CN111698999A - Injectable solution with pH7 comprising at least one basal insulin with PI between 5.8 and 8.5 and a polyamino acid with carboxylate charge and hydrophobic group - Google Patents
Injectable solution with pH7 comprising at least one basal insulin with PI between 5.8 and 8.5 and a polyamino acid with carboxylate charge and hydrophobic group Download PDFInfo
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- CN111698999A CN111698999A CN201880088662.5A CN201880088662A CN111698999A CN 111698999 A CN111698999 A CN 111698999A CN 201880088662 A CN201880088662 A CN 201880088662A CN 111698999 A CN111698999 A CN 111698999A
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- insulin
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 561
- 102000004877 Insulin Human genes 0.000 title claims abstract description 273
- 108090001061 Insulin Proteins 0.000 title claims abstract description 273
- 229940125396 insulin Drugs 0.000 title claims abstract description 267
- 239000002253 acid Substances 0.000 title claims abstract description 175
- 125000001165 hydrophobic group Chemical group 0.000 title claims description 149
- 150000007942 carboxylates Chemical class 0.000 title claims description 48
- 229940102223 injectable solution Drugs 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 387
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 108010057186 Insulin Glargine Proteins 0.000 claims description 92
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 claims description 92
- 229960002869 insulin glargine Drugs 0.000 claims description 91
- 239000002243 precursor Substances 0.000 claims description 85
- 235000001014 amino acid Nutrition 0.000 claims description 83
- 230000002209 hydrophobic effect Effects 0.000 claims description 80
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 125000004432 carbon atom Chemical group C* 0.000 claims description 75
- 150000001413 amino acids Chemical class 0.000 claims description 67
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 58
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 56
- 235000013922 glutamic acid Nutrition 0.000 claims description 56
- 125000006850 spacer group Chemical group 0.000 claims description 56
- 150000001412 amines Chemical group 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 41
- 230000006870 function Effects 0.000 claims description 39
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 37
- 239000004220 glutamic acid Substances 0.000 claims description 37
- 238000006116 polymerization reaction Methods 0.000 claims description 37
- 238000009472 formulation Methods 0.000 claims description 33
- 150000001408 amides Chemical group 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
- 239000003629 gastrointestinal hormone Substances 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 24
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 21
- -1 alkali metal cations Chemical class 0.000 claims description 20
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 20
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 229920006395 saturated elastomer Polymers 0.000 claims description 19
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 18
- 102400000319 Oxyntomodulin Human genes 0.000 claims description 17
- 101800001388 Oxyntomodulin Proteins 0.000 claims description 17
- 125000002091 cationic group Chemical group 0.000 claims description 17
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims description 15
- 108010011459 Exenatide Proteins 0.000 claims description 15
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 15
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- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 claims description 15
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- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 claims description 15
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
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Abstract
The present invention relates to a physically stable composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0 comprising at least: a) a basal insulin having isoelectric points (pI) of 5.8 and 8.5, and b) a copolyamino acid Q [ Hy ] according to formula 1]j[PLG]kFormula I wherein: j is more than or equal to 1; k is more than or equal to 2.
Description
The present invention relates to insulin injection therapy for the treatment of diabetes.
The present invention relates to a physically stable composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0 comprising at least one basal insulin having an isoelectric point (pI) of 5.8 to 8.5 and a co-amino acid bearing a carboxylate charge and a hydrophobic group.
In recent years, insulin therapy or treatment of diabetes by insulin injection has made significant progress, particularly due to the development of new insulin, patients have better correction of blood glucose than human insulin, and this has made it possible to improve the simulation of pancreatic physiological activity.
Treatment is gradually administered when a patient is diagnosed with type two diabetes. First, the patient orally administers an antidiabetic (OAD), such as metformin. When OAD alone is not sufficient to control glucose levels in the blood, the treatment must be changed and different combinations of treatments can be implemented depending on the patient's specific circumstances. For example, in addition to OAD, patients may be treated with insulin glargine-type basal insulin or insulin detemir and then, depending on the progression of the disease, treated with basal insulin and prandial insulin.
Furthermore, today, in order to transition from treatment by OAD (when the latter is no longer able to control glucose levels in the blood) to basal insulin/prandial insulin treatment, injections of GLP-1RA analogues are suggested.
For glucagon-like peptide 1 receptor agonists, GLP-1RA is an insulinotropic peptide or incretin and belongs to the family of gastrointestinal hormones (or gut hormones) that stimulate insulin secretion when blood glucose is too high, e.g., after a meal.
The gastrointestinal hormones (gut hormones) are also known as satiety hormones. In particular, they comprise GLP-1RA (glucagon-like peptide-1 receptor agonist) and GIP (glucose-dependent insulinotropic peptide), oxyntomodulin (derivative of pro-glucagon), peptide YY, amylin, cholecystokinin, Pancreatic Polypeptide (PP), ghrelin and enterostatin, which are peptide or protein structures. They also stimulate insulin secretion in response to glucose and fatty acids and are therefore themselves potential candidates for the treatment of diabetes.
Among them, GLP-1RA is the one which has so far achieved the best results in drug development. They enable patients with type II diabetes to lose weight while at the same time better controlling blood glucose.
Thus, GLP-1RA analogs or derivatives have been developed, in particular to improve their stability.
On the other hand, in order to meet his daily insulin needs, a diabetic patient may currently plan to use two types of insulin with complementary effects: prandial (or so-called rapid acting) and basal (or so-called slow acting) insulins
Prandial insulin allows for rapid management (metabolism and/or storage) of glucose provided during meals and snacks. Patients must inject themselves with prandial insulin prior to each meal, or about 2 to 3 injections per day. The most widely used prandial insulins are: recombinant human insulin,
(NOVO NORDISK insulin aspart),
(ELILLY insulin aspart) and
(SANOFI insulin glulisine).
Basal insulin ensures that the patient's blood glucose homeostasis is maintained outside the fed period. Essentially, their effect is to block the production of endogenous glucose (hepatic glucose). The daily dose of basal insulin usually corresponds to 40-50% of the total daily insulin requirement. The dose is divided into 1 or 2 injections, depending on the basal insulin used, and is periodically dispensed throughout the day. The most commonly used basal insulin is
(NOVO NORDISK insulin) and
(SANOFI insulin glargine).
For the sake of completeness, it should be noted that NPH (NPH insulin is neutral protamine zinc insulin; Huminine
) Is the oldest basal insulin. The preparation is prepared by precipitating human insulin from cationic protamine (negative at neutral pH)Ionic type). The crystallites formed in this process are dispersed in an aqueous suspension and slowly dissolve after subcutaneous injection. This slow dissolution ensures a prolonged release of insulin. However, this release does not guarantee a constant concentration of insulin over time. The release profile is bell-shaped and lasts only 12 to 16 hours. Therefore, it was injected twice daily. This NPH basal insulin is far inferior to modern basal insulin
And
is effective. NPH is a moderate basal insulin.
The principle of NPH has evolved with the advent of rapid insulin analogues, including products known as "pre-mixes" that provide both rapid and moderate effects. Novollog
(NOVO NORDISK) and Humalilog
(ELILILLY) is a fast insulin analog comprising a complex with a protamine moiety
And
the formulation of (1). These preparations therefore contain the so-called intermediate acting insulin analogue microcrystals and a portion of the fast acting insulin which remains soluble. These formulations do provide the advantages of fast acting insulin, but they also have the disadvantage of NPH, i.e. the duration of action is limited to 12 to 16 hours, and the insulin release profile is "bell-shaped". However, these products enable patients to inject intermediate-acting basal insulin with fast-acting prandial insulin. However, many patients are concerned with reducing their number of injections.
The basal insulins currently on the market can be classified according to the technical solutions that allow obtaining a prolonged action, and two methods are currently employed.
The first approach, insulin detemir, is to bind albumin in vivo. It is an analogue soluble at pH7 comprising a fatty acid side chain (tetradecanoyl) attached at position B29, which in vivo associates the insulin with albumin. The prolonged action is mainly due to this affinity for albumin after subcutaneous injection.
However, its pharmacokinetic profile does not allow it to last for the entire day, and therefore it is most often used as a twice daily injection.
Another insulin that is soluble at pH7 is deglutition insulin, by name
And (5) selling. It also contains a fatty acid side chain (hexadecanediacyl- γ -L-Glu) attached to insulin.
The second method, insulin glargine, is precipitation at physiological pH. Glargine is an analogue of human insulin obtained by extending the C-terminal part of the B-chain of human insulin with two arginine residues and replacing the asparagine residue a21 with a glycine residue (US 5,656,722). The addition of two arginine residues is designed to adjust the pI (isoelectric point) of insulin glargine to physiological pH and thus render this analogue of human insulin insoluble in physiological media.
In addition, substitution of a21 was designed to stabilize insulin glargine at acidic pH and thus enable its formulation as an injectable solution at acidic pH. Upon subcutaneous injection, insulin glargine changes from an acidic pH (pH 4-4.5) to a physiological pH (neutral pH) causing it to precipitate under the skin. The slow re-dissolution of the insulin glargine microparticles ensures a slow and prolonged action.
The hypoglycemic effect of insulin glargine is quasi-constant over a 24 hour period, which allows most patients to inject themselves only once a day.
Insulin glargine is today considered to be the most widely used basal insulin.
However, the necessary acidic pH of a basic insulin formulation with an isoelectric point of the insulin glargine type between 5.8 and 8.5 may be a real problem, since such acidic pH of insulin glargine formulations sometimes causes pain upon injection by the patient and in particular hampers any formulation with other proteins, especially with prandial insulin, since the latter is unstable at acidic pH. The inability to formulate prandial insulin at acidic pH is related to the fact that: prandial insulin undergoes a secondary deamidation reaction at the a21 position under these conditions, which makes it impossible to meet stability requirements suitable for injectable drugs.
At present, in applications WO 2013/021143 a1, WO 2013/104861 a1, WO 2014/124994 a1 and WO2014/124993 a1, it has been demonstrated that it is possible to dissolve these insulin glargine-type basal insulins with isoelectric points between 5.8 and 8.5 at neutral pH, while maintaining the solubility difference between the in vitro medium (container) and the in vivo medium (under the skin) independently of pH.
Application WO 2013/104861 a1 describes, inter alia, compositions in the form of injectable aqueous solutions having a pH of 6.0 to 8.0, comprising at least: a) a basal insulin having an isoelectric point (pI) of 5.8 to 8.5, and b) a co-amino acid having a carboxylate charge and a hydrophobe.
The main drawback of these compositions of the prior art is that they are not stable enough to meet the specifications applicable to pharmaceutical formulations.
Therefore, there is a need to find a solution that allows the dissolution of a basal insulin with an isoelectric point (pI) between 5.8 and 8.5, while maintaining its basal properties after injection, but also allowing to meet the standard physical stability requirements for insulin based drugs.
Surprisingly, the applicant has found that the copolymerized amino acids carrying carboxylate charges and hydrophobic groups according to the invention enable to obtain compositions in solution which not only satisfy the requirements described in WO 2013/104861 a1, but also enable to provide said compositions with improved physical stability without having to increase the amount of excipients used.
These previously unattained properties are also maintained when basal insulin with an isoelectric point between 5.8 and 8.5 is associated in the composition with prandial insulin and/or gastrointestinal hormones.
Therefore, it is surprising that the affinity of the copolyamino acid according to the present invention for insulin glargine is increased, since it allows to obtain the dissolution and stabilization of insulin glargine solution at a lower [ Hy ]/[ basal insulin ] ratio than the prior art; furthermore, as shown in the experimental part, these results were obtained without altering and even improving the tendency of insulin glargine to precipitate.
This improvement in affinity also makes it possible to limit the level of exposure to said excipients in the case of long-term treatment.
The copolymerized amino acid having a carboxylate charge and a hydrophobic group Hy according to the present invention has excellent hydrolysis resistance. This can be verified in particular under accelerated conditions, for example by hydrolysis tests at basic pH (pH 12).
Furthermore, forced oxidation tests, for example of the fenton oxidation type, show that the polyamino acids carrying a carboxylate charge and a hydrophobe Hy exhibit good oxidation resistance.
The present invention therefore relates to a physically stable composition in the form of an injectable aqueous solution having a pH comprised between 6.0 and 8.0, comprising at least:
a) basal insulin whose isoelectric points (pI) include 5.8 and 8.5, and
b) a polyamino acid according to formula 1
Q[Hy]j][PLG]k[Hy]hy[Hy]hy′
Of formula I'
Wherein:
j≥1；k≥2
hy is greater than or equal to 0 and hy' is greater than or equal to 0
The polyamino acids according to formula I' carry a carboxylate charge and consist of at least two chains of PLG glutamic or aspartic acid units bound together by at least trivalent, linear or branched groups or spacers Q [ - ] I (i.gtoreq.3, wherein I ═ j + k), said groups or spacers consisting of: a group comprising one or more heteroatoms selected from nitrogen and oxygen atoms and/or alkyl chains bearing one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl groups, said group Q [ - ] i bearing at least one monovalent hydrophobic group-Hy;
-said group or spacer Q [ - ]]iIs bound to at least two PLG chains of glutamic acid or aspartic acid units via an amide function, and,
-said group or spacer Q [ - ]]iBound to at least one hydrophobic group-Hy according to formula X defined below via an amide function.
-subjecting said group or spacer Q [ - ]]iThe amide function bound to at least two chains of glutamic or aspartic acid units results from a reaction between an amine function and an acid function, respectively consisting of the said group or spacer Q [ - ]]iOr a glutamic acid or aspartic acid unit.
-subjecting said group or spacer Q [ - ]]iSaid amide function bound to at least one hydrophobic group-Hy according to formula X results from a reaction between an amine function and an acid function consisting of said group or spacer Q [ - ]]iOr a precursor Hy' of said hydrophobe-Hy; and is
-when Hy and Hy' ≠ 0, then at least one hydrophobic group-Hy binds to the carboxyl function carried by the terminal "amino acid" unit or by one of the glutamic or aspartic acid units of the PLG chain.
In one embodiment, hy and hy' are equal to 0, and thus, the present invention relates to a physically stable composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0 comprising at least:
a) basal insulin with isoelectric points (pI) of 5.8 and 8.5, and
b) a copolymerized amino acid according to formula 1
Q[Hy]j[PLG]k
Formula I
Wherein:
j≥1；k≥2
the polyamino acids according to formula I carry a carboxylate charge and consist of at least two chains of PLG glutamic or aspartic acid units bound together by at least trivalent, linear or branched groups or spacers Q [ - ] I (i.gtoreq.3, wherein I ═ j + k), said groups or spacers consisting of: a group comprising one or more heteroatoms selected from nitrogen and oxygen atoms and/or alkyl chains bearing one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl groups, said group Q [ - ] i bearing at least one monovalent hydrophobic group according to formula X-Hy;
-said group or spacer Q [ - ]]iIs bound to at least two chains of PLG glutamic acid or aspartic acid units via an amide function, and
-said group or spacer Q [ - ]]iBound to at least one hydrophobic group-Hy according to formula X via an amide function.
By reacting said radicals or spacers Q [ - ]]iThe amide function bound to at least two chains of glutamic or aspartic acid units results from a reaction between an amine function and an acid function, respectively consisting of the said group or spacer Q [ - ]]iOr a glutamic acid or aspartic acid unit.
By reacting said radicals or spacers Q [ - ]]iSaid amide function bound to at least one hydrophobic group-Hy according to formula X results from a reaction between an amine function and an acid function consisting of said group or spacer Q [ - ]]iOr a precursor Hy' of said hydrophobic group-Hy.
The pH of the composition according to the invention is between 6.0 and 8.0, preferably between 7 and 7.8, preferably between 6.6 and 7.8, or even more preferably between 6.8 and 7.6.
Said polyamino acid bearing a carboxylate charge and at least one hydrophobe-Hy group is soluble in aqueous solution at a pH of between 6.0 and 8.0, at a temperature of 25 ℃ and at a concentration at least equal to 60 mg/ml.
The term "physically stable composition" refers to a composition that meets the visual inspection criteria described in the european, us and international pharmacopoeias, i.e., a composition that is clear and free of visible particles, but is also colorless.
By "injectable aqueous solution" is meant a solution in which the solvent is water and which complies with the conditions of the european and us pharmacopoeias.
The term "polyamino acid composed of glutamic acid or aspartic acid units" refers to a non-cyclic linear chain of glutamic acid or aspartic acid units joined together by peptide bonds, said chain having a C-terminal part corresponding to the carboxylic acid at one end and an N-terminal part corresponding to the amine at the other end of the chain.
The term "soluble" as used herein means suitable for preparing a clear, particle-free solution at a concentration of less than 60mg/ml in distilled water at 25 ℃.
The term "alkyl" denotes a straight or branched carbon chain containing no heteroatoms.
The copolymerized amino acid is a statistical copolymerized amino acid in a glutamic acid and/or aspartic acid unit chain.
In the formula, the binding sites of the different elements represented are indicated.
In one embodiment, the composition according to the invention is characterized in that Hy comprises 30 to 70 carbon atoms.
In one embodiment, said group or spacer Q [ - ] i (i.gtoreq.3) is represented by a group according to formula II:
Q[-*]i＝([Q′]q)[-*]i
formula II
Wherein l is less than or equal to q is less than or equal to 5
The groups Q' are identical or different and are selected from groups according to the formulae III to VI below, so as to form Q [ - ]]i(i≥3)
Wherein t is more than or equal to 1 and less than or equal to 8
Wherein:
u1"or u2At least one of "is different from 0.
If u is1"≠ 0, then u1' ≠ 0, and if u2"≠ 0, then u2′≠0，
u1' and u2Are' the same or different, and
2≤u≤4，
0≤u1′≤4，
0≤u1”≤4，
0≤u2′≤4
0≤u2is ≦ 4, and
wherein:
v, v 'and v' are the same or different,
v+v′+v”≤15
wherein:
w1' a different value from 0 is used for the,
0≤w2″≤1，
w1w is not more than 61' < 6 > and/or w2W is not more than 62′≤6
Wherein Fx ═ Fa, Fb, Fc, Fd, Fa ', Fb ', Fc "and Fd ', which are identical or different, represent the functional groups-NH-or-CO-, and Fy represents the trivalent nitrogen atom-N ═ by,
two groups Q' are bound between the carboxyl function Fx ═ CO-and the amine function Fx ═ NH-or Fy ═ N ═ by a covalent bond between them, forming an amide bond,
in one embodiment, if Fa and Fa' are-NH-, t.gtoreq.2.
In one embodiment, if Fa and Fa' are-CO-, t.gtoreq.1.
In one embodiment, if Fa and Fa' are-CO-and-NH-, t.gtoreq.1.
In one embodiment, if Fb and Fb' are-NH-, u and u1' > 2 and/or u2′≥2。
In one embodiment, if Fc, Fc 'and Fc "are-NH-, at least two of v, v' and v" are different from 0.
In one embodiment, if Fc, Fc' and Fc "are 2-NH-and 1-CO-, then at least one of the subscripts of- (CH2) -with nitrogen is different from 0.
In one embodiment, there is no condition if Fc, Fc' and Fc "are 1-NH-and 2-CO-.
In one embodiment, if Fc, Fc 'and Fc "are-CO-, at least one of v, v' and v" is different from 0.
In one embodiment, if Fd and Fd ' are-NH-, w1 and w1 ' ≧ 2 and/or w2 and w ' 2 ≧ 2.
In one embodiment, if Fd and Fd ' are-CO-, w1 and w1 ' ≧ 1 and/or w2 and w2 ' ≧ 1.
In one embodiment, if Fd and Fd ' are-CO-and-NH-, w1 and w1 ' ≧ 1 and/or w2 and w2 ' ≧ 1.
Hy and PLG are covalently bonded to Q < - > through the Fx or Fy functional group to form an amide bond with the-NH-or-CO-functional group of PLG or Hy.
In one embodiment, l.ltoreq.q.ltoreq.4.
In one embodiment, v + v' + v "≦ 15.
In one embodiment, at least one of Q' is a group according to formula III,
the precursor is a diamine.
In one embodiment, the precursor of the group according to formula III is a diamine selected from the group consisting of ethylenediamine, butanediamine, hexamethylenediamine, 1, 3-diaminopropane and 1, 5-diaminopentane.
In one embodiment, t ═ 2 and the precursor of the group according to formula III is ethylenediamine.
In one embodiment, t ═ 4 and the precursor of the group according to formula III is butanediamine.
In one embodiment, t ═ 6 and the precursor of the group according to formula III is hexamethylenediamine.
In one embodiment, t ═ 3 and the precursor of the group according to formula III is 1, 3-diaminopropane.
In one embodiment, t ═ 5 and the precursor of the group according to formula III is 1, 5-diaminopropane.
In one embodiment, the precursor of the group according to formula III is an amino acid.
In one embodiment, the precursor of the group according to formula III is an amino acid selected from the group consisting of aminobutyric acid, aminocaproic acid and β -alanine.
In one embodiment, t ═ 2 and the precursor of the group according to formula III is β -alanine.
In one embodiment, t ═ 6 and the precursor of the group according to formula III is aminocaproic acid.
In one embodiment, t ═ 4 and the precursor of the group according to formula III is aminobutyric acid.
In one embodiment, the precursor of the group according to formula III is a diacid.
In one embodiment, the precursor of the group according to formula III is a diacid selected from succinic, glutaric and adipic acids.
In one embodiment, t ═ 2 and the precursor of the group according to formula III is succinic acid.
In one embodiment, t ═ 3 and the precursor of the group according to formula III is glutaric acid.
In one embodiment, t ═ 4 and the precursor of the group according to formula III is adipic acid.
In one embodiment, at least one of Q' is a group according to formula IV,
the precursor is a diamine.
In one embodiment, the precursor of the radical according to formula IV is a diamine selected from the group consisting of diethylene glycol diamine, triethylene glycol diamine, 1-amino-4, 9-dioxa-12-dodecylprimary amine and 1-amino-4, 7, 10-trioxa-13-n-tridecylamine.
In one embodiment, u ═ u'1＝2，u”1＝1，u”20 and the precursor of the group according to formula IV is diethylene glycol diamine.
In one embodiment, u ═ u'1＝u’2＝2，u”1＝u”21 and the precursor of the group according to formula IV is triethylene glycol diamine.
In one embodiment, u ═ u'2＝3，u’1＝4，u”1＝u”2Is 1 and the precursor of the group according to formula IV is 4, 9-dioxa-1.12-dodecanediamine.
In one embodiment, u ═ u'2＝3，u’1＝u”1＝2，u”21 and the precursor of the group according to formula IV is 4, 7, 10-trioxa-1, 13-n-tridecanediamine.
In one embodiment, at least one of Q' is a group according to formula V,
the precursor is selected from amino acids.
In one embodiment, the precursor of the group according to formula V is an amino acid selected from lysine, ornithine and 2, 3-diaminopropionic acid.
In one embodiment, at least one of Q' is a group according to formula V,
the precursor is selected from triacids.
In one embodiment, the precursor of the group according to formula V is a triacid selected from tricarballylic acid.
In one embodiment, V ═ 0, V' ═ V ═ 1, and the precursor of the group according to formula V is tricarballylic acid.
In one embodiment, at least one of Q' is a group according to formula V,
the precursors are selected from triamines.
In one embodiment, the precursor of the group according to formula V is a triamine selected from (2- (aminomethyl) propane-1, 3-diamine).
In one embodiment, V ═ V' ═ V ═ 1, and the precursor of the group according to formula V is (2- (aminomethyl) propane-1, 3-diamine).
In one embodiment, at least one of Q' is a group according to formula VI,
the precursor is triamine.
In one embodiment, w "20 and the precursor of the group according to formula VI is a triamine selected from the group consisting of spermidine, norspermidine (norspermidine) and diethylenetriamine and bis (hexamethylene) triamine.
In one embodiment, w "20 and the precursor of the group according to formula VI is spermidine.
In one embodiment, w "20 and the precursor of the group according to formula VI is norspermidine.
In one embodiment, w "20 and the precursor of the group according to formula VI is diethylenetriamine.
In one embodiment, w "20 and the precursor of the group according to formula V is bis (hexamethylene) triamine.
In one embodiment, w "21 and the precursor of a group according to formula VI is tetraAn amine.
In one embodiment, w "21 and the precursor of the group according to formula VI is a tetraamine selected from spermine and triethylenetetramine.
In one embodiment, w "21 and the precursor of the group according to formula VI is spermine.
In one embodiment, w "21 and the precursor of the group according to formula VI is triethylenetetramine. In one embodiment, PLG is bound to Fx (where Fx ═ NH-) or Fy at least through the carboxyl functionality of PLG.
In one embodiment, PLG is bound to Fx (where Fx ═ NH-) or Fy at least through a carboxyl functional group not at the C-terminal position of PLG.
In one embodiment, PLG is bound to Fx (where Fx ═ NH-) or Fy through a carboxyl functional group at the C-terminal position of PLG.
In one embodiment, PLG is bound to Fx (wherein Fx ═ NH —) through a carboxyl functional group at the C-terminal position of PLG.
In one embodiment, PLG is bound to Fx (where Fx ═ Fy) through a carboxyl functional group at the C-terminal position of PLG.
In one embodiment, Hy is bound to Fx (where Fx ═ NH-) or Fy via the carboxyl functionality of Hy carried by GpR, GpA, GpG, ghph, GpL or GpC.
In one embodiment, Hy is bound to Fy via the carboxyl function of Hy carried by GpR, GpA, GpG, ghph, GpL, or GpC.
In one embodiment, Hy is bound to Fx (where Fx ═ NH-), through the carboxyl function of Hy carried by GpR, GpA, GpG, ghph, GpL or GpC.
In one embodiment, PLG is bound to Fx (wherein Fx ═ CO-) via a nitrogen atom at the N-terminal position of PLG.
In one embodiment, Hy is bound to Fx (where Fx ═ CO-) via a nitrogen atom of Hy carried by GpR, GpA, GpG, GpL or ghph.
In one embodiment Q Q' is selected from groups according to formulae VI, III and IV, and Q comprises a group according to formula VI, wherein Q ≧ 1, and Q [ one ] i is a group wherein i ═ 3
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 1 and k is 2
-Hy according to formula X is bound to Q 'via a covalent bond to Fa, Fa', Fb ', Fd' or Fy, forming an amide bond
-2 PLG chains are bound to Q 'via covalent bonds to Fa, Fa', Fb ', Fd' or Fy, forming amide bonds
In one embodiment, q is 1.
In one embodiment, Hy is bound to Q' via a covalent bond between Fy and the carboxyl functionality of Hy carried by GpR, GpA, GpG, ghph, GpC, or GpL to form an amide bond.
In one embodiment, PLG is bound to Q ' via a covalent bond between Fd, Fd ' (Fd and Fd ' -NH-) and a carbonyl function at the C-terminal position of the PLG chain, forming an amide bond.
In one embodiment, Q' is a group according to formula VI,
in one embodiment, Q' is a group according to formula VI, wherein:
w2＝w”20 and 3 ≤ w1W is not less than 4 and not more than 31’≤4。
In one embodiment, Q' is a group according to formula VI, wherein w2＝w”20 and w13 and w1’＝4。
In one embodiment, Q' is a group according to formula VI, wherein w2＝w”20 and w1＝w1’＝3。
In one embodiment, Fd ═ Fd' ═ NH-, and each independently bind via a covalent bond through the terminal carbonyl functional group of PLG to form an amide bond, and Fy binds via a covalent bond to the carbonyl functional group of hydrophobe Hy to form an amide bond.
In one embodiment Q Q' is selected from groups according to formula III, IV and V, and Q comprises at least one group according to formula V, wherein Q ≧ 1, and Q [ - ] i is a group wherein i ═ 3
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 1 and k is 2
-Hy according to formula X is bound to Q 'via a covalent bond to Fc, Fc', Fc ", Fb ', Fa or Fa', forming an amide bond
-2 PLG chains are bound to Q 'via a covalent bond to Fc, Fc', Fc ", Fb ', Fa or Fa' forming an amide bond.
In one embodiment, Hy is bound to Q' via a covalent bond with the carboxyl functionality of Hy carried by GpR, GpG, GpA, ghph, GpL, or GpC to form an amide bond.
In one embodiment, Hy is bound to Q' via a covalent bond with the amine functionality of Hy carried by GpR, GpG, GpA, GpL, or ghph to form an amide bond.
In one embodiment, the PLG chain is bound to Q ' by a covalent bond between Fc, Fc ", Fb ', Fa or Fa ' and a carbonyl function at the C-terminal position of the PLG chain, thereby forming an amide bond.
In one embodiment, the PLG chain is bound to Q ' by a covalent bond between Fc, Fc ", Fb ', Fa or Fa ' and a functional amine at the N-terminal position of the PLG chain, thereby forming an amide bond.
In one embodiment, Q' is a group according to formula V, and Q ═ 1.
In one embodiment, Q' is a group according to formula V in combination with one or two groups according to formula III, and 2. ltoreq. q.ltoreq.3.
In one embodiment, Q' is a group according to formula V in combination with one or two groups according to formula IV, and 2. ltoreq. q.ltoreq.3.
In one embodiment, Q' is a group according to formula V in combination with a group according to formula III, and Q ═ 2.
In one embodiment Q Q' is selected from groups according to formula III, IV and V, and Q comprises at least two groups according to formula V, wherein 2 ≦ Q ≦ 4, and Q [ - ] I is a group wherein I ═ 4, and the copolymeric amino acid according to formula I is a copolymeric amino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 2 and k is 2
-2 Hy according to formula X are bound to Q 'via a covalent bond with Fa, Fa', Fb 'or Fc, Fc', Fc "forming an amide bond,
-2 PLG chains are bound to Q 'via covalent bonds to Fa, Fa', Fb 'or Fc, Fc', Fc ", thereby forming amide bonds.
In one embodiment, 2 Hy according to formula X are bound to Q ' via a covalent bond with Fc ' forming an amide bond, and 2 PLG chains are bound to Q ' via a covalent bond with Fc ″, forming an amide bond.
In one embodiment, q is 2.
In one embodiment, q is 3.
In one embodiment, q is 4.
In one embodiment, Fc is-CO-, and Fa, Fa ', Fb and Fb' are-NH-.
In one embodiment, Fc 'is-NH-, and Hy is bound to Fc' via a carbonyl function carried by GpR, GpG, GpA, ghph, GpC, or GpL de Hy.
In one embodiment, Fc 'is-NH-, and PLG is bound to Fc' via a carbonyl functional group at the C-terminal position of PLG.
In one embodiment, Q is a group consisting of a group selected from the group according to formula IV or V and at least two groups according to formula V, wherein 2 ≦ Q ≦ 3, and Q [ - ] i is a group wherein i ═ 4.
In one embodiment Q is a group consisting of a group selected from the group according to formula III or V and at least two groups according to formula V, wherein 2 ≦ Q ≦ 3, and Q [ - ] i is a group wherein i ═ 4.
In one embodiment Q is a group consisting of a group selected from the group according to formula V and at least two groups according to formula V, wherein 2 ≦ Q ≦ 3, and Q [ - ] i is a group according to formula (la) wherein i ═ 4.
In one embodiment Q Q' is selected from groups according to formulae VI and III, and Q comprises at least two groups according to formula VI, wherein 2 ≦ Q ≦ 3, and Q [ - ] I is a group wherein I ═ 4, and the copolymeric amino acid according to formula I is a copolymeric amino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 2 and k is 2
-2 Hy according to formula X are bound to Q' via a covalent bond with Fy forming an amide bond,
-2 PLG chains are bound to Q 'via a covalent bond to Fd or Fd' forming an amide bond.
In one embodiment Q Q' is selected from groups according to formulae VI and III, and Q comprises at least two groups according to formula VI, wherein Q ═ 3, and Q [ - ] i is a group wherein i ═ 4.
In one embodiment, Q and Q' are selected from groups according to formula III, IV, V or VI, wherein at least two groups are selected from groups according to formula V and groups according to formula VI, wherein 2. ltoreq. q.ltoreq.5, and Q [ - ] i is a group wherein 4. ltoreq. i.ltoreq.6
And the polyamino acid is a polyamino acid according to general formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 1, and k is 3. ltoreq. k.ltoreq.5
-Hy according to formula X is bound to Q' via a covalent bond with Fa, Fb, Fc or Fy forming an amide bond,
-PLG k chain is bound via a covalent bond to Fa, Fa ', Fb ', Fc ", Fd or Fd ' forming an amide bond.
In one embodiment Q Q' is selected from a group according to formula III, IV, V or VI, wherein at least two groups are selected from a group according to formula V and a group according to formula VI, wherein 2 ≦ Q ≦ 3, and Q [ - ] I is a group wherein I ═ 4, and the copolymeric amino acid is a copolymeric amino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 1 and k is not less than 3
-Hy according to formula X is bound to Q' via a covalent bond with Fc forming an amide bond,
-3 PLG chains are covalently bound to Fc ", Fd' forming amide bonds.
In one embodiment, Q is a group consisting of at least one group according to formula VI and at least one group according to formula V, wherein Q ≧ 2, and Q [ - ] i is a group wherein i ═ 4
In one embodiment, j is 1 and k is 3
Fc '(wherein Fc' ═ CO-) is bound to Fy by a covalent bond to form an amide bond
Fc "is covalently bound to the PLG chain to form an amide bond.
In one embodiment, Fc "is-NH-and is bound to PLG through a carbonyl group at the C-terminal position to form an amide bond.
In one embodiment, Fc is-NH-and binds to the carbonyl of Hy carried by GpR, GpA, GpG, ghph, GpL, or GpC.
In one embodiment, the hydrophobic group-Hy is selected from a group of formula X defined as follows:
wherein,
-GpR is selected from a group according to formula VII, VII' or VII ":
-GpG and GpH, equal or different, are selected from groups according to formula XI or XI':
-GpA is selected from the group according to formula VIII
Wherein A ' is selected from a group according to formula VIII ', VIII ", or VIII '"
-GpL is selected from the group according to formula XII
-GpC is a group according to formula IX:
-;
-a is an integer equal to 0 or equal to 1, and if a ═ 0, then a' ═ 1; and if a is 1, then a' is 1,2 or 3;
a' is an integer equal to 1, equal to 2 or equal to 3
-b is an integer equal to 0 or equal to 1;
-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;
-d is an integer equal to 0, equal to 1 or equal to 2;
-e is an integer equal to 0 or equal to 1;
-g is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-h is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-l is an integer equal to 0 or 1, and if l ═ 0, then l' ═ 1; and if l is 1, then l' is 2;
-r is an integer equal to 0 or equal to 1, and
-s' is an integer equal to 0 or 1;
-A、A1、A2and A3Identical or different, are linear or branched alkyl groups containing from 1 to 6 carbon atoms.
-B is a linear or branched alkyl group, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
-Cx is a monovalent linear or branched alkyl group, wherein x represents the number of carbon atoms, and
■ when the hydrophobic group-Hy carries 1-GpC, then x is more than or equal to 9 and less than or equal to 25,
■ when the hydrophobic group-Hy carries 2-GpCs, x is more than or equal to 9 and less than or equal to 15,
■ when the hydrophobic group-Hy carries 3-GpCs, then x is more than or equal to 7 and less than or equal to 13,
■ when the hydrophobic group-Hy carries 4-GpCs, then x is more than or equal to 7 and less than or equal to 11,
■ when the hydrophobic group-Hy carries at least 5-GpC, then x is greater than or equal to 6 and less than or equal to 11,
-G is a branched alkyl group of 1 to 8 carbon atoms, said alkyl group bearing one or more carboxyl functions.
-H is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions.
-R is chosen from among a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, comprising from 1 to 12 carbon atoms and bearing one or more-CONH2A divalent linear or branched alkyl group of a functional group, or a group of unsubstituted ether or polyether groups containing from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
-one or more hydrophobic groups according to formula X-Hy bound to Q:
formation of an amide function by reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor of the hydrophobic group-Hy', via a covalent bond between the carbonyl group of the hydrophobic group-Hy and the nitrogen atom carried by Q, and
formation of an amide function by reaction of the amine function of the precursor Hy' of the hydrophobic group-Hy and of the acid function of the precursor of the group Q, via a covalent bond between the nitrogen atom of the hydrophobic group-Hy and the carbonyl group carried by Q,
-the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is 0 < M.ltoreq.0.5;
when several hydrophobic groups are carried by the polyamino acid, they are identical or different,
-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;
-the free carboxylic acid function is chosen from Na+And K+Basic cationic form of (a).
In one embodiment, the at least one hydrophobic group-Hy is selected from a group according to formula X, wherein
-l＝0，
-according to formula Xd defined below
Wherein,
-GpR is selected from a group according to formula VII, VII' or VII ":
-GpG is selected from a group according to formula XI or XI':
-GpA is selected from a group according to formula VIII, wherein s '═ 1 is according to formula VIIIa or according to formula VIII, wherein s' ═ 0 is according to formula VIIIb:
-GpC is a group according to formula IX:
-;
-a is an integer equal to 0 or equal to 1, and if a ═ 0, then a' ═ 1; and if a is 1, then a ' is 1 or a ' is 2 or a ' is 3;
-a' is an integer equal to 1 or 2, and
if a' is equal to 1, then a is equal to 0 or equal to 1 and GpA is a group according to formula VIIIb, and
if a' is equal to 2, a is equal to 1 and GpA is a group according to formula VIIIa;
-b is an integer equal to 0 or equal to 1;
-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;
-d is an integer equal to 0, equal to 1 or equal to 2;
-e is an integer equal to 0 or equal to 1;
-g is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-h is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-r is an integer equal to 0 or equal to 1, and
-s' is an integer equal to 0 or 1;
-A1is a straight or branched alkyl group containing 1 to 6 carbon atoms;
-B is a linear or branched alkyl group, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
-Cxis a monovalent linear or branched alkyl radical, wherein x represents the number of carbon atoms, and
■ when the hydrophobic group-Hy carries 1-GpC, then x is more than or equal to 9 and less than or equal to 25,
■ when the hydrophobic group-Hy carries 2-GpCs, x is more than or equal to 9 and less than or equal to 15,
■ when the hydrophobic group-Hy carries 3-GpCs, then x is more than or equal to 7 and less than or equal to 13,
■ when the hydrophobic group-Hy carries 4-GpCs, then x is more than or equal to 7 and less than or equal to 11,
■ when the hydrophobic group-Hy carries at least 5-GpC, then x is greater than or equal to 6 and less than or equal to 11,
g is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions,
-H is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions,
-R is a group selected from a divalent linear or branched alkyl group comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl group comprising from 1 to 12 carbon atoms and bearing one or more functional groups-CONH 2, or an unsubstituted ether or polyether group comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
-one or more hydrophobic groups Hy according to formula X are bound to Q:
formation of an amide function by reaction of an amine function carried by a precursor of Q and an acid function carried by a precursor of a hydrophobic group, via a covalent bond between the carbonyl group of the hydrophobic group and the nitrogen atom carried by Q, and
o via a covalent bond between the nitrogen atom of the hydrophobic group and the carbonyl group carried by Q, so that an amide function is formed by the reaction of the amine function of the precursor of the hydrophobic group-Hy' and of the acid function carried by the precursor of the group Q.
-the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is 0 < M.ltoreq.0.5;
when several hydrophobic groups are carried by the polyamino acid, they are identical or different,
-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;
-the free carboxylic acid function is chosen from Na+And K+Basic cationic form of (a).
In one embodiment, the hydrophobic group-Hy is selected from groups of formula X, as defined below, wherein l ═ 0,
-GpA is selected from a group according to formula VIII, wherein s ' ═ 1 and a ' is selected from a group according to formula VIII "or VIII '":
wherein,
-GpR is selected from a group according to formula VII, VII' or VII ":
-GpG is selected from a group according to formula XI or XI':
-GpA is selected from a group according to formula VIIIc or VIIId:
-GpC is a group according to formula IX:
-;
-a is an integer equal to 0 or equal to 1, and if a ═ 0, then a' ═ 1; and if a is 1, then a' is 2;
-a' is an integer equal to 2 or equal to 3, and
if a' is equal to 1, then a is equal to 0, and
if a' is equal to 2 or 3, a is equal to 1 and GpA is a group according to formula VIIIc or VIIId;
-b is an integer equal to 0 or equal to 1;
-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;
-d is an integer equal to 0, equal to 1 or equal to 2;
-e is an integer equal to 0 or equal to 1;
-g is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-h is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;
-r is an integer equal to 0 or equal to 1, and
-s' is an integer equal to 1;
-A1、A2、A3identical or different, are linear or branched alkyl groups containing from 1 to 6 carbon atoms.
-B is a linear or branched alkyl group, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
-Cxis a monovalent linear or branched alkyl radical, wherein x represents the number of carbon atoms, and
■ when the hydrophobic group-Hy carries 1-GpC, then x is more than or equal to 9 and less than or equal to 25,
■ when the hydrophobic group-Hy carries 2-GpCs, x is more than or equal to 9 and less than or equal to 15,
■ when the hydrophobic group-Hy carries 3-GpCs, then x is more than or equal to 7 and less than or equal to 13,
■ when the hydrophobic group-Hy carries 4-GpCs, then x is more than or equal to 7 and less than or equal to 11,
■ when the hydrophobic group-Hy carries at least 5-GpC, then x is greater than or equal to 6 and less than or equal to 11,
-one or more hydrophobic groups Hy according to formula X are bound to Q:
formation of an amide function by reaction of an amine function carried by a precursor of Q and an acid function carried by a precursor of a hydrophobic group Hy', via a covalent bond between the carbonyl group of the hydrophobic group and the nitrogen atom carried by Q, and
the amide function is formed by reaction of the amine function of the precursor Hy' of the hydrophobic group and of the acid function of the precursor of the group Q, via a covalent bond between the nitrogen atom of the hydrophobic group and the carbonyl group carried by Q.
G is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions,
-H is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions,
-R is a group selected from a divalent linear or branched alkyl group comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl group comprising from 1 to 12 carbon atoms and bearing one or more functional groups-CONH 2, or an unsubstituted ether or polyether group comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
-the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is 0 < M.ltoreq.0.5;
when several hydrophobic groups are carried by the polyamino acid, they are identical or different,
-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;
-the free carboxylic acid function is chosen from Na+And K+Basic cationic form of (a).
In one embodiment, R is a group selected from:
a divalent linear or branched alkyl group comprising from 2 to 12 carbon atoms if GpR is a group according to formula VII, or from 1 to 11 carbon atoms if GpR is a group according to formula VII';
○ is a divalent linear or branched alkyl group containing from 2 to 11 carbon atoms if GpR is a group according to formula VII or from 1 to 11 carbon atoms if GpR is a group according to formula VII', the alkyl group bearing one or more functional groups-CONH2And are and
unsubstituted ether or polyether groups containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms.
In the formula, a represents a binding site of a hydrophobic group to Q < - > i. The group-Hy is bound to Q < - > i via an amide function.
In formulas VII, VII' and VII ", from left to right represent the binding sites from GpR to the following, respectively:
-to Q [ - ]]i(ii) a And
-if g ═ 1, to GpG; or to GpA if g ═ 0.
In formulas VIIIa, VIIIb, VIIIc and VIIId, binding sites from GpA to GpA are indicated, respectively:
-if g ═ 1, to GpG; or if r ═ 1 and g ═ 0, to GpR; or if g ═ r ═ 0, to Q [ - ] i; and
-if l ═ 1, to GpL; or to GpH if h ═ 1 and 1 ═ 0; or to GpC if 1 ═ h ═ 0
In formula IX, denotes the binding site of GpC to:
-to ghh if h ═ 1;
-if l ═ 1 and h ═ 0, to GpL
-if a ═ 1 and h ═ l ═ 0, to GpA
-if g ═ 1 and h ═ l ═ a ═ 0, to GpG
-if r-1 and h-l-a-g-0, to GpR
-if h ═ l ═ g ═ r ═ 0, to Q [ - ] i
All linkages between different groups of GpR, GpG, GpA, GpL, GpH and GpC are amide functions.
The groups Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently the same or different.
In one embodiment, r ═ 0, and the hydrophobic group according to formula X is bound to Q via a covalent bond between the carbonyl group of the hydrophobic group and the nitrogen atom carried by Q, so that an amide function is formed from the reaction of the amine function carried by the precursor of Q and the acid function carried by the precursor of the hydrophobic group Hy'.
In one embodiment, r ═ 1, and a hydrophobic group according to formula X is bound to Q:
■ through a covalent bond between the nitrogen atom of the hydrophobic group and the carbonyl group carried by Q, an amide function being formed by the reaction of the amine function of the precursor Hy' of the hydrophobic group and of the acid function carried by the precursor of the group Q, or
■ through a covalent bond between the carbonyl group of the hydrophobic group and the nitrogen atom carried by Q, an amide function being formed by the reaction of the acid function of the precursor Hy 'of the hydrophobic group-Hy and of the amine function of the precursor Q' of the group Q.
In one embodiment, if GpA is a group according to formula VIIIc and r ═ 1, then:
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα1And Nα2And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)β1Or is or
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα1And Nβ1And Q [ - ]]i via-GpR-GpG-or-GpR- (if g ═ 0) bound to Nα2(ii) a Or
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα2And Nβ1And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)α1。
In one embodiment, if GpA is a group according to formula VIIIc and r ═ 0, then:
binding of GpC to Nα1And Nα2And Q [ - ]]i (if g ═ 0) or GpG binds to Nβ1(ii) a Or
Binding of GpC to Nα1And Nβ1And Q [ - ]]i (if g ═ 0) or GpG binds to Nα2(ii) a Or
Binding of GpC to Nα2And Nβ1And Q [ - ]]i (if g ═ 0) or GpG binds to Nα1。
In one embodiment, if GpA is a group according to formula VIIId and r ═ 1, then:
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα1、Nα2And Nβ1And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)β2(ii) a Or
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα1、Nα2And Nβ2And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)β1(ii) a Or
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα1、Nβ1And Nβ2And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)α2(ii) a Or
-GpL or ghh (if l ═ 0) or GpC (if l ═ h ═ 0) bound to Nα2、Nβ1And Nβ2And Q [ - ]]i binding to N via-GpR-GpG-or-GpR- (if g ═ 0)α1
In one embodiment, if GpA is a group according to formula VIIId and r ═ 0, then:
binding of GpC to Nα1、Nα2And Nβ1And Q [ - ]]i (if g ═ 0) or GpG binds to Nβ2(ii) a Or
Binding of GpC to Nα1、Nα2And Nβ2And Q [ - ]]i (if g ═ 0) or GpG binds to Nβ1(ii) a Or
Binding of GpC to Nα1、Nβ1And Nβ2And Q [ - ]]i (if g ═ 0) or GpG binds to Nα2(ii) a Or
Binding of GpC to Nα2、Nβ1And Nβ2And Q [ - ]]i (if g ═ 0) or GpG binds to Nα1
In one embodiment, when a' is 1, x consists of 11 and 25 (11 ≦ x ≦ 25). In particular, when x consists of 15 and 16 (x ═ 15 or 16), then R ═ 1, and R is an ether group or a polyether; and when x is greater than 17(x ≧ 17), then R ═ 1, and R is an ether group or a polyether.
In one embodiment, when a' is 2, x consists of 9 and 15 (9 ≦ x ≦ 15).
In one embodiment, the at least one hydrophobic group-Hy is selected from groups according to formula X, wherein according to formula Xa, a ═ 1 and a' ═ 1 defined below:
wherein GpA is a group according to formula VIII and A ' is selected from a group according to formula VIII ', wherein s ' ═ 0, and GpA is a group according to formula VIIIb
And GpR, GpG, GpA, GpL, GpH, GpC, A1, r, g, h, l and l' are as defined above.
In one embodiment, the at least one hydrophobic group-Hy is selected from groups according to formula X, wherein a is 1 according to formula Xb, as defined below:
wherein GpA is a group according to formula VIII and A ' is selected from a group according to formula VIII ', wherein s ' ═ 1, and GpA is a group according to formula VIIIa
And GpR, GpG, GpA, GpL, GpH, GpC, A1, a ', r, g, h, l and l' are as defined above.
In one embodiment, the hydrophobic group-Hy is selected from groups of formula X defined as follows, wherein a ═ 1:
wherein GpA is a group according to formula VIII and A is selected from a group according to formula VIII ", wherein s' ═ 1, and GpA is a group according to formula VIIIc
And GpR, GpG, GpA, GpL, GpH, GpC, A1, A2, r, g, h, a ', l and l' are as defined above.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula X defined as follows, wherein a ═ 1:
wherein GpA is a group according to formula VIII and A is selected from a group according to formula VIII '", wherein s' ═ 1, and GpA is a group according to formula VIIId
And GpR, GpG, GpA, GpL, GpH, GpC, A1, A2, A3, a ', r, g, h, l and l' are as defined above.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups according to formula X, wherein according to formula Xc, r ═ 1, defined as follows:
wherein GpR is a group according to formula VII.
And GpR, GpG, GpA, GpL, GpH, GpC, R, a ', g, h, l and l' are as defined above.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula Xc defined according to the following:
wherein GpR is a group according to formula VII'.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula Xc defined according to the following:
wherein GpR is a group according to formula VII ".
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula X defined as follows:
wherein GpC is a group according to formula IX, wherein e ═ 0, and GpC is a group according to formula IXa
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula X defined as follows:
wherein GpC is a group according to formula IX, wherein e ═ 1, b ═ 0, and GpC is a group according to formula IXd
In one embodiment, said at least one hydrophobic group-Hy is selected from groups of formula X defined as follows:
wherein GpC is a group according to formula IX, wherein e ═ 1, and GpC is a group according to formula IXb.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups according to formula X, wherein X, r, g, a, l, h are equal to 0 according to formula Xd, defined as follows:
the formula of January-GpC Xd'.
In one embodiment, said at least one hydrophobic group-Hy is selected from groups according to formula X, wherein r, g, a, l, h are equal to 0 according to formula Xc, defined as follows:
-GpC type Xd'
Wherein GpC is a group according to formula IX, wherein e ═ 0, b ═ 0, and GpC is a group according to formula IXc
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein GpA is a group according to formula VIIIb, according to the following formula Xe, a' ═ 1, and l ═ 0:
GpR, GpG, GpA, GpH, GpC, r, g, h and a are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xf, a ═ 2, and a ═ 1, and l ═ 0, according to the following formulae:
GpR, GpG, GpA, GpH, GpC, r, g and h are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xg, h ═ 0, l ═ 0, and l ═ 1 according to the following formula:
GpR, GpG, GpA, GpC, r, g, a and a' are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xh, h ═ 0, a ═ 1 according to the following formula:
GpR, GpG, GpA, GpC, r, a and g are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xi, h ═ 0, a ═ 2, and a ═ 1 according to the following formulae:
GpR, GpG, GpA, GpC, r and g are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xj, h ═ 0, and g ═ 0 according to the following formula:
GpR, GpA, GpC, r, a' and a are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is selected from hydrophobic groups according to formula X, wherein Xk, h ═ 0, and g ═ 0, and a ═ 1 according to the following formulae:
GpR, GpA, GpC, r and a are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X is selected from hydrophobic groups according to formula X, wherein Xl, h ═ 0, and g ═ 0, and a ═ 1, and a ═ 2:
wherein GpR, GpA, GpC and r are as defined above.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X is selected from hydrophobic groups according to formula X, wherein a ═ 1, and g ═ l ═ 0:
according to the following formula Xn:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X is selected from hydrophobic groups according to formula X, wherein Xp, a ═ 1, and a ═ 2, and g ═ l ═ 0, according to the following formulae:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X is selected from hydrophobic groups according to formula X, wherein Xm, a ═ 1, g, h and l ═ 0, and a ═ 3, according to the following formulae:
wherein GpA is a group selected from the group according to formula VIIId and GpR, GpC, r are as defined above.
In one embodiment, a-0,
in one embodiment, h is 1, and g is 0,
in one embodiment, h is 0, and g is 1,
in one embodiment Q Q' is selected from groups according to formulas VI, III and IV and Q comprises at least one group according to formula VI wherein Q ≧ 1 and Q [ - ] i is a group wherein i ═ 3
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Where j is 1 and k is 2.
In one embodiment Q Q' is selected from groups according to formula III, IV and V, and Q comprises at least one group according to formula V, wherein Q ≧ 1, and Q [ - ] i is a group wherein i ═ 3
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Where j is 1 and k is 2.
In one embodiment Q Q' is selected from a group according to formula III, IV or V and Q comprises at least two groups according to formula V wherein 2 ≦ Q ≦ 3 and Q [ - ] i is a group wherein i ═ 4, and the co-moieties are conjugated to form a conjugated polymer
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Where j is 2 and k is 2.
In one embodiment Q Q' is selected from groups according to formula III, IV, V or VI, wherein at least one group is according to formula V and at least one group is according to formula VI, wherein 2 ≦ Q ≦ 3 and Q [ - ] i is a group wherein 4 ≦ i ≦ 6
The polyamino acid is a polyamino acid according to formula I:
Q[Hy]j[PLG]k
formula I
Wherein j is 1, and k is 3. ltoreq. k.ltoreq.5
In one embodiment, r is 0, g is 1, and h is 0.
In one embodiment, r ═ 1, and GpR are selected from groups according to formula VII' or VII ", and h ═ 0.
In one embodiment, r ═ 1, g ═ 0, and GpR are groups according to formula VII', and h ═ 0.
In one embodiment, r ═ 1, g ═ 0, and GpR are groups according to formula VII', and h ═ 1.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is selected from groups according to formula VIIIa or VIIIb, and h ═ 0.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is selected from groups according to formula VIIIa or VIIIb, and h ═ 1.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is a group according to formula VIIIa, and h ═ 0.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is a group according to formula VIIIa, and h ═ 1.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is a group according to formula VIIIb, and h ═ 0.
In one embodiment, r ═ 1, g ═ 0, GpR are groups according to formula VII', GpA is a group according to formula VIIIb, and h ═ 1.
In one embodiment, r ═ 0, and GpA is selected from groups according to formulas VIIIa and VIIIb.
In one embodiment, r ═ 0, g ═ 0, and GpA is selected from groups according to formulas VIIIa and VIIIb.
In one embodiment, r ═ 0, GpA is selected from groups according to formulas VIIIa and VIIIb, and h ═ 0.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xc, Xe, Xd, Xg, XhXj or Xk, wherein r is equal to 1(r ═ 1) and a is equal to 0(a ═ 0).
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xd' Xe, Xg, XhXj or Xk, wherein r is equal to 0(r ═ 0) and a is equal to 0(a ═ 0).
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein r is equal to 1(r ═ 1) and a is equal to 1(a ═ 1).
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is according to formula X, Xa, Xb, Xc, Xd, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl; xn, Xp or Xm, wherein r ═ 1, and GpR is a group according to formula VII.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xa, Xe, Xh, Xk or Xl, wherein r ═ 1 and GpR is a group according to VII.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xf, Xi or Xl, wherein r ═ 1, and GpR is a group according to formula VII.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xm, wherein r ═ 1, and GpR is a group according to formula VII.
In one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, wherein R is a divalent straight chain alkyl group comprising 2 to 12 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, X1, Xd, Xn, Xp or Xm, wherein R is 1 and GpR is a group according to formula VII, wherein R is a divalent alkyl group comprising 2 to 6 carbon atoms.
In one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, wherein R is a divalent straight chain alkyl group comprising 2 to 6 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, wherein R is a divalent alkyl group comprising 2 to 4 carbon atoms.
In one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, wherein R is a divalent straight chain alkyl group comprising 2 to 4 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, wherein R is a divalent alkyl group comprising 2 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein r ═ 1 and GpR is a group according to formula VII'.
In one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1 and GpR is a group according to formula VII', wherein R is a divalent straight chain alkyl group comprising 1 to 11 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII', wherein R is a divalent alkyl group comprising 1 to 6 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, where R is 1, and GpR is a group according to formula VII or VII', where R is a group containing 2 to 5 carbon atoms and bearing one or more amide functions (-CONH), or (-CONH)2) A divalent alkyl group of (a).
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, where R is 1, and GpR is a group according to formula VII' or VII, where R is a group containing 2 to 5 carbon atoms and bearing one or more amide functions (-CONH)2) Is/are as followsA divalent straight chain alkyl group.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R ═ 1, and GpR is a group according to formula VII, VII', or VII ", wherein R is a group selected from the group represented by the following formulae:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, VII' or VII ", wherein R is an unsubstituted linear ether or polyether group comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, VII' or VII ", wherein R is an ether group.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R ═ 1, and GpR is a group according to formula VII, VII', or VII ", wherein R is an ether group comprising 4 to 6 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and CpR is a group according to formula VII, VII' or VII ", wherein R is an ether group represented by formula (la).
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, VII' or VII ", wherein R is a polyether group.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R is 1, and GpR is a group according to formula VII, VII' or VII ", wherein R is a linear polyether group comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R ═ 1, and GpR are a group according to formula VII, VII' or VII ", wherein R is a polyether group selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group according to formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, Xl, Xd, Xn, Xp or Xm, wherein R ═ 1, and GpR are groups, wherein R is a polyether group selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe, Xg, Xf, Xh or Xi, wherein g ═ 1, and GpG is selected from the group according to formula XIa, XIb, XIc, XId, Xi 'e or Xi' f, represented below.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe or Xf, wherein h ═ 1 and the ghh is selected from the group according to formula XIa, XIb, XIc, XId, XI 'e or XI' f, represented below.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk or Xn, wherein a is equal to 1(a ═ 1) and a ═ 1, the group GpA is a group according to formula VIIIb, and a ═ 11Selected from the group represented by the following formula.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIa is selected from the group of formulae VIIIaa and VIIIab according to the following representation:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIa is a group according to formula VIIIab represented below:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or XpGroup GpA of VIIIc is selected from groups in which A1And A2Identical or different, selected from linear alkyl groups.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is selected from the group wherein a is1And A2Identical or different, from linear alkyl groups comprising from 3 to 4 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is selected from the group wherein a is1Selected from linear alkyl radicals containing 3 carbon atoms, A2Selected from linear alkyl groups comprising 4 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is selected from the group wherein a is1And A2And are selected from straight chain alkyl groups containing 3 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is selected from the group consisting of
Groups VIIIca and VIIIcb:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is a group according to formula VIIIca.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the group GpA according to formula VIIIc is a group according to formula VIIIcb.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the precursors of the group GpA according to formula VIIIc are selected from triamines, which are spermidine and spermidine nor:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the precursor of the group GpA according to formula VIIIc is spermidine.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xb, Xc, Xg, Xf, Xi, Xj, Xl or Xp, wherein the precursor of the group GpA according to formula VIIIc is norspermidine.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xm, wherein the group GpA is selected from the group according to formula VIIId, wherein a is1、A2And A3Identical or different, from linear alkyl groups comprising from 3 to 4 carbon atoms.
In one embodiment of the process of the present invention,the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xm, wherein the group GpA according to formula III' is selected from the group according to formula VIIId, wherein A is1And A3Is selected from straight-chain alkyl radicals containing 3 carbon atoms, and A2Selected from linear alkyl groups comprising 4 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xm, wherein the group GpA according to formula VIIId is a group according to formula VIIIda:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula Xm, wherein the precursor of the group GpA according to formula VIIId is spermine:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd ', Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xpou Xm, wherein the group GpC according to formula IX is selected from the group according to formula IXa', IXb 'or IXc' represented below:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd ', Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein the group GpC is according to formula IXa'.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein the group GpC according to formula IX is selected from a group according to formula IXa ', IXb ' or IXc ', wherein b is equal to 0, respectively of formula IXd, IXe and IXf, represented below:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein the group GpC is according to formula IX or IXa', wherein b is 0 and is according to formula IXd.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein the group GpC according to formula IX (wherein B ═ 1) is selected from the group wherein B is an amino acid residue selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, Xl, Xn, Xp or Xm, wherein the group GpC according to formula is according to formula IX or IXa, wherein B ═ 1, is selected from the group wherein B is an amino acid residue selected from the group represented by the following formula:
in one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from straight chain alkyl groups comprising 11 to 25 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from branched alkyl groups comprising 11 to 25 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 11 to 14 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group of X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 15 to 16 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 17 to 25 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 17 to 18 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 19 to 25 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn, wherein a '═ 1 or l' ═ 1, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 18 to 19 carbon atoms.
a '═ 2 or l' ═ 2
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from linear alkyl groups comprising 9 to 15 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from branched alkyl groups comprising 9 to 15 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 9 or 10 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 11 to 15 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 11 to 13 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 14 or 15 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, Xl, Xp, wherein a '═ 2 or l' ═ 2, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from the group represented by the following formula:
in one embodiment the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xg, Xj, Xm, wherein a' ═ 3, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from linear alkyl groups comprising 7 to 13 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xg, Xj, Xm, wherein a' ═ 3, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from branched alkyl groups comprising 7 to 13 carbon atoms.
In one embodiment, the composition according to the invention is characterized in that the hydrophobic group is a group according to formula X, Xa, Xb, Xc, Xg, Xj, Xm, wherein a' ═ 3, wherein the group GpC according to formula IX is selected from groups wherein Cx is selected from alkyl groups comprising 7, 9 or 11 carbon atoms.
When the polyamino acid contains one or more aspartic acid units, the latter may undergo structural rearrangements.
In one embodiment, the composition according to the invention is characterized in that the copolymerized amino acid carrying a carboxylate charge and the at least one hydrophobic group-Hy are chosen from copolymerized amino acids according to the following formula XXXa:
wherein,
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
● X represents a cationic entity selected in the group comprising alkali metal cations,
●Raand Ra' identical or different, is a group selected from H, C2 to C10 straight acyl, C3 to C10 branched acyl, benzyl, terminal amino acid unit and pyroglutamate,
● Q, Hy and j are as defined above.
●
To representThe degree of polymerization DP of the copolymerized amino acid, namely the average number of monomer units in the copolymerized amino acid chain, and n + m is more than or equal to 5 and less than or equal to 250;
in one embodiment, the composition according to the invention is characterized in that the copolyamino acid carrying a carboxylate charge and at least one hydrophobe-Hy is selected from copolyamino acids according to formula XXXA, wherein R isaAnd Ra' same or different, selected from H and pyroglutamate.
In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobe-Hy are selected from the group consisting of copolyamino acids according to the following formula XXXa':
wherein:
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
● X represents a cationic entity selected in the group comprising alkali metal cations,
● Q, Hy and j are as defined above.
●RaAnd Ra' identical or different, are a radical selected from the group consisting of H, C2 to C10 straight-chain acyl, C3 to C10 branched-chain acyl, benzyl, terminal amino acid unit and pyroglutamate,
●n1+m1represents the number of glutamic acid or aspartic acid units of the PLG chain of a polyamino acid having a group-Hy,
●n2+m2represents the number of glutamic acid or aspartic acid units of the PLG chain of a polyamino acid having a group-Hy,
●n1+n2n, and m1+m2＝m
● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250;
in one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula:
XXXa”：
wherein:
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
● X represents a cationic entity selected in the group comprising alkali metal cations,
● Q, Hy and j are as defined above.
●RaAnd Ra' identical or different, is at least one hydrophobic group-Hy and a group selected from-Hy, H, C2 to C10 linear acyl, C3 to C10 branched acyl, benzyl, terminal "amino acid" units and pyroglutamate,
● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250;
in one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula:
XXXb：
wherein,
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
●R2represents the formula Q-according to the previous definition]The group or spacer of i,
● X represents a cationic entity selected in the group comprising alkali metal cations,
●Rband Rb'same or different' is a-NR 'R' group, R 'and R' are same or different and are selected from H, C2 to C10 linear or branched or cyclic alkyl, benzyl andsaid R' and R "alkyl groups may together form one or more saturated, unsaturated and/or aromatic carbocyclic rings and/or may contain a heteroatom selected from O, N and S;
● Q, Hy and j are as defined above.
● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250.
XXXb’
In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula:
XXXh’：
wherein:
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
● X represents a cationic entity selected in the group comprising alkali metal cations,
● Q, Hy and j are as defined above.
●RbAnd Rb'same or different, -is an-NR' R "group, R 'and R" same or different, selected from H, C2 to C10 linear or branched or cyclic alkyl groups, benzyl and said R' and R "alkyl groups may together form one or more saturated, unsaturated and/or aromatic carbocyclic rings and/or may contain heteroatoms selected from O, N and S;
● n1+ m1 denotes the number of glutamic acid or aspartic acid units of the PLG chain of the polyamino acid bearing the group-Hy,
● n2+ m2 denotes the number of glutamic acid or aspartic acid units of the PLG chain without the polyamino acid having a group-Hy,
● n1+ n2 ═ n, and m1+ m2 ═ m
n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250;
in one embodiment, the composition according to the invention is characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula XXXb ":
wherein:
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),
● X represents a cationic entity selected in the group comprising alkali metal cations,
●Rband Rb'same or different, is at least one hydrophobic group-Hy and a group selected from hydrophobic groups-Hy and-NR' R ", R 'and R" same or different, selected from H, C2 to C10 linear or branched or cyclic alkyl, benzyl and said R' and R "alkyl groups may together form one or several saturated, unsaturated and/or aromatic carbocyclic rings and/or may contain heteroatoms selected from O, N and S;
● Q, Hy and j are as defined above.
● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250;
in one embodiment, the composition according to the invention is characterized in that when the copolymeric amino acid comprises aspartic acid units, then the copolymeric amino acid may further comprise monomer units according to formula XXXX and/or XXXX':
the term "random graft copolymeric amino acids" refers to copolymeric amino acids with a carboxylate charge and at least one hydrophobic group, i.e. according to formulae XXXa 'and XXXb'.
The term "defined graft copolymeric amino acids" refers to copolymeric amino acids with a carboxylate charge and at least one hydrophobic group, i.e. according to formulae XXXa, XXXa '", XXXb and XXXb'".
In one embodiment, the composition according to the invention is characterized in that the co-amino acid carrying a carboxylate charge and a hydrophobe is selected from co-amino acids according to formula XXXA, XXXA ' ', XXXB ', or XXXB ' ', wherein the co-amino acid is selected from wherein the group D is-CH2-a radical (aspartic acid units).
In one embodiment the composition according to the invention is characterized in that the copolymeric amino acid carrying a carboxylate charge and a hydrophobic group is selected from the group consisting of the copolymeric amino acids according to formula XXXa, XXXa ', XXXa ", XXXb' or XXXb", wherein the copolymeric amino acid is selected from the group consisting of those wherein the group D is-CH2-CH2-a radical (glutamic acid unit).
The ratio of hydrophobe to basal insulin is defined as the ratio of their respective molarity: [ Hy ]/[ basal insulin ] (mol/mol) for obtaining the desired properties, i.e. dissolution of the basal insulin at a pH of 6.0 to 8.0, precipitation of the basal insulin and stability of the composition according to the invention.
The minimum measure of the ratio of hydrophobic group to basal insulin [ Hy ]/[ basal insulin ] is the value of the basal insulin to be dissolved, since dissolution is the minimum effect to be obtained. This dissolution is a condition for all other technical effects which are only observed when basal insulin is dissolved at a pH of 6.0 to 8.0.
In the composition according to the present invention, the ratio of hydrophobic group to basal insulin [ Hy ]/[ basal insulin ] may be greater than a minimum value determined by the solubility limit.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 2.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 1.75.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 1.5.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 1.25.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 1.00.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 0.75.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 0.5.
In one embodiment, the ratio of hydrophobe to basal insulin [ Hy ]/[ basal insulin ] ≦ 0.25.
In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic bases and the number of glutamic acid or aspartic acid units is comprised between 0.007 and 0.3.
In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is between 0.01 and 0.3.
In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is between 0.02 and 0.2.
In one embodiment, the composition according to the invention is characterized in that n + m is from 10 to 200.
In one embodiment, the composition according to the invention is characterized in that n + m is from 15 to 150.
In one embodiment, the composition according to the invention is characterized in that n + m is from 15 to 100.
In one embodiment, the composition according to the invention is characterized in that n + m is from 15 to 80.
In one embodiment, the composition according to the invention is characterized in that n + m is from 15 to 65.
In one embodiment, the composition according to the invention is characterized in that n + m is from 20 to 60.
In one embodiment, the composition according to the invention is characterized in that n + m is from 20 to 50.
In one embodiment, the composition according to the invention is characterized in that n + m is from 20 to 40.
The invention further relates to a process for the preparation of the stable injectable composition.
In one embodiment, the invention also relates to a precursor of said hydrophobic group according to formula X.
In one embodiment, the invention also relates to a polyamino acid according to formula I
Q[Hy]j[PLG]k
Formula J
Wherein:
j≥1；k≥2
-said polyamino acids according to formula I carry a carboxylate charge and consist of at least two chains of PLG glutamic or aspartic acid units bound together by at least trivalent, linear or branched groups or spacers Q [ - ] I (i.gtoreq.3, wherein I ═ j + k), said groups or spacers consisting of: a group comprising one or more heteroatoms selected from nitrogen and oxygen atoms and/or alkyl chains bearing one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl groups, said group Q [ - ] i bearing at least one monovalent hydrophobic group-Hy;
-said group or spacer Q [ - ]]iIs bound to at least two chains of PLG glutamic acid or aspartic acid units via an amide function, and
-said group or spacer Q [ - ]]iBound to at least one hydrophobic group-Hy according to formula X defined below via an amide function.
The amide function binding the group or spacer Q < - > i to at least two chains of glutamic or aspartic acid units results from a reaction between the amine function and the acid function carried respectively by the precursor Q' of the group or spacer Q < - > i or by the glutamic or aspartic acid unit.
-the amide function binding said group or spacer Q < - > i to at least one hydrophobic group-Hy according to formula X results from a reaction between the amine function and the acid function carried respectively by the precursor Q 'of the group or spacer Q < - > i or by the precursor Hy' of the hydrophobic group-Hy,
the group-Hy is as defined above,
the group or spacer Q < - > i is as defined above,
in one embodiment, the invention also relates to a compound according to formula Ib, which is a precursor of a copolymeric amino acid according to formula I defined above:
Q”’[Hy]j
formula Ib
Wherein:
j≥1
-said compound according to formula Ib consists of a precursor of a linear or branched group or spacer Q' "[ - ] j, said group or spacer consisting of: a group comprising one or more heteroatoms selected from nitrogen and oxygen atoms and/or alkyl chains bearing one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl groups, said group Q' "[ - ] j bearing at least one monovalent hydrophobic group-Hy bound via an amide bond;
-precursors of said groups or spacers Q' [ - ] j carry at least k free amine or acid reactive functional groups,
-the amide function linking said group or spacer Q '[ - ] j to at least the hydrophobic group-Hy results from the reaction between the amine function and the acid function carried by the precursor Q' of the group or spacer Q '- ] j or the precursor Hy' of the hydrophobic group-Hy, respectively,
-said group or spacer Q '"[ - ]jis selected from groups according to the formula Q [ - ] j ═ ([ Q' ] Q ] [ - ] j, wherein 1 ≦ Q ≦ 5
● the groups Q 'are identical or different and are selected from the groups of formulae III to VI as defined above, to form Q [ - ] j (j.gtoreq.3), the identical or different functional groups Fx ═ Fa, Fb, Fc, Fd, Fa', Fb ', Fc "and Fd' of which represent the functional groups-NH-or-CO-, and Fy represents the trivalent nitrogen atom-N ═ by,
● two groups Q' are bound between them by a covalent bond and a carboxyl function Fx-CO-and an amine function Fx-NH-or Fy-N-to form an amide bond,
● and when the at least two reactive functional groups are not bound to the group Q' or the hydrophobic group-Hy, they constitute a free carboxylic acid or amine function.
In one embodiment, the invention also relates to a polyamino acid according to formula Ia, which is a precursor of a polyamino acid according to formula I defined above:
Q”[PLG]k
formula Ia
Wherein:
k≥2
-said polyamino acids according to formula Ia carrying carboxylate groups and consisting of at least two PLG glutamic or aspartic acid unit chains bound between them by a precursor of a linear or branched group or spacer Q "[ - ] k, said group or spacer consisting of: containing one or more heteroatoms selected from nitrogen and oxygen atoms and/or alkyl chains with one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or with one or more heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl groups,
-said group or spacer Q "[ - ]]kBound to said at least two PLG glutamic or aspartic acid unit chains by an amide function and, after binding to said at least two PLG glutamic or aspartic acid unit chains, carrying at least j reactive free amine or acid functions
The amide function binding the group or spacer Q "[ - ] k to at least two chains of glutamic or aspartic acid units results from the reaction between the amine function and the acid function carried by the precursor Q' or glutamic or aspartic acid unit of the group or spacer Q" [ - ] k, respectively.
-said group or spacer Q "[ - ] k is selected from the group according to the formula Q" [ - ] k ═ ([ Q' ] Q ] [ - ] k, wherein 1. ltoreq. q.ltoreq.5
● the groups Q ' are identical or different and are selected from the groups of formulae III to VI as defined above, to form Q [ - ] k (k.gtoreq.3) whose functional groups Fx ═ Fa, Fb, Fc, Fd, Fa ', Fb ', Fc ' and Fd ' are identical or different and represent the functional groups-NH-or-CO-, and Fy represents the trivalent nitrogen atom-N ═ N,
● the two groups Q' are bound between them by a covalent bond between the carboxyl function Fx-CO-and the amine function Fx-NH-or Fy-N-to form an amide bond,
● and which constitute a free carboxylic acid or amine function when said at least one reactive function is not bound to the group Q' or to at least two chains of glutamic or aspartic acid units.
In one embodiment, the composition according to the invention is characterized in that the PLG chains forming the copolyamino acids are obtained by polymerization.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by ring-opening polymerization of an N-carboxyanhydride glutamic acid derivative or an N-carboxyanhydride aspartic acid derivative.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the copolyamino acid is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative or an N-carboxyanhydride aspartic acid derivative as described in the article adv.polym.sci.2006, 202, 1-18(Deming, T.J.).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of N-carboxyanhydride glutamic acid derivatives.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the copolyamino acid is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative selected from the group consisting of: n-carboxy anhydride poly (methyl glutamate) (GluOMe-NCA), N-carboxy anhydride poly (benzyl glutamate) (GluOBzl-NCA) and N-carboxy anhydride poly (tert-butyl glutamate) (GluOtBu-NCA).
In one embodiment, the N-carboxyanhydride glutamic acid derivative is N-carboxyanhydride poly-L-glutamic acid methyl ester (L-GluOMe-NCA).
In one embodiment, the N-carboxyanhydride glutamic acid derivative is N-carboxyanhydride poly-benzyl L-glutamate (L-GluOBzl-NCA).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative or an N-carboxyanhydride aspartic acid derivative using an organometallic transition metal complex as initiator, as described in Nature 1997, 390, 386-389(Deming, T.J.).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of N-carboxyanhydride glutamic acid derivatives or N-carboxyanhydride aspartic acid derivatives using ammonia or a primary amine as initiator, as described in patent FR 2,801,226(Torraud, F.; et al) and the references cited therein.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the copolymeric amino acids is obtained by polymerization of N-carboxyanhydride glutamic acid derivatives or N-carboxyanhydride aspartic acid derivatives, using hexamethyldisilazane as initiator, as described in the article J.Am.chem.Soc.2007, 129, 14114-14115(Lu H.; et al), or using silylized amines, as described in the article J.Am.chem.Soc.2008, 130, 12562-12563(Lu H.; et al).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative or an N-carboxyanhydride aspartic acid derivative, said polymerization being obtained from a group or spacer Q [ - ]]iInitiated by the amine function carried.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of N-carboxyanhydride glutamic acid derivatives selected from the group consisting of N-carboxyanhydride polymethyl glutamate (GluOMe-NCA), N-carboxyanhydride polybenzyl glutamate (GluOBzl-NCA) and N-carboxyanhydride polybutyl glutamate (GluOtBu-NCA), said polymerization being initiated by an amine function carried by a group or spacer Q < - > i.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of N-carboxyanhydride poly-L-glutamic acid methyl ester (L-GluOMe-NCA), said polymerization being initiated by an amine function carried by a group or spacer Q < - > i.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of N-carboxyanhydride poly-benzyl L-glutamate (L-GluOBzl-NCA), initiated by the amine function carried by the group or spacer Q < - > i.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative or an N-carboxyanhydride aspartic acid derivative, said polymerization being obtained by a group Q [ - ]]k[Hy]jInitiated by the amine function carried by the precursor(s).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained by polymerization of an N-carboxyanhydride glutamic acid derivative selected from the group consisting of poly-methyl N-carboxyanhydride glutamate (GluOMe-NCA), poly-benzyl N-carboxyanhydride glutamate (GluOBzl-NCA) and poly-tert-butyl N-carboxyanhydride glutamate (GluOtBu-NCA), said polymerization consisting of a group Q [ - ]]k[Hy]jInitiated by the amine function carried by the precursor(s).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid is obtained by polymerization of N-carboxyanhydride poly-L-glutamic acid methyl ester (L-GluOMe-NCA) resulting from a group Q [ - ]]k[Hy]jInitiated by the amine function carried by the precursor(s).
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid is obtained by polymerization of N-carboxyanhydride poly-benzyl L-glutamate (L-GluOBzl-NCA) resulting from a group Q [ - ]]k[Hy]jInitiated by the amine function carried by the precursor(s).
In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of the glutamic acid derivative of the N-carboxyanhydride or the aspartic acid derivative of the N-carboxyanhydride (from which the polyamino acid is obtained) comprises a step of hydrolysis of the ester function.
In one embodiment, the ester function hydrolysis step may comprise hydrolysis in an acidic medium or hydrolysis in a basic medium, or may be carried out by hydrogenation.
In one embodiment, the ester group hydrolysis step is hydrolysis in an acidic medium.
In one embodiment, the ester group hydrolysis step is carried out by hydrogenation.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid is obtained from a polyamino acid obtained via depolymerization of a higher molecular weight polyamino acid.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the copolyamino acid is obtained from a polyamino acid obtained via enzymatic depolymerization of a higher molecular weight polyamino acid.
In one embodiment, the composition according to the invention is characterized in that the PLG chains forming the copolyamino acids are obtained from polyaminoacids obtained via chemical depolymerization of higher molecular weight polyaminoacids.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the (contistuant) polyamino acid is obtained from a polyamino acid obtained via enzymatic and chemical depolymerization of a higher molecular weight polyamino acid.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid copolymer is obtained from a polyamino acid obtained via depolymerization of a higher molecular weight polyamino acid selected from sodium polyglutamate and sodium polyaspartate.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the copolyamino acid is obtained from a polyamino acid obtained by depolymerization of a higher molecular weight sodium polyglutamate.
In one embodiment, the composition according to the invention is characterized in that the PLG chain forming the polyamino acid is obtained from a polyamino acid obtained by depolymerization of a higher molecular weight sodium polyaspartate.
In one embodiment, the composition according to the invention is characterized in that the amide bond in the co-amino acid is obtained by a method for forming an amide bond well known to the person skilled in the art.
In one embodiment, the composition according to the invention is characterized in that the amide bond in the co-polymerized amino acid is obtained by an amide bond forming method used in peptide synthesis.
In one embodiment, the composition according to the invention is characterized in that the amide bond in the polyamino acid is obtained by a method for forming an amide bond as described in patent FR 2.840.614(Chan, Y.P.; et al).
In one embodiment, the composition according to the invention is characterized in that the amide bonds between the PLG chain and the group or spacer Q [ - ] i and between the group or spacer Q [ - ] i and the hydrophobic group-Hy in the polyamino acid are obtained by amide bond formation methods well known to the person skilled in the art.
In one embodiment, the composition according to the invention is characterized in that the polyamino acids are copolymerized in PLG chains and groups or spacers Q [ - ]]iAnd in the radical or spacer Q [ - ]]iAnd the amide bond between the hydrophobic group-Hy is obtained by a method for forming an amide bond used in peptide synthesis.
In one embodiment, the composition according to the invention is characterized in that the polyamino acids are copolymerized in PLG chains and groups or spacers Q [ - ]]iAnd in the radical or spacer Q [ - ]]iAnd the amide bond between the hydrophobic group-Hy is obtained by the method for forming an amide bond as described in patent FR 2.840.614(Chan, Y.P.; et al).
In the following, the units for insulin are pharmacopoeial recommended units, the mg/ml equivalents of which are provided in the table below:
| insulin | European pharmacopoeia 8.0 (2014) | United states Pharmacopeia-USP 38(2015) |
| Insulin of winter | 0.0350mg of insulin aspart | 1USP is 0.0350mg insulin aspart |
| Insulin lispro | 0.0347mg of insulin lispro | 1USP ═ 0.0347mg insulin lispro |
| Human being | 0.0347mg of human insulin 1UI ═ 0.0347mg | 1USP ═ 0.0347mg human insulin |
| Insulin glargine | 0.0364mg of insulin glargine | 1USP 0.0364mg insulin glargine |
| Pig | 1UI 0.0345mg porcine insulin | 1 USP-0.0345 mg porcine insulin |
| Cattle | 0.0342mg bovine insulin 1UI ═ 0.0342mg | 1U0.0342mg of bovine insulin |
Basal insulin having an isoelectric point of 5.8 to 8.5 refers to insulin that is insoluble at pH7 and has a time of action of 8 to 24 hours or more in a standard diabetes model.
These basal insulins having an isoelectric point of 5.8 to 8.5 are recombinant insulins, and the primary structure thereof is mainly modified by introducing basic amino acids such as arginine or lysine. They are described, for example, in the following patents, patent applications or publications: WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the contents of which are incorporated by reference.
In one embodiment, the basal insulin having an isoelectric point between 5.8 and 8.5 is insulin glargine. Insulin glargine is manufactured by SANOFI under the trademark SANOFI
(100U/ml) or
(300U/ml) was marketed.
In one embodiment, the basal insulin having an isoelectric point between 5.8 and 8.5 is a biosimilar insulin glargine.
Biomimic insulin glargine is marketed by ELI LILLY
Or
And (4) marketing.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point between 5.8 and 8.5 between 40 and 500U/mL.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point between 5.8 and 8.5 at 40U/mL.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point of 5.8 to 8.5 at 100U/mL (i.e. about 3.6 mg/mL).
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point between 5.8 and 8.5 at 150U/mL.
In one embodiment, the composition according to the invention comprises basal insulin with an isoelectric point between 5.8 and 8.5 at 200U/mL.
In one embodiment, the composition according to the invention comprises a basal insulin with an isoelectric point between 5.8 and 8.5 of 225U/mL.
In one embodiment, the composition according to the invention comprises 250U/mL basal insulin having an isoelectric point between 5.8 and 8.5.
In one embodiment, the composition according to the invention comprises basal insulin with an isoelectric point between 5.8 and 8.5 at 300U/mL.
In one embodiment, the composition according to the invention comprises basal insulin with an isoelectric point between 5.8 and 8.5 at 400U/mL.
In one embodiment, the composition according to the invention comprises 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5.
In one embodiment, the mass ratio between the basal insulin and the polyamino acid or polyamino acid/basal insulin with isoelectric point between 5.8 to 8.5 is between 0.2 and 8.
In one embodiment, the mass ratio is from 0.2 to 6.
In one embodiment, the mass ratio is from 0.2 to 5.
In one embodiment, the mass ratio is from 0.2 to 4.
In one embodiment, the mass ratio is 0.2 to 3.
In one embodiment, the mass ratio is from 0.2 to 2.
In one embodiment, the mass ratio is from 0.2 to 1.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 60 mg/mL.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 40 mg/mL.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 20 mg/mL.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 10 mg/mL.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 5 mg/mL.
In one embodiment, the concentration in the copolymerized amino acid having a carboxylate charge and a hydrophobe is at most 2.5 mg/mL.
In one embodiment, the composition according to the invention further comprises prandial insulin. Prandial insulin is soluble at pH7.
Prandial insulin refers to so-called rapid or "regular" insulin.
So-called fast-meal insulin is insulin that must respond to the needs caused by protein and sugar intake at the meal; they must function in less than 30 minutes.
In one embodiment, the so-called "regular" prandial insulin is human insulin.
In one embodiment, the prandial insulin is recombinant human insulin as described in the european pharmacopoeia and the us pharmacopoeia.
Human insulin, e.g. under the trademark
(ELi LILLY) and
(NOVO NORDISK) was marketed.
So-called fast-acting prandial insulin is insulin obtained by recombination and its primary structure has been modified to reduce its duration of action.
In one embodiment, the so-called fast-acting prandial insulin is selected from insulin lispro
Insulin glulisine
And insulin aspart
In one embodiment, the prandial insulin is insulin lispro.
In one embodiment, the prandial insulin is insulin glulisine.
In one embodiment, the prandial insulin is insulin aspart.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 40 to 500U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin having an isoelectric point between 5.8 and 8.5 for a total of 60 to 800U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 100 to 500U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 800U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 700U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 600U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 500U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 400U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 300U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 266U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 200U/mL insulin.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 100U/mL insulin.
For the above described formulations comprising 60 to 800U/mL, the ratio between basal insulin and prandial insulin with isoelectric point between 5.8 to 8.5 is, for example, 25/75, 30/70, 40/60, 50/50, 60/40, 63/37, 70/30, 75/25, 80/20, 83/17, 90/10 in percent. However, any other ratio may be implemented.
In one embodiment, the composition according to the invention comprises a combination of prandial insulin and basal insulin with an isoelectric point between 5.8 and 8.5 for a total of 40U/mL insulin.
In one embodiment, the composition according to the invention further comprises a gastrointestinal hormone.
"gastrointestinal hormone" refers to a hormone selected from the group consisting of: GLP-1RA (glucagon-like peptide-1 receptor agonist) and GIP (glucose-dependent insulinotropic peptide), oxyntomodulin (derivative of pro-glucagon), YY peptide, amylin, cholecystokinin, Pancreatic Polypeptide (PP), ghrelin and enterostatin, their analogs or derivatives and/or their pharmaceutically acceptable salts.
In one embodiment, the oxyntomodulin is an analog or derivative of GLP-1RA selected from the group consisting of: exenatide or
(ASTRA-ZENECA), liraglutide or
(NOVO NORDISK), lixisenatide or
(SANOFI), albiglutide or
(GSK) or dulaglutide or
(ELI LILLY&CO), their analogs or derivatives or their pharmaceutically acceptable salts.
In one embodiment, the oxyntomodulin is pramlintide or
(ASTRA-ZENECA)。
In one embodiment, the oxyntomodulin is exenatide or
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In one embodiment, the gastrointestinal hormone is liraglutide or liraglutide
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In one embodiment, the gastrointestinal hormone is lixisenatide or
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In one embodiment, the gastrointestinal hormone is albiglutide or
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In one embodiment, the oxyntomodulin is dulaglutide or
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In one embodiment, the oxyntomodulin is pramlintide or
Analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
The term "analogue" when used in reference to a peptide or protein refers to a peptide or protein in which one or more of its constituent amino acid residues have been substituted with other amino acid residues, and/or in which one or more of its constituent amino acid residues have been removed, and/or in which one or more of its constituent amino acid residues have been added. The definition of analogs according to the invention allows a percentage homology of 50%.
The term "derivative" when used in reference to a peptide or protein refers to a peptide or protein or analogue that is chemically modified by a substituent that is not present in the peptide or protein or analogue in question, i.e., a peptide or protein that has been modified by creating a covalent bond to introduce a substituent.
In one embodiment, the substituents are selected from fatty chains.
In one embodiment, the concentration of oxyntomodulin is in the range of 0.01 to 100 mg/mL.
In one embodiment, the concentration of oxyntomodulin is in the range of 0.01 to 10 mg/mL.
In one embodiment, the concentration of exenatide, an analog or derivative thereof or a pharmaceutically acceptable salt thereof is in the range of 0, 04 to 0, 5 mg/mL.
In one embodiment, the concentration of liraglutide, analogs or derivatives thereof, and pharmaceutically acceptable salts thereof is in the range of 1 to 10 mg/mL.
In one embodiment, the concentration of lixisenatide, an analog or derivative thereof, and a pharmaceutically acceptable salt thereof, is in the range of 0, 01 to 1 mg/mL.
In one embodiment, the concentration of albiglutide, analogs or derivatives thereof, and pharmaceutically acceptable salts thereof is from 5 to 100 mg/mL.
In one embodiment, the concentration of dulaglutide, an analog or derivative thereof, and a pharmaceutically acceptable salt thereof is 0, 1 to 10 mg/mL.
In one embodiment, the concentration of pramlintide, an analog or derivative thereof, and a pharmaceutically acceptable salt thereof is 0, 1 to 5 mg/mL.
In one embodiment, the composition according to the invention is obtained by mixing a commercially available solution of a basal insulin having an isoelectric point between 5.8 and 8.5 and a commercially available solution of GLP-1RA, an analogue or derivative of GLP-1RA in a volume ratio in the range of 10/90 to 90/10.
In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of oxyntomodulin.
In one embodiment, the composition according to the invention comprises between 40U/mL and 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and between 0.05 and 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises between 40U/mL and 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and between 1 and 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises between 40U/mL and 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and between 0.01 and 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 40 to 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL of albiglutide.
In one embodiment, the composition according to the invention comprises between 40U/mL and 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and between 0.1 and 10mg/mL of dulaglutide.
In one embodiment, the composition according to the invention comprises 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 500U/mL basal insulin with an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises 500U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.1 to 10mg/mL dulaglutide.
In one embodiment, the composition according to the invention comprises 400U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises 400U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises 400U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 400U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point of 5.8 to 8.5 at 400U/mL and dulaglutide in an amount of 0.1 to 10 mg/mL.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point of between 5.8 and 8.5 and exenatide in an amount of between 0.04 and 0.5mg/mL at 300U/mL.
In one embodiment, the composition according to the invention comprises 300U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL liraglutide.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point of between 5.8 and 8.5 at 300U/mL and lixisenatide at 0.01 to 1 mg/mL.
In one embodiment, the composition according to the invention comprises basal insulin with an isoelectric point between 300U/mL and 8.5 and albiglutide with an isoelectric point between 5 and 100 mg/mL.
In one embodiment, the composition according to the invention comprises basal insulin having an isoelectric point of between 5.8 and 8.5 at 300U/mL and dulaglutide in an amount of between 0.1 and 10 mg/mL.
In one embodiment, the composition according to the invention comprises 225U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises 225U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL liraglutide.
In one embodiment, the composition according to the invention comprises 225U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 225U/mL basal insulin with an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises 225U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.1 to 10mg/mL dulaglutide.
In one embodiment, the composition according to the invention comprises 200U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises 200U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises 200U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 200U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises 200U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.1 to 10mg/mL dulaglutide.
In one embodiment, the composition according to the invention comprises 100U/mL (i.e. about 3.6mg/mL) of basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL of exenatide.
In one embodiment, the composition according to the invention comprises 100U/mL (i.e. about 3.6mg/mL) of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises 100U/mL (i.e. about 3.6mg/mL) of basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL of lixisenatide.
In one embodiment, the composition according to the invention comprises 100U/mL basal insulin with an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises 100U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.1 to 10mg/mL dulaglutide.
In one embodiment, the composition according to the invention comprises 40U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.04 to 0.5mg/mL exenatide.
In one embodiment, the composition according to the invention comprises 40U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
In one embodiment, the composition according to the invention comprises 40U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL lixisenatide.
In one embodiment, the composition according to the invention comprises 40U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 5 to 100mg/mL albiglutide.
In one embodiment, the composition according to the invention comprises 40U/mL basal insulin having an isoelectric point between 5.8 and 8.5 and 0.1 to 10mg/mL dulaglutide.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 0 to 5000 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 0 to 4000 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 0 to 3000 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 0 to 2000 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 0 to 1000 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 50 to 600 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 100 to 500 μ M.
In one embodiment, the composition according to the invention further comprises a zinc salt in a concentration of 200 to 500 μ M.
In one embodiment, the composition according to the invention further comprises a buffering agent.
In one embodiment, the composition according to the invention comprises a buffer in a concentration of 0 to 100 mM.
In one embodiment, the composition according to the invention comprises a buffer in a concentration of 15 to 50 mM.
In one embodiment, the composition according to the invention comprises a buffer selected from the group consisting of phosphate buffer, Tris (Tris) and sodium citrate.
In one embodiment, the buffering agent is sodium phosphate.
In one embodiment, the buffer is Tris (Tris hydroxymethyl aminomethane).
In one embodiment, the buffer is sodium citrate.
In one embodiment, the composition according to the invention further comprises a preservative.
In one embodiment, the preservative, alone or in a mixture, is selected from m-cresol and phenol.
In one embodiment, the concentration of the preservative is 10 to 50 mM.
In one embodiment, the concentration of the preservative is 10 to 40 mM.
In one embodiment, the composition according to the invention further comprises a surfactant.
In one embodiment, the surfactant is selected from propylene glycol and polysorbate.
The composition according to the invention may further comprise additives, such as tonicity agents.
In one embodiment, the tonicity agent is selected from the group consisting of glycerin, sodium chloride, mannitol, and glycine.
The composition according to the invention may further comprise all excipients which comply with the pharmacopoeia and which are compatible with insulin used in standard concentrations.
The invention also relates to a pharmaceutical preparation according to the invention, characterized in that it is obtained by drying and/or lyophilization.
In the case of local and systemic release, suitable routes of administration are intravenous, subcutaneous, intradermal or intramuscular.
Transdermal, oral, nasal, vaginal, ocular, oral and pulmonary routes of administration are also contemplated.
The invention also relates to a single dose formulation at a pH of 6.0 to 8.0 comprising a basal insulin having an isoelectric point of 5.8 to 8.5.
The invention also relates to a single dose formulation at a pH of 6.0 to 8.0 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a prandial insulin.
The invention also relates to a single dose formulation at a pH of 7.0 to 7.8 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a prandial insulin.
The invention also relates to a single dose formulation at a pH of 6.0 to 8.0 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a gastrointestinal hormone as defined previously. The invention also relates to a single dose formulation at a pH of between 7.0 and 7.8 comprising a basal insulin having an isoelectric point of between 5.8 and 8.5 and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 6.0 to 8.0 comprising basal insulin having an isoelectric point of 5.8 to 8.5, prandial insulin and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 7.0 to 7.8 comprising basal insulin having an isoelectric point of 5.8 to 8.5, prandial insulin and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.8 comprising a basal insulin having an isoelectric point of 5.8 to 8.5.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.8 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a prandial insulin.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.8 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.8 comprising basal insulin having an isoelectric point of 5.8 to 8.5, prandial insulin and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.6 comprising a basal insulin having an isoelectric point of 5.8 to 8.5.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.6 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a prandial insulin.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.6 comprising a basal insulin having an isoelectric point of 5.8 to 8.5 and a gastrointestinal hormone as defined previously.
The invention also relates to a single dose formulation at a pH of 6.6 to 7.6 comprising basal insulin having an isoelectric point of 5.8 to 8.5, prandial insulin and a gastrointestinal hormone as defined previously.
In one embodiment, the single dose formulation further comprises a co-amino acid as defined previously.
In one embodiment, the formulation is in the form of an injectable solution.
In one embodiment, the basal insulin having an isoelectric point between 5.8 and 8.5 is insulin glargine.
In one embodiment, the prandial insulin is human insulin.
In one embodiment, the insulin is recombinant human insulin as described in the european pharmacopoeia and the us pharmacopoeia.
In one embodiment, the prandial insulin is selected from insulin lispro
Insulin glulisine
And insulin aspart
In one embodiment, the prandial insulin is insulin lispro.
In one embodiment, the prandial insulin is insulin glulisine.
In one embodiment, the prandial insulin is insulin aspart.
In one embodiment, GLP-1RA, an analog or derivative of GLP-1RA is selected from exenatide
Liraglutide
Lixisenatide
Abelitide
Dola glycopeptides
Or one of its derivatives.
In one embodiment, the gastrointestinal hormone is exenatide.
In one embodiment, the gastrointestinal hormone is liraglutide.
In one embodiment, the gastrointestinal hormone is lixisenatide.
In one embodiment, the gastrointestinal hormone is albiglutide.
In one embodiment, the oxyntomodulin is dulaglutide.
The dissolution of the copolyamino acid having a carboxylate charge and at least one hydrophobic group according to the present invention at a pH of 6.0 to 8.0 to the basal insulin having an isoelectric point of 5.8 to 8.5 can be simply observed and controlled with the naked eye by means of the change in appearance of the solution.
The dissolution of the copolyamino acid having a carboxylate charge and at least one hydrophobic group according to the present invention to a basal insulin having an isoelectric point of 5.8 to 8.5 at a pH of 6.6 to 7.8 can be simply observed and controlled with the naked eye by means of the change in appearance of the solution.
Furthermore and equally important, the applicant has been able to demonstrate that basal insulin with an isoelectric point between 5.8 and 8.5, dissolved in the presence of a copolymerized amino acid bearing a carboxylate charge and at least one hydrophobic group according to the invention at a pH between 6.0 and 8.0, retains its slow-acting insulin action, either alone or in combination with prandial insulin or gastrointestinal hormone.
The applicant can also verify that prandial insulin mixed at a pH of 6.0 to 8.0 maintains its rapid onset insulin action in the presence of a copolymerized amino acid bearing a carboxylate charge and at least one hydrophobic group according to the present invention and a basal insulin having an isoelectric point of 5.8 to 8.5.
The composition according to the invention can advantageously be prepared by simply mixing an aqueous solution of a basal insulin having an isoelectric point between 5.8 and 8.5 and a co-amino acid according to the invention bearing a carboxylate charge and at least one hydrophobic group, in aqueous solution or in lyophilized form. If necessary, the pH of the formulation is adjusted to a pH of 6.0 to 8.0.
The composition according to the invention can advantageously be prepared by simply mixing an aqueous solution of a basal insulin having an isoelectric point between 5.8 and 8.5, a solution of a prandial insulin and the co-amino acid according to the invention carrying a carboxylate charge and at least one hydrophobic group, in aqueous solution or in lyophilized form. If necessary, the pH of the formulation is adjusted to a pH of 6.0 to 8.0.
The composition according to the invention can advantageously be prepared by simply mixing an aqueous solution of a basal insulin having an isoelectric point between 5.8 and 8.5, a solution of GLP-1RA, an analogue or derivative of GLP-1RA and the co-amino acid according to the invention carrying a carboxylate charge and at least one hydrophobic group, in aqueous solution or in lyophilized form. If necessary, the pH of the formulation is adjusted to a pH of 6.0 to 8.0.
The composition according to the invention can advantageously be prepared by simply mixing an aqueous solution of a basal insulin having an isoelectric point between 5.8 and 8.5, a solution of a prandial insulin, GLP-1RA or an analogue or derivative of GLP-1RA and a co-amino acid according to the invention carrying a carboxylate charge and at least one hydrophobic group, in aqueous solution or in lyophilized form. If necessary, the pH of the formulation is adjusted to a pH of 6.0 to 8.0.
In one embodiment, the mixture of base insulin and co-amino acids is concentrated by ultrafiltration prior to mixing with prandial insulin in aqueous solution or lyophilized form.
If necessary, with excipients such as glycerin, m-cresol, zinc chloride and polysorbate
The composition of the mixture is adjusted by adding concentrated solutions of these excipients to the mixture. If necessary, the pH of the formulation is adjusted to a pH of 6.0 to 8.0.
During the synthesis of the intermediate Hy compound and the grafting, classical protection and deprotection methods are used:
protection of one or more carboxyl functions of Hy, for example by esterification using methanol, ethanol, benzyl alcohol (alcool benzylic) or tert-butanol, can be carried out before grafting onto PLG via an acid protection group. After grafting, the functional groups are deprotected, i.e. a deprotection reaction is carried out, leaving the carboxyl functional groups free or in the form of basic cations selected from Na + and K +.
Protection of one or more amine functions, for example by acidic or basic hydrolysis under heat via phenylmethoxycarbonyl or 1, 1-dimethylethoxycarbonyl, can be carried out before grafting onto the PLG via an amine protecting group. After grafting, the functional groups are deprotected, i.e. a deprotection reaction is carried out, freeing the amine function or functions.
FIG. 1:
FIG. 1 depicts simultaneous and separate administration
(100IU/mL, 0.17 IU/kg)
Percent deviation of the mean curve for blood glucose after (100IU/mL, 0.50U/kg) (closed circles) and composition CB3-10(266U/mL, 0.67U/kg) (open squares) from the base level. + -. mean standard error; dogs (n-10) have been administered by subcutaneous injection.
Examples
The invention is described in more detail by the following examples in a non-limiting manner.
Synthesis of the hydrophobic Compound Hyd, part A-intermediate allowing the group-Hy to be obtained
In table 1, the intermediate hydrophobic compound bound to the spacer is represented by the corresponding hydrophobic molecule prior to grafting onto the polyamino acid copolymer.
TABLE 1
Table 1: list of intermediate hydrophobic compounds bound to the spacer.
Example A1-molecule A1
Molecule 1: product obtained by coupling lauric acid and L-proline
To a solution of lauric acid (31.63g, 157.9mmol) in THF (1L) was added N, N-Dicyclohexylcarbodiimide (DCC) (33.24g, 161.1mmol) and N-hydroxysuccinimide (NHS) (18.54g, 161.1mmol) in that order at room temperature. After stirring at room temperature for 18h, the medium is cooled at 0 ℃ in 20 minutes and filtered through a frit. L-proline (20g, 173.72mmol), Diisopropylethylamine (DIPEA) (137.5mL) and water (120mL) were added to the filtrate. After stirring at room temperature for 24h, the solvent was evaporated and the residue was dissolved in water (500 mL). The aqueous phase was washed with ethyl acetate (2X 500mL), acidified to pH-1 with 1N aqueous HCl, and extracted with dichloromethane (3X 300 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo.
Yield: 34.3g (73%)
1H NMR(CDCl3，ppm)：0.87(3H)；1.26(16H)；1.70(2H)；1.90-2.10(3H)；2.35(2H)；2.49(1H)；3.48(1H)；3.56(1H)；4.60(1H)。
LC/MS (ESI): 298.2, respectively; (calculated value ([ M + H)]+)：298.2)。
Molecule 2: product obtained by reacting molecule 1 with L-lysine
Applying to molecule 1(33.72g, 113.36mmol) and to L-lysine (8.70g, 59.51mmol) in a similar manner as for the preparation of molecule 1 gave molecule 2 as a white solid.
Yield: 26.2g (66%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.26(32H)；1.35-1.65(8H)；1.85-2.35(15H)；2.87(1H)；3.40-3.75(5H)；4.50-4.75(3H)；7.87(1H)。
LC/MS (ESI): 705.6, respectively; (calculated value ([ M + H)]+)：705.6)。
Molecule 3: reaction of spermidine with 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (Boc-ON)
To a solution of spermidine (4.07g, 28.00mmol) in THF (70mL) was added triethylamine (TEA, 8.50g, 84.01mmol) and the reaction medium was cooled at 0 ℃. A solution of Boc-ON (13.66g, 55.45mmol) in THF (220mL) was added dropwise over 6.5h, then the medium was stirred at room temperature for 18 h. The reaction medium was concentrated under reduced pressure, the residue was dissolved in DCM (280mL) and the organic phase was washed successively with 1N aqueous soda (2X 140mL), water (140mL), saturated aqueous NaCl (140mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in chloroform, concentrated under reduced pressure and dried in vacuo to give molecule 3 as a white solid.
Yield: 10.25g (quantitative)
1H NMR(CDCl3，ppm)：1.38-1.59(23H)；1.61-1.70(2H)；2.60(2H)；2.66(2H)；3.12(2H)；3.20(2H)；4.83(1H)；5.17(1H)。
LC/MS (ESI): 346.3, respectively; (calculated value ([ M + H)]+)：346.3)。
Molecule 4: product obtained by coupling molecule 2 and molecule 3
To a solution of molecule 2(5.56g, 7.89mmol) in chloroform (110mL) was added triethylamine (1.04g, 10.26mmol), 1-hydroxybenzotriazole (HOBt, 1.39g, 10.26mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide (EDC, 1.97g, 10.26mmol) in that order. After 15 minutes, molecule 3(3.00g, 8.68mmol) is added and the reaction medium is stirred at room temperature for 18 h. The organic phase was washed successively with saturated aqueous NH4Cl solution (110mL), saturated aqueous NaHCO3 solution (110mL), saturated aqueous NaCl solution (110mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (eluent: DCM, methanol) gave molecule 4 as a yellowish oil.
Yield: 6.20g (78%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.22-2.46(78H)；2.96-3.31(6H)；3.31-3.76(8H)；4.29-4.55(2H)；4.65-4.85(1H)。
Molecule A1
To a solution of molecule 4(6.20g, 6.00mmol) in DCM (75mL) was added a solution of 4N HCl in dioxane (15mL) and the reaction medium was stirred at room temperature for 18h and then concentrated under reduced pressure. After the residue was dissolved in DCM and concentrated under reduced pressure, molecular a1 was obtained as a white solid.
Yield: 5.25g (96%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.21-2.46(60H)；2.81-3.34(6H)；3.34-3.77(8H)；4.30-4.80(3H)。
LC/MS (ESI): 417.0; (calculated value ([ M + 2H)]2+)：416.9)。
Example A2-molecule A2
Molecule 5: product obtained by reaction of myristoyl chloride and L-proline
To a solution of L-proline (300.40g, 2.61mol) in 2N soda (1.63L) was slowly added a solution of myristoyl chloride (322g, 1.30mol) in DCM (1.63L) over 1h at 0 deg.C, upon completion, the reaction medium was warmed to 20 deg.C over 2h, then stirred for 2h, the mixture was cooled at 0 deg.C, and 37% HCl solution (215mL) was added over 15 min, the reaction medium was stirred for 10 min at 0 deg.C, then stirred for 1h between 0 deg.C and 20 deg.C, the organic phase was separated, washed with 10% HCl solution (3 × 430mL), saturated aqueous NaCl (430mL), washed with Na2SO4Dried, filtered over cotton, and then concentrated under reduced pressure. The residue was dissolved in heptane (315mL) and pentane (1.6L) was added with mechanical stirring. After filtration on a frit and drying under reduced pressure, a white solid was obtained.
Yield: 410.6g (97%)
1H NMR(CDCl3，ppm)：0.88(3H)；1.28(20H)；1.70(2H)；1.90-2.10(3H)；2.36(2H)；2.51(1H)；3.47(1H)；3.56(1H)；4.61(1H)。
LC/MS (ESI): 326.4, respectively; 651.7, respectively; (calculated value ([ M + H)]+)：326.3；([2M+H]+)：651.5)。
Molecule 6: product obtained by reacting molecule 5 with L-lysine
Recrystallization from ethyl acetate using a method similar to that used for the preparation of molecule 2 and applied to molecule 5(20.02g, 61.5mmol) and L-lysine (4.72g, 32.29mmol) gave molecule 6 as a white solid.
Yield: 12.30g (53%)
1HNMR(DMSO-d6，ppm)：0.85(6H)；1.26(40H)；1.35-1.50(6H)；1.50-2.10(10H)；2.10-2.25(4H)；3.01(2H)；3.31-3.55(4H)；4.10-4.40(3H)；7.68(0.6H)；7.97(1H)；8.27(0.4H)；12.50(1H)。
LC/MS (ESI): 761.8, respectively; (calculated value ([ M + H)]+)：761.6)。
Molecule 7: product obtained by reacting molecule 3 with molecule 6
Using a method similar to that used for the preparation of molecule 4 and applied to molecule 3(3.00g, 8.68mmol) and to molecule 6(6.00g, 7.89mmol), a colorless oil of molecule 7 was obtained.
Yield: 5.71g (66%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.23-2.48(86H)；2.96-3.75(14H)；4.30-4.56(2H)；4.65-4.88(1H)。
Molecule A2
Using a method similar to that used for the preparation of molecule A1 and applied to molecule 7(5.71g, 5.24mmol), a colorless oil of molecule A2 was obtained.
Yield: 5.19g (99%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.21-2.46(68H)；2.81-3.32(6H)；3.32-3.78(8H)；4.31-4.82(3H)。
LC/MS (ESI): 445.1; (calculated value ([ M + 2H)]2+)：444.9)。
Example A3-molecule A3
Molecule 8: product obtained by reaction of norspermidine and tert-butyl phenyl carbonate
To a solution of norspermidine (15mL, 107.22mmol) in DMF (70mL) was slowly added a solution of tert-butyl phenylcarbonate (49.6mL, 268.06mmol) in DMF (37mL) and the mixture was stirred at room temperature for 16 h. The reaction medium is concentrated under reduced pressure, the residue is taken up in water (200mL) and then acidified to pH 1.4 with 10% aqueous HCl. The aqueous phase was washed with methyl tert-butyl ether (MTBE, 2X 500mL), basified to pH12 with 10% aqueous soda, and the product extracted with DCM (4X 250 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. Crystallization in heptane gave molecule 8 as a white solid.
Yield: 27.97g (79%)
1H NMR(CDCl3，ppm)：1.44(18H)；1.64(4H)；2.64(4H)；3.20(4H)；5.16(2H)
LC/MS (ESI): 332.3; (calculated value ([ M + H)]+)：332.3)。
Molecule 9: product of reaction of molecule 6 with molecule 8
Using a method similar to that used for the preparation of molecule 4 and applied to molecule 6(18.00g, 23.65mmol) and to molecule 8(9.41g, 28.38mmol), a colorless oil of molecule 9 was obtained.
Yield: 22.83g (90%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.12-2.02(80H)；2.02-2.30(4H)；2.77-3.60(14H)；4.16-4.4I(2H)；4.45-4.62(1H)；6.59-6.94(2H)；7.60-8.38(2H)。
LC/MS (ESI): 1075.3, respectively; (calculated value ([ M + H)]+)：1074.9)。
Molecule A3
Using a method similar to that used for the preparation of molecule a1 and applied to molecule 9(22.80g, 21.22mmol), the resulting residue was dissolved in DCM and the organic phase was washed with 2N aqueous soda solution, dried over Na2SO4, filtered and concentrated in vacuo. After dissolving the residue in water (1.5L) and freeze-drying, a colorless solid of molecule a3 was obtained.
Yield: 17.76g (96%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.13-2.28(70H)；2.42-2.61(4H)；2.83-3.61(10H)；4.15-4.43(2H)；4.52-4.73(1H)；7.63-8.34(2H)。
LC/MS (ESI): 438.0, 874.9; (calculated value ([ M + 2H)]2+)：437.9，([M+H]+)：874.7)。
Example a 4: molecule A4
Molecule 10: product obtained by reacting molecule 6 with [2- (2-aminoethoxy) ethoxy ] acetic acid
To a solution of molecule 6(8.08g, 10.61mmol) in anhydrous DMF (65mL) was added NHS (1.23g, 10.72mmol) followed by DCC (2.21g, 10.72mmol) and the medium was stirred at room temperature for 18 h. The mixture was filtered on a frit, then a solution of [2- (2-aminoethoxy) ethoxy ] acetic acid (1.78g, 10.91) suspended in DMF (50mL) was added slowly. After stirring at room temperature for 24h, ethyl acetate (220mL) and 0.1N aqueous HCl (100mL) were added. The organic phase was separated, washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (eluent: DCM, methanol) gave molecule 10 as a colorless oil.
Yield: 4.90g (51%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.22-2.49(62H)；3.09-3.29(2H)；3.32-3.46(2H)；3.46-3.61(4H)；3.61-3.72(6H)；4.13(2H)；4.28-4.55(3H)；7.83-8.26(1H)。
LC/MS (ESI): 906.8, respectively; (calculated value ([ M + H)]+)：906.7)。
Molecule 11: product of reaction of molecule 3 with molecule 10
Using a method similar to that used for the preparation of molecule 4, applying it to molecule 3(2.24g, 6.49mmol) and molecule 10(4.90g, 5.41mmol) in DMF (15mL) solution, after purification by flash chromatography (eluent: DCM, methanol) gives molecule 11 as a colorless oil.
Yield: 5.30g (79%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.20-2.37(86H)；2.99-3.52(14H)；3.52-3.72(8H)；4.14-4.26(2H)；4.35-4.57(3H)；4.78-5.75(2H)；7.00-7.57(3H)。
Molecule A4
Using a method similar to that used for the preparation of molecule A1 and applied to molecule 11(5.30g, 4.29mmol), a colorless oil of molecule A4 was obtained.
Yield: 4.30g (99%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.16-2.62(68H)；2.95-3.93(22H)；4.30-4.79(5H)；7.52-8.67(9H)。
LC/MS (ESI): 517.8, 1033.8; (calculated value ([ M + 2H)]2+)：517.4，([M+H]+)：1033.8)。
Example a 5: molecule A5
Molecule 12: product of reaction of molecule 6 with N-tert-butyloxycarbonyl-L-lysine methyl ester (HLys (Boc) OMe)
To a solution of molecule 6(43.00g, 56.49mmol) in THF (375mL) at 0 deg.C was added DIPEA (8.76g, 67.79mmol), HOBt (865mg, 5.65mmol) and EDC (11.91g, 62.14 mmol). After stirring for 15 minutes, HLys (Boc) OMe (20.12g, 67.79mmol) is added and the reaction medium is stirred at 0 ℃ for 24 h. The residue was concentrated under reduced pressure, taken up in ethyl acetate (300mL) and the organic phase was washed with saturated aqueous NaHCO3 (150mL), 5% aqueous HCl (2x150mL) and then with saturated aqueous NaCl (2x150 mL). After drying over Na2SO4 and filtration, the medium is concentrated under reduced pressure. A clear solid of molecule 12 was obtained.
Yield: 55.80g (98%)
1H NMR(CDCl3，ppm)：0.87(6H)；1.18-1.74(61H)；1.74-2.07(8H)；2.07-2.38(8H)；2.96-3.17(3H)；3.30-3.50(3H)；3.54-3.67(2H)；3.71(3H)；4.25-4.40(1H)；4.44-4.63(3H)；4.74-4.98(1H)；7.10(1H)；7.48(1H)；7.65(1H).
LC/MS (ESI): 1003.8 (calculated ([ M + H))]+)：1003.8).
Molecule 13: product obtained by saponification of the methyl ester of molecule 12
A solution of molecule 12(55.8g, 55.61mmol) in THF/methanol 1: 1(370mL) was cooled at 0 deg.C, then a solution of LiOH (2.0g, 83.41mmol) in water (185mL) was slowly added. The reaction medium is stirred at 0 ℃ for 16h and then at room temperature for 30 minutes. The residue was concentrated under reduced pressure, taken up in DCM (500mL) and acidified with 10% aqueous HCl until pH 1. DCM (500mL) was added, the organic phase was separated and the aqueous phase was extracted with DCM (2 × 300 mL). The combined organic phases were washed with saturated aqueous NaCl (2 × 300mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Crystallization in acetone (acrasterne) gave molecule 13 as a white solid.
Yield: 46.1g (84%)
1H NMR (pyridine-d)5，ppm)：0.88(6H)；1.14-2.08(67H)；2.08-2.68(10H)；3.14-3.97(8H)；4.55-5.22(4H)；7.29-7.42(1H)；8.28-8.59(1H)；8.91-9.39(2H).
LC/MS (ESI): 989.8 (calculated ([ M + H))]+)：989.8).
Molecule 14: product from the reaction of molecule 13 with N-Boc ethylenediamine
Using a method similar to that used for the preparation of molecule 10, applied to molecule 13(14.0g, 14.15mmol) in DCM (94mL) solution and applied to N-Boc ethylenediamine (2.72g, 16.98mmol) gave molecule 14 as a white solid after recrystallization from acetonitrile.
Yield: 13.80g (86%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.10-2.34(86H)；2.77-3.18(8H)；3.27-3.68(4H)；4.00-4.46(4H)；6.26-6.84(2H)；7.45-8.30(4H).
LC/MS (ESI): 1131.8 (calculated ([ M + H))]+)：1131.9).
Molecule A5
Using a method similar to that used for the preparation of molecule a1 and applied to molecule 14(13.80g, 12.19mmol), the resulting residue was dissolved in DCM and the organic phase was washed with 2N aqueous soda solution, dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization from acetonitrile gave molecular a5 as a colorless solid.
Yield: 9.76g (86%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.05-2.43(72H)；2.43-2.60(4H)；2.89-3.14(4H)；3.28-3.64(4H)；4.00-4.46(4H)；7.49-8.31(4H).
LC/MS (ESI): 466.4, 931.8 (calculated ([ M + 2H)]2+)：466.4，([M+H]+)：931.8).
Example a 6: molecule A6
Molecule 15: reaction of molecule 5 with N-t-butyloxycarbonyl-L-lysine (HLys) (Boc) OH)
Using a method analogous to that used for the preparation of molecule 1, applied to molecule 5(37.00g, 113.67mmol) and to (hlys (boc) OH) (30.80g, 125.04mmol), the reaction medium was concentrated under reduced pressure, the residue was dissolved in water (500mL), the aqueous phase was washed with ethyl acetate (2 × 250mL), then acidified to pH1 and the resulting precipitate was filtered to give molecule 15 as a white solid.
Yield: 61.83g (98%)
1H NMR(DMSO-d6，ppm)：0.85(3H)；1.13-2.05(41H)；2.05-2.28(2H)；2.81-2.95(2H)；3.23-3.55(2H)；4.07-4.15(0.5H)；4.15-4.23(0.5H)；4.30-4.40(1H)；6.30-6.84(1H)；7.99(0.5H)；8.28(0.5H)；12.51(1H).
LC/MS (ESI): 554.4 (calculated ([ M + H))]+)：554.4).
Molecule 16: product of the reaction of molecule 15 with tri (ethylene glycol) diamine
To a solution of molecule 15(45.00g, 81.26mmol) in DCM (540mL) at 0 deg.C was added HOBt (1.24g, 8.13mmol), tri (ethylene glycol) diamine (6.02g, 40.63mmol) in that order, followed by EDC (17.14g, 89.38 mmol). The reaction mixture was stirred at 0 ℃ for 1h, then at room temperature for 15 h. The medium was washed with saturated aqueous NaHCO3 (2X 250mL), 1N aqueous HCl (2X 250mL), saturated aqueous NaCl (250mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. A colorless solid of molecule 16 was obtained.
Yield: 47.02g (95%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.11-2.32(86H)；2.80-2.92(4H)；3.12-3.28(4H)；3.28-3.59(12H)；4.08-4.19(1.3H)；4.19-4.34(2H)；4.34-4.46(0.7H)；6.32-6.81(2H)；7.64-7.74(1.3H)；7.74-7.83(1.3H)；7.93-8.00(0.7H)；8.11-8.18(0.7H).
LC/MS (ESI): 1220.0 (calculated ([ M + H))]+)：1219.9).
Molecule A6
Application to molecule 16(23.00g, 18.86mmol) using a method similar to that used for the preparation of molecule a5 gave molecule a6 as a white solid.
Yield: 16.43g (85%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.11-2.05(68H)；2.08-2.31(4H)；2.44-2.54(4H)；3.10-3.58(16H)；4.08-4.18(1.3H)；4.22-4.32(2H)；4.37-4.46(0.7H)；7.66-7.87(2.6H)；7.96-8.06(0.7H)；8.13-8.23(0.7H).
LC/MS (ESI): 510.5, 1020.0 (calculated ([ M + 2H)]2+)：510.4，([M+H]+)：1019.8).
Example a 7: molecule A7
Molecule 17: product of reaction of molecule 5 with N-beta- (tert-butoxycarbonyl) -L-2.3-diaminopropionic acid (HDap (Boc) OH)
In analogy to the procedure used for the preparation of molecule 1, applying to molecule 5(100.00g, 307.23mmol) and to HDap (Boc) OH (65.88g, 322.59mmol), the organic phase was concentrated under reduced pressure to give molecule 17 as a white solid. The latter can be used directly without further purification.
Yield: 141.6g (90%)
1H NMR(CDCl3，ppm)：0.87(3H)；1.18-1.49(29H)；1.54-1.68(2H)；1.82-2.41(6H)；3.37-3.78(4H)；4.31-4.74(2H)；5.61(1H)；7.63(1H)；9.59(1H).
LC/MS (ESI): 512.2 (calculated ([ M + H))]+)：512.4).
Molecule 18: product of reaction of molecule 17 with ethylenediamine
Following a similar procedure to that used for the preparation of molecule 16 and application to molecule 17(41.00g, 80.12mmol) and to ethylenediamine (2.41g, 40.06mmol) in the presence of DIPEA (20.71g, 160.25mmol), recrystallization in acetonitrile gave molecule 18 as a white solid.
Yield: 40.80g (97%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.16-2.40(74H)；2.97-3.63(12H)；4.11-4.25(3H)；4.25-4.41(1H)；6.54-6.79(2H)；7.58-8.07(4H).
LC/MS (ESI): 1047.8 (calculated ([ M + H))]+)：1047.8).
Molecule A7
Using a method similar to that used for the preparation of molecule A5, and applied to molecule 18(35.90g, 34.27mmol), a white solid of molecule A7 was obtained.
Yield: 16.43g (85%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.12-1.55(48H)；1.67-2.31(12H)；2.64-2.82(4H)；2.99-3.25(4H)；3.25-3.61(4H)；4.02-4.12(1.4H)；4.12-4.22(0.6H)；4.22-4.34(1.4H)；4.38-4.45(0.6H)；7.70-8.20(4H).
LC/MS (ESI): 424.4, 847.7 (calculated ([ M + 2H)]2+)：424.4，([M+H]+)：847.7).
Example A8: molecule A8
Molecule 19: product obtained by reacting molecule 15 with ethylenediamine
Recrystallization in acetonitrile using a method similar to that used for the preparation of molecule 18, applied to molecule 15(16.05g, 29.0mmol) and applied to ethylenediamine (0.96g, 16.0mmol) gave molecule 19 as a white solid.
Yield: 19.78g (60%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.09-2.38(86H)；2.80-2.91(4H)；3.00-3.60(8H)；4.04-4.15(1.3H)；4.15-4.23(0.7H)；4.23-4.31(1.3H)；4.36-4.45(0.7H)；6.27-6.82(2H)；7.60-8.21(4H).
LC/MS (ESI): 1131.8, 1153.8 (calculated ([ M + H)]+)：1131.9，([M+Na]+)：1153.9).
Molecule A8
Using a method analogous to the method used for the preparation of molecule a1 and applied to molecule 19(19.78g, 17.48mmol), the residue was dissolved in water, 2N aqueous soda solution was added until a precipitate formed, filtered and dried under reduced pressure to give molecule A8 as a white solid.
Yield: 9.93g (61%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.16-2.25(68H)；2.25-2.39(4H)；2.65-2.83(4H)；3.22-3.54(6H)；3.54-3.74(2H)；4.23-4.37(2H)；4.43-4.58(2H)；7.40(2H)；7.63(2H).
LC/MS (ESI): 466.7, 931.8 (calculated ([ M + 2H)]2+)：466.4，([M+H]+)：931.8).
Example a 9: molecule A9
Molecule 20: product of the reaction of molecule 17 with 4, 7, 10-trioxa-1, 13-tridecanediamine
Using a method similar to that used for the preparation of molecule 18, applied to molecule 17(32.00g, 62.54mmol) and to 4, 7, 10-trioxa-1, 13-tridecanediamine (6.89g, 31.27mmol), gave molecule 20 as a white solid.
Yield: 29.23g (77%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.17-2.38(78H)；3.01-3.15(4H)；3.15-3.62(20H)；4.09-4.24(3H)；4.28-4.40(1H)；6.58-6.87(2H)；7.41-8.03(4H).
LC/MS (ESI): 1207.9 (calculated ([ M + H))]+)：1207.9).
Molecule A9
Using a method similar to that used for the preparation of molecule A5, and applying to molecule 20(28.30g, 23.43mmol), a white solid of molecule A9 was obtained.
Yield: 15.76g (67%)
1HNMR(DMSO-d6，ppm)：0.85(6H)；1.10-2.33(64H)；2.60-2.86(4H)；3.01-3.19(4H)；3.27-3.62(16H)；4.01-4.13(1.4H)；4.13-4.20(0.6H)；4.20-4.30(1.4H)；4.36-4.46(0.6H)；7.57-7.70(1.4H)；7.70-7.85(1.4H)；7.91-8.03(0.6H)；8.03-8.19(0.6H).
LC/MS (ESI): 504.4, 1007.9 (calculated ([ M + 2H)]2+)：504.4，([M+H]+)：1007.8).
Example a 10: molecule A10
Molecule 21: product of reaction of molecule 8 with molecule 13
Using a method similar to the method used for the preparation of molecule 4, applied to molecule 8(7.12g, 21.47mmol) and applied to molecule 13(17.70g, 17.89mmol), stirring for 16h between 0 ℃ and room temperature, washing the reaction medium in dichloromethane with saturated aqueous NaHCO 3(2 x100mL), 10% aqueous HCl (2x100mL), saturated aqueous NaCl (50mL) gives a white foam of molecule a10, which is dried over Na2SO4, filtered and concentrated in vacuo.
Yield: 20.10g (86%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.11-2.04(95H)；2.04-2.32(4H)；2.76-3.61(16H)；4.09-4.62(4H)；6.26-7.01(3H)；7.57-8.43(3H).
LC/MS (ESI): 1303.1, 1325.1 (calculated ([ M + H))]+)：1303.0，([M+Na]+)：1325.0).
Molecule A10
Using a method similar to that used for the preparation of molecule A5, and applying to molecule 21(20.10g, 15.43mmol), a pale yellow solid of molecule A10 was obtained.
Yield: 10.70g (69%)
1H NMR(DMSO-d6，ppm)：0.85(6H)；1.11-2.31(78H)；2.41-2.70(6H)；2.87-3.68(10H)；4.06-4.50(3H)；4.56-4.77(1H)；7.59-8.35(3H).
LC/MS (ESI): 501.9, 1002.7 (calculated ([ M + 2H)]2+)：501.9，([M+H]+)：1002.8).
Example a 11: molecule A11
Molecule 22: the product of the reaction of molecule 6 with α -tert-butyl- γ -benzyl L-glutamate gave, after purification by flash chromatography (eluent: DCM, MeOH), a white solid of molecule 22, using a method analogous to that used for the preparation of molecule 12, applied to a solution of molecule 6(5.0g, 6.57mmol) in chloroform (34mL) and to α -tert-butyl- γ -benzyl L-glutamate (2.167g, 6.57 mmol).
Yield: 6.16g (90%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.18-2.51(75H)；2.89-3.68(6H)；4.18-4.66(4H)；5.11(2H)；7.11(1H)；7.28-7.41(5H)；7.55(1H)；7.70(1H).
LC/MS (ESI): 1037.0 (calculated ([ M + H))]+)：1036.8).
Molecule 23: reaction of molecule 22 with HCl
To a solution of molecule 22(6.16g, 5.94mmol) in DCM (60mL) was added a 4N HCl in dioxane (15 mL). After 48h at room temperature, the reaction medium is concentrated under reduced pressure and the residue is purified by flash chromatography (eluent: DCM, MeOH).
Yield: 3.05g (51%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.14-2.58(66H)；2.98-3.69(6H)；4.24-4.61(4H)；5.l0(2H)；7.27-7.40(5H)；6.75-7.60(3H).
LC/MS (ESI): 980.8 (calculated ([ M + H))]+)：980.7).
Molecule 24: product of reaction of molecule 23 with molecule 3
Purification by flash chromatography (eluent: DCM, methanol) using a method analogous to that used for the preparation of molecule 4, applied to molecule 23(1.5g, 1.53mmol) and to molecule 3(0.582g, 1.683mmol) in chloroform (23mL) gave molecule 24 as a colorless oil.
Yield: 1.54g (77%)
1H NMR(CDCl3，ppm)：0.88(6H)；1.18-2.53(90H)；2.85-3.68(14H)；4.24-4.63(3H)；4.80-4.98(1H)；5.06-5.21(2H)；7.28-7.39(5H).
Molecule A11
Using a method similar to that used for the preparation of molecule Al and applying to molecule 24(1.54g, 1.18mmol), a white solid of molecule A11 was obtained as the hydrochloride salt.
Yield: 1.32g (95%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.17-2.28(66H)；2.34-3.60(6H)；2.84-3.07(4H)；3.07-3.29(2H)；3.37-3.80(8H)；4.16-4.46(3H)；4.84-4.98(1H)；5.14(2H)；7.30-7.40(5H).
LC/MS (ESI): 554.7, respectively; 1108.0, respectively; (calculated value ([ M + 2H)]2+)：554.4；([M+H]+)：1107.9).
Example a 12: molecule A12
Molecule 25: Fmoc-Lys (Fmoc) -OH and 2-Cl-trityl chloride resin
DIPEA (4.32mL, 24.80mmol) was added to Fmoc-Lys (Fmoc) -OH (7.32g, 12.40mmol) suspended in dichloromethane (60mL) at room temperature. After complete dissolution (10 min), the resulting solution was poured onto 2-Cl-trityl chloride resin previously washed with dichloromethane (100-200 mesh, 1% DVB, 1.24mmol/g) (4.00g, 4.96mmol) in a suitable reactor for peptide synthesis on a solid support. After stirring at room temperature for 2h, HPLC grade methanol (0.8mL/g resin, 3.2mL) was added and the medium was stirred at room temperature for 15 min. The resin was filtered and washed successively with dichloromethane (3X 60mL), DMF (2X 60mL), dichloromethane (2X 60mL), isopropanol (1X60mL) and dichloromethane (3X 60 mL).
Molecule 26: molecules 25 and 80: product obtained by reaction of 20 DMF/piperidine mixture
Molecule 25, previously washed with DMF, was washed with 80: 20 DMF/piperidine mixture (60 mL). After stirring at room temperature for 30 minutes, the resin was filtered and washed sequentially with DMF (3X 60mL), isopropanol (1X60mL) and dichloromethane (3X 60 mL).
Molecule 27: reaction of molecule 26 with Fmoc-Glu (OtBu) -OH
To a suspension of Fmoc-Glu (OtBu) -OH (10.55g, 24.80mmol) and 1- [ bis (dimethylamino) methylene ] -1H-1, 2, 3-triazolo [4, 5-b ] pyridinium 3-oxide hexafluorophosphate (HATU, 9.43g, 24.80mmol) in a 1: 1 DMF/dichloromethane mixture (60mL) was added DIPEA (8.64mL, 49.60 mmol). After complete dissolution, the resulting solution is poured over molecule 26. After stirring at room temperature for 2h, the resin was filtered and washed sequentially with DMF (3X 60mL), isopropanol (1X60mL), and dichloromethane (3X 60 mL).
Molecule 28: reaction of molecule 27 with a 50: 50 DMF/morpholine mixture
Molecule 27, previously washed with DMF, was treated with a 50: 50 DMF/morpholine mixture (60 mL). After stirring at room temperature for 1h15, the resin was filtered and washed sequentially with DMF (3X 60mL), isopropanol (1X60mL) and dichloromethane (3X 60 mL).
Molecule 29: product of reaction of molecule 28 with molecule 5
Using a method similar to that used for molecule 27, applied to molecule 28 and to molecule 5(8.07g, 24.80mmol) in DMF (60mL) gave molecule 29.
Molecule 30: molecules 29 and 80: product obtained by reaction of 20 dichloromethane/1.1.1.3.3.3-hexafluoro-2-propanol (HFIP) mixture
Molecule 29 was measured using 80: a20 dichloromethane/1.1.1.3.3.3-hexafluoro-2-propanol (HFIP) mixture (60mL) was treated. After stirring at room temperature for 20 min, the resin was filtered and washed with dichloromethane (2 × 60 mL). The solvent was evaporated under reduced pressure. The residue was then co-evaporated twice with dichloromethane (60mL) followed by diisopropyl ether (60 mL). The product was purified by silica gel chromatography (dichloromethane, methanol). A white solid of molecule 30 was obtained.
Yield: 2.92g (6 steps, 52%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.22-2.47(88H)；3.13-3.25(2H)；3.45-3.76(4H)；4.24-4.55(5H).
LC/MS (ESI +): 1131.9 (calculated ([ M + H))]+)：1131.8).
Molecule 31: product of reaction of molecule 30 with molecule 3
Purification by flash chromatography (eluent: DCM, methanol) using a method analogous to that used for the preparation of molecule 4, applied to molecule 30(3.12g, 2.76mmol) and to a solution of molecule 3(1.048g, 3.03mmol) in chloroform (40mL) gave molecule 31 as a colorless oil.
Yield: 2.57g (64%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.21-2.47(112H)；2.82-3.74(14H)；4.16-4.53(4H)；4.53-4.78(1H).
Molecule A12
Using a method similar to that used for the preparation of molecule A1, and applying to molecule 31(2.56g, 1.75mmol), a white solid of molecule A12 was obtained as the hydrochloride salt. The latter was dissolved in water (40mL), a 1N NaOH solution was added until pH7 was reached, and the solution was then lyophilized to give molecule a12 as a white solid.
Yield: 2.1g (95%)
1H NMR(CD3OD，ppm)：0.90(6H)；1.19-2.32(68H)；2.32-2.54(8H)；2.82-3.15(4H)；3.15-3.79(10H)；4.23-4.76(5H).
LC/MS (ESI): 1146.9, respectively; (calculated value ([ M + H)]+)：1146.8).
Synthesis of B part-hydrophobic copolyamino acid
The hydrophobic copolyamino acids are shown in table 2.
Table 2: list of hydrophobic copolyamino acids.
Example B1:
co-amino acid B1-poly-L-sodium glutamate modified with molecule A1 and having a number average molecular weight (Mn) of 6850g/mol
The hydrochloride salt of molecule A1(3.70g, 4.09mmol), chloroform (40mL), in that order, was introduced into a suitable vessel,
Molecular sieves (1.5g) and Amberlite IRN-150 ion exchange resin (1.5 g). After stirring on a roller for 2.5h, the medium was filtered and the resin was rinsed with chloroform. Evaporating the mixture and then co-evaporating with tolueneAnd (4) evaporating. The residue was dissolved in anhydrous DMF (5mL) and used directly for the next reaction.
In an oven dried round bottom flask, gamma-benzyl-L-glutamic acid N-carboxy anhydride (43.04g, 163.50mmol) was placed under vacuum for 2h, then dry DMF (80mL) was introduced. The mixture was stirred under argon until completely dissolved, cooled to 4 ℃, and then a solution of molecule a1 prepared as described before was rapidly introduced. The mixture was stirred between 4 ℃ and room temperature for 2 days and then heated at 65 ℃ for 2 h. The reaction mixture was then cooled at room temperature and then poured dropwise into diisopropyl ether (3.2L) with stirring. The white precipitate was collected by filtration, washed twice with diisopropyl ether (150mL) and then dried under vacuum at 30 ℃ to give a white solid. This solid was dissolved in trifluoroacetic acid (152mL) and a solution of 33% HBr in acetic acid (106mL) was added dropwise at 0 ℃. The solution was stirred at room temperature for 2h and then poured dropwise under stirring in a 1: 1(v/v) diisopropyl ether/water mixture (1.8L). After stirring for 2h, the heterogeneous mixture was left overnight. The white precipitate was collected by filtration, then diluted with 1: 1(v/v) diisopropyl ether/water mixture (150mL) and water (150 mL). The solid obtained is dissolved in water (750mL), the pH is adjusted to 7.5 by adding 1N aqueous soda solution and then the theoretical concentration of the polymer is adjusted to 20g/L by adding water. The mixture was filtered on a 0.45 μm frit and then purified by ultrafiltration with 0.9% NaCl solution followed by water until the conductivity of the permeate was below 50 μ S/cm. The polyamino acid solution is then concentrated to a theoretical value of about 30g/L and the pH is adjusted to 7.0. The aqueous solution was filtered on a 0.2 μm frit and maintained at 4 ℃.
Dry extract: 25.8mg/g
DP (estimated by 1H NMR) is 45, i.e. the ratio j/(m + n) is 0.022, said ratio j/(m + n) being called i'.
The number average molecular weight of the resulting polyamino acid B1 was calculated to be 7552 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 6850 g/mol.
Example B2:
co-amino acid B2-poly-L-sodium glutamate modified with molecule A1 and having a number average molecular weight (Mn) of 3330g/mol
poly-L-sodium glutamate modified with molecule a1 was obtained using a method similar to that used for the preparation of the copolyamino acid B1, applied to the hydrochloride salt of molecule a1(4.76g, 5.26mmol) and to gamma-benzyl-L-glutamic acid N-carboxy anhydride (27.68g, 105.1 mmol).
Dry extract: 25.6mg/g
DP (estimated by 1H NMR) ═ 22, and i ═ 0.045
The number average molecular weight of the resulting polyamino acid B2 was 4076 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3330 g/mol.
Example B3:
co-amino acid B3-poly-L-sodium glutamate modified with molecule A2 and having a number average molecular weight (Mn) of 3360g/mol
Using a method similar to that used for the preparation of the copoly amino acid B1, applying to the hydrochloride of molecule A2(4.90g, 5.10mmol) and to the γ -benzyl-L-glutamic acid N-carboxyanhydride (26.83g, 101.9mmol), a co-L-sodium glutamate modified with molecule A2 was obtained.
Dry extract: 29.7mg/g
DP (estimated by 1H NMR) 20, and i' 0.05
The number-average molecular weight of the resulting polyamino acid B3 was 3830 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3360 g/mol.
Example B4:
co-polyamino acid B4-poly-sodium L-glutamate modified with molecule A2 and having a number average molecular weight (Mn) of 7050g/mol
Using a method similar to the method used to prepare copoly amino acid B1, applied to the hydrochloride salt of molecule a2(5.90g, 6.14mmol) and to gamma-benzyl-L-glutamic acid N-carboxy anhydride (64.63g, 245.50mmol), yielded co-L-sodium glutamate modified with molecule a 2.
Dry extract: 24.1mg/g
DP (estimated by 1H NMR) 46, and i' 0.022
The number-average molecular weight of the resulting copolyamino acid B4 was calculated to be 7759 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 7050 g/mol.
Example B5:
co-amino acid B5-poly-L-sodium glutamate modified with molecule A2 and having a number average molecular weight (Mn) of 10440g/mol
Using a method similar to the method used to prepare copoly amino acid B1, applied to the hydrochloride salt of molecule a2(3.09g, 3.21mmol) and to gamma-benzyl-L-glutamic acid N-carboxy anhydride (52.09g, 197.9mmol), yielded co-L-sodium glutamate modified with molecule a 2.
Dry extract: 27.2mg/g
DP (estimated by 1H NMR) 66, and i' 0.015
The number average molecular weight of the resulting copolyamino acid B5 was calculated to be 10781 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn 10440 g/mol.
Example B6:
polyamino acid B6-poly-L-monosodium glutamate modified with molecule A3 and having a number average molecular weight (Mn) of 3020g/mol
Using a method similar to the method used to prepare the copoly amino acid B1, applied to molecule A3(4.15g, 4.75mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (25.0g, 95.0mmol), yielded a co-L-sodium glutamate modified with molecule A3.
Dry extract: 20.4mg/g
DP (estimated by 1H NMR) 18, and i' 0.056
The number average molecular weight of the resulting polyamino acid B6 was calculated to be 3514 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3020 g/mol.
Example B7:
co-amino acid B7-poly-L-sodium glutamate modified with molecule A4 and having a number average molecular weight (Mn) of 3360g/mol
Using a method similar to the method used to prepare the copolyamino acid B1, applied to molecule a4(2.06g, 1.99mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (10.5g, 39.9mmol), yielded a co-L-sodium glutamate modified with molecule a 4.
Dry extract: 17.6mg/g
DP (estimated by 1H NMR) 23, and i' 0.043
The number average molecular weight of the resulting polyamino acid B7 was 4429 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3360 g/mol.
Example B8:
co-amino acid B8-poly-L-sodium glutamate modified with molecule A5 and having a number average molecular weight (Mn) of 3360g/mol
Using a method similar to the method used to prepare the copoly amino acid B1, applied to molecule a5(3.89g, 4.18mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (22.00g, 84.00mmol), yielded a co-L-sodium glutamate modified with molecule a 5.
Dry extract: 17.9mg/g
DP (estimated by 1H NMR) 20, and i' 0.050
The number average molecular weight of the resulting polyamino acid B8 was 3873 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3360 g/mol.
Example B9:
co-amino acid B9-poly-L-sodium glutamate modified with molecule A6 and having a number average molecular weight (Mn) of 3340g/mol
Using a method similar to that used for the preparation of the copoly amino acid B1, applied to molecule A6(5.81g, 5.70mmol) as free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (30.00g, 114mmol), a co-L-sodium glutamate modified with molecule A6 was obtained.
Dry extract: 16.4mg/g
DP (estimated by 1H NMR) 20, and i 0.05
The number average molecular weight of the resulting polyamino acid B9 was calculated to be 3961 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3340 g/mol.
Example B10:
co-amino acid B10-poly-L-sodium glutamate modified with molecule A7 and having a number average molecular weight (Mn) of 2920g/mol
Using a method similar to the method used to prepare the copoly amino acid B1, applied to molecule a7(3.54g, 4.18mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (22.00g, 84.00mmol), yielded a co-L-sodium glutamate modified with molecule a 7.
Dry extract: 18.4mg/g
DP (estimated by 1H NMR) 20, and i' 0.05
The number-average molecular weight of the resulting polyamino acid B10 was calculated to be 3789 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 2920 g/mol.
Example B11:
co-polyamino acid B11-poly-sodium L-glutamate modified with molecule A8 and having a number average molecular weight (Mn) of 3750g/mol
Using a method similar to the method used to prepare the copolyamino acid B1, applied to molecule a8(2.51g, 2.69mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (14.19g, 53.90mmol), yielded a co-L-sodium glutamate modified with molecule a 8.
Dry extract: 20.9mg/g
DP (estimated by 1H NMR) 24, and i' 0.042
The number average molecular weight of the resulting polyamino acid B11 was calculated to be 4478 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 3750 g/mol.
Example B12:
co-amino acid B12-poly-L-sodium glutamate modified with molecule A9 and having number average molecular weight (Mn) of 3660g/mol
Using a method similar to the method used to prepare the copoly amino acid B1, applied to molecule a9(4.21g, 4.18mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (22.00g, 84.00mmol), yielded a co-L-sodium glutamate modified with molecule a 9.
Dry extract: 18.6mg/g
DP (estimated by 1H NMR) 20, and i' 0.050
The number average molecular weight of the resulting polyamino acid B12 was calculated to be 3949 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn 3660 g/mol.
Example B13:
co-polyamino acid B13-poly-sodium L-glutamate modified with molecule A10 and having a number average molecular weight (Mn) of 4170g/mol
Using a method similar to that used for the preparation of the copoly amino acid B1, applied to molecule A10(3.81g, 3.80mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (30.00g, 114.00mmol), a co-L-sodium glutamate modified with molecule A10 was obtained.
Dry extract: 22.3mg/g
DP (estimated by 1H NMR) 27, and i' 0.037
The number-average molecular weight of the resulting polyamino acid B13 was 4962 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 4170 g/mol.
Example B14:
copolymerized amino acid B14-poly-L-sodium glutamate modified with molecule A11 and having a number average molecular weight (Mn) of 6500g/mol
Using a method similar to that used for the preparation of the copoly amino acid B1, applied to molecule A11(1.21g, 1.09mmol) and to γ -benzyl-L-glutamic acid N-carboxy anhydride (10.8g, 41.0mmol), a co-L-sodium glutamate modified with molecule A11 was obtained.
Dry extract: 22.2mg/g
DP (estimated by 1H NMR) ═ 38, and i ═ 0.026
The number average molecular weight of the resulting polyamino acid B14 was 6701 g/mol.
Aqueous HPLC-SEC (calibrator PEG): and Mn is 6500 g/mol.
Example B15:
polyamino acid B15-poly-L-monosodium glutamate modified with molecule A12 and having a number average molecular weight (Mn) of 4300g/mol
Using a method similar to that used for the preparation of the copoly amino acid B1, applied to molecule A12(2.00g, 1.58mmol) as the free amine and to γ -benzyl-L-glutamic acid N-carboxy anhydride (8.34g, 31.7mmol), a co-L-sodium glutamate modified with molecule A12 was obtained.
Dry extract: 15.1mg/g
DP (estimated by 1H NMR) 24, and i' 0.042
The number average molecular weight of the resulting polyamino acid B15 was calculated to be 4737 g/mol.
Aqueous HPLC-SEC (calibrator PEG): mn is 4300 g/mol.
Part C-commercial composition
Example C1: 100U/mL fast-acting insulin analog solutions
The solution is named by ELI LILLY
A commercial solution of insulin lispro sold. The product is a fast acting insulin analogue.
The excipients in (1) were m-cresol (3.15mg/mL), glycerol (16mg/mL), disodium phosphate (1.88mg/mL), zinc oxide (to have 0.0197mg zinc ions/mL), sodium hydroxide and hydrochloric acid to adjust the pH (pH 7-7.8) and water.
Example C2: fast insulin analogues of 100U/mL
Solutions of
The solution is obtained from NOVO NORDISK
In the United states and in
A commercially available solution of insulin aspart sold in europe. The product is a fast insulin analogue.
The excipient of (1)Glycerol (16mg), phenol (1.50mg/mL), m-cresol (1.72mg/mL), zinc (19.6. mu.g/mL), disodium phosphate dihydrate (1.25mg/mL), sodium chloride (0.5mg/mL), sodium hydroxide and hydrochloric acid for adjusting pH (pH 7.2-7.6), and water.
Example C3: fast insulin analogues of 100U/mL
Solutions of
The solution is manufactured by the company SANOFI under the name
A commercial solution of insulin glulisine is sold. The product is a fast insulin analogue.
The excipients in (1) were m-cresol (3.15mg/mL), tromethamine (6mg/mL), sodium chloride (5mg/mL), polysorbate 20(0.01mg/mL), sodium hydroxide and hydrochloric acid for adjusting the pH (pH 7.3), and water.
Example C4: slow acting insulin analogues of 100U/mL
Solutions of
The solution is manufactured by the company SANOFI under the name
Marketed solutions of insulin glargine are sold. The product is a slow acting insulin analogue. In that
The excipients in (1) were zinc chloride (30. mu.g/mL), m-cresol (2.7mg/mL), glycerol (85%) (20mg/mL), sodium hydroxide and hydrochloric acid for pH adjustment (pH 4) and water.
Example C5: human insulin 100IU/mL
Liquid container
The solution is prepared byIs named by NOVO NORDISK
Commercial solutions of commercial human insulin were sold. The product is human insulin. In that
The excipients in (1) are zinc chloride, glycerol, m-cresol, sodium hydroxide and hydrochloric acid for adjusting the pH (pH 6.9-7.8) and water.
Example C6: 100IU/mL human insulin (Umuline)
) Solutions of
The solution is prepared by ELI LLY under the name Umuline
Commercial solutions of commercial human insulin were sold. The product is human insulin. In Umuline
The excipients in (1) are glycerol, m-cresol, sodium hydroxide and hydrochloric acid for adjusting the pH (pH 7.0-7.8) and water.
CA moiety-compositions comprising insulin glargine
Preparation method CA 1: a dilute composition of 50U/mL of copolyamino acid/insulin glargine at pH7.1 was prepared according to the method using insulin glargine in liquid form (in solution) and copolyamino acid in liquid form (in solution).
To a stock solution of the polyamino acid, pH7.1, was added a concentrated solution of m-cresol and glycerol, to obtain a concentration CCopoly amino acid storage/excipient(mg/mL) of a solution of a copolyamino acid. The amount of excipient added was adjusted to obtain a concentration of 35mM meta-cresol and 184mM glycerol in a pH7.1 copolyamino acid/insulin glargine 50U/mL composition.
In a sterile tank, the volume V isInsulin glargiaBy name of element
Marketed solution of insulin glargine sold at a concentration of 100U/mL is added to volume VCopoly amino acid storage/excipientIs C in a concentration ofCopoly amino acid storage/excipient(mg/mL) of a solution of a copolyamino acid to give C at pH7.1Rare copolymerized amino acid(mg/mL)/insulin glargine 50U/mL. Turbidity appeared. The pH was adjusted to pH7.1 by addition of concentrated NaOH and the solution was placed in an oven at 40 ℃ for 2 hours under static conditions until complete dissolution. The visually clear solution was placed at +4 ℃.
Preparation method CA 2: according to the method for concentrating dilute compositions, a co-amino acid/insulin glargine concentrate composition of pH7.1 is prepared with the aid of co-amino acids.
The pH7.1 copolyamino acid/insulin glargine 50U/mL composition described in example CA1 was concentrated by ultrafiltration through a 3kDa membrane made of regenerated cellulose (sold by Millipore Inc.)
Ultra-15). After this ultrafiltration step, the retentate was clear and the concentration of insulin glargine in the composition was determined by reverse phase chromatography (RP-HPLC). The concentration of insulin glargine in the composition was then adjusted to the desired value by dilution in a solution of m-cresol/glycerol excipient such that the final concentration of m-cresol was 35mM and the osmolarity was 300 mOsm/kg. The pH was measured and adjusted to 7.1 by adding concentrated NaOH and HCl. The solution has a pH of 7.1, is visually clear, and has a concentration of insulin glargine CInsulin glargine(U/mL) and a copolyamino acid concentration CCopolyamino acids(mg/mL)＝CRare copolymerized amino acid(mg/mL)x CInsulin glargine(U/mL)/50(U/mL)。
According to this preparation method, CA2, a copolyamino acid/insulin glargine composition was prepared, for example, at pH7.1, with insulin glargine concentrations of 200U/mL and 400U/mL.
Example CA 3: a composition of Coamino acid/insulin glargine 200U/mL at pH7.1 was prepared.
A composition of copolyamino acid/insulin glargine 200U/mL was prepared according to the method described in example CA2 to obtain insulin glargine concentration CInsulin glargine200U/mL and a copolyamino acid concentration CCopolyamino acids(mg/mL)。
These compositions are shown in table 3.
Table 3: composition of insulin glargine (200U/mL) in the presence of a copolyaminoacid.
CB moiety-composition comprising insulin glargine and insulin lispro
Preparation method CB 1: preparation of a Dilute composition of Copolyamino acid/insulin glargine 43 (U/mL)/insulin lispro 13.5(U/mL)
To volume V described in example CA1Copolymerized amino acid/diluted insulin glargineThe diluted composition of 50U/mL of the polyamino acid/insulin glargine of pH7.1 is added with a volume VInsulin lispro100U/mL insulin lispro
To obtain a composition of copolyamino acid/insulin glargine 43 (U/mL)/insulin lispro 13, 5 (U/mL).
Preparation method CB 2: preparation of a concentrated composition of Copolyamino acid/insulin glargine/insulin lispro with pH7, 1
The composition of copolyamino acid/insulin glargine 43 (U/mL)/insulin lispro 13.5(U/mL) described in example CB1 was concentrated by ultrafiltration through a 3kDa membrane made of regenerated cellulose (sold by MILLIPORE Inc.)
Ultra-15). After this ultrafiltration step, the retentate was clear and the concentration of insulin glargine in the composition was determined by reverse phase chromatography (RP-HPLC). Then adding the mixture into m-cresol/glycerolThe concentrations of insulin glargine and insulin lispro in the composition were adjusted to the desired values by dilution in a solution of the formulation so that the final concentration of m-cresol was 35mM and the osmolarity was 300 mOsm/kg. The pH was measured and adjusted to 7.1 by adding concentrated NaOH and HCl if necessary. The solution has a pH of 7.1, is visually clear, and has a concentration of insulin glargine CInsulin glargine(U/mL), insulin concentration of lispro CInsulin lispro＝CInsulin glarginex 0.33 and the concentration of copolymerized amino acids CCopolyamino acids(mg/mL)＝CRare copolymerized amino acid(mg/mL)x CInsulin glargine(U/mL)/50(U/mL)。
Example CB 3: a composition of copolyamino acid/insulin glargine 200U/mL/insulin lispro 66U/mL pH7, 1 was prepared.
A composition of copolyamino acid/insulin glargine 200U/mL/insulin lispro 66U/mL was prepared according to the method described in example CB2 to obtain insulin glargine concentration CInsulin glargine200U/mL, insulin concentration C of lisproInsulin lispro66U/mL and a copolyamino acid concentration CCopolyamino acids(mg/mL)。
These compositions are shown in table 4. Watch (A)
Table 4: insulin glargine (200U/mL) and insulin lispro (66U/mL) compositions in the presence of a polyamino acid.
The previously obtained compositions (CA3 to CB3) were injectable physically stable compositions.
Part D-result
Physical stability of the composition prepared as described above
Example D1: accelerated stability at 25 ℃ and under dynamic conditions.
3-mL vials containing 1mL of the copolyamino acid/insulin glargine or copolyamino acid/insulin glargine/prandial insulin composition were placed vertically on an orbital agitator. The stirrer was placed in an oven at 25 ℃ and the vials were stirred at 50 or 250 rpm. The vials were visually inspected daily/weekly to detect the presence of visible particles or turbidity. This examination is carried out according to the recommendations of the european pharmacopoeia (EP 2.9.20): the vials were illuminated at least 2000lux and observed on a white background and a black background. The days of stability correspond to the duration of visible particles or turbidity appearing in at least two vials thereafter.
The results of accelerated stability (obtained with different compositions) are in tables 4 and 5.
Table 4: stability results of the copolyaminoacid/insulin glargine (200U/mL) composition at 25 ℃ and under dynamic conditions (stirring at 250 rpm). (. when the pH of the insulin glargine solution was adjusted at pH7, precipitation occurred).
Table 5: stability results of the copolyamino acid/insulin glargine (200U/mL)/insulin lispro (66U/mL) composition at 25 ℃ and under dynamic conditions (stirring at 250 rpm). (. when the pH of the insulin glargine solution was adjusted at pH7, precipitation occurred).
The composition according to the invention with insulin glargine and insulin lispro show good stability under dynamic conditions.
Example D2: accelerated stability at 30 ℃ and static conditions.
53 mL vials containing 1mL of the composition were placed vertically in an oven maintained at 30 ℃. The vials were visually inspected daily to detect the presence of visible particles or turbidity. This examination is carried out according to the recommendations of the european pharmacopoeia (EP 2.9.20): the vials were illuminated at least 2000lux and observed on a white background and a black background. The number of weeks of stability corresponds to the duration of time after which at least half of the vials show visible particles or turbidity.
These results are consistent with the United states pharmacopoeia (USP <790 >).
The results of accelerated stability (obtained with different compositions) are in tables 8a and 8b below.
| Composition comprising a metal oxide and a metal oxide | Copolyamino acids | Stability at 30 ℃ and static State (in weeks) |
| CA3 | - | * |
| CA3-2 | B4 | ＞16 |
| CA3-1 | B3 | ＞19 |
| CA3-9 | B14 | ＞19 |
| CA3-4 | B5 | ＞19 |
| CA3-5 | B6 | ＞19 |
| CA3-6 | B7 | ＞18 |
| CA3-8 | B11 | ＞19 |
Table 8 a: stability results of the copolyamino acid/insulin glargine (200U/mL) composition at 30 ℃ and static conditions. (. when the pH of the insulin glargine solution was adjusted at pH7, precipitation occurred).
| Composition comprising a metal oxide and a metal oxide | Copolyamino acids | Stability at 30 ℃ and static State (in weeks) |
| CB3 | - | * |
| CB3-1 | B1 | ＞16 |
| CB3-2 | B4 | ＞16 |
| CB3-4 | B3(8) | ＞16 |
| CB3-12 | B14 | ＞16 |
| CB3-6 | B5 | ＞16 |
| CB3-7 | B6 | ＞16 |
| CB3-8 | B7 | ＞16 |
| CB3-10 | B11 | ＞16 |
| CB3-11 | B12 | ＞16 |
Table 8 b: stability results for the copolyamino acid/insulin glargine (200U/mL)/insulin lispro (66UI/mL) composition at 30 ℃ and static conditions. (. when the pH of the insulin glargine solution was adjusted at pH7, precipitation occurred).
The composition according to the invention with insulin glargine and insulin lispro showed good stability at 30 ℃ and under static conditions.
Example D3: accelerated stability at 40 ℃ and static conditions.
The accelerated stability of the compositions at 40 ℃ and static conditions was also tested using the same method as described in example D2.
These results are consistent with the United states pharmacopoeia (USP <790 >).
The results of accelerated stability (obtained with different compositions) are in table 8c below.
| Composition comprising a metal oxide and a metal oxide | Copolyamino acids | Stability at 40 ℃ under static conditions (in weeks) |
| CB3 | - | * |
| CB3-2 | B3 | ＞3 |
| CB3-4 | B3(8) | ＞3 |
Table 8 c: stability results for the copolyamino acid/insulin glargine (200U/mL)/insulin lispro (66UI/mL) composition at 40 ℃ and static conditions. (. when the pH of the insulin glargine solution was adjusted at pH7, precipitation occurred).
The composition according to the invention with insulin glargine and with insulin lispro showed good stability at 40 ℃ and under static conditions.
Example D3:precipitation of insulin glargine in 200U/mL copolyamino acid/insulin glargine composition
1mL of the copolyamino acid/insulin glargine solution prepared in example CA3 was added to 2mL of PBS solution (phosphate buffered saline ) containing 20mg/mL BSA ((bovine serum albumin, bovine serum albumin)). The mixture PBS/BSA mimics the composition in the subcutaneous medium. Precipitation occurs.
To separate the precipitate from the supernatant, centrifugation at 4000rpm was performed. Insulin glargine was then determined in the supernatant by RP-HPLC. The result is that insulin glargine is mostly present in precipitated form.
The results are in table 7.6
Table 7: a copolyamino acid/insulin glargine (200U/mL) composition; insulin glargine dissolution/precipitation. 6
The co-amino acid allows the preparation of insulin glargine solutions at neutral pH and when said solutions are added to a medium mimicking the subcutaneous medium, the latter can be precipitated.
Example D4:precipitation of insulin glargine in pH7.1 copolyamino acid/insulin glargine 200U/mL/insulin lispro 66U/mL composition
1mL of the copolyamino acid/insulin glargine/insulin lispro solution prepared in example CB3 was added to 2mL of PBS solution containing 20mg/mL BSA (bovine serum albumin). The PBS/BSA mixture mimics the composition of the subcutaneous environment. Precipitation occurs.
To separate the precipitate from the supernatant, centrifugation at 4000rpm was performed. Insulin glargine was then determined in the supernatant by RP-HPLC. The result is that insulin glargine is mostly present in precipitated form. The results are shown in Table 8.7
Table 8: a copolyamino acid/insulin glargine (200U/mL)/insulin lispro (66U/mL) composition; dissolving and precipitating insulin glargine. 7
The polyamino acid allows the preparation of a solution of insulin glargine in the presence of insulin lispro at neutral pH and when said solution is added to a medium mimicking the subcutaneous medium, the latter can be precipitated.
Example D5: pharmacodynamics of dogs
To evaluate the pharmacodynamics of insulin after administration of a combination of the copolyamino acid B11 and insulin (composition CB3-10), a study was conducted in dogs.
The composition has blood sugar lowering effect, and can be injected with insulin glargine simultaneously or separately
(pH 4) and prandial insulin lispro
(ratio of 75% insulin glargine/25% insulin lispro (dose/dose)) were compared for their effects.
10 animals fasted for about 18 hours received a cervical injection over the interscapular region at a dose of 0.67U/kg. One hour prior to the insulin injection, 3 blood samples were taken to determine the basal level of glucose. Blood glucose was determined by a blood glucose meter within 24 h.
The mean pharmacokinetic profile of glucose is expressed as percent deviation from the basal level, as shown in figure 1.
Separate and simultaneous administration, in contrast to the pharmacodynamic results obtained with the composition described in example CB3-10
(example C1) and
the pharmacodynamic results obtained (example C4) are shown in figure 1. The hypoglycemic activity of the composition described in example CB3-10 is biphasic. The first rapid phase is defined as a significant decrease in blood glucose for about 60 minutes, a characteristic of the rapid action of insulin lispro. The first stage is in dual
It is also visible in the injection, indicating that the composition according to the invention does not change
The fast nature of (2). After about 60 minutes, the blood glucose rises to 3 hours, then a second, slower phase occurs, characterized by a diminished hypoglycemic activity, which lasts until 18-20 hours after injection. This basal second phase is characteristic of the basal action of insulin glargine, also seen in the double injection, indicating that this action is indeed maintained with the composition according to the invention described in example CB 3-10.
Claims (32)
- A physically stable composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0 comprising at least:a) basal insulin with isoelectric points (pI) of 5.8 and 8.5, andb) a copolymerized amino acid according to formula 1Q[Hy]j[PLG]kFormula IWherein:j≥1；k≥2said polyamino acids according to formula I are charged with carboxylate groups and are composed of at least two linear or branched groups or spacers Q-by at least three valences]i (i ≧ 3, where i ═ j + k) consists of a chain of PLG glutamic or aspartic acid units bound together, said group or spacer consisting of: containing one or more hetero atoms selected from the group consisting of nitrogen and oxygen atoms and/or alkyl chains with one or more hetero atoms consisting of nitrogen and oxygen atoms and/or with one or more hetero atoms consisting of nitrogen and oxygen atomsA group of hetero atoms and/or carboxyl groups, said group Q [ - ]]iWith at least one monovalent hydrophobic group according to formula X-Hy;-said group or spacer Q [ - ]]iIs bound to at least two chains of PLG glutamic acid or aspartic acid units via an amide function, and-said group or spacer Q [ - ]]iBound to at least one hydrophobic group-Hy according to formula X via an amide function.
- 2. The composition according to claim 1, wherein said group or spacer Q [ - ]]i(i.gtoreq.3) is represented by a group according to formula II:Q[-*]i＝([Q′]q)[-*]iformula IIWherein q is more than or equal to 1 and less than or equal to 5The groups Q' are identical or different and are selected from the group consisting of the groups according to the formulae III to VI below, to form Q [ - ]]i(i≥3)
Wherein t is more than or equal to 1 and less than or equal to 8
Wherein:u1"or u2At least one of "is different from 0.If u is1"≠ 0, then u1' ≠ 0, and if u2"≠ 0, then u2′≠0，u1' and u2Are' the same or different, and2≤u≤4，0≤u1′≤4，0≤u1”≤4，0≤u2′≤40≤u2is ≦ 4, and
wherein:v, v 'and v' are the same or different,v+v′+v”≤15
wherein:w1' a different value from 0 is used for the,0≤w2″≤1，w1w is not more than 61' < 6 > and/or w2W is not more than 62′≤6Wherein Fx ═ Fa, Fb, Fc, Fd, Fa ', Fb ', Fc ", and Fd ', which are the same or different, represent a functional group-NH-or-CO-, and Fy represents a trivalent nitrogen atom-N ═ by,two groups Q' are bound between the carboxyl function Fx ═ CO-and the amine function Fx ═ NH-or Fy ═ N ═ by a covalent bond between them, forming an amide bond, - 3. composition according to any one of the preceding claims, characterized in that the hydrophobic group-Hy is chosen from groups of formula X defined according to the following:
wherein:-GpR is selected from a group according to formula VII, VII' or VII ":
-GpG and GpH, equal or different, are selected from groups according to formula XI or XI':＊ -NH-G-NH- ＊ formula XI'
-GpA is selected from the group according to formula VIII
Wherein A ' is selected from a group according to formula VIII ', VIII ", or VIII '"
-GpL is selected from the group according to formula XII
-GpC is a group according to formula IX:
-;-a is an integer equal to 0 or equal to 1, and if a ═ 0, then a' ═ 1; and if a is 1, then a' is 1,2 or 3;a' is an integer equal to 1, equal to 2 or equal to 3-b is an integer equal to 0 or equal to 1;-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;-d is an integer equal to 0, equal to 1 or equal to 2;-e is an integer equal to 0 or equal to 1;-g is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;-h is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;-l is an integer equal to 0 or 1, and if l ═ 0, then l' ═ 1; and if l is 1, then l' is 2;-r is an integer equal to 0 or equal to 1, and-s' is an integer equal to 0 or 1;-A、A1、A2and A3Identical or different, are linear or branched alkyl groups containing from 1 to 6 carbon atoms.-B is a linear or branched alkyl group, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;-Cxis a monovalent linear or branched alkyl radical, wherein x represents the number of carbon atoms, and■ when the hydrophobic group-Hy carries 1-GpC, then x is more than or equal to 9 and less than or equal to 25,■ when the hydrophobic group-Hy carries 2-GpCs, x is more than or equal to 9 and less than or equal to 15,■ when the hydrophobic group-Hy carries 3-GpCs, then x is more than or equal to 7 and less than or equal to 13,■ when the hydrophobic group-Hy carries 4-GpCs, then x is more than or equal to 7 and less than or equal to 13,■ when the hydrophobic group-Hy carries at least 5-GpC, then x is greater than or equal to 6 and less than or equal to 11,-G is a branched alkyl group of 1 to 8 carbon atoms, said alkyl group bearing one or more carboxyl functions.-H is a branched alkyl group of 1 to 8 carbon atoms bearing one or more carboxyl functions.-R is a group selected from the group consisting of: a divalent linear or branched alkyl radical containing from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical containing from 1 to 12 carbon atoms and bearing one or more functional groups-CONH2Or an unsubstituted ether or polyether group containing from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:-one or more hydrophobic groups according to formula X-Hy bound to Q:formation of an amide function by reaction of the amine function carried by the precursor of Q and the acid function carried by the precursor of the hydrophobic group-Hy', via a covalent bond between the carbonyl group of said hydrophobic group-Hy and the nitrogen atom carried by Q, andformation of an amide function by reaction of an amine function carried by the precursor Hy' of the hydrophobic group-Hy and of an acid function carried by the precursor of the group Q, via a covalent bond between the nitrogen atom of said hydrophobic group-Hy and the carbonyl group carried by Q,-the ratio M between the number of hydrophobic groups and the number of glutamic acid or aspartic acid units is 0 < M.ltoreq.0.5;when several hydrophobic groups are carried by a polyamino acid, they are identical or different,-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;-said free carboxylic acid function is chosen from Na+And K+Basic cationic form of the group. - 4. Composition according to any one of the preceding claims, characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobic group-Hy are chosen from those according to formula XXXa below:
wherein,● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),● X represents a cationic entity selected in the group comprising alkali metal cations,●Raand Ra' identical or different, are a group selected from the group consisting of H, C2 to C10 straight-chain acyl, C3 to C10 branched-chain acyl, benzyl, terminal amino acid unit, and pyroglutamate,● Q, Hy and j are as defined above.● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 5. Composition according to claims 1 to 3, characterized in that the copolymerized amino acids carrying a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula XXXa':
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),● X represents a cationic entity selected in the group comprising alkali metal cations,● Q, Hy and j are as defined above.●RaAnd Ra' identical or different, are a group selected from the group consisting of H, C2 to C10 straight-chain acyl, C3 to C10 branched-chain acyl, benzyl, terminal amino acid unit, and pyroglutamate,●n1+m1represents the number of glutamic acid or aspartic acid units of the PLG chain of a polyamino acid having a group-Hy,●n2+m2indicates the number of glutamic acid or aspartic acid units of the PLG chain without the copolymerized amino acid of the group-Hy,●n1+n2n, and m1+m2＝m● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 6. Composition according to claims 1 to 3, characterized in that said copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula XXXa ":
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),● X represents a cationic entity selected in the group comprising alkali metal cations,● Q, Hy and j are as defined above.●RaAnd Ra' identical or different, is at least one hydrophobic group-Hy and a group selected from the group consisting of-Hy, H, C2 to C10 linear acyl, C3 to C10 branched acyl, benzyl, terminal "amino acid" units and pyroglutamate,● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 7. Composition according to claims 1 to 3, characterized in that the copolymerized amino acids carrying a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to formula XXXB below:
wherein,d independently represents a-CH 2-group (aspartic acid unit) or a-CH 2-CH 2-group (glutamic acid unit),● X represents a cationic entity selected in the group comprising alkali metal cations,●Rband Rb'same or different, -NR' R "group, R 'and R" same or different, selected from the group consisting of H, C2 to C10 linear or branched or cyclic alkyl groups, said benzyl group and said R' and R "alkyl groups may together form one or more saturated, unsaturated and/or aromatic carbocyclic rings and/or may contain heteroatoms selected from the group consisting of O, N and S;● Q, Hy and j are as defined above.● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 8. Composition according to claims 1 to 3, characterized in that the copolymerized amino acids carrying a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula XXXB':
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),● X represents a cationic entity selected in the group comprising alkali metal cations,● Q, Hy and j are as defined above.●RbAnd Rb'same or different, -NR' R "group, R 'and R" same or different, selected from the group consisting of H, C2 to C10 linear or branched or cyclic alkyl groups, said benzyl group and said R' and R "alkyl groups may together form one or more saturated, unsaturated and/or aromatic carbocyclic rings and/or may contain heteroatoms selected from the group consisting of O, N and S;● n1+ m1 denotes the number of glutamic acid or aspartic acid units of the PLG chain of the polyamino acid bearing the group-Hy,● n2+ m2 denotes the number of glutamic acid or aspartic acid units of the PLG chain without the polyamino acid having a group-Hy,● n1+ n2 ═ n, and m1+ m2 ═ m,● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 9. Composition according to claims 1 to 3, characterized in that said copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to the following formula XXXB ":
● D independently represents a-CH 2-group (aspartic acid units) or a-CH 2-CH 2-group (glutamic acid units),●，● X represents a cationic entity selected in the group comprising alkali metal cations,●Rband Rb'same or different, is at least one hydrophobic group-Hy and a group selected from the group consisting of hydrophobic groups-Hy and-NR' R "groups, R 'and R" being same or different, selected from the group consisting of H, C2 to C10 linear or branched or cyclic alkyl groups, said benzyl group and said R' and R "alkyl groups may together form one or several saturated, unsaturated and/or aromatic carbocyclic rings and/or may comprise heteroatoms selected from the group consisting of O, N and S;● Q, Hy and j are as defined above.● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units in the copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250. - 10. The composition according to any one of claims 1 to 9, wherein the basal insulin having an isoelectric point between 5.8 and 8.5 is insulin glargine
- 11. The composition according to any one of claims 1 to 10, characterized in that it comprises 40 to 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5.
- 12. Composition according to any one of claims 1 to 11, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes is at most 60 mg/mL.
- 13. Composition according to any one of claims 1 to 11, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes is at most 40 mg/mL.
- 14. Composition according to any one of claims 1 to 11, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes is at most 20 mg/mL.
- 15. Composition according to any one of claims 1 to 11, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes is at most 10 mg/mL.
- 16. The composition according to any one of claims 1 to 15, characterized in that it further comprises prandial insulin.
- 17. The composition of claim 16, wherein the prandial insulin is human insulin.
- 18. The composition according to any one of claims 16 to 17, characterized in that it comprises a combination of prandial insulin and basal insulin having an isoelectric point between 5.8 and 8.5, in total between 40 and 500U/mL insulin.
- 19. The composition according to any one of claims 16 to 18, characterized in that the ratio between the basal insulin and the prandial insulin having an isoelectric point between 5.8 to 8.5 is 25/75, 30/70, 40/60, 50/50, 60/40, 70/30, 80/20 or 90/10 in percent.
- 20. The composition according to any one of claims 1 to 19, characterized in that it further comprises a gastrointestinal hormone.
- 21. The composition of claim 20, wherein the oxyntomodulin is selected from the group consisting of exenatide, liraglutide, lixisenatide, abiraglutide, and dulaglutide, analogs or derivatives thereof, and pharmaceutically acceptable salts thereof.
- 22. The composition of any one of claims 20 to 21, wherein said oxyntomodulin is said dulaglutide, an analogue or derivative thereof, and a pharmaceutically acceptable salt thereof.
- 23. The composition according to any one of claims 20 to 21, wherein the oxyntomodulin is exenatide, an analogue or derivative thereof, and a pharmaceutically acceptable salt thereof.
- 24. The composition of any one of claims 20 to 21, wherein the oxyntomodulin is liraglutide, an analogue or derivative thereof, and a pharmaceutically acceptable salt thereof.
- 25. The composition of any one of claims 20 to 21, wherein the oxyntomodulin is lixisenatide, an analogue or derivative thereof, and a pharmaceutically acceptable salt thereof.
- 26. The composition according to any one of claims 20 to 28, wherein the concentration of oxyntomodulin is in the range of 0.01 to 10 mg/mL.
- 27. The composition according to any one of claims 21 or 23, characterized in that it comprises 40 to 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 0.05 to 0.5mg/mL of exenatide.
- 28. The composition according to any one of claims 21 or 24, characterized in that it comprises 40 to 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 1 to 10mg/mL of liraglutide.
- 29. The composition according to any one of claims 21 or 25, characterized in that it comprises 40 to 500U/mL of basal insulin having an isoelectric point between 5.8 and 8.5 and 0.01 to 1mg/mL of lixisenatide.
- A single dose formulation having a pH of 7.0 to 7.8 comprising a basal insulin having an isoelectric point of 5.8 to 8.5, a prandial insulin and a co-amino acid.
- A single dose formulation having a pH of from 7.0 to 7.8 comprising basal insulin having an isoelectric point of from 5.8 to 8.5, a gastrointestinal hormone and a co-amino acid.
- A single dose formulation having a pH of 7.0 to 7.8 comprising basal insulin having an isoelectric point of 5.8 to 8.5, prandial insulin, a gastrointestinal hormone and a co-amino acid.
Applications Claiming Priority (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1761736 | 2017-12-06 | ||
| FR1761736A FR3074422B1 (en) | 2017-12-06 | 2017-12-06 | SOLUTION FOR INJECTION AT PH 7 COMPRISING AT LEAST ONE BASAL INSULIN WHOSE PI IS BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACID CARBOXYLATE CHARGES AND HYDROPHOBIC RADICALS |
| US201762606138P | 2017-12-07 | 2017-12-07 | |
| US62/606,138 | 2017-12-07 | ||
| FR1761807A FR3074681B1 (en) | 2017-12-07 | 2017-12-07 | PH 7 INJECTION SOLUTION COMPRISING AT LEAST ONE BASAL INSULIN WITH A PI BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACID CARRYING CARBOXYLATES AND HYDROPHOBIC RADICALS |
| FR1761807 | 2017-12-07 | ||
| FR1856067A FR3083089A1 (en) | 2018-06-29 | 2018-06-29 | PH 7 INJECTION SOLUTION COMPRISING AT LEAST ONE BASAL INSULIN WITH A PI BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACID CARRYING CARBOXYLATES AND HYDROPHOBIC RADICALS |
| EP181810375 | 2018-06-29 | ||
| FR1855934A FR3083088B1 (en) | 2018-06-29 | 2018-06-29 | SOLUTION FOR INJECTION AT PH 7 INCLUDING AT LEAST ONE BASAL INSULIN WHOSE PI IS BETWEEN 5.8 AND 8.5 AND A CO-POLYAMINOACID CARBOXYLATE CHARGES AND HYDROPHOBIC RADICALS |
| FR1856067 | 2018-06-29 | ||
| EP18010375 | 2018-06-29 | ||
| FR1855934 | 2018-06-29 | ||
| PCT/EP2018/083558 WO2019110625A1 (en) | 2017-12-06 | 2018-12-04 | Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals |
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| CN111698999A true CN111698999A (en) | 2020-09-22 |
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| CN201880088662.5A Pending CN111698999A (en) | 2017-12-06 | 2018-12-04 | Injectable solution with pH7 comprising at least one basal insulin with PI between 5.8 and 8.5 and a polyamino acid with carboxylate charge and hydrophobic group |
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