib, Nabumetone, Mefenamic Acid, Carprofen, Amfenac Sodium monohydrate, Asaraldehyde and Suprofen and includes non-steroidal anti-inflammatory drugs (NSAIDs). Examples of non- steroidal anti-inflammatory drugs (also referred to herein as a "NSAID") includes, but is not limited to, Salicylates, including, but not limited to, Salicyclic Acid, Acetylsalicylic Acid, Salsalate, Diflunisal; Propionic Acid derivatives, including, but not limited to, Ibuprofen, Dexibuprofen, Naproxen, Denoprofen, Ketoprofen, Dexke to profen, Flubirpofen, Oxaprozin and loxoprofen; Acetic Acid derivatives, including, but not limited to, Indoemthacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone; Enolic Acid (Oxicam) derivatives, including, but not limited to, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam and Phenylbutazone; Anthranilic Acid derivatives, including, but not limited to, Mefenamic Acid, Meclofenamic Acid, Flufenamic Acid, Tolfenamic Acid; COX-2 Inhibitors, including, but not limited to, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib; Sulfonamides, including, but not limited to, Nimesulide; Clonixin; and Licofelone.

By way of further illustration, cilazapril or quinapril, known angiotensin converting enzyme inhibitors (also referred to as "ACE inhibitors" or "ACEi"), may be switched with one or more other ACE inhibitors including, but not limited to, Benazepril (Lotesin), Captopril (Capoten), Enalapril (Vasotec, Renitec), Fosinopril (Monopril), Lisinopril (Lisodur, Lopril, Novatec, Prinivil, Zestril), Moexipril, Perindopril (Coversay, Aceon), Ramipril (Altace, Tritace, Ramace, Ramiwin), Trandolapril, Delapril, Zofenopril and Imidapril. Also according to the pharmaceutical compositions described herein, cilazapril or quinapril may be switched for one or more angiotensin receptor blockers (also referred to as "ARBs") including but not limited to Losartan, Irbesartan, Candesartan, Eprosartan, Olmesartan, Telmisartan, PD123319 and Valsartan.

The term "a pharmaceutically effective excipient" refers to one or more pharmaceutical excipients effective in formulating the pharmaceutically active ingredients (e.g. drugs) in a dosage form suitable for administration to a patient. As would be known to a person skilled in the art of drug formulation chemistry, pharmaceutical excipients may perform one or more functions to assist with the formulation and administration properties of the pharmaceutical composition (e.g.) as a lubricant, binder, disintegrant, diluent, hydrophobic or hydrophilic extended release matrix, glidant etc. Examples of pharmaceutically effective excipients according to the present invention include, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, sodium starch glycolate, lactose monohydrate, ethylcellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, providone, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate. Further information concerning pharmaceutically effective excipients is described later.

The pharmaceutical compositions according to the present invention may be formulated for administration to a patient by any administration route including, but not limited to, oral, transdermal delivery, topical application, suppository delivery, transmucosal delivery, injection (including subcutaneous administration, subdermal administration, intramuscular administration, depot administration, and intravenous administration, including delivery via bolus, slow intravenous injection, and intravenous drip), infusion devices (including implantable infusion devices, both active and passive), administration by inhalation or insufflation, buccal administration and sublingual administration.

Any of the pharmaceutical compositions of the present invention may for example be formulated for oral administration. In certain examples of the present invention, the oral formulations include, but are not limited to, tablets, soft or hardgell capsules, lozenges, or like forms, or any liquid forms such as syrups, aqueous solutions, emulsions and the like, capable of providing a therapeutically effective amount of the pharmaceutical actives described herein.

In other examples, where the pharmaceutical composition comprises propanolol and the pharmaceutical composition is formulated for oral administration, propanolol is present in the oral formulation in an amount of between about 40 mg and about 80 mg. In another related example, propanolol is present in the pharmaceutical composition in an amount of about 60 mg.

A person skilled in the art will appreciate that reference to a range of numbers disclosed herein (for example an amount of between about 40 mg and about 80 mg) also incorporates reference to all related numbers within that range (for example, 40, 40.1, 42, 43, 43.9, 44, 45, 46, 46.5, 47, 48, 49) and also any range of rational numbers within that range (for example 42 to 48, 41.5 to 55.5 and 53.1 to 57.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

For any avoidance of doubt, an amount of between about 40 mg and about 80 mg propanolol includes an amount that is 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 mg of propanolol.

In the pharmaceutical compositions of the present invention, propranolol may be present in a dose amount of at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, or at least 60 mg; and/or up to 80 mg, up to 75 mg, up to 70 mg, up to 65 mg, or up to 60 mg. In preferred examples, propranolol may be present in a dose amount of between 40 mg and 80 mg, more preferably about 60 mg.

In other example, where the pharmaceutical composition comprises metformin and the pharmaceutical composition is formulated for oral administration, metformin is present in the oral formulation in an amount of between about 400 mg and about 600 mg. In a related example, metformin is present in the pharmaceutical composition in an amount of about 500 mg.

For any avoidance of doubt, an amount of between about 400 mg and about 600 mg metformin includes an amount that is 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 or 600 mg of metformin.

In other examples, where the pharmaceutical composition comprises celecoxib and the pharmaceutical composition is formulated for oral administration, celecoxib is present in the oral formulation in an amount of between about 75 mg and about 125 mg. In a related example, celecoxib is present in the pharmaceutical composition in an amount of about 100 mg.

For any avoidance of doubt, an amount of between about 75 mg and about 125 mg celecoxib includes an amount that is 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 or 125 mg of celecoxib.

In the pharmaceutical compositions of the present invention, metformin may be present in a dose amount of at least 400 mg, at least 410 mg, at least 420 mg, at least 430 mg, at least 440 mg, at least 450 mg, at least 460 mg, at least 470 mg, at least 480 mg or at least 490 mg; and/or up to 600 mg, up to 590 mg, up to 580 mg, up to 570 mg, up to 560 mg, up to 550 mg, up to 540 mg, up to 530 mg, up to 520 mg, up to 510 mg, or up to 500 mg. In preferred examples, metformin may be present in a dose amount of between 400 mg and 600 mg, more preferably about 500 mg.

In other examples, where the pharmaceutical composition comprises aliskiren and the pharmaceutical composition is formulated for oral administration, aliskiren is present in the oral formulation in an amount of between about 60 mg and about 90 mg. In a related example, aliskiren is present in the pharmaceutical composition in an amount of about 75 mg.

For any avoidance of doubt, an amount of between about 60 mg and about 90 mg aliskiren includes an amount that is 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 mg of aliskiren.

In the pharmaceutical compositions of the present invention, aliskiren may be present in a dose amount of at least 60 mg, at least 65 mg, at least 70 mg, or at least 75 mg; and/or up to 90 mg, up to 85 mg, up to 80 mg, or up to 75 mg. In preferred examples, propranolol may be present in a dose amount of between 60 mg and 90 mg, more preferably about 75 mg.

In other examples, where the pharmaceutical composition comprises cilazapril and the pharmaceutical composition is formulated for oral administration, cilazapril is present in the oral formulation in an amount of between about 1.0 mg and about 1.5 mg. In a related example, cilazapril is present in the pharmaceutical composition in an amount of about 1.25 mg.

For any avoidance of doubt, an amount of between about 1.0 mg and about 1.5 mg cilazapril includes an amount that is 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11,

1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43,

1.44, 1.45, 1.46, 1.47, 1.48, 1.49 or 1.50 mg of cilazapril. In the pharmaceutical compositions of the present invention, cilazapril may be present in a dose amount of at least 1 mg, at least 1.05 mg, at least 1.10 mg, at least 1.15 mg, at least 1.20 or at least 1.25 mg; and/or up to 1.5 mg, up to 1.45 mg, up to 1.4 mg, up to 1.35 mg, up to 1.30 mg or up to 1.25 mg. In preferred examples, propranolol may be present in a dose amount of between 1.0 mg and 1.5 mg, more preferably about 1.25 mg.

In other examples, where the pharmaceutical composition comprises quinapril and the pharmaceutical composition is formulated for oral administration, quinapril is present in the oral formulation in an amount of between about 4 mg and about 6mg. In yet a related example, quinapril is present in the pharmaceutical composition in an amount of about 5 mg.

For any avoidance of doubt, an amount of between about 4 mg and about 6 mg quinapril includes an amount that is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0 mg of quinapril.

In the pharmaceutical compositions of the present invention, quinaparil may be present in a dose amount of at least 4.0 mg, at least 4.1 mg, at least 4.2 mg, at least 4.3 mg, or at least 4.4 mg, at least 4.5 mg, at least 4.6 mg, at least 4.7 mg, at least 4.8 mg, at least 4.9 mg, at least 5.0 mg; and/or up to 6.0 mg, up to 5.9 mg, up to 5.8 mg, up to 5.7 mg, up to 5.6 mg, up to 5.5 mg, up to 5.4 mg, up to 5.3 mg, up to 5.2 mg, up to 5.1 mg or up to 5.0 mg. In preferred examples, propranolol may be present in a dose amount of between 4 mg and 6 mg, more preferably about 5 mg.

In another aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of between about 40 mg and about 80 mg, (ii) metformin in a dose amount of between about 400 mg and about 600 mg and (iii) celecoxib in a dose amount of between about 75 mg and about 125 mg, together with a pharmaceutically effective excipient.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of about 60 mg, (ii) metformin in a dose amount of about 500 mg and (iii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical compositions are formulated as an extended release tablet for extended release of propanolol, metformin and celecoxib following oral administration of the tablet.

In a further aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of between about 60 mg and about 90 mg and (ii) cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, together with a pharmaceutically effective excipient.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of about 75 mg and (ii) cilazapril in a dose amount of about 1.25 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical compositions are formulated as an immediate release tablet for immediate release of aliskiren and cilazapril following oral administration of the tablet.

In yet another aspect the present invention provides a pharmaceutical composition formulated for oral administration, the pharmaceutical composition comprising (i) metformin in a dose amount of between about 400 mg and about 600 mg, (ii) propranolol in a dose amount of between about 40 mg and about 80 mg and (iii) cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, together with a pharmaceutically effective excipient.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) metformin in a dose amount of about 500 mg, (ii) propranolol in a dose amount of about 60 mg and (iii) cilazapril in a dose amount of about 1.25 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical composition for oral administration is formulated as an immediate release tablet for immediate release of metformin, propanolol and cilazapril following oral administration of the tablet.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) aliskiren in a dose amount of about 75 mg and (ii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical composition for oral administration is formulated as an immediate tablet for immediate release of aliskiren and celecoxib following oral administration of the tablet.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) propanolol in a dose amount of about 60 mg and (ii) quinapril in a dose amount of about 5 mg, together with a pharmaceutically effective excipient. In an example of these formulation aspects, the pharmaceutical composition for oral administration is formulated as an extended release tablet for extended release of propanolol and quinapril following oral administration of the tablet.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising (i) metformin in a dose amount of about 500 mg and (ii) celecoxib in a dose amount of about 100 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical composition for oral administration is formulated as an extended release tablet for extended release of metformin and celecoxib following oral administration of the tablet.

In a related aspect the present invention provides a pharmaceutical composition formulated for oral administration comprising aliskiren in a dose amount of about 75 mg, together with a pharmaceutically effective excipient.

In an example of these formulation aspects, the pharmaceutical composition for oral administration is formulated as an immediate release tablet for immediate release of aliskiren following oral administration of the tablet.

The pharmaceutical compositions described herein may be useful in treating and/or managing a patient having a disease or disorder, including (e.g.) cancer. By way of illustration only, exemplary pharmaceutical compositions according to the present invention include those described in formulation Examples 1-7. Further, these formulation examples may be advantageously used in one or more cancer treatment regimes contemplated by the present invention. Again, by way of illustration only, exemplary treatment regimes include those described in Examples 9-14 which follow.

Accordingly, in a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

In other aspects, the present invention provides a method for treating and/or managing cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising : (i) propanolol in a dose amount of between about 40 mg and about 80 mg, metformin in a dose amount of between about 400 mg and about 600 mg celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient;

In an example according to this aspect of the present invention, the pharmaceutical compositions are those described in formulation Examples 1-7, below.

In a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof comprising :

(ii) for a further time interval of about another two weeks, administering the

pharmaceutical composition defined in (i) to the patient twice daily;

(ii) for a further time interval of about another two weeks, administering the

In related aspects the present invention provides: (i) a pharmaceutical composition comprising propranolol, metformin and celecoxib being administered once daily for time interval of about two weeks;

(ii) a pharmaceutical composition comprising propranolol, metformin and

celecoxib being administered twice daily for time interval of about two weeks;

(iii) a pharmaceutical composition comprising aliskiren and cilazapril being

administered once daily for time interval of about two weeks; or

(iv) a pharmaceutical composition comprising aliskiren and cilazapril being

administered twice daily for time interval of about two weeks.

(ii) for a further time interval of about another two weeks, administering the

(ii) for a further time interval of about two weeks, administering a

pharmaceutical composition defined in (i) to the patient twice daily;

(iii) for a further time interval of about another two weeks, administering :

b. a pharmaceutical composition comprising about 500 mg of metformin, about 60 mg of propranolol, about 1.25 mg cilazapril and a pharmaceutically effective excipient to the patient once daily; (iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i) and the pharmaceutical composition defined in (iii)b to the patient twice daily.

In related aspects the present invention provides:

(i) a pharmaceutical composition comprising aliskiren and celecoxib being

administered once daily for time interval of about two weeks;

(ii) a pharmaceutical composition comprising aliskiren and celecoxib being

administered twice daily for time interval of about two weeks;

(iii) a pharmaceutical composition comprising metformin, propranolol and

cilazapril being administered once daily for time interval of about two weeks; or

(iv) a pharmaceutical composition comprising metformin, propranolol and

cilazapril being administered twice daily for time interval of about two weeks.

(i) for an initial time interval of about two weeks, administering :

(ii) for a further time interval of about two weeks, administering :

a. the pharmaceutical composition defined in (i)a. to the patient once daily; b. the pharmaceutical composition defined in (i)b. to the patient twice daily; and

c. a pharmaceutical composition comprising 75 mg of aliskiren to the patient once daily;

(iii) for a further time interval of about another two weeks, administering :

(iv) for yet a further time interval of about another two weeks, administering the pharmaceutical composition defined in (i)a., the pharmaceutical composition defined in (i)b. and the pharmaceutical composition defined in (iii)c. to the patient twice daily. In yet a further aspect the present invention provides a method for treating and/or managing cancer in a patient in need thereof comprising :

(i) for an initial time interval of about two weeks, administering :

(ii) for a further time interval of about two weeks, administering the

(iii) for a further time interval of about another two weeks, administering :

In related aspects the present invention provides:

(i) a pharmaceutical composition comprising propranolol and quinapril being

administered once daily for time interval of about two weeks;

(ii) a pharmaceutical composition comprising propranolol and quinapril being

administered twice daily for time interval of about two weeks;

(iii) a pharmaceutical composition comprising metformin and celecoxib being

administered once daily for time interval of about two weeks;

(iv) a pharmaceutical composition comprising metformin and celecoxib being

administered once daily for time interval of about two weeks;

(v) a pharmaceutical composition comprising aliskiren being administered once daily for time interval of about two weeks; or

(vi) a pharmaceutical composition comprising aliskiren being administered twice daily for time interval of about two weeks.

In an example according to these and other aspects of the present invention, the methods further comprise administering about 1000 mg of curcumin to the patient twice daily throughout the time intervals defined in (i) to (iv). In another example according to these and other aspects of the present invention, the methods further comprise administering about 100 mg of aspirin to the patient once daily throughout the time intervals defined in (i) to (iv). In yet another example according to these and other aspects of the present invention, the methods further comprise administering about 1000 mg of curcumin to the patient twice daily and about 100 mg of aspirin to the patient once daily throughout the time intervals defined in (i) to (iv).

In other examples according to these and other aspects of the present invention, the term "initial time interval of about two weeks" means, in context of the therapeutic regimes exemplified in this specification, once or twice daily administration of the pharmaceutical compositions as defined at any given time between day 0 and day 14 in a two week time interval from the commencement of treatment. For the avoidance of doubt, this means administration of the one or more pharmaceutical compositions to the patient on day 0, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13 and/or day 14 of the two week time interval. In Examples 9-14 which follow, this time interval aligns with Weeks 0-2.

The term "further time interval of about two weeks" or "further time interval of about another two weeks" means any 14 day period after the initial two week window, for example, days 15 to 28 (including day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27 and day 28) or days 29 to 42 (including day 26, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day 41 and day 42), or days 43 to 56 (including day 43, day 44, day 45, day 46, day 47, day 48, day 49, day 50, day 51, day 52, day 53, day 54, day 55 and day 56), from the commencement of treatment or first administration of a pharmaceutical composition as described herein to a patient requiring treatment. In Examples 9-14 which follow, these time intervals align with Weeks 2-4, Weeks 4-6 and Weeks 6-8, respectively.

In a further aspect the present invention provides a pharmaceutical composition as described herein for use in a method of treating and/or managing cancer in a patient in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition to the patient.

In other aspects, the present invention provides a pharmaceutical composition for use in a method of treating or managing cancer in a patient in need thereof, wherein the pharmaceutical composition comprises:

(i) propanolol in a dose amount of between about 40 mg and about 80 mg, metformin in a dose amount of between about 400 mg and about 600 mg celecoxib in a dose amount of between about 75 mg and about 125 mg, and a pharmaceutically effective excipient;

(ii) propanolol in a dose amount of about 60 mg, metformin in a dose amount of 500 mg, celecoxib in a dose amount of about 100 mg, and a pharmaceutically effective excipient; (iii) aliskiren in a dose amount of between about 60 mg and about 90 mg, cilazapril in a dose amount of between about 1.0 mg and about 1.5 mg, and a pharmaceutically effective excipient;

In certain examples according to the methods and uses described herein, the cancer is selected from the group consisting of squamous cell carcinoma of the upper aerodigestive tract (including oral cavity), squamous cell carcinoma of the skin, melanoma, lung cancer, breast cancer, kidney cancer, brain cancer, bowel cancer, thyroid cancer, prostate cancer, lymphoma, leukemia and sarcomas. In a related example, the cancer is selected from oral cavity squamous cell carcinoma (OCSCC), recurrent locally advanced and/or metastatic head and neck cutaneous SCC (HNcSCC), recurrent malignant melanoma (MM) and recurrent glioblastoma multiforme (GBM).

In other examples according to the present invention, the cancer treatment regimes are those described in Examples 9-14, below.

The present invention also contemplates articles of manufacture, suitable for commercial sale. The articles of manufacture may comprise a kit of parts, and include one or more of the pharmaceutical compositions described herein. The articles of manufacture according to the present invention may also comprise instructions for how to administer the pharmaceutical compositions as described herein to a patient in need of treatment. In certain examples, the articles of manufacture described herein are useful in the treatment and/or management of a patient having cancer.

Accordingly, in a further aspect the present invention provides an article of manufacture comprising one or more of the pharmaceutical compositions described herein.

(i) propranolol, metformin, celecoxib, aliskiren, cilazapril;

(ii) propanolol, metformin, celecoxib, aliskiren;

(iii) propanolol, metformin, celecoxib, aliskiren;

(iv) propanolol, metformin, celecoxib, cilazapril;

(v) propanolol, metformin, aliskiren, cilazapril;

(vi) metformin, celecoxib, aliskiren, cilazapril;

(vii) propanolol, metformin, celecoxib;

(viii) propanolol, metformin, aliskiren;

(ix) propanolol, metformin, cilazapril; (x) propanolol, celecoxib, aliskiren;

(xi) propanolol, celecoxib, cilazapril;

(xii) propanolol, aliskiren, cilazapril;

(xiii) metformin, celecoxib, aliskiren;

(xiv) metformin, celecoxib, cilazapril;

(xv) metformin, aliskiren, cilazapril;

(xvi) celecoxib, aliskiren, cilazapril;

(xvii) propanolol, metformin;

(xviii) propanolol, celecoxib;

(xix) propanolol, aliskiren;

(xx) propanolol, cilazapril;

(xxi) metformin, celecoxib;

(xxii) metformin, aliskiren;

(xxiii) metformin, cilazapril;

(xxiv) celecoxib, aliskiren;

(xxv) celecoxib, cilazapril;

(xxvi) aliskiren, cilazapril

(xxvii) propranolol, metformin, celecoxib, aliskiren, quinapril;

(xxviii) propanolol, metformin, celecoxib, quinapril;

(xxix) propanolol, metformin, aliskiren, quinapril;

(xxx) metformin, celecoxib, aliskiren, quinapril;

(xxxi) propanolol, metformin, quinapril;

(xxxii) propanolol, celecoxib, quinapril;

(xxxiii) propanolol, aliskiren, quinapril;

(xxxiv) metformin, celecoxib, quinapril;

(xxxv) metformin, aliskiren, quinapril;

(xxxvi) celecoxib, aliskiren, quinapril;

(xxxvii) propanolol, quinapril;

(xxxviii) metformin, quinapril;

(xxxix) celecoxib, quinapril; and/or

(xl) aliskiren, quinapril

In yet another aspect the present invention provides an article of manufacture comprising :

(ii) instructions for once or twice daily dosing by administration of the pharmaceutical composition to a patient in need of treatment.

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg and cilazapril in an amount of about 1.25 mg; and

(ii) instructions for daily or twice daily dosing by administration of the pharmaceutical composition to a patient in need of treatment.

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg and celecoxib in an amount of about 100 mg; and (ii) instructions for daily or twice daily dosing by administration of the pharmaceutical composition to a patient in need of treatment.

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising metformin in an amount of about 500 mg and celecoxib in an amount of about 100 mg; and

(i) multiple discrete doses of a pharmaceutical composition formulated for oral administration to a patient, the pharmaceutical composition comprising aliskiren in an amount of about 75 mg; and

(ii) instructions for daily or twice daily dosing by administration of the pharmaceutical composition to a patient in need of treatment. In yet a further aspect the present invention provides an article of manufacture comprising :

According to these and other aspects of the present invention, the articles of manufacture may further comprise discrete doses of curcumin and aspirin.

In an example according to these aspects, the article of manufacture comprises discrete dose amounts of between about 800 to about 1200 mg of curcumin. In a related example, the article of manufacture comprises a discrete dose amount of about 1000 mg of curcumin.

In another example according to these aspects, the article of manufacture comprises discrete dose amounts of between about 80 to about 120 mg of asprin. In a related example, the article of manufacture comprises a discrete dose amount of about 100 mg of asprin.

In other aspects, the articles of manufacture described herein are suitable for treating and/or managing a patient having cancer. Accordingly, in yet another aspect of the present invention there is provided an article of manufacture comprising one or more of the pharmaceutical compositions as described herein, and optionally instructions for how to prevent, treat and/or manage cancer in a patient in need thereof.

In certain examples according to the articles of manufacture useful in the treatment and/or management of cancer in a patient, the cancer is selected from the group consisting of squamous cell carcinoma of the upper aerodigestive tract (including oral cavity), squamous cell carcinoma of the skin, melanoma, lung cancer, breast cancer, kidney cancer, brain cancer, bowel cancer, thyroid cancer, prostate cancer, lymphoma, leukemia and sarcomas. In a related example, the cancer is selected from oral cavity squamous cell carcinoma (OCSCC), recurrent locally advanced and/or metastatic head and neck cutaneous SCC (HNcSCC), recurrent malignant melanoma (MM) and recurrent glioblastoma multiforme (GBM). The pharmaceutical compositions and articles of manufacture according to the present invention are also useful in the prevention, treatment and/or management of non-cancerous tumours including benign tumours. Accordingly, in yet another aspect of the present invention there is provided an article of manufacture comprising one or more of the pharmaceutical compositions as described herein, and optionally instructions for how to prevent, treat and/or manage a non-cancerous tumour in patient in need thereof.

Renin-Anaiotensin System

The Renin-Angiotensin System (RAS) is traditionally known to preserve fluid volume during periods of restricted dietary salt and also prevents ischaemia during acute volume loss. The main effector peptide of the RAS is angiotensin II (ATII). It induces vasoconstriction and sympathetic activation, raises aldosterone levels, and promotes renal salt and water retention via the angiotensin II receptor 1 (ATIIR1). Over the last few decades, the RAS has been a drug target of particular interest because of its involvement in cardiovascular disease (CVD) and renovascular disease. The CVD and renovascular disease can be understood as a continuum of risk factors, target organ damage, events, and mortality. Risk factors (such as hypertension, dyslipidemia, diabetes, and smoking) lead to the development of target organ damage including atherosclerosis, left ventricular hypertrophy (LVH), and renal impairment. Target organ damage progressively worsens, leading ultimately to myocardial infarction (MI), heart failure (HF), end-stage renal disease (ESRD), stroke, or death.

Angiotensin II, the main effector peptide of the RAS, plays an active role during all stages of this continuum. The first step in the RAS cascade is the formation of angiotensin I (ATI) from the precursor angiotensinogen under the action of renin; early evidence for the importance of RAS in CVD came from the consistent finding that renin activity is predictive of the risk of cardiovascular (CV) events. Angiotensin I is then converted to ATII, the principal effector peptide of the RAS, by angiotensin-converting enzyme (ACE). In addition, ATII can be produced in tissues by enzymes such as chymase. This locally produced ATII is believed to mediate paracrine and autocrine functions. Angiotensin II acts via ATIIR1 and ATIIR2. Activation of ATIIR1 results in vasoconstriction, aldosterone and vasopressin secretion, sodium retention, and decreased renal perfusion. Hence, these receptors mediate the deleterious effects of ATII, including elevated blood pressure (BP) and cardiac and vascular remodelling. The effects of the ATII receptors have been less clearly defined because of the limited expression of these receptors in adults, because of their unconventional signalling pathways, and because many ATII-mediated actions are masked by opposing ATI-mediated effects. However, it is now recognised that ATIIR2 generally opposes the actions of ATIIR1, mediating various anti-proliferative and anti-inflammatory effects and promoting tissue differentiation and regeneration and apoptosis. Additional components of the RAS have been identified in the last decade, including bioactive angiotensin peptides, such as angiotensin III, angiotensin IV, and angiotensin-(l- 7), the effects of which have not yet been fully elucidated for the CV and renal system.

The discovery of the renin receptor has shed further light on the biology of the RAS. Renin, simply considered until recently as the rate-limiting enzyme of RAS activation, has also turned out to be the ligand for a protein known as the renin/prorenin receptor that binds renin and prorenin about equally, regardless of their biologic activities. Prorenin, which represents 70% to 90% of total circulating renin, when bound to the receptor induces an increase in the catalytic efficiency of angiotensinogen conversion to ATI, which contributes to the local production of ATII and its systemic levels, as well as binding of renin/prorenin to the renin/prorenin receptor, exerting physiologic effects that are independent of ATII, including activation of intracellular signal pathways, enhanced synthesis of DNA, and stimulation of the release of plasminogen activator inhibitor 1, collagen 1, fibronectin, and transforming growth factor b-1.6

There are a number of known drugs which target the RAS. The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs). Although both of these drug classes target ATII, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events.

Direct inhibition of renin, the most proximal aspect of the RAS, became clinically feasible from 2007 with the introduction of Aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations such as congestive heart failure (HF) and proteinuria with diverse results.

RAS drugs include, but are not limited to, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARBs), Direct Renin Inhibitors (DRIs), Beta-Blockers, Cyclo-oxygenase 2 Inhibitors, Chymase Inhibitors, Cathepsin Inhibitors including Cathepsin Inhibitors, Cathepsin D Inhibitors and Cathepsin G Inhibitors, Calcium Channel Blockers, Calcium Supplements and Vitamin D, as described above.

Cancer TheraDv Aaents

The methods and therapeutic regimes described herein for the treatment and/or management of a cancer, e.g., oral cavity squamous cell carcinoma (OCSCC), recurrent locally advanced and/or metastatic head and neck cutaneous SCC (HNcSCC), recurrent malignant melanoma (MM) and recurrent glioblastoma multiforme (GBM), comprise administration of various drug combinations comprising therapeutically effective agents that target or modulate the Renin-Angiotensin System (RAS). Examples of therapeutically effective agents, which form part of the pharmaceutical compositions and formulations that target or modulate RAS of the present invention, include, but are not limited to, COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. Specific examples of therapeutically effective agents which fall within the definition of these drug classes have been listed elsewhere in this specification and are incorporated herein by reference. In accordance with the present invention, the RAS modulating drugs (including compositions, pharmaceutical compositions, formulations, articles of manufacture and kits) may be administered in series or in combination with (e.g., in physical combination, provided as a combined preparation) with one or more other cancer therapy agents.

Accordingly, also contemplated within the scope of the present invention is the selection of other inhibitors/pharmaceutically active molecules that target the Renin- Angiotensin System (RAS) expressed by cancer stem/cells, for use in the drug combinations and/or pharmaceutical compositions described herein. Examples include, but are not limited to, angiotensin receptor blockers, cyclo-oxygenase 2 inhibitors, inhibitors of cathepsin D, inhibitors of cathepsin G, calcium channel blockers, calcium supplements and vitamin D.

Examples of angiotensin receptor blockers include, but are not limited to, Losartan, Irbesartan, Candesartan, Eprosartan, Olmesartan, Telmisartan, PD123319 and Valsartan.

Examples of inhibitors of cathepsin D include, but are not limited to, non-peptidic acylguanidine inhibitors of Cathepsin D, Pepstatin A, Bm-Aspin, SIPI, Via, RNAi-Rab27A and Solanum lycopersicum aspartic protease inhibitor (SLAPI).

Examples of inhibitors of cathepsin G include, but are not limited to, WFDC12, Phenylmethylsulfonyl fluoride (PMSF), Ecotin, SerpinBl, SerpinA3, CeEI, or Caesalpinia echinata elastase inhibitor, SLPI (secretory leukocyte protease inhibitor), Alpha 1-Antitrypsin (AAT), Bauhinia bauhinoides cruzipain inhibitor, Alpha-Aminoalkylphosphonate diaryl esters, Greglin, [2-[3-[[(l-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-l-(l- naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA), Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI), Trappin-2 A62L, SV-66, SCGI, Bortezomib, Human monocyte/neutrophil elastase inhibitor (MNEI), a 42-kDa serpin protein and Anti-leukoproteinase (ALP).

Examples of calcium channel blockers include, but are not limited to, dihydropyridine calcium channel blockers, phenylalkylamine calcium channel blockers, benzothiazepine calcium channel blockers, non-selective calcium channel blockers.

Examples of dihydropyridine calcium channel blockers include, but are not limted to, Amlodipine (Norvasc), Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Isradipine (DynaCirc, Prescal), Efonidipine (Landel), Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), Pranidipine (Acalas).

Examples of phenylalkylamine calcium channel blockers include, but are not limited to, Verapamil (Calan, Isoptin), Gallopamil and Fendiline.

Examples of benzothiazepine calcium channel blockers include, but are not limited to, Diltiazem (Cardizem) and Fendiline.

Examples of non-selective calcium channel blockers include, but are not limited to, Mibefradil, Bepridil, Flunarizine, Fluspirilene and Fendiline.

Examples of other calcium channel blockers include, but are not limited to, Gabapentin, Pregabalin and Ziconotide.

In the methods of the present invention for the prevention and/or treatment of a cancer, e.g., squamous cell carcinoma of the upper aerodigestive tract (including oral cavity), squamous cell carcinoma of the skin, melanoma, lung cancer, breast cancer, kidney cancer, brain cancer, bowel cancer, thyroid cancer, prostate cancer, lymphoma, leukemia and sarcomas, sub-therapeutically effective amounts of RAS modulating pharmaceutical compositions as described herein, and one or more other cancer therapy agents are used or provided for combined administration (separately or jointly as a combined preparation) to provide a combined action that is therapeutically effective.

Treatment of a subject or patient with the combinations, compositions or formulations as described herein may comprise their acute or sustained administration and, in the case of combinations, their simultaneous, separate, or sequential administration, as further described herein.

The pharmaceutical compositions of the present invention may be administered to a subject in need of treatment, such as a subject with any of the diseases, disorders or conditions mentioned herein. The condition of the subject can thus be improved. Thus, in accordance with the invention, there are provided pharmaceutical compositions by which cancers can be treated.

A therapeutically effective amount of each of the combinations of therapeutically active agents (e.g., COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors) may be administered simultaneously, separately or sequentially and in any order, and in particular as a "polypill" pursuant to the pharmaceutical compositions described herein. The therapeutically active agents may be administered separately or as a fixed combination. When not administered as a fixed combination, preferred methods include the sequential administration of the therapeutically active agents, either or both of which are provided in amounts or doses that are less than those used when the drug or drugs are administered alone, i.e., when they are not administered in combination, either physically or in the course of treatment. Such lesser amounts of drugs administered are typically from about one-twentieth to about one-tenth the amount or amounts of the agent when administered alone, and may be about one-eighth the amount, about one-sixth the amount, about one-fifth the amount, about one-fourth the amount, about one-third the amount, and about one-half the amount when administered alone. Preferably, the agents are administered sequentially within at least about one-half hour of each other. The agents may also be administered within about one hour of each other, within about one day to about one week of each other, or as otherwise deemed appropriate.

Dosage Forms and Formulations and Administration

The therapeutically active agents administered as part of the compositions or formulations according to the present invention may be present in an isolated or substantially or essentially pure form. It will be understood that the compositions or formulations may be mixed with pharmaceutically effective excipients which will not interfere with the intended purpose of the product and still be regarded as isolated or substantially pure. A product of the invention may also be in a substantially or essentialy purified form, preferably comprising or consisting essentially of about 80%, 85%, or 90%, e.g. at least about 95%, at least about 98% or at least about 99% of the compound or dry mass of the preparation.

Depending on the intended route of administration, the combinations, compositions or formulations including medicaments of the invention may, for example, take the form of solutions, suspensions, instillations, sustained release formulations, or powders, and typically contain about 0.1%-95% of active ingredient(s), preferably about 0.2%-70%. Other suitable formulations include injection- and infusion-based formulations. Other useful formulations include sustained release preparations, including, for example, controlled, slow or delayed release preparations.

Aspects of the present invention include controlled or other doses, dosage forms, formulations, compositions and/or devices containing two or more therapeutically active agents, wherein the therapeutically active agents are, for example, COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. The present invention includes, for example, doses and dosage forms for at least oral administration, transdermal delivery, topical application, suppository delivery, transmucosal delivery, injection (including subcutaneous administration, subdermal administration, intramuscular administration, depot administration, and intravenous administration, including delivery via bolus, slow intravenous injection, and intravenous drip), infusion devices (including implantable infusion devices, both active and passive), administration by inhalation or insufflation, buccal administration and sublingual administration. It will be appreciated that any of the dosage forms, compositions, formulations or devices described herein particularly for intravenous administration may be utilised, where applicable or desirable, in a dosage form, composition, formulation or device for administration by any of the other routes herein contemplated or commonly employed. For example, a dose or doses could be given parenterally using a dosage form suitable for parenteral administration which may incorporate features or compositions described in respect of dosage forms suitable for oral administration, or be delivered in an sustained dosage form, such as a modified release, extended release, delayed release, slow release or repeat action dosage form.

In certain examples according to the present invention, the therapeutically active agents of the invention are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition. Suitable carriers and diluents include isotonic saline solutions, for example phosphate-buffered saline. Suitable diluents and excipients also include, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired substances such as wetting or emulsifying agents, stabilizing or pH buffering agents may also be present.

The term "pharmaceutically acceptable carrier" refers to any useful carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed, and include pharmaceutical carriers that do not induce the production of antibodies harmful to the individual receiving the composition. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, and amino acid copolymers. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Other examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween, polyethylene glycol (PEG), and Pluronics.

Pharmaceutically acceptable salts can also be present, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.

Suitable carrier materials include any carrier or vehicle commonly used as a base for creams, lotions, gels, emulsions, or paints for topical administration. Examples include emulsifying agents, inert carriers including hydrocarbon bases, emulsifying bases, non-toxic solvents or water-soluble bases. Particularly suitable examples include pluronics, HPMC, CMC and other cellulose-based ingredients, lanolin, hard paraffin, liquid paraffin, soft yellow paraffin or soft white paraffin, white beeswax, yellow beeswax, cetostearyl alcohol, cetyl alcohol, dimethicones, emulsifying waxes, isopropyl myristate, microcrystalline wax, oleyl alcohol and stearyl alcohol. An auxiliary agent such as casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose or polyvinyl alcohol may also be included in the formulation of the invention.

The dosage forms, combinations, compositions, formulations and/or devices of the invention may be formulated to optimize bioavailability and to maintain plasma concentrations within the therapeutic range, including for extended periods. Sustained delivery preparations, e.g., controlled delivery preparations, also optimize the drug concentration at the site of action and minimize periods of under and over medication, for example.

The dosage forms, devices and/or compositions useful in the invention may be provided for periodic administration, including once daily administration, for low dose controlled and/or low dose long-lasting in vivo release of (e.g.) COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors.

Examples of dosage forms suitable for oral administration include, but are not limited to tablets, capsules, lozenges, or like forms, or any liquid forms such as syrups, aqueous solutions, emulsions and the like, capable of providing a therapeutically effective amount of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors.

Examples of dosage forms suitable for transdermal administration include, but are not limited to, transdermal patches, transdermal bandages, and the like. Examples of dosage forms suitable for topical administration of the compounds and formulations useful in the invention are any lotion, stick, spray, ointment, paste, cream, gel, etc., whether applied directly to the skin or via an intermed.

Examples of dosage forms suitable for suppository administration of the compounds and formulations useful in the invention include any solid dosage form inserted into a bodily orifice particularly those inserted rectally, vaginally and urethrally.

Examples of dosage forms suitable for transmucosal delivery of the compounds and formulations useful in the invention include depositories solutions for enemas, pessaries, tampons, creams, gels, pastes, foams, nebulised solutions, powders and similar formulations containing in addition to the active ingredients such carriers as are known in the art to be appropriate.

Examples of dosage of forms suitable for injection of the compounds and formulations useful in the invention include delivery via bolus such as single or multiple administrations by intravenous injection, subcutaneous, subdermal, and intramuscular administration or oral administration.

Examples of dosage forms suitable for depot administration of the compounds and formulations useful in the invention include pellets or small cylinders of active agent or solid forms wherein the active agent is entrapped in a matrix of biodegradable polymers, microemulsions, liposomes or is microencapsulated.

Examples of infusion devices for compounds and formulations useful in the invention include infusion pumps containing one or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, at a desired amount for a desired number of doses or steady state administration, and include implantable drug pumps.

Examples of implantable infusion devices for compounds and formulations useful in the invention include any solid form in which the active agent is encapsulated within or dispersed throughout a biodegradable polymer or synthetic, polymer such as silicone, silicone rubber, silastic or similar polymer.

Examples of dosage forms suitable for inhalation or insufflation of compounds and formulations useful in the invention include compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixture thereof and/or powders.

Examples of dosage forms suitable for buccal administration of the compounds and formulations useful in the invention include lozenges, tablets and the like, compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof and/or powders.

Examples of dosage forms suitable for sublingual administration of the compounds and formulations useful in the invention include lozenges, tablets and the like, compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof and/or powders.

Examples of controlled drug formulations for delivery of the compounds and formulations useful in the invention are found in, for example, Sweetman, S.C. (Ed.). Martindale. The Complete Drug Reference, 33rd Edition, Pharmaceutical Press, Chicago, 2002, 2483 pp.; Aulton, M. E. (Ed.) Pharmaceutics. The Science of Dosage Form Design. Churchill Livingstone, Edinburgh, 2000, 734 pp.; and, Ansel, H. C., Allen, L. V. and Popovich, N. G. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, 676 pp. Excipients employed in the manufacture of drug delivery systems are described in various publications known to those skilled in the art including, for example, Kibbe, E. H. Handbook of Pharmaceutical Excipients, 3rd Ed., American Pharmaceutical Association, Washington, 2000, 665 pp. The USP also provides examples of modified-release oral dosage forms, including those formulated as tablets or capsules. See, for example, The United States Pharmacopeia 23/National Formulary 18, The United States Pharmacopeial Convention, Inc., Rockville MD, 1995 (hereinafter "the USP"), which also describes specific tests to determine the drug release capabilities of extended-release and delayed-release tablets and capsules. Further guidance concerning the analysis of extended release dosage forms has been provided by the FDA. See Guidance for Industry. Extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. Rockville, MD: Center for Drug Evaluation and Research, Food and Drug Administration (1997).

Further examples of dosage forms useful in the methods of the invention include, but are not limited to, modified-release (MR) dosage forms including delayed-release (DR) forms; prolonged-action (PA) forms; controlled-release (CR) forms; extended-release (ER) forms; timed-release (TR) forms; and long-acting (LA) forms. For the most part, these terms are used to describe orally administered dosage forms, however these terms may be applicable to any of the dosage forms, formulations, compositions and/or devices described herein. These formulations effect delayed total drug release for some time after drug administration, and/or drug release in small aliquots intermittently after administration, and/or drug release slowly at a controlled rate governed by the delivery system, and/or drug release at a constant rate that does not vary, and/or drug release for a significantly longer period than usual formulations.

Modified-release dosage forms of the invention include dosage forms having drug release features based on time, course, and/or location which are designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms. See, for example, Bogner, R.H. U.S. Pharmacist 22 (Suppl.) :3-12 (1997); Scale-up of oral extended-release drug delivery systems: part I, an overview, Pharmaceutical Manufacturing 2:23-27 (1985). Extended-release dosage forms of the invention include, for example, as defined by The United States Food and Drug Administration (FDA), a dosage form that allows a reduction in dosing frequency to that presented by a conventional dosage form, e.g., a solution or an immediate-release dosage form. See, for example, Bogner, R.H. (1997) supra. Repeat action dosage forms of the invention include, for example, forms that contain two single doses of medication, one for immediate release and the second for delayed release. Bi-layered tablets, for example, may be prepared with one layer of drug for immediate release with the second layer designed to release drug later as either a second dose or in an extended-release manner. Targeted-release dosage forms of the invention include, for example, formulations that facilitate drug release and which are directed towards isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action.

Also useful in the invention are coated beads, granules or microspheres containing one or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, which may be used to achieve modified release of one or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors by incorporation of the drug into coated beads, granules, or microspheres. In such systems, the one or more COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors are distributed onto beads, pellets, granules or other particulate systems. See Ansel, H.C., Allen, L.V. and Popovich, N.G., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, p. 232.

Methods for manufacture of microspheres suitable for drug delivery have been described. See, for example, Arshady, R. Polymer Eng Sci 30: 1746-1758 (1989); see also, Arshady, R., Polymer Eng Sci 30:905-914 (1990); see also: Arshady R., Polymer Eng Sci 30:915-924 (1990). Various coating systems are commercially available. E.g., Aquacoat™ [FMC Corporation, Philadelphia] and Surerelease™ [Colorcon]; Aquacoat aqueous polymeric dispersion. Philadelphia : FMC Corporation, 1991; Surerelease aqueous controlled release coating system. West Point, PA: Colorcon, 1990; Butler, J., et ai., Pharm Tech 22: 122-138 (1998); Yazici, E., et a/., Pharmaceut Dev Techno! 1 : 175-183 (1996).

Variation in the thickness of the coats and in the type of coating materials used affects the rate at which the body fluids are capable of penetrating the coating to dissolve the COX- 2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. Generally, the thicker the coat, the more resistant to penetration and the more delayed release and dissolution of the therapeutic agents. See Madan, P. L. U.S. Pharmacist 15:39-50 (1990). This provides the different desired sustained or extended release rates and the targeting of the coated beads to the desired segments of the gastrointestinal tract. Examples of film-forming polymers which can be used in water- insoluble release-slowing intermediate layer(s) (to be applied to a pellet, spheroid or tablet core) include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc. Each of Eudragit® RS and Eudragit® RL is an ammonio methacrylate copolymer. The release rate can be controlled not only by incorporating therein suitable water-soluble pore formers, such as lactose, mannitol, sorbitol, etc., but also by the thickness of the coating layer applied. Multi-tablets may be formulated which include small spheroid-shaped compressed mini- tablets that may have a diameter of between 3 to 4 mm and can be placed in a gelatin capsule shell to provide the desired pattern of COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors release. Each capsule may contain 8-10 minitablets, some uncoated for immediate release and others coated for extended release of the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. A number of methods may be employed to generate modified-release dosage forms of one or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors suitable for oral administration to humans and other mammals. Two basic mechanisms available to achieve modified release drug delivery include altered dissolution or diffusion of drugs and excipients. Within this context, for example, four processes may be employed, either simultaneously or consecutively. These are as follows: (i) hydration of the device (e.g., swelling of the matrix); (ii) diffusion of water into the device; (iii) controlled or delayed dissolution of the drug; and (iv) controlled or delayed diffusion of dissolved or solubilized drug out of the device.

In order to formulate a range of dosage values, cell culture assays and animal studies can be used. The dosage of such compounds preferably lies within the dose that is therapeutically effective for at least 50% of the population, and that exhibits little or no toxicity at this level.

The effective dosage of each of COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors employed in the methods and compositions of the invention may vary depending on a number of factors including the particular COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors employed, the cancer therapeutic combinational partner if present, the mode of administration, the frequency of administration, the condition being treated, the severity of the condition being treated, the route of administration, the needs of a patient sub-population to be treated or the needs of the individual patient whose different needs can be due to age, sex, body weight, relevant medical condition specific to the patient.

A suitable dose may be from about 0.001 to about 1 or to about 10 mg/kg body weight such as about 0.01 to about 0.5 mg/kg body weight. A suitable dose may however be from about 0.001 to about 0.1 mg/kg body weight such as about 0.01 to about 0.05 mg/kg body weight. Doses from about 1 to 100, 100-200, 200-300, 300-400, and 400-500 miligrams are appropriate, as are doses of about 500-750 micrograms and about 750-1000 micrograms. Other useful doses include from about 300 to about 1000 picomoles per dose, and about 0.05 to about 0.2 nanomoles per dose. Still other doses are within the following claims.

For example, in certain examples, the COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors composition may be administered at about 0.01 nanomolar (mM) or 0.05 nM to about 200 nM final concentration. Preferably, the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors composition is administered at about 0.1 nM to about 150 nM final concentration, more preferably, the COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors composition is applied at about 1 nM to about 100 nM final concentration, and more preferably, the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors composition is administered at about 10-20 nM to about 100-150 nM final concentration. Additionally, COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors dose amounts include, for example, about 0.1-1, 1-2, 2-3, 3-4, or 4-5 milligrams (mg), from about 5 to about 10 mg, from about 10 to about 15 mg, from about 15 to about 20 mg, from about 20 to about 30 mg, from about 30 to about 40 mg, from about 40 to about 50 mg, from about 50 to about 75 mg, from about 75 to about 100 mg, from about 100 mg to about 250 mg, and from 250 mg to about 500 mg. Dose amounts from 500 to about 1000 and from 1000 to about 2000 milligrams or more or also provided, as noted above.

Still other dosage levels between about 1 nanogram (ng)/kg and about 1 mg/kg body weight per day of each of the agents described herein. In certain examples, the dosage of each of the subject compounds will generally be in the range of about 1 ng to about 1 microgram per kg body weight, about 1 ng to about 0.1 microgram per kg body weight, about 1 ng to about 10 ng per kg body weight, about 10 ng to about 0.1 microgram per kg body weight, about 0.1 microgram to about 1 microgram per kg body weight, about 20 ng to about 100 ng per kg body weight, about 0.001 mg to about 0.01 mg per kg body weight, about 0.01 mg to about 0.1 mg per kg body weight, or about 0.1 mg to about 1 mg per kg body weight. In certain embodiments, the dosage of each of the subject compounds will generally be in the range of about 0.001 mg to about 0.01 mg/kg body weight, about 0.01 mg to about 0.1 mg/kg body weight, about 0.1 mg to about 1 mg/kg body weight. Where more than one COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is used, the dosage of each COX-2 inhibitor including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors need not be in the same range as the other.

Conveniently, if infused, the COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors are administered for at least about 0.5 to 1 hour, at least about 1-2 hours, at least about 2-4 hours, at least about 4-6 hours, at least about 6-8 hours, at least about 8-10 hours, at least about 12 hours, or at least about 24 hours.

As noted herein, the doses of COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, for example, administered in combination, or other cancer therapeutic agents administered in combination with either or both, can be adjusted down from the doses administered when given alone.

The combined use of several agents may reduce the required dosage for any individual agent because the onset and duration of effect of the different agents may be complementary. In a preferred example, the combined use of two or more COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors and/or cancer therapeutic agents has an additive, synergistic or super-additive effect.

In some cases, the combination of COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors and cancer therapeutic agent, or other agents administered in combination with either or both, has an additive effect. In other cases, the combination can have greater-than-additive effect. Such an effect is referred to herein as a "supra-additive" effect, and may be due to synergistic or potentiated interaction.

In another preferred example, the combined use of COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors and another cancer therapeutic agent, reduces the frequency in which said agent is administered compared to the frequency when said agent is administered alone. Thus, these combinations allow the use of lower and/or fewer doses of each agent than previously required to achieve desired therapeutic goals.

Doses may be administered in single or divided applications. The doses may be administered once, or the application may be repeated. Typically, administration can be by infusion in addition to or instead of multiple single adminstrations.

One or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, combinations thereof and optionally inclusive of another cancer therapeutic agent, if desired, may be administered by the same or different routes. The various agents of the invention can be administered separately at different times during the course of therapy, or concurrently in divided or single combination forms. In one example of the invention a COX-2 inhibitor including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is administered in one composition and another cancer therapeutic agent (including a COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors) is administered in a second composition. In another example the first composition comprising COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is administered before the second composition comprising another cancer therapeutic agent. In a further example the first composition comprising a COX-2 inhibitor including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is administered after the second composition comprising another cancer therapeutic agent. In yet a further example, the first composition comprising a COX- 2 inhibitor including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is administered before and after the second composition comprising another cancer therapeutic agent. In yet another example the second composition comprising another cancer therapeutic agent (including COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors) is administered before and after the first composition comprising a COX-2 inhibitor including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In yet another example the first composition comprising a COX-2 inhibitor including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors is administered about the same time as the second composition comprising another cancer therapeutic agent.

The delivery of a formulation comprising a COX-2 inhibitor including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, alone or together with another cancer therapeutic agent, including COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, over a period of time, in some instances for about 1-2 hours, about 2-4 hours, about 4-6 hours, about 6-8, or about 24 hours or longer, may also be accomplished using slow release or depot formulations, for example, as well as transdermal formulations and devices. Strategies to improve the oral bioavailability of proteins have ranged from changing their physicochemical properties by modification of their lipophilicity and enzyme susceptibility, to adding novel functionality using transport-carrier molecules that are recognized by endogenous transport-carrier systems in the gastrointestinal tract and/or to their inclusion in specially adapted drug carrier systems. Marketed polymeric-based systems have attracted considerable attention in the controlled release in targeting particular organs/tissues, and in their ability to deliver proteins and peptides. They can effectively deliver the proteins to a target site and thus increase the therapeutic benefit, while minimizing side effects. Protein association with polymer-based carriers, such as polymeric microparticles, nanoparticles, hydrogels or patches is a useful approach to improve oral protein bioavailability. Polymer-based carriers can protect proteins from the gastrointestinal environment and allow the modulation of physicochemical and protein release properties and consequently the biological behavior. Also, from the perspective of improving oral absorption, the major effect of carriers is to increase epithelial membrane permeability, thereby leading to higher bioavailability.

Dosage forms of the compounds and formulations of the invention, extended therapeutic agent action may be achieved by affecting the rate at which the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, is released from the dosage form and/or by slowing the transit time of the dosage form through the gastrointestinal tract (see Bogner, R.H., US Pharmacist 22 (Suppl.) :3-12 (1997)). The rate of drug release from solid dosage forms may be modified by the technologies described below which, in general, are based on the following : 1) modifying drug dissolution by controlling access of biologic fluids to the drug through the use of barrier coatings; 2) controlling drug diffusion rates from dosage forms; and 3) chemically reacting or interacting between the drug substance or its pharmaceutical barrier and site-specific biological fluids. Systems by which these objectives are achieved are also provided herein. In one approach, employing digestion as the release mechanism, the COX- 2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof are either coated or entrapped in a substance that is slowly digested or dispersed into the intestinal tract. The rate of availability of the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, is a function of the rate of digestion of the dispersible material. Therefore, the release rate, and thus the effectiveness of the therapeutic agent varies from subject to subject depending upon the ability of the subject to digest the material. A further form of slow release dosage form of the compounds and formulations of the invention is any suitable osmotic system where semi-permeable membranes of for example cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, is used to control the release of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof. These can be coated with aqueous dispersions of enteric lacquers without changing release rate. An example of such an osmotic system is an osmotic pump device, such as the Oros™ device developed by Alza Inc. (U.S.A.).

Other devices useful in the methods of the invention utilize monolithic matrices including, for example, slowly eroding or hydrophilic polymer matrices, in which one or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are compressed or embedded.

Monolithic matrix devices comprising compounds and formulations useful in the invention include those formed using, for example, COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, dispersed in a soluble matrix, which become increasingly available as the matrix dissolves or swells; examples include hydrophilic colloid matrices, such as hydroxypropylcellulose (BP) or hydroxypropyl cellulose (USP); hydroxypropyl methylcellulose (HPMC; BP, USP); methylcellulose (MC; BP, USP); calcium carboxymethylcellulose (Calcium CMC; BP, USP); acrylic acid polymer or carboxy polymethylene (Carbopol) or Carbomer (BP, USP); or linear glycuronan polymers such as alginic acid (BP, USP), for example those formulated into microparticles from alginic acid (alginate)-gelatin hydrocolloid coacervate systems, or those in which liposomes have been encapsulated by coatings of alginic acid with poly-L-lysine membranes. Release of the therapeutic agent(s) occurs as the polymer swells, forming a matrix layer that controls the diffusion of aqueous fluid into the core and thus the rate of diffusion of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, from the system.

In such systems, the rate of COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, release depends upon the tortuous nature of the channels within the gel, and the viscosity of the entrapped fluid, such that different release kinetics can be achieved, for example, zero-order, or first-order combined with pulsatile release. Where such gels are not cross-linked, there is a weaker, non-permanent association between the polymer chains, which relies on secondary bonding. With such devices, high loading of the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, is achievable, and effective blending is frequent. Devices may contain 20 - 80% of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, (w/w), along with gel modifiers that can enhance therapeutic agent diffusion; examples of such modifiers include sugars that can enhance the rate of hydration, ions that can influence the content of cross-links, and pH buffers that affect the level of polymer ionization. Hydrophilic matrix devices may also contain one or more pH buffers, surfactants, counter- ions, lubricants such as magnesium stearate (BP, USP) and a glidant such as colloidal silicon dioxide (USP; colloidal anhydrous silica, BP) in addition to COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, and hydrophilic matrix.

Monolithic matrix devices comprising compounds and formulations useful in the invention also include those formed using, for example, COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are dissolved in an insoluble matrix, from which the therapeutic agent(s) becomes available as the solvent enters the matrix, often through channels, and dissolves the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, particles. Examples include systems formed with a lipid matrix, or insoluble polymer matrix, including preparations formed from Carnauba wax (BP; USP); medium-chain triglyceride such as fractionated coconut oil (BP) or triglycerida saturata media (PhEur); or cellulose ethyl ether or ethylcellulose (BP, USP). Lipid matrices are simple and easy to manufacture, and incorporate the following blend of powdered components: lipids (20-40% hydrophobic solids w/w) which remain intact during the release process; e.g., channeling agent, such as sodium chloride or sugars, which leaches from the formulation, forming aqueous micro-channels (capillaries) through which solvent enters, and through which COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are released. In this system, the COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are embedded in an inert insoluble polymer and are released by leaching of aqueous fluid, which diffuses into the core of the device through capillaries formed between particles, and from which the COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, diffuse out of the device. The rate of release is controlled by the degree of compression, particle size, and the nature and relative content (w/w) of excipients. An example of such a device is that of Ferrous Gradumet (Martindale 33rd Ed., 1360.3). A further example of a suitable insoluble matrix is an inert plastic matrix. By this method, COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are granulated with an inert plastic material such as polyethylene, polyvinyl acetate, or polymethacrylate, and the granulated mixture is then compressed into tablets. Once ingested, the COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are slowly released from the inert plastic matrix by diffusion. See, for example, Bodmeier, R. & Paeratakul, O., J Pharm Sci 79:32-26 (1990); Laghoueg, N., et al., Int J Pharm 50: 133-139 (1989); Buckton, G., et a!., Int J Pharm 74: 153-158 (1991). The compression of the tablet creates the matrix or plastic form that retains its shape during the leaching of the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, and through its passage through the gastrointestinal tract. An immediate-release portion of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, may be compressed onto the surface of the tablet. The inert tablet matrix, expended of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, is excreted with the feces. An example of a successful dosage form of this type is Gradumet (Abbott; see, for example, Ferro-Gradumet, Martindale 33rd Ed., p. 1860.4).

Further examples of monolithic matrix devices useful in the methods of the invention include compositions and formulations of the invention incorporated in pendent attachments to a polymer matrix. See, for example, Scholsky, K.M. and Fitch, R.M., J Controlled Release 3:87-108 (1986). In these devices, COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, may be attached by means of an ester linkage to poly(acrylate) ester latex particles prepared by aqueous emulsion polymerization. Still further examples of monolithic matrix devices of the invention incorporate dosage forms in which the therapeutic agent(s) is bound to a biocompatible polymer by a labile chemical bond, e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug : methacryloyl chloride and the sodium salt of methoxy benzoic acid) have been used to form a matrix with a second polymer (Eudragit RL) which releases drug on hydrolysis in gastric fluid. See Chafi, N., et al., Int J Pharm 67:265-274 (1992).

Modified release forms of one or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, may also be prepared by microencapsulation. Microencapsulation is a process by which solids, liquids, or even gasses may be encapsulated into microscopic size particles through the formation of thin coatings of "wall" material around the substance being encapsulated such as disclosed in U.S. Patent Nos. 3,488,418; 3,391,416 and 3,155,590. Gelatin (BP, USP) is commonly employed as a wall-forming material in microencapsulated preparations, but synthetic polymers such as polyvinyl alcohol (USP), ethylcellulose (BP, USP), polyvinyl chloride, and other materials may also be used. See, for example, Zentner, G.M., et al., J Controlled Release 2:217-229 (1985); Fites, A.L., et al., J Pharm Sci 59:610- 613 (1970); Samuelov, Y., et al., J Pharm Sci 68:325-329 (1979). Different rates of theraeutic agent release may be obtained by changing the core-to-wall ratio, the polymer used for the coating, or the method of microencapsulation. See, for example,: Yazici, E., Oner, et al.,Pharmaceut Dev Technol·, 1 : 175-183 (1996).

Other useful approaches include those in which the COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are incorporated into polymeric colloidal particles or microencapsulates (microparticles, microspheres or nanoparticles) in the form or reservoir and matrix devices. See: Douglas, S. J., et al., C.R. C. Crit Rev Therap Drug Carrier Syst 3:233-261 (1987); Oppenheim, R.C., Int J Pharm 8:217-234 (1981); Higuchi, T., J Pharm Sci 52: 1145-1149 (1963).

Formulations of drugs suitable for transdermal delivery are known to those skilled in the art, and are described in references such as Ansel et al., {supra). Methods known to enhance the delivery of drugs by the percutaneous route include chemical skin penetration enhancers, which increase skin permeability by reversibly damaging or otherwise altering the physicochemical nature of the stratum corneum to decrease its resistance to drug diffusion. See Shah, V., Peck, C.C., and Williams, R.L., Skin penetration enhancement: clinical pharmacological and regulatory considerations, In: Walters, K.A. and Hadgraft, 1 (Eds.) Pharmaceutical skin penetration enhancement. New York: Dekker, (1993). Skin penetration enhancers suitable for formulation with COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, in transdermal drug delivery systems may be chosen from the following list: acetone, laurocapram, dimethylacetamide, dimethylformamide, dimethylsulphoxide, ethanol, oleic acid, polyethylene glycol, propylene glycol and sodium lauryl sulphate. Further skin penetration enhancers may be found in publications known to those skilled in the art. See, for example, Osborne, D.W., & Henke, J.J., Pharm Tech 21 : 50-66 (1997); Rolf, D., "Pharm Tech 12: 130-139 (1988). In addition to chemical means, there are physical methods that enhance transdermal drug delivery and penetration of the compounds and formulations of the invention. These include iontophoresis and sonophoresis. Formulations suitable for administration by iontophoresis or sonophoresis may be in the form of gels, creams, or lotions.

Transdermal delivery, methods or formulations of the invention, may utilize, among others, monolithic delivery systems, drug-impregnated adhesive delivery systems (e.g., the Latitude™ drug-in-adhesive system from 3M), active transport devices and membrane- controlled systems. Transdermal delivery dosage forms of the invention include those which substitute the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, for the diclofenic or other pharmaceutically acceptable salt thereof referred to in the transdermal delivery systems disclosed in, by way of example, U.S. Patent Nos. 6,193,996, and 6,262,121.

Other dosage forms include variants of the oral dosage forms adapted for suppository or other parenteral use. When rectally administered in the form of suppositories, for example, these compositions may be prepared by mixing one or more compounds and formulations of the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof. Suppositories are generally solid dosage forms intended for insertion into body orifices including rectal, vaginal and occasionally urethrally and can be long acting or slow release. Suppositories include a base that can include, but is not limited to, materials such as alginic acid, which will prolong the release of the pharmaceutically acceptable active ingredient over several hours (5-7). Transmucosal administration of the compounds and formulations useful in the invention may utilize any mucosal membrane but commonly utilizes the nasal, buccal, vaginal and rectal tissues. Formulations suitable for nasal administration of the compounds and formulations of the invention may be administered in a liquid form, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, including aqueous or oily solutions of the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof. Formulations for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, of less than about 100 microns, preferably less, most preferably one or two times per day than about 50 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Compositions in solution may be nebulized by the use of inert gases and such nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a facemask, tent or intermittent and COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof may be administered orally or nasally from devices that deliver the formulation in an appropriate manner. Formulations may be prepared as aqueous solutions for example in saline, solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bio-availability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.

Compositions may be prepared according to conventional methods by dissolving or suspending an amount of a COX-2 inhibitor including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, in a diluent. The amount of therapeutic agent is from between 0.1 mg to 1000 mg per ml of diluent. In some examples, dosage forms of 100 mg and 200 mg of therapeutic agent(s) are provided. By way of example only, the amount of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, may range from about 1 mg to about 750 mg or more (for example, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 1000 mg, and about 1200 mg). Other amounts within these ranges may also be used and are specifically contemplated though each number in between is not expressly set out. Therapeutic agents, including COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, can be provided and administered in forms suitable for once-a-day dosing. An acetate, phosphate, citrate or glutamate buffer may be added allowing a pH of the final composition to be from about 5.0 to about 9.5; optionally a carbohydrate or polyhydric alcohol tonicifier and, a preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol may also be added. Water for injection, tonicifying agents such as sodium chloride, as well as other excipients, may also be present, if desired. For parenteral administration, formulations are isotonic or substantially isotonic to avoid irritation and pain at the site of administration.

The terms buffer, buffer solution and buffered solution, when used with reference to hydrogen-ion concentration or pH, refer to the ability of a system, particularly an aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution with a solvent. Characteristic of buffered solutions, which undergo small changes of pH on addition of acid or base, is the presence either of a weak acid and a salt of the weak acid, or a weak base and a salt of the weak base. An example of the former system is acetic acid and sodium acetate. The change of pH is slight as long as the amount of hydroxyl ion added does not exceed the capacity of the buffer system to neutralize it.

Maintaining the pH of the formulation in the range of approximately 5.0 to about 9.5 can enhance the stability of the parenteral formulation of the present invention. Other pH ranges, for example, include, about 5.5 to about 9.0, or about 6.0 to about 8.5, or about 6.5 to about 8.0, or, preferably, about 7.0 to about 7.5.

The buffer used may be selected from any of the following, for example, an acetate buffer, a phosphate buffer or glutamate buffer, the most preferred buffer being a phosphate buffer. Carriers or excipients can also be used to facilitate administration of the compositions and formulations of the invention. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, polyethylene glycols and physiologically compatible solvents. A stabilizer may be included, but will generally not be needed. If included, however, an example of a stabilizer useful in the practice of the invention is a carbohydrate or a polyhydric alcohol. The polyhydric alcohols include such compounds as sorbitol, mannitol, glycerol, xylitol, and polypropylene/ethylene glycol copolymer, as well as various polyethylene glycols (PEG) of molecular weight 200, 400, 1450, 3350, 4000, 6000, and 8000). The carbohydrates include, for example, mannose, ribose, trehalose, maltose, inositol, lactose, galactose, arabinose, or lactose.

Isotonicity agents, or agents to maintain isotonicity, may also be used or included. The United States Pharmacopeia (USP) states that anti-microbial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple dose containers. They must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while withdrawing a portion of the contents with a hypodermic needle and syringe, or using other invasive means for delivery, such as pen injectors. Antimicrobial agents should be evaluated to ensure compatibility with all other components of the formula, and their activity should be evaluated in the total formula to ensure that a particular agent that is effective in one formulation is not ineffective in another. It is not uncommon to find that a particular agent will be effective in one formulation but not effective in another formulation. While the preservative for use in the practice of the invention can range from 0.005 to 1.0% (w/v), the preferred range for each preservative, alone or in combination with others, is: benzyl alcohol (0.1-1.0%), or m-cresol (0.1-0.6%), or phenol (0.1-0.8%) or combination of methyl (0.05- 0.25%) and ethyl or propyl or butyl (0.005%-0.03%) parabens. The parabens are lower alkyl esters of para-hydroxybenzoic acid. A detailed description of each preservative is set forth in "Remington's Pharmaceutical Sciences" as well as Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 1, 1992, Avis et al. For these purposes, the COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof may be administered parenterally (including subcutaneous injections, intravenous, intramuscular, intradermal injection or infusion techniques) or by inhalation spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

If desired, the parenteral formulation may be thickened with a thickening agent such as a methylcellulose. The formulation may be prepared in an emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example, acacia powder, a non-ionic surfactant or an ionic surfactant. It may also be desirable to add suitable dispersing or suspending agents to the pharmaceutical formulation. These may include, for example, aqueous suspensions such as synthetic and natural gums, e.g., tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

It is possible that other ingredients may be present in a parenteral pharmaceutical formulation useful the invention. Such additional ingredients may include wetting agents, oils (e.g., a vegetable oil such as sesame, peanut or olive), analgesic agents, emulsifiers, antioxidants, bulking agents, tonicity modifiers, metal ions, oleaginous vehicles, proteins (e.g., human serum albumin, gelatin or proteins) and a zwitterion (e.g., an amino acid such as betaine, taurine, arginine, glycine, lysine and histidine). Such additional ingredients, of course, should not adversely affect the overall stability of the pharmaceutical formulation of the present invention. Regarding pharmaceutical formulations, see also, Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 1, 2nd ed., Avis et al., Eds., Mercel Dekker, New York, N.Y. 1992.

Suitable routes of parenteral administration include intramuscular, intravenous, subcutaneous, intraperitoneal, subdermal, intradermal, intraarticular, intrathecal and the like. Mucosal delivery is also permissible. The dose and dosage regimen will depend upon the weight and health of the subject.

In addition to the above means of achieving extended drug action, the rate and duration of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, delivery may be controlled by, for example by using mechanically controlled drug infusion pumps.

The COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, can be administered in the form of a depot injection that may be formulated in such a manner as to permit a sustained release of the therapeutic agents. The therapeutic agents can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly. The pellets or cylinders may additionally be coated with a suitable biodegradable polymer chosen so as to provide a desired release profile. The COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof may alternatively be micropelleted. The micropellets using bioacceptable polymers can be designed to allow release rates to be manipulated to provide a desired release profile. Alternatively, injectable depot forms can be made by forming microencapsulated matrices of the therapeutic agents in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, to polymer, and the nature of the particular polymer employed, the rate of therapeutic agent release can be controlled. Depot injectable formulations can also be prepared by entrapping the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof in liposomes, examples of which include unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyl amine or phosphatidylcholines. Depot injectable formulations can also be prepared by entrapping the therapeutic agent in microemulsions that are compatible with body tissue. By way of example, reference is made to U.S. Patent Nos. 6,410,041 and 6,362,190.

Implantable infusion devices may employ inert material such as biodegradable polymers listed above or synthetic silicones, for example, cylastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation. The polymer may be loaded with COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof and any excipients. Implantable infusion devices may also comprise a coating of, or a portion of, a medical device wherein the coating comprises the polymer loaded with COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, and any excipient. Such an implantable infusion device may be prepared as disclosed in U.S. Patent No. 6,309,380 by coating the device with an in vivo biocompatible and biodegradable or bioabsorbable or bioerodible liquid or gel solution containing a polymer with the solution comprising a desired dosage amount of therapeutic agent and any excipients. The solution is converted to a film adhering to the medical device thereby forming the implantable therapeutic-deliverable medical device. An implantable infusion device may also be prepared by the in situ formation of a therapeutic agent containing solid matrix as disclosed in U.S. Patent No. 6,120,789. Implantable infusion devices may be passive or active, as known in the art.

Also useful in methods of the invention are microemulsions, i.e., such as fluid and stable homogeneous solutions composed of a hydrophilic phase, a lipophilic phase, at least one surfactant (SA) and at least one cosurfactant (CoSA). Examples of suitable surfactants include mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters. A cosurfactant, also sometimes known as "co-surface-active agentm," is a chemical compound having hydrophobic character, intended to cause the mutual solubilization of the aqueous and oily phases in a microemulsion. Examples of suitable co-surfactants include ethyl diglycol, lauric esters of propylene glycol, oleic esters of polyglycerol, and related compounds.

Therapeutic agents, including COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, may also be delivered using various polymers to enhance bioavailability by increasing adhesion to mucosal surfaces, by decreasing the rate of degradation by hydrolysis or enzymatic degradation of the therapeutic agents, and by increasing the surface area of the therapeutic agent relative to the size of the particle. Suitable polymers can be natural or synthetic, and can be biodegradable or non-biodegradable. Delivery of low molecular weight active agents may occur by either diffusion or degradation of the polymeric system. Representative natural polymers include proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, and collagen, polysaccharides such as cellulose, dextrans, and polyhyaluronic acid. Synthetic polymers are generally preferred due to the better characterization of degradation and release profiles. Representative synthetic polymers include polyphosphazenes, poly(vinyl alcohols), polyamides, polycarbonates, polyacrylates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. Examples of suitable polyacrylates include poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate). Synthetically modified natural polymers include cellulose derivatives such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Examples of suitable cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt. Each of the polymers described above can be obtained from commercial sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich Chemical Co., Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif, or can be synthesized from monomers obtained from these suppliers using standard techniques.

The polymers described above can be separately characterized as biodegradable, non- biodegradable, and bioadhesive polymers. Representative synthetic degradable polymers include polyhydroxy acids such as polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), poly(lactide-co- caprolactone), polyanhydrides, polyorthoesters and blends and copolymers thereof. Representative natural biodegradable polymers include polysaccharides such as alginate, dextran, cellulose, collagen, and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), and proteins such as albumin, zein and copolymers and blends thereof, alone or in combination with synthetic polymers. Examples of non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylphenol, and copolymers and mixtures thereof. Hydrophilic polymers and hydrogels tend to have bioadhesive properties. Hydrophilic polymers that contain carboxylic groups (e.g., poly[acrylic acid]) tend to exhibit the best bioadhesive properties. Polymers with the highest concentrations of carboxylic groups are preferred when bioadhesiveness on soft tissues is desired. Various cellulose derivatives, such as sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose also have bioadhesive properties. Some of these bioadhesive materials are water-soluble, while others are hydrogels. Polymers such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP) may be utilized to enhance the bioavailability of therapeutic agents with which they are complexed. Rapidly bioerodible polymers such as poly(lactide-co-glycolide), polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes, can also be used for bioadhesive therapeutic agent systems. In addition, polymers containing labile bonds, such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone. Upon degradation, these materials also expose carboxylic groups on their external surface, and can also be used as B natriuretic signal peptide fragment agent delivery systems.

Other agents that may enhance bioavailability or absorption of one or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof can act by facilitating or inhibiting transport across the intestinal mucosa. For example, agents that increase blood flow, such as vasodilators, may increase the rate of absorption of orally administered therapeutic agents by increasing the blood flow to the gastrointestinal tract. Vasodilators constitute another class of agents that may enhance the bioavailability of COX-2 inhibitors including non- steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof.

Other mechanisms of enhancing bioavailability of the compositions and formulations useful in the invention include the inhibition of reverse active transport mechanisms. For example, it is now thought that one of the active transport mechanisms present in the intestinal epithelial cells is p-glycoprotein transport mechanism which facilitates the reverse transport of substances, which have diffused or have been transported inside the epithelial cell, back into the lumen of the intestine. Inhibition of this p-glycoprotein mediated active transport system will cause less drug to be transported back into the lumen and will thus increase the net drug transport across the gut epithelium and will increase the amount of drug ultimately available in the blood. Various p-glycoprotein inhibitors are well known and appreciated in the art. These include, water soluble vitamin E; polyethylene glycol; poloxamers including Pluronic F-68; Polyethylene oxide; polyoxyethylene castor oil derivatives including Cremophor EL and Cremophor RH 40; Chrysin, (+)-Taxifolin; Naringenin; Diosmin; Quercetin; and the like.

Thus, while the delivery period will be dependent upon both the condition and the agent and the therapeutic effect which is desired, continuous or slow-release delivery for about 0.5-1 hour, about 1-2 hours, about 2-4 hours, about 4-6 hours, about 6-8, or about 24 hours or longer is provided. In accordance with the present invention, this is achieved by inclusion of a COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, optionally alone or together with another cancer therapeutic agent, in a formulation together with a pharmaceutically acceptable carrier or vehicle, particularly in the form of a formulation for continuous or slow-release administration.

The routes of administration and dosages described herein are intended only as a guide since a skilled physician will consider the optimum route of administration and dosage for any particular patient and condition.

Any of the methods of treating a subject having or at risk for cancer may utilize the administration of any of the doses, dosage forms, formulations, and/or compositions herein described.

Treatment

The combinations, compositions and formulations of the present invention may be used for preventing and/or treating cancer in a patient in need thereof.

The inventions also include methods of treatment of a subject having cancer or at risk for recurrence of cancer, comprising administering to the subject a therapeutically effective amount of a combination, composition and/or formulation described herein. In one non- limiting example, the cancer is selected from squamous cell carcinoma of the upper aerodigestive tract (including oral cavity), squamous cell carcinoma of the skin, melanoma, lung cancer, breast cancer, kidney cancer, brain cancer, bowel cancer, thyroid cancer, prostate cancer, lymphoma, leukemia and sarcomas.

The inventions include methods of treating a subject having cancer or at risk for recurrence of cancer, comprising administering a therapeutically effective amount of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, and a pharmaceutically acceptable carrier. In one example, the non-steriodal antiinflammatory drug includes, but is not limited to, Salicylates, including, but not limited to, Salicyclic Acid, Acetylsalicylic Acid, Salsalate, Diflunisal; Propionic Acid derivatives, including, but not limited to, Ibuprofen, Dexibuprofen, Naproxen, Denoprofen, Ketoprofen, Dexke to profen, Flubirpofen, Oxaprozin and loxoprofen; Acetic Acid derivatives, including, but not limited to, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone; Enolic Acid (Oxicam) derivatives, including, but not limited to, Piroxicam, Meloxicam, Tenoxicam, Droxicam, lornoxicam, Isoxicam and Phenylbutazone; Anthranilic Acid derivatives, including, but not limited to, Mefenamic Acid, Meclofenamic Acid, Flufenamic Acid, Tolfenamic Acid; COX-2 Inhibitors, including, but not limited to, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, lumiracoxib, Etoricoxib; Sulfonamides, including, but not limited to, Nimesulide; Clonixin; and Licofelone. In other examples, the beta-blocker includes, but is not limited to, Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol (Betoptic), Bisoprolol (Cardicor, Emcor, Zebeta), Carteolol (Teoptic), Carvedilol (Coreg, Eucardic), Celiprolol (Celectol), Labetalol (Trandate), Levobunolol (Betagan), Metipranolol (Metipranolol Minims), Metoprolol (Betaloc, Lopresor, Lopressor, Toprol XL), Nadolol (Corgard), Nebivolol (Bystolic, Nebilet), Oxprenolol (Trasicor), Pindolol (Visken), Propranolol (Inderal LA), Sotalol (Beta-Cardone, Sotacor), and Timolol (Betim, Nyogel, Timoptol). In yet a further example, the cathepsin inhibitor includes, but is not limited to, Curcumin, Cystatin B, Cystatin C, Cysteine peptidase inhibitor E64, [Pt(dmba)(aza-Nl)(dmso)] complex 1 (a potential anti-tumoral drug with lower IC50 than cisplatin in several tumoral cell lines), 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), CA- 074Me, Lipidated CtsB inhibitor incorporated into the envelope of a liposomal nanocarrier (LNC-NS-629), Proanthocyanidin (PA) and ahpatinin Ac (1) and ahpatinin Pr (2). In yet another example, the angiotensin converting enzyme inhibitor includes, but is not limited to, Benazepril (Lotesin), Captopril (Capoten), Cilazapril, Enalapril (Vasotec, Renitec), Fosinopril (Monopril), Lisinopril (Lisodur, Lopril, Novatec, Prinivil, Zestril), Moexipril, Perindopril (Coversay, Aceon), Quinapril (Accupril), Ramipril (Altace, Tritace, Ramace, Ramiwin), Trandolapril, Delapril, Zofenopril and Imidapril. In yet another example, the IGFR-1 pathway inhibitor includes but is not limited to, metformin, tyrphostins such as AG538 and AG1024, pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541 and Figitumumab (also called CP- 751871). In yet another example, the renin inhibitor includes but is not limited to, Aliskiren.

In other examples, the two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are administered in a single dose. In another example, the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are administered in more than one dose. In yet another example, the COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta- blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, are administered continuously over a period of time, for example a predetermined period of time. In another aspect, the inventions include methods for treatment of a patient, comprising administering to the patient a therapeutically effective amount of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors, including combinations thereof, wherein the administration is after the onset of one or more symptoms of cancer.

The inventions also include methods for treating a patient suffering from squamous cell carcinoma of the upper aerodigestive tract (including oral cavity), comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from squamous cell carcinoma of the skin, comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from melanoma, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from lung cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from breast cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from kidney cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from brain cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from bowel cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from prostate cancer, comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from lymphoma, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from leukemia, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from sarcomas, comprising administration of two or more COX-2 inhibitors including non-steroidal anti- inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from oral cavity squamous cell carcinoma (OCSCC), comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from recurrent locally advanced and/or metastatic head and neck cutaneous squamous cell carcinoma (HNcSCC), comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from recurrent malignant melanoma (MM), comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

The inventions also include methods for treating a patient suffering from recurrent glioblastoma multiforme (GBM), comprising administration of two or more COX-2 inhibitors including non-steroidal anti-inflammatory drugs, beta-blockers, inhibitors of the IGFR-1 pathway, inhibitors of cathepsin, angiotensin converting enzyme inhibitors and (direct) renin inhibitors. In a further example, the administration is continuous over a period of time, including a predetermined period of time.

In another aspect, the treated subject is a mammal, preferably a human. Other mammals may include domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, and cats.

Any of the methods of treating a subject having or suspected of having or predisposed to a disease, disorder, and/or condition referenced or described herein may utilize the administration of any of the doses, dosage forms, formulations, combinations, compositions and/or devices herein described. c==|ί=|ί Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field.

The invention is further described with reference to the following examples. It will be appreciated that the invention as claimed is not intended to be limited in any way by these examples.

EXAMPLE 1: FORMULATION 1A - PROPRANOLOL-METFORMIN-CELECOXIB EXTENDED RELEASE TABLET

^specified in Inactive Ingredients Database (March 2018)

EXAMPLE 2: FORMULATION 2A - ALISKIREN-CILAZAPRIL IMMEDIATE RELEASE TABLET

^specified in Inactive Ingredients Database (March 2018)

EXAMPLE 3: FORMULATION IB - ALISKIREN-CELECOXIB IMMEDIATE RELEASE TABLET

^specified in Inactive Ingredients Database (March 2018)

EXAMPLE 4: FORMULATION 2B - PROPRANOLOL-METFORMIN-CELECOXIB IMMEDIATE RELEASE TABLET

“•'specified in Inactive Ingredients Database (March 2018)

EXAMPLE 5: FORMULATION 1C - PROPRANOLOL-QUINAPRIL EXTENDED RELEASE TABLET

^specified in Inactive Ingredients Database (March 2018)

EXAMPLE 6: FORMULATION 2C - METFORMIN-CELECOXIB EXTENDED RELEASE TABLET

^specified in Inactive Ingredients Database (March 2018)

5

EXAMPLE 7: FORMULATION 3C - ALISKIREN IMMEDIATE RELEASE TABLET

“•'specified in Inactive Ingredients Database (March 2018)

EXAMPLE 8: FORMULATION MANUFACTURING PROCESSES

The following manufacturing processes were followed to prepare each of the Formulation Examples 1-7:

Direct Compression

1. use direct compression grade excipients;

2. blend dry ingredients;

3. blend lubricant; and

4. compress.

Wet Granulation

1. dry blend active pharmaceutical ingredient(s), diluent, disintegrant and

release modifiers;

2. apply binder in solution;

3. sieve wet mass;

4. dry granules;

5. blend granules;

6. blend lubricant; and

7. compress.

Dry Granulation

1. blend active pharmaceutical ingredient(s), diluent, disintegrant, release

modifiers and lubricant;

2. roller compaction;

3. blend granules;

4. blend lubricant; and

5. compress.

EXAMPLE 9: THERAPEUTIC REGIME # 1

The following therapeutic regime was followed for the treatment of cancer patients.

Table 1 : Therapeutic Regime #1

Formulation la (Example 1) comprises active pharmaceutical ingredients: propranolol (60 mg), metformin (500mg) and celecoxib (lOOmg) formulated as an extended release tablet

Formulation 2a (Example 2) comprises active pharmaceutical ingredients: aliskiren (75 mg) and cilazapril (1.25 mg) formulated as an immediate release tablet

EXAMPLE 10: THERAPEUTIC REGIME #2

As a variation to Example 9, the following therapeutic regime was followed for the treatment of cancer patients.

Table 2: Therapeutic Regime #2

EXAMPLE 11: THERAPEUTIC REGIME #3

As a variation to Examples 9-10, the following therapeutic regime was followed for the treatment of cancer patients.

Table 3: Therapeutic Regime #3

Formulation lb (Example 3) comprises active pharmaceutical ingredients: aliskiren (75 mg) and celecoxib (100 mg) formulated as an immediate release tablet

Formulation 2b (Example 4) comprises active pharmaceutical ingredients: metformin (500 mg), propranolol (60 mg) and cilazapril (1.25 mg) formulated as an immediate release tablet

EXAMPLE 12: THERAPEUTIC REGIME #4

As a variation to Examples 9-11, the following therapeutic regime was followed for the treatment of cancer patients.

Table 4: Therapeutic Regime #4

EXAMPLE 13: THERAPEUTIC REGIME #5

As a variation to Examples 9-12, the following therapeutic regime was followed for the treatment of cancer patients.

Table 5: Therapeutic Regime #5

Formulation lc (Example 5) comprises active pharmaceutical ingredients: Propranolol (60 mg), Quinapril (5 mg) formulated as an extended release tablet Formulation 2c (Example 6) comprises active pharmaceutical ingredients: Metformin (500 mg), Celecoxib (100 mg) formulated as an extended release tablet Formulation 3c (Example 7) comprises active pharmaceutical ingredient: Aliskiren (75 mg) formulated as an immediate release tablet

EXAMPLE 14: THERAPEUTIC REGIME #6

As a variation to Examples 9-13, the following therapeutic regime was followed for the treatment of cancer patients.

Table 6: Therapeutic Regime #6

Although the invention has been described by way of example, it should be appreciated that variations and modifications may be made without departing from the scope of the invention as defined in the claims. Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred in this specification.

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Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of propranolol, metformin, celecoxib and a pharmaceutically effective excipient.

2. A pharmaceutical composition comprising a therapeutically effective amount of aliskiren, cilazapril and a pharmaceutically effective excipient.

3. A pharmaceutical composition comprising a therapeutically effective amount of propranolol, metformin, cilazapril and a pharmaceutically effective excipient.

4. A pharmaceutical composition comprising a therapeutically effective amount of propranolol, quinapril and a pharmaceutically effective excipient.

5. A pharmaceutical composition comprising a therapeutically effective amount of metformin, celecoxib and a pharmaceutically effective excipient.

6. A pharmaceutical composition according to any one of claims 1 to 6 formulated for oral administration to a patient.

7. A pharmaceutical composition according to claim 6 formulated as a tablet, soft or hardgell capsule, lozenge, or like forms, or any liquid form such as a syrup, aqueous solution, or emulsion.

8. A pharmaceutical composition according to claim 7 formulated as a tablet for oral administration.

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein:

(i) propranolol is present in a dose amount of between about 40 mg and about 80 mg, preferably about 60 mg;

(ii) metformin is present in a dose amount of between about 400 mg and about 600 mg, preferably about 500 mg;

(iii) celecoxib is present in a dose amount of between about 75 mg and about 125 mg, preferably about 100 mg;

(iv) aliskiren is present in a dose amount of between about 60 mg and about 90 mg, preferably about 75 mg; (v) cilazapril is present in a dose amount of between about 1.0 mg and about 1.5 mg, preferably about 1.25 mg;

(vi) quinapril is present in a dose amount of between about 4.0 mg and about 6.0 mg, preferably about 5.0 mg.

10. A pharmaceutical composition according to any one of claims 1 to 9 for use in a method of treating cancer in a patient.

11. A method for treating cancer in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of any one of claims 1 to 9.

12. An article of manufacture comprising a pharmaceutical composition according to any one of claims 1 to 9, and optionally instructions for how to administer the pharmaceutical composition to a cancer patient in need thereof.