Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog, and a co-polyamino acid
Inventors
DURACHER, DAVID • MEIFFREN, GREGORY • Soula, Remi
Assignees
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Publication Number
US-10463717-B2
Publication Date
2019-11-05
Expiration Date
Abstract
The invention relates to a composition in the form of an injectable aqueous solution, of which the pH is from 6.0 to 8.0, comprising at least: a) amylin, an amylin receptor agonist or an amylin analog;b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy having the following formula I: *GpRrGpAaGpC)p I characterized in that the composition does not comprise a basal insulin of which the isoelectric point pI is from 5.8 to 8.5. It also relates to a composition characterized in that it moreover comprises a prandial insulin.
Core Innovation
The invention relates to an injectable aqueous solution having a pH from 6.0 to 8.0. The solution comprises amylin or pramlintide together with a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy. The co-polyamino acid consists of glutamic or aspartic units, and the hydrophobic radicals Hy are defined by formula I with radicals GpR, GpA and GpC and specific parameter constraints.
The hydrophobic radicals Hy are covalently attached to the co-polyamino acid to form an amide function. The attachment is determined according to the variable r, with different bond-forming relationships between carbonyl groups and nitrogen atoms in N-terminal position or between nitrogen of the hydrophobic radical and a carbonyl of the co-polyamino acid. The composition further specifies defined radicals R, A, B and Cx, the ratio i between hydrophobic radicals and glutamic or aspartic units, and the degree of polymerization DP of glutamic or aspartic units.
The composition is defined so that it does not comprise a basal insulin having an isoelectric point pI from 5.8 to 8.5. The disclosure includes co-polyamino acid architectures of formula VII or VIIb, examples of defined co-polyamino acids, and mention of optional prandial insulin or GLP-1/GLP-1 analog/GLP-1 receptor agonist in some described formulations. It also refers to stability and pharmacokinetic behavior of example formulations in the context of the amylin-based compositions.
Claims Coverage
The independent claim coverage is directed to an injectable aqueous composition at pH 6.0 to 8.0 containing amylin or pramlintide plus a defined glutamic/aspartic co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, while excluding basal insulin with pI 5.8 to 8.5. The inventive features combine the defined polymer/hydrophobic-radical structure, covalent amide attachment rules, quantitative limits on i and DP, alkali-salt carboxylate functions, and the basal-insulin exclusion.
Injectable aqueous solution at pH 6.0 to 8.0
An injectable aqueous solution having a pH from 6.0 to 8.0 comprising at least amylin or pramlintide.
Amylin or pramlintide with a carboxylate-charged co-polyamino acid
A composition comprising at least amylin or pramlintide and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, the co-polyamino acid consisting of glutamic or aspartic units.
Defined hydrophobic radicals Hy and covalent amide attachment
Hydrophobic radicals Hy are defined by formula I with radicals GpR, GpA and GpC, and are covalently attached to the co-polyamino acid to form an amide function according to the variable r.
Controlled hydrophobic radical-to-unit ratio i and degree of polymerization DP
The ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is from 0 to 0.5, and the degree of polymerization DP of glutamic or aspartic units is from 5 to 250.
Alkali-salt free acid functions
The free acid functions are in the form of a salt of an alkali cation selected from Na+ and K+.
Exclusion of basal insulin with isoelectric point pI 5.8 to 8.5
The composition does not comprise a basal insulin of which the isoelectric point pI is from 5.8 to 8.5.
The claim coverage centers on a near-neutral pH injectable aqueous composition combining amylin or pramlintide with a precisely defined glutamic/aspartic co-polyamino acid architecture bearing hydrophobic radicals Hy. The claims further narrow the composition by attachment mode, i and DP ranges, salt form, and an explicit basal-insulin exclusion.
Stated Advantages
Stabilizes amylin or amylin receptor agonists/analogs at near-neutral pH by increasing fibril latency time.
Enables clear formulations.
Higher ThT-measured stability than a reference composition containing amylin or pramlintide without any co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy.
Slower absorption of pramlintide for specific example formulations CA3/CA4 versus a double-injection reference CA1/CA2.
Documented Applications
Injectable aqueous formulations for amylin or pramlintide, including formulations that can also include prandial insulin.
Artificial pancreas system that calculates and delivers two injections/doses, including a composition dose plus a glucagon dose, with configurations including two pumps and an intelligent pen using glucose sensing and control algorithms.
Stabilization of amylin-based compositions containing amylin or pramlintide with the defined co-polyamino acid, supported by ThT fluorescence stability measurement and pharmacokinetic behavior for example formulations CA3/CA4.
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