U.S. patent application number 17/367339 was filed with the patent office on 2022-01-27 for stabilized pharmaceutical formulations of insulin aspart.
The applicant listed for this patent is SANOFI. Invention is credited to Harald Berchtold, Bernd Bidlingmaier, Oliver Bley, Walter Kamm, Petra Loos.
Application Number | 20220023392 17/367339 |
Document ID | / |
Family ID | 1000005898069 |
Filed Date | 2022-01-27 |
United States Patent
Application |
20220023392 |
Kind Code |
A1 |
Bley; Oliver ; et
al. |
January 27, 2022 |
STABILIZED PHARMACEUTICAL FORMULATIONS OF INSULIN ASPART
Abstract
Stabilized pharmaceutical formulations of insulin aspart are
disclosed.
Inventors: |
Bley; Oliver; (Frankfurt am
Main, DE) ; Loos; Petra; (Frankfurt am Main, DE)
; Bidlingmaier; Bernd; (Frankfurt am Main, DE) ;
Kamm; Walter; (Frankfurt am Main, DE) ; Berchtold;
Harald; (Frankfurt am Main, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI |
Paris |
|
FR |
|
|
Family ID: |
1000005898069 |
Appl. No.: |
17/367339 |
Filed: |
July 3, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15727263 |
Oct 6, 2017 |
|
|
|
17367339 |
|
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|
|
14592739 |
Jan 8, 2015 |
9895423 |
|
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15727263 |
|
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61925472 |
Jan 9, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 33/30 20130101; A61K 38/28 20130101; A61K 47/42 20130101; A61K
38/1825 20130101; A61K 9/08 20130101; A61K 47/02 20130101; A61K
45/06 20130101; A61K 47/10 20130101; A61K 38/26 20130101 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61K 47/42 20060101 A61K047/42; A61K 47/02 20060101
A61K047/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2014 |
EP |
14305023.5 |
Claims
1. A pharmaceutical formulation comprising (a) insulin aspart; (b)
Zn(II); and (c) optionally protamine, wherein the pharmaceutical
formulation contains less than 0.17 mg/mL sodium chloride.
2. The pharmaceutical formulation according to claim 1, wherein the
pharmaceutical formulation is an aqueous pharmaceutical
formulation.
3. The pharmaceutical formulation according to claim 1, wherein the
pharmaceutical formulation has a pH value in the range from 6.0 to
9.0.
4. The pharmaceutical formulation according to claim 3, wherein the
pharmaceutical formulation has a pH value in the range from 7.0 to
7.8.
5. The pharmaceutical formulation according to claim 1, wherein
insulin aspart is present in a concentration from 10 U/mL to 1000
U/mL.
6. The pharmaceutical formulation according to claim 1, wherein
Zn(II) is present in a concentration from 0.0100 to 0.0600 mg/100 U
of insulin aspart.
7. The pharmaceutical formulation according to claim 1, wherein the
pharmaceutical formulation is essentially free of sodium
chloride.
8. The pharmaceutical formulation according to claim 1, wherein
protamine is present in a concentration from 0.1 to 0.5 mg/mL.
9. The pharmaceutical formulation according to claim 1, wherein the
pharmaceutical formulation further contains a buffering agent.
10. The pharmaceutical formulation according to claim 1, wherein
the pharmaceutical formulation comprises one or more further active
pharmaceutical ingredients.
11. The pharmaceutical formulation according to claim 10, wherein
the further active pharmaceutical ingredient is an antidiabetic
agent.
12. The pharmaceutical formulation according to claim 10, wherein
the further active pharmaceutical ingredient is an antidiabetic
agent selected from the group consisting of: (a) a GLP-1 receptor
agonist; (b) a dual GLP-1 receptor/glucagon receptor agonist; (c)
human FGF-21; (d) a FGF-21 analogue; (e) a FGF-21 derivative; (f)
insulin; (g) human insulin; (h) an analogue of insulin; and (i) a
derivative of insulin.
13. The pharmaceutical formulation according to claim 1, wherein
the pharmaceutical formulation further comprises a fast acting
analogue and/or derivative of insulin or a long acting analogue
and/or derivative of insulin.
14. The pharmaceutical formulation according to claim 13, wherein
the fast acting insulin is one or more insulin selected from the
group consisting of insulin lispro and insulin glulisine and
wherein the long acting insulin is one or more insulin selected
from the group consisting of insulin detemir, insulin glargine, and
insulin degludec.
15-16. (canceled)
17. A method for preparing the pharmaceutical formulation according
to claim 1, wherein the components are mixed together in the form
of a solution or suspension, the pH is adjusted to reach a desired
pH, and water is added to reach a final volume.
18. A kit comprising one or more separate packages of (a) the
pharmaceutical formulation according to claim 1; and (b) a medical
device.
19. A kit comprising one or more separate packages of (a) the
pharmaceutical formulation according to claim 1; (b) at least one
further active pharmaceutical ingredient; and (c) optionally a
medical device.
20. The kit according to claim 19, wherein the further active
pharmaceutical ingredient is an antidiabetic agent.
21. The kit according to claim 19, wherein the further active
pharmaceutical ingredient is an antidiabetic agent selected from
the group consisting of: (a) a GLP-1 receptor agonist; (b) a dual
GLP-1 receptor/glucagon receptor agonist; (c) human FGF-21; (d) a
FGF-21 analogue; (e) a FGF-21 derivative; (f) insulin; (g) human
insulin; (h) an analogue of insulin; and (i) a derivative of
insulin.
22. The kit according to claim 19, wherein the further active
pharmaceutical ingredient is an analogue or derivative of insulin
selected from the group consisting of fast acting insulin and long
acting insulin.
23. The kit according to claim 22, wherein the fast acting insulin
is selected from the group consisting of insulin aspart, insulin
lispro and insulin glulisine and wherein the long acting insulin is
selected from the group consisting of insulin glargine, insulin
detemir, and insulin degludec.
24. A method of treating diabetes mellitus in a subject in need
thereof comprising using the kit of claim 18 to administer to the
subject the pharmaceutical formulation of the kit employing the
medical device of the kit.
25. A method of treating hyperglycemia in a subject in need thereof
comprising using the kit of claim 18 to administer to the subject
the pharmaceutical formulation of the kit employing the medical
device of the kit.
26. A method of lowering blood glucose level in a subject in need
thereof comprising using the kit of claim 18 to administer to the
subject the pharmaceutical formulation of the kit employing the
medical device of the kit.
27. A method of treating diabetes mellitus in a subject in need
thereof comprising administering to the subject a therapeutically
effective amount of the pharmaceutical formulation of according to
claim 1.
28. A method of treating hyperglycemia in a subject in need thereof
comprising administering to the subject a therapeutically effective
amount of the pharmaceutical formulation of according to claim
1.
29. A method of lowering blood glucose levels in a subject in need
thereof comprising administering to the subject a therapeutically
effective amount of the pharmaceutical formulation of according to
claim 1.
30. A medical device comprising the pharmaceutical formulation
according to claim 1 for administering the pharmaceutical
formulation to an animal and/or human.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/727,263, filed Oct. 6, 2017, which is a
continuation of U.S. patent application Ser. No. 14/592,739, filed
Jan. 8, 2015, now U.S. Pat. No. 9,895,423, which claims priority to
U.S. Provisional Patent Application Ser. No. 61/925,472, filed Jan.
9, 2014, and European Patent Application No. 14305023.5, filed Jan.
9, 2014, the entire disclosures of which are hereby incorporated
herein by reference.
INTRODUCTION
[0002] The present invention relates to a pharmaceutical
formulation of insulin aspart, a process for preparing the
pharmaceutical formulation of insulin aspart, and to a related kit.
It also relates to the pharmaceutical formulation of insulin aspart
and to the related kit for use in the treatment of diabetes
mellitus, hyperglycemia, and/or for use in lowering blood glucose
levels. The present invention also relates to the use of a medical
device for administering the pharmaceutical formulation of insulin
aspart to an animal and/or human.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus is a metabolic disorder in which the
ability to utilize glucose is more or less completely lost.
[0004] For decades, insulin has been used in the treatment of
diabetes mellitus. Several insulin formulations have been
developed, e.g. insulin zinc (Zn (II)) suspension, formulations
containing protamine, etc. Further, the active pharmaceutical
ingredient insulin itself has been modified by developing fast
acting insulin analogues (e.g. insulin aspart, insulin lispro,
insulin glulisine) and long acting insulin analogues and
derivatives (e.g. insulin detemir, insulin degludec, insulin
glargin). Fast acting insulin preparations are usually solutions of
insulin, while long acting insulin preparations can be suspensions
containing insulin in crystalline and/or amorphous form
precipitated by the addition of zinc (Zn(II)) salts alone or by
addition of protamine or by a combination of both.
[0005] The chemical and physical stability of insulin formulations
is very important. Insulin formulations are often administered by
using pen injection devices or insulin pumps in which an insulin
formulation is stored (in cartridges) until the entire cartridge is
empty. Insulin formulations may also be stored in vials, requiring
a stable formulation with respect to chemical and physical
stability across the shelf life of the formulation.
[0006] The chemical and/or physical stability of insulin, insulin
analogues and/or insulin derivatives strongly depends on the
pharmaceutical formulation, e.g. the solvent, the pH value and the
excipients. Brange et al. (Acta Pharm. Nord. 4(3), pp. 149-158,
1992) disclose several aspects in connection with the chemical
stability of insulin. WO 2004/080480 discloses pharmaceutical
preparations comprising acid-stabilized insulin. GB 835,638
discloses insulin crystal suspensions having a protracted effect.
WO 98/56406 discloses stable insulin formulations. U.S. Pat. No.
6,489,292 discloses stable aqueous insulin preparations without
phenol and cresol. U.S. Pat. No. 6,211,144 discloses stable
concentrated insulin preparations for pulmonary delivery. Bhatt et
al. (Pharmaceutical Research, Vol. 7, No. 6, pp. 593-599, 1990)
disclose chemical pathways of peptide degradation. Patel et al.
(Pharmaceutical Research, Vol. 7, No. 7, pp. 703-711, 1990)
disclose chemical pathways of peptide degradation. Tyler-Cross et
al. (The Journal of Biological Chemistry, Vol. 266, No. 33, Issue
of November 25, pp. 22549-22556, 1991) disclose effects of amino
acid sequence, buffers, and ionic strength on the rate and
mechanism of deamidation of asparagine residues in small peptides.
GB 840,870 discloses improvements in or relating to insulin
preparations. U.S. Pat. No. 6,852,694 discloses stabilized insulin
formulations. Galloway et al. (Diabetes--The Journal of the
American Diabetes Association, Vol. 21, No. Suppl. 2, pp. 637-648,
1972) disclose new forms of insulin. Jackson et al. disclose
several aspects with regard to neutral regular insulin
(Diabetes--The Journal of the American Diabetes Association, Vol.
21, No. 4, pp. 235-245, 1972). Lill (Pharmazie in unserer Zeit, No.
1, pp. 56-61, 2001) discloses general aspects in connection with
insulin formulations. The German product specification of the
medicinal product Berlinsulin.RTM. H Normal 3 mL Pen discloses a
formulation containing human insulin, metacresol, glycerol, water
and optionally hydrochloric acid and sodium hydroxide for pH
adjustment. The German product specification of the medicinal
product Actrapid.RTM. discloses a formulation containing human
insulin, zinc chloride, glycerol, metacresol, water and optionally
sodium hydroxide and hydrochloric acid for pH adjustment. The FDA
label of the medicinal product Lantus.RTM. discloses a formulation
containing insulin glargine, zinc, m-cresol, glycerol 85%,
polysorbate 20 and water for injection, wherein the pH is adjusted
to approximately 4 by addition of aqueous solutions of hydrochloric
acid and/or sodium hydroxide. The FDA label of the medicinal
product Humalog.RTM. discloses a formulation containing insulin
lispro, glycerin, dibasic sodium phosphate, metacresol, zinc oxide,
phenol and water for injection, wherein the pH is adjusted to
7.0-7.8 by addition of aqueous solutions of hydrochlorid acid
and/or sodium hydroxide.
[0007] The solubility of insulin, insulin analogues and/or insulin
derivatives in aqueous media depends on the pH value. For example,
the lowest solubility is shown close to the isoelectric point which
for human insulin is around pH 5.3 and 5.4. Very good solubility
can be observed at pH values below 4 and above 7. However, insulin
suffers from degradation at strong acidic conditions and strong
alkaline conditions. Therefore, most of the medicinal products
containing insulin, insulin analogues and/or insulin derivatives
have a pH value in the range of 7.2 to 7.4 and mostly buffering
agents are used to achieve and maintain the pH within this
range.
[0008] It has now surprisingly been found that an alternative
aqueous pharmaceutical formulation of insulin aspart having less
than 0.17 mg/mL sodium chloride shows an excellent chemical and
physical stability which qualifies this aqueous pharmaceutical
formulation as a medicinal product having a defined shelf life.
SUMMARY OF THE INVENTION
[0009] One embodiment of the present invention relates to a
pharmaceutical formulation comprising
[0010] (a). insulin aspart; and
[0011] (b). Zn(II); and
[0012] (d). optionally protamine;
[0013] wherein the pharmaceutical formulation contains no or less
than 0.17 mg/mL sodium chloride.
[0014] In another embodiment, the pharmaceutical formulation
according to the present invention consists of (a). insulin aspart;
and (b). Zn(II); and (c). sodium chloride; and (d). optionally
protamine; and (e). metacresol; (f). phenol; and (g). disodium
phosphate (Na.sub.2HPO.sub.4); (h). glycerol; and (i). sodium
hydroxide and/or hydrochloric acid for pH adjustment to a pH value
in the range of from 6.0 to 9.0; and (j). water.
[0015] In another embodiment, the pharmaceutical formulation
according to the present invention is an aqueous pharmaceutical
formulation.
[0016] In another embodiment, the pharmaceutical formulation
according to the present invention comprises at least one analogue
and/or derivative of insulin which has or have an isoelectric point
(IEP) from 4.0 to 6.0, from 4.5 to 6.0, from 4.5 to 5.5, from 5.0
to 5.5, from 5.0 to 5.2 or 5.1.
[0017] In another embodiment, the pharmaceutical formulation
according to the present invention has a pH value in the range from
6.0 to 9.0, from 6.5 to 8.5, from 7.0 to 8.0, from 7.0 to 7.8, from
7.1 to 7.6, or 7.2, 7.3, 7.4 or 7.5, or 7.4.
[0018] In another embodiment, the pharmaceutical formulation
according to the present invention comprises insulin aspart which
is present in a concentration from 10 U/mL to 1000 U/mL, from 10
U/mL to 600 U/mL, from 10 U/mL to 300 U/mL, from 50 U/mL to 300
U/mL or 100 U/mL.
[0019] In another embodiment, the pharmaceutical formulation
according to the present invention comprises insulin aspart which
is present in a concentration from 60 to 6000 nmol/mL, from 60
nmol/mL to 3600 nmol/mL, from 60 nmol/mL to 1800 nmol/mL, from 300
nmol/mL to 1800 nmol/mL or 600 nmol/mL.
[0020] In another embodiment, the pharmaceutical formulation
according to the present invention comprises Zn(II) which is
present in a concentration from 0.0100 mg/mL to 0.0600 mg/mL, from
0.0150 mg/mL to 0.0500 mg/mL, from 0.0150 mg/mL to 0.0300 mg/mL,
from 0.0150 mg/mL to 0.0200 mg/mL, from 0.0190 mg/mL to 0.0200
mg/mL, or 0.0196 mg/mL.
[0021] In another embodiment, the pharmaceutical formulation
according to the present invention comprises zinc chloride
(ZnCl.sub.2) or zinc oxide (ZnO) or zinc acetate (anhydrous:
C.sub.4H.sub.6O.sub.4Zn or dehydrate
C.sub.4H.sub.6O.sub.4Zn.times.2H.sub.2O).
[0022] In another embodiment, the pharmaceutical formulation
according to the present invention comprises Zn(II) which is
present in a concentration from 0.0100 mg/100 U to 0.0600 mg/100 U,
from 0.0150 mg/100 U to 0.0500 mg/100 U, from 0.0150 mg/100 U to
0.0300 mg/100 U, from 0.0150 mg/100 U to 0.0200 mg/100 U, from
0.0190 mg/100 U to 0.0200 mg/100 U, or 0.0196 mg/100 U.
[0023] In another embodiment, the pharmaceutical formulation
according to the present invention comprises sodium chloride which
is present in a concentration of less than 0.17 mg/mL, from 0 mg/mL
to 0.17 mg/mL, from 0 mg/mL to 0.10 mg/mL, from 0 mg/mL to 0.05
mg/mL, or from 0 mg/mL to 0.01 mg/mL.
[0024] In another embodiment, the pharmaceutical formulation
according to the present invention does not contain any sodium
chloride.
[0025] In another embodiment, the pharmaceutical formulation
according to the present invention is essentially free of sodium
chloride.
[0026] In another embodiment, the pharmaceutical formulation
according to the present invention further contains a buffering
agent.
[0027] In another embodiment, the pharmaceutical formulation
according to the present invention comprises protamine or protamine
sulfate which is present in a concentration from 0.10, 0.15, 0.20,
0.25, 0.30, 0.32, 0.35, 0.40, 0.45 or 0.5 mg/mL.
[0028] In another embodiment, the pharmaceutical formulation
according to the present invention comprises a stabilizing agent,
which is in one embodiment a surfactant, a polyoxyethylene
derivative of sorbitan monolaurate (e.g. polysorbate 20), a
polyethoxylethylene derivate of oleic acid (e.g. polysorbate 80),
poloxamer (which is a polyoxyethylene-polyoxypropylene copolymer),
or polysorbate 20 or polysorbate 80 or mixtures thereof. In another
embodiment, the stabilizing agent, in one embodiment the
surfactant, the polyoxyethylene derivative of sorbitan monolaurate
(e.g. polysorbate 20), the polyethoxylethylene derivate of oleic
acid (e.g. polysorbate 80), poloxamer (which is a
polyoxyethylene-polyoxypropylene copolymer), or polysorbate 20 or
polysorbate 80 or mixtures thereof are/is present in a
concentration from 0.01 to 0.05 mg/mL or in a concentration of
0.010 mg/mL, 0.015 mg/mL, 0.020 mg/mL, 0.025 mg/mL, 0.03 mg/mL, or
0.02 mg/mL.
[0029] In another embodiment, the pharmaceutical formulation
according to the present invention comprises insulin aspart and one
or more further analogues and/or derivatives of insulin, including
the following combinations
[0030] (i). insulin aspart and one or more further analogue of
insulin;
[0031] (ii). insulin aspart and one or more derivative of
insulin;
[0032] (iii). Insulin aspart and one or more analogues of insulin
and in addition one or more derivative of insulin.
[0033] In each combination, the one or more analogue of insulin may
be a fast acting insulin or a long acting insulin. In each
combination, the one or more derivative of insulin may be a fast
acting insulin or a long acting insulin. In another embodiment, the
fast acting insulin is selected from the group comprising insulin
aspart, insulin lispro and/or insulin glulisine. In another
embodiment, the long acting insulin is selected from the group
comprising insulin glargin, insulin detemir and/or insulin
degludec. In another embodiment, pharmaceutical formulation
according to the present invention comprises insulin aspart and a
long acting insulin (either an analogue or a derivative of
insulin), wherein the long acting insulin is in one embodiment
selected from the group comprising insulin glargin, insulin detemir
and/or insulin degludec.
[0034] In another embodiment, the pharmaceutical formulation
according to the present invention comprises one or more further
active pharmaceutical ingredients. In one embodiment, the further
active pharmaceutical ingredient is an antidiabetic agent. In
another embodiment, the pharmaceutical formulation according to the
present invention comprises one or more antidiabetic agents as
further active pharmaceutical ingredients selected from the group
comprising: GLP-1 receptor agonists, dual GLP-1 receptor/glucagon
receptor agonists, human FGF-21, FGF-21 analogues, FGF-21
derivatives, insulins, human insulin, analogues of insulin, and
derivatives of insulin. In another embodiment, the pharmaceutical
formulation according to the present invention comprises one or
more further active pharmaceutical ingredients selected from the
group comprising: insulin and insulin derivatives, GLP-1, GLP-1
analogues and GLP-1 receptor agonists, polymer bound GLP-1 and
GLP-1 analogues, dual GLP1/GIP agonists, dual GLP1/Glucagon
receptor agonists, PYY3-36 or analogues thereof, pancreatic
polypeptide or analogues thereof, glucagon receptor agonists or
antagonists, GIP receptor agonists or antagonists, ghrelin
antagonists or inverse agonists, Xenin and analogues thereof,
DDP-IV inhibitors, SGLT2 inhibitors, dual SGLT2/SGLT1 inhibitors,
biguanides thiazolidinediones, dual PPAR agonists, sulfonylureas,
meglitinides, alpha-glucosidase inhibitors, amylin and amylin
analogues, GPR119 agonists, GPR40 agonists, GPR120 agonists, GPR142
agonists, systemic or low-absorbable TGR5 agonists, Cycloset,
inhibitors of 11-beta-HSD, activators of glucokinase, inhibitors of
DGAT, inhibitors of protein tyrosinephosphatase 1, inhibitors of
glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase,
inhibitors of glycogen phosphorylase, inhibitors of phosphoenol
pyruvate carboxykinase, inhibitors of glycogen synthase kinase,
inhibitors of pyruvate dehydrogenase kinase, alpha2-antagonists,
CCR-2 antagonists, modulators of glucose transporter-4,
somatostatin receptor 3 agonists, HMG-CoA-reductase inhibitors,
fibrates, nicotinic acid and the derivatives thereof, nicotinic
acid receptor 1 agonists, PPAR-alpha, gamma or alpha/gamma)
agonists or modulators, PPAR-delta agonists, ACAT inhibitors,
cholesterol absorption inhibitors, bile acid-binding substances,
IBAT inhibitors, MTP inhibitors, modulators of PCSK9, LDL receptor
up-regulators by liver selective thyroid hormone receptor .beta.
agonists, HDL-raising compounds, lipid metabolism modulators, PLA2
inhibitors, ApoA-I enhancers, cholesterol synthesis inhibitors,
lipid metabolism modulators, omega-3 fatty acids and derivatives
thereof, active substances for the treatment of obesity, such as
sibutramine, tesofensine, orlistat, CB-1 receptor antagonists,
MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5
or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or
leptin mimetics, agonists of the 5HT2c receptor, or the
combinations of bupropione/naltrexone (CONTRAVE),
bupropione/zonisamide (EMPATIC), bupropione/phentermine or
pramlintide/metreleptin, QNEXA (Phentermine+topiramate), lipase
inhibitors, angiogenesis inhibitors, H3 antagonists, AgRP
inhibitors, triple monoamine uptake inhibitors (norepinephrine and
acetylcholine), MetAP2 inhibitors, nasal formulation of the calcium
channel blocker diltiazem, antisense oligonucleotides against
production of fibroblast growth factor receptor 4, prohibitin
targeting peptide-1, drugs for influencing high blood pressure,
chronic heart failure or atherosclerosis, such as angiotensin II
receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics,
beta-blockers, calcium antagonists, centrally acting hypertensives,
antagonists of the alpha-2-adrenergic receptor, inhibitors of
neutral endopeptidase, thrombocyte aggregation inhibitors.
[0035] In another embodiment, the pharmaceutical formulation
according to the present invention consists of (a). 3.5 mg/mL
insulin aspart; and (b). 1.72 mg/mL metacresol; and (c). 1.50 mg/mL
phenol; and (d). 0.0196 mg/mL Zn(II); and (e). 1.88 mg/mL
Na.sub.2HPO.sub.4.times.7 H.sub.2O; (f). 17.88 mg/mL glycerol; and
(g). sodium hydroxide and/or hydrochloric acid to adjust the pH to
7.4 and (h). water.
[0036] In another embodiment, the pharmaceutical formulation
according to the present invention consists of (a). 3.5 mg/mL
insulin aspart; and (b). 1.72 mg/mL metacresol; and (c). 1.50 mg/mL
phenol; and (d). 0.0196 mg/mL Zn(II); and (e). 1.88 mg/mL
Na.sub.2HPO.sub.4.times.7 H.sub.2O; (f). 17.88 mg/mL glycerol; (g).
from 0.1 mg/mL to 0.5 mg/mL protamine sulfate; and (h). sodium
hydroxide and/or hydrochloric acid to adjust the pH to 7.4 and (i).
water.
[0037] In another embodiment, the pharmaceutical formulation
according to the present invention consists of (a). 3.5 mg/mL
insulin aspart; and (b). 1.72 mg/mL metacresol; and (c). 1.50 mg/mL
phenol; and (d). 0.0196 mg/mL Zn(II); and (e). 1.88 mg/mL
Na.sub.2HPO.sub.4.times.7 H.sub.2O; (f). 17.88 mg/mL glycerol; (g).
0.1 or 0.15 or 0.2 or 0.25 or 0.3 or 0.32 or 0.35 or 0.4 or 0.45 or
0.5 mg/mL protamine sulfate; (h). less than 0.17 mg/mL sodium
chloride; and (j). sodium hydroxide and/or hydrochloric acid to
adjust the pH to 7.4 and (i). water.
[0038] The present invention also provides to a pharmaceutical
formulation according to the present invention for use in the
treatment of diabetes mellitus, hyperglycemia and/or for use in
lowering blood glucose levels.
[0039] The present invention also provides to a process for
preparing the pharmaceutical formulation according to the present
invention, wherein the components are mixed together in the form of
a solution or suspension, the desired pH is adjusted and the
mixture is made up to the final volume with water.
[0040] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention and of a medical device. In one
embodiment, the medical device is selected from the group
comprising: syringe, insulin injection system, insulin infusion
system, insulin pump, insulin pen injection device.
[0041] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device. In
one embodiment, the medical device is selected from the group
comprising: syringe, insulin injection system, insulin infusion
system, insulin pump, insulin pen injection device.
[0042] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device,
wherein the further active pharmaceutical ingredient is an
antidiabetic agent.
[0043] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device,
wherein the further active pharmaceutical ingredient is an
antidiabetic agent selected from the group comprising: GLP-1
receptor agonists, dual GLP-1 receptor/glucagon receptor agonists,
human FGF-21, FGF-21 analogues, FGF-21 derivatives, insulins, human
insulin, analogues of insulin, and derivatives of insulin. In
anotherembodiment, the pharmaceutical formulation according to the
present invention comprises one or more further active
pharmaceutical ingredients selected from the group comprising:
insulin and insulin derivatives, GLP-1, GLP-1 analogues and GLP-1
receptor agonists, polymer bound GLP-1 and GLP-1 analogues, dual
GLP1/GIP agonists, dual GLP1/Glucagon receptor agonists, PYY3-36 or
analogues thereof, pancreatic polypeptide or analogues thereof,
glucagon receptor agonists or antagonists, GIP receptor agonists or
antagonists, ghrelin antagonists or inverse agonists, Xenin and
analogues thereof, DDP-IV inhibitors, SGLT2 inhibitors, dual
SGLT2/SGLT1 inhibitors, biguanides thiazolidinediones, dual PPAR
agonists, sulfonylureas, meglitinides, alpha-glucosidase
inhibitors, amylin and amylin analogues, GPR119 agonists, GPR40
agonists, GPR120 agonists, GPR142 agonists, systemic or
low-absorbable TGR5 agonists, Cycloset, inhibitors of 11-beta-HSD,
activators of glucokinase, inhibitors of DGAT, inhibitors of
protein tyrosinephosphatase 1, inhibitors of glucose-6-phosphatase,
inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen
phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase,
inhibitors of glycogen synthase kinase, inhibitors of pyruvate
dehydrogenase kinase, alpha2-antagonists, CCR-2 antagonists,
modulators of glucose transporter-4, somatostatin receptor 3
agonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid
and the derivatives thereof, nicotinic acid receptor 1 agonists,
PPAR-alpha, gamma or alpha/gamma) agonists or modulators,
PPAR-delta agonists, ACAT inhibitors, cholesterol absorption
inhibitors, bile acid-binding substances, IBAT inhibitors, MTP
inhibitors, modulators of PCSK9, LDL receptor up-regulators by
liver selective thyroid hormone receptor .beta. agonists,
HDL-raising compounds, lipid metabolism modulators, PLA2
inhibitors, ApoA-I enhancers, cholesterol synthesis inhibitors,
lipid metabolism modulators, omega-3 fatty acids and derivatives
thereof, active substances for the treatment of obesity, such as
sibutramine, tesofensine, orlistat, CB-1receptor antagonists, MCH-1
antagonists, MC4 receptor agonists and partial agonists, NPY5 or
NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin
mimetics, agonists of the 5HT2c receptor, or the combinations of
bupropione/naltrexone (CONTRAVE), bupropione/zonisamide (EMPATIC),
bupropione/phentermine or pramlintide/metreleptin, QNEXA
(Phentermine+topiramate), lipase inhibitors, angiogenesis
inhibitors, H3 antagonists, AgRP inhibitors, triple monoamine
uptake inhibitors (norepinephrine and acetylcholine), MetAP2
inhibitors, nasal formulation of the calcium channel blocker
diltiazem, antisense oligonucleotides against production of
fibroblast growth factor receptor 4, prohibitin targeting
peptide-1, drugs for influencing high blood pressure, chronic heart
failure or atherosclerosis, such as angiotensin II receptor
antagonists, ACE inhibitors, ECE inhibitors, diuretics,
beta-blockers, calcium antagonists, centrally acting hypertensives,
antagonists of the alpha-2-adrenergic receptor, inhibitors of
neutral endopeptidase, thrombocyte aggregation inhibitors.
[0044] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device,
wherein the kit comprises more than one analogue and/or derivative
of insulin, wherein one analogue and/or derivative of insulin is a
fast acting insulin and one analogue and/or derivative of insulin
is a long acting insulin. In one embodiment, the fast acting
insulin is selected from the group comprising insulin aspart,
insulin lispro and/or insulin glulisine and wherein the long acting
insulin is selected from the group comprising insulin glargin,
insulin detemir and/or insulin degludec.
[0045] The present invention also relates to a kit or combination
comprising separate packages of the pharmaceutical formulation
according to the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device for
use in the treatment of diabetes mellitus, hyperglycemia and/or for
use in lowering blood glucose levels.
[0046] The present invention also relates to a kit comprising
separate packages of the pharmaceutical formulation according to
the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device,
wherein the further active pharmaceutical ingredient is an analogue
or derivative of insulin selected from the group of fast acting
insulin and long acting insulin.
[0047] The present invention also relates to a kit comprising
separate packages of the pharmaceutical formulation according to
the present invention, of at least one further active
pharmaceutical ingredient and optionally of a medical device,
wherein the further active pharmaceutical ingredient is an analogue
or derivative of insulin selected from the group of fast acting
insulin and long acting insulin and wherein the fast acting insulin
is selected from the group comprising insulin aspart, insulin
lispro and/or insulin glulisine and wherein the long acting insulin
is selected from the group comprising insulin glargin, insulin
detemir and/or insulin degludec.
[0048] In anotherembodiment, the present invention also relates to
a kit or combination comprising separate packages of the
pharmaceutical formulation according to the present invention, of
at least one further active pharmaceutical ingredient and
optionally of a medical device, wherein the pharmaceutical
formulation according to the present invention and the further
active pharmaceutical ingredient, in one embodiment an antidiabetic
agent, are administered continuously, separately, sequentially
and/or stepwise.
[0049] The present invention also relates to the use of a medical
device for administering the pharmaceutical formulation to an
animal and/or human. In another embodiment, the medical device is
selected from the group comprising: syringe, insulin injection
system, insulin infusion system, insulin pump, insulin pen
injection device
DETAILED DESCRIPTION
[0050] As used herein, the singular forms "a", "an", and "the"
include plural reference unless the context clearly dictates
otherwise. Thus, for example, reference to a fill materiel
containing "a carrier" includes one or more carriers, reference to
"an additive" includes reference to one or more of such
additives.
[0051] As used herein, the term "active pharmaceutical ingredient"
(API) includes any pharmaceutically active chemical or biological
compound and any pharmaceutically acceptable salt thereof and any
mixture thereof, that provides some pharmacologic effect and is
used for treating or preventing a condition. Exemplary
pharmaceutically acceptable salts include hydrochloric, sulfuric,
nitric, phosphoric, hydrobromic, maleric, malic, ascorbic, citric,
tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic,
lauryl sulfuric, naphthalinesulfonic, linoleic, linolenic acid, and
the like. As used herein, the terms "active pharmaceutical
ingredient", "drug", "active agent", "active ingredient", "active
substance" and "drug" are meant to be synonyms, i.e., have
identical meaning. In a one embodiment the active pharmaceutical
ingredient is an antidiabetic agent. Examples of antidiabetic
agents are found in the Rote Liste 2012, chapter 12. Examples of
antidiabetic agents include but are not limited to (a) insulin,
insulin analogues and insulin derivatives, (b)
glucagon-like-peptide 1 (GLP-1) and its analogues and receptor
agonists, (c) dual GLP-1/GIP agonists, and (d) dual GLP-1/glucagon
receptor agonists, as described in detail next.
[0052] (a). Insulin, insulin analogues and insulin derivatives
Examples of insulin, insulin analogues, and insulin derivatives
include but are not limited to insulin glargine (Lantus.RTM.),
insulin glulisine (Apidra.RTM.), insulin detemir (Levemir.RTM.),
insulin lispro (Humalog.RTM./Liprolog.RTM.), insulin degludec
(Tresiba.RTM.), insulin aspart (NovoLog.RTM./NovoRapid.RTM.), basal
insulin and analogues (e.g. LY2605541, LY2963016), PEGylated
insulin lispro, Humulin.RTM., Linjeta.RTM., SuliXen.RTM., NN1045,
insulin plus Symlin.RTM., fast-acting and short-acting insulins
(e.g. Linjeta.RTM., PH20 insulin, NN1218, HinsBet.RTM.), oral,
inhalable, transdermal and sublingual insulins (e.g. Exubera.RTM.,
Nasulin.RTM., Afrezza.RTM., insulin tregopil, TPM-02/Insulin,
Capsulin.RTM., Oral-lyn.RTM., Cobalamin.RTM. oral insulin,
ORMD-0801, NN1953, VIAtab.RTM.). Additionally included are also
those insulin derivatives which are bonded to albumin or another
protein by a bifunctional linker.
[0053] (b). Glucagon-like-peptide 1 (GLP-1), GLP-1 analogues and
GLP-1 receptor agonists Examples: GLP-1, GLP-1 analogues and GLP-1
receptor agonists include but are not limited to lixisenatide
(Lyxumia.RTM.), exenatide/exendin-4 (Byetta.RTM./Bydureon.RTM./ITCA
650, liraglutide/Victoza.RTM.), semaglutide, taspoglutide,
albiglutide, dulaglutide, rExendin-4, CJC-1134-PC, PB-1023,
TTP-054, HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN9924, Nodexen,
Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, MAR-701, ZP-2929, ZP-3022,
CAM-2036, DA-15864, ARI-2651, ARI-2255, exenatide-XTEN and
glucagon-XTEN, AMX-8089+VRS-859 and polymer bound GLP-1 and GLP-1
analogues.
[0054] (c). Dual GLP-1/glucose-dependent insulinotropic peptides
(GIP) agonists Examples of dual GLP-1/GIP agonists include but are
not limited to MAR701, MAR-709, BHM081/BHM089/BHM098).
[0055] (d). Dual GLP-1/glucagon receptor agonists
[0056] Examples of dual GLP-1/glucagon receptor agonists include
but are not limited to OAP-189 (PF-05212389, TKS-1225), TT-401/402,
ZP2929, LAPS-HMOXM25, MOD-6030).
[0057] Other suitable active pharmaceutical ingredients which may
be included in the pharmaceutical formulations of the invention
include but are not limited to the following: Further
gastrointestinal peptides such as peptide YY 3-36 (PYY3-36) or
analogues thereof and pancreatic polypeptide (PP) or analogues
thereof.
[0058] Glucagon receptor agonists or antagonists, GIP receptor
agonists or antagonists, ghrelin antagonists or inverse agonists
and xenin and analogues thereof.
[0059] Dipeptidyl peptidase-IV (DPP-4) inhibitors, for example:
alogliptin/Nesina.RTM.,
linagliptin/BI-1356/Ondero.RTM./Trajenta.RTM./Tradjenta.RTM./Trayenta.RTM-
., saxagliptin/Onglyza.RTM.,
sitagliptin/Januvia.RTM./Xelevia.RTM./Tesavel.RTM.,
sitagliptin+metformin/Janumet.RTM./Velmetia.RTM., aildagliptin,
anagliptin, aemigliptin, tenegliptin, melogliptin, trelagliptin,
DA-1229, MK-3102, KM-223, KRP-104 and Ari-2243.
[0060] Sodium-dependent glucose transporter 2 (SGLT2) inhibitors,
for example: canagliflozin, dapagliflozin, remogliflozin,
sergliflozin, empagliflozin, ipragliflozin, tofogliflozin
(RO-4998452), luseogliflozin, LX-4211, ertugliflozin (PF-04971729),
EGT-0001442 and DSP-3235.
[0061] Dual SGLT2/SGLT1 inhibitors.
[0062] Biguanides (e.g. metformin, buformin, phenformin),
thiazolidinediones (e.g. pioglitazone, rivoglitazone,
rosiglitazone, troglitazone), dual PPAR agonists (e.g. aleglitazar,
muraglitazar, tesaglitazar), sulfonylureas (e.g. tolbutamide,
glibenclamide, glimepiride/Amaryl.RTM., glipizide), meglitinides
(e.g. nateglinide, repaglinide, mitiglinide), alpha-glucosidase
inhibitors (e.g. acarbose, miglitol, voglibose), amylin and amylin
analogues (e.g. pramlintide/Symlin.RTM.).
[0063] G-protein coupled receptor 119 (GPR119) agonists (e.g.
GSK-1292263, PSN-821, MBX-2982, APD-597, ARRY-981).
[0064] GPR40 agonists (e.g. TAK-875, TUG-424, P-1736, JTT-851,
GW9508).
[0065] GPR120 agonists and GPR142 agonists.
[0066] Systemic or low-absorbable TGR5 (GPBAR1=G-protein-coupled
bile acid receptor 1) agonists (e.g. INT-777, XL-475,
SB756050).
[0067] Bromocriptine/Cycloset.RTM., inhibitors of
11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) (e.g. LY2523199,
BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585),
activators of glucokinase (e.g. PF-04991532, TTP-399, GK1-399,
ARRY-403 (AMG-151), TAK-329, ZYGK1), inhibitors of diacylglycerol
O-acyltransferase (DGAT) (e.g. pradigastat (LCQ-908), LCQ-908),
inhibitors of protein tyrosinephosphatase 1 (e.g. trodusquemine),
inhibitors of glucose-6-phosphatase, inhibitors of
fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase,
inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of
glycogen synthase kinase, inhibitors of pyruvate dehydrogenase
kinase, alpha2 adrenergic receptor antagonists, C-C chemokine
receptor type 2 (CCR-2) antagonists, modulators of glucose
transporter-4 and somatostatin receptor 3 agonists (e.g.
MK-4256).
[0068] One or more lipid lowering agents are also suitable as
active pharmaceutical ingredients, such as for example:
3-hydroxy-3-methylglutaryl-coenzym-A-reductase (HMG-CoA-reductase)
inhibitors (e.g. simvastatin, atorvastatin, rosuvastatin), fibrates
(e.g. bezafibrate, fenofibrate), nicotinic acid and derivatives
thereof (e.g. niacin, including slow release formulations of
niacin), nicotinic acid receptor 1 agonists (e.g. GSK-256073),
peroxisome proliferator-activated receptors (PPAR-)(alpha, gamma or
alpha/gamma) agonists or modulators (e.g. aleglitazar), PPAR-delta
agonists, acetyl-CoA-acetyltransferase (ACAT) inhibitors (e.g.
avasimibe), cholesterol absorption inhibitors (e.g. ezetimibe),
bile acid-binding substances (e.g. cholestyramine, colesevelam),
ileal bile acid transport inhibitors (IBAT) (e.g. GSK-2330672),
microsomal triglyceride transfer protein (MTP) inhibitors (e.g.
lomitapide (AEGR-733), SLx-4090, granotapide), modulators of
proprotein convertase subtilisin/kexin type 9 (PCSK9) (e.g.
REGN727/SAR236553, AMG-145, LGT-209, PF-04950615, MPSK3169A,
LY3015014, ALD-306, ALN-PCS, BMS-962476, SPC5001, ISIS-394814,
1B20, LGT-210, 1D05, BMS-PCSK9Rx-2, SX-PCK9, RG7652), LDL receptor
up-regulators, for example liver selective thyroid hormone receptor
beta agonists (e.g. eprotirome (KB-2115), MB07811, sobetirome
(QRX-431), VIA-3196, ZYT1), HDL-raising compounds such as: CETP
inhibitors (e.g. torcetrapib, anacetrapib (MK0859), dalcetrapib,
evacetrapib, JTT-302, DRL-17822, TA-8995, R-1658, LY-2484595) or
ABC1 regulators, lipid metabolism modulators (e.g. BMS-823778,
TAP-301, DRL-21994, DRL-21995), phospholipase A2 (PLA2) inhibitors
(e.g. darapladib/Tyrisa.RTM., varespladib, rilapladib), ApoA-I
enhancers (e.g. RVX-208, CER-001, MDCO-216, CSL-112, VRX-HDL,
VRX-1243, VIRxSYS), cholesterol synthesis inhibitors (e.g.
ETC-1002) and lipid metabolism modulators (e.g. BMS-823778,
TAP-301, DRL-21994, DRL-21995) and omega-3 fatty acids and
derivatives thereof (e.g. icosapent ethyl (AMR101), Epanova.RTM.,
AKR-063, NKPL-66).
[0069] Other suitable active pharmaceutical ingredients ingredients
which may be included in the pharmaceutical formulations include
one or more active substances for the treatment of obesity,
including but not limited to: Sibutramine, tesofensine, orlistat,
cannabinoid receptor 1 (CB1) antagonists (e.g. TM-38837),
melanin-concentrating hormone (MCH-1) antagonists (e.g. BMS-830216,
ALB-127158(a)), MC4 receptor agonists and partial agonists (e.g.
AZD-2820, RM-493), neuropeptide Y5 (NPY5) or NPY2 antagonists (e.g.
velneperit, S-234462), NPY4 agonists (e.g. PP-1420),
beta-3-adrenergic receptor agonists, leptin or leptin mimetics,
agonists of the 5-hydroxytryptamine 2c (5HT2c) receptor (e.g.
lorcaserin), or the combinations of bupropione/naltrexone
(Contrave.RTM.), bupropione/zonisamide (Empatic.RTM.),
bupropione/phentermine or pramlintide/metreleptin,
phentermine/topiramate (Qsymia.RTM.), lipase inhibitors (e.g.
cetilistat/Cametor.RTM.), angiogenesis inhibitors (e.g. ALS-L1023),
histamine H3 antagonists (e.g. HPP-404), AgRP (agouti related
protein) inhibitors (e.g. TTP-435), triple monoamine uptake
inhibitors (dopamine, norepinephrine and serotonin reuptake) (e.g.
tesofensine), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g.
beloranib), nasal formulations of the calcium channel blocker
diltiazem (e.g. CP-404) and antisense oligonucleotides against
production of fibroblast growth factor receptor 4 (FGFR4) (e.g.
ISIS-FGFR4Rx) or prohibitin targeting peptide-1 (e.g.
Adipotide.RTM.).
[0070] Further suitable active pharmaceutical ingredients which may
be included in the pharmaceutical formulations include but are not
limited to:
[0071] Angiotensin II receptor antagonists (e.g. telmisartan,
candesartan, valsartan, losartan, eprosartan, irbesartan,
olmesartan, tasosartan, azilsartan), angiotensin converting enzyme
(ACE) inhibitors, endothelin converting enzyme (ECE) inhibitors,
diuretics, beta-blockers, calcium antagonists, centrally acting
hypertensives, antagonists of the alpha-2-adrenergic receptor,
inhibitors of neutral endopeptidase, thrombocyte aggregation
inhibitors and others or combinations thereof are suitable.
[0072] As used herein, the terms "analogue of insulin" and "insulin
analogue" refers to a polypeptide which has a molecular structure
which formally can be derived from the structure of a naturally
occurring insulin, for example that of human insulin, by deleting
and/or exchanging at least one amino acid residue occurring in the
naturally occurring insulin and/or adding at least one amino acid
residue. The added and/or exchanged amino acid residue can either
be codable amino acid residues or other naturally occurring
residues or purely synthetic amino acid residues. Examples of
analogues of insulin include, but are not limited to, the
following: (i). `Insulin aspart` is created through recombinant DNA
technology so that the amino acid B28 in human insulin (i.e. the
amino acid no. 28 in the B chain of human insulin), which is
proline, is replaced by aspartic acid; (ii). `Insulin lispro` is
created through recombinant DNA technology so that the penultimate
lysine and proline residues on the C-terminal end of the B-chain of
human insulin are reversed (human insulin: Pro.sup.B28Lys.sup.B29;
insulin lispro: Lys.sup.B28Pro.sup.B29); (iii). `Insulin glulisine`
differs from human insulin in that the amino acid asparagine at
position B3 is replaced by lysine and the lysine in position B29 is
replaced by glutamic acid; (iv). "Insulin glargine" differs from
human insulin in that the asparagine at position A21 is replaced by
glycine and the B chain is extended at the carboxy terminal by two
arginines.
[0073] As used herein, the term "aqueous" refers to a solution in
which the solvent is water and/or to a suspension in which the
external phase is water and/or to an emulsion in which the
dispersed or continuous phase is water.
[0074] As used herein, the term "buffering agent" refers to a weak
acid or base used to maintain the acidity (pH) of a solution, a
suspension and/or an emulsion near a chosen value after the
addition of another acid or base. The function of a buffering agent
is to prevent a rapid change in the pH value when acids or bases
are added to the solution. In an aqueous solution, suspension
and/or emulsion, a buffering agent is present in a mixture of a
weak acid and its conjugate base or a in a mixture of a weak base
and its conjugated acid. Examples of buffering agents include, but
are not limited to, the following: sodium bicarbonate; acetic acid
or acetate salts (e.g. sodium acetate, zinc acetate); boric acid or
boric salts; N-cyclohexyl-2-aminoethanesulfonic acid (CHES) or
salts thereof;
3-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]propane-1-sulfonic
acid (TAPS) or salts thereof; 2-(N-morpholino)ethanesulfonic acid
(MES) and salts thereof; piperazine-N,N'-bis(2-ethanesulfonic acid
(PIPES) and salts thereof; N-(2-acetamido)-2-aminoethane-sulfonic
acid (ACES) and salts thereof; cholamine chloride; BES;
2-[[1,3-dihydroxy-2-(hydroxymethyl)-propan-2-yl]amino]ethanesulfonic
acid (TES) and salts thereof;
2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) and
salts thereof; acetamidoglycine;
N-(2-hydroxy-1,1-bis(hydroxyl-methyl)ethyl)glycine (tricine);
glycinamide; 2-(bis(2-hydroxyethyl)amino)acetic acid (bicine) and
salts thereof; propionate salts;
3-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]-amino]-2-hydroxy-propane--
1-sulfonic acid (TAPSO) and salts thereof;
3-morpholinopropane-1-sulfonic acid (MOPS) and salts thereof;
saline-sodium citrate (SSC) buffer;
2-amino-2-hydroxymethyl-propane-1,3-diol (synonyms: TRIS,
trisamine, THAM, tromethamine, trometamol, tromethane); citric acid
or citrate salts (e.g. sodium citrate); trisodium phosphate,
disodium hydrogen phosphate, sodium dihydrogen phosphate,
tripotassium phosphate, dipotassium phosphate, monopotassium
phosphate and/or any other buffering agent containing
phosphate.
[0075] Amino acids (having free basic or acidic functional groups,
e.g. methionin, arginine) or peptides (having free basic or acidic
functional groups) may also be used as buffering agent. As used
herein, the term "buffering agent" also comprises amino acids,
peptides and proteins. As insulin analogues and/or insulin
derivatives and/or protamine are peptides or derivatives of
peptides (i.e. both contain amino acids having free basic or acidic
functional groups), they may also have a certain buffering
capacity, i.e. are also to be considered as buffering agent.
[0076] As used herein, the term "fast acting insulin" or "short
acting insulin" refers to insulin analogues and/or insulin
derivatives, wherein the insulin-mediated effect begins within 5 to
15 minutes and continues to be active for 3 to 4 hours. Examples of
fast acting insulins include, but are not limited to, the
following: (i). insulin aspart; (ii). insulin lispro and (iii).
insulin glulisine.
[0077] As used throughout the description and the claims of this
specification, the word "comprise" and variations of the word, such
as "comprising" and "comprises" is not intended to exclude other
additives, components, integers or steps.
[0078] As used herein, the terms "derivative of insulin" and
"insulin derivative" refers to a polypeptide which has a molecular
structure which formally can be derived from the structure of a
naturally occurring insulin, for example that of human insulin, in
which one or more organic substituent (e.g. a fatty acid) is bound
to one or more of the amino acids. Optionally, one or more amino
acids occurring in the naturally occurring insulin may have been
deleted and/or replaced by other amino acids, including
non-codeable amino acids, or amino acids, including non-codeable,
have been added to the naturally occurring insulin. Examples of
derivatives of insulin include, but are not limited to, the
following: (i). `Insulin detemir` which differs from human insulin
in that the C-terminal threonine in position B30 is removed and a
fatty acid residue (myristic acid) is attached to the epsilon-amino
function of the lysine in position B29. (ii). `Insulin degludec`
which differs from human insulin in that the last amino acid is
deleted from the B-chain and by the addition of a glutamyl link
from Lys.sup.B29 to a hexadecandioic acid.
[0079] As used herein, the term "FGF-21" means "fibroblast growth
factor 21". FGF-21 compounds may be human FGF-21, an analogue of
FGF-21 (referred to "FGF-21 analogue") or a derivative of FGF-21
(referred to "FGF-21 derivative").
[0080] As used herein, the term "formulation" refers to a product
comprising specified ingredients in predetermined amounts or
proportions, as well as any product that results, directly or
indirectly, from combining specified ingredients in specified
amounts. In relation to pharmaceutical formulations, this term
encompasses a product comprising one or more active ingredients,
and an optional carrier comprising inert ingredients, as well as
any product that results, directly or indirectly, from combination,
complexation or aggregation of any two or more of the ingredients,
or from dissociation of one or more of the ingredients, or from
other types of reactions or interactions of one or more of the
ingredients. In general, pharmaceutical formulations are prepared
by uniformly bringing the active pharmaceutical ingredient (i.e.
the analogue and/or derivative of insulin) into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. The
pharmaceutical formulation includes enough of the active
pharmaceutical ingredient to produce the desired effect upon the
progress or condition of diseases. As used herein, the term
"formulation" may refer to a solution as well as to a suspension or
to an emulsion. As used herein, the terms "formulation" and
"composition" are meant to be synonyms, i.e., have identical
meaning. The pharmaceutical compositions are made following
conventional techniques of pharmaceutical technology involving
mixing, filling and dissolving the ingredients, as appropriate, to
give the desired oral, parenteral, rectal, transdermal, or topical
products.
[0081] As used herein, the term "GLP-1 receptor agonist" refers to
compounds which have an agonistic activity at the glucagon-like
peptide-1 receptor. Examples of GLP-1 receptor agonists include,
but are not limited to, the following: exenatide/exendin-4,
liraglutide, lixisenatide, dulaglutide, albiglutide, semaglutide,
taspoglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, HM-11260C,
CM-3, GLP-1 Eligen, ORMD-0901, NN9924, Nodexen, Viador-GLP-1,
CVX-096, ZYOG-1, ZYD-1, MAR-701, ZP-2929, ZP-3022, CAM-2036,
DA-15864, ARI-2651, ARI-2255, exenatide-XTEN and glucagon-XTEN,
AMX-8089+VRS-859 and polymer bound GLP-1 and GLP-1 analogues.
[0082] As used herein, the term "dual GLP-1 receptor/glucagon
receptor agonist" refers to compounds which have agonistic activity
at both the GLP-1 receptor and the glucacon receptor. Examples of
dual GLP-1 receptor/glucagon receptor agonist include, but are not
limited to, the following: oxyntomodulin, MAR701, MAR-709, and
BHM081/BHM089/BHM098.
[0083] As used herein, the term "human insulin" refers to the human
hormone whose structure and properties are well-known. Human
insulin has two polypeptide chains (chains A and B) that are
connected by disulphide bridges between cysteine residues, namely
the A-chain and the B-chain. The A-chain is a 21 amino acid peptide
and the B-chain is a 30 amino acid peptide, the two chains being
connected by three disulphide bridges: one between the cysteins in
position 6 and 11 of the A-chain; the second between the cysteine
in position 7 of the A-chain and the cysteine in position 7 of the
B-chain; and the third between the cysteine in position 20 of the
A-chain and the cysteine in position 19 of the B-chain.
[0084] As used herein, the term "including" is used to mean
"including but not limited to". "Including" and "including but not
limited to" are used interchangeably.
[0085] As used herein, the term "isoelectric point" (pl, IEP)
refers to the pH value at which a particular molecule carries no
net electrical charge. The isoelectric point can be determined by
using isoelectric focusing, which is a technique for separating
different molecules by differences in their isoelectric point and
which is well known in the art. It can also be calculated (see e.g.
Levene and Simms, `Calculation of isoelectric point` J. Biol.
Chem., 1923, pp. 801-813).
[0086] As used herein, the term "kit" refers to a product (e.g.
medicament, kit-of-parts) comprising one package or one or
moreseparate packages of:
[0087] (i). A pharmaceutical formulation containing an active
pharmaceutical ingredient and at least one further active
pharmaceutical ingredient and optionally a medical device. The at
least one further active pharmaceutical ingredient may be present
in said pharmaceutical formulation, i.e. the kit may comprise one
or more packages, wherein each package comprises one pharmaceutical
formulation which comprises two or more active pharmaceutical
ingredients. The further active pharmaceutical ingredient may also
be present in a further pharmaceutical formulation, i.e. the kit
may comprise separate packages of two or more pharmaceutical
formulations, wherein each pharmaceutical formulation contain one
active pharmaceutical ingredient.
[0088] Or
[0089] (ii). A pharmaceutical formulation containing an active
pharmaceutical ingredient and medical device.
[0090] A kit may comprise one package only or may comprise one or
more separate packages For example, the kit may be a product (e.g.
medicament) containing two or more vials each containing a defined
pharmaceutical formulation, wherein each pharmaceutical formulation
contains at least one active pharmaceutical ingredient. For
example, the kit may comprise (i.) a vial containing a defined
pharmaceutical formulation and (ii). further a tablet, capsule,
powder or any other oral dosage form which contains at least one
further active pharmaceutical ingredient. The kit may further
comprise a package leaflet with instructions for how to administer
the pharmaceutical formulation and the at least one further active
pharmaceutical ingredient.
[0091] As used herein, the term "medical device" means an
instrument, apparatus, implant, in vitro reagent or similar or
related article that is used to diagnose, prevent, or treat a
disease of other condition, and does not achieve its purpose
through pharmacological action within or on the body. As used
herein, a medical device may be a syringe, an insulin injection
system, an insulin infusion system, an insulin pump or an insulin
pen injection device. As used herein, a medical device may be
mechanically or electromechanically driven.
[0092] As used herein, unless specifically indicated otherwise, the
conjunction "or" is used in the inclusive sense of "and/or" and not
the exclusive sense of "either/or".
[0093] As used herein, the term "pH" and "pH value" refer to the
decimal logarithm of the reciprocal of the hydrogen ion activity in
a solution.
[0094] As used herein, the term "pharmaceutical" refers to the
intended use in the medical diagnosis, cure, treatment and/or
prevention of diseases.
[0095] As used herein, the term "pharmaceutically acceptable"
refers to physiologically well tolerated by a mammal or a
human.
[0096] As used herein, the term "protamine" refers to a mixture of
strongly basic peptides. It was originally isolated from the sperm
of salmon and other species of fish but is now produced primarily
recombinant through biotechnology. It contains more than two-thirds
of L-arginine. As protamine contains amino acids having free basic
side chains, it has a certain buffering capacity and is therefore
considered to be a buffering agent. Protamine may be used as
protamine sulfate or protamine hydrochloride.
[0097] Concentrations, amounts, solubility in different liquid
systems, particle size, wavelength, pH values, weight mass,
molecular weight, percent and other numerical date may be expressed
or presented herein in a range format. It is to be understood that
such a range format is used merely for convenience and brevity and
thus should be interpreted flexibly to include not only the
numerical values explicitly recited as the limits of the range, but
also to include all the individual numerical values or sub-ranges
encompassed within that range as if each numerical value and
sub-range is explicitly recited.
[0098] As used herein, the term "long acting insulin" refers to
insulin analogues and/or insulin derivatives, wherein the
insulin-mediated effect begins within 0.5 to 2 hours and continues
to be active, for about or more than 24 hours. Examples of fast
acting insulins include, but are not limited to, the following:
(i). insulin glargin; (ii). insulin detemir and (iii). insulin
degludec.
[0099] As used herein, the term "stability" refers to the chemical
and/or physical stability of active pharmaceutical ingredients, in
particular of insulin analogues and/or derivatives. The purpose of
stability testing is to provide evidence on how the quality of an
active pharmaceutical ingredient or dosage form varies with time
under the influence of a variety of environmental factors such as
temperature, humidity, and light, and to establish a shelf life for
the active pharmaceutical ingredient or dosage form and recommended
storage conditions. Stability studies can include testing of those
attributes of the active pharmaceutical ingredient that are
susceptible to change during storage and are likely to influence
quality, safety, and/or efficacy. The testing can cover, as
appropriate, the physical, chemical, biological, and
microbiological attributes, preservative content (e.g.,
antioxidant, antimicrobial preservative), and functionality tests
(e.g. for a dose delivery system). Analytical procedures can be
fully validated and stability indicating. In general, significant
changes for an active pharmaceutical ingredient and/or dosage form
with regard to stability are defined as: [0100] a 5% change in
assay from its initial value; or failure to meet the acceptance
criteria for potency when using biological or immunological
procedures; [0101] any degradation products exceeding its
acceptance criterion; [0102] failure to meet the acceptance
criteria for appearance, physical attributes, and functionality
test (e.g., color, phase, separation, resuspendibility, caking,
hardness, dose delivery per actuation); however, some changes in
physical attributes (e.g. softening of suppositories, melting of
creams) may be expected under accelerated conditions; [0103] and,
as appropriate for the dosage form: [0104] failure to meet the
acceptance criterion for pH; or
[0105] The significant changes may also be evaluated against
established acceptance criteria prior to starting the evaluation of
the stability.
[0106] Acceptance criteria can be derived from the monographs (e.g.
monographs for the European Pharmacopeia, of the United States
Pharmacopeia, of the British Pharmacopeia, or others), and from the
analytical batches of the active pharmaceutical ingredient and
medicinal product used in the preclinical and clinical studies.
Acceptable limits should be proposed and justified, taking into
account the levels observed in material used in preclinical and
clinical studies. Product characteristics may be visual appearance,
purity, color and clarity for solutions/suspensions, visible
particulates in solutions, and pH. As a non-limiting example,
suitable acceptance criteria for insulin aspart formulations are
shown below:
TABLE-US-00001 Test item Acceptance criteria for clinical trials
Appearance of solution (visual) Clarity and degree of opalescence
Monitoring Degree of coloration Monitoring Assay insulin aspart
units (HPLC) 90.0 insulin aspart units/mL to 110.0 insulin aspart
units/mL Related impurities (HPLC) B28isoAsp insulin aspart equal
or below to 2.5% Total of A21Asp insulin aspart, equal or below to
5.0% B3Asp insulin aspart and B3isoAsp insulin aspart Any other
unspecified, unidentified equal or below to 2.0% impurity Total of
other impurities equal or below to 3.5% High molecular weight
proteins equal or below to 1.5% (HPSEC) pH 7.0 to 7.8 Particulate
matter (visible particles) Practically free of visible particles
Particulate matter (subvisible Number of particles per container:
particles) equal or larger to 10 .mu.m: equal or below to 6000
equal or larger to 25 .mu.m: equal or below to 600 Assay m-cresol
1.55 to 1.89 [mg/mL] Assay phenol 1.35 to 1.65 [mg/mL] Zinc (Zn
(II)) (AAS) below 40 .mu.g per 100 units insulin aspart
[0107] The acceptance criteria shown above are based on monographed
acceptance limits (e.g. British Pharmacopoeia, Volume III, 2012 or
Pharmacopoeial Forum, Volume 36(6), November-December 2010) and/or
are derived from extensive experience in the development of insulin
formulations.
[0108] As used herein, the term "treatment" refers to any treatment
of a mammalian, for example human condition or disease, and
includes: (1) inhibiting the disease or condition, i.e., arresting
its development, (2) relieving the disease or condition, i.e.,
causing the condition to regress, or (3) stopping the symptoms of
the disease.
[0109] As used herein, the unit of measurement "U" and/or
"international units" refers to the blood glucose lowering activity
of insulin and is defined (according to the World Health
Organization, WHO) as follows: 1 U corresponds to the amount of
highly purified insulin (as defined by the WHO) which is sufficient
to lower the blood glucose level of a rabbit (having a body weight
of 2-2.5 kg) to 50 mg/100 mL within 1 hour and to 40 mg/100 mL
within 2 hours. For human insulin, 1 U corresponds to approximately
35 .mu.g (Lill, Pharmazie in unserer Zeit, No. 1, pp. 56-61, 2001).
For insulin aspart, 100 U correspond to 3.5 mg (product information
NovoRapid.RTM.). For insulin lispro, 100 U correspond to 3.5 mg
(product information Humalog.RTM.). For insulin glulisine, 100 U
correspond to 3.49 mg (product information Apidra.RTM. cartridges).
For insulin determir, 100 U correspond to 14.2 mg (product
information Levemir.RTM.). For insulin glargin, 100 U correspond to
3.64 mg (product information Lantus.RTM.).
[0110] Further embodiments of the present invention include the
following:
[0111] In one aspect, the invention provides a pharmaceutical
formulation comprising (a). insulin aspart; and (b). Zn(II); and
(c). optionally protamine; wherein the pharmaceutical formulation
contains less than 0.17 mg/mL sodium chloride.
[0112] In one aspect, the pharmaceutical formulation of the
invention is an aqueous pharmaceutical formulation.
[0113] In one aspect, the pharmaceutical formulation of the
invention has a pH value in the range from 6.0 to 9.0.
[0114] In one aspect, the pharmaceutical formulation of the
invention has a pH value in the range from 7.0 to 7.8.
[0115] In one aspect, the pharmaceutical formulation of the
invention comprises insulin aspart which is present in a
concentration from 10 U/mL to 1000 U/mL.
[0116] In one aspect, the pharmaceutical formulation of the
invention comprises Zn(II) which is present in a concentration from
0.0100 to 0.0600 mg/100 U of insulin aspart.
[0117] In one aspect, the pharmaceutical formulation of the
invention is essentially free of sodium chloride.
[0118] In one aspect, the pharmaceutical formulation of the
invention comprises protamine which is present in a concentration
from 0.1 to 0.5 mg/mL.
[0119] In one aspect, the pharmaceutical formulation of the
invention further contains a buffering agent.
[0120] In one aspect, the pharmaceutical formulation of the
invention comprises one or more further active pharmaceutical
ingredients.
[0121] In one aspect, the pharmaceutical formulation of the
invention comprises a further active pharmaceutical ingredient
which is an antidiabetic agent.
[0122] In one aspect, the pharmaceutical formulation of the
invention comprises a further active pharmaceutical ingredient
which is an antidiabetic agent selected from the group consisting
of: (a). a GLP-1 receptor agonist; (b). a dual GLP-1
receptor/glucagon receptor agonist; (c). human FGF-21; (d). a
FGF-21 analogue; (e). a FGF-21 derivative; (f). insulin; (g). human
insulin; (h). an analogue of insulin; and (i). a derivative of
insulin.
[0123] In one aspect, the pharmaceutical formulation of the
invention further comprises a fast acting analogue and/or
derivative of insulin or a long acting analogue and/or derivative
of insulin.
[0124] In one aspect, the pharmaceutical formulation of the
invention comprises a fast acting analogue and/or derivative of
insulin or a long acting analogue and/or derivative of insulin,
wherein the fast acting insulin is one or more insulin selected
from the group consisting of insulin lispro and insulin glulisine
and wherein the long acting insulin is one or more insulin selected
from the group consisting of insulin detemir, insulin glargin and
insulin degludec.
[0125] In one aspect, the pharmaceutical formulation of the
invention consists of: (a). 3.5 mg/mL insulin aspart; (b). 0.0196
mg/mL Zn(II); (c). 1.88 mg/mL Na.sub.2HPO.sub.4.times.7 H.sub.2O;
(d). 1.72 mg/mL m-cresol; (e). 1.5 mg/mL phenol; (f). 17.88 mg/mL
glycerol; (g). sodium hydroxide and/or hydrochloric acid to adjust
the pH to 7.4; and (h). water.
[0126] In one aspect, the pharmaceutical formulation of the
invention consists of: (a). 3.5 mg/mL insulin aspart; (b). 0.0196
mg/mL Zn(II); (c). 1.88 mg/mL Na.sub.2HPO.sub.4.times.7 H.sub.2O;
(d). 1.72 mg/mL m-cresol; (e). 1.5 mg/mL phenol; (f). 17.88 mg/mL
glycerol; (g). from 0.1 mg/mL to 0.5 mg/mL protamine sulfate; (h).
sodium hydroxide and/or hydrochloric acid to adjust the pH to 7.4;
and (i). water.
[0127] In one aspect, the invention provides a process for
preparing the pharmaceutical formulation of the invention, wherein
the components are mixed together in the form of a solution or
suspension, the pH is adjusted to reach the desired pH, and water
is added to reach the final volume.
[0128] In one aspect, the invention provides a kit comprising one
or more separate packages of (a). the pharmaceutical formulation of
the invention; and (b). a medical device.
[0129] In one aspect, the invention provides as kit comprising one
or more separate packages of (a). the pharmaceutical formulation if
the invention; and (b). at least one further active pharmaceutical
ingredient; (c). and optionally a medical device.
[0130] In one aspect, the kit of the invention comprises a further
active pharmaceutical ingredient which is an antidiabetic
agent.
[0131] In one aspect, the kit of the invention comprises a further
active pharmaceutical ingredient which is an antidiabetic agent
selected from the group consisting of: (a). a GLP-1 receptor
agonist; (b). a dual GLP-1 receptor/glucagon receptor agonist; (c).
human FGF-21; (d). a FGF-21 analogue; (e). a FGF-21 derivative;
(f). insulin; (g). human insulin; (h). an analogue of insulin; and
(i). a derivative of insulin.
[0132] In one aspect, the kit of the invention comprises a further
active pharmaceutical ingredient which is an analogue or derivative
of insulin selected from the group consisting of fast acting
insulin and long acting insulin.
[0133] In one aspect, the kit of the invention comprises an
analogue or derivative of insulin selected from the group
consisting of fast acting insulin and long acting insulin, wherein
the fast acting insulin is selected from the group consisting of
insulin aspart, insulin lispro and insulin glulisine and wherein
the long acting insulin is selected from the group consisting of
insulin glargin, insulin detemir and insulin degludec.
[0134] In one aspect, the invention provides a pharmaceutical
formulation or a kit for use in the treatment of diabetes
mellitus.
[0135] In one aspect, the invention provides a pharmaceutical
formulation or a kit for use in the treatment of hyperglycemia.
[0136] In one aspect, the invention provides a pharmaceutical
formulation or a kit for use in lowering blood glucose level.
[0137] In one aspect, the invention provides a method of treating
diabetes mellitus in a subject in need thereof comprising
administering the pharmaceutical formulation of the invention.
[0138] In one aspect, the invention provides a method of treating
hyperglycemia in a subject in need thereof comprising administering
the pharmaceutical formulation of the invention.
[0139] In one aspect, the invention provides a method of lowering
blood glucose levels in a subject in need thereof comprising
administering the pharmaceutical formulation of the invention.
[0140] In one aspect, the invention provides a medical device for
administering the pharmaceutical formulation of the invention to an
animal and/or human.
[0141] The present invention is illustrated by the following
Examples. However, it should be understood that the present
invention is not limited to the specific details of these
examples.
EXAMPLES
Example 1
[0142] Manufacturing Process
[0143] (a) Zinc Oxide Solution
[0144] Zinc oxide Solution (containing Zn(II)) was prepared by
suspending 0.8539 g zinc oxide in 500 mL water for injection and
dissolving by adding 1N hydrochloric acid. The solution is filled
up with water for injection to final volume of 1000 mL.
[0145] (b) Solution A
[0146] The final composition of Solution A is given in Table 1:
TABLE-US-00002 TABLE 1 Composition of Solution A Composition
Composition per Excipient per 200 mL 2000 mL 1. di-Natriumhydrogen-
1.88 g 18.8 g phosphat * 7 H.sub.2O 2. Phenol 1.5 g 15.0 g 3.
m-Cresol 1.72 g 17.2 g 4. Glycerol 85% 21.04 g.sup.(1) 210.4 g 5.
Sodium hydroxide ad pH 8.65 ad pH 8.65 6. Hydrochloric acid ad pH
8.65 ad pH 8.65 7. Water for Injection ad 200 mL = ad 2000 mL =
201.5 g 2015 g .sup.(1)21.04 mg glycerol 85% corresponds to 17.88
mg glycerol.
[0147] Solution A was prepared as described in the following:
[0148] 1. It was started with approximately 1000 g water for
injection. [0149] 2. 18.8 g di-Natriumhydrogen-phosphat*7 H.sub.2O,
210.4 g Glycerol 85%, 15.0 g phenol and 17.2 g m-cresol were
dissolved while stirring constantly. [0150] 3. Solution was filled
up to approximately 1800 g with water for injection. [0151] 4.
Solution was stirred for approximately 15 min using a magnetic
stirrer. [0152] 5. pH was checked (pH should be 8.65). If pH value
is not 8.65, the pH was adjusted to said range using hydrochloric
acid 0.03 N or sodium hydroxide solution 1 N. [0153] 6. Solution
was filled up to 2015 g (=2000 mL) with water for injection.
[0154] (c) Final Solution
[0155] The final composition of Final Solution is given in Table
2:
TABLE-US-00003 TABLE 2 Composition of Final Solution Composition
Composition Composition Excipient per mL per 1000 mL per 2000 mL 1.
Insulin aspart 3.5 mg 3.5 g 7.0 g 2. Zn(II) 19.6 .mu.g 0.0196 g
0.0392 g 3. di-Natriumhydrogen- 1.88 mg 1.88 g 3.76 g phosphat * 7
H.sub.2O 4. Glycerol 85% 21.04 mg.sup.(1) 21.04 g 42.08 g 5. Phenol
1.50 mg 1.50 g 3.0 g 6. m-Cresol 1.72 mg 1.72 g 3.44 g 7. Sodium
hydroxide ad pH 7.4 ad pH 7.4 ad pH 7.4 solution 8. Hydrochloric
acid ad pH 7.4 ad pH 7.4 ad pH 7.4 9. Water for Injection ad 1 mL =
ad 1000 mL = ad 2000 mL = 1.005 g 1005 g 2010 g .sup.(1)21.04 mg
glycerol 85% corresponds to 17.88 mg glycerol.
[0156] Final Solution was prepared as described in the following:
[0157] 1. It was started with 300 mL water for injection. [0158] 2.
7.0 g insulin aspart was added to the 300 mL water for injection
while stirring constantly (a suspension of insulin aspart in water
for injection is formed). [0159] 3. pH value was checked. [0160] 4.
pH value was changed to approximately 3.1 to 3.2 by adding
hydrochloric acid 0.03 N or sodium hydroxide solution 0.02 N to
dissolve the insulin aspart. [0161] 5. Solution was stirred for
approximately 15 min using a magnetic stirrer. [0162] 6. 57 mL zinc
oxide solution was added to the solution while stirring constantly.
[0163] 7. Solution was filled up to 600 g with water for injection.
[0164] 8. 400 mL Solution A was added slowly and carefully while
stirring constantly. [0165] 9. pH was adjusted to 7.4 (range 7.2 to
7.6) using hydrochloric acid 0.03 N or sodium hydroxide solution
0.02 N. [0166] 10. Solution was filled up to 2010 g with water for
injection (corresponds to 100% of the Final Solution).
[0167] Due to the addition of NaOH and HCl (for pH-adjustments and
dissolving zinc oxide, see above), 0.17 mg/mL NaCl can be formed in
the final solution
[0168] Quality control: Final solution was a clear and uncoloured
solution, showed a pH value of 7.4 (plus/minus 0.2; at
20-25.degree. C.).
[0169] The Final Solution was applied to sterile filtration using
`Sartopore Minisart high flow` filter (filter material:
polyethersulfone; pore size: 0.2 .mu.m; supplier: Sartorius).
[0170] The Final Solution after sterile filtration was a clear and
uncoloured solution and showed an osmolarity of 260 mOsmol/kg
(plus/minus 30).
[0171] The Final Solution after sterile filtration was filled into
appropriate vials (volume: 5 and 10 mL; 13 mm; clear glass; glass
type 1).
[0172] The vials--containing the Final Solution after sterile
filtration--were stored between +2.degree. C. and +8.degree. C. and
protected from light.
Example 2
[0173] Control of the Formulation
[0174] (a) Analytical Procedures
[0175] Tests are carried out using compendial analytical test
methods, where applicable. The quality control concept has been
established taking into account the cGMP requirements as well as
the current status of the ICH process.
[0176] The non-compendial and chromatographic analytical procedures
used to control the formulation are summarized in the
following:
[0177] Description
[0178] Visually examine a number of containers for conformance to
the acceptance criteria.
[0179] Identification (HPLC)
[0180] The identity of the active ingredient is ensured by
comparing the retention time of the drug formulation sample with
the retention time of the reference standard using a reversed phase
HPLC method. The method is also used for the determination of assay
of the active ingredient, for the determination of the related
compounds and impurities, and for quantifying the preservatives
m-cresol and phenol.
[0181] Assay (HPLC)
[0182] The test is carried out by reverse phase liquid
chromatography (HPLC). The method is also used for the
identification, the determination of assay of the active
ingredient, for the determination of the related compounds and
impurities, and for quantifying the preservatives m-cresol and
phenol. Column: Lichrosorb RP18, particle size 5 .mu.m, pore size
100 {acute over (.ANG.)} (250 mm.times.4.0 mm), thermostated at
+35.degree. C. Autosampler: Thermostated at .ltoreq.8.degree. C.
Mobile phase A: Sodium sulfate solved in water, 14 g/mL, adjusted
with phosphoric acid and sodium hydroxide to a pH of 3.4. Mobile
phase B: Water/acetonitrile (50:50 v/v). Gradient is shown in Table
3.
TABLE-US-00004 TABLE 3 HPLC gradient Time [min] Mobile phase A [%]
Mobile phase B [%] 0 to 42 57.7 42.3 42 to 47 linear to 20 80 47 to
52 20 80 52 to 53 linear to 57.7 42.3 53 to 60 equilibration 57.7
42.5
[0183] Flow rate: 1.0 mL/min. Injection volume: 10 .mu.L.
Detection: 214 nm (for the active ingredient) and 260 nm (for
m-cresol and phenol). Typical run time: 60 min.
[0184] Assay of the active ingredient, m-cresol and phenol are
calculated by external standardization.
[0185] Impurities are calculated using the peak area percent
method.
[0186] Test solution: The formulation is used without any dilution
or further treatment.
[0187] Related Compounds and Impurities (HPLC)
[0188] The same chromatographic conditions as for "Assay (HPLC)"
are used for the determination of related compounds and impurities.
Related compounds and Impurities are calculated using the peak area
percent method.
[0189] High Molecular Weight Proteins (HMWPs)
[0190] The high molecular weight proteins are determined using high
pressure size exclusion chromatography (HPSEC). Column: Waters
Insulin HMWP, particle size 5-10 .mu.m, pore size 12-12.5 nm (300
mm.times.7.8 mm), thermostated at room temperature. Autosampler:
thermostated at .ltoreq.+8.degree. C. Mobile phase: 650 mL of
arginine solution (1 g/L) is mixed with 200 mL of acetonitrile and
150 mL of glacial acetic acid. Isocratic elution Flow rate: 1.0
mL/min. Injection volume: 100 .mu.L.
[0191] Detection: 276 nm. Typical run time: 35 min.
[0192] HMWPs are calculated using the peak area percent method.
Test solution: The formulation is used without any dilution or
further treatment.
[0193] Antimicrobial Preservative Assay
[0194] The same chromatographic conditions as for "Assay (HPLC)"
are used for the determination of assay of m-Cresol and of phenol
m-cresol and phenol are calculated by external standardization.
[0195] (b) Validation of Analytical Procedures
[0196] The HPLC analytical procedure for the formulation for the
determination of identification, assay, and related compounds and
impurities was validated to demonstrate specificity, linearity,
limit of detection and limit of quantification, accuracy, precision
and range.
[0197] (c) Justification of the Acceptance Criteria
[0198] Tests and acceptance criteria, as previously presented, were
selected based on ICH Q6B and on published monographs, analytical
results obtained, precision of procedures used, Pharmacopoeial
and/or regulatory guidelines, and are in agreement with the
standard limits at this stage of development.
Example 3
[0199] Stability of the Formulation
[0200] (a) Stability of the Formulation
[0201] Stability studies for the formulation were initiated
according to the stability protocol summary described in the
following table. The composition and manufacturing method of the
stability batches are representative of the material. The stability
profile was assessed for storage under long term, accelerated, and
stress testing conditions according to ICH guidelines. Samples were
packed and stored in glass vials with flanged cap with inserted
disc and flip-off lid. The stability data obtained using this
packaging material are representative for the preliminary shelf
life and storage direction for both packaging configurations (10 mL
glass vials and 3 mL cartridges). 1 month stability data are
available from ongoing stability studies of the formulation.
TABLE-US-00005 TABLE 4 Storage Conditions Storage Condition
Sampling Intervals Container Long Term +5.degree. C. .+-. 3.degree.
C. 1, 10 mL vials Accelerated +25.degree. C. .+-. 2.degree. C./60%
.+-. 5% RH 1, 10 mL vials Stress +40.degree. C. .+-. 5.degree.
C./75% .+-. 5% RH 1 month 10 mL vials Photostability Sun test
according to ICH 1 day 10 mL vials guidelines* Indoor light** 14
days 10 mL vials *Overall illumination of not less than 1.2 million
lux hours and an integrated near ultraviolet energy of not less
than 200 watt hours/m2. A dark control sample is stored under the
same conditions to eliminate any effects due to local temperature
changes **Variolux, Heraeus, standard fluorescent tubes,
GE-Lightening, Type F40/33, irradiance approximately 8 W/m2, 2000
Lux. A dark control sample is stored under the same conditions to
evaluate any effects due to local temperature changes
[0202] The following tests were performed during stability testing:
appearance, assay, related impurities, high molecular weight
proteins, pH, particulate matter (visible and subvisible
particles), assay of antimicrobial preservatives (m-cresol and
phenol), content of Zn(II). The investigations on physical and
chemical properties after 1 month of storage at long term storage
condition of +5.degree. C. confirm the stability of the formulation
when stored at the recommended storage condition. Only very slight
changes of the related impurities could be observed.
[0203] When stored at accelerated conditions (1 months at
+25.degree. C./60% RH) the related impurities and high molecular
weight proteins increased, however stayed well within the current
acceptance limit. When stored at accelerated conditions (1 month at
+40.degree. C./75% RH) one of the related impurities increased
above the acceptance criterion. The content of the active
ingredient decreased below the acceptance criteria. The content of
the microbial preservatives, m-cresol and phenol, remained
basically unchanged under accelerated conditions.
[0204] When stored exposed to light (sun test according to ICH
guidelines for 1 day and indoor light for 14 days) the related
impurities and high molecular weight proteins increased above the
acceptance criteria. The content of the active ingredient, m-cresol
and phenol, remained basically unchanged after photostability
testing.
[0205] Due to the present results of the stability studies of the
formulation, the chemical and physical stability of the formulation
can be confirmed.
[0206] Tables 5 and 6 show the long term stability results, wherein
batch no. "_0021" is referring to a formulation according to the
present invention.
[0207] The stability of the formulation as presently claimed shows
an excellent chemical and physical stability which qualifies said
aqueous pharmaceutical formulation as medicinal product having a
defined shelf life.
TABLE-US-00006 TABLE 5 Stability data of batch_0021 stored for 1
month at long term storage condition +5.degree. C., at accelerated
condition +25.degree. C., and at stress condition +40.degree. C.
Storage condition Acceptance Long term Accelerated criteria for
condition condition Stress condition Test item clinical trials
Initial results (+5.degree. C.) (+25.degree. C./60% RH)
(+40.degree. C./75% RH) Appearance of solution (visual) Clarity
Monitoring <I (water clear) <I (water clear) <I (water
clear) <I (water clear) Color Monitoring B9 B9 B9 B8 Assay in
insulin aspart units 90.0 insulin aspart 107.7 insulin aspart 104.3
insulin 102.0 insulin aspart 88.9 insulin aspart (HPLC) units/mL to
110.0 units/mL aspart units/mL units/mL units/mL insulin aspart
(3.77 mg/mL) (3.65 mg/mL) (3.57 mg/mL) (3.11 mg/mL) units/mL
Related Compounds(HPLC) B28isoAsp insulin aspart .ltoreq.2.5% 0.19%
0.18% 0.74% 4.13% Total of A21Asp insulin aspart, .ltoreq.5.0%
1.30% 1.29% 2.37% 6.38% B3Asp insulin aspart and B3isoAsp insulin
aspart Any other unspecified, .ltoreq.2.0% 0.36% 0.38% 0.48% 1.03%
unidentified impurity Total of other impurities .ltoreq.3.5% 0.57%
0.54% 0.71% 4.27% High molecular weight proteins .ltoreq.1.5% 0.21%
0.21% 0.40% 1.92% (HPSEC) pH Between 7.0 to 7.8 7.42 7.42 7.42 7.41
Particulate matter Practically free Complies Complies Complies
Complies (visible particles) from visible particles Particulate
matter Number of (subvisible particles) particles per container
.gtoreq.10 .mu.m:.ltoreq.6000 5 Not tested Not tested 3 .gtoreq.25
.mu.m:.ltoreq.600 0 0 Assay m-cresol 1.55 to 1.89 1.76 mg/mL 1.73
mg/mL 1.76 mg/mL 1.76 mg/mL mg/mL (102.3%) (100.6%) (102.3%)
(102.3%) (90.0% to 110.0% of label claim) Assay phenol 1.35 to 1.65
1.49 mg/mL 1.47 mg/mL 1.48 mg/mL 1.48 mg/mL mg/mL (99.3%) (98.0%)
(98.6%) (98.7%) (90.0% to 110.0% of label claim) Zinc (Zn(II))
(AAS) <40 .mu.g per 100 18.9 .mu.g per 100 units Not tested Not
tested 22.7 .mu.g per 100 units units insulin aspart insulin aspart
insulin aspart (20.4 .mu.g/mL) (20.2 .mu.g/mL)
TABLE-US-00007 TABLE 6 Photostability Suntest batch_0021 Storage
condition: Suntest per ICH guideline and indoor light Test item
Acceptance Time criteria for clinical Sun test (ICH) trials Dark
Indoor light Initial value control 1 day Dark control 14 days
Appearance of solution (visual) Clarity Monitoring <| (water
<| (water <| (water <| (water <| (water clear) clear)
clear) clear) clear) Color Monitoring B9 B9 B5 B9 B7 Assay in
insulin aspart 90.0 insulin aspart 107.7 insulin 108.0 insulin 91.4
insulin 102.9 insulin 96.0 insulin aspart units (HPLC) units/mL to
110.0 aspart aspart aspart aspart units/mL units/mL insulin aspart
units/mL units/mL units/mL units/mL (3.60 mg/mL) (3.36 mg/mL) (3.77
mg/mL) (3.78 mg/mL) (3.20 mg/mL) Related Compounds(HPLC) B28isoAsp
insulin .ltoreq.2.5% 0.19% 0.29% 0.28% 0.45% 0.42% aspart Total of
A21Asp insulin .ltoreq.5.0% 1.30% 1.26% 1.58% 1.57% 1.62% aspart,
B3Asp insulin aspart and B3isoAsp insulin aspart Any other
unspecified, .ltoreq.2.0% 0.36% 0.28% 1.09% 0.51% 0.66%
unidentified impurity Total of other impurities .ltoreq.3.5% 0.57%
0.84% 14.9% 0.86% 5.33% High molecular weight .ltoreq.1.5% 0.21%
0.23% 6.57% 0.29% 4.07% proteins (HPSEC) pH Between 7.0 to 7.8 7.42
7.44 7.41 7.41 7.40 Particulate matter (visible Practically free
from complies Complies Complies Complies Complies particles)
visible particles Particulate matter Number of particles per 5 2 1
1 1 (subvisible particles) container 0 0 0 0 1 .ltoreq.10 .mu.m:
.ltoreq.6000 .ltoreq.25 .mu.m: .ltoreq.600 Assay m-cresol 1.55
mg/mL to 1.89 1.76 mg/mL 1.75 mg/mL 1.72 mg/mL 1.75 mg/mL 1.74
mg/mL mg/mL (102.3%) (101.7%) (100.0%) (101.7%) (101.2%) (90.0% to
110.0% of label claim) Assay phenol 1.35 mg/mL to 1.65 1.49 mg/mL
1.50 mg/mL 1.48 mg/mL 1.48 mg/mL 1.48 mg/mL mg/mL (99.3%) (100.0%)
(98.7%) (98.7%) (98.7%) (90.0% to 110.0% of label claim) Zinc (Zn
(II) ) (AAS) <40 .mu.g per 100 units 18.9 .mu.g Per 18.9 .mu.g
per 22.8 .mu.g per 19.7 .mu.g per 100 21.0 .mu.g per 100 insulin
aspart 100 units 100 units 100 units units insulin units insulin
aspart insulin aspart insulin aspart insulin aspart aspart (20.2
.mu.g/mL) (20.4 .mu.g/mL) (20.4 .mu.g/mL) (20.8 .mu.g/mL) (20.3
.mu.g/mL)
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