[go: up one dir, main page]

WO2006053754A1 - COMBINAISONS DE PEPTIDES ANTI-ATHEROSCLEREUX ET D’UN AGENT INHIBANT LA mTOR ET PROCEDES POUR LES UTILISER - Google Patents

COMBINAISONS DE PEPTIDES ANTI-ATHEROSCLEREUX ET D’UN AGENT INHIBANT LA mTOR ET PROCEDES POUR LES UTILISER Download PDF

Info

Publication number
WO2006053754A1
WO2006053754A1 PCT/EP2005/012333 EP2005012333W WO2006053754A1 WO 2006053754 A1 WO2006053754 A1 WO 2006053754A1 EP 2005012333 W EP2005012333 W EP 2005012333W WO 2006053754 A1 WO2006053754 A1 WO 2006053754A1
Authority
WO
WIPO (PCT)
Prior art keywords
rapamycin
arthritis
peptide
amino acid
renal
Prior art date
Application number
PCT/EP2005/012333
Other languages
English (en)
Inventor
Anthony Rosenberg
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2006053754A1 publication Critical patent/WO2006053754A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • a mTOR inhibiting agent e.g. rapamycin or a rapamycin derivative
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • a mTOR inhibiting agent e.g. rapamycin or a rapamycin derivative
  • 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.
  • a mTOR inhibiting agent e.g. rapamycin or a rapamycin derivative.
  • 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 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.
  • a mTOR inhibiting agent e.g. rapamycin or a rapamycin derivative for the treatment or prevention of cardiac and renal related conditions or diseases.
  • 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 .
  • 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, 16
  • 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 mTOR inhibiting agent e.g. rapamycin or a rapamycin derivative
  • a pharmaceutically acceptable carrier e.g. rapamycin or a rapamycin derivative
  • 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.
  • 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
  • Ri is CH 3 or C 3- 6alkynyl
  • R 2 is H, -CH 2 -CH 2 -OH, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propanoyl or tetrazolyl, and
  • 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.
  • Example 8 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 derivative examples are those disclosed under the name TAFA-93, biolimus-7 or biolimus-9.
  • 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,
  • 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.
  • 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).
  • 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.
  • treatment refers 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.
  • 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.
  • diluents e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g. silica, talcum, stearic acid, its magnesium or calcium
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • 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.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • 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
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • ApoE null female mice three months old on a chow diet are given drinking water alone (Water), or drinking water containing 1 ⁇ g/ml of D-4F, or 0.05 mg/ml of Compound A, or 1 ⁇ g/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.
  • PAPC 1-palmitoyl-2- arachidonyl-sn-glycero-3-phosphorylc- holine
  • HPODE hydroperoxyeicosatetraenoic acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L’invention concerne des compositions pharmaceutiques comprenant un peptide long d’environ 10 à environ 30 acides aminés, ledit peptide comprenant au moins une hélice amphipathique de classe A et au moins un résidu d’acide aminé « D », et un agent inhibant la mTOR, par exemple la rapamycine ou l’un de ses dérivés, éventuellement en présence d’un excipient de qualité pharmaceutique.
PCT/EP2005/012333 2004-11-19 2005-11-17 COMBINAISONS DE PEPTIDES ANTI-ATHEROSCLEREUX ET D’UN AGENT INHIBANT LA mTOR ET PROCEDES POUR LES UTILISER WO2006053754A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62975604P 2004-11-19 2004-11-19
US60/629,756 2004-11-19

Publications (1)

Publication Number Publication Date
WO2006053754A1 true WO2006053754A1 (fr) 2006-05-26

Family

ID=35965948

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/012333 WO2006053754A1 (fr) 2004-11-19 2005-11-17 COMBINAISONS DE PEPTIDES ANTI-ATHEROSCLEREUX ET D’UN AGENT INHIBANT LA mTOR ET PROCEDES POUR LES UTILISER

Country Status (1)

Country Link
WO (1) WO2006053754A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137148A2 (fr) * 2007-05-03 2008-11-13 Abraxis Bioscience, Llc Procédés et compositions permettant le traitement de l'hypertension pulmonaire
US8911786B2 (en) 2007-03-07 2014-12-16 Abraxis Bioscience, Llc Nanoparticle comprising rapamycin and albumin as anticancer agent
US8927019B2 (en) 2007-06-01 2015-01-06 Abraxis Bioscience, Llc Methods and compositions for treating recurrent cancer

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665772A (en) * 1992-10-09 1997-09-09 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US5985890A (en) * 1995-06-09 1999-11-16 Novartis Ag Rapamycin derivatives
US20030045460A1 (en) * 2000-08-24 2003-03-06 Fogelman Alan M. Orally administered peptides to ameliorate atherosclerosis
WO2003034067A1 (fr) * 2001-10-12 2003-04-24 Novartis Forschungsstiftung, Zweigniederlassung Friedrich Miescher Institute For Biomedical Research Dosage et utilisation medicale de composes modulant l'activite de tor
WO2003057218A1 (fr) * 2002-01-10 2003-07-17 Novartis Ag Systemes de liberation de medicament pour la prevention et le traitement de maladies vasculaires, comprenant de la rapamycine et des derives de celle-ci
US20030171277A1 (en) * 2000-08-24 2003-09-11 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US20030229015A1 (en) * 2000-08-24 2003-12-11 The Regents Of The University Of California Orally administered peptides synergize statin activity
WO2005053661A2 (fr) * 2003-12-01 2005-06-16 Novartis Ag Compositions pharmaceutiques

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665772A (en) * 1992-10-09 1997-09-09 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US5985890A (en) * 1995-06-09 1999-11-16 Novartis Ag Rapamycin derivatives
US20030045460A1 (en) * 2000-08-24 2003-03-06 Fogelman Alan M. Orally administered peptides to ameliorate atherosclerosis
US20030171277A1 (en) * 2000-08-24 2003-09-11 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US20030229015A1 (en) * 2000-08-24 2003-12-11 The Regents Of The University Of California Orally administered peptides synergize statin activity
WO2003034067A1 (fr) * 2001-10-12 2003-04-24 Novartis Forschungsstiftung, Zweigniederlassung Friedrich Miescher Institute For Biomedical Research Dosage et utilisation medicale de composes modulant l'activite de tor
WO2003057218A1 (fr) * 2002-01-10 2003-07-17 Novartis Ag Systemes de liberation de medicament pour la prevention et le traitement de maladies vasculaires, comprenant de la rapamycine et des derives de celle-ci
WO2005053661A2 (fr) * 2003-12-01 2005-06-16 Novartis Ag Compositions pharmaceutiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8911786B2 (en) 2007-03-07 2014-12-16 Abraxis Bioscience, Llc Nanoparticle comprising rapamycin and albumin as anticancer agent
WO2008137148A2 (fr) * 2007-05-03 2008-11-13 Abraxis Bioscience, Llc Procédés et compositions permettant le traitement de l'hypertension pulmonaire
WO2008137148A3 (fr) * 2007-05-03 2009-02-19 Abraxis Bioscience Llc Procédés et compositions permettant le traitement de l'hypertension pulmonaire
EP3326630A3 (fr) * 2007-05-03 2018-08-29 Abraxis BioScience, LLC Procédés et compositions permettant de traiter l'hypertension pulmonaire
US8927019B2 (en) 2007-06-01 2015-01-06 Abraxis Bioscience, Llc Methods and compositions for treating recurrent cancer

Similar Documents

Publication Publication Date Title
US20210077461A1 (en) New use
EP3294283B1 (fr) Schéma posologique du sacubitril-valsartan pour le traitement de l'insuffisance cardiaque
EP3528820B1 (fr) Nouvelles formulations liposomales pegylées d'apeline pour le traitement de maladies liées au système cardiovasculaire
HUE029661T2 (en) A therapeutic combination and use of DLL4 antagonist antibodies and antihypertensive agents
US9839634B2 (en) Antibacterial agents: combination of a rifamycin and a switch region inhibitor
US20080194614A1 (en) Combination of Organic Compounds
WO2017006254A1 (fr) Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes
WO2006053754A1 (fr) COMBINAISONS DE PEPTIDES ANTI-ATHEROSCLEREUX ET D’UN AGENT INHIBANT LA mTOR ET PROCEDES POUR LES UTILISER
WO2006041763A1 (fr) Inhibiteurs de renine pour le traitement de maladies induites par transplantation
MXPA06011823A (es) Terapia de combinacion, que comprende un antagonista del receptor de la adenosina a1 y un inhibidor de la aldosterona.
AU2001225625A1 (en) Use of melagatran for manufacture of a medicament for the treatment of ischemic disorders
WO2002036157A1 (fr) Utilisation de melagatran pour la production d'un medicament destine au traitement de troubles ischemiques
US20080280939A1 (en) Combination of Organic Compounds
US20120172389A1 (en) Treatment of fibrosing disorders
WO2006051648A1 (fr) Médicament contenant un antagoniste du récepteur de la thrombine au titre de principe actif et destiné au traitement d'angiospasmes causés par une hémorragie sous-arachnoïdienne
ZA200409200B (en) Combination of angiotensin II receptor blocker and betablocker for secondary prevention of myocardial infarction
US20160166577A1 (en) Treatment of pulmonary fibrosis using an inhibitor of cbp/catenin
CA2937504A1 (fr) Combinaisons pharmaceutiques comprenant un inhibiteur de pi3k permettant le traitement du cancer
AU2012201911A1 (en) Rapamycin and its derivatives for the treatment of liver-associated fibrosing disorders

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05810875

Country of ref document: EP

Kind code of ref document: A1