U.S. patent application number 15/747532 was filed with the patent office on 2018-08-09 for a pharmaceutical preparation for improving absorption and postprandial hypoglycemic action of insulin.
This patent application is currently assigned to SOCIETE DE COMMERCIALISATION DES PRODUITS DE LA RECHERCHE APPLIQUEE SOCPRA SCIENCES SANTE ET. The applicant listed for this patent is SOCIETE DE COMMERCIALISATION DES PRODUITS DE LA RECHERCHE APPLIQUEE SOCPRA SCIENCES SANTE ET. Invention is credited to Jean-luc ARDILOUZE, Jean-Patrice BAILLARGEON, Pascal BRASSARD, aude GAGNON-AUGER, Fernand GOBEIL, Julie MENARD.
Application Number | 20180221385 15/747532 |
Document ID | / |
Family ID | 57883869 |
Filed Date | 2018-08-09 |
United States Patent
Application |
20180221385 |
Kind Code |
A1 |
ARDILOUZE; Jean-luc ; et
al. |
August 9, 2018 |
A PHARMACEUTICAL PREPARATION FOR IMPROVING ABSORPTION AND
POSTPRANDIAL HYPOGLYCEMIC ACTION OF INSULIN
Abstract
The present disclosure relates to compositions and combinations
comprising one or more insulin(s) and one or more vasoactive
agent(s), and use thereof for increasing subcutaneous insulin
absorption and/or treating diabetes and/or treating or preventing
hyperglycemia or complications in a patient in need thereof.
Inventors: |
ARDILOUZE; Jean-luc;
(Sherbrooke, CA) ; GAGNON-AUGER; aude;
(Sherbrooke, CA) ; GOBEIL; Fernand; (Sherbrooke,
CA) ; MENARD; Julie; (Sherbrooke, CA) ;
BAILLARGEON; Jean-Patrice; (Sherbrooke, CA) ;
BRASSARD; Pascal; (Magog, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SOCIETE DE COMMERCIALISATION DES PRODUITS DE LA RECHERCHE APPLIQUEE
SOCPRA SCIENCES SANTE ET |
Sherbrooke |
|
CA |
|
|
Assignee: |
SOCIETE DE COMMERCIALISATION DES
PRODUITS DE LA RECHERCHE APPLIQUEE SOCPRA SCIENCES SANTE ET
Sherbrooke
QC
|
Family ID: |
57883869 |
Appl. No.: |
15/747532 |
Filed: |
July 28, 2016 |
PCT Filed: |
July 28, 2016 |
PCT NO: |
PCT/CA2016/050886 |
371 Date: |
January 25, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62197833 |
Jul 28, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
C07D 217/20 20130101; C07K 14/62 20130101; A61K 38/28 20130101;
A61K 31/557 20130101; C07D 487/04 20130101; A61K 45/06 20130101;
A61K 31/137 20130101; A61K 31/5578 20130101; C07D 215/20 20130101;
A61P 3/10 20180101; A61K 31/5585 20130101; A61K 31/519 20130101;
A61K 31/472 20130101; A61K 38/28 20130101; A61K 2300/00 20130101;
A61K 31/5578 20130101; A61K 2300/00 20130101; A61K 31/472 20130101;
A61K 2300/00 20130101; A61K 31/137 20130101; A61K 2300/00 20130101;
A61K 31/519 20130101; A61K 2300/00 20130101; A61K 31/5585 20130101;
A61K 2300/00 20130101; A61K 31/557 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/5578 20060101
A61K031/5578; A61P 3/10 20060101 A61P003/10; A61K 9/00 20060101
A61K009/00; A61K 38/28 20060101 A61K038/28; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method for treating diabetes comprising simultaneously
administering subcutaneously to the same site in a subject in need
thereof, a therapeutically effective amount of one or more insulins
and a subcutaneously effective amount of one or more vasoactive
agents.
2. The method of claim 1, wherein said insulin is transformed
insulin.
3. The method of claim 2, wherein said insulin is a short-acting
insulin analogues (SAIA).
4. The method of claim 1, wherein said insulin is insulin lispro,
insulin glulisine or insulin aspart.
5. The method of claim 1, wherein said vasoactive agent is a
prostacyclin IP.sub.1 receptor agonist, a purinergic class 2
receptor agonist, a tachykinin receptor agonist, a histaminergic
class 2 receptor agonist, a kinin B.sub.2 receptor agonist, a
potassium channel opener, or a combination thereof; or a
combination of a nitrogen oxide donor and inhibitors of cyclic
guanosine monophosphate phosphodiesterases; or an analog of cAMP or
cGMP.
6. The method of claim 5, wherein said vasoactive agent is
prostacyclin IP.sub.1 receptor agonist.
7. The method of claim 1, wherein said subject is a human Type 2
diabetes (T2D) patient.
8. The method of claim 1, wherein said subject is an obese human
Type 2 diabetes (T2D) patient.
9. The method of claim 1 further comprising administering a
therapeutically effective amount of at least one or more
therapeutic that is a sulfonylurea, a meglitinide, a biguanide, a
thiazolidinedione, a dipeptidyl peptidase-4 inhibitor, a
glucagon-like peptide analog, a gastric inhibitory peptide analog,
an inhibitor of renal sodium-dependent glucose cotransporters, or a
combination thereof.
10. A pharmaceutical composition comprising a therapeutically
effective amount of one or more insulin(s) and a subcutaneously
effective amount of one or more vasoactive agents.
11. The composition of claim 10, wherein said insulin is
transformed insulin.
12. The composition of claim 11, wherein said insulin is a
short-acting insulin analogues (SAIA).
13. The composition of claim 10, wherein said insulin is insulin
lispro, insulin glulisine or insulin aspart.
14. The composition of claim 10, wherein said vasoactive agent is a
prostacyclin IP.sub.1 receptor agonist, a purinergic class 2
receptor agonist, a tachykinin receptor agonist, a histaminergic
class 2 receptor agonist, a kinin B.sub.2 receptor agonist, a
potassium channel opener, or a combination thereof; or a
combination of a nitrogen oxide donor and inhibitors of cyclic
guanosine monophosphate phosphodiesterases; or an analog of cAMP or
cGMP.
15. The composition of claim 14 wherein said vasoactive agent is
prostacyclin IP.sub.1 receptor agonist.
16.-26. (canceled)
27. A method for the treatment or prevention of hyperglycemia
comprising simultaneously administering subcutaneously to the same
site in a subject in need thereof, a therapeutically effective
amount of one or more insulins and a subcutaneously effective
amount of one or more vasoactive agents.
Description
FIELD OF THE DISCLOSURE
[0001] The present disclosure relates to novel compositions,
combinations and methods for increasing subcutaneous insulin
absorption and/or treating diabetes and/or treating or preventing
hyperglycemia in a patient in need thereof.
BACKGROUND OF THE DISCLOSURE
[0002] Diabetes is a chronic metabolic disease that is
characterised by high glucose levels in the blood (hyperglycemia).
Depending on the type of diabetes, the organism does not produce
insulin (type 1) and/or has difficulty reacting to its signal (type
2). Insulin is a hormone produced by beta pancreatic cells and its
secretion is mainly stimulated by an increase of glucose in the
blood, but also by free fatty acids, amino acids, incretins, and
other factors. Insulin controls hyperglycemia by stimulating the
capting of glucose by the tissues. In other words, insulin
activates energy storage and simultaneously inhibits the release of
energy reserves.
[0003] Among the diabetic population, 10% of patients are of type 1
(T1D) and 90% are of type 2 (T2D).
[0004] Short-acting insulin analogues (SAIA) are widely used
nowadays. Originally, they were designed to synchronize plasma
insulin increase and food absorption. SAIA are indeed absorbed more
quickly than regular human insulin (RHI). Insulin's physicochemical
properties explain differences in absorption between RHI and SAIA.
SAIA are insulins with a reduced tendency to self-associate,
providing faster absorption, lesser within- and between-subjects
variability and better reproducibility. Accordingly, rises in
plasma and expected hypoglycemic responses are more rapid. Of note
these studies were conducted in normal weight healthy subjects or
in subjects with T1D; accordingly, only small dosages of insulin
were assessed.
[0005] Therefore, in patients with T2D, SAIA therapy is essentially
based on the pharmacokinetic (PK) and pharmacodynamic (PD) data of
the above small-dosage studies conducted in subjects with T1D,
normal weight or moderately obese subjects. The paradox is that 75%
of all insulin users are, in fact, obese insulin-resistant patients
with T2D who inject insulin or mixed insulin one to four times
daily at much larger dosages (30, 60, 90 units (U) and more).
[0006] Although improvements were noted in T1D subjects, no
consistent and constant improvement in glycemic control was ever
observed in T2D subjects using SAIA instead of RHI. Consequently,
there is still a need to improve the therapy of diabetic patients,
especially with the goal of reducing the risk of heart attacks and
other cardiovascular diseases, kidney failure, lower limb
amputation and blindness.
SUMMARY
[0007] In an aspect of the disclosure, there is provided a method
for treating diabetes comprising simultaneously administering
subcutaneously to the same exact location/site in a subject in need
thereof, a therapeutically effective amount of one or more insulins
and a subcutaneously effective amount of one or more vasoactive
agents.
[0008] In another aspect of the disclosure, there is provided a
pharmaceutical composition comprising a therapeutically effective
amount of one or more insulins and a subcutaneously effective
amount of one or more vasoactive agents.
[0009] In another aspect of the disclosure, there is provided a
combination comprising a therapeutically effective amount of one or
more insulins and a subcutaneously effective amount of one or more
vasoactive agents.
[0010] In another aspect of the disclosure, there is provided a
method for increasing subcutaneous insulin absorption in a subject
in need thereof comprising simultaneously administering
subcutaneously to the same site in a subject a subcutaneously
effective amount of one or more vasoactive agents and said
insulin.
[0011] In an aspect of the disclosure, there is provided a method
for delaying or preventing the progression of T2D or conditions
related to the progression of T2D comprising simultaneously
administering subcutaneously to the same site in a subject in need
thereof, a therapeutically effective amount of one or more insulins
and a subcutaneously effective amount of one or more vasoactive
agents.
[0012] In an aspect of the disclosure, there is provided a method
for the treatment or prevention of hyperglycemia comprising
simultaneously administering subcutaneously to the same site in a
subject in need thereof, a therapeutically effective amount of one
or more insulins and a subcutaneously effective amount of one or
more vasoactive agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIGS. 1 and 2 represent the area under the curve observed
for subcutaneous adipose tissue blood flow (ATBF) in obese subjects
with T2D (ODT2) following the subcutaneous administration of
iloprost, papaverine, isoproterenol and sildenafil;
[0014] FIG. 3 represents the ATBF in control subjects (circles) and
in OT2D subjects (squares) after subcutaneous iloprost
administration;
[0015] FIG. 4 represents the ATBF in control subjects and OT2D
subjects after subcutaneous iloprost administration;
[0016] FIG. 5 represents the mean plasmatic lispro concentrations
over the 8-hour euglycemic clamp following its administration in
OT2D subjects;
[0017] FIG. 6 represents the mean plasmatic lispro concentrations
over the first 2-hour of the 8-hour euglycemic clamp following its
administration in OT2D subjects;
[0018] FIG. 7 represents fractional AUCs of plasmatic lispro
concentrations at the early absorption phase (10 to 40 min) of the
8-hour euglycemic clamp following its administration in OT2D
subjects;
[0019] FIG. 8 represents the glucose infusion rate over the first
2-hour of the 8-hour euglycemic clamp following lispro
administration in OT2D subjects; and
[0020] FIG. 9 represents the total glucose infusion at the early
action phase (30 to 60 min) of the 8-hour euglycemic clamp
following lispro administration in OT2D subjects.
DESCRIPTION OF THE EMBODIMENTS
[0021] In accordance with one embodiment, there is provided a
method for treating diabetes comprising simultaneously
administering subcutaneously to the same site in a subject in need
thereof, a therapeutically effective amount of an insulin and a
subcutaneously effective amount of one or more vasoactive
agents.
[0022] In accordance with one embodiment, there is provided a
method for treating diabetes comprising simultaneously
administering subcutaneously to the same site in a subject in need
thereof, a therapeutically effective amount of an insulin and a
subcutaneously effective amount of a vasoactive agent.
[0023] In another embodiment of the disclosure, there is provided a
pharmaceutical composition comprising a therapeutically effective
amount of an insulin and an effective amount of one or more
vasoactive agents.
[0024] In another embodiment of the disclosure, there is provided a
pharmaceutical composition comprising a therapeutically effective
amount of an insulin and a subcutaneously effective amount of a
vasoactive agent.
[0025] In another embodiment of the disclosure, there is provided a
combination comprising a therapeutically effective amount of an
insulin and a subcutaneously effective amount of one or more
vasoactive agents.
[0026] In another embodiment of the disclosure, there is provided a
combination comprising a therapeutically effective amount of an
insulin and a subcutaneously effective amount of a vasoactive
agent.
[0027] In another embodiment of the disclosure, there is provided a
method for increasing subcutaneous insulin absorption in a subject
in need thereof comprising simultaneously administering
subcutaneously to the same site in a subject a subcutaneously
effective amount of a vasoactive agent and said insulin.
[0028] In an embodiment of the disclosure, there is provided a
method for delaying or preventing the progression of T2D or
conditions related to the progression of T2D comprising
simultaneously administering to a subject in need thereof, a
therapeutically effective amount of an insulin and a subcutaneously
effective amount of a vasoactive agent.
[0029] In an embodiment of the disclosure, there is provided a
method for the treatment or prevention of hyperglycemia comprising
simultaneously administering to a subject in need thereof, a
therapeutically effective amount of an insulin and a subcutaneously
effective amount of a vasoactive agent.
[0030] As used herein "simultaneous" or "simultaneously" refers to
the administration of one or more vasoactive agents and one or more
insulins substantially at the same time. What is understood by
administration substantially at the same time is that the
vasoactive agent(s) must be administered sufficiently close in time
with regard to the insulin, to allow sufficient exposure time of
the insulin to the local increase of subcutaneous ATBF caused by
the vasoactive agents. Preferably, the administration of one or
more vasoactive agents and one or more insulins is at the same
time.
[0031] What is understood by administration "to the same site", is
that the vasoactive agent(s) must be administered in a vicinity
sufficiently close to the insulin injection site to allow an
exposure of the insulin to the local increase of subcutaneous ATBF
caused by the vasoactive agent(s).
[0032] In one embodiment, the vasoactive agent(s) and insulin(s)
are administered as a pharmaceutical composition comprising the
vasoactive agent(s) and insulin(s) (i.e. in a combined dosage
form).
[0033] In one embodiment, the vasoactive agent(s) and insulin(s)
are used in combination (i.e. as separate or combined formulations)
and administered simultaneously. The separate formulations may be
administered by separate administration devices (such as syringes
and subcutaneous needles) or any device allowing the delivery of
the two formulations to the same site.
[0034] In one embodiment, the one or more vasoactive agent(s) is
used in combination with regular mammalian insulin(s) or any
transformed (genetically or by any other means) insulin such as
currently available SAIA (e.g., insulin lispro (Humalog.RTM.),
insulin glulisine (Apidra.RTM.), insulin aspart (Novolog.RTM.)),
and whichever the composition of excipients or dilution liquid.
[0035] In one embodiment of the methods, composition or combination
described herein, said insulin is transformed insulin, preferably a
short-acting insulin analogues (SAIA) such as is insulin lispro,
insulin glulisine or insulin aspart. In one embodiment, the said
insulin is insulin lispro.
[0036] As defined herein "patient" refers to both human and
non-human subjects (e.g., dog, cat, horse, other). The subject is
preferably human.
[0037] Diabetes can be divided into two broad types of diseases:
T1D and T2D. T1D is caused by beta-cell destruction, usually
leading to insulin deficiency. T2D (historically called
non-insulin-dependent diabetes) may range from predominantly
insulin resistance with relative insulin deficiency to a
predominantly secretory defect with insulin resistance, leading to
insulin therapy.
[0038] In one embodiment, the patient is a human T1D patient, said
patient being underweight, normal weight, overweight, or obese.
[0039] In one embodiment, the patient is a human T2D patient,
underweight, normal weight, overweight, or obese.
[0040] In a further embodiment, the patient is an obese human T2D
patient.
[0041] Still in a further embodiment, the patient is uncontrolled
T2D patient.
[0042] As used herein, "underweight" refers to an adult patient
having a body mass index (BMI)<18.50 kg/m.sup.2 or a child
having a weight under the 5.sup.th percentile, "normal weight"
refers to an adult patient having a BMI between 18.50 and 24.99
kg/m.sup.2 or a child having a weight at the 5.sup.th percentile to
less than the 85.sup.th percentile, "overweight" refers to an adult
patient having a BMI between 25.00 and 29.99 kg/m.sup.2 or a child
having a weight at the 85.sup.th percentile to less than the
95.sup.th percentile, and "obese" refers to an adult patient having
a BMI.gtoreq.30.00 kg/m.sup.2 or a child having a weight at the
95.sup.th percentile or greater.
[0043] As used herein "uncontrolled diabetes" refers to patient
characterized by elevated levels of A.sub.1c (also referred to as
hemoglobin A.sub.1c, or HbA.sub.1c).
[0044] According to the 2015 American Diabetes Association
recommendations, "a reasonable A.sub.1c goal for many non-pregnant
adults is <7%. Providers might reasonably suggest more stringent
A.sub.1c goals, such as <6.5%, for selected individual patients
if this can be achieved without significant hypoglycemia or other
adverse effects of treatment. Less stringent A.sub.1c goals, such
as <8%, may be appropriate for patients with a history of severe
hypoglycemia, limited life expectancy, advanced micro- or
macrovascular complications, or long-standing diabetes in whom the
general goal is difficult to attain" (Diabetes Care 2015; 38
Suppl:S33-S40). "If the A.sub.1c target is not achieved after
approximately 3 months, the diabetes is considered uncontrolled
with the actual therapy. In the case of patients with T1D, insulin
doses will be adjusted. In regard of patients with T2D, it is
suggested to the attending physician to apply the next step of the
antihyperglycemic therapy recommendations. After the attempt of
controlling diabetes by an intervention on patient's lifestyle
(i.e. healthy eating, increased physical activity, weight control,
etc.), recommended therapies are as following: monotherapy, dual
therapy, triple therapy, and combination injectable therapy"
(Diabetes Care 2015; 38 Suppl:S41-S48). "All therapies involve oral
antihyperglycemic agents and only the last one requires mealtime
insulin therapy. However, in patients with newly diagnosed T2D and
markedly symptomatic and/or elevated blood glucose levels or
A.sub.1c, initiating insulin therapy is recommended. More
precisely, starting combination insulin therapy is to consider when
A.sub.1c is .gtoreq.10-12%" (Diabetes Care 2015; 38
Suppl:S41-S48).
[0045] As used herein, progression of T2D can be seen as the
increase in glycated hemoglobin (A1c) or development or worsening
of complications recognized as related to diabetes for example
retinopathy, nephropathy, neuropathy, cardiovascular diseases but
many other could be listed).
[0046] The term "Short Acting Insulin Analogue" or "SAIA" is
understood to mean a polypeptide derived from the naturally
occurring insulin, such as human insulin. The analog is typically
obtained by addition and/or deletion and/or substitution and/or
inversion of one or more amino acids of the naturally occurring
insulin (Hirsch I B. N Engl J Med 2005; 352(2):174-83). SAIA are
also sometimes referred to as "Rapid Acting Insulin Analog". The
expressions can be used interchangeably herein.
[0047] In the present disclosure, it is contemplated that
vasoactive agents for use herein should be appropriate to cause a
local increase of blood flow in subcutaneous adipose tissue (ATBF),
it would be desirable that the vasoactive agents: 1) is operative
in diabetic patients 2) provide a sufficient stability into the
subcutaneous adipose tissue in the patient and/or 3) be compatible
(i.e. not detrimental) for use in patients.
[0048] ATBF was assessed using the .sup.133Xe washout technique,
the gold standard technique, as described below in Examples
(Experimental protocol for Assessment of ATBF) and also in (Karpe
F, et al. J Physiol 2002; 540(Pt 3):1087-93; Martin E, et al. Can J
Physiol Pharmacol 2011; 89(6):383-91; Sotornik R, et al. Methods
Enzymol. 2014; 537:227-42). In one embodiment, the vasoactive
agents for use herein cause a local increase of ATBF that is
sufficient to be detected using the .sup.133Xe washout technique or
by any other accurate methods.
[0049] An example of a suitable class of vasoactive agent includes
prostacyclin IP.sub.1 receptor agonists such as iloprost
(Ilomedine.RTM., Ventavis.RTM.), epoprostenol (Flolan.RTM. and
Veletri.RTM.) or treprostinil (Remodulin.RTM. & Tyvaso.RTM.).
The IP.sub.1 receptors are known to mediate endothelium-independent
dilatation of vessels, increasing blood flow in the area (Duthois
S, et al. Diabetes Metab 2003; 29(1):36-43). Other suitable classes
of very powerful vasoactive agents and agonists of protein
G-coupled receptors are: purinergic class 2 receptor agonists such
as regadenoson (Lexiscan.RTM.), which is an adenosine A.sub.2A
receptor agonist (Ghimire G, et al. J Nucl. Cardiol. 2013;
20(2):284-8); tachykinin receptor agonists such as Homspera.RTM.,
which is a substance P NK.sub.1 receptor agonist (Pedersen K E, et
al. J Pharmacol Exp. Ther 2000; 292(1):319-25); histaminergic class
2 receptor agonists such as betazole, which is an histamine H.sub.2
receptor agonist (Sandilands E A, et al. Br. J Clin Pharmacol 2013;
76(5):699-707); and kinin B.sub.2 receptor agonist such as
labradimil, which is a bradykinin B.sub.2 receptor agonist (Emerich
D F, et al. Clin Pharmacokinet. 2001; 40(2):105-23). Another
suitable class of vasoactive agents is the potassium channel
openers, like minoxidil, nicorandil and maxipost (Sandhiya S, Dkhar
S A. Indian J Med Res 2009; 129(3):223-32).
[0050] Another efficient way to increase ATBF is to use two
complementary classes of vasoactive agents such as nitrogen oxide
donors class (e.g., nitroglycerin, nitroprusside, etc.) coupled to
the inhibitors of cyclic guanosine monophosphate phosphodiesterases
(ex: sildenafil, tadalafil, papaverine, etc.) The first vasoactive
agent class increases the production of cyclic guanosine
monophosphate and the second class decreases its degradation (Lin C
S, et al. Curr Pharm. Des 2006; 12(27):3439-57; Vanhoutte P M.
Arterioscler. Thromb. Vasc. Biol. 2009; 29(8):1156-60).
[0051] An additional way to increase ATBF is to use cell-permeable,
non-hydrolysable analogs of cAMP (e.g., db-cAMP, 8-bromo-cAMP,
Sp-5,6-DCI-cBiMPS) and cGMP (e.g., 8-p-CPT-cGMP, 8-bromo-cGMP).
[0052] In any embodiment of the methods, composition or combination
described herein, said vasoactive agent is prostacyclin IP.sub.1
receptor agonist, such as iloprost, epoprostenol or treprostinil;
especially iloprost.
[0053] Vasoactive agents for use herein are used at dosages
typically substantially lower than typical doses approved by health
and medical authorities. Such dosages can be used in the present
method because the vasoactive agent locally provides an immediate
action where insulin is administered. At body scale the dose
injected is minimal (about 9 to 140 times inferior with regard to
i.v. doses) although at local site, this dose is pharmacologically
active. It is believed that the use of lower doses may offer
advantages such as reducing side effects normally encountered by
effective systemic doses. It is also believed that subcutaneous
administration reduces the bioavailability of the agents compared
to the doses delivered by i.v. bolus. An example of a suitable dose
of vasoactive agent (IP.sub.1 receptor agonists) such as iloprost
is provided in Table 1.
TABLE-US-00001 TABLE 1 Comparison of typical i.v. doses of iloprost
and maximum subcutaneous doses used in this description.
Recommended Recommended iv Our Vasoactive intravenous (iv) dose in
a standard subcutaneous iv/sc agent doses 70-kg patient (sc) dose
ratio iloprost 0.72 .mu.g/kg 50.4 .mu.g or 140 nmol 1 nmol 140
IP.sub.1 receptor (over 6 hrs) (over 6 hrs) (bolus) agonist
[0054] In another embodiment, the dosage form of the disclosure can
be adjusted by varying the amount and types of vasoactive agents
for a greater effect in increasing local blood flow.
[0055] The excipient(s) for use in pharmaceutical compositions in
accordance with the disclosure must be "pharmaceutically
acceptable" in the sense of being compatible with the other
ingredients of the formulation and not being deleterious to the
recipient thereof. The pharmaceutical composition, or for instance
each component of the combination, in particular the composition
comprising insulin, may optionally comprise excipients such as
preservatives, chelating agents, tonicity modifiers, bulking
agents, stabilizers, antioxidants, polymers and surfactants, metal
ions, oleaginous vehicles and proteins (e.g., human serum albumin,
gelatine or proteins).
[0056] Examples of buffer include sodium acetate, sodium carbonate,
citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate,
sodium phosphate, and tris(hydroxymethyl)-aminomethan, bicine,
tricine, malic acid, succinate, maleic acid, fumaric acid, tartaric
acid, aspartic acid or mixtures thereof.
[0057] Examples of preservative in the composition comprising
insulin include those of conventional insulin compositions, such as
phenol, m-cresol, methylparaben, and zinc or other ions.
[0058] In one embodiment, the present disclosure further comprises,
in the methods, compositions and combinations described herein, a
therapeutically effective amount of at least one or more useful
therapeutic agents. Examples of such agents include sulfonylureas,
meglitinides, biguanides, thiazolidinediones, dipeptidyl
peptidase-4 inhibitors, glucagon-like peptide analogs, gastric
inhibitory peptide analogs, and inhibitor of renal sodium-dependent
glucose cotransporters.
[0059] It will be clear to a person of ordinary skill that if a
further additional therapeutic agent is required or desired, ratios
will be readily adjusted. It will be understood that the scope of
combinations described herein is not particularly limited, but
includes in principle any therapeutic agent useful for the
prevention and treatment of diseases and conditions related to
diabetes described herein.
[0060] Pharmaceutical compositions and combinations suitable for
use herein may be presented as a solution, a suspension or as an
emulsion. The compositions and combinations may be presented in
unit dose form in ampoules, bottles, vials, pre-filled syringes,
multi-needles, microneedles, etc. and any other tool for
subcutaneous injection. Further description of methods suitable for
use in preparing pharmaceutical compositions and combinations of
the present disclosure and of ingredients suitable for use in said
compositions and combinations is provided in Remington's
Pharmaceutical Sciences, 18(th) edition, edited by A. R. Gennaro,
Mack Publishing Co., 1990. The subcutaneous administration of the
vasoactive agent and said insulin can be done by means of a
syringe, including a pen-like syringe, an infusion pump or
transdermal administration (such as by needle-free injection,
microneedles, and/or from a patch).
[0061] In any embodiment of the methods, composition or combination
herein described, said vasoactive agent(s) and insulin(s) are in a
combined dosage form.
[0062] In any embodiment of the methods, composition or combination
the subcutaneous administration of the vasoactive agent and said
insulin is by means of a syringe, an infusion pump or by
transdermal administration.
[0063] In an embodiment, said composition and combination defined
herein are for use in any method defined herein, in particular the
treatment of diabetes in a subject in need thereof.
Examples
Patient Recruitment and Inclusion
[0064] The OT2D subjects were recruited among CHUS
endocrinologists' patients. Healthy subjects were recruited via
media. All of the recruited subjects arrived in the morning with an
empty stomach (visit 0) to record medical history, to carry out
blood and urine samples, to measure the height, the weight, the
waist and the body composition (bioelectric impedance, TANITA
Corp., United States).
[0065] The inclusion criteria for subjects with T2D were: males and
females, 18 to 75 years of age, BMI.gtoreq.30 kg/m.sup.2, under
insulin, A.sub.1c<10%, non-smoker and <2 alcoholic
consumptions/day. We excluded: subjects under the analogue of
glucagon-like peptide 1, under dipeptidyl peptidase-4 inhibitor,
with hepatic or renal function anomalies (glomerular filtration
rate--GFR<50 ml/min), with an unstable thyroid function or
abnormal blood and/or urinary tests. Since we were recruiting T2D
subjects, the fasting blood glucose, A.sub.1c and the lipid profile
could be abnormal.
[0066] The recruitment criteria for the control healthy normal
weight subjects were: males and females, 18 to 75 years of age,
BMI>18.5 and <25 kg/m.sup.2, non-smoker and <2 alcoholic
consumptions/day. We excluded: subjects who did intense physical
activity on a regular basis, those with abnormal hepatic, cardiac
and renal functions, those with an unstable thyroid or abnormal
urinary/blood tests, those with a history of gestational diabetes
or a family history of T2D to the first degree.
Statistical Analysis of Patient Clinical Profiles
[0067] OT2D subjects were different from normal weight subjects for
all parameters, except for gender (Table 2). ODT2 subjects were
representative of patients with T2D commonly treated by physicians
and endocrinologists: obese, over 60 year's old, taking insulin,
taking medications (which explains their low mean LDL level), and
with an A.sub.1c value over the recommended target of 7%.
TABLE-US-00002 TABLE 2 Characteristics of subjects involved in our
experiments. Characteristics Units Normal Weight OT2D Gender M/F
4/2 12/4 Age yrs 51.5 .+-. 14.1 63.6 .+-. 9.9* Weight kg 60.3 .+-.
7.3 115.2 .+-. 23.14*** BMI kg/m.sup.2 22.0 .+-. 1.8 40.6 .+-.
7.2*** Fat mass % 19.4 .+-. 5.3 42.1 .+-. 10.7*** Waist
circumference cm 76.8 .+-. 8.2 127.9 .+-. 13.2*** A.sub.1c % 5.6
.+-. 0.4 7.9 .+-. 1.2*** HDL mmol/l 1.62 .+-. 0.29 0.97 .+-.
0.26*** LDL mmol/l 2.69 .+-. 0.72 1.59 .+-. 0.56* Triglycerides
mmol/l 0.94 .+-. 0.45 1.91 .+-. 1.26* Insulin U/day -- 131 .+-. 76
T2D duration yrs -- 18.7 .+-. 3.8 Means .+-. SD; *compared to
Normal Weight subjects; *p < 0.05; ***p < 0.001; exact Fisher
test and Mann-Whitney test.
Pre-Dosing Instructions to Patients
[0068] A 2-day menu was chosen based on the basal metabolic rate
given by the bioelectric impedance device and the physical activity
habits of the subjects. All of the subjects were given instructions
to follow this menu, to not consume alcohol or coffee and to do
vigorous exercise during the 48 hours prior to an experimental
visit. The volunteers also could not modify their lifestyle between
visits of the research project.
Experimental Protocol for Assessment of ATBF
[0069] Each volunteer participated in experimental visits at a
2-month interval (radioprotection rules). The technique used was
the .sup.133Xe wash-out technique coupled with a micro-injection of
a vasoactive agent or vehicle (saline solution) dose (Martin, E. et
al. Can J Physiol Pharmacol 2011; 89(6):383-91; Sotornik, R. et al.
Methods Enzymol. 2014; 537:227-42). During an experiment, four
measurement sites of ATBF were evaluated simultaneously on the
abdomen: two over and two under the navel, to the left and to the
right of the navel. Therefore, a site above and a site below can
both receive a vasoactive agent dose and both contralateral sites
of the saline solution. Each subject is therefore his own
control.
[0070] The morning of an experiment, the subjects arrived fasting
with their dietary report. The weight and body composition were
measured once again. The rest of the experiment was conducted in a
lying position. Four subcutaneous micro-catheters (Quick-Set
infusion set, Medtronic Canada Ltee.) were inserted in the abdomen
at each of the 4 measurement sites of ATBF. The micro-cateters were
6 mm for the normal weight subjects and 9 mm for the OT2D subjects.
They allowed the injection of a radioactive tracer (.sup.133Xe) and
the vasoactive agent at the same exact location as well as limit
the subcutaneous tissue lesions. Their insertion is practically
painless. Thereafter, 1 to 2 MBq of .sup.133Xe (Lantheus Medical
Imaging, Canada) dissolved in a saline solution to 4.degree. C. was
injected at each of the measurement sites. Sixty min were allotted
to the equilibration of the .sup.133Xe in the tissue in order to
obtain stable readings. The recording of the data was done with the
help of probes detecting the gamma radiations (gamma-counter probe
CsI(T1) scintillator detector, John Caunt Scientific Ltd, Oxford,
UK).
[0071] An ATBF value is obtained at each 10 min block of reading.
The disappearance of .sup.133Xe is reflected in the decrease in
quantity of the gamma emissions which is cumulated every 20 sec.
The negative slope of the time every 10 min is therefore converted
to an ATBF value (ml/100 g tissuemin) (see Karpe, F. et al. J
Physiol 2002; 540(Pt 3):1087-93; Martin, E. et al. Can J Physiol
Pharmacol 2011; 89(6): 383-91; Sotornik, R. et al. Methods Enzymol.
2014; 537:227-42).
Assessment of ATBF Following Administration of Iloprost,
Papaverine, Isoproterenol and Sildenafil
[0072] Six normal weight subjects and 17 OT2D subjects participated
in these experiments. In order to measure the reactivity of ATBF,
we administered 3 doses (increasing concentrations) to a same
experimental site. Each experiment began with a 60 min reading of
ATBF while fasting and without stimulation to calculate the base of
the ATBF (ATBF.sub.b). Then, a dose of vasoactive agent or saline
(100 .mu.l) was injected (bolus) and the ATBF was recorded for 40
min. This volume (100 .mu.l) corresponds to the one of 10 U of
insulin. This procedure was repeated for each of the administered
doses; about 5 min was necessary for manipulations between the
three recording phases. In order to measure the ATBF reactivity
duration, OT2D subjects participated to experiments in which one
vasoactive agent dose or saline was injected as a volume of 300
.mu.l (corresponding to the volume of 30 U of insulin) and the ATBF
was recorded for 120 min.
[0073] FIG. 1 represents the ATBF from 0-40 min in OT2D subjects
(n=8 or 9) observed following the subcutaneous administration of
iloprost, papaverine, isoproterenol or sildenafil. Each result (n)
corresponds to the incremental area under the curve (iAUC) of the
40-min post-injection ATBF monitoring period for the more effective
dose of each vasoactive agent in 100 .mu.l: iloprost 1 nmol,
papaverine 8.65 .mu.mol, isoproterenol 10 nmol, and sildenafil 100
nmol. Means.+-.standard deviations (SD); * compared to iloprost; *
p<0.05; ** p<0.01; Kruskal-Wallis test followed by Dunn's
multiple comparisons, p value adjusted for 6 comparisons.
[0074] FIG. 2 represents the ATBF from 0-120 min of OT2D subjects
(n=7 to 9) observed following the subcutaneous administration of
iloprost, papaverine, isoproterenol or sildenafil. Each result (n)
corresponds to the incremental area under the curve (iAUC) of the
120-min post-injection ATBF monitoring period for the more
effective dose of each vasoactive agent in 300 .mu.l: iloprost 1
nmol, papaverine 8.65 .mu.mol, isoproterenol 10 nmol, and
sildenafil 100 nmol. Means.+-.SD; * compared to iloprost; *
p<0.05; *** p<0.001; Kruskal-Wallis test followed by Dunn's
multiple comparisons, p value adjusted for 6 comparisons.
[0075] FIG. 3 represents the ATBF in control normal weight subjects
(circles) and OT2D subjects (squares) after subcutaneous iloprost
administration. The baseline corresponds to the 1-hour monitoring
mean of fasting ATBF. The ATBF under stimulation is express as the
mean of the 3 higher values. Three incremental doses of iloprost
have been applied (0.01, 0.1 and 1 nmol) and the effects on ATBF
were monitored over 40-min periods. Group's means are indicated in
boxes and fold increase factors of stimulated ATBF are compared to
unstimulated ATBF.
[0076] FIG. 4 represents the ATBF in OT2D subjects (n=9) at two
120-min recording sites: after subcutaneous administration of 1
nmol of iloprost (white squares) or of saline (black squares). The
baseline corresponds to the 1-hour monitoring mean of fasting ATBF.
The black arrow corresponds to the injection time (t=0).
Means.+-.SD; * compared to saline; * p<0.05; ** p<0.01; ***
p<0.001; Friedman test followed by Dunn's multiple comparisons,
p value adjusted for 13 comparisons.
Statistical Method and Analysis
[0077] The ATBF.sub.b represents the average of the 3 last values
(before 0) out of the 6 obtained during the one-hour basal
measurement because they are the most stable. For the dose-response
study, the response of ATBF to a vasoactive agent (ATBF.sub.max)
represented the average of the last 3 consecutive highest points
out of the 4 values obtained. The multiplication factor of a
vasoactive agent corresponds to the ratio
ATBF.sub.max/ATBF.sub.b.
[0078] The AUC were calculated by the trapezoidal method: the iAUC
(incremental USC) of the response to a vasoactive agent was
calculated from the values of ATBF minus the ATBF.sub.b for the
dose-response test (iAUC.sub.0-40 min) or the tests of 120 min
(iAUC.sub.0-120 min).
[0079] All of the data is expressed in means.+-.SD. The
significance of the nominal variables were calculated with the
Fisher's Exact Test. The significance of continuous dependant
variables was calculated with the Friedman test followed by Dunn's
multiple comparisons, with values ofp adjusted for the number of
comparisons. The significance of the continuous independent
variables was calculated with the Kruskal-Wallis test followed by
Dunn's multiple comparisons test, with values of p adjusted for the
number of comparisons (GraphPad Prism.RTM., version 6.02). A value
of p<0.05 is considered to be significant.
Experimental Protocol for Assessment of SAIA Absorption
[0080] Euglycemic Clamp.
[0081] .circle-solid. Subjects were admitted to the Sherbrooke
University Hospital Clinical Research Center (CRC) at 8 PM the
evening prior to each study. An i.v. antecubital cannula was
installed to allow venous sampling for immediate whole blood
glucose level measurements by a glucose analyzer (FreeStlyle Lite
Glucometer, Abbott Diabetes Care Inc.) at 30-min intervals until
glycemic target is reached and at 2-hour intervals thereafter. A
second contralateral cannula was installed for continuous i.v.
administration of regular insulin and glucose, as needed, and
plasma glucose has been brought progressively into the normal
target range of 5-7 mmol/L overnight and then kept at this level.
.circle-solid. Experiments started around 8 AM. Patients have been
kept fasting (drinking water permitted) during the entire 8-hour
clamp study. Another venous catheter was inserted in the hand of
sampling limb for arterialized blood sampling, the hand kept warm
in a heating pad. After two baseline measurements, 20 min after
stopping the overnight regular i.v. insulin infusion (for
disappearance of regular insulin from blood), a euglycemic clamp
(glucose clamped within a 0.5 mmol/L interval, comprised between
5.0 to 6.5 mmol/L) was performed following sc injection of 10 or 30
U of lispro.+-.iloprost. .circle-solid. Plasma glucose levels were
monitored every 5 min for the first 4 hours and at 10-min intervals
thereafter. Glucose infusion rates have then been adjusted
accordingly. Blood samples (2 ml) for specific determination of
lispro were collected at 10-min intervals for the first 3 hours,
and at 20-min intervals thereafter, in tubes containing
sodium-citrate and a cocktail of protease inhibitors. Samples were
then immediately centrifuged, frozen in liquid nitrogen and stored
at -80.degree. C. until assayed. .circle-solid. Study procedures
ended around 4 PM. Subjects received a meal and self-injected a
personalised insulin dose as prescribed by the endocrinologist.
Subjects were allowed to leave when glucose levels were stabilised
over 6 mmol/L. .circle-solid. Plasma lispro was measured by an
ultra-specific radioimmunoassay (Linco Research Inc.) Detection
limit is 18 pmol/L, intra-assay CV is 2.5% in our hands
(Gagnon-Auger M, et al. Diabetes Care 2010; 33(12):2502-7).
Effects of Adding a Vasoactive Agent on the Absorption of SAIA
[0082] OT2D subjects participated to these experiments in which 10
and 30 U of lispro f iloprost were tested. PK profiles were
obtained from blood samples collected during the 8-hour euglycemic
clamp PD profiles are the glucose infusion rates needed to maintain
plasma glucose levels stable and correspond to the hypoglycemic
effect of insulin.
[0083] FIG. 5 represents the mean plasmatic lispro concentrations
over the 8-hour euglycemic clamp following its administration in
OT2D subjects with a A.sub.1c>8%. The SAIA lispro was
subcutaneously injected (t=0), at doses of 10 U (n=4) or 30 U (n=3)
and with or without 1 nmol of iloprost. Means.+-.SD; A.sub.1c,
glycated hemoglobin; ILO, iloprost; U, insulin units.
[0084] FIG. 6 represents the 2 first hours of mean plasmatic lispro
concentrations of the 8-hour euglycemic clamp following its
administration in OT2D subjects with a A.sub.1c>8%. The SAIA
lispro was subcutaneously injected (t=0), at doses of 10 U (n=4) or
30 U (n=3) and with or without 1 nmol of iloprost. Means.+-.SD;
A.sub.1c, glycated hemoglobin; ILO, iloprost; U, insulin units.
[0085] FIG. 7 represents fractional AUCs of plasmatic lispro
concentrations at 10, 20, 30, and 40 min following its
administration in OT2D subjects with a A.sub.1c>8%. The SAIA
lispro was subcutaneously injected (t=0), at doses of 10 U (n=4) or
30 U (n=3) and with or without 1 nmol of iloprost. Means; A.sub.1c,
glycated hemoglobin; AUC, area under the curve; ILO, iloprost; U,
insulin units.
[0086] FIG. 8 represents the 2 first hours of mean glucose infusion
rate of the 8-hour euglycemic clamp following lispro administration
in OT2D subjects with a A.sub.1c>8%. The SAIA lispro was
subcutaneously injected (t=0), at doses of 10 or 30 U and with or
without 1 nmol of iloprost. Means; A.sub.1c, glycated hemoglobin;
GIR, glucose infusion rate; ILO, iloprost; U, insulin units.
[0087] FIG. 9 represents the total glucose infusion at 30, 40, 50,
and 60 min following lispro administration in OT2D subjects with a
A.sub.1c>8%. The SAIA lispro was subcutaneously injected (t=0),
at doses of 10 or 30 U and with or without 1 nmol of iloprost.
Means; A.sub.1c, glycated hemoglobin; GI, glucose infusion; ILO,
iloprost; U, insulin units.
Statistical Method and Analysis
[0088] The fractional plasmatic lispro AUCs were calculated by the
trapezoidal method. Total glucose infusion (GI) is obtained by
multiplying the glucose infusion rate (GIR) by the time (min). All
of the data is expressed in means.
[0089] To conclude, maximal plasma lispro concentrations and
maximal glucose infusion rates were both rapidely increased with
the addition of iloprost (FIGS. 5 and 8). Both lispro absorption
and hypoglycemic effect were accelerated by iloprost in regard to
fractional AUCs and early total glucose infusion (FIGS. 7 and 9).
Altogether, these data suggest that 1) the ATBF is increased
pharmacologically with specific vasoactive agents not only in
normal subjects but also in insulin resistant OT2D patients, and 2)
the simultaneous administration of a vasoactive agent (capable of
increasing ATBF at the injection site) and insulin accelerates the
subcutaneous absorption and effectiveness of the latter with no
side effects in insulin resistant OT2D patients. These findings
provide clinical proof-of-concept for the effectiveness of
combining a specific vasoactive agent to insulin (or its analogs)
in order to enhance its pharmacokinetic (absorption) and
pharmacodynamic activity (hypoglycemic action) in patients under
insulin therapy. Moreover, because of the fast onset of action of
the combination of insulin(s) with vasoactive agent(s), it may be
more effective at reducing postprandial hyperglyceamic peaks and
ensuing diabetes complications, which are of major clinical
importance.
[0090] While the disclosure has been described in connection with
specific embodiments thereof, it is understood that it is capable
of further modifications and that this application is intended to
cover any variation, use, or adaptation of the disclosure
following, in general, the principles of the disclosure and
including such departures from the present disclosure that come
within known, or customary practice within the art to which the
disclosure pertains and as may be applied to the essential features
hereinbefore set forth.
* * * * *