NZ535386A - Combination comprising an HMG-CoA reductase inhibitor and an insulin secretor enhancer or an insulin senstizer - Google Patents

Abstract

Disclosed is a combination, especially a pharmaceutical composition, consisting of: (i) a HMG CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simuvastatin and (ii) pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) useful in the treatment of hyperlipidaemia, dyslipidaemia, diabetes mellitus type 2 and obesity.

Description

New Zealand Paient Spedficaiion for Paient Number 535386 s-ifzfb COMBINATION COMPRISING PYRROLIDINE, 1-[(3-HYDROXY-1-ADAMANTYL)AMINO]ACETYL-2-CYANO-, (S) AND HMG COA REDUCTASE INHIBITORS The present invention relates to a combination of at least two components selected from the group consisting of: (i) a HMG CoA reductase inhibitor or a pharmaceutical^ acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and (ii) pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S)ora pharmaceutical^ acceptable salt thereof.

The invention furthermore relates to the use of pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutical^ acceptable salt thereof in combination with a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin for the manufacture of a medicament for the prevention of, delay of progression of or treatment of a disease or condition selected from the group consisting of hyperlipidaemia, dyslipidaemia, diabetes mellitus type 2 and obesity.

The invention furthermore relates to the use of pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutically acceptable salt thereof in combination with a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin for the manufacture of a medicament for the prevention of, delay of progression of or treatment of hypertension.

Another embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, and simvastatin.

Another preferred embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of fluvastatin, pitavastatin, and simvastatin.

Another more preferred embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or apharmaceutically acceptable salt intellectual property office of n.z. 1 7 JUL 2007 I dcpciv/ph thereof is atorvastatin.

The invention furthermore relates to a combination according to the invention wherein the the HMG CoA reductase inhibitor or apharmaceutically acceptable salt thereof is simvastatin.

The invention furthermore also relates to a combination according to the invention wherein the combination is adapted for administration simultaneously or sequentially in any order or for separate use.

The invention furthermore also relates to a combination wherein the combination is in the form of a fixed combination.

Especially, the combination according to the present invention may be used, e.g., for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hypertension, type 2 diabetes mellitus, hyperlipidaemia, obesity, dyslipidaemia, hypertension in the elderly, familial dyslipidaemic hypertension, modest hypertension or isolated systolic hypertension.

A further aspect of the invention is that the combination may be used e.g. for the prevention, delay of progression or treatment of modest hypertension or isolated systolic hypertension in diabetic patients. This use may further more reduce the risk of negative cardiovascular events.

The term "antidiabetic" generally comprises the compounds, substances and compositions known to those of ordinary skill to be used in the treatment of type 1 and type 2 diabetes mellitus. This term in particular comprises insulin secretion enhancers.

The insulin secretion enhancer is a pharmacologically active compound having the property to promote secretion of insulin from pancreatic (3-cells.

The structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g.

Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vfy-n anrj jn viy^H|Y intellectual^ ^ 1 7 JUL 2007 i rfheivec The term "short-acting insulin secretion enhancer" comprises corresponding agents with a maximum secretion of insulin that is attained within one hour, preferably within 30 minutes, after the administration of the agent, most preferably within 20 minutes having a biological half-life, T !4, of less than two hours, preferably, 1.5 hours. The term "long-acting insulin secretion enhancer" comprises corresponding agents with a maximum secretion of insulin that is attained more than one hour after administration of the agent.

The insulin secretion enhancing properties of the combination according to the present invention may be determined by following the methodology as disclosed, for example, in the publication of T.lkenoue et al. Biol.Pharm.Bull. 29(4), 354-359 (1997).

The corresponding subject matter of these four references is herewith incorporated by reference in this specification.

The compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases.

Preferably, the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, e.g. separately or in a fixed combination.

Under certain circumstances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different modes of action but acting in the similar field does not necessarily lead to combinations with advantageous effects.

All the more surprising is the experimental finding that the combination of the present invention results not only in a beneficial, especially a potentiating or a synergistic, therapeutic effect. Independent thereof, additional benefits resulting from combined treatment can be achieved such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with diabetes, e.g. less gain of weight. An additional and preferred aspect of the present invention is the prevention, delay of progression or treatment of the condition of intellectual property office of n.z. 17 JUL 2007 RRP.FIVFn isolated systolic hypertension and impaired vascular compliance which means decreased vascular elasticity.

In particular, all the more surprising is the experimental finding that the combination of the present invention results in a beneficial, especially a synergistic, therapeutic effect but also in benefits resulting from combined treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions as specified hereinbefore or hereinafter.

The pharmaceutical activities as effected by administration of the combination of active agents used according to the present invention can be demonstrated e. g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.

The pharmaceutical activities as effected by administration of representatives of the combination of active agents used according to the present invention can be demonstrated e.g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.

A "disease or condition which may be inhibited by the enhancement of insulin secretion" or a "disease or condition that may be inhibited by insulin sensitization" as defined in this application comprises, but is not limited to hyperlipidaemia, obesity, hypertension, dyslipidaemia and diabetes mellitus type 2, and diseases, illnesses, conditions or symptoms related to or encountered or associated therewith.

Furthermore, it has been found that the chronic co-administration of either an insulin sensitizer or an insulin secretion enhancer imparts the beneficial effect on blood vessel morphology and function and results in a decrease of vascular stiffness and correspondingly in a maintenance and in an improvement of vascular compliance.

Accordingly, it has been found that the combination of the present invention would potentiate the effect on systolic blood pressure and further improve vascularstiffness/compliance. The benefit of these combinations may also extend to an additional or potentiated effect on endothelial function, and improve vascular function and structure in various organs/tissues including the kidney, heart, eye and brain. Through the reduction in glucose levels, an anti- intellectual property office of n.z 1 7 JUL 2007 thrombotic and anti-atherosclerotic effect can also be demonstrated. Reduction of glucose would prevent or minimize the glycosylation of any structural or functional protein within the cardio-renal system.

All the more surprising is the experimental finding that the combination of the present invention results not only in a beneficial, especially a potentiating or a synergistic, therapeutic effect. Independent thereof, additional benefits resulting from combined treatment can be achieved such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with diabetes, e.g. less gain of weight.

The term "potentiation" shall mean an increase of a corresponding pharmacological activity or therapeutical effect, respectively. Potentiation of one component of the combination according to the present invention by co-administration of an other component according to the present invention means that an effect is being achieved that is greater than that achieved with one component alone.

The term "synergistic" shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone.

Hypertension, in connection with a "disease or condition which may be inhibited by the inhibition of HMG-CoA reductase inhibitor", a "disease or condition which may be inhibited by the enhancement of insulin secretion", a ="disease or condition that may be inhibited by insulin sensitization" includes and is not limited to mild, moderate and severe hypertension as defined in Journal of Hypertension 1999,17: 151-183, especially on page 162.

Further benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.

For example, it has turned out that the combination according to the present invention provides benefit especially in the treatment of modest hypertension or isolated systolic hypertension that is beneficial to all diabetic patients regardless of their hypertensive status, e.g. reducing the risk of negative cardiovascular events by two different modes of action.

■N7ELLECT;jAL"?S0PERTY OFFICE of im.z I 7 JUL 2007 ir Ai-n » — — The pharmaceutical composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.

Under certain circumstances, drugs with different mechanisms of action may be combined.

However, just considering any combination of drugs having different modes of action but acting in the similar field does not necessarily lead to combinations with advantageous effects.

The pharmaceutical composition according to the present invention comprises a "kit of parts" in the sense that the components can be dosed independently or by use of different fixed combinations with distinguished amounts of the components at different time points. The parts of the "kit of parts" can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the "kit of parts". Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components. Preferably, there is at least one beneficial effect, e.g. a mutual enhancing of the effect of (i) a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof; (ii) pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutically acceptable salt thereof; in particular a potentiation or a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or each of the components, especially a potentiation or a strong synergism.

These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound.

Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the OF N.2 1 7 JUL 2007 RECEIVED i with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.

The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.

Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutical effective dosages, especially those which are commercially available.

Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.

The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.

In case of HMG-CoA reductase inhibitors, preferred dosage unit forms of HMG-CoA reductase inhibitors are, for example, tablets or capsules comprising e.g. from about 5 mg to about 120 mg, preferably, when using fluvastatin, for example, 20 mg, 40 mg or 80 mg (equivalent to the free acid) of fluvastatin, for example, administered once a day.

Although the combinations of the following Examples fall outside the scope of the claims of the present application, the Examples help to illustrate the invention and are therefore retained for clarity and completeness.

•NTELlECTUAi SROPFRTv office OF l\lv 1 ? JUL 2007 RECFlvPn Example 12: Hard gelatin capsule: , -"if - r Capsule Fluvastatin Sodium 1} 21.481 Z) Calcium Carbonate 62.840 Sodium Bicarbonate 2.000 Microcrystalline Cellulose 57.220 Pregelatinized Starch 41.900 Purified Water 3) Q.S.

Magnesium Stearate 1.050 Talc 9.430 Target Capsule Fill Weight 195.92 Capsule Shell Hard gelatin Capsule Shell 48.500 Branding Ink (pre-printed) White Ink Trace Red Ink Trace Target Capsule Weight 244.42 1) includes a 2% overage for moisture 2) 20 mg of free acid is equivalent to 21.06 mg Na salt 3) partially removed during processing !ntellect|jai oropertv office of N.7 1 7 JUL 2007 RPrcu/cn Example 13: Hard gelatin capsule Ruvastatin Sodium 42.962 Calcium Carbonate 125.680 Sodium Bicarbonate 4.000 Microcrystalline Cellulose 114.440 Pregelatinized Starch 83.800 Purified Water 3) Q.S.

Magnesium Stearate 2.100 Talc 18.860 Target Capsule Fill Weight 391.840 Capsule Shell *Hard gelatin Capsule Shell ;A ;76.500 ;Branding Ink (pre-printed) ;White Ink ;Trace ;Red Ink ;Trace ;Target Capsule Weight ;468.34 ;1) includes a 2% overage for moisture ;2) 20 mg of free acid equivalent to 21.06 mg Na salt ;3) partially removed during processing intellectual property office of n.z ;1 7 JUL 2007 ;- 10- ;Example 14: ;Round, slightly bi-convex, film-coated tablets with beleved edges: ;•. •. -r . ■ ■■ ) ;.-A; ^ ;Table Core ;Fluvastatin Sodium 1} ;84.24 2} ;Cellulose Microcrystalline / Micro-crystalline cellulose fine powder ;111.27 ;Hypromellose / Hydroxypropyl methyl cellulose (Methocel K100LVP CR; HPMC100 cps) ;97.50 ;Hydroxypropyl cellulose (Klucel HXF) ;16.25 ;Potassium hydrogen carbonate / potassium bicarbonate ;8.42 ;Povidone ;4.88 ;Magnesium stearate ;2.44 ;Core Tablet Weight ;325.00 ;Coating ;Coating premix - Opadry Yellow (00F22737) ;9.75 ;Total Weight ;334.75 ;Water, purified 3) ;Q.S. ;1) 84.24 mg of the sodium salt of fluvastatin is equivalent to 80 mg of fluvastatin free acid ;2) to be adjusted for moisture (LOD) ;3) removed during processing ;~NTEL«.tOTliA: ;W V-I ;1 7 JUL 2007 ;RECEIVED ;Example 12: ;108,000 tablets, each which contain 120 mg of nategiinide are prepared as follows: ;Preparation process: The microcrystalline cellulose, povidone, part of the croscarmellose sodium, nategiinide and lactose are mixed in a high shear mixer and afterwards granulated using purified water. Alternatively, the microcrystalline cellulose, povidone, a portion of the croscarmellose sodium, nategiinide and lactose are granulated in a collette gral granulator with the addition of purified water. The wet granules are dried in a fluid bed dryer and passed through a screen. The colloidal silicon dioxide and the rest of the croscarmellose sodium are mixed, passed through a screen and blended with the dried granules in a V-blender. The magnesium stearate is passed through a screen, blended with the blend from the V-blender and afterwards the total mixture is compressed to tablets. The opadry yellow is suspended in purified water and the tablets are coated with the coating suspension. ;Composition: nategiinide lactose, NF ;12.960 kg 30.564 kg 15.336 kg 2.592 kg 3.974 kg 1.382 kg 1.231 kg 1.944 kg Q.S. ;microcrystalline cellulose, NF povidone, USP croscarmellose sodium, NF colloidal silicon dioxide, NF magnesium stearate, NF coating: opadry yellow purified water, USP* removed during process v intellectual property office of n.z 1 7 JUL 2007 RECEIVED

Claims (19)

- 12- Examples13-15: Component 60mg 120mg 180mg Starlix DS (H-form crystal modification) 60 120 180 Lactose Monohydrate 141.5 283 214 MicrocrystallineCellulose 71 142 107 Povidone K30 12 24 23 Croscarmellose Sodium 12 24 34 Sub-Total (Granulation) 296.5 593 558 Croscarmellose Sodium 6.4 12.8 24.5 Colloidal Silicone Dioxide 6.4 12.8 12.3 Magnesium Stearate 5.7 11.4 15.2 ^Sub-Total (Core) (315) (630) (610) Opadry 9 18 18 Total 324 648 628 intellectual property office of n.z 17 JUL 2007 RECEIVED -13- What is claimed is:

1 ■ A combination of at least two components selected from the group consisting of: (i) a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and (ii) pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutically acceptable salt thereof.

2. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, and simvastatin.

3. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of fluvastatin, pitavastatin, and simvastatin.

4. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is atrovastatin.

5. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is simvastatin.

6. A combination according to any one of claims 1 to 5 wherein the combination is adapted for administration simultaneously or sequentially in any order or for separate use.

7. A combination according to any one of claims 1 to 5 wherein the combination is in the form of a fixed combination.

8. Use of pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutically acceptable salt thereof in combination with a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin for the manufacture of a medicament for the prevention of, delay of progression of or treatment of a disease or condition selected from the group consisting of hyperlipidaemia, dyslipidaemia, diabetes mellitus type 2 and obesity.

9. Use according to claim 8, wherein the condition is hyperlipidaemia._ INTELLECTUAi ■■^O'^KT'V ORCL of mi 1 7 JUL 2007 ocrciupn - 14-

10. Use according to claim 8, wherein the condition is dysiipidaemia.

11. Use according to claim 8, wherein the condition is diabetes mellitus type 2.

12. Use of pyrrolidine, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) or a pharmaceutically acceptable salt thereof in combination with a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin for the manufacture of a medicament for the prevention of, delay of progression of or treatment of hypertension.

13. Use according to claim 12, wherein the hypertension is hypertension in the elderly or familial dysiipidaemic hypertension.

14. Use according to claim 12, wherein the hypertension is modest hypertension or isolated systolic hypertension.

15. Use according to claim 13, wherein the hypertension is modest hypertension or isolated systolic hypertension in diabetic patients.

16. Use according to claim 15, for furthermore reducing the risk of negative cardiovascular events.

17. A combination according to claim 1, substantially as herein described with reference to any one of the Examples thereof.

18. A combination according to any one of claims 1 to 7, substantially as herein described.

19. Use according to any one of claims 8 to 16, substantially as herein described. intellectual property office of n.z 17 JUL 2007 ocrciwcn