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  Pharmaceutical Patents  

 

Title:  Superior control of blood glucose in diabetes treatment
United States Patent: 
7,943,572
Issued: 
May 17, 2011

Inventors:
 Cheatham; Wayman Wendell (Columbia, MD), Boss; Anders Hasager (Princeton, NJ)
Assignee:
  MannKind Corporation (Valencia, CA)
Appl. No.:
 11/278,381
Filed:
 March 31, 2006


 

George Washington University's Healthcare MBA


Abstract

Methods related to the treatment of diabetes and improving the control of blood glucose levels are provided. In particular, methods are provided for effectively reducing postprandial glucose excursions while reducing the incidence of clinically significant late postprandial hypoglycemia by administered an insulin composition in a form suitable for pulmonary administration. Additionally, methods for effectively reducing post-prandial glucose excursions while reducing the incidence of clinically significant late postprandial hypoglycemia by administered an insulin composition in a form suitable for pulmonary administration along with a long-acting basal insulin.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides methods of treating diabetes and yielding superior control of blood glucose levels in patient with diabetes. The method enables reassertion of homeostatic control of postprandial glucose levels while reducing the risk of hypoglycemia by administering an inhaled insulin composition at or shortly after the beginning of a meal which mimics the insulin release kinetics of a non-diabetic individual.

In one embodiment according to the present invention, a method of reducing postprandial glucose excursions in a patient with an insulin-related disorder is provided comprising administering an insulin composition in a form suitable for pulmonary administration wherein the incidence of clinically relevant late postprandial hypoglycemia is reduced.

In another embodiment according to the present invention, the insulin composition is administered in proximity to beginning a meal. In one embodiment the insulin composition is administered from approximately 10 minutes prior to beginning a meal to approximately 30 minutes after beginning a meal.

In yet another embodiment, the insulin composition comprises a complex between a diketopiperazine and human insulin and the diketopiperazine is fumaryl diketopiperazine. In an embodiment according to the present invention, the composition is administered by inhalation as a dry powder.

In yet another embodiment of the present invention, the method of reducing postprandial glucose excursions in a patient with an insulin-related disorder is provided comprising administering an insulin composition in a form suitable for pulmonary administration wherein the incidence of clinically relevant late postprandial hypoglycemia is reduced further comprises administering a long-acting basal insulin.

In an embodiment, the insulin-related disorder is diabetes mellitus. In another embodiment, the insulin-related disorder is type 2 diabetes mellitus. In yet another embodiment, the insulin-related disorder is type 1 diabetes mellitus.

In another embodiment, a method is provided for reducing postprandial glucose excursions in a patient with an insulin-related disorder comprising administering an insulin composition in a form suitable for pulmonary administration, wherein the postprandial glucose excursions are less that the postprandial glucose excursions resulting from a dose of subcutaneously administered insulin providing substantially similar insulin exposure and wherein the mean glucose excursion is at least about 25% less than for subcutaneous administration.

In yet another embodiment, the postprandial glucose excursions are reduced from those produced by treatment with an appropriate subcutaneous dose of insulin alone.

In another embodiment, the frequency of episodes of clinically relevant late postprandial hypoglycemia are reduced compared to treatment with an appropriate subcutaneous dose of insulin alone.

In another embodiment according to the present invention, a method of reducing postprandial glucose excursions in a patient with an insulin-related disorder is provided comprising administering an inhaled insulin composition comprising human insulin and fumaryl diketopiperazine in proximity to beginning a meal wherein the incidence of clinically relevant late postprandial hypoglycemia is reduced. In one embodiment the insulin composition is administered from approximately 10 minutes prior to beginning a meal to approximately 30 minutes after beginning a meal. In another embodiment, the insulin-related disorder is diabetes mellitus. In yet another embodiment, the method further comprises administering a long-acting basal insulin.

In one embodiment according to the present invention, a method of reducing postprandial glucose excursions in a patient with an insulin-related disorder being treated with basal insulin is provided comprising administering an inhaled insulin composition comprising human insulin and fumaryl diketopiperazine in proximity to beginning a meal, wherein the incidence of clinically relevant late postprandial hypoglycemia is reduced.

In another embodiment of the present invention, a method is provided for reducing postprandial glucose excursions in a patient with an insulin-related disorder comprising administering an insulin composition in a form suitable for pulmonary administration wherein the patient's total insulin exposure (INS-AUC.sub.0-y, 3.ltoreq.y.ltoreq.6 hours) does not substantially exceed that produced by an appropriate subcutaneous dose of insulin, and wherein postprandial glucose excursion is reduced. In yet another embodiment of the method, the risk of late postprandial hypoglycemia is not increased.

DETAILED DESCRIPTION OF THE INVENTION

A common problem with insulin therapy for the treatment of diabetes is that insulin doses sufficient to control prandial glucose loads produce elevated glucose elimination rates for extended intervals that can persist after the meal, leading to postprandial hypoglycemia. The increase in blood levels of insulin, after subcutaneous administration, is significantly slower in diabetics than the physiologic response to prandial glucose seen in normal individuals. Therefore insulin compositions and methods which result in a more rapid rise in serum insulin levels, which then decline, result in an more physiologic means to achieve maximal glucose elimination rates. This has the effect of compressing the bulk of the effect of the administered insulin to the periprandial time interval thereby reducing the risks of post-prandial hypoglycemia and resulting in a more normal physiologic insulin response to prandial glucose.

It has been generally assumed that the rate of glucose elimination at any point in time is a function of insulin concentration at that point in time. In point of fact the glucose elimination rate achieved by any particular insulin concentration is influenced by prior insulin concentration. Thus glucose elimination rate is potentiated by previous high insulin levels such that, for any particular insulin concentration, the glucose elimination rate is greater when the subject has experienced a high insulin concentration in a preceding time interval. The present inventors have now surprisingly discovered that this potentiation drives the glucose elimination rate to maximum much more quickly in response to a large and rapid peak in insulin concentration than when peak insulin concentration is approached more gradually.

When the inhaled insulin composition of the present invention, an insulin/diketopiperazine microparticle (TECHNOSPHERE.RTM./Insulin, TI), is administered at or shortly after the beginning of a meal, blood glucose levels after the meal are more tightly controlled than if patients attempt to control their disease with subcutaneous insulin or oral medications.

With a typical fast-acting subcutaneous (SC) administered insulin, maximal insulin concentrations can be achieved in about 30 to 45 minutes and remain at this plateau for several hours (FIG. 2 (see Original Patent)). The glucose elimination rate (measured as the glucose infusion rate [GIR]) however continues to rise throughout this plateau phase (FIG. 5 (see Original Patent)), peaking only as insulin concentration begins to decay (FIG. 4 (see Original Patent)). In contrast, with an administration that mimics a physiological first-phase insulin release, insulin concentration peaks at a much higher level and begins to fall by about 15 minutes (FIG. 1 (see Original Patent)). The GIR, however, continues to rise after the peak in insulin concentration but reaches its maximum in less than an hour and then falls in concert with insulin concentration (FIG. 4). By three hours, the bulk of glucose elimination to be accomplished by this insulin has occurred, yet the subcutaneous insulin has exerted less than a third of its effect (FIG. 5).

By taking advantage of the potentiating effects of a rapid spike in insulin concentration, an insulin therapy methodology that mimics first-phase kinetics can offer several advantages. Such insulin formulations are generally administered within a few minutes of commencing a meal, unlike more slowly absorbed insulins which are usually taken at defined period before a meal. The interval is generally based on the time needed to achieve maximal insulin concentration on the tacit assumption that glucose elimination rate is a function of insulin concentration. However, since glucose elimination rate continues to increase throughout the plateau in insulin concentration, doses large enough to keep glucose levels from exceeding the normal range pose a risk that the resultant high glucose elimination rate hours after the meal will lead to hypoglycemia. Due to the potentiating effect of an insulin preparation causing a rapid peak in serum insulin concentration, it can be more readily coordinated with a meal. The quick acquisition of maximal glucose elimination rate is well suited to mealtime administration, or even up to an hour after commencing a meal. The second-phase decay in insulin concentration reduces the risk of inducing hypoglycemia hours after the meal. Further advantages are realized in diabetics who retain some ability to produce insulin in that their endogenous second-phase and basal insulin will also be potentiated, increasing the effectiveness of that limited insulin and reducing pancreatic stress. Methods of reducing pancreatic stress with the exogenously-administered insulin compositions of the present invention are disclosed in co-pending U.S. Provisional Patent Application No. 60/704,295 entitled "Methods of Preserving the Function of Insulin-Producing Cells in Diabetes," which is incorporated by reference herein for all it teaches regarding methods of reducing pancreatic stress by administering diketopiperazine/insulin compositions. The administration of exogenous insulin also suppresses insulin secretion from the pancreas. The quicker return to baseline achieved with a rapidly peaking insulin allows for earlier reassertion of pancreatic secretion and re-establishment of homeostatic control of blood glucose levels, further reducing the risk of post-treatment hypoglycemia and excursions of blood glucose levels. Similar advantages are contemplated from combined treatment with rapid-peaking and long acting exogenous insulin for diabetics who do not produce significant levels of insulin.

As used herein, mimicking physiologic mealtime or first-phase insulin release (or pharmacokinetics) does not necessarily indicate exact replication of all features of the physiologic response. It can refer to methodologies producing a spike or peak of insulin concentration in the blood that constitutes both a relatively quick rise (less than about 15 minutes from administration or first departure from baseline) and fall (descent through half maximal by 80 minutes, preferably 50 minutes, more preferably 35 minutes after peak) in concentration. This is in contrast to methods producing a more gradual rise (from over 20 minutes to several hours) to the maximal insulin concentration achieved and a prolonged plateau at near maximal concentrations. It can also refer to methodologies in which the spike in insulin concentration can be reliably coordinated with the start of a meal. It can also refer to methodologies achieving maximal glucose elimination rate within about 30-90 minutes, preferably around 45-60 minutes, after administration. A methodology that mimics first-phase release is generally also one that can be practiced by diabetics upon themselves without special medical training, such as training in intravenous injection. Special medical training would not include training to use medical devices, such as dry powder inhalers, that are routinely used by persons who are not medical professionals. As used herein, "meal", "meals", and/or "mealtime", etc. include traditional meals and meal times; however, these also include the ingestion of any sustenance regardless of size and/or timing.

Superior blood glucose control can be appreciated as reduced exposure to (elevated) glucose concentrations (AUC.sub.GLU), reduced levels of HbA1c (glycosylated hemoglobin), lessened potential (risk) or incidence of hypoglycemia, reduced variability of response to treatment, and the like. Glycosylated hemoglobin levels correlate with the overall blood glucose control over the past three months. Generally one compares outcomes of different procedures at similar levels of exposure to insulin (AUC.sub.INS) for various time intervals. Glucose exposure and risk of hypoglycemia ultimately depends on how well glucose elimination rate matches glucose load over time. This in turn will generally depend on the shape of the insulin concentration curve rather than simply on the area under the curve. The rapid rise and fall of insulin concentration typical of physiologic first-phase response is well suited to matching glucose elimination rate to prandial glucose load.

The desirable first-phase kinetics can be obtained through the pulmonary administration of a dry powder insulin formulation containing insulin complexed to 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine (hereinafter fumaryl diketopiperazine or FDKP). The use of diketopiperazines for drug delivery is known in the art (see for example U.S. Pat. No. 5,352,461 entitled "Self Assembling Diketopiperazine Drug Delivery System; U.S. Pat. No. 5,503,852 entitled Method for Making Self-Assembling Diketopiperazine Drug Delivery System; U.S. Pat. No. 6,071,497 entitled Microparticles for Lung Delivery Comprising Diketopiperazine; and U.S. Pat. No. 6,331,318 entitled Carbon-Substituted Diketopiperazine Delivery System, each of which is incorporated herein by reference for all that they teach regarding diketopiperazines and diketopiperazine-mediated drug delivery). Pulmonary drug delivery using diketopiperazine and other microparticles is disclosed in U.S. Pat. No. 6,428,771 entitled "Method for Drug Delivery to the Pulmonary System," which is hereby incorporated by reference for all that it teaches regarding delivery of diketopiperazine-based compositions to the pulmonary system. Complexes of insulin and FDKP, their formation, properties, and use are disclosed in U.S. Pat. Nos. 6,444,226 and 6,652,885 both entitled "Purification and Stabilization of Peptide and Protein Pharmaceutical Agents," each of which is incorporated herein by reference for all that they teach regarding formation and administration of FDKP-complexed agents. Additional methods of manufacture of complexes of diketopiperazines and insulin are disclosed in co-pending U.S. Provisional Patent Application No. 60/717,524 entitled "Method of Drug Formulation Based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces," which is incorporated herein by reference for all it teaches regarding manufacture of complexes of diketopiperazines and insulin. Particularly advantageous devices for delivery of the powder are disclosed in U.S. patent application Ser. No. 10/655,153 entitled "Unit Dose Cartridge and Dry Powder Inhaler" and in U.S. Pat. No. 6,923,175 entitled "Inhalation Apparatus", each of which is incorporated herein by reference for all that they teach regarding pulmonary delivery of insulin compositions.

Administration of TECHNOSPHERE.RTM./Insulin, by inhalation, leads to serum insulin levels that rise more rapidly than subcutaneously administered insulin (FIG. 9A), more closely approximating the insulin response to meal-associated glucose in normal individuals. Additionally, post-meal excursions of glucose are limited after TI administration in the post-meal period to a greater extent than with SC administered insulin (FIG. 10). In controlled clinical trials, the total exposure of the patient to insulin is the same whether the patient has been administered TI or SC, however the post-meal excursions from normal blood glucose levels are significantly less (about half) with TI than with SC insulin (FIG. 10). Therefore the delivery of insulin in a manner that approximates the insulin response of healthy individuals allows patients with diabetes to achieve greater control over their blood glucose levels during the post-meal period.

In patients with moderately severe elevations of HbA1c (a marker of control of blood glucose levels over a three month time period), treatment with TI resulted in a reduction of HbA1c levels compared to control-treated individuals (FIG. 17) demonstrating superior control of blood glucose levels over time with TI treatment.

Furthermore, addition of TI to regular basal insulin administration produces a statistically significant, dose-dependent reduction in HbA1c levels and a dose dependent effect on post-meal glucose excursions.

The ability of TI to substantially mimic normal insulin responses to glucose and substantially reduced post-meal glucose excursions may have additional benefits to the general health of diabetics. Excessive post-meal glucose excursions are linked to atherosclerosis and diabetic vascular disease, a complication of diabetes that affects the yeye, kinesy and peripheral autonomic nervous systems. Therefore administration of TI according to the teachings of the present invention provides superior control of blood glucose levels leading to better management of diabetic symptoms and better overall health of the diabetic patient.

Complexation of large polymers, such as proteins and peptides, in diketopiperazines can be used to remove impurities or contaminants such as metal ions or other small molecules. The diketopiperazines also serve both to stabilize and enhance delivery of the complexed materials. Formulations also have been developed facilitate transport of active agents across biological membranes. These formulations include microparticles formed of (i) the active agent, which may be charged or neutral, and (ii) a transport facilitator that masks the charge of the agent and/or that forms hydrogen bonds with the membrane. The formulations can provide rapid increases in the concentration of active agent in the blood following administration of the formulations.

TECHNOSPHERE.RTM. refers to a diketopiperazine-based drug delivery system which can complex and stabilize peptides in small particles. Diketopiperazines, particularly fumaryl diketopiperazine (FDKP), self-assemble into microparticles with a mean diameter of about 2 microns. In the process it can entrap or complex with peptides, such as insulin, present in the solution during or after self-assembly. Once dried, these microparticles become a suitable composition for pulmonary delivery to the systemic circulation. When administered by the pulmonary route, TECHNOSPHERE.RTM. particles dissolve in the pH neutral environment of the deep lung and facilitate the rapid and efficient absorption of the peptide into systemic circulation. The FDKP molecules are excreted un-metabolized in the urine within hours of administration.

Additionally, salts of diketopiperazines can be used in the compositions of the present invention as disclosed in co-pending U.S. patent application Ser. No. 11/210,710 entitled "Diketopiperazine Salts for Drug Delivery and Related Methods" which is incorporated by reference herein for all it teaches regarding diketopiperazine salts and their use to in pulmonary delivery of insulin.

Insulin, a polypeptide with a nominal molecular weight of 6,000 daltons, traditionally has been produced by processing pig and cow pancreas to isolate the natural product. More recently, however, recombinant technology has been used to produce human insulin in vitro. Natural and recombinant human insulin in aqueous solution is in a hexameric conformation, that is, six molecules of recombinant insulin are noncovalently associated in a hexameric complex when dissolved in water in the presence of zinc ions. Hexameric insulin is not rapidly absorbed. In order for recombinant human insulin to be absorbed into a patient circulation, the hexameric form must first disassociate into dimeric and/or monomeric forms before the material can move into the bloodstream.

For example, it was discovered that insulin can be delivered to the lung in fumaryl diketopiperazine formulation, reaching peak blood concentrations within 3-10 minutes. In contrast, hexameric insulin administered by the pulmonary route without fumaryl diketopiperazine typically takes between 25-60 minutes to reach peak blood concentrations, while hexameric insulin takes 30-90 minutes to reach peak blood level when administered by subcutaneous injection. This feat has been successfully replicated several times and in several species, including humans.

Removing zinc from insulin typically produces unstable insulin with an undesirably short shelf life. Purification to remove zinc, stabilization and enhanced delivery of insulin has been demonstrated using diketopiperazine microparticles. Formulations of insulin complexed with fumaryl diketopiperazine were found to be stable and have an acceptable shelf life. Measurement of the zinc levels demonstrated that when a washing step was included the zinc had been largely removed during the complexation process, yielding monomeric insulin in a stable delivery formulation.

The insulin compositions of the present invention can be administered to patients in need of insulin therapy. The compositions preferably are administered in the form of microparticles, which can be in a dry powder form for pulmonary administration or suspended in an appropriate pharmaceutical carrier, such as saline.

The microparticles preferably are stored in dry or lyophilized form until immediately before administration. The microparticles then can be administered directly as a dry powder, such as by inhalation using, for example, dry powder inhalers known in the art. Alternatively, the microparticles can be suspended in a sufficient volume of pharmaceutical carrier, for example, as an aqueous solution for administration as an aerosol. The microparticles also can be administered via oral, subcutaneous, and intravenous routes.

The inhalable insulin compositions can be administered to any targeted biological membrane, preferably a mucosal membrane of a patient. In one embodiment, the patient is a human suffering from an insulin-related disorder such as diabetes mellitus. In another embodiment, the inhalable insulin composition delivers insulin in biologically active form to the patient, which provides a spike of serum insulin concentration which simulates the normal response to eating.

In another embodiment, the inhalable insulin composition is administered to a patient in combination with long-acting basal insulin. The dose and administration of the long-acting basal insulin is established by the patient's physician according to standard medical practice. The inhalable insulin composition is administered periprandially according the teachings of the present invention, independently of the administration parameters of the basal insulin. Therefore for the purposes of this disclosure "in combination" refers to a patient administered both the inhalable insulin composition of the present invention and a long-acting basal insulin however, the two forms of insulin are administered independently.

In one embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, induces a lower coefficient of variation at the 95% confidence interval of insulin exposure, INS-AUC.sub.0-x, x.ltoreq.3, than subcutaneously administered insulin, wherein total insulin exposure [INS-AUC.sub.0-y, 3.ltoreq.y.ltoreq.6] is substantially similar.

In another embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, induces a lower coefficient of variation at the 95% confidence interval in glucose elimination than subcutaneously administered insulin, wherein glucose elimination is measured as glucose infusion rate (GIR-)AUC.sub.0-x, x.ltoreq.3 hours, wherein total insulin exposure [INS-AUC.sub.0-y, 3.ltoreq.y.ltoreq.6] is substantially similar.

In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, produces a mean glucose excursion that is less than subcutaneous administration of a dose of insulin providing substantially similar insulin exposure wherein the mean glucose excursion is at least about 28%, particularly at least about 25%, less than for the subcutaneous administration.

In an embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, produces a mean glucose exposure that is less than subcutaneous administration of a dose of insulin providing substantially similar insulin exposure wherein the mean glucose exposure is at least about 35% less than for the subcutaneous administration, preferably about 50% less than for the subcutaneous administration.

In another embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, exhibits a ratio of HbA1c after treatment to HbA1c before treatment, that is less than for subcutaneous administration of a dose of insulin providing substantially similar insulin exposure.

In an embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a form suitable for pulmonary administration which, when administered in proximity in time to the beginning of a meal, exhibits a ratio of glucose exposure, AUC.sub.GLU in min*mg/dL, to insulin exposure, AUC.sub.INS in .mu.U/mL, that is less than the ratio for subcutaneous administration of a dose of insulin providing substantially similar insulin exposure.

In another embodiment of the present invention, a pharmaceutical composition is provided comprising insulin in a rapidly absorbable form suitable for administration to an ambulatory patient which, when administered in proximity in time to the beginning of a meal, exhibits a ratio of glucose exposure, AUC.sub.GLU in min*mg/dL, to insulin exposure, AUC.sub.INS in .mu.U/mL, that is less than 1. In an embodiment of the present invention the pharmaceutical composition is suitable for pulmonary delivery.

In an embodiment of the present invention, a pharmaceutical composition is provided wherein the insulin is complexed with a diketopiperazine microparticle, preferably fumaryl diketopiperazine.

In another embodiment of the present invention, a method of improving the reproducibility of insulin therapy is provided comprising administering the pharmaceutical composition in proximity in time to beginning meals.

In one embodiment of the present invention, a method of treating an insulin-related disorder is provided comprising administering to a patient having an insulin-related disorder an exogenously-administered composition such that the exogenously-administered insulin composition mimics first-phase insulin kinetics, and wherein the exogenously-administered insulin composition is not administered intravenously.

In another embodiment of the method of treating an insulin-related disorder of the present invention, the exogenously-administered insulin composition comprises a complex between a diketopiperazine and human insulin. In another embodiment, the diketopiperazine is fumaryl diketopiperazine. In yet another embodiment, the exogenously-administered insulin composition is inhaled.

In yet another embodiment of the method of treating an insulin-related disorder of the present invention, the insulin-related disorder is diabetes mellitus, such as type 1 or type 2 diabetes mellitus.

In one embodiment of the present invention, a method of maintaining blood glucose levels in a patient with an insulin-related disorder in a normal range is provided comprising providing an exogenously-administered insulin composition wherein first-phase insulin pharmacokinetics are obtained within about 30 minutes of administration, alternatively within about 15 minutes of administration and wherein the exogenously-administered insulin composition is not administered intravenously.

In another embodiment of the method of maintaining blood glucose levels of the present invention, the exogenously-administered insulin composition comprises a complex between a diketopiperazine and human insulin. In another embodiment, the diketopiperazine is fumaryl diketopiperazine.

In another embodiment of the method of maintaining blood glucose levels of the present invention, the exogenously administered insulin composition is a non-naturally occurring form of insulin.

In one embodiment of the present invention, a method of restoring normal insulin kinetics in a patient in need thereof is provided comprising administering to a patient having an insulin-related disorder an inhaled insulin composition such that the inhaled insulin composition mimics first-phase insulin kinetics. In another embodiment, the insulin-related disorder is diabetes mellitus. In yet another embodiment, the method further comprises administering a long-acting basal insulin.
 

Claim 1 of 16 Claims

1. A method of reducing postprandial glucose excursions in a patient with an insulin-related disorder comprising: selecting a patient with an insulin-related disorder; administering a long-acting basal insulin; administering an insulin composition comprising fumaryl diketopiperazine in a form suitable for pulmonary administration in proximity to beginning a meal, wherein the patient's total insulin exposure (INS-AUC.sub.0-y, 3<y<6 hours) does not substantially exceed that produced by an appropriate subcutaneous dose of insulin; and reducing the postprandial glucose excursions relative to treatment with the appropriate subcutaneous dose of insulin.

 

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