US 2015/0174209 A1 · INSULIN-PRAMLINTIDE COMPOSITIONS AND METHODS FOR MAKING AND USING THEM

Abstract

In alternative embodiments, the invention provides formulations, pharmaceutical compositions, devices and other products of manufacture comprising a therapeutically effective mixture of an insulin and a pramlintide, and methods for making and using them. For example, methods and compositions of the invention are used in the treatment or amelioration of a diabetes, a dementia or Alzheimer's disease, any abnormality of blood glucose control, an inability to control blood glucose, an elevation of fasting glucose or Impaired Fasting Glucose (IFG), an abnormality of tolerance to a glucose load or Impaired Glucose Tolerance (IGT), a hyperglycemia induced by an illness, a trauma, a medication administration or a form of metabolic, psychological or physical stress, or a hyperglycemia induced by steroids (steroid-induced diabetes), a latent autoimmune diabetes in adults (LADA), a postprandial or reactive Hypoglycemia or an insulin resistance, a PolyCystic Ovary Syndrome (PCOS), a ketoacidosis, a gestational diabetes, a hyperkalemia, a cancer or cachexia, a beta blocker overdose, or a jaundice. In alternative embodiments, the invention provides insulin pumps, devices, subcutaneous insulin infusion therapy devices, continuous subcutaneous insulin infusion therapy devices, infusion therapy devices, reservoirs, ampoules, vials, syringes, cartridges, disposable pen or jet injectors, prefilled pens or syringes or cartridges, cartridge or disposable pen or jet injectors, two chambered or multi-chambered pumps, syringes, cartridges or pens or jet injectors, or an artificial pancreas, comprising a formulation having an insulin:pramlintide ratio of the invention.

A liquid pharmaceutical composition or a formulation, or a reconstitutable dried pharmaceutical composition or formulation, comprising:
(a) (i) a pramlintide or a pramlintide peptide, or a physiologically acceptable salt thereof;
and
(ii) a human insulin or a human insulin peptide (HIP) or an analog thereof, or a physiologically acceptable salt thereof,
and optionally the human insulin, human insulin peptide (HIP), or analog thereof is or comprises:
an aspart, a NOVOLOG™ or a NOVORAPID™ (Novo Nordisk, Bagsværd, Denmark);
a glulisine or an APIDRA™ (Sanofi S.A., Paris, France);
a lispro, an insulin lispro protamine or a HUMALOG™ (Eli Lilly and Company, Indianapolis, Ind.);
a HUMULIN R™, a HUMULIN N™, a HUMULIN 70/30™ or a HUMULIN 70/30™ (Eli Lilly and Company, Indianapolis, Ind.);
or a regular (wild type) isolated or a recombinant human insulin, or a fast-acting human insulin analog or variant thereof,
and optionally the pramlintide peptide comprises or consists of a C-terminal amide form of a peptide
(SEQ ID NO:
1)
KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY;
wherein the ratio of the pramlintide or pramlintide peptide to the human insulin, human insulin peptide (HIP) in the liquid, reconstitutable dried pharmaceutical composition or formulation is:
4 μgm:1 U;
or 5.92 mole insulin to 1 mole pramlintide;
4.5 μgm:1 U;
or 5.26 mole insulin to 1 mole pramlintide;
5 μgm:1 U;
or 4.74 mole insulin to 1 mole pramlintide;
5.5 μgm:1 U;
or 4.31 mole insulin to 1 mole pramlintide;
6 μgm or 1.52 nmoles pramlintide:1 U (international unit) or 6.0 nmoles human insulin or equivalent nmoles of human insulin peptide providing 1 U of insulin activity, or 0.25 mole pramlintide to 1 mole human insulin (6 μgm:1 U) or moles of human insulin peptide providing the same unit of activity as 0.25 mole human insulin, or 3.98 mole human insulin or equivalent moles of human insulin peptide to 1 mole pramlintide;
6.5 μgm:1 U;
or 3.63 mole insulin to 1 mole pramlintide;
7 μgm:1 U;
or 3.38 mole insulin to 1 mole pramlintide;
8 μgm:1 U;
or 2.96 mole insulin to 1 mole pramlintide;
8.5 μgm:1 U;
or 2.79 mole insulin to 1 mole pramlintide;
9 μgm:1 U;
or 2.63 mole insulin to 1 mole pramlintide;
9.5 μgm:1 U;
or 2.49 mole insulin to 1 mole pramlintide;
10 μgm:1 U;
or 2.37 mole insulin to 1 mole pramlintide;
11 μgm:1 U;
or 2.15 mole insulin to 1 mole pramlintide;
12 μgm:1 U;
or 1.97 mole insulin to 1 mole pramlintide;
13 μgm:1 U;
or 1.82 mole insulin to 1 mole pramlintide;
14 μgm:1 U;
or 1.69 mole insulin to 1 mole pramlintide;
15 μgm:1 U;
or 1.58 mole insulin to 1 mole pramlintide;
16 μgm:1 U;
or 1.48 mole insulin to 1 mole pramlintide;
17 μgm:1 U;
or 1.39 mole insulin to 1 mole pramlintide;
18 μgm:1 U;
or 1.31 mole insulin to 1 mole pramlintide;
19 μgm:1 U;
or 1.25 mole insulin to 1 mole pramlintide;
20 μgm:1 U;
or 1.18 mole insulin to 1 mole pramlintide;
21 μgm:1 U;
or 1.13 mole insulin to 1 mole pramlintide;
22 μgm:1 U;
or 1.08 mole insulin to 1 mole pramlintide;
23 μgm:1 U;
or 1.03 mole insulin to 1 mole pramlintide;
24 μgm:1 U, or 0.99 mole insulin to 1 mole pramlintide;
or
between about 4 or 5 μgm:1 U to about 24 μgm:1 U,
between about 5.5 μgm:1 U to about 16 μgm:1 U,
between about 6 μgm:1 U to about 12 μgm:1 U,
between about 7 μgm:1 U to about 24 μgm:1 U,
between about 7.5 μgm:1 U to about 16 μgm:1 U,
between about 8 μgm:1 U to about 9, 10, 11 or 12 μgm:1 U,
and the liquid pharmaceutical composition or formulation has a pH of between about 3.3 to 4.3, about 3.0 and 5.5, about 3.5 to 4.5, about 3.7 to about 4.35, about 4.0, or a pH of about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.05, 4.1, 4.15, 4.2, 4.25, 4.3, 4.35 or 4.4,
or optionally, when the reconstitutable dried pharmaceutical composition or formulation is reconstituted, it has a pH of between about 3.3 to 4.3, about 3.0 and 5.5, about 3.5 to 4.5, about 3.7 to about 4.35, about 4.0, or a pH of about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.05, 4.1, 4.15, 4.2, 4.25, 4.3, 4.35 or 4.4;
or optionally, the pH range is more than 3.5 to less than 4.4, or 3.8 to less than 4.4;
or pramlintide peptide formulations and final co-formulation pH include about 3.8, 3.85, 3.9, 3.95, 4.0, 4.05, 4.1, 4.15, 4.2, 4.25, 4.3, and 4.35;
or the pH range is each range that is selected from the group of ranges where the pH values 3.8, 3.85, 3.9, 3.95, 4.0, 4.05, 4.1, 4.15, 4.2, 4.25, 4.3, and 4.35 are selected as a lower and an upper end of the range, including for example 3.8 to 4.35, 3.85 to 4.35, 3.85 to 4.2, 3.85 to 4.15, 3.8 to 4.2, 3.9 to 4.1, 3.9 to 4.0, and 4.0 to 4.1;
or the pH range is about pH 3.9, 4.0 and 4.1, and ranges 3.9 to 4.1, 3.9 to 4.0, and 4.0 to 4.1,
wherein when calculating the ratios, a weight of the pramlintide or pramlintide peptide is based on the weight of pramlintide acetate, and an International Unit (U) of human insulin is based on U of human insulin as formulated using a HUMULIN R™ at pH 7.4;
(b) the liquid or reconstitutable dried pharmaceutical composition or formulation of (a), wherein the pramlintide or pramlintide peptide is or comprises a salt form, and optionally the pramlintide or pramlintide peptide is an acetate salt, or a trifluoroacetate (TFA) salt, or a chloride salt, or a mixture thereof;
(c) the liquid or reconstitutable dried pharmaceutical composition or formulation of (a) or (b), wherein the human insulin or human insulin peptide (HIP) is complexed with a metal ion;
(d) the liquid or reconstitutable dried pharmaceutical composition or formulation of (c), wherein the human insulin or human insulin peptide (HIP) is complexed with a zinc or a Zn+2;
(e) the liquid or reconstitutable dried pharmaceutical composition or formulation of (d), wherein the human insulin or human insulin peptide (HIP) is complexed with the zinc in a ratio of molar ratio of at least 6:2;
(f) the liquid or reconstitutable dried pharmaceutical composition or formulation of (d) or (e), wherein the human insulin or human insulin peptide (HIP) is complexed with the zinc and is substantially hexameric;
(g) the liquid or reconstitutable dried pharmaceutical composition or formulation of (f), wherein the human insulin or human insulin peptide (HIP) is complexed with the zinc and the insulin is greater than about 95%, 96%, 97%, 98%, 99% or more hexameric, or is between about 90% and 100% hexameric;
(h) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (g), wherein the pramlintide or pramlintide peptide or the insulin or human insulin peptide (HIP) is a recombinant peptide,
and optionally the recombinant peptide is produced in a prokaryote or a eukaryote, and optionally the prokaryote is an E. coli, and optionally the eukaryote is a yeast;
and optionally the yeast is a Saccharomyces or a Pichia,
and optionally where the human insulin or HIP are comprised of an A chain and a B chain, the A chain and B chain are separately synthesized or recombinantly produced, and optionally the recombinant A chain and B chain are synthesized in the same cell;
(i) the liquid pharmaceutical composition or formulation of any of (a) to (h), comprising:
a liquid vehicle comprising a water, or an aqueous or an organic solvent mixture, or an substantially isotonic aqueous or organic solvent mixture;
(j) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of claims (a) to (i), further comprising a pharmaceutically acceptable excipient;
(k) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (i), further comprising a buffer,
and optionally the buffer comprises an acetate, a phosphate, a citrate, a tartrate, or a glutamate buffer, or a mixture or a combination thereof,
and optionally the buffer is between about 0.02 to 0.5% (w/v) of an acetate, phosphate, citrate, tromethamine or glutamate buffer, or the buffer has an acetate concentration of between about 3.4 and 84.7 mM, a phosphate concentration of between about 2.1 and 52.6 mM, a citrate concentration of between about 1.1 and 26.4 mM, or a glutamate concentration of between about 1.4 and 34.2 mM;
(l) the liquid or reconstitutable dried pharmaceutical composition or formulation of (k), wherein the buffer is an acetate buffer, and optionally the acetate is formulated at between about 15 to 20 mM, 17 to 25 mM, 25 to 65 mM, or about 25 to 80 mM or is formulated at about 15 mM, 16 mM, 17 mM, 20 mM, 25 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM or 120 mM,
and optionally the buffer does not or substantially does not chelate a zinc, and optionally for the reconstitutable dried pharmaceutical composition or formulation, the buffer is a non-volatile buffer;
(m) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (k) to (l), wherein the buffer is present at a concentration providing a buffer capacity equivalent to the buffer capacity of sodium acetate buffer formulated at between about 15 to 20 mM, 17 to 25 mM, 25 to 65 mM, 25 to 80 mM, or at about 15 mM, 16 mM, 17 mM, 20 mM, 25 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM or 120 mM,
(n) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (m), further comprising an isotonicity agent or a bulking agent, wherein optionally the isotonicity agent or bulking agent is or comprises a sodium chloride, a carbohydrate, a polyol, or a polyhydric alcohol or a combination or mixture thereof;
(o) the liquid or reconstitutable dried pharmaceutical composition or formulation of (n), wherein the isotonicity agent carbohydrate or polyhydric alcohol or amino acid is formulated as a substantially isotonic formulation, optionally at about 1.0 to 10% (w/v) of the carbohydrate or the polyhydric alcohol or amino acid;
(p) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (n) to (o), wherein the polyhydric alcohol comprises a mannitol (D-mannitol), a sorbitol, an inositol, a glycerol, a xylitol, an ethylene glycol, a propylene/ethylene glycol copolymer, a PEG 8000, a PEG 400, a PEG 4000, a PEG 200, a PEG 1450 or a PEG 3350, or a combination thereof;
(q) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (n) to (p), wherein the carbohydrate comprises a mannitol, a mannose, a ribose, a trehalose, a maltose, a glycerol, a inositol, a lactose, a sucrose, a fructose, a galactose, or an arabinose, or a mixture or a combination thereof;
(r) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (q), wherein further comprising a glycerol, a glycerin, a mannitol, glycine or a mixture or a combination thereof,
and optionally the glycerol, when present, is between about 12 to 20 mg/ml, or about 16 mg/ml, and the mannitol, when present, is between about 3% to 6%, or about 4.3% (w/v);
(s) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (r), further comprising an isotonicity agent comprising a mixture of a glycerol and a mannitol;
(t) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (s), further comprising a preservative, wherein optionally the buffer is a meta-cresol (or m-cresol, m-methylphenol, or m-methylphenylol) or a phenol,
and optionally the m-cresol is formulated at between about 2 and 4 mg/mL, or at about 3 mg/mL, 2.25 mg/mL, 2.5 mg/mL or 2.0 mg/mL, wherein optionally the m-cresol is formulated at one-half of between about 2 and 4 mg/mL, or at about 3 mg/mL, 2.25 mg/mL, 2.5 mg/mL or 2.0 mg/mL, due to dilution;
(u) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (t), further comprising a metal ion, and optionally the metal ion is or comprises:
a salt of a metal ion, a zinc or a Zn+2,
wherein optionally the metal salt is a zinc chloride, a zinc acetate, a zinc oxide and optionally the zinc chloride is formulated at about 7 micrograms/mL (mgm/mL), and optionally the Zn+2 is formulated at an amount equivalent to a zinc in a zinc chloride at about 7 mcg/mL, wherein optionally the zinc is formulated at about 0.015 mg/100 units;
(v) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (u), further comprising a surfactant,
and optionally the surfactant comprises a polyoxyethylene (20) sorbitan monolaurate, a polyoxyethylene (20) sorbitan monooleate, a 3-[(3-cholamidopropyl) dimethylammonio]1-propanol sulfonate, a polyoxyethylene (23) lauryl ether, a poloxamer or a non-ionic surfactant or a mixture or combination thereof;
(w) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (v), wherein the dried pharmaceutical composition or formulation is prepared by spray drying, rotary evaporation, freeze-drying or lyophilisation;
(x) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (w), comprising or formulated as:
an aqueous solution, an injectable solution, an aqueous or an organic solvent mixture, a suspension, a lozenge, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel and/or a spray or an aerosol;
(y) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (x), comprising or packaged in:
a continuous subcutaneous insulin infusion therapy device;
an insulin pump device;
an ampoule;
a vial;
a cartridge;
a syringe, cartridge or disposable pen or jet injector;
a needleless injector or a needle free injector;
a prefilled pen or syringe or cartridge, or a disposable syringe or pen or jet injector;
an AUTOPEN™;
a two chambered syringe, cartridge or disposable pen or jet injector;
a multi-chambered syringe, cartridge or disposable pen or jet injector;
(z) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (y), further comprising instructions for using the liquid pharmaceutical composition or formulation to treat a patient, wherein optionally the patient is being treated for, and the instructions are for use of the liquid or reconstitutable dried pharmaceutical composition or formulation for treating:
a diabetes mellitus (diabetes), wherein optionally the diabetes mellitus is Type 1 diabetes or Type 2 diabetes, or a prediabetic condition (prediabetes),
a dementia or Alzheimer's disease,
an abnormality of blood glucose control, or inability to control blood glucose
an elevation of fasting glucose or Impaired Fasting Glucose (IFG),
an abnormality of tolerance to a glucose load or Impaired Glucose Tolerance (IGT),
a hyperglycemia induced by an illness, a trauma, a medication administration or a form of metabolic, psychological or physical stress, or a hyperglycemia induced by steroids (steroid-induced diabetes),
a latent autoimmune diabetes in adults (LADA),
a postprandial or reactive Hypoglycemia or an insulin resistance,
a PolyCystic Ovary Syndrome (PCOS),
a ketoacidosis,
a gestational diabetes,
a hyperkalemia,
a cancer or cachexia,
a beta blocker overdose, or
a jaundice,
and optionally the patient is being treated with a basal insulin, or the insulin is administered to maintain a basal insulin level,
and optionally the patient is treated with an oral or injectable anti-diabetic medicine, or one or more other medications, or the patients can be those naïve to insulin other anti-diabetes medicines, and whether naïve or not, the formulations of the invention can be the patients only anti-diabetes medication;
(aa) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (z), wherein the liquid insulin concentration is at about 100 Units/mL, 200 Units/mL, 300 Units/mL, 400 Units/mL, 500 Units/mL or 600 Units/mL, or is between about 100 Units/mL to about 600 Units/mL,
or the reconstitutable dried pharmaceutical composition or formulation is formulated such that upon reconstitution the liquid insulin concentration will be at about 100 Units/mL, 200 Units/mL, 300 Units/mL, 400 Units/mL, 500 Units/mL or 600 Units/mL, or will be between about 100 Units/mL to about 600 Units/mL,
and optionally the reconstitutable dried pharmaceutical composition or formulation is reconstituted by a health practitioner or by a pharmacist, or is reconstituted by a patient;
(bb) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (aa), wherein the liquid formulation or the reconstituted pharmaceutical composition or formulation is usable by a patient for 1 day to 1 month, or for 1 day to 7 days, or for 1 day to 3 days, or for 1 day, 3 days, 1 week, 2 weeks or 1 month;
or
(cc) the liquid or reconstitutable dried pharmaceutical composition or formulation of any of (a) to (bb), comprising or consisting of:
a formulation as set forth in FIGS. 8 to 11, 34A, 34B, 34C, 34D or 34E, or FIG. 35;
or
an insulin 100 U/mL, pramlintide 600 microgram/mL, in 30 mM acetate buffer pH 4, 0.225% metra-cresol, 4.3% mannitol;
or
an insulin 100 U/mL, pramlintide 900 microgram/mL, in 30 mM acetate buffer pH 4, 0.225% metra-cresol, 4.3% mannitol;
or
a lyophilized insulin 1000 U powder with bulking agent+10 mL of Pramlintide solution where Pramlintide 600 microgram/mL in 30 mM acetate buffer pH 4, 0.225% metra-cresol, 4.3% mannitol;
or
a lyophilized insulin 1000 U powder with bulking agent+10 mL of Pramlintide solution where Pramlintide 900 microgram/mL in 30 mM acetate buffer pH 4, 0.225% metra-cresol, 4.3% mannitol.

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Insulin-pramlintide compositions and methods for making and using them

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Insulin-pramlintide compositions and methods for making and using them

Life of this patent

Abstract

Claims22