Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
  • C07K14/68—Melanocyte-stimulating hormone [MSH]
  • C07K14/685—Alpha-melanotropin

Definitions

• the present invention relates to an aqueous pharmaceutical composition
• an aqueous pharmaceutical composition comprising one or more water-soluble or water-dispersible gelling agents and a peptide as the active substance, in particular a peptide as melanocortin receptor ligand.
• Melanocortins are a family of regulatory peptides which are formed by post-translational processing of pro-hormone pro-opiomelanocortin. Melanocortins have been found in a wide variety of normal human tissues including the brain, adrenal, skin, testis, spleen, kidney, ovary, lung, thyroid, liver, colon, small intestine and pancreas.
• M-R melanocortin receptors
• MC1 -R melanocyte-specific receptor
• M2-R corticoadrenal-specific ACTH receptor
• M3-R melacortin-3
• MC4-R melanocortin-4
• M5-R melanocortin-5 receptor
• melanocortin (MC-R) receptors have been great interest in melanocortin (MC-R) receptors as targets for the design of novel therapeutics to treat disorders of body weight such as obesity and cachexia. Both genetic and pharmacological evidence points toward central MC4-R receptors as the principal target.
• this composition makes it possible to obtain satisfactory physical properties, in particular in terms of solubility and filterability.
• the Applicant has also found that the composition according to the invention ensures a peptide chemical stability.
• the treatment using such a composition permits to modify the in vitro peptide release.
• composition according to the present invention allows a sustained-release of the active ingredient over at least 2 hours.
• One subject of the present invention is thus an aqueous pharmaceutical composition
• a peptide as the active substance and one or more water-soluble or water- dispersible gelling agents.
• peptide is understood to mean a peptide containing up to 50 amino acids and/or with a molecular weight up to about 6,000 Da (6,000 ⁇ 200 Da) .
• water-soluble gelling agent is understood to mean that the gelling agent used in the composition according to the present invention is soluble in water.
• the gelling agent has solubility in water measured at 25° C higher than 10 mg/mL, and preferably higher than 30 mg/mL.
• water-dispersible gelling agent is understood to mean that the gelling agent used in the composition according to the present invention is miscible or can be dispersed in water at a concentration measured at 25° C higher than 10 mg/mL, and preferably higher than 30 mg/m L.
• gelling agent defines a compound that can be solubilized, dispersed or mixed with the pharmaceutical composition to modify its rheological behaviour, more particularly its viscosity, and can lead to a higher viscosity composition or the formation of a hydrogel.
• gelling agent means a gelling agent or a mixture of gelling agents.
• the active ingredient of the pharmaceutical composition of the present invention is a peptide.
• the peptide is selected from a ligand of one or more of the melanocortin receptors (MC-R).
• the melanocortin receptor may be selected from melanocyte-specific receptor (MC1 -R), corticoadrenal-specific ACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-5 receptor (MC5-R).
• the active ingredient of the drug of the composition of the present invention may be selected from those described in the PCT applications WO 2007/008704 or WO 2008/147556.
• the peptide is a ligand of melanocortin MC4 receptor.
• the peptide is a compound of formula (I) :
• a 1 is Acc, HN-(CH 2 ) m -C(0), L- or D-amino acid or deleted;
• a 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;
• a 3 is Gly, Ala, ⁇ -Ala, Gaba, Aib, D-amino acid or deleted;
• a 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
• a 5 is D-Phe, D-1 -Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe or D-(Et)Tyr;
• a 6 is Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH 2 ) n -N(R 4 R 5 ))-C(0) ;
• a 7 is Trp, 1 -Nal, 2-Nal, Bal, Bip, D-Trp, D-1 -Nal, D-2-Nal, D-Bal or D-Bip;
• a 8 is Gly, D-Ala, Acc, Ala, ⁇ -Ala, Gaba, Apn, Ahx, Aha, HN-(CH 2 ) s -C(0) or deleted ;
• a 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;
• a 10 is Acc, HN-(CH 2 ) t -C(0), L- or D-amino acid or deleted;
• R 1 is -OH or -NH 2 ;
• R 2 and R 3 is, independently for each occurrence, H, (d-C 3 o)alkyl, (d-do)heteroalkyl, (d-do)acyl, (C 2 -C 3 o)alkenyl, (C 2 -C 3 o)alkynyl, aryl(d-do)alkyl, aryl(d-do)acyl, substituted (d-do)alkyl, substituted (d-do)heteroalkyl, substituted (d-do)acyl, substituted (d-do)alkenyl, substituted (d-do)alkynyl, substituted aryl(d-do)alkyl or substituted aryl(d-do)acyl;
• R 4 and R 5 is, independently for each occurrence, H, (d-do)alkyl, (d-do)heteroalkyl, (d-do)acyl, (C 2 -do)alkenyl, (d-do)alkynyl, aryl(d-do)alkyl, aryl(d-do)acyl, substituted (d-do)alkyl, substituted (d-C 4 o)heteroalkyl, substituted (d-do)acyl, substituted (d-do)alkenyl, substituted (C 2 -do)alkynyl, substituted aryl(d-do)alkyl, substituted aryl(d-do)acyl, (d-do)alkylsulfonyl or -C(NH)-NH 2 ; m is, independently for each occurrence, 1 , 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1
• X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, CI, Br, I, (d-do)alkyl, substituted (d-do)alkyl, (C 2 -d 0 )alkenyl, substituted (C 2 -d 0 )alkenyl, (C 2 -do)alkynyl, substituted (C 2 -C 10 )alkynyl, aryl, substituted aryl, OH, NH 2 , N0 2 , or CN; provided that:
• R 4 when R 4 is (d-do)acyl, aryl(d-do)acyl, substituted (d-do)acyl, substituted aryl(d-do)acyl, (d-do)alkylsulfonyl or -C(NH)-NH 2 , then R 5 is H, (d-do)alkyl, (d-do)heteroalkyl, (C 2 -do)alkenyl, (C 2 -do)alkynyl, aryl(d-do)alkyl, substituted (d-do)alkyl, substituted (d-C 4 o)heteroalkyl, substituted (C 2 -do)alkenyl, substituted (d-do)alkynyl or substituted aryl(d-do)alkyl;
• R 2 when R 2 is (d-do)acyl, aryl(d-do)acyl, substituted (d-C 3 o)acyl or substituted aryl(d-do)acyl, then R 3 is H, (d-do)alkyl, (d-do)heteroalkyl, (d-do)alkenyl, (d-do)alkynyl, aryl(d-do)alkyl, substituted (d-do)alkyl, substituted (d-do)heteroalkyl, substituted (d-do)alkenyl, substituted (C 2 - C 30 )alkynyl or substituted aryl(d-do)alkyl;
• the peptide is a compound of formula (I) wherein A 1 is Arg, D-Arg, hArg or D-hArg; or a pharmaceutically acceptable salt thereof.
• the active substance of the drug composition of the present invention is the peptide of formula:
• the peptide is a compound of formula (I I) :
• X is selected from the group consisting of -CH 2 -S-S-CH 2 -, -C(CH 3 ) 2 -S-S-CH 2 -, -CH 2 - S-S-C(CH 3 ) 2 -, -C(CH 3 ) 2 -S-S-C(CH 3 ) 2 -, -(CH 2 ) 2 -S-S-CH 2 -, -CH 2 -S-S-(CH 2 ) 2 -, -(CH 2 ) 2 -S-S-(CH 2 ) 2 -, -C(CH 3 ) 2 -S-S-(CH 2 ) 2 -, -(CH 2 ) 2 -S-S-C(CH 3 ) 2 , -(CH 2 ) t -C(0)-NR 8 -(CH 2 ) r - and -(CH 2 ) r NR 8 -C(0)-(CH 2 ) r ;
• R 1 and R 2 each is, independently for each occurrence thereof, H, (d -do)alkyl or substituted (d -do)alkyl;
• R 3 is -OH or -NH 2 ;
• R 4 and R 5 each is, independently for each occurrence thereof, H, (d -do)alkyl or substituted (d -do)alkyl;
• a 1 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or deleted;
• a 2 is D-Bal, D-1 -Nal, D-2-Nal, D-Phe or D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe;
• a 3 is Arg, hArg, Dab, Dap, Lys or Orn;
• a 4 is Bal, 1 -Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp;
• R 6 and R 7 each is, independently for each occurrence thereof, H, (d -do)alkyl, (d -do)heteroalkyl, aryl(d -d)alkyl, substituted (d -do)alkyl, substituted (d -do)heteroalkyl or substituted aryl(d -d)alkyl or R 6 and R 7 may be joined together form a cyclic moiety;
• R 8 is H, (d -d o)alkyl or substituted (d-C 10 )alkyl; r is, independently for each occurrence thereof, 1 , 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or a pharmaceutically acceptable salt thereof.
• the active substance of the drug composition of the present invention is the peptide of formula:
• Abu a-aminobutyric acid; Ac: acyl group; Acc: 1 -amino-1 -cyclo(C 3 -C 9 )alkyl carboxylic acid; A3c: 1 -amino-1 -cyclopropanecarboxylic acid; A4c: 1 -amino-1 -cyclobutanecarboxylic acid; A5c: 1 -amino-1 -cyclopentanecarboxylic acid; A6c: 1 -amino-1 -cyclohexanecarboxylic acid ; Aha: 7-aminoheptanoic acid; Ahx: 6-aminohexanoic acid; Aib: a-aminoisobutyric acid ; Ala or A: alanine; ⁇ -Ala: ⁇ -alanine; Apn: 5-aminopentanoic acid (HN-(CH2) 4 -C(0) ; Arg or R: arginine;
• Bpa 4-benzoylphenylalanine; 4-Br-Phe: 4-bromo-phenylalanine; Cha: ⁇ -cyclohexylalanine; hCha: homo-cyclohexylalanine; Chg: cyclohexylglycine; Cys or C: cysteine; hCys: homocysteine; Dab: 2,4-diaminobutyric acid; Dap: 2,3-diaminopropionic acid; Dip: ⁇ , ⁇ -diphenylalanine; Doc: 8-amino-3,6-dioxaoctanoic acid with the structure of: 2-Fua: p-(2-furyl)-alanine; Gaba: 4-aminobutyric acid; Gin or Q: glutamine; Glu or E: glutamic acid; Gly or G : glycine; His or H : histidine; 3-Hyp: trans-3-hydroxy-L-proline,
• Ser or S serine; Tie: tert-Leucine; Taz: -(4-thiazolyl)alanine; 2-Thi: -(2-thienyl)alanine; 3-Thi: -(3-thienyl)alanine; Thr or T: threonine; Trp or W: tryptophan; Tyr or Y: tyrosine; D-(Et)Tyr has a structure of:
• Val or V valine.
• alkyl refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that the group may contain.
• the group R d may be selected from the same groups as R a , R b and R c but is not hydrogen. Alternatively, the groups R a and R b may together form a heterocycio or heteroaryl ring.
• alkyl when a substituted alkyl group is substituted with an aryl, cycloalkyl, heteroaryl, or heterocycio, such rings are as defined below and thus may have one to three substituents as set forth below in the definitions for these terms.
• alkyl when used as a suffix following another specifically named group, e.g., arylalkyl or heteroarylalkyl, the term defines, with more specificity, at least one of the substituents that the substituted alkyl will contain.
• arylalkyl refers to an aryl bonded through an alkyl, or in other words, a substituted alkyl group having from 1 to 12 carbon atoms and at least one substituent that is aryl (e.g., benzyl or biphenyl).
• “Lower arylalkyl” refers to substituted alkyl groups having 1 to 4 carbon atoms and at least one aryl substituent.
• alkenyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one double bond. Alkenyl groups of 2 to 6 carbon atoms and having one double bond are most preferred.
• alkynyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bond are most preferred. A substituted alkenyl or alkynyl will contain one, two, or three substituents as defined above for alkyl groups.
• alkylene refers to bivalent straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, e.g., ⁇ -CH 2 - ⁇ n , wherein n is 1 to 12, preferably 1 to 8. Lower alkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, are most preferred.
• alkenylene and alkynylene refer to bivalent radicals of alkenyl and alkynyl groups, respectively, as defined above. Substituted alkylene, alkenylene, and alkynylene groups may have substituents as defined above for substituted alkyl groups.
• alkoxy refers to the group OR e wherein R e is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, or cycloalkyl.
• R e is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, or cycloalkyl.
• an alkoxy includes such groups as methoxy, ethoxy, cyclopropyloxy, pyrrolidinyloxy, and so forth.
• aryloxy refers to the groups O(aryl) or O(heteroaryl), wherein aryl and heteroaryl are as defined below.
• alkylthio refers to an alkyl or substituted alkyl group as defined above bonded through one or more sulfur (-S-) atoms, e.g., -S (alkyl) or -S (alkyl-R a ).
• alkylamino refers to an alkyl or substituted alkyl group as defined above bonded through one or more nitrogen (-NR r ) groups, wherein R f is hydrogen, alkyl, substituted alkyl, or cycloalkyl.
• halo or “halogen” refers to chloro, bromo, fluoro and iodo. Unless otherwise indicated, any haloalkyl, haloalkoxy or haloalkylthio group contains one or more halo atoms which halo atoms may be the same or different.
• Carboxy when used alone refers to the group C0 2 H.
• Carboxyalkyl refers to the group C0 2 R, wherein R is alkyl or substituted alkyl.
• sulphonyl refers to a sulphoxide group (i.e., -S(0)i -2 -) linked to an organic radical including an alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynyl group, as defined above.
• the organic radical to which the sulphoxide group is attached may be monovalent (e.g., -S0 2 -alkyl), or bivalent (e.g., -S0 2 -alkylene, etc.).
• cycloalkyi refers to substituted and unsubstituted monocyclic or bicyclic hydrocarbon groups of 3 to 9 carbon atoms which are, respectively, fully saturated or partially unsaturated, including a fused aryl ring, for example, an indan.
• cycloalkylene refers to a cycloalkyi forming a link or spacer between two other groups, i.e., a cycloalkylene is a cycloalkyi that is bonded to at least two other groups.
• cycloalkyi includes saturated or partially unsaturated carbocyclic rings having a carbon-carbon bridge of three to four carbon atoms or having a benzene ring joined thereto.
• said further ring may have one to two substituents selected from R k , wherein R k is lower alkyl, hydroxy, lower alkoxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, and lower alkyl substituted with one to two hydroxy, lower alkoxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, and/or nitro.
• aryl refers to substituted and unsubstituted phenyl, 1 -naphthyl and 2-naphthyl, with phenyl being preferred.
• arylene refers to an aryl as defined above forming a link or spacer between two other groups, i.e., an arylene is an aryl that is bonded to at least two other groups.
• said further ring may have one to two substituents selected from R k , wherein R k is defined as above.
• heterocyclicio refers to substituted and unsubstituted non- aromatic 3- to 7-membered monocyclic groups, 7- to 1 1 -membered bicyclic groups, and 10- to 1 5-membered tricyclic groups which have at least one heteroatom (0, S or N) in at least one of the rings.
• Each ring of the heterocycio group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom .
• the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated , or unsaturated.
• the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quatemized.
• the heterocycio group may be attached at any available nitrogen or carbon atom .
• heterocycio group When the heterocycio group is substituted with a further ring, said further ring may have one to two substituents selected from R k , wherein R k is defined as above.
• exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl s
• heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 1 0-membered bicyclic groups, and 1 1 - to 14-membered tricyclic groups which have at least one heteroatom (0, S or N) in at least one of the rings.
• Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
• the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
• the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
• Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
• the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
• Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
• Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
• Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• the peptide of the drug composition of the present invention may be in the form of a salt or as a free base.
• the peptide is in a salt form.
• the pharmaceutically acceptable salt of the peptide is acetate or heptanoate.
• the pharmaceutically acceptable salt of the peptide is acetate.
• the active substance of the composition of the present invention is the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 in a salt form , preferably in an acetate or heptanoate salt.
• the peptide Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 is in an acetate salt.
• the peptide or the salt thereof is present in a concentration ranging from 0.1 to 25 % by weight relative to the total weight of the composition. More preferably, the peptide or the salt thereof is present in a concentration ranging from 0.1 to 10 % by weight, even more preferentially from 0.2 to 6 % by weight and even more preferentially still from 0.3 to 2 % by weight relative to the total weight of the composition.
• the pharmaceutical composition comprises a water-soluble or water-dispersible gelling agent.
• gelling agent means an agent which, when introduced at a concentration between 0.5 and 40 % by weight in an aqueous solution makes it possible to achieve a dynamic viscosity of at least 1 00 cPs and preferably of at least 500 cPs, at 25° C and at a shear rate between 1 and 1 0 s "1 .
• This viscosity may be measured using a viscometer, for example a controlled-stress viscometer in cone-plate geometry, for instance a Haake RS1 viscometer from Thermo Electron.
• gelling agents for example, of polyols such as glycerol and propylene glycol, polyethers such as polyethylene glycols, cellulose derivatives such as microcrystalline cellulose, sodium caboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, mono- or polysaccharides such as sodium hyalunorate, chitosan, starch and starch derivatives, polyvinylpyrrolidone, gelatin, zinc acetate, and mixtures thereof.
• polyols such as glycerol and propylene glycol
• polyethers such as polyethylene glycols
• cellulose derivatives such as microcrystalline cellulose, sodium caboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose
• mono- or polysaccharides such as sodium
• the gelling agent contains one or more polyethers, one or more polyols and a mixture thereof.
• the gelling agent is chosen from polyethers, polyols and mixtures thereof.
• the gelling agent is chosen from polyethers and polyols.
• the gelling agent is present in a concentration ranging from 0.5 to 70 % by weight relative to the total weight of the composition . More preferably, the gelling agent is present in a concentration ranging from 10 to 50 % by weight, even more preferentially from 15 to 40 % by weight and even more preferentially still from 20 to 40 % by weight relative to the total weight of the composition.
• the present invention relates to an aqueous pharmaceutical composition
• an aqueous pharmaceutical composition comprising:
• the peptide being selected from a ligand of one or more of melanocortin receptors (MC-R) or a pharmaceutically acceptable salt thereof, and
• the gelling agent being present in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition.
• the present invention relates to an aqueous pharmaceutical composition comprising:
• the peptide being selected from a ligand of one or more of melanocortin receptors (MC4-R) or a pharmaceutically acceptable salt thereof, and
• the gelling agent being present in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition.
• the aqueous composition according to the present invention comprises, as active ingredient, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, and a gelling agent in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition.
• the aqueous composition according to the present invention comprises, as active ingredient, an acetate or a heptanoate salt of Ac-Arg-c(Cys- D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, and a gelling agent in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition.
• the active ingredient is the acetate salt of Ac-Arg-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Cys)-NH 2 ,
• the gelling agent is a polyether or a mixture of polyethers.
• the gelling agent is a polyether present in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition. More preferably, the gelling agent is a polyether and present in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition. Even more preferentially, the gelling agent is a polyether and present in a concentration ranging from 20 to 35 % by weight relative to the total weight of the composition.
• the gelling agent is a polyether chosen from polyethylene glycols. In another preferred embodiment, the gelling agent is the polyether PEG 400.
• the gelling agent is the polyether PEG 400 and is present in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition. More preferably, the gelling agent is the polyether PEG 400 and is present in a concentration ranging from 20 to 35 % by weight relative to the total weight of the composition.
• the aqueous composition according to the present invention comprises, as active ingredient, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, and a polyethylene glycol as gelling agent in a concentration ranging from 15 to 40 % by weight, and more preferably from 20 to 35 % by weight relative to the total weight of the composition.
• the aqueous composition according to the present invention comprises, as active ingredient, an acetate or a heptanoate salt of Ac-Arg-c(Cys- D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 in a concentration of 0.1 to 10 % by weight relative to the total weight of the composition, and a polyethylene glycol as gelling agent in a concentration ranging from 15 to 40 % by weight, and more preferably from 20 to 35 % by weight relative to the total weight of the composition.
• the active ingredient is the acetate salt of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ,
• the gelling agent is a polyol or a mixture of polyols.
• the gelling agent is a polyol present in a concentration ranging from 10 to 50 % by weight relative to the total weight of the composition. More preferably, the gelling agent is a polyol present in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition. Even more preferentially, the gelling agent is a polyol and present in a concentration ranging from 25 to 40 % by weight relative to the total weight of the composition.
• the gelling agent is glycerol as polyol.
• the gelling agent is glycerol as polyol and is present in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition. More preferably, the gelling agent is glycerol as polyol and is present in a concentration ranging from 25 to 40 % by weight relative to the total weight of the composition.
• the aqueous composition according to the present invention comprises, as active ingredient, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, and glycerol as gelling agent in a concentration ranging from 15 to 40 % by weight, and more preferably from 25 to 40 % by weight relative to the total weight of the composition.
• the composition according to the present invention comprises, as active ingredient, an acetate or a heptanoate salt of Ac-Arg-c(Cys-D-Ala- His-D-Phe-Arg-Trp-Cys)-N H 2 in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, and glycerol as gelling agent in a concentration ranging from 15 to 40 % by weight, and more preferably from 25 to 40 % by weight relative to the total weight of the composition.
• the active ingredient is the acetate salt of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ,
• composition according to the invention may also comprise one or more additives such as surfactants.
• additives include fatty acids and salts thereof, polyols, polyoxyethers, poloxamers, polysorbates and polyoxyethylene fatty acid esters.
• the composition according to the invention comprises only the peptide as active substance and the water-soluble or water-dispersible gelling agent.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof and one or more polyols as gelling agent.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof and glycerol as gelling agent.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition and glycerol as gelling agent in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition.
• water water of injectable grade
• the aqueous composition according to the present invention comprises, as active ingredient, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, glycerol as gelling agent in a concentration ranging from 25 to 40 % by weight relative to the total weight of the composition, and water (WFI q.s. 100 %).
• the aqueous composition according to the present invention comprises, as active ingredient, an acetate or a heptanoate salt of Ac-Arg-c(Cys- D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, glycerol as gelling agent in a concentration ranging from 25 to 40 % by weight relative to the total weight of the composition , and water (WFI q.s. 100 %).
• the active ingredient is the acetate salt of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 .
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.3 to 2 % by weight relative to the total weight of the composition and glycerol as gelling agent in a concentration ranging from 25 to 40 % by weight relative to the total weight of the composition.
• water water of injectable grade
• composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-N H 2 or a pharmaceutically acceptable salt thereof and one or more polyethers as gelling agent.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof and one or more polyethylene glycols as gelling agent.
• the composition according to the present invention comprises, as active ingredient, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, a polyethylene glycol as gelling agent in a concentration ranging from 15 to 40 % by weight, and more preferably from 20 to 35 % by weight relative to the total weight of the composition, and water (WFI q.s. 100 %).
• the composition according to the present invention comprises, as active ingredient, an acetate or a heptanoate salt of Ac-Arg-c(Cys-D-Ala- His-D-Phe-Arg-Trp-Cys)-N H 2 in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition, a polyethylene glycol as gelling agent in a concentration ranging from 20 to 35 % by weight relative to the total weight of the composition, and water (WFI q.s. 100 %).
• the active ingredient is the acetate salt of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 .
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof and PEG 400 as gelling agent.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.1 to 10 % by weight relative to the total weight of the composition and PEG 400 as gelling agent in a concentration ranging from 15 to 40 % by weight relative to the total weight of the composition.
• the composition according to the invention comprises only the peptide of formula Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 or a pharmaceutically acceptable salt thereof in a concentration ranging from 0.3 to 2 % by weight relative to the total weight of the composition and PEG 400 as gelling agent in a concentration ranging from 20 to 35 % by weight relative to the total weight of the composition.
• water water of injectable grade
• composition of the present invention may be prepared by mixing the peptide, the water-soluble or water-dispersible gelling agent(s) and the optional additives (if any) in water.
• composition according to the invention is administered by parenteral route.
• composition of the present invention is administered by subcutaneous route, and preferably by a subcutaneous infusion.
• the pharmaceutical composition according to the invention is easily administered by the parenteral route through 27 Gauge (G) needle and more preferably through 29 G needle.
• composition according to the invention is formulated such that the peptide is released within a subject in need thereof for an extended period of time.
• composition according to the invention may be useful for a parenteral administration with a sustained-release of the peptide for at least 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours or 24 hours.
• the composition according to the invention allows a sustained release for at least 2 hours. In another preferred embodiment, the composition according to the invention allows a sustained release for at least 3 hours. In another preferred embodiment, the composition according to the invention allows a sustained release for at least 6 hours. In a more preferred embodiment, the composition according to the invention allows a sustained release for at least 8 hours. In another more preferred embodiment, the composition of the present invention allows a sustained release for at least 10 hours and more preferably 12 hours.
• the pharmaceutical composition according to the invention is particularly useful to treat disorders of body weight such as obesity and cachexia.
• compositions according to the present invention are prepared with peptide 1 as active ingredient according to the following process:
• the gelling agent is blended (when miscible) or dissolved (when soluble) in water for injection under magnetic stirring at room temperature for 15 min at least.
• the peptide salt is precisely weighed and dissolved in the previously prepared composition under magnetic stirring until obtaining a clear solution. Examples of formulation compositions are reported in Table 1 :
• the content of peptide salt is expressed in weight percentage of product relative to the total weight of the composition.
• the content of gelling agent is expressed in weight percentage of agent relative to the total weight of the composition.
• compositions 1 -4 were evaluated manually using a Millex GV PVDF (low protein binding Durapore ® PolyVinylidene DiFluoride) 0.22 ⁇ filter equipped with a 1 ml_ Terumo syringe.
• Millex GV PVDF low protein binding Durapore ® PolyVinylidene DiFluoride
• the peptide salts presented a solubility of at least 4 mg/mL. More precisely, the peptide 1 acetate salt showed a solubility of 100 mg/mL at least, in 32 % PEG 400 and in 38 % glycerol. The peptide 1 heptanoate salt showed a solubility of 28.1 mg/mL in 32 % PEG 400. This means that in all formulations of Table 1 , the peptide salt is entirely solubilized.
• Example 4 Iniectabilitv testing
• compositions 1 -4 were evaluated using a traction/compression machine which measures the injection strength during the simulated injection of the formulation from a 1 mL syringe fitted with a needle.
• the maximal tolerated strength is 1 5 N and the most suitable needle diameter for a daily subcutaneous injection is not less than 27 Gauge.
• agarose 100 mg was dissolved at 80° C in 5 mL of water under magnetic stirring. After the total agarose dissolution, the solution was cooled at 60° C. 200 ⁇ of the formulation, which corresponds to 800 ⁇ g of peptide, were introduced in a vial. The formulation was suspended with 300 ⁇ of the warm agarose solution heated at 60° C. The blend was then mixed and cooled at room temperature for 10 min, resulting in the first gel layer.
• the second agarose layer was topped with 3.4 mL of PBS buffer kept at 37° C, as a release medium .
• the vial was stoppered with a stirring rod and put in a horizontally rotating shaker in 200 rpm at 37° C.
• 500 ⁇ of release medium was withdrawn for UV analysis in the upper part of the vial at the following times after the start of the test: 15 min, 30 min, 1 h, 3 h, 5 h, 9 h, 16 h, 24 h and 30 h.
• the concentration of the peptide released in the medium was reported as a function of the time.
• T 50% The time when 50 % of the peptide is released from the formulation to the release medium (T 50% ) was evaluated graphically, and used to compare various formulations.
• Formulations manufactured with PEG 400 or glycerol as gelling agent were stored for 3 months at 40° C and 6 months at 5° C and 25° C.
• the selected formulations were manufactured at the maximal tolerated excipient content and
• the increase of the total impurities is moderate after 6 months at 25° C and does not exceed 5 %. After 6 months at 5° C, these formulations do not present any significant increase of the total impurities level.
• Formulation C also presents a moderate increase of the total impurities after 3 months at 25° C which does not exceed 5 %.
• this formulation presents a moderate increase of the total impurities level; this increase of total impurities tends to be quite higher than the one obtained for the previous formulations with acetate salt, but still remains lower than 5 %.
• Example 7 In vivo testing
• PK profiles of the formulations according to the invention were evaluated in rats. Eight rats divided in two groups of four were used per formulation. Each animal received a subcutaneous (SC) injection at a dose of 0.5 mg/kg, and then blood sampling was performed via a jugular catheter at different time points alternately on each group. Plasma concentrations were determined by LC-MS analysis. PK parameters were calculated by a WinNonLin analysis.
• PK values were compared to the one obtained after the injection of the peptide in a saline solution under the same conditions.
• PK profile is presented in Figure 2 (PK profiles in rats - 450 nmole/kg, 0.5 mg/kg, SC).
• C max maximum plasma concentration of the drug appearing in the PK profile
• AUC Area Under the Curve
• MRT Medium Residence Time
• T max time corresponding to the C max value
• T 1/2 half-life.
• PK profile and parameters of formulation 4 are presented in Figure 3 (PK profiles in rats -450 nmole/kg, 0.5 mg/kg, SC) and Table 9 (PK parameters of the formulation 4 and DMA/saline reference) respectively.
• formulation 4 presents a C max decrease by more than a factor 2 and a T max increase by a factor 2.

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