WO2006053754A1 - COMBINATIONS OF ANTI-ATHEROSCLEROTIC PEPTIDES AND AN mTOR INHIBITING AGENT AND THEIR METHODS OF USE - Google Patents

Abstract

The invention relates to a pharmaceutical compositions comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one 'D' amino acid residue and an mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative, optionally in the presence of a pharmaceutically acceptable carrier.

Description

Combinations of Anti-atherosclerotic peptides and an mTOR inhibiting agent and their Methods of Use

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue and a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative, optionally in the presence of a pharmaceutically acceptable carrier for simultaneous, separate or sequential use, especially in the prevention, delay of progression or treatment of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases; the use of such combination for the preparation of a pharmaceutical preparation for the prevention, delay of progression or treatment of such conditions; a method of prevention, delay of progression or treatment of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases.

The present invention relates to pharmaceutical combinations or compositions comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue and a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative, optionally in the presence of a pharmaceutically acceptable carrier and their uses in treating cardiac and renal related conditions or diseases and their uses in treating or preventing arthritis or rheumatic arthritis related conditions or diseases.

The present invention furthermore relates to pharmaceutical combinations or compositions which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue and a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative selected from the group of: 32-deoxorapamycin, 16-pent-2-ynyloxy-32- deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate]-rapamycin (also called CCI779) , 40-epi-(tetrazolyl)-rapamycin (also called ABT578) ,40-O-(2-hydroxyethyl) -rapamycin, 32-deoxorapamycin and 16-pent-2- ynyloxy-32(S)-dihydro-rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In a preferred embodiment, the present invention relates to pharmaceutical combinations or compositions which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially the peptide of SEQ ID NO. 5 of the '230 patent, wherein all amino acids are in the "D" configuration (peptide A) and a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative selected from the group of : 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16- pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2- (hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779) , 40-epi-(tetrazolyl)- rapamycin (also called ABT578) ,40-O-(2-hydroxyethyl) -rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination an a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 32-deoxorapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 16-pent-2-ynyloxy-32-deoxorapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 16-pent-2-ynyloxy-32(S or R)-dihydro- rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 16-pent-2-ynyloxy-32(S or R)-dihydro-40- 0-(2-hydroxyethyl)~rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 40-[3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate]-rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In one aspect the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 40-epi-(tetrazolyl)-rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In a preferred embodiment the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 32-deoxorapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

In another preferred embodiment the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination an a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 16-pent-2- ynyloxy-32(S)-dihydro-rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use. In a most preferred embodiment the present invention relates to pharmaceutical combinations or compositions according to the invention for the treatment or prevention of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases which comprise in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and 40-O-(2-hydroxyethyl) -rapamycin and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

A further aspect of the present invention provides a pharmaceutical composition according to the invention , e.g, for the treatment or prevention of cardiac and renal related conditions or diseases,! e, selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, restenosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke , and for the treatment or prevention of arthritis or rheumatic arthritis related conditions or diseases ,i e, selected from the group consisting of, arthritis or rheumatic arthritis, e.g. including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism, particularly joints or vertebrae, including also slowing the progression (destruction of the joints) in moderate to severe rheumatoid arthritis, progressive, or erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs and the reduction of the side-effects (signs and symptoms) of arthritis or rheumatic arthritis comprising administering a therapeutically effective amount of combination of (i) a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and (ii) a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative for example rapamycin or a rapamycin derivative selected from the group of : 32-deoxorapamycin, 16-pent-2-ynyloxy- 32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy- 32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate]-rapamycin (also called CCI779), 40-epi-(tetrazolyl)-rapamycin (also called ABT578), 40-O-(2-hydroxyethyl) -rapamycin, 32-deoxorapamycin and 16-pent-2- ynyloxy-32(S)-dihydro-rapamycin and a pharmaceutically acceptable carrieror to a mammal in need of such treatment.

In this composition, components (i) and (ii) can be obtained and administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms. The unit dose form may also be a fixed combination.

Furthermore the invention provides the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases.

In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of cardiac and renal related conditions or diseases ,i e, selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, restenosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke , and for the treatment or prevention of arthritis or rheumatic arthritis related conditions or diseases ,i e, selected from the group consisting of, arthritis or rheumatic arthritis, e.g. including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism, particularly joints or vertebrae, including also slowing the progression (destruction of the joints) in moderate to severe rheumatoid arthritis, progressive, or erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs and the reduction of the side-effects (signs and symptoms) of arthritis or rheumatic arthritis. In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the treatment or prevention of hypertension, heart failure such as (acute and chronic) congestive heart failure.

The present invention provides a kit comprising in separate containers in a single package pharmaceutical combinations or compositions comprising in one container a pharmaceutical composition comprising a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative, and in a second container a pharmaceutical composition comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A.

The present invention provides a kit comprising in separate containers in a single package pharmaceutical combinations or compositions comprising in one container a pharmaceutical composition comprising a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative.and in a second container a pharmaceutical composition comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A.

The kit form is particularly advantageous when the separate components must be administered in different dosage forms or are administered at different dosage intervals.

The present invention relates to a package comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A together with instructions for use in combination with a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative for the treatment or prevention of cardiac and renal related conditions or diseases.

In a preferred embodiment, the package according to the invention comprises in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and rapamycin .

In another preferred embodiment, the package according to the invention comprises in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and a rapamycin derivative selected from the group of : 32- deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)- dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779), 40- epi-(tetrazolyl)-rapamycin (also called ABT578), 40-O-(2-hydroxyethyl) -rapamycin, 32- deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin.

In another embodiment the present invention relates to methods of prevention or treatment of cardiac and renal related conditions or diseases and arthritis or rheumatic arthritis related conditions or diseases by administration of a therapeutically effective amount of any preferred pharmaceutical composition according to the invention comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A plus a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative and a pharmaceutically acceptable carrier to a mammal in need thereof.

A peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue are understood to be those peptides disclosed in US Patent No. 6,664,230 issued December 16, 2003, incorporated herein by reference in its entirety as if set forth in full herein. Particulary preferred is the peptide of SEQ ID NO. 5 of the '230 patent, even more preferred is this peptide wherein all amino acids are in the "D" configuration.

A mTOR inhibitor is a compound which targets intracellular mTOR ("mammalian Target Of Rapamycin"). mTOR is a family member of phosphatidylinositol 3-kinase (PI3-kinase) related kinase. Rapamycin and rapamycin derivatives inhibit the mTOR pathway via a complex with its intracellular receptor FKBP12 (FK506-binding protein 12).

Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus. By rapamycin derivative is meant a substituted rapamycin having mTOR inhibiting properties, e.g. rapamycin substituted in position 40 and/or 16 and/or 32, for example a compound of formula I

wherein

Ri is CH₃ or C_3-6alkynyl,

R₂ is H, -CH₂-CH₂-OH, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propanoyl or tetrazolyl, and

X iS =O, (H₁H) or (H₁OH) provided that R₂ is other than H when X is =0 and Ri is CH₃, or a prodrug thereof when R₂ is -CH₂-CH₂-OH, e.g. a physiologically hydrolysable ether thereof.

Representative rapamycin derivatives of formula I are e.g. 32-deoxorapamycin, 16-pent-2- ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2- ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2- (hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779) or 40-epi-(tetrazolyl)- rapamycin (also called ABT578). A preferred compound is e.g. 40-O-(2-hydroxyethyl) -rapamycin disclosed in Example 8 (referred hereinafter as Compound A) in US Patent No. 5,665,772 issued September 9, 1997, incorporated herein by reference in its entirety as if set forth in full herein, or 32-deoxorapamycin or 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin as disclosed in US Patent No. 5,985,890 issued November 16, 1999, incorporated herein by reference in its entirety as if set forth in full herein.

Rapamycin derivatives may also include the so-called rapalogs, e.g. as disclosed in WO 98/02441 and WO01/14387, e.g. AP23573, AP23464, AP23675 or AP23841.

Further examples of a rapamycin derivative are those disclosed under the name TAFA-93, biolimus-7 or biolimus-9.

It has surprisingly been found that the pharmaceutical combinations or compositions according to the invention can be used for the treatment or prevention of cardiac and renal related conditions or diseases ,i e, selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, restenosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke , and for the treatment or prevention of arthritis or rheumatic arthritis related conditions or diseases ,i e, selected from the group consisting of, arthritis or rheumatic arthritis, e.g. including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism, particularly joints or vertebrae, including also slowing the progression (destruction of the joints) in moderate to severe rheumatoid arthritis, progressive, or erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs and the reduction of the side-effects (signs and symptoms) of arthritis or rheumatic arthritis.

It has surprisingly been found that, a combination of a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and a mTOR inhibiting agent, e.g. rapamycin or a rapamycin derivative achieves greater therapeutic effect ( a potentiation) than the administration of valsartan or the mTOR inhibiting agent alone. The combination surprisingly elicits an increased antihypertensive effect in rodent models of hypertension.

The combination also surprisingly ameliorates symptoms and improves mortality rates in animal models of heart failure.

Greater efficacy can also be documented as a prolonged duration of action. The duration of action can be monitored as either the time to return to baseline prior to the next dose or as the area under the curve (AUC) and is expressed as the product of the change in blood pressure in millimeters of mercury (change in mmHg) and the duration of the effect (minutes, hours or days).

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 to diminish the incidence of side effects.

Preferred are low dose combination of peptide A and an mTOR inhibiting agent. The combined administration of a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A and a mTOR inhibiting agent results in a significant response in a greater percentage of treated patients, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated.

It can be shown that combination therapy with a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A, and a mTOR inhibiting agent results in a more effective antihypertensive therapy through improved efficacy as well as a greater responder rate.

It can further be shown that a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A, and mTOR inhibiting agent therapy proves to be beneficial in the treatment and prevention of myocardial infarction and its sequelae. A combination of the invention is also useful in treating renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy.

Thus in the present description the terms "treatment" or "treat" refer to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.

The Agents of the Invention, i.e. the mTOR inhibiting agent and a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A, are preferably used in the form of pharmaceutical preparations that contain the relevant therapeutically effective amount of each active ingredient (either separately or in combination) optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration. The Agents of the Invention may be present in the same pharmaceutical compositions, though are preferably in separate pharmaceutical compositions. Thus the active ingredients may be administered at the same time (e.g. simultaneously) or at different times (e.g. sequentially) and over different periods of time, which may be separate from one another or overlapping. The unit dose form may also be a fixed combination.

Preferably, the pharmaceutical compositions are adapted for oral or parenteral (especially oral) administration. Intravenous and oral, first and foremost oral, administration is considered to be of particular importance. The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral, rectal, aerosol inhalation or nasal administration, and parenteral such as intravenous or subcutaneous administration, or compositions for transdermal administration (e.g. passive or iontophoretic) to mammals (warm-blooded animals), including man. Such compositions comprise a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions. Typical injectable formulations include solutions and suspensions. Tablets may be either film coated or enteric coated according to methods known in the art. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 85%, preferably about 1 to 70%, of the active ingredient.

The typical pharmaceutically acceptable carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and com oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.

Pharmaceutical preparations for enteral and parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets or capsules and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, where appropriate granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or dragee cores.

Other orally administrable pharmaceutical preparations are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers to be added.

Parenteral formulations are especially injectable fluids that are effective in various manners, such as intravenously, intramuscularly, intraperitoneal^, intranasally, intradermal^ or subcutaneously. Such fluids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations which contain the active ingredient alone or together with a pharmaceutically acceptable carrier. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.

Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Suitable formulations for topical application, e.g. to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like.

For example, the pharmaceutical preparations consist of from about 0.1-90%, preferably of from about 1 % to about 80 %, of the active compounds. Pharmaceutical preparations for enteral or parenteral 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 which 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 active compounds 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 therapeutically effective dosages, especially those which are commercially available.

Effective dosages of a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, especially peptide A are set forth in US Patent 6,664,230 and incorporated herein by reference.

Daily dosages for the mTOR inhibitor will, of course, vary depending on a variety of factors, for example the compound chosen, the particular condition to be treated and the desired effect. In general, however, satisfactory results are achieved on administration of the mTOR inhibitor at daily dosage rates of the order of ca. 0.01 to 5 mg/kg per day, particularly 0.5 to 5 mg/kg per day, as a single dose or in divided doses. A preferred daily dosage range is about from 0.1 to 30 mg as a single dose or in divided doses. The mTOR inhibitor, e.g. Compound A, may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions or parenterally, e.g. in the form of injectable solutions or suspensions. Suitable unit dosage forms for oral administration comprise from ca. 0.05 to 15 mg active ingredient, usually 0.25 to 10 mg, e.g. Compound A, together with one or more pharmaceutically acceptable diluents or carriers therefore.

Rapamycin or derivatives thereof are well tolerated at dosages required for use in accordance with the present invention. For example, the NTEL for Compound A in a 4-week toxicity study is 0.5 mg/kg/day in rats and 1.5 mg/kg/day in monkeys.

The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the efficacy of a combination of the present invention in the hereinbefore and hereinafter indicated therapeutic indications. For example, the following animal model may be employed.

ApoE null female mice three months old on a chow diet are given drinking water alone (Water), or drinking water containing 1 μg/ml of D-4F, or 0.05 mg/ml of Compound A, or 1 μg/ml of D-4F together with 0.05 mg/ml of Compound A. After 24 hours the mice are bled and their HDL is tested in a human artery wall coculture model. Twenty μg of 1-palmitoyl-2- arachidonyl-sn-glycero-3-phosphorylc- holine (PAPC) is added together with 1 μg/ml of hydroperoxyeicosatetraenoic acid (HPODE) to cocultures of human artery wall cells as described in (Navab et al. (2001) J Lipid Res. 42: 1308-1317). Human HDL (h, HDL) is added at 350 μg/ml cholesterol or no addition is made to the cocultures (No Addition), or mouse HDL isolated by FPLC from the mice given drinking water alone (Water) or the additions shown on the X-axis are added to the cocultures at 50 μg/ml HDL-cholesterol. After 8 hours of incubation, supernatants are collected and assayed for monocyte chemotactic activity using standard neuroprobe chambers.

The results will show that when D-4F 1 μg/ml is added to the drinking water together with 0.05 mg/ml of Compound A there is a significant improvement in HDL function. The available results indicate an unexpected therapeutic effect of a combination according to the invention.

All publications and patents mentioned herein are incorporate by reference in their entirety as if set forth in full herein.

Claims

What is claimed is:

1. A pharmaceutical composition comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue, and a mTOR inhibiting agent.

2. The pharmaceutical composition according to claim 1 which comprises in combination a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue and a mTOR inhibiting agent and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

3. The pharmaceutical composition of claim 2 wherein the mTOR inhibiting agent is selected from the group consisting of rapamycin or a rapamycin derivative selected from the group of 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy- 32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)- rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779), 40-epi-(tetrazolyl)-rapamycin (also called ABT578) , 40-O-(2-hydroxyethyl) - rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin.

4. The pharmaceutical composition of claim 2 wherein the peptide comprises an amino acid sequence comprising D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F wherein all the amino acid are in the D configuration.

5. The pharmaceutical composition of claim 2 wherein the mTOR inhibiting agent is 40-O-(2-hydroxyethyl) -rapamycin.

6. A pharmaceutical composition comprising a peptide comprising an amino acid sequence comprising D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F wherein all the amino acid are in the D configuration and 40-O-(2-hydroxyethyl)-rapamycin.

7. A method for the treatment or prevention of cardiac and renal related conditions and for the treatment or prevention of arthritis or rheumatic arthritis related conditions which comprises administering a therapeutically effective amount of a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue and a mTOR inhibiting agent and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

8. The method of claim 7 wherein the cardiac and renal related conditions or diseases are selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, restenosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke , and for the treatment or prevention of arthritis or rheumatic arthritis related conditions or diseases ,i e, selected from the group consisting of, arthritis or rheumatic arthritis, e.g. including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism, particularly joints or vertebrae, including also slowing the progression (destruction of the joints) in moderate to severe rheumatoid arthritis, progressive, or erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs and the reduction of the side-effects (signs and symptoms) of arthritis or rheumatic arthritis.

9. A kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a mTOR inhibiting agent and in a second container a pharmaceutical composition comprising a peptide which ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix and comprises at least one "D" amino acid residue.

10. The kit according to claim 9 wherein the^' peptide comprises an amino acid sequence comprising D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F wherein all the amino acid are in the D configuration and the mTOR inhibiting agent is 40-O-(2-hydroxyethyl)-rapamycin.

11. Use of the pharmaceutical composition according to claim 1 for the manufacture of a medicament for treating cardiac and renal related conditions or diseases are selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, restenosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke , and for the treatment or prevention of arthritis or rheumatic arthritis related conditions or diseases ,i e, selected from the group consisting of, arthritis or rheumatic arthritis, e.g. including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism, particularly joints or vertebrae, including also slowing the progression (destruction of the joints) in moderate to severe rheumatoid arthritis, progressive, or erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs and the reduction of the side-effects (signs and symptoms) of arthritis or rheumatic arthritis.