U.S. patent application number 15/377641 was filed with the patent office on 2017-03-30 for superior control of blood glucose in diabetes treatment.
The applicant listed for this patent is MannKind Corporation. Invention is credited to Anders Hasager Boss, Wayman Wendell Cheatham.
Application Number | 20170087217 15/377641 |
Document ID | / |
Family ID | 37054222 |
Filed Date | 2017-03-30 |
United States Patent
Application |
20170087217 |
Kind Code |
A1 |
Cheatham; Wayman Wendell ;
et al. |
March 30, 2017 |
SUPERIOR CONTROL OF BLOOD GLUCOSE IN DIABETES TREATMENT
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.
Inventors: |
Cheatham; Wayman Wendell;
(Columbia, MD) ; Boss; Anders Hasager; (Princeton,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MannKind Corporation |
Valencia |
CA |
US |
|
|
Family ID: |
37054222 |
Appl. No.: |
15/377641 |
Filed: |
December 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13077361 |
Mar 31, 2011 |
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15377641 |
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11278381 |
Mar 31, 2006 |
7943572 |
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13077361 |
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11329686 |
Jan 10, 2006 |
9006175 |
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11278381 |
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60667393 |
Mar 31, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 3/00 20180101; A61P
5/50 20180101; A61K 47/545 20170801; Y10S 514/866 20130101; A61P
3/10 20180101; A61K 9/0073 20130101; A61K 9/0075 20130101; A61K
38/28 20130101; A61K 9/007 20130101; A61P 3/08 20180101; A61K
31/495 20130101 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61K 9/00 20060101 A61K009/00; A61K 31/495 20060101
A61K031/495 |
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 dose of
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) from said dose 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.
2. The method of claim 1 wherein the risk of late postprandial
hypoglycemia is not increased.
3. The method of claim 1, wherein the insulin composition is
administered by inhalation as a dry powder.
4. The method of claim 1, wherein the insulin composition is
administered from approximately 10 minutes prior to beginning a
meal to approximately 30 minutes after beginning a meal.
5. The method of claim 1, wherein the insulin-related disorder is
diabetes mellitus.
6. The method of claim 1, wherein a mean glucose excursion is at
least about 25% less than for said appropriate subcutaneous dose of
insulin.
7. The method of claim 1, wherein glucose excursions are measured
by a method selected from the group consisting of AUC.sub.0-240,
AUC.sub.0-120, and maximum glucose excursion.
8. The method of claim 7, wherein the maximum glucose excursion
does not exceed a blood glucose concentration of 180 mg/dL.
9. The method of claim 7, wherein the maximum glucose excursion
does not exceed a premeal baseline blood glucose concentration by a
value of more than 59 mg/dL.
10. The method according to claim 1 wherein as a result of said
administering step, said patient exhibits a ratio of HbA1c after
treatment to HbA1c before treatment less than for subcutaneous
administration of a dose of insulin providing substantially similar
insulin exposure.
11. A method of treating a patient with an insulin related disorder
comprising: administering an insulin composition comprising a
diketopiperazine and insulin in a form suitable for pulmonary
administration from between from 10 minutes prior to beginning a
meal to 30 minutes after beginning a meal; wherein said composition
induces a maximum glucose elimination rate in said patient within
60 minutes of administration.
12. The method according to claim 11 wherein said glucose
elimination rate falls to half-maximal within 80 minutes of
reaching the maximum.
13. The method according to claim 11 wherein said diketopiperazine
is fumaryl diketopiperazine.
14. The method according to claim 11 wherein said insulin-related
disorder is diabetes mellitus.
15. The method according to claim 11 wherein the risk of late
postprandial hypoglycemia is not increased.
16. The method according to claim 11 wherein as a result of said
administering step, said patient exhibits a ratio of HbA1c after
treatment to HbA1c before treatment less than for subcutaneous
administration of a dose of insulin providing substantially similar
insulin exposure.
17. A method of treating a patient with an insulin related disorder
comprising: administering an insulin composition comprising a
diketopiperazine and insulin in a form suitable for pulmonary
administration from between 10 minutes prior to beginning a meal to
30 minutes after beginning a meal; wherein said composition induces
a lower coefficient of variation at the 95% confidence interval of
insulin exposure, (INS-AUC.sub.0-x, x.ltoreq.3 hours) or glucose
elimination ((GIR-)AUC.sub.0-x, x.ltoreq.3 hours), in said patient
than subcutaneously administered insulin, where the total insulin
exposure [INS-AUC.sub.0-y, 3.ltoreq.y.ltoreq.6] is substantially
similar.
18. The method according to claim 17 wherein said diketopiperazine
is fumaryl diketopiperazine.
19. The method according to claim 17 wherein said insulin-related
disorder is diabetes mellitus.
20. The method according to claim 17 wherein the risk of late
postprandial hypoglycemia is not increased.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/077,361 filed Mar. 31, 2011, which is a
continuation of U.S. patent application Ser. No. 11/278,381 filed
Mar. 31, 2006, which claims priority under 35 U.S.C. .sctn.119(e)
to U.S. Provisional Patent Application No. 60/667,393 filed Mar.
31, 2005 and is a continuation-in-part of U.S. patent application
Ser. No. 11/329,686, filed Jan. 10, 2006, all of which are
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of treating
diabetes and improving control of blood glucose. Specifically, the
method of the present invention provides superior control of
postprandial glucose levels while reducing the risk of late
postprandial hypoglycemia by mimicking the insulin response
kinetics of a non-diabetic individual.
BACKGROUND TO THE INVENTION
[0003] Diabetes mellitus currently afflicts at least 200 million
people worldwide. Type 1 diabetes accounts for about 10% of this
number, and results from autoimmune destruction of
insulin-secreting .beta.-cells in the pancreatic islets of
Langerhans. Survival depends on multiple daily insulin injections.
Type 2 diabetes accounts for the remaining 90% of individuals
affected, and the rate of prevalence is increasing. Type 2 diabetes
is often, but not always, associated with obesity, and although
previously termed late-onset or adult diabetes, is now increasingly
manifest in younger individuals. It is caused by a combination of
insulin resistance and inadequate insulin secretion.
[0004] In a non-stressed normal individual, the basal glucose level
will tend to remain the same from day to day because of an
intrinsic feedback loop. Any tendency for the plasma glucose
concentration to increase is counterbalanced by an increase in
insulin secretion and a suppression of glucagon secretion, which
regulate hepatic glucose production (gluconeogenesis and release
from glycogen stores) and tissue glucose uptake to keep the plasma
glucose concentration constant. If the individual gains weight or
becomes insulin resistant for any other reason, blood glucose
levels will increase, resulting in increased insulin secretion to
compensate for the insulin resistance. Therefore the glucose and
insulin levels are modulated to minimize changes in these
concentrations while relatively normal production and utilization
of glucose are maintained.
[0005] Five different phases of insulin secretion have been
identified: (1) basal insulin secretion wherein insulin is released
in the postabsorptive state; (2) the cephalic phase wherein insulin
secretion is triggered by the sight, smell and taste of food,
before any nutrient is absorbed by the gut, mediated by pancreatic
innervation; (3) first-phase insulin secretion wherein an initial
burst of insulin is released within the first 5-10 minutes after
the .beta.-cell is exposed to a rapid increase in glucose, or other
secretagogues; (4) second-phase insulin secretion wherein the
insulin levels rise more gradually and are related to the degree
and duration of the stimulus and (5) a third-phase of insulin
secretion that has only been described in vitro. During these
stages, insulin is secreted, like many other hormones, in a
pulsatile fashion, resulting in oscillatory concentrations in the
blood. Oscillations include rapid pulses (occurring every 8-15
minutes) superimposed on slower oscillations (occurring every
80-120 minutes) that are related to fluctuations in blood glucose
concentration.
[0006] Insulin secretion can be induced by other energetic
substrates besides glucose (particularly amino acids) as well as by
hormones and drugs. Of note is that the insulin response observed
after food ingestion cannot be accounted for solely by the increase
in blood glucose levels, but also depends on other factors such as
the presence of free fatty acids and other secretagogues in the
meal, the neurally activated cephalic phase and gastrointestinal
hormones.
[0007] When an individual is given an intravenous glucose
challenge, a biphasic insulin response is seen which includes a
rapid increase with a peak, an interpeak nadir and a subsequent
slower increasing phase. This biphasic response is only seen when
glucose concentration increases rapidly, such as after a glucose
bolus or glucose infusion. A slower increase in glucose
administration, what is seen under physiologic conditions, induces
a more gradually increasing insulin secretion without the
well-defined biphasic response seen in response to bolus infusion
of glucose.
[0008] Modeling of first-phase insulin responses under normal
physiologic conditions has demonstrated that, after a meal, glucose
concentration increases more gradually (C.sub.max reached in
approximately 20 minutes) than seen with intravenous bolus
injections of glucose (C.sub.max reached in approximately 3-10
minutes).
[0009] Healthy pancreatic .beta.-cells generate an early response
to a meal-like glucose exposure that rapidly elevates serum insulin
both in the portal circulation and in the periphery. Conversely,
defective .beta.-cells, which have an impaired first-phase insulin
response, generate a sluggish response to the meal-like glucose
exposure.
[0010] Increasingly, evidence indicates that an early relatively
rapid insulin response following glucose ingestion plays a critical
role in the maintenance of postprandial glucose homeostasis. An
early surge in insulin concentration can limit initial glucose
excursions, mainly through the inhibition of endogenous glucose
production. Therefore the induction of a rapid insulin response in
a diabetic individual is expected to produce improved blood glucose
homeostasis.
[0011] In a normal individual, a meal induces the secretion of a
burst of insulin, generating a relatively rapid spike in serum
insulin concentration that then decays relatively quickly (see FIG.
1). This early-phase insulin response is responsible for the
shut-off of release of glucose from the liver. Homeostatic
mechanisms then match insulin secretion (and serum insulin levels)
to the glucose load. This is observed as a slow decay of modestly
elevated serum insulin levels back to baseline and is second-phase
kinetics.
[0012] Type 2 diabetics typically exhibit a delayed response to
increases in blood glucose levels. While normal individuals usually
begin to release insulin within 2-3 minutes following the
consumption of food, type 2 diabetics may not secrete endogenous
insulin until blood glucose begins to rise, and then with
second-phase kinetics, that is a slow rise to an extended plateau
in concentration. As a result, endogenous glucose production is not
shut off and continues after consumption and the patient
experiences hyperglycemia (elevated blood glucose levels).
[0013] Loss of eating-induced insulin secretion is one of the
earliest disturbances of .beta.-cell function. While genetic
factors play an important role, some insulin secretory disturbances
seem to be acquired and may be at least partly reversible through
optimal glucose control. Optimal glucose control via insulin
therapy after a meal can lead to a significant improvement in
natural glucose-induced insulin release by requiring both normal
tissue responsiveness to administered insulin and an abrupt
increase in serum insulin concentrations. Therefore, the challenge
presented in treatment of early stage type 2 diabetics, those who
do not have excessive loss of .beta.-cell function, is to restore
the rapid increase in insulin following meals.
[0014] In addition to the loss of first-phase kinetics, early stage
type 2 diabetics do not shut-off endogenous glucose release after a
meal. As the disease progresses, the demands placed on the pancreas
further degrades its ability to produce insulin and control of
blood glucose levels gradually deteriorates. If unchecked, the
disease can progress to the point that the deficit in insulin
production approaches that typical of fully developed type 1
diabetes. However, type 1 diabetes can involve an early "honeymoon"
stage, following an initial crisis, in which insulin is still
produced but defects in release similar to early type 2 disease are
exhibited.
[0015] Most early stage type 2 diabetics are currently treated with
oral agents, but with limited success. Subcutaneous injections are
also rarely ideal in providing insulin to type 2 diabetics and may
actually worsen insulin action because of delayed, variable and
shallow onset of action. It has been shown, however, that if
insulin is administered intravenously with a meal, early stage type
2 diabetics experience the shutdown of hepatic glucose release and
exhibit increased physiologic glucose control. In addition their
free fatty acids levels fall at a faster rate that without insulin
therapy. While possibly effective in treating type 2 diabetes,
intravenous administration of insulin, is not a reasonable
solution, as it is not safe or feasible for patients to
intravenously administer insulin at every meal.
[0016] Significant pathology (and morbidity) in diabetics is
associated with inadequate control of blood glucose. Excursions of
blood glucose concentration both above and below the desired,
normal range are problematic. In treatments that fail to mimic
physiologic insulin release, the rise in insulin concentration does
not produce sufficiently high glucose elimination rates to
completely respond to the glucose load resulting from a meal. This
can be further exacerbated by failure to shut off glucose release
from the liver. Additionally, with many forms of insulin therapy,
serum insulin levels and glucose elimination rates also remain
elevated after the prandial glucose load has abated, threatening
hypoglycemia. Attempts to better control peak glucose loads by
increasing insulin dose further increase this danger. Indeed,
postprandial hypoglycemia is a common result of insulin therapy
often causing, or even necessitating, patients to eat snacks
between meals, depending on the severity of hypoglycemia. This
contributes to the weight gain often associated with insulin
therapy. These risks and their frequency and severity of occurrence
are well understood in the art.
[0017] Current insulin therapy modalities can supplement or replace
endogenously-produced insulin to provide basal and
second-phase-like profiles but do not mimic first-phase kinetics
(see FIG. 2). Additionally, conventional insulin therapy often
involves only one or two daily injections of insulin. However, more
intensive therapy such as three or more administrations a day,
providing better control of blood glucose levels, are clearly
beneficial (see for example Nathan, D. M., et al., N Engl J Med
353:2643-53, 2005), but many patients are reluctant to accept the
additional injections.
[0018] Until recently, subcutaneous (SC) injection has been the
only route of delivering insulin to patients with both type 1 and
type 2 diabetes. However, SC insulin administration does not lead
to optimal pharmacodynamics for the administered insulin.
Absorption into the blood (even with rapid acting insulin
analogues) does not mimic the prandial physiologic insulin
secretion pattern of a rapid spike in serum insulin concentration.
Since the discovery of insulin, alternative routes of
administration have been investigated for their feasibility in
improving the pharmacodynamics of the administered insulin and
improving compliance by reducing the discomfort associated with SC
injections.
[0019] The alternative routes of insulin administration which have
been evaluated in detail include the dermal, oral, buccal, nasal
and pulmonary routes. Dermal insulin application does not result in
reproducible and sufficient transfer of insulin across the highly
efficient skin barrier. Effective oral insulin administration has
not yet been achieved, primarily due to digestion of the protein
and lack of a specific peptide carrier system in the gut. Nasal
insulin application leads to a more rapid absorption of insulin
across the nasal mucosa, however not with first-phase kinetics. The
relative bioavailability of nasal administered insulin is low and
there is a high rate of side effects and treatment failures.
Buccally absorbed insulin also fails to mimic a first-phase release
(Raz, I. et al., Fourth Annual Diabetes Meeting, Philadelphia, Pa.,
2004).
[0020] Recently, pulmonary application of insulin has become a
viable insulin delivery system. Some pulmonary insulin formulations
in development provide faster appearance of insulin in the blood
than typical subcutaneously delivered products (see FIG. 3), but
apparently do not adequately reproduce all aspects of first-phase
kinetics.
[0021] Therefore, a need exists for an insulin formulation which
can mimic first-phase kinetics to provide physiologic postprandial
insulin pharmacokinetics and pharmacodynamics for improved control
of blood glucose levels.
SUMMARY OF THE INVENTION
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] In yet another embodiment, the postprandial glucose
excursions are reduced from those produced by treatment with an
appropriate subcutaneous dose of insulin alone.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 depicts the measurement of first-phase insulin
release kinetics following artificial stimulation by bolus glucose
infusion.
[0035] FIG. 2 depicts serum insulin concentration after
administration of subcutaneous (SC) regular human insulin or SC
fast acting insulin (insulin aspart; NOVOLOG.TM., Novo Nordisk
Pharmaceuticals, Bagsvaerd, Denmark).
[0036] FIG. 3 depicts a composite of time-action profiles of a
variety of forms of inhaled (MannKind, Pfizer/Aventis/Nektar,
Alkermes, Aerogen, KOS, Novo Nordisk/Aradigm) and injected (Lispro
SC) insulin from different manufacturers (from: Br J Diab Vasc. Dis
4:295-301, 2004).
[0037] FIG. 4 depicts the relationship over time between serum
insulin concentration and glucose elimination rate, as glucose
infusion rate (GIR) under a glucose clamp, for a fast-acting
subcutaneously administered insulin (SC) and a pulmonary dry powder
insulin formulated with furnaryl diketopiperazine
(TECHNOSPHERE.RTM./Insulin, TI) according to the teachings of the
present invention.
[0038] FIG. 5 depicts increased postprandial glucose elimination
for TECHNOSPHERE.RTM./Insulin (48 U TI) versus a fast-acting
subcutaneously administered insulin (24 IU SC) in individuals with
type 2 diabetes mellitus according to the teachings of the present
invention.
[0039] FIGS. 6A-B depict comparisons in intra-patient variability
in GIR (FIG. 6A) and insulin concentration (FIG. 6B) in individuals
with type 2 diabetes mellitus at various time points for
subcutaneous (SC) and pulmonary (TI) insulin according to the
teachings of the present invention.
[0040] FIGS. 7A-B depict the mean serum insulin concentration (FIG.
7A) and insulin absorption, as AUC (FIG. 7B), in individuals with
type 2 diabetes mellitus at different dose levels of TI and SC
insulin according to the teachings of the present invention.
[0041] FIG. 8 depicts a comparison of insulin concentration and
glucose elimination rate over time in individuals with type 2
diabetes mellitus after administration of 48 U of TI according to
the teachings of the present invention.
[0042] FIGS. 9A-B depict blood insulin (FIG. 9A) and glucose levels
(FIG. 9B) in individuals with type 2 diabetes mellitus after
administration of 14 IU SC insulin or 48 U TI according to the
teachings of the present invention.
[0043] FIG. 10 depicts the improved postprandial glucose exposure
with similar insulin exposure in individuals with type 2 diabetes
mellitus after administration of 14 IU SC insulin or 48 U TI
according to the teachings of the present invention.
[0044] FIG. 11 depicts maintenance of the effects of inhaled
insulin on postprandial glucose levels after three months of
insulin therapy in individuals with type 2 diabetes mellitus with
TI or placebo (PL) according to the teachings of the present
invention.
[0045] FIGS. 12A-B depict total (FIG. 12A) and maximum (FIG. 12B)
postprandial glucose excursion in individuals with type 2 diabetes
mellitus after administration of TI or PL according to the
teachings of the present invention.
[0046] FIG. 13 depicts the dose effect on maximal postprandial
glucose excursions after administration of TI compared to the
assumed dose in a control group (Control) in individuals with type
2 diabetes mellitus according to the teachings of the present
invention.
[0047] FIGS. 14A-B depict the insulin appearance rate over time for
TI and endogenous insulin after administration of TI in patients
with type 2 diabetes according to the teachings of the present
invention
[0048] FIG. 15 depicts the relationship between insulin
concentration and glucose elimination rate in individuals with type
2 diabetes mellitus after administration of intravenous (IV, 5 IU),
SC (10 IU) or inhaled (TI, 100 U) insulin according to the
teachings of the present invention.
[0049] FIG. 16 depicts the levels of C-peptide after administration
of TI or SC insulin in individuals with type 2 diabetes mellitus
according to the teachings of the present invention.
[0050] FIG. 17 depicts the change in mean glycosylated hemoglobin
(HbA1c) levels after 12 weeks of administration of TI or placebo in
individuals with type 2 diabetes mellitus according to the
teachings of the present invention.
[0051] FIG. 18 depicts weight levels in individuals with type 2
diabetes mellitus administered TI or placebo (PL) according to the
teachings of the present invention.
[0052] FIGS. 19A-B depict pulmonary function, expressed as forced
expiratory volume in one second (FEV1, FIG. 19A) and forced vital
capacity (FVC, FIG. 19B) over time in a three month
placebo-controlled clinical study with TI according to the
teachings of the present invention.
[0053] FIG. 20 depicts the study schema for the clinical trial
disclosed in Example 6.
[0054] FIGS. 21A-B depict the baseline-corrected blood glucose
concentration versus time by treatment group after administration
of TI and a isocaloric meal (FIG. 21A) or a hypercaloric meal (FIG.
21B) according to the teachings of the present invention.
[0055] FIGS. 22A-B depict the baseline-corrected serum insulin
concentration versus time by treatment group after administration
of TI and a isocaloric meal (FIG. 22A) or a hypercaloric meal (FIG.
22B) according to the teachings of the present invention.
[0056] FIGS. 23A-B depict the mean blood glucose levels (FIG. 23A)
or C-peptide levels (FIG. 23B) over time after administration of
IV, SC or TI (inhaled) insulin according to the teachings of the
present invention.
[0057] FIGS. 24A-B depict glucose infusion rate (FIG. 24A) or mean
insulin concentration (FIG. 24B) over time after administration of
IV, SC or TI (inhaled) insulin according to the teachings of the
present invention.
DEFINITION OF TERMS
[0058] Prior to setting forth the invention, it may be helpful to
provide an understanding of certain terms that will be used
hereinafter:
[0059] Dry powder: As used herein "dry powder" refers to a fine
particulate composition that is not suspended or dissolved in a
propellant, carrier, or other liquid. It is not meant to imply a
complete absence of all water molecules.
[0060] Early phase: As used herein "early phase" refers to the rise
in blood insulin concentration induced in response to a meal. This
early rise in insulin in response to a meal is sometimes referred
to as first-phase.
[0061] Excursion: As used herein, "excursion" refers to blood
glucose concentrations that fall either above or below a pre-meal
baseline or other starting point. Excursions are generally
expressed as the area under the curve (AUC) of a plot of blood
glucose over time. AUC can be expressed in a variety of ways. In
some instances there will be both a fall below and rise above
baseline creating a positive and negative area. Some calculations
will subtract the negative AUC from the positive, while others will
add their absolute values. The positive and negative AUCs can also
be considered separately. More sophisticated statistical
evaluations can also be used. In some instances it can also refer
to blood glucose concentrations that rise or fall outside a normal
range. A normal blood glucose concentration is usually between 70
and 110 mg/dL from a fasting individual, less than 120 mg/dL two
hours after eating a meal, and less than 180 mg/dL after
eating.
[0062] First-Phase: As used herein, "first-phase" refers to the
spike in insulin levels as induced by a bolus intravenous injection
of glucose. A first-phase insulin release generates a spike in
blood insulin concentration that is a rapid peak which then decays
relatively quickly.
[0063] Glucose Elimination Rate: As used herein, "glucose
elimination rate" is the rate at which glucose disappears from the
blood and is determine by the amount of glucose infusion required
to maintain stable blood glucose, often around 120 mg/dL during the
study period. This glucose elimination rate is equal to the glucose
infusion rate, abbreviated as GIR.
[0064] Hyperglycemia: As used herein, "hyperglycemia" is a higher
than normal fasting blood glucose concentration, usually 126 mg/dL
or higher. In some studies hyperglycemic episodes were defined as
blood glucose concentrations exceeding 280 mg/dL (15.6 mM).
[0065] Hypoglycemia: As used herein, "hypoglycemia" is a lower than
normal blood glucose concentration, usually less than 63 mg/dL 3.5
mM). Clinically relevant hypoglycemia is defined as blood glucose
concentration below 63 mg/dL or causing patient symptoms such as
hypotonia, flush and weakness that are recognized symptoms of
hypoglycemia and that disappear with appropriate caloric intake.
Severe hypoglycemia is defined as a hypoglycemic episode that
required glucagon injections, glucose infusions, or help by another
party.
[0066] In proximity: As used herein, "in proximity," as used in
relation to a meal, refers to a period near in time to the
beginning of a meal.
[0067] Insulin Composition: As used herein, "insulin composition"
refers to any form of insulin suitable for administration to a
mammal and includes insulin isolated from mammals, recombinant
insulin, insulin associated with other molecules and also includes
insulin administered by any route including pulmonary,
subcutaneous, nasal, oral, buccal and sublingual. Insulin
compositions can be formulated as dry powders or aqueous solutions
for inhalation; aqueous solutions for subcutaneous, sublingual,
buccal, nasal or oral administration and solid dosage forms for
oral and sublingual administration.
[0068] Insulin-Related Disorder: As used herein, "insulin-related
disorders" refers to disorders involving production, regulation,
metabolism, and action of insulin in a mammal. Insulin related
disorders include, but are not limited to, type 1 diabetes
mellitus, type 2 diabetes mellitus, hypoglycemia, hyperglycemia,
insulin resistance, loss of pancreatic beta cell function and loss
of pancreatic beta cells.
[0069] Microparticles: As used herein, the term "microparticles"
includes microcapsules having an outer shell composed of either a
diketopiperazine alone or a combination of a diketopiperazine and
one or more drugs. It also includes microspheres containing drug
dispersed throughout the sphere; particles of irregular shape; and
particles in which the drug is coated in the surface(s) of the
particle or fills voids therein.
[0070] Periprandial: As used herein, "periprandial" refers to a
period of time starting shortly before and ending shortly after the
ingestion of a meal or snack.
[0071] Postprandial: As used herein, "postprandial" refers to a
period of time after ingestion of a meal or snack. As used herein,
late postprandial refers to a period of time 3, 4, or more hours
after ingestion of a meal or snack.
[0072] Potentiation: Generally, potentiation refers to a condition
or action that increases the effectiveness or activity of some
agent over the level that the agent would otherwise attain.
Similarly it may refer directly to the increased effect or
activity. As used herein, "potentiation" particularly refers to the
ability of elevated blood insulin concentrations to boost
effectiveness of subsequent insulin levels to, for example, raise
the glucose elimination rate.
[0073] Prandial: As used herein, "prandial" refers to a meal or a
snack.
[0074] Second-Phase: As used herein, "second-phase" refers to the
slow decay of modestly elevated blood insulin levels back to
baseline after the first-phase has passed. Second-phase can also
refer to the non-spiking release of insulin in response to elevated
blood glucose levels.
[0075] TECHNOSPHERE.RTM./Insulin: As used herein,
"TECHNOSPHERE.RTM./Insulin" or "TI" refers to an insulin
composition comprising regular human insulin and TECHNOSPHERE.RTM.
microparticles, a drug delivery system. TECHNOSPHERE.RTM.
microparticles comprise a diketopiperazine, specifically
3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine (furnaryl
diketopiperazine, FDKP). Specifically, TECHNOSPHERE.RTM./Insulin
comprises a FDKP/human insulin composition.
[0076] As used herein, "diketopiperazine" or "DKP" includes
diketopiperazines and salts, derivatives, analogs and modifications
thereof falling within the scope of the general Formula 1, wherein
the ring atoms E.sub.1 and E.sub.2 at positions 1 and 4 are either
O or N and at least one of the side-chains R.sub.1 and R.sub.2
located at positions 3 and 6 respectively contains a carboxylic
acid (carboxylate) group. Compounds according to Formula 1 include,
without limitation, diketopiperazines, diketomorpholines and
diketodioxanes and their substitution analogs.
##STR00001##
[0077] Diketopiperazines, in addition to making aerodynamically
suitable microparticles, also facilitate transport across cell
layers, further speeding absorption into the circulation.
Diketopiperazines can be formed into particles that incorporate a
drug or particles onto which a drug can be adsorbed. The
combination of a drug and a diketopiperazine can impart improved
drug stability. These particles can be administered by various
routes of administration. As dry powders these particles can be
delivered by inhalation to specific areas of the respiratory
system, depending on particle size. Additionally, the particles can
be made small enough for incorporation into an intravenous
suspension dosage form. Oral delivery is also possible with the
particles incorporated into a suspension, tablets or capsules.
Diketopiperazines may also facilitate absorption of an associated
drug.
[0078] In another embodiment of the present invention, the DKP is a
derivative of 3,6-di(4-aminobutyl)-2,5-diketopiperazine, which can
be formed by (thermal) condensation of the amino acid lysine.
Exemplary derivatives include 3,6-di(succinyl-4-aminobutyl)-,
3,6-di(maleyl-4-aminobutyl)-, 3,6-di(glutaryl-4-aminobutyl)-,
3,6-di(malonyl-4-aminobutyl)-, 3,6-di(oxalyl-4-aminobutyl)-, and
3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine. The use of DKPs
for drug delivery is known in the art (see for example U.S. Pat.
Nos. 5,352,461, 5,503,852, 6,071,497, and 6,331,318'', each of
which is incorporated herein by reference for all that it teaches
regarding diketopiperazines and diketopiperazine-mediated drug
delivery). The use of DKP salts is described in co-pending U.S.
patent application Ser. No. 11/210,710 filed Aug. 23, 2005, which
is hereby incorporated by reference for all it teaches regarding
diketopiperazine salts. Pulmonary drug delivery using DKP
microparticles is disclosed in U.S. Pat. No. 6,428,771, which is
hereby incorporated by reference in its entirety.
[0079] TECHNOSPHERE.RTM./Placebo: As used herein,
"TECHNOSPHERE.RTM./Placebo" refers to TECHNOSPHERE.RTM. particles
which are not associated with insulin.
[0080] Units of measure: Subcutaneous and intravenous insulin
dosages are expressed in IU which is defined by a standardized
biologic measurement. Amounts of insulin formulated with fumaryl
diketopiperazine are also reported in IU as are measurements of
insulin in the blood. TECHNOSPHERE.RTM./Insulin dosages are
expressed in arbitrary units (U) which are numerically equivalent
to the amount of insulin formulated in the dosage.
DETAILED DESCRIPTION OF THE INVENTION
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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). The glucose elimination rate (measured as the glucose infusion
rate [GIR]) however continues to rise throughout this plateau phase
(FIG. 5), peaking only as insulin concentration begins to decay
(FIG. 4). 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). 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).
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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 teache
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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] TECHNOSPHERE.RTM. refers to a diketopiperazine-based drug
delivery system which can complex and stabilize peptides in small
particles.
[0095] Diketopiperazines, particularly furnaryl 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.
[0096] 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.
[0097] 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's circulation, the
hexameric form must first disassociate into dimeric and/or
monomeric forms before the material can move into the
bloodstream.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] 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 peri-prandially 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] In an embodiment of the present invention, a pharmaceutical
composition is provided wherein the insulin is complexed with a
diketopiperazine microparticle, preferably fumaryl
diketopiperazine.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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 furnaryl diketopiperazine.
[0118] 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.
[0119] 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.
EXAMPLES
Example 1
Insulin Concentration at Different Dose Levels Indicates Linear
Absorption
[0120] Various dosages of TECHNOSPHERE.RTM./Insulin (TI, MannKind
Corporation) were administered to human subjects and insulin
concentration in the blood was measured (FIG. 7A). Insulin
absorption, as AUC, was linear with dosage at least up to 100 U TI
(FIG. 7B).
Example 2
Mimicry of the Early Phase Insulin Response in Humans with Rapidly
Bioavailable Inhaled Insulin Accelerates Post Prandial Glucose
Disposal Compared to Insulin with Slower Bioavailability
[0121] The relationship between time, insulin concentration and
glucose elimination rate in a group of 12 subjects with type 2
diabetes, during an isoglycemic clamp was studied. Each subject
received 24 IU subcutaneous soluble human insulin (ACTRAPID.RTM.,
Novo Nordisk) or 48 U TECHNOSPHERE.RTM./Insulin (TI) on separate
study days in a cross-over design.
[0122] The glucose elimination rate (GIR) was determined by the
amount of glucose infusion required to maintain stable blood
glucose of 120 mg/dL during the 540 min study period (FIG. 4).
Forty-eight units TI provided a mean maximum concentration of
insulin (C.sub.max) of 114.8.+-.44.1 (mean.+-.SD) mIU/L and had a
median time to maximum concentration (T.sub.max) of 15 min, whereas
24 IU subcutaneous insulin (SC) had a C.sub.max of 63.+-.10.1 mIU/L
with a T.sub.max of 150 min. TECHNOSPHERE.RTM./Insulin reached
maximal GIR values, 3.33.+-.1.35 mg/min/kg, at 45 min, while at
that timepoint, SC was only 1.58.+-.1.03 and did not reach maximal
value, 3.38.+-.1.45 before 255 min, despite almost constant insulin
concentrations. The data for GIR and insulin concentration for TI
are also plotted individually versus time in FIG. 8. Once maximal
insulin effect was reached, the concentration-effect relationship
was the same for TI and SC (FIG. 4). At 180 min, glucose disposal
was 326.+-.119 mg/kg or 61% of total for TI and 330.+-.153 mg/kg
(27% of total) for SC.
[0123] A fast, sharp increase in insulin concentration, similar to
the early phase insulin response, provided maximal glucose
elimination rate. Forty-eight units TI achieved maximal effect
within 45 min, whereas it took 270 min for 24 IU SC to reach
similar effect. This phenomenon is not caused by differences in the
dose-effect relationship for the two insulin types, but reflects a
difference in response when the increment in insulin concentration
is more modest over time as opposed to the more rapid bioavailable
insulin provided by TECHNOSPHERE.RTM./Insulin. This can have
consequences for postprandial glucose control.
[0124] Additionally, three hours after dosing, 48 U TI and 24 IU SC
had exerted the same glucose lowering effect. However, less than
one-third of the total glucose lowering effect for the SC dose had
been obtained. The percent of total glucose lowering activity
provided within 180 minutes after a meal was 74% for TI and 29% for
SC insulin (FIG. 5). If the prandial insulin dose is titrated
towards a goal of normoglycemia at three hours after a meal, the
large remaining glucose lowering effect of SC insulin may increase
the risk of late post-prandial hypoglycemia, as compared to TI. In
addition to confining the bulk of glucose lowering activity to a
time period more similar to the glucose load created by a meal, the
kinetics exhibited by TI also allowed for the reassertion of
endogenous insulin secretion sooner, that is glycemic control is
returned to homeostatic mechanisms. At late time points (>150
minutes), the fall in insulin concentration lags behind what would
have been expected based on the decay rate seen at earlier time
points. This can be understood as the superimposition of falling
exogenous insulin (from TI) and rising endogenous insulin (FIG.
14).
[0125] Endogenous insulin secretion should be accompanied by the
production of C-peptide. Mean serum C-peptide concentrations over
time for inhaled TI and injectable SC regular insulin are presented
in FIG. 16. C-peptide concentrations were essentially unchanged
during SC treatment but rose with TI treatment with a timing
consistent with the model depicted in FIG. 14.
[0126] One of the most important aims of drug therapy in patients
with type 2 diabetes is to restore or to replace the first phase of
the meal-related insulin response which is lost early in the course
of type 2 diabetes mellitus. The rapid onset and short duration of
action of inhaled TI should make it suitable for replacement of
prandial insulin secretion in patients with diabetes mellitus.
Example 3
A Fast Insulin Spike does not Increase Risk of Hypoglycemia
[0127] It might be feared that the large concentrations of insulin,
especially combined with their potentiation effect, would drive
glucose elimination rates so high that they would pose a danger of
inducing hypoglycemia. However this is not the case. Healthy human
subjects under a euglycemic clamp were given intravenous,
subcutaneous, or pulmonary insulin and the GIR was plotted against
blood insulin concentration starting 20 minutes after
administration. In normal subjects GIR hysteresis in response to
insulin is much less pronounced than that for type 2 diabetics as
disclosed in Example 1 above. Thus for normal subjects, 20 minutes
after insulin administration and onward the relation between GIR
and insulin concentration approximates a true mathematical
function. It was observed that while at lower insulin
concentrations the function appeared linear, consideration of
higher concentrations showed that the relationship was actually
logarithmic; as insulin concentration rose, ever smaller increases
in GIR were obtained (FIG. 15). Thus glucose elimination did not
reach catastrophically high rates and appeared unable to do so.
Example 4
The Variability and Time-Action Profile of Inhaled
TECHNOSPHERE.RTM./Insulin Compares Favorably to that of
Subcutaneous Human Regular Insulin
[0128] Timing and reproducibility and of insulin's metabolic effect
is critical to achieve near-normal glucose control and to enable
patients and doctors to make appropriate dose adjustments. The
time-action profiles and the intra-subject variability in insulin
absorption and insulin effect between repeated doses of 48 U
inhaled TECHNOSPHERE.RTM./Insulin (TI) and 24 IU subcutaneous
injected human regular insulin (SC) was compared.
[0129] TECHNOSPHERE.RTM./Insulin and SC were given on three
separate occasions each on separate study days in a randomized
sequence in 12 insulin-treated subjects with type 2 diabetes (10
males, 2 females, age 56 (range 40-65) years, diabetes duration
14.4 (3-29) years, HbA1c 6.9.+-.0.9% (mean.+-.SD), all normal lung
function (FVC, FEV1 and VC=80% of predicted normal)). Using a
euglycemic glucose clamp (clamp level 120 mg/dL), pharmacokinetic
(PK) and pharmacodynamic (PD) time-action profiles were measured
over 540 min following each form of insulin administration.
Variability of absorption and effect, expressed as CV % of
AUC.sub.0-t, was determined at 120, 180 and 540 min after
dosing.
[0130] TECHNOSPHERE.RTM./Insulin showed a more rapid onset of
action (INS-T.sub.max 17.+-.6 vs. 135.+-.68 min, TI vs. SC,
p<0.0001) and higher peak insulin concentrations (INS-C.sub.max)
than SC (Table 1). TECHNOSPHERE.RTM./Insulin reached maximal
glucose infusion rate (GIR) values already at 79.+-.47 min, while
the maximum effect of the SC dose occurred at 293.+-.83 min
(p<0.00001). The AUCs for both INS and GIR curves were higher
for TI compared to SC in the first two and three hours after
administration (Table 1). The variability in both insulin
concentrations and insulin action was lower for TI compared to SC
in the first three hours after administration. Specifically, for TI
the variability in insulin effect (GIR) was 23%, 22% and 26% at
120, 180 and 540 min respectively, as compared to 39%, 33% and 18%
for SC (FIG. 6A). The variability in insulin concentrations (FIG.
6B) followed a similar pattern (19%, 18% and 16% for TI and 27%,
25% and 15% for SC). At 270 min, GIR for TI had returned to
baseline, and the variability in measured plasma insulin at 540 min
was comparable to the variation of SC (CV %: GIR-AUC.sub.0-540 min
26% vs. 18% (TI vs. SC); INS-AUC.sub.0-540 min 16% vs. 15%).
[0131] TECHNOSPHERE.RTM./Insulin showed a more rapid onset and a
shorter duration of action than subcutaneous regular human insulin
which can make it suitable for replacement of prandial insulin
secretion in patients with type 2 diabetes. In particular, TI can
provide a lower risk of late postprandial hypoglycemia as, in
contrast to SC, most of its glucose lowering effect occurred before
the three hour point. Furthermore, the intra-patient variability of
repeated inhalations of TI was superior to SC insulin during the
first three hours after dosing which can facilitate dose
titration.
TABLE-US-00001 TABLE 1 Pharmacokinetic Parameters after Pulmonary
Administration of TI Inhaled TECHNOSPHERE .RTM. Insulin SC Human
Regular Insulin CV (%) CV (%) mean .+-. SD [95% CI] mean .+-. SD
[95% CI] Pharmacodynamic (PD) Parameters, based on glucose infusion
rates (GIR) GIR-AUC.sub.0-2 h 265 .+-. 83 23.4 211 .+-. 84 39.2
(mg/kg) (44% of total) [13.9-33.0] (16% of total) [23.2-55.2]
GIR-AUC.sub.0-3 h 355 .+-. 119 21.7 363 .+-. 153 33.4 (mg/kg) (59%
of total) [12.9-30.6] (27% of total) [19.8-47.1] GIR.sub.max .sup.
4.5 .+-. 1.0.sup.+ 22.0 5.5 .+-. 1.4 17.3 (mg/kg/min) [13.0-30.9]
[10.3-24.4] Pharmacokinetic (PK) Parameters, based on plasma
insulin (INS) concentrations INS-AUC.sub.0-2 h 6965 .+-. 2233* 19.1
5509 .+-. 1094 27.1 (.mu.U/ml) (56% of total) [11.3-26.9] (24% of
total) [16.1-38.2] INS-AUC.sub.0-3 h 8030 .+-. 2561 18.2 8672 .+-.
1442 25.0 (.mu.U/ml) (64% of total) [10.8-24.6] (38% of total)
[14.8-35.2] INS-C.sub.max 124 .+-. 44.sup.+ 20.4 63 .+-. 10 29.2
(.mu.U/ml) [12.1-28.8] [17.3-41.2] CI: Confidence Interval *p <
0.05 vs. SC, .sup.+p < 0.0005 vs. SC (ANOVA, Mixed Effects
Models)
Example 5
A Randomized, Double-Blind, Placebo Controlled Study of the
Efficacy and Safety of Inhaled TECHNOSPHERE.RTM./Insulin in
Patients with Type 2 Diabetes
[0132] TECHNOSPHERE.RTM. dry powder pulmonary insulin delivered via
a small inhaler (MEDTONE.TM., MannKind Corp., Valencia, Calif.) has
a bioavailability that mimics normal, meal-related, first- or
early-phase insulin release. This multicenter, randomized,
double-blind, placebo-controlled study was conducted in type 2
diabetes mellitus patients inadequately controlled on diet or oral
agent therapy (HbA1c>6.5% to 10.5%). A total of 123 patients
were enrolled and 119, the intention-to-treat population (ITT),
were randomized in a 1:1 ratio to receive prandial inhaled
TECHNOSPHERE.RTM./Insulin (TI) from unit dose cartridges containing
between 6 to 48 units of human insulin (rDNA origin) or inhaled
TECHNOSPHERE.RTM./placebo for 12 weeks. TI was inhaled at the time
of the first mouthful of food at each main or substantive meal of
the day, amounting to 3 or 4 administrations per day throughout the
12 week trial. Subjects continued whatever oral diabetes drugs they
were using prior to entering the study. Differences in HbA1c from
the first and final treatment visits, and between the first and two
intermediate visits, were determined, as was the change in blood
glucose, as AUC at various time points, and C.sub.max and
T.sub.max, after a meal challenge.
[0133] Patients were given a standardized meal several times during
the study and their blood glucose levels measured. The study drug
was administered at the study site in conjunction with a
standardized breakfast that was prepared at the site. Fasting
plasma glucose was measured immediately before the meal. Spirometry
was performed before the subject took the first dose of study drug.
Subjects then inhaled the study drug and, within 60 seconds,
performed a single spirometry test procedure. Within 90 seconds of
the study drug inhalation, and after the spirometry test, the
subject began eating the test meal. Once the meal was completed,
the plasma glucose values and glucose meter readings were obtained
at immediately before and at 30, 60 and 120 minutes after beginning
the meal.
[0134] For patients receiving either TI or placebo, blood glucose
rose after meal challenge, but significantly less for the TI group
and returned to baseline sooner (FIG. 11). Thus total glucose
exposure, expressed as AUC.sub.0-120, (FIG. 12A) and maximal
glucose excursion (C.sub.max FIG. 12B) were reduced. FIG. 13 shows
the observed difference in maximal glucose excursions between the
patients receiving different dosages of TI versus those in the
control arm. Note that at a dose of 30 U the maximal glucose
excursions for the TI patients were 50% of the level for the
patients in the control group. Also note that the average glucose
excursion was about 28 mg/dL vs. 50 mg/dL when the TI patients
entered the study. An excursion of only 28 mg/dL is within the
range that is a goal of clinical treatment.
[0135] Glycosylated hemoglobin A1c (HbA1c) results were analyzed by
a pre-determined statistical analysis plan for the Primary Efficacy
Population (PEP, defined prior to un-blinding as those who adhered
to study requirements including minimal dosing and no adjustments
of concomitant diabetes drugs), for a PEP Sub-group A (those with
baseline HbA1c of 6.6 to 7.9%), for a PEP Sub-group B (those with
baseline HbA1c of 8.0 to 10.5%), as well as for the ITT. These
results are summarized in Table 2, and for PEP Sub-group B in FIG.
17. In this "individualized dose" study, the mean dose of TI used
before each meal in the active treatment group was approximately 30
units, with 28 units used in PEP Sub-group A and 33.5 units used in
PEP Sub-group B.
TABLE-US-00002 TABLE 2 HbA1c Pharmacokinetics TECHNOSPHERE .RTM./
TECHNOSPHERE .RTM./ Placebo Insulin PEP n = 90 n = 42 n = 48 Mean
HbA1c Baseline 7.75 7.74 (%) Mean .DELTA. from baseline -0.32 (p =
0.0028) -0.76 (p < 0.0001) Comparison to Placebo p = 0.0019 PEP
Sub-group B n = 35 n = 18 n = 17 Mean HbA1c Baseline 8.52 8.72 (%)
Mean .DELTA. from baseline -0.51 (p = 0.0094) -1.37 (p < 0.0001)
Comparison to Placebo p = 0.0007 PEP Sub-group A n = 55 n = 24 n =
31 Mean HbA1c Baseline 7.16 7.19 (%) Mean .DELTA. from baseline
-0.18 (p = 0.1292) -0.43 (p = 0.0001) Comparison to Placebo p <
0.05 IIT (LOCF) n = 119 n = 61 n = 58 Mean HbA1c Baseline 7.78 7.87
(%) Mean .DELTA. from Baseline -0.31 (p = 0.0020) -0.72 (p <
0.0001) (%) Comparison to Placebo p = 0.0016
[0136] No episodes of severe hypoglycemia occurred in the TI group.
There was no statistically significant difference in the rate of
hypoglycemic events between those subjects receiving placebo and
those receiving TI. (Table 3).
TABLE-US-00003 TABLE 3 Incidence of Hypoglycemia after Pulmonary
Administration of TI TECHNOSPHERE .RTM./ TECHNOSPHERE .RTM./
Insulin Placebo Hypoglycemia 42.6% 35.5% (% of patients)
Hypoglycemia 0.16 0.20 (events/week)
[0137] Pulmonary function tests, including DLco (diffusing capacity
of the lung for carbon monoxide) (Table 4), FEV1 (forced expiratory
volume in one second), and total alveolar volume (forced vital
capacity, FVC) showed no significant differences between patients
on TI compared to their baseline values or compared to the results
of those receiving placebo (FIG. 19).
TABLE-US-00004 TABLE 4 Pulmonary Function After Pulmonary
Administration of TI TECHNOSPHERE .RTM./ TECHNOSPHERE .RTM./ DLco
Insulin Placebo 0 weeks 24.9 .+-. 4.8 26.5 .+-. 5.6 12 weeks 25.0
.+-. 4.5 25.7 .+-. 5.2
[0138] There was no evidence of induction of insulin antibodies
with TI (Table 5) or of weight gain (FIG. 18) during the 12 week
period of exposure.
TABLE-US-00005 TABLE 5 Incidence of Antibodies to Insulin after
Pulmonary Administration of TI TECHNOSPHERE .RTM./ TECHNOSPHERE
.RTM./ Insulin Placebo Negative at Visit 1/ 38 34 Negative at Visit
9 Negative at Visit 1/ 2 3 Positive at Visit 9 Positive at Visit 1/
8 10 Positive at Visit 9 Positive at Visit 1/ 2 4 Negative at Visit
9
[0139] In conclusion, this study has demonstrated that
TECHNOSPHERE.RTM. pulmonary insulin, in replication of the kinetics
of the early phase of insulin release, when used in patients with
inadequate glycemic control previously on only diet and exercise
alone or on oral agent therapy, safely and significantly improved
glycemic control with no significantly increased incidence of
hypoglycemia, no induction of insulin antibodies, no tendency
toward weight gain, and no evidence of overall impact on pulmonary
function.
Example 6
FDKP/Insulin Provides Glycemic Control when Administered from 10
Minutes Before to 30 Minutes after the Beginning of a Meal
[0140] A clinical trial was conducted to evaluate the effect of the
timing of pulmonary administration of an FDKP-insulin complex as a
dry powder (FDKP/Insulin, also referred to as
TECHNOSPHERE.RTM./Insulin, TI). Subjects were type 1 diabetics who
were not receiving any drug, other than insulin, for treatment of
their diabetes, nor any other drug affecting carbohydrate
metabolism. The trial was a prospective, single-center, randomized,
crossover, open-label study. At each of 8 treatment visits, human
subjects inhaled a single individualized dose 10 min before (B10),
immediately before (C0), 15 min after (A15), or 30 min after (A30)
eating an isocaloric (I; approximately 500 kcal) or hypercaloric
(H; approximately 720 kcal) meal. Each subject received each of the
eight possible timings of administration/meal combinations (i.e.,
B10I, B10H, C0I, C0H, A15I, A15H, A30I, and A30H) on separate
occasions and in random order, with 1 to 14 days elapsing between
treatment visits (see FIG. 20). Blood samples taken before and
after inhalation of the TI and meal consumption were used to
determine pharmacokinetic parameters for glucose and insulin.
[0141] The dose of TI was individualized for each subject. The
individualized dose was based on the carbohydrate content of the
meal to be consumed during the treatment visit, a correction factor
for TI bioavailability, and the subject's individual "insulin
factor" (Fi), which was determined during a preliminary visit
before the first treatment visit. The method of dose
individualization was calculated at each treatment visit according
to the following formula:
IUdose=(BE*Fi)/0.30
[0142] where: [0143] IUdose was the number of IU of TI to be
administered [0144] BE (Brot-Einheit, bread unit) was 1/10 of the
carbohydrate content (in grams) of the meal to be consumed (5 for
the isocaloric and 8.5 for the hypercaloric meals, respectively)
[0145] Fi was the individual insulin factor, equivalent to the
units of insulin required to cover one BE. [0146] 0.30 was the
correction factor for TI bioavailability.
[0147] After calculation, the dose of TI was rounded to the nearest
dose that could be administered using multiples of the TI
cartridges, which contained 6 U, 12 U, or 24 U insulin.
[0148] During treatment visits, insulin was infused intravenously
at a rate of 1 IU/hour and glucose was infused at a rate adjusted
to achieve a stable capillary blood glucose concentration within
the range of 80 to 140 mg/dL before meal consumption and/or TI
inhalation. This infusion was continued without adjustment during
the study. Venous blood samples were collected at varying
intervals, starting at 45 min prior to meal consumption and
continuing until four hours after consumption. The samples were
used for determination of blood (serum) glucose and serum insulin
concentrations.
[0149] The primary efficacy variable was blood glucose
concentration. As well as providing a profile of the blood glucose
concentration before and after TI and meal administration, the
blood glucose concentration values were used to calculate the
following pharmacokinetic parameters to describe total glucose
excursion: [0150] Maximal (C.sub.max) and minimal (C.sub.min) blood
glucose concentrations after the start of meal consumption,
corrected for baseline values. [0151] Minimal (C.sub.min) blood
glucose concentrations after TI inhalation, corrected for baseline
values. [0152] Time to C.sub.max (T.sub.max), time to C.sub.min
(T.sub.min), and time to last glucose excursion above baseline
levels after start of meal (T.sub.x). [0153] Area under the blood
glucose concentration curve (AUC) was calculated using trapezoidal
method for three separate time periods: [0154] AUC: from 10 min
before to 240 min after start of meal [0155] AUC1: from 10 min
before to T.sub.x, and [0156] AUC2: from T.sub.x to 240 min after
start of meal. [0157] Blood glucose concentration at 1 hour (BG1)
and 2 hours (BG2) after start of meal.
[0158] To ensure baselines were comparable between treatments,
blood glucose and serum insulin baselines were computed based on
the average of the -45, -30 and -20 min pre-meal measurements.
[0159] The secondary efficacy variable was serum insulin
concentration. Insulin absorption was assumed to be independent of
the time of dose relative to meals. The pharmacokinetic profile for
insulin was determined based on serum insulin values normalized for
dose and using dosing time as T=0 for all data sets. Mean C.sub.max
(peak insulin concentration), AUC (area under the insulin
concentration time curve), Tmax (time from dosing to peak
concentration), time from dosing to reach 50% of C.sub.max (early
T.sub.50%), and time from T.sub.max to 50% decline in C.sub.max
(late T.sub.50%) were calculated. Following normalization (to a
hypothetical 100 IU) for individual dose, intra- and
inter-individual variation was determined as the CV % for the mean
of individual C.sub.max and AUC.
[0160] The primary efficacy variable was blood glucose
concentration. The effect of timing of administration of TI on the
mean (SD) baseline-corrected blood glucose concentrations before
and after an isocaloric or hypercaloric meal is illustrated in FIG.
21 for the primary efficacy population. Overall, the comparative
excursions in blood glucose, while greater after the hypercaloric
meal than the isocaloric meal, were similar in profile for the two
meal types but were dependent upon the timing of administration of
TI (FIG. 21). Notably, when TI was inhaled 10 min before either
meal, there was an initial decrease in blood glucose levels. After
reaching a nadir about 10 min after the start of the meal, blood
glucose levels rose above baseline levels approximately 30 min
later. By comparison, when TI was inhaled 15 or 30 min after the
start of the meal, glucose levels rose above baseline approximately
10-15 min after starting meal consumption (FIG. 21).
[0161] A comparison of pharmacokinetic parameters for blood glucose
following each type of meal and for each timing of administration
of TI is shown in Table 6 for the primary efficacy population. As
indicated by the mean minimum blood glucose levels (C.sub.min,
expressed as change from baseline) and initial period of the area
under the glucose concentration curve (AUC1), the greatest
reduction in blood glucose occurred when TI was inhaled 10 min
before subjects started eating either the isocaloric or
hypercaloric meal (C.sub.min -21 mg/dL and -27 mg/dL, respectively;
AUC1 -722 and -907 min*mg/dL, respectively) (Table 6). When TI was
inhaled either 10 min before or immediately before meal
consumption, blood glucose levels reached a nadir in approximately
10 to 13 min (as indicated by the median T.sub.min), and did not
rise above baseline levels until 20 to 30 min later (as indicated
by the median T.sub.x) (Table 6). By comparison, when TI was
inhaled either 15 min or 30 min after the start of meal
consumption, reductions in blood glucose were smaller (C.sub.min
-10 to -13 mg/dL; AUC1 -141 to -176 min*mg/dL), they occurred
sooner (T.sub.min 3 to 5 min), and they were more short-lived
(approximately 6 to 7 min). The largest individual reductions in
blood glucose were in subjects who inhaled TI immediately before
isocaloric or hypercaloric meal consumption (C.sub.min -58 mg/dL
and -57 mg/dL, respectively).
TABLE-US-00006 TABLE 6 Summary of Blood Gluclose Pharmacokinetic
Parameters by Meal and Timing of Administration of TECHNOSPHERE
.RTM./Insulin Isocaloric Meal Hypercaloric Meal Timing of Dosing
Timing of Dosing B10 C0 A15 A30 B10 C0 A15 A30 Parameter (N = 12)
(N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12)
C.sub.min (mg/dL) -21 -18 -11 -13 -27 -16 -11 -10 (14) (15) (14)
(7) (8) (14) (7) (7) T.sub.min (minutes) 10 13 5 5 13 10 5 3
C.sub.max (mg/dL) 86 84 88 81 119 130 116 113 (28) (38) (36) (23)
(46) (40) (50) (47) T.sub.max (minutes) 165 135 150 120 180 180 150
165 AUC1 (min*mg/dL) -722 -648 -154 -176 -907 -418 -149 -141 (950)
(840) (180) (176) (511) (549) (148) (149) AUC2 (min*mg/dL) 11499
10989 13055 12431 14818 17395 16346 18402 (4640) (7030) (7616)
(4682) (6018) (6050) (8326) (8968) AUC (min*mg/dL) 10777 10342
12901 12255 13911 16977 16197 18261 (5339) (7349) (7739) (4895)
(5840) (6008) (8407) (8982) BG1 (mg/dL) 21 23 41 55 16 33 38 65
(32) (25) (32) (23) (23) (21) (31) (24) BG2 (mg/dL) 68 71 78 68 81
101 82 89 (34) (34) (32) (32) (28) (33) (47) (46) T.sub.x (minutes)
36.6 36.9 11.7 11.3 42.2 33.2 12.4 10.3 All values are presented as
mean (SD) except for T.sub.min, T.sub.max and T.sub.x, which are
median.
[0162] Mean C.sub.max values (expressed as change from baseline),
AUC, and AUC2 were generally comparable whether TI was given before
or after a particular type of meal, though all were lower after the
isocaloric meal than the hypercaloric meal (Table 6). The median
time to C.sub.max (T.sub.max) ranged between 120 and 165 min for
the isocaloric meal and between 150 to 180 min for the hypercaloric
meal. Mean blood glucose levels one hour (BG1) and two hours (BG2)
after the start of meal showed no consistent relationship to time
of inhalation of TI relative to either meal (Table 6), although BG1
was lowest when TI was given 10 min before the start of a meal and
highest when given 30 min after the start of a meal.
[0163] The comparative effects of different times of TI inhalation
on selected glucose pharmacokinetic parameters was expressed as a
ratio of the value at the corresponding C0 (i.e, B10/C0,
A15/C0.sub.3 and A30/C0) for each meal type. These ratios, along
with their 95% confidence intervals (CI), are summarized in Table 7
(primary efficacy population). These results indicated that the
comparative effects of inhalation of TI immediately before meal
consumption were no different than that of inhalation 10 min before
meal consumption on any pharmacokinetic parameter (i.e, most B10/C0
ratios were close to 1 and the 95% CI encompassed 1 within their
range). Most comparisons also yielded no differences between TI
immediately before meal consumption and 15 or 30 min after.
TABLE-US-00007 TABLE 7 Comparison of Blood Glucose Pharmacokinetic
Parameters Relative to Inhalation of TECHNOSPHERE .RTM./Insulin
Immediately Before Meal Consumption Isocaloric Meal Hypercaloric
Meal Ratio of Test to Reference Parameter Ratio of Test to
Reference Parameter B10/C0 A15/C0 A30/C0 B10/C0 A15/C0 A30/C0
Parameter (N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12)
C.sub.min 0.997 0.425 0.581 1.748 0.988 0.532 (0.470, 2.112)
(0.210, 0.860) (0.302, 2.112) (0.470, 2.112) (0.470, 2.112) (0.470,
2.112) AUC1 0.608 0.300 0.214 1.995 0.381 0.334 (0.133, 2.775)
(0.067, 1.334) (0.053, 0.863) (0.803, 4.762) (0.154, 0.942) (0.137,
0.814) C.sub.max 1.002 1.088 0.953 0.848 0.778 0.814 (0.809, 1.240)
(0.887, 1.334) (0.784, 1.157) (0.630, 1.143) (0.581, 1.041) (0.616,
1.076) AUC2 1.077 1.035 1.158 0.780 0.771 0.907 (0.727, 1.596)
(0.711, 1.506) (0.809, 1.657) (0.497, 1.226) (0.496, 1.198) (0.594,
1.385) AUC 1.105 0.722 1.245 0.727 0.753 0.910 (0.555, 2.200)
(0.378, 1.380) (0.671, 2.310) (0.426, 1.238) (0.448, 1.266) (0.553,
1.500) BG1 0.833 1.203 7.932 0.768 1.256 1.985 (0.451, 1.536)
(0.656, 2.207) (1.143, 3.267) (0.491, 1.200) (0.810, 1.948) (1.379,
2.857) BG2 0.630 1.109 0.906 0.771 0.665 0.758 (0.258, 1.536)
(0.468, 2.627) (0.399, 2.058) (0.533, 1.114) (0.464, 0.953) (0.537,
1.069) All values are presented as ratio (95% confidence
interval).
[0164] The secondary efficacy variable was serum insulin
concentration. The profile of the mean (SD) baseline-corrected
serum insulin concentrations after TI inhalation is illustrated in
FIG. 22 for the primary efficacy population. There was a sharp
increase in serum insulin immediately after inhalation of TI, which
was independent of dosing time and meal type. Serum insulin
concentrations peaked approximately 15 min after dosing and
thereafter rapidly declined until 60 min after administration,
after which there was a slower decline, consistent with first-order
elimination.
[0165] A comparison of pharmacokinetic parameters for serum insulin
for each timing of administration of TI relative to each type of
meal is shown in Table 8 for the primary efficacy population.
Overall, the mean C.sub.max (expressed as change from baseline) and
AUC values for serum insulin were generally comparable,
irrespective of meal type and whether TI was given before or after
the meal (Table 8). Irrespective of meal type and time of dosing
relative to the meal, serum insulin concentrations rose rapidly
after TI inhalation, with the early T.sub.50% ranging between three
and five min and peak concentrations being observed 10 to 20 min
after administration. Thereafter, serum insulin concentrations
declined, with the late T.sub.50% ranging between 33 and 43 min,
and again showed no consistent variation with time of inhalation of
TI or meal type (Table 8).
TABLE-US-00008 TABLE 8 Summary of Serum Insulin Pharmacokinetic
Parameters by Meal and Timing of Administration of TECHNOSPHERE
.RTM./Insulin Isocaloric Meal Hypercaloric Meal Timing of Dosing
Timing of Dosing B10 C0 A15 A30 B10 C0 A15 A30 Parameter (N = 12)
(N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12) (N = 12)
C.sub.max (mlU/L) 207 179 188 215 211 137 191 193 (145) (125) (137)
(196) (138) (74) (114) (163) T.sub.max (minutes) 13 15 15 15 10 20
15 15 AUC (min*mlU/L) 12635 11291 11642 12649 10654 7710 12874
11662 (15681) (17449) (18373) (14838) (7623) (7313) (16785) (13210)
Early T.sub.50% (min) 4 4 3 3 4 5 4 3 Late T.sub.50% (min) 40 40 33
43 43 42 39 39 All values are presented as mean (SD) except for
T.sub.max, and T.sub.50%, which are median.
[0166] Thus inhalation of an individualized dose of TI provides
glycemic control in subjects with type 1 diabetes who consume
isocaloric or hypercaloric meals. There were no differences in the
pharmacokinetics of insulin based on the timing of administration
relative to the meals. The administration of TI between 10 minutes
prior to the time of the first bite of food and up to 30 minutes
after starting a meal provides comparable glycemic control in the
postprandial period.
Example 7
Bioavailability of Insulin in Diketopiperazine Pulmonary
Formulation
[0167] Subjects and Methods
[0168] The study was conducted with 5 healthy male volunteers.
Inclusion criteria were good health, as judged by physical
examination, age: 18 to 40 years, body mass index: 18 to 26
kg/m.sup.2, capability to reach peak inspiratory flow of .gtoreq.4
L/sec measured by a computer assisted spirometry and a FEV1 equal
to or greater than 80% of predicted normal (FEV1=forced expiratory
volume in one second). Exclusion criteria were diabetes mellitus
type 1 or 2, prevalence of human insulin antibodies, history of
hypersensitivity to the study medication or to drugs with similar
chemical structures, history or severe or multiple allergies,
treatment with any other investigational drug in the last three
months before study entry, progressive fatal disease, history of
drug or alcohol abuse, current drug therapy with other drugs,
history significant cardiovascular, respiratory, gastrointestinal,
hepatic, renal, neurological, psychiatric and/or hematological
disease, ongoing respiratory tract infection or subjects defined as
being smokers with evidence or history of tobacco or nicotine
use.
[0169] Conduct of the Study
[0170] On the morning of the study days, the subjects came to the
hospital (fasting, except for water, from midnight onward) at 7:30
a.m. The subjects were restricted from excessive physical
activities and an intake of alcohol for 24 hours before each
treatment day. They were randomly assigned to one of the three
treatment arms. The subjects received a constant intravenous
regular human insulin infusion, which was kept at 0.15 mU
min.sup.-1 kg.sup.-1 so that serum insulin concentrations were
established at 10-15 .mu.U/mL during a period of two hours before
time point 0. This low-dose infusion was continued throughout the
test to suppress endogenous insulin secretion. Blood glucose was
kept constant at a level of 90 mg/dL throughout the glucose clamp
by a glucose controlled infusion system (BIOSTATOR.TM.). The
glucose clamp algorithm was based on the actual measured blood
glucose concentration and the grade of variability in the minutes
before to calculate the glucose infusion rates for keeping the
blood glucose concentration constant. The insulin application (5 IU
IV or 10 IU SC injection or three deep breaths inhalation per
capsule (2 capsules with 50 U each) applied with a commercial
inhalation device (Boehringer Ingelheim)) had to be finished
immediately before time point 0. The duration of the clamp
experiment was six hours from time point 0. Glucose infusion rates,
blood glucose, serum-insulin and C-peptide were measured.
[0171] Bioefficacy and Bioavailability
[0172] To determine bioefficacy, the areas under the curve of the
glucose infusion rates were calculated for the first three hours
(AUC.sub.0-180) after the administration and for the overall
observation period of six hours after the administration
(AUC.sub.0-360) and were correlated to the amount of insulin
applied. To determine bioavailability, the areas under the curve of
the insulin concentrations were calculated for the first three
hours (AU.sub.0-180) after the administration and for the overall
observation period of six hours after the administration
(AUC.sub.0-360) and correlated to the amount of insulin
applied.
[0173] In this clamp study, inhalation of 100 U of
TECHNOSPHERE.RTM./Insulin was well tolerated and was demonstrated
to have a substantial blood glucose lowering effect with a relative
bioavailability of 25.8% for the first three hours as calculated
from the achieved serum insulin concentrations. TECHNOSPHERES.RTM.
are microparticles (also referred to herein as microspheres) formed
of diketopiperazine that self-assembles into an ordered lattice
array at particular pHs, typically a low pH. They typically are
produced to have a mean diameter between about 1 and about 5
.mu.m.
[0174] Results
[0175] The pharmacokinetic results are illustrated in FIGS. 23 and
24 and in Table 9.
[0176] Efficacy Results
[0177] Inhalation of 100 U of TI revealed a peak of insulin
concentration after 13 min (intravenous (IV) (5 IU): 5 min,
subcutaneous (SC) (10 IU): 121 min) and a return of the insulin
levels to baseline after 180 min (IV: 60 min, SC: 360 min).
Biological action as measured by glucose infusion rate peaked after
39 min IV: 14 min, SC: 163 min) and lasted for more than 360 min
(IV: 240 min, SC: >360 min). Absolute bioavailability
(comparison to IV application) was 14.6.+-.5.1% for the first three
hours and 15.5.+-.5.6% for the first six hours. Relative
bioavailability (comparison to SC application) was 25.8.+-.11.7%
for the first three hours and 16.4.+-.7.9% for the first six
hours.
TABLE-US-00009 TABLE 9 Pharmacokinetic Parameters after Pulmonary
Administration of TI Pharmacokinetic Parameters Intravenous
Subcutaneous Administration Inhaled TI Administration Parameter
Calculated on Glucose Infusion Rate T.sub.50%* 9 min 13 min 60 min
T.sub.max 14 min 39 min 163 min T.sub.-50%** 82 min 240 min 240 min
T to baseline 240 min >360 min >360 min Parameter Calculated
on Insulin Levels T.sub.50%* 2 min 2.5 min 27 min T.sub.max 5 min
13 min 121 min T.sub.-50%** 6 min 35 min 250 min T to baseline 60
min 180 min 360 min *time from baseline to half-maximal values
**time from baseline to half-maximal after passing Tmax
[0178] Safety Results
[0179] TECHNOSPHERE.RTM./Insulin was shown to be safe in all
patients. One patient was coughing during the inhalation without
any further symptoms or signs of deterioration of the breathing
system.
CONCLUSIONS
[0180] Inhalation of 100 U of TI was well tolerated and was
demonstrated to have a substantial blood glucose lowering effect
with a relative bioavailability of 25.8% for the first three hours
as calculated from the achieved serum insulin concentrations.
SUMMARY
[0181] In this study, the inhalation of TI was demonstrated in
healthy human subjects to have a time-action profile with a rapid
peak of insulin concentration (T.sub.max: 13 min) and rapid onset
of action (T.sub.max: 39 min) and a sustained action over more than
six hours. The total metabolic effect measured after inhalation of
100 U of TI was larger than after subcutaneous injection of 10 IU
of insulin. The relative bioefficacy of TI was calculated to be
19.0%, while the relative bioavailability was determined to be
25.8% in the first three hours.
[0182] The data also show that inhalation of TI resulted in a much
more rapid onset of action than SC insulin injection that was close
to the onset of action of IV insulin injection, while duration of
action of TI was comparable to that of SC insulin injection.
[0183] The drug was well tolerated and no serious adverse events
were reported during the entire trial.
Example 8
Prandial TECHNOSPHERE.RTM./Insulin Provides Significantly Better
Control of Meal-Related Glucose Excursions than Prandial
Subcutaneous Insulin
[0184] TECHNOSPHERE.RTM./Insulin (TI) is a dry powder formulation
of human insulin comprising insulin complexed to furnaryl
diketopiperazine microparticles. TECHNOSPHERE.RTM./Insulin was
delivered by pulmonary administration with a dry powder inhaler
(MEDTONE.RTM. Inhaler) accomplishing a rapid onset of action and a
duration of action long enough to cover meal-related glucose
absorption. The primary objective of this study was to assess
safety and efficacy of pre-prandially administered TI compared to
subcutaneous (SC) regular insulin on blood glucose concentration
over a 7 day treatment period.
[0185] Sixteen non-smoking subjects with type 2 diabetes (age 59
(range 39-69) yrs; BMI 29.6 (23.8-34.9) kg/m.sup.2; mean diabetes
duration 12.3 yrs; with normal pulmonary function (forced
expiratory volume in 1 sec and forced vital capacity >80% of
predicted normal)) and treated with intensified insulin therapy
were enrolled in this randomized, open-label, two period cross-over
study. Subjects covered their prandial insulin needs either by
inhaled TI or by SC insulin over a treatment period of one week,
respectively, while continuing their usual basal insulin therapy.
The doses of TI and SC insulin were determined during a 24 hour
in-house period prior to randomization. TECHNOSPHERE.RTM./Insulin
was inhaled using a 12 U or 24 U cartridge via a hand-held inhaler.
After an out-patient period during which subjects administered the
assigned pre-meal therapy with either SC or TI, performed 4-point
blood glucose self-measurements, and pursued their usual activities
and diet for 5 to 7 days, postprandial blood glucose and serum
insulin (INS) excursions were determined under in-house conditions
after ingestion of a standardized breakfast (496 kcal, 55%
carbohydrates) covered with either 48.+-.9 (mean.+-.SD) U of TI or
14.+-.5 IU of SC insulin.
[0186] When treated with SC insulin, subjects demonstrated insulin
median T.sub.max of 120 min with median C.sub.max of 54 .mu.U/mL.
In comparison, when treated with TI, subjects demonstrated insulin
median T.sub.max of 14 min and median C.sub.max of 102 .mu.U/mL
(FIG. 9). Total insulin exposure for each treatment cycle was
comparable for SC and for TI with mean AUC.sub.INS measured at 9155
and 9180 .mu.U/mL respectively (FIG. 10). Mean excursion of glucose
from baseline for SC was 85 mg/dL and AUC.sub.GLU was 10925
min*mg/dL. In comparison, mean excursion of glucose from baseline
for TI was 59 mg/dL and AUC.sub.GLU was 6969 min*mg/dL (FIG. 10).
Thus the ratio of glucose excursion to insulin exposure in the
above units, an indication of the effectiveness of the absorbed
insulin dose, was only about 0.76 versus about 1.2 for TI and SC,
respectively. The data demonstrate a 31% reduction (p=0.0022) of
mean glucose excursion and a 36% reduction (p=0.0073) of glucose
exposure over the 240 min measured for TI relative to SC.
[0187] With comparable exposure to insulin (as measured in the
plasma), to meal quantity, and to meal composition, prandial TI
resulted in significantly improved control of post-prandial peak
glucose and total glucose exposure compared to prandial SC. The
only differences between therapies were the insulin formulations
and the methods of insulin administration. TI provided insulin Tmax
that mimicked first-phase insulin release kinetics and which
occurred at a time when it would be expected to have an effect on
hepatic glucose release. Subcutaneous insulin levels were much
lower than TI during the early post-prandial period, did not
exhibit a clear "peak" as did TI, and demonstrated a slow rise to
maximum concentration--too late to be expected to control hepatic
glucose release but sufficient to represent a risk for late
post-prandial hypoglycemia.
Example 9
Markedly Reduced Postprandial Glucose Excursions Through Inhaled
TECHNOSPHERE.RTM./Insulin in Comparison to SC Injected Regular
Insulin in Subjects With Type 2 Diabetes--Example 8 Data Reanalysis
with ANOVA
[0188] Baseline adjusted postprandial total insulin exposure
(INS-AUC.sub.0-240 min) was comparable for TI and for SC
(8187.+-.4269 vs 8302.+-.4025 min*.mu.U/dL, ns) whereas baseline
adjusted postprandial glucose excursion (BG-AUC.sub.0-240 min) for
TI was only about 50% of that of SC (5095.+-.5923 min*mg/dL vs
9851.+-.5593 min*mg/dL; p<0.008). Thus the ratio of glucose
excursion to insulin exposure in the above units, an indication of
the effectiveness of the absorbed insulin dose was only about 0.62
for TI versus about 1.2 for SC. In other words, unit for unit of
absorbed insulin, TI was nearly twice as efficient in removing
glucose from the blood. With TI, median insulin Tmax was shorter
(15 vs 120 min; p<0.001) and median Cmax was higher (100 vs 54
.mu.U/mL; p=0.001) than with SC. Accordingly, postprandial maximum
adjusted blood glucose excursions were 28% lower with TI compared
to SC (49 vs 82 mg/dL; p<0.003). The incidence of hypoglycemia
(BG<63 mg/dL or hypoglycemic symptoms) was comparable between TI
and SC (6 vs. 5 episodes) as was the number of treatment emerged
(mild to moderate) adverse events (5 vs. 4 episodes). Hyperglycemia
(BG>280 mg/dL) occurred more often with TI (12 vs. 4
episodes)--with two patients alone accounting for 8 episodes.
[0189] TECHNOSPHERE.RTM./Insulin markedly improved post-prandial
glucose control compared to prandial SC while total serum insulin
concentrations were comparable between both treatments. This was
attributed to a rapid onset of action of TI in which insulin Tmax
resembles first-phase insulin release kinetics. In contrast SC
insulin levels were much lower than TI during the early
post-prandial period and did not exhibit the clear peak observed
with TI. These results support the conclusion that preprandial TI
was superior to SC insulin in providing prandial insulin needs and
reducing meal related blood glucose excursions.
Example 10
Multi-Center Study of Type 2 Patients Taking Prandial TI in an
Ambulatory Setting
[0190] Studies of the pharmacokinetics and pharmacodynamics of
administering regular human insulin by pulmonary inhalation using
TECHNOSPHERE.RTM./Insulin (TI) have indicated that maximal plasma
insulin concentration can be achieved in a median of about 10 to 14
minutes after inhalation, which is ideal for replicating the
first-phase insulin release. The administration of insulin with
this highly reproducible kinetic profile to ambulatory patients
with diabetes has not been possible with other currently available
insulin systems. Studies, such as the examples above, have
demonstrated a 48% reduction in post-prandial glucose excursion
with TI compared to a bio-available equivalent dose of subcutaneous
insulin (SC) given before meals. In another multi-center study of
type 2 patients taking prandial TI in an ambulatory setting for 12
weeks, the frequency of prospectively monitored hypoglycemia was
less than 10% of the frequency historically reported for SC in
ambulatory use.
[0191] In a randomized, prospective double blind, placebo
controlled study of the forced titration of prandial
TECHNOSPHERE.RTM./Insulin in patients with type 2 diabetes mellitus
subjects received inhaled TECHNOSPHERE.RTM./Insulin (TI), dosed
prandially, in addition to basal administration of SC insulin
glargine (LANTUS.RTM.; a form of long acting insulin), 227 patients
were studied over 18 weeks. During the initial 4 weeks, patients
were followed on their existing therapy and then removed from all
oral anti-hyperglycemic therapy and placed on fixed doses of SC
insulin glargine taken once daily, in a dose sufficient to
replicate their documented pre-manipulation fasting plasma glucose
levels and stabilized at this dose. The patients were then
randomized to blinded doses of added inhaled placebo or blinded
doses of inhaled TI containing 14, 28, 42 or 56 U of regular human
insulin taken at the time of each main meal of the day in a forced
titration scenario over 4 weeks. Specifically, the subjects,
divided into five cohorts, initially received placebo
(TECHNOSPHERE.RTM. microparticles without any insulin) along with
the SC long acting insulin. After a week one cohort continued to
receive placebo and four cohorts were switched to a TI dose of 14 U
of insulin. After another week three cohorts were switched to a TI
dose of 28 U, and so on until a final cohort reached a TI dose of
56 U. All cohorts then continued on the same dose for the remaining
eight weeks of the trial.
[0192] HbA1c levels and meal challenges (300 min) were evaluated at
the initial visit, at the start of randomized treatment and at
completion. Comparisons were made between treatment groups and the
placebo group. Safety was assessed by the frequency of defined
hypoglycemic episodes and by the measurement of serial pulmonary
function tests including FEV.sub.1 and DL.sub.co. The addition of
TI to insulin glargine produced a dose-dependent reduction in HbA1c
levels. In patients treated for eight weeks at 56 units, the mean
reduction was 0.79% greater than that observed in the insulin
glargine/placebo group (p=0.0002). TECHNOSPHERE.RTM./Insulin also
produced a dose-dependent reduction in post-prandial glucose
excursions with a maximal excursion averaging only 34 mg/dL at 56 U
(p<0.0001). There were no severe hypoglycemic episodes, and the
frequency of mild/moderate hypoglycemic episodes was not increased
above that in subjects on insulin glargine alone. No changes were
observed from baseline or between dosage groups in weight or
pulmonary function. Thus inhaled TI was able to improve the
glycemic control of patients with type 2 diabetes without
increasing the risk of hypoglycemia.
Example 11
A 3 Month Comparison in Type 1 Diabetes of Inhaled
TECHNOSPHERE.RTM./Insulin to SC Administered Rapid-Acting Insulin
Analogue as Prandial Insulin in a Basal/Prandial Regimen
[0193] This study represents the first evaluation of long-term
control in patients with type 1 diabetes, comparing
TECHNOSPHERE.RTM./Insulin (TI) with a rapid-acting insulin analogue
(RAA, NOVOLOG.RTM.) as a comparator. Previous studies of TI has
shown significantly better postprandial control than regular human
insulin over 240 min in patients with type 2 diabetes.
[0194] Patients with type 1 diabetes (111 subjects, 18 to 80 years
of age; HbA1c.gtoreq.7.0% and .ltoreq.11.5%) were enrolled in a
randomized, open label study to receive TI or RAA as meal-time
insulin in addition to basal insulin (LANTUS.RTM.) for 12 weeks.
Titration of both prandial and basal insulin was permitted at the
physician's discretion. At baseline, week 8 and week 12,
standardized meal tests were conducted to assess glucose excursions
over 300 min (420 min at week 12), and HbA1c levels and lung
function (FEV.sub.1 and DLco) was evaluated in both groups. Lower
maximum and total glucose excursions were observed in the first two
hours following a standard meal in the group receiving TI insulin
compared to those who were dosed with SC insulin. Over the
following 3-4 hours, glycemia was maintained close to baseline
levels in the TI group but fell below baseline in the patients
receiving rapid acting insulin. No significant difference in HbA1c
levels were observed between the two treatment groups. The
reduction from baseline was 0.83 (1.11); p<001 (mean (SD) in the
TI group and 0.99 (1.07); p<0.001 in the group receiving SC RAA,
with no statistical difference between the groups (p=0.458). At the
same time, body weight decreased by 0.41 (2.22) kg in the TI group,
while it increased by 0.89 (1.92) kg in the group receiving SC
insulin. The difference between groups was statistically
significant (p=0.0016). An improvement in postprandial blood
glucose excursions was observed in subjects receiving TI as
compared to RAA. Maximal postprandial excursion at visit 10 was
0.92 mmol/L for TI vs. 3.0 mmol/L for RAA. The total postprandial
glucose elevation (AUC.sub.GLU) was 96.7 mmol/L*min for TI and
400.6 mmol/L*min for RAA. No adverse effects on pulmonary function
were seen after 3 months treatment, (change in FEV1 was -0.064 I
(0.189) for TI and -0.072 (0.193) for RAA (p=0.82; n.s.), and for
DLco -1.62 (3.29) and -1.094 (3.08) (p=0.39; n.s.) respectively.
Therefore, in a basal/prandial regimen in patients with type 1
diabetes, inhaled TI was an appropriate alternative to SC
administered RAA providing similar overall glycemic control
(expressed as change from baseline HbA1c) to RAA while
post-prandial excursions were significantly less.
[0195] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should at least be construed in
light of the number of reported significant digits and by applying
ordinary rounding techniques. Notwithstanding that the numerical
ranges and parameters setting forth the broad scope of the
invention are approximations, the numerical values set forth in the
specific examples are reported as precisely as possible. Any
numerical value, however, inherently contains certain errors
necessarily resulting from the standard deviation found in their
respective testing measurements.
[0196] The terms "a" and "an" and "the" and similar referents used
in the context of describing the invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0197] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is herein deemed to contain the
group as modified thus fulfilling the written description of all
Markush groups used in the appended claims.
[0198] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Of course, variations on those preferred
embodiments will become apparent to those of ordinary skill in the
art upon reading the foregoing description. The inventor expects
skilled artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0199] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above cited references and printed publications are herein
individually incorporated by reference in their entirety.
[0200] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *