US20180221385A1 - A pharmaceutical preparation for improving absorption and postprandial hypoglycemic action of insulin - Google Patents

A pharmaceutical preparation for improving absorption and postprandial hypoglycemic action of insulin Download PDF

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US20180221385A1
US20180221385A1 US15/747,532 US201615747532A US2018221385A1 US 20180221385 A1 US20180221385 A1 US 20180221385A1 US 201615747532 A US201615747532 A US 201615747532A US 2018221385 A1 US2018221385 A1 US 2018221385A1
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insulin
receptor agonist
effective amount
vasoactive
subcutaneously
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Jean-luc ARDILOUZE
aude GAGNON-AUGER
Fernand Gobeil
Julie MENARD
Jean-Patrice BAILLARGEON
Pascal Brassard
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Societe de Commercialisation des Produits de la Recherche Appliquee SOCPRA
Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins

Definitions

  • 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.
  • 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.
  • T1D type 1
  • T2D type 2
  • SAIA Short-acting insulin analogues
  • RHI regular human insulin
  • 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.
  • these studies were conducted in normal weight healthy subjects or in subjects with T1D; accordingly, only small dosages of insulin were assessed.
  • 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.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • 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.
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more insulins and a subcutaneously effective amount of one or more vasoactive agents.
  • a combination comprising a therapeutically effective amount of one or more insulins and a subcutaneously effective amount of one or more vasoactive agents.
  • 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.
  • 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.
  • 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.
  • 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;
  • ATBF subcutaneous adipose tissue blood flow
  • ODT2D T2D
  • FIG. 3 represents the ATBF in control subjects (circles) and in OT2D subjects (squares) after subcutaneous iloprost administration;
  • FIG. 4 represents the ATBF in control subjects and OT2D subjects after subcutaneous iloprost administration
  • FIG. 5 represents the mean plasmatic lispro concentrations over the 8-hour euglycemic clamp following its administration in OT2D subjects;
  • 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;
  • 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;
  • FIG. 8 represents the glucose infusion rate over the first 2-hour of the 8-hour euglycemic clamp following lispro administration in OT2D subjects.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition comprising a therapeutically effective amount of an insulin and an effective amount of one or more vasoactive agents.
  • a pharmaceutical composition comprising a therapeutically effective amount of an insulin and a subcutaneously effective amount of a vasoactive agent.
  • a combination comprising a therapeutically effective amount of an insulin and a subcutaneously effective amount of one or more vasoactive agents.
  • a combination comprising a therapeutically effective amount of an insulin and a subcutaneously effective amount of a vasoactive agent.
  • 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.
  • 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.
  • 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.
  • vasoactive 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.
  • 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).
  • 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).
  • 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.
  • 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®), insulin glulisine (Apidra®), insulin aspart (Novolog®)), and whichever the composition of excipients or dilution liquid.
  • SAIA e.g., insulin lispro (Humalog®), insulin glulisine (Apidra®), insulin aspart (Novolog®)
  • said insulin is transformed insulin, preferably a short-acting insulin analogues (SAIA) such as is insulin lispro, insulin glulisine or insulin aspart.
  • SAIA short-acting insulin analogues
  • the said insulin is insulin lispro.
  • patient refers to both human and non-human subjects (e.g., dog, cat, horse, other).
  • subject is preferably human.
  • 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.
  • the patient is a human T1D patient, said patient being underweight, normal weight, overweight, or obese.
  • the patient is a human T2D patient, underweight, normal weight, overweight, or obese.
  • the patient is an obese human T2D patient.
  • the patient is uncontrolled T2D patient.
  • underweight refers to an adult patient having a body mass index (BMI) ⁇ 18.50 kg/m 2 or a child having a weight under the 5 th percentile
  • normal weight refers to an adult patient having a BMI between 18.50 and 24.99 kg/m 2 or a child having a weight at the 5 th percentile to less than the 85 th percentile
  • overweight refers to an adult patient having a BMI between 25.00 and 29.99 kg/m 2 or a child having a weight at the 85 th percentile to less than the 95 th percentile
  • “obese” refers to an adult patient having a BMI ⁇ 30.00 kg/m 2 or a child having a weight at the 95 th percentile or greater.
  • uncontrolled diabetes refers to patient characterized by elevated levels of A 1c (also referred to as hemoglobin A 1c , or HbA 1c ).
  • a 1c goal for many non-pregnant adults is ⁇ 7%. Providers might reasonably suggest more stringent A 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 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 1c target is not achieved after approximately 3 months, the diabetes is considered uncontrolled with the actual therapy.
  • 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).
  • A1c glycated hemoglobin
  • SAIA Short Acting Insulin Analogue
  • 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.
  • 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.
  • ATBF subcutaneous adipose tissue
  • the vasoactive agents for use herein cause a local increase of ATBF that is sufficient to be detected using the 133 Xe washout technique or by any other accurate methods.
  • vasoactive agent includes prostacyclin IP 1 receptor agonists such as iloprost (Ilomedine®, Ventavis®), epoprostenol (Flolan® and Veletri®) or treprostinil (Remodulin® & Tyvaso®).
  • the IP 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).
  • purinergic class 2 receptor agonists such as regadenoson (Lexiscan®), which is an adenosine A 2A receptor agonist (Ghimire G, et al. J Nucl. Cardiol. 2013; 20(2):284-8); tachykinin receptor agonists such as Homspera®, which is a substance P NK 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 2 receptor agonist (Sandilands E A, et al.
  • kinin B 2 receptor agonist such as labradimil, which is a bradykinin B 2 receptor agonist
  • kinin B 2 receptor agonist such as labradimil
  • 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).
  • 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).
  • 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).
  • cAMP e.g., db-cAMP, 8-bromo-cAMP, Sp-5,6-DCI-cBiMPS
  • cGMP e.g., 8-p-CPT-cGMP, 8-bromo-cGMP
  • said vasoactive agent is prostacyclin IP 1 receptor agonist, such as iloprost, epoprostenol or treprostinil; especially iloprost.
  • 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 1 receptor agonists) such as iloprost is provided in Table 1.
  • 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.
  • 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).
  • buffer examples 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.
  • preservative in the composition comprising insulin examples include those of conventional insulin compositions, such as phenol, m-cresol, methylparaben, and zinc or other ions.
  • 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.
  • useful therapeutic 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.
  • 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).
  • 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).
  • vasoactive agent(s) and insulin(s) are in a combined dosage form.
  • 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.
  • 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.
  • 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).
  • subjects with T2D were: males and females, 18 to 75 years of age, BMI ⁇ 30 kg/m 2 , under insulin, A 1c ⁇ 10%, non-smoker and ⁇ 2 alcoholic consumptions/day.
  • 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 2 , non-smoker and ⁇ 2 alcoholic consumptions/day.
  • ODT2D 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 1c value over the recommended target of 7%.
  • 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.
  • An ATBF value is obtained at each 10 min block of reading.
  • the disappearance of 133 Xe 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).
  • OT2D subjects participated to experiments in which one vasoactive agent dose or saline was injected as a volume of 300 ⁇ l (corresponding to the volume of 30 U of insulin) and the ATBF was recorded for 120 min.
  • 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 ⁇ l: iloprost 1 nmol, papaverine 8.65 ⁇ mol, isoproterenol 10 nmol, and sildenafil 100 nmol.
  • 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 ⁇ l: iloprost 1 nmol, papaverine 8.65 ⁇ mol, isoproterenol 10 nmol, and sildenafil 100 nmol.
  • 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.
  • the baseline corresponds to the 1-hour monitoring mean of fasting ATBF.
  • the ATBF 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.
  • ATBF max the response of ATBF to a vasoactive agent
  • the multiplication factor of a vasoactive agent corresponds to the ratio ATBF max /ATBF b .
  • 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 b for the dose-response test (iAUC 0-40 min ) or the tests of 120 min (iAUC 0-120 min ).
  • 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° C. until assayed. ⁇ 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.
  • 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).
  • 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.
  • FIG. 5 represents the mean plasmatic lispro concentrations over the 8-hour euglycemic clamp following its administration in OT2D subjects with a A 1c >8%.
  • 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 1c >8%.
  • 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 1c >8%.
  • 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 1c >8%.
  • FIG. 9 represents the total glucose infusion at 30, 40, 50, and 60 min following lispro administration in OT2D subjects with a A 1c >8%.
  • 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.

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