Pth compounds with low peak-to-trough ratios

Abstract

The present invention relates to a pharmaceutical composition comprising a PTH compound, wherein after subcutaneous administration the pharmacokinetic profile of the PTH compound exhibits a peak to trough ratio of less than 4 within one injection interval.

1 . A pharmaceutical composition comprising a controlled-release PTH compound, wherein after subcutaneous administration the pharmacokinetic profile of the PTH compound exhibits a peak to trough ratio of less than 4 within one injection interval. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the time period between two consecutive subcutaneous administrations is one week. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the subcutaneous administration is via subcutaneous injection. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the subcutaneous administration occurs with a pen device. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the peak to trough ratio is less than 3. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the administration is to a non-human primate. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the non-human primate is a cynomolgus monkey. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the administration is to a human. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the controlled-release PTH compound is water-insoluble. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres and microspheres. 
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound is a microparticle comprising at least one PTH molecule or PTH moiety. 
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound is a nanosphere comprising at least one PTH molecule or PTH moiety. 
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound is a microsphere comprising at least one PTH molecule or PTH moiety. 
     
     
         14 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound comprises at least one PTH moiety covalently and reversibly conjugated to a water-insoluble polymer. 
     
     
         15 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble polymer comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lacticacids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof. 
     
     
         16 . The pharmaceutical composition of  claim 9 , wherein the water-insoluble controlled-release PTH compound is a compound comprising a conjugate D-L, wherein
 -D is a PTH moiety; and   -L comprises a reversible prodrug linker moiety -L 1 -, which moiety -L 1 - is connected to the PTH moiety -D through a functional group of PTH;   wherein -L 1 - is substituted with -L 2 -Z′ and is optionally further substituted;   wherein   -L 2 - is a single chemical bond or a spacer moiety; and   —Z′ is a water-insoluble carrier moiety to which a multitude of moieties -L 2 -L 1 -D is connected.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein -D has the sequence of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 or SEQ ID NO:115. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein -D has the sequence of SEQ ID NO:51. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to a functional group of the side chain of an amino acid residue of -D, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D or to a nitrogen atom in the backbone polypeptide chain of -D. 
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of PTH selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to a functional group of the side chain of a lysine residue of PTH. 
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to a functional group of the side chain of a serine residue of PTH. 
     
     
         23 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to the N-terminal amine functional group of PTH. 
     
     
         24 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is conjugated to the C-terminal functional group of PTH. 
     
     
         25 . The pharmaceutical composition of  claim 16 , wherein L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. 
     
     
         26 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is a reversible prodrug linker from which PTH is released in its free form. 
     
     
         27 . The pharmaceutical composition of  claim 16 , wherein -L 1 - is of formula (IV): 
       
         
           
           
               
               
           
         
         wherein 
         the dashed line indicates attachment to -D and wherein attachment is through a functional group of -D selected from the group consisting of —OH, —SH and —NH 2 ; 
         m is 0 or 1; 
         at least one or both of —R and —R 2  is/are independently of each other selected from the group consisting of —CN, —NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, —C(O)R 3 , —S(O)R 3 , —S(O) 2 R 3 , and —SR 4 , 
         one and only one of —R 1  and —R 2  is selected from the group consisting of —H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; 
         —R 3  is selected from the group consisting of —H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 9  and —N(R 9 ) 2 ; 
         —R 4  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 
         each —R 5  is independently selected from the group consisting of —H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         —R 9  is selected from the group consisting of —H and optionally substituted alkyl; 
         —Y— is absent and —X— is —O— or —S—; or 
         —Y— is —N(Q)CH 2 — and —X— is —O—; 
         Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         optionally, —R 1  and —R 2  may be joined to form a 3 to 8-membered ring; and 
         optionally, both —R 9  together with the nitrogen to which they are attached form a heterocyclic ring; 
         wherein -L 1 - is substituted with -L 2 -Z′ and wherein -L 1 - is optionally further substituted. 
       
     
     
         28 . The pharmaceutical composition of  claim 16 , wherein -L 1 - of formula (IV) is substituted with one moiety -L 2 -Z′. 
     
     
         29 . The pharmaceutical composition of  claim 16 , wherein -L 2 - is a chemical bond. 
     
     
         30 . The pharmaceutical composition of  claim 16 , wherein -L 2 - is a spacer moiety. 
     
     
         31 . The pharmaceutical composition of  claim 16 , wherein -L 2 - is preferably selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl; wherein -T-, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally substituted with one or more —R y2 , which are the same or different and wherein C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y3 )—, —S(O) 2 N(R y3 )—, —S(O)N(R y3 )—, —S(O) 2 —, —S(O)—, —N(R y3 )S(O) 2 N(R y3a )—, —S—, —N(R y3 )—, —OC(OR y3 )(R y3a )—, —N(R y3 )C(O)N(R y3a )—, and —OC(O)N(R y3 )—;
 —R y1  and —R y1a  are independently of each other selected from the group consisting of —H, -T, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl; wherein -T, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally substituted with one or more —R 2 , which are the same or different, and wherein C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y4 )—, —S(O) 2 N(R y4 )—, —S(O)N(R y4 )—, —S(O) 2 —, —S(O)—, —N(R y4 )S(O) 2 N(R y4a )—, —S—, —N(R y4 )—, —OC(OR y4 )(R y4a )—, —N(R y4 )C(O)N(R y4a )—, and —OC(O)N(R y4 )—; 
 each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10  cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more —R 2 , which are the same or different; 
 each —R y2  is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR y5 , —OR y5 , —C(O)R y5 , —C(O)N(R y5 R y5a ), —S(O) 2 N(R y5 R y5a ), —S(O)N(R y5 R y5a ), —S(O) 2 R 5 , —S(O)R y5 , —N(R y5 )S(O) 2 N(R y5a R y5b ), —SR 5 , —N(R y5 R y5a ), —NO 2 , —OC(O)R y5 , —N(R y5 )C(O)R y5a , —N(R y5 )S(O) 2 R y5a , —N(R y5 )S(O)R y5a , —N(R y5 )C(O)OR y5a , —N(R y5 )C(O)N(R y5a R y5b ), —OC(O)N(R y5 R y5a ), and C 1-6  alkyl; 
 wherein C 1-6  alkyl is optionally substituted with one or more halogen, which are the same or different; and 
 each —R y3 , —R y3a , —R 4 , —R y4a , —R y5 , R y5a  and —R y5b  is independently selected from the group consisting of —H, and C1.6 alkyl, wherein C1.6 alkyl is optionally substituted with one or more halogen, which are the same or different. 
 
     
     
         32 . The pharmaceutical composition of  claim 16 , wherein -L 2 - is a C 1-20  alkyl chain, which is optionally interrupted by one or more groups independently selected from —O—, -T- and —C(O)N(R y1 )—; and which C 1-20  alkyl chain is optionally substituted with one or more groups independently selected from —OH, -T and —C(O)N(R y6 R y6a ); wherein —R y1 , —R y6 , —R y6a  are independently selected from the group consisting of H and C 1-4  alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10  cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl. 
     
     
         33 . The pharmaceutical composition of  claim 16 , wherein -L 2 - has a molecular weight in the range of from 14 g/mol to 750 g/mol. 
     
     
         34 . The pharmaceutical composition of  claim 16 , wherein -L 2 - has a chain length of 1 to 20 atoms. 
     
     
         35 . The pharmaceutical composition of  claim 16 , wherein —Z′ is a hydrogel. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the hydrogel comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the hydrogel comprises PEG or hyaluronic acid. 
     
     
         38 . The pharmaceutical composition of  claim 35 , wherein the hydrogel comprises PEG. 
     
     
         39 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition has a pH ranging from and including pH 3 to pH 8. 
     
     
         40 . A method of treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more diseases which can be treated with PTH, comprising the step of administering to said patient in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         41 . The method of  claim 40 , wherein the disease is selected from the group consisting of hypoparathyroidism, hyperphosphatemia, osteoporosis, fracture repair, osteomalacia, osteomalacia and osteoporosis in patients with hypophosphatasia, steroid-induced osteoporosis, male osteoporosis, arthritis, osteoarthritis, osteogenesis imperfect, fibrous dysplasia, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, and thrombocytopenia. 
     
     
         42 . The method of  claim 40 , wherein the condition is hypoparathyroidism.