Compositions comprising pemvidutide and an acylated amino acid
The invention relates to a pharmaceutical composition, in particular a solid composition, including a compound of (i), which is a permeation enhancer according to Formula I, said permeation enhancer being an acylated aminoacid substituted on the amine function, also called AC-aa-NS, and a compound of (ii) having at least 90% sequence identity to SEQ ID NOS: 1-23. Also disclosed are methods of preparing the pharmaceutical composition, formulations, and their use in medicine.
1 . A pharmaceutical composition comprising of (i) a compound comprising a structure of:
wherein R 1 is an alkyl comprising 5 to 15 carbon atoms, an alkyl comprising 7 to 17 carbon atoms and a carboxyl group, or an alkyl comprising 7 to 17 carbon atoms and a hydroxyl group; and R 3 is hydrogen or a cation;
and
(ii) a compound comprising a sequence having at least 90% sequence identity to:
(SEQ ID NO: 1)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-(17-carboxyl-heptadecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -
Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 2)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 3)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -
Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 4)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -
Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 5)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-octadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -
Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 6)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-dodecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-
omega(1-dodecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 7)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -
Lys(N-omega(1-tetradecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 8)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -
Lys(N-omega(1-hexadecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 9)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-(13-carboxyl-tridecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -
Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 10)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys(N-omega(1-(15-carboxyl-pentadecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -
Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 11)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Gln17Ala 18 -Ala 19 -Lys 20 Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 12)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Gln 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 13)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Gln 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-pentadecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 14)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -
Lys(N-omega(1-(13-carboxyl-tridecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -
Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 15)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -
Lys(N-omega(1-(15-carboxyl-pentadecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -
Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 16)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -
Lys(N-omega(1-(17-carboxyl-heptadecyloxy)beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -
Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 17)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -Gln 17 -
Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 18)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -Gln 17 -
Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 19)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -Gln 17 -
Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy)beta-D-
glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 20)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Lys 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Lys 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 21)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu 16 -
Gln 17 -Ala 18 -Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Lys 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
(SEQ ID NO: 22)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -Lys 17 -
Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ; or
(SEQ ID NO: 23)
His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Sers-Asp 9 -Glu 10 -Ser 11 -Lys 12 -Tyr 13 -Lys 14 -Asp 15 -Ser 16 -Gln 17 -
Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;
and
a pharmaceutically acceptable carrier or excipient.
2 . The pharmaceutical composition of claim 1 , wherein in (i): R 1 is a linear alkyl group comprising 7 carbon atoms; or R 1 is an alkyl comprising 7 to 17 carbon atoms and a carboxyl group, wherein the carboxyl group is a carboxyl group of a carboxylic acid, acid anhydride, or ester; or R 1 is an alkyl comprising 7 to 17 carbon atoms and a carboxyl group, wherein the carboxyl group is a terminal carboxyl group.
3 . The pharmaceutical composition of claim 1 , wherein R 3 is hydrogen or an alkali metal cation, wherein the alkali metal cation is a lithium, sodium, or potassium cation.
4 . The pharmaceutical composition of claim 1 , wherein in (i), the compound comprises NaGly(N-Bn)C8 having the structure:
5 . The pharmaceutical composition of claim 1 , wherein the compound of (ii) comprises pemvidutide.
6 . The pharmaceutical composition of claim 1 , wherein the compound of (ii) has at least 90% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2; or
the compound has at least 95% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2; or
the compound has at least 99% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2.
7 . The pharmaceutical composition of claim 1 , comprising about 0.5 to about 20 wt % of the compound of (ii).
8 . The pharmaceutical composition of claim 1 , comprising at least 300 mg/g of the compound of (i) relative to the total weight of the composition; or the weight ratio of the compound of (i) to the compound of (ii) is from about 1:1 to about 200:1.
9 . The pharmaceutical composition of claim 1 , comprising an excipient, wherein the excipient comprises a lubricant, surfactant, pH modifier, disintegrant, binders, filler, glidant, diluent, polymer for sustained or delayed release, or a preservative.
10 . The pharmaceutical composition of claim 9 , wherein the pH modifier comprises sodium carbonate, phosphates, citrates, citric acid, tartarate or tartaric acid; or the lubricant comprises magnesium stearate or glyceryl dibehenate; or
the disintegrant comprises croscarmellose.
11 . The pharmaceutical composition of claim 9 , comprising at most 15% w/w of the pH modifier; or
comprising less than 5% w/w of the lubricant; or
comprising about 0.25 and about 2.5% w/w of the disintegrant.
12 . The pharmaceutical composition of claim 1 , further comprising a serine protease inhibitor or a permeation enhancer.
13 . The pharmaceutical composition of claim 12 , wherein the serine protease inhibitor comprises soybean tripsin inhibitor (SBTI); or
the permeation enhancer comprises sodium salcaprozate.
14 . The pharmaceutical composition of claim 12 , comprising 100 to 400 mg/g of the serine protease inhibitor; or
comprising at least 300 mg/g of the permeation enhancer.
15 . The pharmaceutical composition of claim 4 , wherein the compound of (ii) comprises pemvidutide, and the composition further comprises sodium carbonate, and SBTI.
16 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is an oral composition.
17 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a solid composition.
18 . The pharmaceutical composition of claim 17 , wherein the solid composition is a unitary solid dosage.
19 . The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition comprises a solid composition in a unitary solid dosage, and the compound of (ii) comprises pemvidutide.
20 . The pharmaceutical composition of claim 18 , wherein the unitary solid dosage is in the form of capsules, tablets, dragees, pills, lozenges, powders, or granules.
21 . A method of treating obesity, type II diabetes, or non alcoholic steatohepatitis comprising administering to a subject, the pharmaceutical composition of claim 1 .
22 . The method of claim 21 , wherein the administering step comprises orally administering the pharmaceutical composition.
23 . The method of claim 22 , comprising orally administering to the subject the pharmaceutical composition comprising pemvidutide and NaGly(N-Bn)C8.
24 . The method of claim 23 , wherein the pharmaceutical composition adminstered orally further comprises SBTI.
25 . The method of claim 21 , wherein the administering step occurs once daily; or
the administering step occurs twice daily; or
the administering step occurs weekly; or
the administering step occurs monthly.
26 . The pharmaceutical composition of claim 4 , wherein the compound of (ii) comprises pemvidutide.
27 . The pharmaceutical composition of claim 4 , wherein the compound of (ii) has at least 90% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2; or
the compound has at least 95% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2; or
the compound has at least 99% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2.
28 . The pharmaceutical composition of claim 26 , comprising about 0.5 to about 20 wt % of the compound of (ii); or, comprising at least 300 mg/g of the compound of (i) relative to the total weight of the composition; or wherein the weight ratio of the compound of (i) to the compound of (ii) is from about 1:1 to about 200:1.
29 . The pharmaceutical composition of claim 26 , comprising an excipient, wherein the excipient comprises a lubricant, surfactant, pH modifier, disintegrant, binders, filler, glidant, diluent, polymer for sustained or delayed release, or a preservative; or, wherein the excipient comprises a pH modifier that comprises sodium carbonate, phosphates, citrates, citric acid, tartarate or tartaric acid; or the excipient comprises a lubricant that comprises magnesium stearate or glyceryl dibehenate; or the excipient comprises a disintegrant that comprises croscarmellose; or, the excipient comprises a pH modifier and the pharmaceutical composition comprises at most 15% w/w of the pH modifier; or the excipient comprises a lubricant and the pharmaceutical composition comprises less than 5% w/w of the lubricant; or the excipient comprises a disintegrant and the pharmaceutical composition comprises about 0.25 and about 2.5% w/w of the disintegrant.
30 . The pharmaceutical composition of claim 26 , further comprising a serine protease inhibitor or a permeation enhancer.