U.S. patent application number 14/139714 was filed with the patent office on 2014-07-03 for val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome.
This patent application is currently assigned to Rose Pharma A/S. The applicant listed for this patent is MannKind Corporation, Rose Pharma A/S. Invention is credited to Scott Daniels, Marshall L. Grant, Stephanie Greene, Per Hellstrom, Edna Kenny, Peter Richardson, Anthony Smithson, Grayson W. Stowell.
Application Number | 20140187490 14/139714 |
Document ID | / |
Family ID | 43544949 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140187490 |
Kind Code |
A1 |
Richardson; Peter ; et
al. |
July 3, 2014 |
Val (8) GLP-1 Composition and Method for Treating Functional
Dyspepsia and/or Irritable Bowel Syndrome
Abstract
A method of treating functional dyspepsia and/or irritable bowel
syndrome in mammals in need of treatment is disclosed herein. The
method comprises administering to the mammal a formulation by
inhalation, wherein the formulation avoids first pass metabolism of
the active ingredient. The method comprises administering a
formulation by pulmonary inhalation comprising a diketopiperazine
and a glucagon-like peptide (GLP-1), analog, ROSE-010.
Inventors: |
Richardson; Peter; (Ringoes,
NJ) ; Kenny; Edna; (Killiney, IE) ; Hellstrom;
Per; (Bromma, SE) ; Grant; Marshall L.;
(Newtown, CT) ; Stowell; Grayson W.;
(Gaylordsville, CT) ; Daniels; Scott; (Cheshire,
CT) ; Smithson; Anthony; (Santa Clarita, CA) ;
Greene; Stephanie; (Ventura, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rose Pharma A/S
MannKind Corporation |
Copenhagen
Valencia |
CA |
DK
US |
|
|
Assignee: |
Rose Pharma A/S
Copenhagen
CA
MannKind Corporation
Valencia
|
Family ID: |
43544949 |
Appl. No.: |
14/139714 |
Filed: |
December 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13389410 |
Feb 7, 2012 |
8642548 |
|
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PCT/US2010/044600 |
Aug 5, 2010 |
|
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14139714 |
|
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61232373 |
Aug 7, 2009 |
|
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61232380 |
Aug 7, 2009 |
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Current U.S.
Class: |
514/11.7 ; 264/5;
530/308 |
Current CPC
Class: |
A61P 7/12 20180101; A61P
1/04 20180101; A61K 31/513 20130101; A61P 9/00 20180101; A61K
31/496 20130101; A61P 3/10 20180101; A61K 9/0075 20130101; A61K
31/357 20130101; A61K 38/26 20130101; A61P 1/00 20180101; A61K
38/26 20130101; C07K 14/605 20130101; A61K 38/12 20130101; A61K
31/357 20130101; A61K 9/1682 20130101; A61K 38/10 20130101; A61K
2300/00 20130101; A61K 38/12 20130101; A61K 31/496 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/11.7 ;
530/308; 264/5 |
International
Class: |
C07K 14/605 20060101
C07K014/605; A61K 31/513 20060101 A61K031/513; A61K 9/16 20060101
A61K009/16; A61K 38/10 20060101 A61K038/10 |
Claims
1. A process for forming a particle comprising Val (8) GLP-1 and a
diketopiperazine comprising the steps of: providing a Val (8)
GLP-1; providing a diketopiperazine in a form selected from
particle-forming diketopiperazine, diketopiperazine particles, and
combinations thereof; and combining said Val (8) GLP-1 and said
diketopiperazine in the form of a co-solution, wherein said
particle comprising said Val (8) GLP-1 and said diketopiperazine is
formed.
2. The process of claim 1, further comprising removing a solvent
from said co-solution by lyophilization, filtration, or spray
drying.
3. The process of claim 2, wherein said particle comprising said
Val (8) GLP-1 and said diketopiperazine is formed by removing said
solvent.
4. The process of claim 2, wherein said particle comprising said
Val (8) GLP-1 and said diketopiperazine is formed prior to removing
said solvent.
5. The process of claim 1, wherein said Val (8) GLP-1 is provided
in the form of a solution comprising a Val (8) GLP-1 concentration
of about 0.001 mg/ml-50 mg/ml.
6. The process of claim 5, wherein said Val (8) GLP-1 is provided
in the form of a solution comprising a Val (8) GLP-1 concentration
of about 0.1 mg/ml-10 mg/ml.
7. The process of claim 5, wherein said Val (8) GLP-1 is provided
in the form of a solution comprising a Val (8) GLP-1 concentration
of about 0.25 mg/ml.
8. The process of claim 7, wherein said diketopiperazine is
provided in the form of a suspension of diketopiperazine
particles.
9. The process of claim 7, wherein said diketopiperazine is
provided in the form of a solution comprising particle-forming
diketopiperazine, the process further comprising adjusting the pH
of said solution to form diketopiperazine particles.
10. The process of claim 8, further comprising adding an agent to
said suspension, wherein the agent is selected from the group
consisting of salts, surfactants, ions, osmolytes, chaotropes and
lyotropes, acids, bases, and organic solvents.
11. The process of claim 10 wherein said agent promotes association
between said Val (8) GLP-1 and said diketopiperazine particles.
12. The process of claim 11, wherein said agent is sodium
chloride.
13. A method of administering an effective amount of a Val(8) GLP-1
to a subject in need thereof by pulmonary delivery, said method
comprising providing to said subject an inhalable dry powder
formulation comprising Val(8) GLP-1 and a diketopiperazine.
14. The method of claim 13, wherein said pulmonary delivery is
obtained using a dry powder inhalation system.
15. The method of claim 13, wherein the dry powder inhalation
system comprises a cartridge.
16. The method of claim 13, wherein said dry powder formulation
further comprises a pharmaceutically acceptable carrier or
excipient.
17. The method of claim 13, wherein said need comprises the
treatment of diabetes, ischemia, reperfused tissue injury,
dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute
coronary syndrome, obesity, catabolic changes after surgery,
hyperglycemia, irritable bowel syndrome, functional dyspepsia,
stroke, neurodegenerative disorders, memory and learning disorders,
islet cell transplant or regenerative therapy.
18. The method of claim 17, wherein said need comprises the
treatment of irritable bowel syndrome.
19. The method of claim 13, wherein a dosage of from about 10 .mu.g
to about 900 .mu.g of Val(8) GLP-1 is administered per
administration.
20. The method of claim 13, wherein a dosage of from about 25 .mu.g
to about 500 .mu.g of Val(8) GLP-1 is administered per
administration.
21. The method of claim 13, wherein a dosage of from about 50 .mu.g
to about 300 .mu.g of Val(8) GLP-1 is administered per
administration.
22. A method of administering an effective amount of a GLP-1
molecule or a GLP-1 analog to a subject in need of treatment of
irritable bowel syndrome by pulmonary delivery, said method
comprising providing to said subject an inhalable dry powder
formulation comprising a GLP-1 molecule or GLP-1 analog and a
diketopiperazine.
23. A method of forming a powder composition with an improved GLP-1
pharmacokinetic profile, comprising the steps of: providing a Val
(8) GLP-1; providing a particle-forming diketopiperazine in a
solution; forming diketopiperazine particles; combining said Val
(8) GLP-1 and said solution to form a co-solution; and removing
solvent from said co-solution by spray-drying to form a powder with
an improved GLP-1 pharmacokinetic profile.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 13/389,410, filed Feb. 7, 2012, which claims priority from
PCT/US2010/44600 filed Aug. 5, 2010, which claims priority from
U.S. Provisional Application Ser. Nos. 61/232,373 and 61/232,380,
both filed on Aug. 7, 2009, which disclosures are hereby
incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] A composition and method of treating functional dyspepsia
and/or irritable bowel syndrome in a mammal is disclosed herein.
The composition comprising a diketopiperazine and a glucagon-like
peptide 1 (GLP-1), a GLP-1 analog, including the analog ROSE-010
(Val (8) GLP-1), or a combination thereof. The method further
comprises administering to the mammal a GLP-1 formulation by
inhalation.
BACKGROUND
[0003] Drug delivery systems for the treatment of disease which
introduce active ingredients into the circulation are numerous and
include oral, transdermal, subcutaneous and intravenous
administration. While these systems have been used for quite a long
time and can deliver sufficient medication for the treatment of
many diseases, there are numerous challenges associated with these
drug delivery mechanisms. In particular, delivery of effective
amounts of proteins and peptides to treat a target disease has been
problematic. Many factors are involved in introducing the right
amount of the active agent, for example, preparation of the proper
drug delivery formulation so that the formulation contains an
amount of active agent that can reach its site(s) of action in an
effective amount.
[0004] The active agent must be stable in the drug delivery
formulation and the formulation should allow for absorption of the
active agent into the circulation and remain active so that it can
reach the site(s) of action at effective therapeutic levels. Thus,
in the pharmacological arts, drug delivery systems which can
deliver a stable active agent are of utmost importance.
[0005] Making drug delivery formulations therapeutically suitable
for treating disease depends on the characteristics of the active
ingredient or agent to be delivered to the patient. Such
characteristics can include, in a non-limiting manner, solubility,
pH, stability, toxicity, release rate, and ease of removal from the
body by normal physiologic processes. For example, in oral
administration, if the agent is sensitive to acid, enteric coatings
have been developed using pharmaceutically acceptable materials
which can prevent the active agent from being released in the low
pH (acid) of the stomach. Thus, polymers that are not soluble at
acidic pH are used to formulate and deliver a dose containing
acid-sensitive agents to the small intestine where the pH is
neutral. At neutral pH, the polymeric coating can dissolve to
release the active agent which is then absorbed into the systemic
circulation. Orally administered active agents enter the systemic
circulation and pass through the liver. In certain cases, some
portion of the dose is metabolized and/or deactivated in the liver
before reaching the target tissues. In some instances, the
metabolites can be toxic to the patient, or can yield unwanted side
effects.
[0006] Similarly, subcutaneous and intravenous administrations of
pharmaceutically-active agents are not devoid of degradation and
inactivation of the active ingredients. With intravenous
administration of drugs, the drugs or active ingredients can also
be metabolized, for example in the liver, before reaching the
target tissue. With subcutaneous administration of certain active
agents, including various proteins and peptides, there is
additionally degradation and deactivation by peripheral and
vascular tissue enzymes at the site of drug delivery and during
travel through the venous blood stream. In order to deliver a dose
that will yield an acceptable quantity for treating disease with
subcutaneous and intravenous administration of an active agent,
dosing regimes will always have to account for the inactivation of
the active agent by peripheral and vascular venous tissue and
ultimately the liver.
SUMMARY
[0007] The present disclosure relates to a pharmaceutical
composition comprising GLP-1, a GLP-1 analog including the
Val.sup.8 glucagon-like peptide-1(7-37)OH (ROSE-010) having the
following amino acid sequence:
TABLE-US-00001 (ROSE-010; SEQ ID NO: 1)
H-His-Val-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-
Trp-Leu-Val-Lys-Gly-Arg-Gly-OH
wherein Val (8) GLP-1 is a truncated version of human GLP-1, and
wherein human GLP-1 has the following amino acid sequence:
His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-T-
yr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
(SEQ ID NO: 2). Furthermore Val (8) GLP-1 has an Ala.fwdarw.Val
amino acid substitution at position 8 of human GLP-1.
[0008] The pharmaceutical composition further comprises a
diketopiperazine. In one embodiment, the diketopiperazine is
selected from the group consisting of
2,5-diketo-3,6-di(4-X-aminobutyl)piperazine; wherein X is selected
from the group consisting of succinyl, glutaryl, maleyl, and
fumaryl, or a pharmaceutically acceptable salt thereof.
[0009] Also disclosed is a method of treating any disease or
disorder wherein GLP-1 is indicated including, but not limited to,
diabetes, ischemia, reperfused tissue injury, dyslipidemia,
diabetic cardiomyopathy, myocardial infarction, acute coronary
syndrome, obesity, catabolic changes after surgery, hyperglycemia,
irritable bowel syndrome, stroke, neurodegenerative disorders,
memory and learning disorders, islet cell transplant functional
dyspepsia and/or regenerative therapy in mammals in need of
treatment. The method comprises administering to the mammal a
formulation by pulmonary inhalation, wherein the formulation avoids
first pass metabolism of the active ingredient. In one embodiment,
the method of treating functional dyspepsia and/or irritable bowel
syndrome in a mammal in need of treatment comprises administering
to the mammal a therapeutically effective amount of a formulation
by pulmonary inhalation, comprising a diketopiperazine having the
formula:
3,6-bis[4-(N-carboxy-2-propenyl)amidobutyl]-2,5-diketopiperazine
(fumaryl diketopiperazine, FDKP) and ROSE-010, a GLP-1 analog.
[0010] In yet another embodiment, there is provided a method for
treating irritable bowel syndrome in a patient having the disease,
the method comprising administering to the patient a
therapeutically effective amount of a formulation by pulmonary
inhalation, which formulation comprises FDKP and GLP-1 or a GLP-1
analog, such as the GLP-1 analog ROSE-010, which inhibits
gastrointestinal smooth muscle motor activity and inhibits
secretory activity of gastroinstestinal glands for about 6 to 8
hours after administration.
[0011] In another embodiment, the method of treating irritable
bowel syndrome comprises a dry powder inhalation system comprising
a cartridge containing a dry powder formulation for pulmonary
delivery and a breath powered inhaler. In one aspect of this
embodiment, the inhaler can be a high resistance inhaler.
[0012] In one embodiment disclosed herein, a pharmaceutical
composition is provided comprising Val (8) glucagon-like peptide-1
(GLP-1) and a diketopiperazine or a pharmaceutically acceptable
salt, solvate or prodrug thereof. In another embodiment, the
composition is an inhalable dry powder composition.
[0013] In another embodiment, the diketopiperazine is a
diketopiperazine having the formula
2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected
from the group consisting of succinyl, glutaryl, maleyl, and
fumaryl. In another embodiment, the diketopiperazine is a
diketopiperazine salt. In yet another embodiment, the
diketopiperazine is
2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine.
[0014] In another embodiment, Val (8) GLP-1 is an amidated Val (8)
GLP-1.
[0015] In one embodiment disclosed herein, a process is provided
for forming a particle comprising Val (8) GLP-1 and a
diketopiperazine comprising the steps of: providing a Val (8)
GLP-1; providing a diketopiperazine in a form selected from
particle-forming diketopiperazine, diketopiperazine particles, and
combinations thereof; and combining said Val (8) GLP-1 and said
diketopiperazine in the form of a co-solution, wherein said
particle comprising said Val (8) GLP-1 and said diketopiperazine is
formed.
[0016] In another embodiment, the process further comprises
removing a solvent from said co-solution by lyophilization,
filtration, or spray drying. In another embodiment, the particle
comprising Val (8) GLP-1 and a diketopiperazine is formed by
removing solvent. In another embodiment, the particle comprising
Val (8) GLP-1 and a diketopiperazine is formed prior to removing
solvent.
[0017] In another embodiment, Val (8) GLP-1 is provided in the form
of a solution comprising a Val (8) GLP-1 concentration of about
0.001 mg/ml-50 mg/ml. In another embodiment, the Val (8) GLP-1
concentration is about 0.1 mg/ml-10 mg/ml. In another embodiment,
the Val (8) GLP-1 concentration is about 0.25 mg/ml.
[0018] In another embodiment, the diketopiperazine is provided in
the form of a suspension of diketopiperazine particles. In yet
another embodiment, the diketopiperazine is provided in the form of
a solution comprising particle-forming diketopiperazine, the
process further comprising adjusting the pH of the solution to form
diketopiperazine particles. In another embodiment, the process
further comprises adding an agent to the solution or suspension,
wherein the agent is selected from the group consisting of salts,
surfactants, ions, osmolytes, chaotropes and lyotropes, acids,
bases, and organic solvents, in one embodiment, sodium chloride. In
another embodiment, the agent promotes association between Val (8)
GLP-1 and the diketopiperazine particles or the particle-forming
diketopiperazine.
[0019] In one embodiment disclosed herein, a method is provided of
administering an effective amount of a Val(8) GLP-1 to a subject in
need thereof, the method comprising providing to the subject an
inhalable dry powder formulation comprising Val(8) GLP-1 and
diketopiperazine, in particularly wherein the administration is
carried out by pulmonary delivery.
[0020] In another embodiment, the pulmonary delivery is obtained
using a dry powder inhalation system. In another embodiment, the
dry powder inhalation system comprises a cartridge. In yet another
embodiment, the dry powder formulation further comprises a
pharmaceutically acceptable carrier or excipient.
[0021] In another embodiment, the need comprises the treatment of a
condition or disease selected from the group consisting of
diabetes, ischemia, reperfused tissue injury, dyslipidemia,
diabetic cardiomyopathy, myocardial infarction, acute coronary
syndrome, obesity, catabolic changes after surgery, hyperglycemia,
irritable bowel syndrome, functional dyspepsia, stroke,
neurodegenerative disorders, memory and learning disorders, islet
cell transplant and regenerative therapy. In another embodiment,
the need comprises the treatment of irritable bowel syndrome.
[0022] In another embodiment, a dosage of from about 10 .mu.g to
about 900 .mu.g of Val(8) GLP-1 is administered per administration,
or a dosage of from about 25 .mu.g to about 500 .mu.g of Val(8)
GLP-1 is administered per administration, or a dosage of from about
50 .mu.g to about 300 .mu.g of Val(8) GLP-1 is administered per
administration.
[0023] In one embodiment disclosed herein, a method is provided of
administering an effective amount of a GLP-1 molecule or a GLP-1
analog to a subject in need of treatment of irritable bowel
syndrome, the method comprising providing to the subject an
inhalable dry powder formulation comprising a GLP-1 molecule or
GLP-1 analog and a diketopiperazine, wherein the administration is
carried out by pulmonary delivery.
[0024] In one embodiment disclosed herein, a method is provided of
forming a powder composition with an improved GLP-1 pharmacokinetic
profile, comprising the steps of: providing a Val (8) GLP-1;
providing a particle-forming diketopiperazine in a solution;
forming diketopiperazine particles; combining the Val (8) GLP-1 and
the solution to form a co-solution; and removing solvent from the
co-solution by spray-drying to form a powder with an improved GLP-1
pharmacokinetic profile.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 depicts a graph of a GLP-1 analog, ROSE-010,
adsorption onto fumaryl diketopiperazine (FDKP) particles as a
function of suspension pH.
[0026] FIG. 2 depicts a representative high pressure liquid
chromatograph (HPLC) chromatogram of an FDKP-GLP-1 analog profile
in an initial assay for powder adsorption studies of the
powder.
[0027] FIG. 3 depicts a representative HPLC chromatogram of an
FDKP-GLP-1 analog in a refined assay for powder and test article
analysis of the powder.
[0028] FIG. 4 depicts a representative HPLC chromatogram of an
FDKP-GLP-1 analog in a related assay of the powder.
[0029] FIG. 5 depicts a representative HPLC chromatogram of the
GLP-1 analog ROSE-010 alone and FDKP-ROSE-010.
[0030] FIG. 6 depicts the particle size distribution for a powder
sample of FDKP-ROSE-010 prepared at pH 4.5 using a SYMPATEC.TM.
RODOS procedure.
[0031] FIG. 7 depicts a representative SYMPATEC.TM. RODOS profile
of the particle size distribution of the FDKP and ROSE-010 powder
formulation prepared at pH 3.0.
[0032] FIG. 8 depicts a representative scanning electron micrograph
of the powder particles comprising the GLP-1 analog ROSE-010, and
FDKP, the powder which was used in the further pharmacodynamic
studies.
[0033] FIG. 9 depicts a graphic representation of the data obtained
from pharmacodynamic studies comparing intravenous, subcutaneous
and pulmonary administration of the GLP-1 analog ROSE-010 in plasma
of rats for a period of time up to 90 minutes after
administration.
[0034] FIG. 10 depicts a bar graph showing the effects of
FDKP-ROSE-010 on myotonic muscle contraction in the
gastrointestinal tract of rats, which measures the duration of
effect in MMC model. INS=insufflation.
[0035] FIG. 11 depicts the mean plasma concentration of active and
native GLP-1 in subjects treated with an inhalable dry powder
formulation containing a GLP-1 dose of 1.5 mg measured at various
times after inhalation.
[0036] FIG. 12 depicts the plasma concentration of GLP-1 in
subjects treated with an inhalable dry powder formulation
containing a GLP-1 dose of 1.5 mg measured at various times after
inhalation compared to subjects treated with a subcutaneous
administration of GLP-1.
DEFINITION OF TERMS
[0037] Prior to setting forth the invention, it may be helpful to
provide an understanding of certain terms that will be used
hereinafter:
[0038] Active Agents: As used herein "active agent" refers to
drugs, pharmaceutical substances and bioactive agents. Active
agents can be organic macromolecules including nucleic acids,
synthetic organic compounds, polypeptides, peptides, proteins,
polysaccharides and other sugars, and lipids. Peptides, proteins,
and polypeptides are all chains of amino acids linked by peptide
bonds. Peptides are generally considered to be less than 40 amino
acid residues, but may include more. Proteins are polymers that
typically contain more than 40 amino acid residues. The term
polypeptide, as is known in the art and as used herein, can refer
to a peptide, a protein, or any other chain of amino acids of any
length containing multiple peptide bonds, though generally
containing at least 10 amino acids. The active agents can fall
under a variety of biological activity classes, such as vasoactive
agents, neuroactive agents, hormones, anticoagulants,
immunomodulating agents, cytotoxic agents, antibiotics, antiviral
agents, antigens, and antibodies. More particularly, active agents
may include, in a non-limiting manner, insulin and analogs thereof,
growth hormone, parathyroid hormone (PTH), ghrelin, granulocyte
macrophage colony stimulating factor (GM-CSF), glucagon-like
peptide 1 (GLP-1), and analogs of such peptides, including
ROSE-010, Texas Red, alkynes, cyclosporins, clopidogrel and PPACK
(D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone),
antibodies and fragments thereof, including, but not limited to,
humanized or chimeric antibodies; F(ab), F(ab).sub.2, or
single-chain antibody alone or fused to other polypeptides;
therapeutic or diagnostic monoclonal antibodies to cancer antigens,
cytokines, infectious agents, inflammatory mediators, hormones, and
cell surface antigens. In some instances, the terms "drug" and
"active agent" are used interchangeably.
[0039] Amino acid residue: An amino acid formed upon chemical
digestion (hydrolysis) of a polypeptide at its peptide linkages.
The amino acid residues described herein are preferably in the "L"
isomeric form. However, the term "amino acid" encompasses every
amino acid such as L-amino acid, D-amino acid, alpha-amino acid,
beta-amino acid, gamma-amino acid, natural amino acid and synthetic
amino acid or the like as long as the desired functional property
is retained by the polypeptide. Further included are natural or
synthetic amino acids which have been modified. NH.sub.2 refers to
the free amino group present at the amino terminus of a
polypeptide. COOH refers to the free carboxy group present at the
carboxy terminus of a polypeptide. Standard abbreviations for amino
acid residues are used herein.
[0040] It should be noted that all amino acid residue sequences
represented herein by formulae have a left-to-right orientation in
the conventional direction of amino terminus to carboxy terminus.
Furthermore, it should be noted that a dash at the beginning or end
of an amino acid residue sequence indicates a peptide bond to a
further sequence of one or more amino acid residues or a covalent
bond to an amino-terminal group such as NH.sub.2 or acetyl or to a
carboxy-terminal group such as COOH.
[0041] Biliary dyskinesia refers to any motility abnormality in the
biliary tree that causes pain and/or discomfort in the patient.
This includes but is not restricted to gallbladder dysfunction,
dysfunction of the biliary tract and dysfunction of the Sphincter
of Oddi. Biliary dysfunction may be increased motility of an area
of the biliary tract, decreased motility of an area of the biliary
tract, or alternatively disordered control of motility, such as
with spasms in the biliary tract.
[0042] Diketopiperazine: 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##
[0043] Diketopiperazines can be formed by cyclodimerization of
amino acid ester derivatives, as described by Katchalski, et ah,
(J. Amer. Chem. Soc. 68:879-80; 1946), by cyclization of dipeptide
ester derivatives, or by thermal dehydration of amino acid
derivatives in high-boiling solvents, as described by Kopple, et
al., (J. Org. Chem. 33:862-64; 1968), the teachings of which are
incorporated herein.
[0044] Methods for synthesis and preparation of diketopiperazines
are well known to one of ordinary skill in the art and are
disclosed in U.S. Pat. Nos. 5,352,461; 5,503,852; 6,071,497;
6,331,318; 6,428,771 and U.S. patent application Ser. No.
11/210,710. U.S. Pat. Nos. 6,444,226 and 6,652,885, describe
preparing and providing microparticles of diketopiperazines in
aqueous suspension to which a solution of active agent is added in
order to bind the active agent to the particle. These patents
further describe a method of removing a liquid medium by
lyophilization to yield microparticles comprising an active agent,
altering the solvent conditions of such suspension to promote
binding of the active agent to the particle is taught in U.S.
patent application Ser. No. 11/532,063 entitled "Method of Drug
Formulation Based on Increasing the Affinity of Active Agents for
Crystalline Microparticle Surfaces"; and Ser. No. 11/532,065
entitled "Method of Drug Formulation Based on Increasing the
Affinity of Active Agents for Crystalline Microparticle Surfaces".
See also U.S. Pat. No. 6,440,463 and U.S. patent application Ser.
Nos. 11/210,709 and 11/208,087. In some instances, it is
contemplated that the loaded diketopiperazine are dried by a method
of spray drying as disclosed in, for example, U.S. patent
application Ser. No. 11/678,046 and entitled "A Method For
Improving the Pharmaceutic Properties of Microparticles Comprising
Diketopiperazine and an Active Agent." Each of these patents and
patent applications is incorporated by reference herein for all
they contain regarding diketopiperazines.
[0045] Diketopiperazines, in addition to making aerodynamically
suitable microparticles, can also facilitate the delivery of active
agents by rapidly dissolving at physiologic pH thereby releasing
the active agent and speeding its 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.
[0046] In one embodiment, the diketopiperazine is
3,6-bis[4-(N-carboxy-2-propenyl)aminobutyl]-2,5-diketopiperazine or
3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine (fumaryl
diketopiperazine, FDKP). The FDKP can comprise microparticles in
its acid form or salt forms which can be aerosolized or
administered in a suspension.
[0047] In another embodiment, 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)-2,5-diketopiperazine,
3,6-di(maleyl-4-aminobutyl)-2,5-diketopiperazine,
3,6-di(glutaryl-4-aminobutyl)-2,5-diketopiperazine,
3,6-di(malonyl-4-aminobutyl)-2,5-diketopiperazine,
3,6-di(oxalyl-4-aminobutyl)-2,5-diketopiperazine,
3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine or
3,6-di(citraconyl-4-aminobutyl)-2,5-diketopiperazine and
derivatives therefrom. 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, 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. Further
details related to adsorption of active agents onto crystalline DKP
particles can be found in co-pending U.S. patent application Ser.
Nos. 11/532,063 and 11/532,065 which are hereby incorporated by
reference in their entirety. In the present disclosure,
diketopiperazines are employed to facilitate the absorption of
ROSE-010, thereby providing a stable formulation that is resistant
to degradation.
[0048] Dissociation constant, Kd refers a measure to describe the
strength of binding (or affinity or avidity) between receptors and
their ligands, for example an antibody and its antigen. The smaller
the Kd, the stronger the binding.
[0049] Drug delivery system: As used herein, "drug delivery system"
refers to a system for delivering one or more active agents.
[0050] 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
necessarily imply a complete absence of all water molecules.
[0051] Early phase: As used herein, "early phase" refers to the
rapid 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. In more recent sources, first-phase is
sometimes used to refer to the more rapid rise in blood insulin
concentration of the kinetic profile achievable with a bolus IV
injection of glucose in distinction to the meal-related
response.
[0052] Effective amount: As used herein, an "effective amount" of a
GLP-1/DKP dry powder formulation refers to that amount which will
relieve to some extent one or more of the symptoms of the disease,
condition or disorder being treated. In one embodiment, an
"effective amount" of a VAL (8) GLP-1/DKP dry powder formulation
would be in dosages of 10 .mu.g to about 900 .mu.g per
administration, such as a dosage of from about 25 .mu.g to about
500 .mu.g per administration, or such as from about 50 .mu.g to
about 300 .mu.g per administration.
[0053] Endocrine disease: The endocrine system is an information
signal system that releases hormones from the glands to provide
specific chemical messengers which regulate many and varied
functions of an organism, e.g., mood, growth and development,
tissue function, and metabolism, as well as sending messages and
acting on them. Diseases of the endocrine system include, but are
not limited to, diabetes mellitus, thyroid disease, and obesity.
Endocrine disease is characterized by dysregulated hormone release
(a productive pituitary adenoma), inappropriate response to
signalling (hypothyroidism), lack or destruction of a gland
(diabetes mellitus type 1, diminished erythropoiesis in chronic
renal failure), reduced responsiveness to signaling (insulin
resistance of diabetes mellitus type 2), or structural enlargement
in a critical site such as the neck (toxic multinodular goiter).
Hypofunction of endocrine glands can occur as result of loss of
reserve, hyposecretion, agenesis, atrophy, or active destruction.
Hyperfunction can occur as result of hypersecretion, loss of
suppression, hyperplastic, or neoplastic change, or
hyperstimulation. The term endocrine disorder encompasses metabolic
disorders.
[0054] Excursion: As used herein, "excursion" can refer 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.
While excursion has been described here in terms of blood glucose,
in other contexts the term may be similarly applied to other
analytes.
[0055] Gallbladder dysfunction refers to any motility abnormality
of the gall bladder including abnormal gallbladder emptying that
causes biliary-type pain or discomfort.
[0056] Glucose elimination rate: As used herein, "glucose
elimination rate" is the rate at which glucose disappears from the
blood. It is commonly determined 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.
[0057] 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).
[0058] 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.
[0059] Individual: As used here, the term "individual" or "subject"
refer to a living animal. In preferred embodiments, the individual
or subject is a mammal, including humans and non-human mammals such
as dogs, cats, pigs, cows, sheep, goats, horses, rats, and mice. In
the most preferred embodiment, the subject is a human.
[0060] 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 or snack.
[0061] Irritable Bowel Syndrome refers to a functional
gastrointestinal disorder characterized most commonly by cramping,
abdominal pain, discomfort, bloating, alteration of bowel habits,
constipation, and/or diarrhea.
[0062] Microparticles: As used herein, the term "microparticles"
includes particles of generally 0.5 to 100 microns in diameter and
particularly those less than 10 microns in diameter. Various
embodiments will entail more specific size ranges. The
microparticles can be assemblages of crystalline plates with
irregular surfaces and internal voids as is typical of those made
by pH-controlled precipitation of the DKP acids. In such
embodiments the active agents can be entrapped by the precipitation
process or coated onto the crystalline surfaces of the
microparticle. The microparticles can also be spherical shells or
collapsed spherical shells comprised of DKP salts with the active
agent dispersed throughout. Typically such particles can be
obtained by spray drying a co-solution of the DKP and the active
agent. The DKP salt in such particles can be amorphous. The
forgoing descriptions should be understood as exemplary. Other
forms of microparticles are contemplated and encompassed by the
term.
[0063] Modified amino acid refers to an amino acid wherein an
arbitrary group thereof is chemically modified. In particular, a
modified amino acid chemically modified at the alpha-carbon atom in
an alpha-amino acid is preferable.
[0064] Obesity refers to a condition in which excess body fat has
accumulated to such an extent that health may be negatively
affected. Obesity is typically assessed by BMI (body mass index)
with BMI of greater than 30 kg/m.sup.2.
[0065] Peripheral tissue: As used herein, "peripheral tissue"
refers to any connective or interstitial tissue that is associated
with an organ or vessel.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] Prandial: As used herein, "prandial" refers to a meal or a
snack.
[0070] Preprandial: As used herein, "preprandial" refers to a
period of time before ingestion of a meal or snack.
[0071] Prodrug: As used herein, the term "prodrug" means a
substance that is transformed in vivo to yield a substance of the
present disclosure. The transformation may occur by various
mechanisms, such as through hydrolysis in blood. For example, when
a compound contains a carboxylic acid functional group, a prodrug
can comprise an ester formed by the replacement of the hydrogen
atom of the acid group with a group including, but not limited to,
groups such as for example (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N (alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4 crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl,
carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0072] Pulmonary inhalation: As used herein, "pulmonary inhalation"
is used to refer to administration of pharmaceutical preparations
by inhalation so that they reach the lungs and, in particular
embodiments, the alveolar regions of the lung. Typically inhalation
is through the mouth, but in alternative embodiments in can entail
inhalation through the nose.
[0073] ROSE-010: As used herein, the term "ROSE-010" is used to
refer to a GLP-1 analog with an Ala to Val amino acid substitution
at position 8. ROSE-010 is also denoted Val (8) GLP-1 and/or
Val.sup.8 glucagon-like peptide-1(7-37)OH.
[0074] Salt: As used herein, the term "salt" includes, but is not
limited to, any possible base or acid addition salts of the
diketopiperazine compounds disclosed herein. The acid addition
salts are formed from basic compounds, whereas the base addition
salts are formed from acidic compounds. All of these forms are
within the scope of the present disclosure. A non-toxic
pharmaceutically acceptable base addition salt of an acidic
compound may be prepared by contacting the free acid form of the
compound with a sufficient amount of a desired base to produce the
salt in the conventional manner. The free acid form of the compound
may be regenerated by contacting the salt form so formed with an
acid, and isolating the free acid of the compound in the
conventional manner. The free acid forms of the compounds differ
from their respective salt forms in certain physical properties
such as solubility, crystal structure, hygroscopicity, and the
like, but otherwise the salts are equivalent to their respective
free acid for purposes of delivering active agents according to the
present disclosure. Non limiting examples of counter ions for the
base additions salts are a metal cation, such as an alkali or
alkaline earth metal cation, or an amine, especially an organic
amine. Examples of suitable metal cations include sodium cation
(Na+), potassium cation (K+), magnesium cation (Mg2+), calcium
cation (Ca2+), and the like. Examples of suitable amines are
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, dicyclohexylamine, ethylenediamine,
N-methylglucamine, and procaine (see, for example, Berge S. M. et
al., "Pharmaceutical Salts," J. of Pharma. Sci., 1977; 66:1).
[0075] SO dysfunction is the term used to define motility
abnormalities of the sphincter of Oddi (see Rome II: The functional
Gastrointestinal Disorders 2.sup.nd Edition)
[0076] Solvate: As used herein, the term "solvate" means a compound
or a salt thereof that further includes a stoichiometric or
non-stoichiometric amount of a solvent bound by non-covalent
intermolecular forces. Preferred solvents are volatile, non-toxic,
and/or acceptable for administration to humans in trace amounts.
The solvated forms, including hydrated forms, are equivalent to
unsolvated forms and are encompassed within the scope of the
present invention.
[0077] TECHNOSPHERE.RTM.: As used herein, "TECHNOSPHERE.RTM."
refers to microparticles comprising a diketopiperazine,
specifically 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine
(fumaryl diketopiperazine, FDKP).
DETAILED DESCRIPTION
[0078] There is disclosed a dry powder composition comprising
glucagon-like peptide 1 (GLP-1) or a GLP-1 analog and a method for
the treatment of a disease or a disorder which utilizes a drug
delivery system that effectively delivers GLP-1 or a GLP-1 analog,
including ROSE-010, to the pulmonary circulation so that the GLP-1
or analog thereof enters the pulmonary circulation and can be
delivered in a therapeutically effective amounts to the site(s) of
action. In one embodiment, the method of treatment of disease or
disorder comprises administering to a patient in need of treatment
a formulation which can deliver the active agent directly into the
pulmonary circulation, and thereby to the arterial circulation, and
can avoid degradation of the active agent such as peptides, which
are degraded by enzymes or other mechanisms in the local peripheral
and/or vasculature tissues of the lungs. In one aspect of this
embodiment, the method comprises the effective therapeutic delivery
of ROSE-010 using a drug delivery system which allows for very
rapid lung absorption of the active agent into the arterial
circulation and increases its effective bioavailability. In this
embodiment, lower dosages of an active agent can be delivered by
this method of administration. In similar embodiments effective
doses can be achieved where they were not feasible by other modes
of administration.
[0079] Indications
[0080] The inventors have identified the need to deliver drugs
directly to the systemic circulation, in particular, the arterial
circulation in a noninvasive fashion so that the drug reaches the
target organ(s) prior to returning through the venous system. This
approach may paradoxically result in a higher peak target organ
exposure to active agents than would result from a comparable
administration via an intravenous, subcutaneous or other parenteral
route. A similar advantage can be obtained versus oral
administration as, even with formulations providing protection from
degradation in the digestive tract, upon absorption, the active
agent will enter the venous circulation.
[0081] In embodiments herein, there is disclosed a pharmaceutical
composition and a method for the treatment of disease, including
but not limited to, Type II diabetes, obesity, cancer, ischemia,
reperfused tissue injury, dyslipidemia, diabetic cardiomyopathy,
myocardial infarction, acute coronary syndrome, catabolic changes
after surgery, hyperglycemia, irritable bowel syndrome, stroke,
neurodegenerative disorders, memory and learning disorders, islet
cell transplant and regenerative therapy or any related diseases
and/or conditions therefrom. Other diseases and/or conditions
contemplated in the present invention are inclusive of any disease
and/or condition related to those listed above that may be treated
by administering a GLP-1/DKP, GLP-1 analog/DKP or ROSE-010/DKP dry
powder formulation to a subject in need thereof. The dry powder
formulation of the present invention may also be employed in the
treatment of induction of beta cell differentiation in human cells
of type-II diabetes and hyperglycemia.
[0082] In one embodiment, pharmaceutical composition and the method
of treatment according to the invention may be used for any
indication wherein GLP-1 is indicated, such as diabetes, ischemia,
reperfused tissue injury, dyslipidemia, diabetic cardiomyopathy,
myocardial infarction, acute coronary syndrome, obesity, catabolic
changes after surgery, hyperglycemia, irritable bowel syndrome,
stroke, neurodegenerative disorders, memory and learning disorders,
islet cell transplant and regenerative therapy.
[0083] In yet another embodiment, a method of treatment of pain or
discomfort and/or dyskinesia in the biliary tract (or "biliary
dyskinesia") is provided. In this embodiment, the method comprises
administering to a patient in need of treatment a therapeutically
effective amount of GLP-1 or a GLP-1 analog, such as ROSE-010,
wherein the formulation is administered by oral inhalation using,
for example, a breath-powered inhaler. Other alternative routes of
administration that may be employed in the present disclosure may
include: bronchial administration by local aerosol delivery,
injection, infusion, continuous infusion, localized perfusion
bathing target cells directly, via a catheter, via a lavage, in
creams, in lipid compositions (e.g., liposomes), or by other
method, or any combination of the foregoing as would be known to
one of ordinary skill in the art (see, for example, Remington's
Pharmaceutical Sciences, 1990, incorporated herein by reference for
all it contains regarding methods of administration).
[0084] In an exemplary embodiment, a method for treating diabetes
and/or hyperglycemia comprises administering to a patient in need
of treatment a dry powder composition or formulation comprising
GLP-1 or a GLP-1 analog, such as ROSE-010, which can stimulate the
rapid secretion of endogenous insulin from pancreatic .beta.-cells
without causing unwanted side effects such as profuse sweating,
nausea, and vomiting. In one embodiment, the method of treating
disease can be applied to a patient, including a mammal, suffering
from Type 2 diabetes mellitus and/or hyperglycemia at dosages
ranging from about 0.01 to about 3 mg of ROSE-010 in the
formulation in a single dose. The method of treating hyperglycemia,
diabetes, and/or obesity can be designed so that the patient can
receive at least one dose of a ROSE-010 formulation in proximity to
a meal or snack. In this embodiment, the dose of ROSE-010 can be
selected depending on the patient's requirements. In one
embodiment, pulmonary administration of ROSE-010 can comprise a
ROSE-010 dose greater than 3 mg for example, in treating patients
with type 2 diabetes.
[0085] In an exemplary embodiment, the method comprises the
administration of the peptide hormone GLP-1 or a GLP-1 analog such
as ROSE-010 to a patient for the treatment of hyperglycemia and/or
diabetes, and obesity. The method comprises administering to a
patient in need of treatment an effective amount of an inhalable
composition or formulation comprising a dry powder formulation
comprising GLP-1 or a GLP-1 analog such as ROSE-010 which can
stimulate the rapid secretion of endogenous insulin from pancreatic
.beta.-cells without causing unwanted side effects, including,
profuse sweating, nausea, and vomiting. In one embodiment, the
method of treating disease can be applied to a patient, including a
mammal, suffering with Type 2 diabetes mellitus and/or
hyperglycemia at dosages ranging from about 0.01 mg to about 3 mg,
or from about 0.2 mg to about 2 mg of GLP-1 in the dry powder
formulation. In one embodiment, the patient or subject to be
treated is a human. The GLP-1 can be administered immediately
before a meal (preprandially), at mealtime (prandially), and/or at
about 15, 30 or 45 minutes after a meal (postprandially). In one
embodiment, a single dose of GLP-1 can be administered immediately
before a meal and another dose can be administered after a meal. In
a particular embodiment, about 0.5 mg to about 1.5 mg of GLP-1 can
be administered immediately before a meal, followed by 0.5 mg to
about 1.5 mg about 30 minutes after a meal. In this embodiment, the
GLP-1 can be formulated with inhalation particles such as a
diketopiperazine with or without pharmaceutical carriers and
excipients. In one embodiment, pulmonary administration of the
GLP-1 formulation can provide plasma concentrations of GLP-1
greater than 100 pmol/L without inducing unwanted adverse side
effects, such as profuse sweating, nausea and vomiting to the
patient.
[0086] In another embodiment, a method for treating a patient
including a human with type 2 diabetes and hyperglycemia is
provided, the method comprises administering to the patient an
inhalable GLP-1 formulation comprising GLP-1 in a concentration of
from about 0.5 mg to about 3 mg in FDKP microparticles wherein the
levels of glucose in the blood of the patient are reduced to
fasting plasma glucose concentrations of from 85 to 70 mg/dL within
about 20 min after dosing without inducing nausea or vomiting in
the patient. In one embodiment, pulmonary administration of GLP-1
at concentration greater than 0.5 mg in a formulation comprising
fumaryl diketopiperazine (FDKP) microparticles lacks inhibition of
gastric emptying.
[0087] In one embodiment, GLP-1 or an analog of GLP-1, including
ROSE-010, can be administered either alone as the active ingredient
in the composition, or with a dipeptidyl peptidase (DPP-IV)
inhibitor such as sitagliptin or vildagliptin, or with one or more
other active agents. DPP-IV is a ubiquitously expressed serine
protease that exhibits postproline or alanine peptidase activity,
thereby generating biologically inactive peptides via cleavage at
the N-terminal region after X-proline or X-alanine, wherein X
refers to any amino acid. Because both GLP-1 and GIP
(glucose-dependent insulinotropic peptide) have an alanine residue
at position 2, they are substrates for DPP-IV. DPP-IV inhibitors
are orally administered drugs that improve glycemic control by
preventing the rapid degradation of incretin hormones, thereby
resulting in postprandial increases in levels of biologically
active intact GLP-1 and GIP.
[0088] In this embodiment, the action of GLP-1 can be further
prolonged, or augmented, in vivo, if required, using DPP-IV
inhibitors. The combination of GLP-1, or an analog thereof and
DPP-IV inhibitor therapy for the treatment of hyperglycemia and/or
diabetes allows for reduction in the amount of active GLP-1 that
may be needed to induce an appropriate insulin response from the
.beta.-cells in the patient. In another embodiment, the GLP-1 or
ROSE-010 analog can be combined, for example, with other molecules
other than a peptide, such as, for example, metformin. In one
embodiment, the DPP-IV inhibitor or other molecules, including
metformin, can be administered by inhalation in a dry powder
formulation together with the GLP-1 or analog thereof in a
co-formulation, or separately in its own dry powder formulation
which can be administered concurrently with or prior to GLP-1
administration. In one embodiment, the DPP-IV inhibitor or other
molecules, including metformin, can be administered by other routes
of administration, including orally. In one embodiment, the DPP-IV
inhibitor can be administered to the patient in doses ranging from
about 1 mg to about 100 mg depending on the patient's need. Smaller
concentrations of the DPP-IV inhibitor may be used when
co-administered, or co-formulated with GLP-1. In this embodiment,
the efficacy of GLP-1 therapy may be improved at reduced dosage
ranges when compared to current dosage forms.
[0089] In embodiments described herein, GLP-1 can be administered
at mealtime (in proximity in time to a meal or snack). In this
embodiment, GLP-1 exposure can be limited to the postprandial
period so it does not cause the long acting effects of current
therapies. In embodiments wherein a DPP-IV inhibitor is
co-administered, the DPP-IV inhibitor may be given to the patient
prior to GLP-1 administration at mealtime. The amounts of DPP-IV
inhibitor to be administered can range, for example, from about
0.10 mg to about 100 mg, depending on the route of administration
selected. In further embodiments, one or more doses of the GLP-1
can be administered after the beginning of the meal instead of or
in addition to a dose administered in proximity to the beginning of
a meal or snack. For example one or more doses can be administered
15 to 120 minutes after the beginning of a meal, such as at 30, 45,
60, or 90 minutes.
[0090] In still yet a further embodiment, the method of treating
hyperglycemia and/or diabetes comprises the administration of an
inhalable dry powder composition comprising a diketopiperazine
having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine,
wherein X is selected from the group consisting of succinyl,
glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder
composition can comprise a diketopiperazine salt. In one
embodiment, the diketopiperazine salt can be an inorganic salt
including, sodium, potassium, magnesium, lithium, cesium, and
calcium. In another embodiment, the diketopiperazine can be an
organic salt, including, triethylamine, butylamine, diethanolamine
and triethanolamine. In still yet another embodiment of the present
invention, there is provided a dry powder composition, wherein the
diketopiperazine is
2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine or a salt
thereof, with or without a pharmaceutically acceptable carrier, or
excipient.
[0091] In certain embodiments, the method of treatment can comprise
a dry powder formulation for inhalation comprising GLP-1, wherein
the GLP-1 molecule is native GLP-1, or an amidated GLP-1 molecule,
wherein the amidated GLP-1 molecule is GLP-1(7-36) amide, or
combinations thereof. In one embodiment, the GLP-1 can be an analog
such as exenatide or ROSE-010.
[0092] In another embodiment, GLP-1 can be administered with
insulin as a combination therapy and given prandially for the
treatment of hyperglycemia and/or diabetes, for example, Type 2
diabetes mellitus. In this embodiment, the GLP-1 or analog thereof
and insulin can be co-formulated in a dry powder formulation or
administered separately to a patient in their own formulations. In
one embodiment, wherein the GLP-1 and insulin are co-administered,
both active ingredients can be co-formulated, for example, the
GLP-1 and insulin can be prepared in a dry powder formulation for
inhalation using diketopiperazine particles as described above.
Alternatively, the GLP-1 and insulin can be formulated separately,
wherein each formulation is for inhalation and comprises
diketopiperazine particles. In one embodiment the GLP-1 and the
insulin formulations can be admixed together in their individual
powder form to the appropriate dosing prior to administration. In
this embodiment, the insulin can be short-, intermediate-, or
long-acting insulin and can be administered prandially.
[0093] In one embodiment for the treatment of Type 2 diabetes using
co-administration of GLP-1 and insulin, an inhalable formulation
comprising GLP-1 or an analog of GLP-1 can be administered to a
patient prandially, simultaneously, or sequentially to an inhalable
formulation of insulin such as insulin/FDKP. In this embodiment, in
a Type 2 diabetic, GLP-1 can stimulate insulin secretion from the
patient's pancreas, which can delay disease progression by
preserving .beta.-cell function (such as by promoting .beta.-cell
growth) while prandially-administered insulin can be used as
insulin replacement which mimics the body's normal response to a
meal. In certain embodiments of the combination therapy, the
insulin formulation can be administered by other routes of
administration. In this embodiment, the combination therapy can be
effective in reducing insulin requirements in a patient to maintain
the euglycemic state. In one embodiment, the combination therapy
can be applied to patients suffering with obesity and/or Type 2
diabetes who have had diabetes for less than 10 years and are not
well controlled on diet and exercise or secretagogues. In one
embodiment, the patient population for receiving GLP-1 and insulin
combination therapy can be characterized by having .beta.-cell
function greater than about 25% of that of a normal healthy
individual and/or, insulin resistance of less than about 8% and/or
can have normal gastric emptying. In one embodiment, the inhalable
GLP-1 and insulin combination therapy can comprise a rapid acting
insulin such as insulin glulisine (APIDRA.RTM.), insulin lispro
(HUMALOG.RTM.) or insulin aspart (NOVOLOG.RTM.), or a long acting
insulin such as insulin detemir (LEVEMIR.RTM.) or insulin glargine
(LANTUS.RTM.), which can be administered by an inhalation powder
also comprising FDKP or by other routes of administration.
[0094] In another embodiment, a combination therapy for treating
type 2 diabetes can comprise administering to a patient in need of
treatment an effective amount of an inhalable insulin formulation
comprising an insulin and a diketopiperazine, wherein the insulin
can be a native insulin peptide, a recombinant insulin peptide, and
further administering to the patient a long acting insulin analog
which can be provided by inhalation in a formulation comprising a
diketopiperazine or by another route of administration such as by
subcutaneous injection. The method can further comprise the step of
administering to the patient an effective amount of a DPP IV
inhibitor. In one embodiment, the method can comprise administering
to a patient in need of treatment, a formulation comprising a rapid
acting or long acting insulin molecule and a diketopiperazine in
combination with formulation comprising a long acting GLP-1, which
can be administered separately and/or sequentially. GLP-1 therapy
for treating diabetes in particular type 2 diabetes can be
advantageous since administration of GLP-1 alone in a dry powder
inhalable formulation or in combination with insulin or non-insulin
therapies can reduce the risk of hypoglycemia.
[0095] In another embodiment, rapid acting GLP-1 and a
diketopiperazine formulation can be administered in combination
with a long acting GLP-1, such as exendin, for the treatment of
diabetes, which can be both administered by pulmonary inhalation.
In this embodiment, a diabetic patient suffering, for example, with
Type 2 diabetes, can be administered prandially an effective amount
of an inhalable formulation comprising GLP-1 so as to stimulate
insulin secretion, while sequentially or sometime after such as
from mealtime up to about 45 min, thereafter administering a dose
of exendin-4. Administration of inhalable GLP-1 can prevent disease
progression by preserving .beta.-cell function while exendin-4 can
be administered twice daily approximately 10 hours apart, which can
provide basal levels of GLP-1 that can mimic the normal physiology
of the incretin system in a patient. Both rapid acting GLP-1 and a
long acting GLP-1 can be administered in separate, inhalable
formulations. Alternatively, the long acting GLP-1 can be
administered by other methods of administration including, for
example, transdermally, intravenously or subcutaneously. In one
embodiment, prandial administration of a short-acting and long
acting GLP-1 combination may result in increased insulin secretion,
greater glucagon suppression and a longer delay in gastric emptying
compared to long acting GLP-1 administered alone. The amount of
long acting GLP-1 administered can vary depending on the route of
administration. For example, for pulmonary delivery, the long
acting GLP-1 can be administered in doses from about 0.1 mg to
about 1 mg per administration, immediately before a meal or at
mealtime, depending on the form of GLP-1 administered to the
patient.
[0096] In an embodiment, a kit for treating diabetes and/or
hyperglycemia is provided which comprises a medicament cartridge
for inhalation comprising a GLP-1 formulation and an inhalation
device which is configured to adapt or securely engage the
cartridge. In this embodiment, the kit can further comprise a
DPP-IV inhibitor co-formulated with GLP-1, or in a separate
formulation for inhalation or oral administration as described
above. In variations of this embodiment, the kit does not include
the inhalation device which can be provided separately.
[0097] In one embodiment, the pharmaceutical composition and the
method for treatment can be utilized in a method for treating
obesity so as to control or reduce food consumption in an animal
such as a mammal. A therapeutically effective amount of an
inhalable GLP-1 formulation can be administered to a patient in
need of treatment, wherein an inhalable dry powder, GLP-1
formulation comprises GLP-1 and a diketopiperazine as described
above. In this embodiment, the inhalable GLP-1 formulation can be
administered alone or in combination with one or more endocrine
hormone and/or anti-obesity active agents for the treatment of
obesity. Exemplary endocrine hormones and/or anti-obesity active
agents include, but are not limited to, peptide YY, oxyntomodulin,
amylin, amylin analogs such as pramlintide acetate, and the like.
In one embodiment, the anti-obesity agents can be administered in a
co-formulation in a dry powder inhalable composition alone or in
combination with GLP-1 together or in a separate inhalable dry
powder composition for inhalation. Alternatively, in the
combination of GLP-1 with one or more anti-obesity agents, or
agents that can cause satiety, the GLP-1 formulation can be
administered in a dry powder formulation and the anti-obesity agent
can be administered by alternate routes of administration. In this
embodiment, the method is targeted to reduce food consumption,
inhibit food intake in the patient, decrease or suppress appetite,
and/or control body weight. In this embodiment, a DPP-IV inhibitor
can be administered to enhance or stabilize GLP-1 delivery into the
pulmonary arterial circulation. In another embodiment, the DPP-IV
inhibitor can be provided in combination with an insulin
formulation comprising a diketopiperazine. In this embodiment, the
DPP-IV inhibitor can be formulated in a diketopiperazine for
inhalation or it can be administered in other formulation for other
routes of administration such as by subcutaneous injection or oral
administration.
[0098] In one embodiment, the present combination therapy using the
drug delivery system can be applied to treat metabolic disorders or
syndromes. In this embodiment, the drug delivery formulation can
comprise a formulation comprising a diketopiperazine and an active
agent, including GLP-1 and/or a long acting GLP-1 alone or in
combination with one or more active agents such as a DPP-IV
inhibitor and exendin, targeted to treat the metabolic syndrome. In
this embodiment, at least one of the active agents to be provided
to the subject in need of treatment and who may exhibit insulin
resistance can be administered by pulmonary inhalation.
[0099] In another embodiment, the pulmonary administration of an
inhalable dry powder formulation comprising GLP-1, or a GLP-1
analog and a diketopiperazine can be used as a diagnostic tool to
diagnose the level or degree of progression of type 2 diabetes in a
patient afflicted with diabetes in order to identify the particular
treatment regime suitable for the patient to be treated. In this
embodiment, a method for diagnosing the level of diabetes
progression in a patient identified as having diabetes, the method
comprising administering to the patient a predetermined amount of
an inhalable dry powder formulation comprising GLP-1 and a
diketopiperazine and measuring the endogenous insulin production or
response. The administration of the inhalable dry powder
formulation comprising GLP-1 can be repeated with predetermined
amounts of GLP-1 until the appropriate levels of an insulin
response is obtained for that patient to determine the required
treatment regime required by the patient. In this embodiment, if a
patient insulin response is inadequate, the patient may require
alternative therapies. Patients who are sensitive or
insulin-responsive can be treated with a GLP-1 formulation
comprising a diketopiperazine as a therapy. In this manner, the
specific amount of GLP-1 can be administered to a patient in order
to achieve an appropriate insulin response to avoid hypoglycemia.
In this and other embodiments, GLP-1 can induce a rapid release of
endogenous insulin which mimics the normal physiology of insulin
release.
[0100] In one embodiment, the pulmonary administration of an
inhalable dry powder formulation comprising a GLP-1 or a GLP-1
analog, including ROSE-010, can be administered in therapeutically
effective amounts to decrease pain and inhibit gastric motility in
patients suffering with irritable bowel syndrome.
[0101] In one aspect of the disclosure, the method of treating
functional dyspepsia and/or irritable bowel syndrome in a mammal in
need of treatment, comprises administering to the mammal a
therapeutically effective amount of a formulation by pulmonary
inhalation, comprising a diketopiperazine having the formula:
3,6-bis[4-(N-carboxy-2-propenyl)amidobutyl]-2,5-diketopiperazine
(fumaryl diketopiperazine, FDKP) and ROSE-010, a GLP-1 analog. In
one embodiment, a method of administering an effective amount of a
GLP-1 molecule or a GLP-1 analog to a subject in need of treatment
of irritable bowel syndrome is provided, wherein the method
comprises providing to said subject an inhalable dry powder
formulation comprising a GLP-1 molecule or GLP-1 analog such as
ROSE-010 and a diketopiperazine, wherein said administration is
carried out by pulmonary delivery. In this and other embodiments
related to the treatment of irritable bowel syndrome, the GLP-1
analog such as ROSE-010 is provided in a dry powder dosage form for
inhalation and the dosage form comprises the GLP-1 analog in
dosages of from about 0.01 mg to about 0.9 mg, from about 0.025 mg
to about 0.5 mg, or from about 0.05 mg to about 0.3 mg is
administered per administration. In one embodiment, the dry powder
formulation can be provided, for example, using a single use
inhaler.
[0102] In another embodiment, a method of forming a powder
composition with an improved GLP-1 pharmacokinetic profile is
provided, the method comprising the steps of: providing a GLP-1
analog such as Val (8) GLP-1, providing a particle-forming
diketopiperazine in a solution, forming diketopiperazine particles,
combining the Val (8) GLP-1 and the solution to form a co-solution,
and removing solvent from the co-solution by spray-drying to form a
powder for pulmonary inhalation with an improved GLP-1
pharmacokinetic profile.
[0103] GLP-1 Analogs
[0104] The present disclosure relates to the use of GLP-1 or a
GLP-1 analog such as ROSE-010 in an inhalable dry powder
formulation for the treatment of irritable bowel syndrome. The term
"GLP-1 or GLP-1 analog" is used herein to refer to any molecule
capable of binding to and activating the GLP-1 receptor. Methods
for assaying the functional activity of the GLP-1 molecules for use
in the present invention is described in the section entitled
"Functional activity of GLP-1 molecule." The activity of the GLP-1
molecules for use in the present invention can be less potent or
more potent than native GLP-1.
[0105] GLP-1 analogs are defined as molecules having one or more
amino acid substitutions, deletions, inversions or additions, such
as 15 or fewer, for example 13 or fewer, such as 11 or fewer, for
example 9 or fewer, such as 7 or fewer for example 5 or fewer, such
as 3 or fewer for example 2 or fewer. The amino acids may include
D-amino acid forms. Numerous GLP-1 analogs are known in the art and
are described in WO2007/028394 which is incorporated by reference.
They include, but are not limited to, GLP-1(7-34), GLP-1(7-35),
GLP-1(7-36)NH.sub.2, Gln9-GLP-1(7-37), d-Gln9-GLP1(7-37),
Thrl6-Lysl8-GLP-1(7-37), and Lysl8-GLP-1(7-37),
Gly-GLP-1(7-36)NH.sub.2, Gly-GLP1(7-37)OH, Val'-GLP-1(7-37)OH,
Met8-GLP-1(7-37)OH, acetyl-Lys9-GLP-1(7-37), Thr9GLP-1(7-37),
D-Thr9-GLP-1(7-37), Asn9-GLP-1(7-37), D-Asn9-GLP-1(7-37),
Ser22-Arg23-Arg24-Gln26-GLP-1(7-37), Arg23-GLP-1(7-37),
Arg24-GLP-1(7-37), a-methyl-Ala8-GLP-1(736)NH.sub.2, and
Gly'-Gln2'-GLP-1(7-37) OH, and the like.
[0106] Other GLP-1 analogs consistent with the present invention
are described by the formula:
R.sub.3--X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Y-Gly-Gln-Ala--
Ala-Lys-Z-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-R.sub.4 (SEQ ID NO:
3) wherein: R.sub.3 is selected from the group consisting of
L-histidine, D-histidine, desaminohistidine, 2-amino-histidine,
beta-hydroxy-histidine, homohistidine, alpha-fluoromethylhistidine,
and alpha-methyl-histidine; X is selected from the group consisting
of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala; Y is selected
from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly; Z is
selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and
Gly; and R.sub.4 is selected from the group consisting of
Gly-NH.sub.2, and Gly-OH.
[0107] GLP-1 analogs also have been described in WO 91/11457, and
include GLP-1(7-34), GLP-1(7-35), GLP-1(7-36), or GLP-1(7-37), or
the amide form thereof, and pharmaceutically-acceptable salts
thereof, having at least one modification selected from the group
consisting of: [0108] (a) substitution of glycine, serine,
cysteine, threonine, asparagine, glutamine, tyrosine, alanine,
valine, isoleucine, leucine, methionine, phenylalanine, arginine,
or D-lysine for lysine at position 26 and/or position 34; or
substitution of glycine, serine, cysteine, threonine, asparagine,
glutamine, tyrosine, alanine, valine, isoleucine, leucine,
methionine, phenylalanine, lysine, or a D-arginine for arginine at
position 36; [0109] (b) substitution of an oxidation-resistant
amino acid for tryptophan at position 31; [0110] (c) substitution
of at least one of: tyrosine for valine at position 16; lysine for
serine at position 18; aspartic acid for glutamic acid at position
21; serine for glycine at position 22; arginine for glutamine at
position 23; arginine for alanine at position 24; and glutamine for
lysine at position 26; [0111] (d) substitution of at least one of:
glycine, serine, or cysteine for alanine at position 8; aspartic
acid, glycine, serine, cysteine, threonine, asparagine, glutamine,
tyrosine, alanine, valine, isoleucine, leucine, methionine, or
phenylalanine for glutamic acid at position 9; serine, cysteine,
threonine, asparagine, glutamine, tyrosine, alanine, valine,
isoleucine, leucine, methionine, or phenylalanine for glycine at
position 10; and glutamic acid for aspartic acid at position 15;
and [0112] (e) substitution of glycine, serine, cysteine,
threonine, asparagine, glutamine, tyrosine, alanine, valine,
isoleucine, leucine, methionine, or phenylalanine, or the D- or
N-acylated or alkylated form of histidine for histidine at position
7; wherein, in the substitutions described in (a), (b), (d), and
(e), the substituted amino acids can optionally be in the D-form
and the amino acids substituted at position 7 can optionally be in
the N-acylated or N-alkylated form.
[0113] Preferred GLP-1 molecules used in the present inventive
formulation also include analogs of GLP-1(7-37)NH.sub.2 and
GLP-1(7-37) in which one or more amino acids which are not present
in the original sequence are added or deleted, and derivatives
thereof.
[0114] Specifically, His and desamino-histidine are preferred for
R.sub.3 and/or Ala, Gly and Val are preferred at the "X" position.
Also, Glu and Gln are preferred for at the "Y" position. Glu and
Gln are preferred at the "Z" position and Gly-OH is preferred for
R.sub.4.
[0115] A particularly preferred GLP-1 analog is known as Val (8)
GLP-1 (ROSE-010: SEQ ID NO: 1).
[0116] Functional Activity of GLP-1 Molecule
[0117] The GLP-1 molecules described herein are capable of binding
to and activating the GLP-1 receptor.
[0118] The receptor activity can be measured using different
techniques such as detecting a change in the intracellular
conformation of the receptor, in the G-protein coupled activities
and/or in the intracellular messengers.
[0119] Different techniques for measuring the receptor activity are
described in WO2007/028394 which is incorporated by reference
herein.
[0120] Formulation
[0121] A method of introducing an active agent into the circulatory
system of a mammal is disclosed herein. The method comprises a drug
delivery system which prevents deactivation or degradation of the
active agent being administered to a patient in need of treatment.
In particular, the drug delivery system is designed for pulmonary
drug delivery such as by inhalation, for delivery of active agents
to the pulmonary circulation in a therapeutically effective manner.
The drug delivery system has advantages over other methods of drug
delivery, for example, oral, subcutaneous and intravenous
administration of drug products such as proteins and peptides that
are sensitive to enzymatic deactivation or degradation in the local
peripheral and vascular tissue before reaching the target site.
[0122] In one embodiment disclosed herein, a method for providing
an active agent to a patient in need thereof is disclosed
comprising selecting an active agent subject to degradation in the
patient wherein effectiveness of the active agent is reduced by the
degradation, associating the active agent with a diketopiperazine
to produce a pharmaceutical composition suitable for pulmonary
inhalation, and providing the pharmaceutical composition to the
patient.
[0123] In another embodiment, the degradation occurs in venous
blood circulation, in a peripheral tissue, in the gastrointestinal
system, or in the liver.
[0124] Also disclosed herein is a method of treating disease
comprising selecting a patient being treated with or a patient with
a condition treatable by a labile active agent, providing a
composition comprising the labile active agent in association with
a diketopiperazine, and administering the composition to the
patient via pulmonary inhalation, thereby treating the disease or
condition.
[0125] In another embodiment, the pharmaceutical composition is an
inhalable dry powder formulation. In yet another embodiment, the
inhalable dry powder formulation further comprises a
pharmaceutically acceptable carrier or excipient.
[0126] In one embodiment, the inhalable dry powder formulation is
provided to the patient by pulmonary inhalation using a dry powder
inhalation system.
[0127] In yet another embodiment, the active agent is a protein, a
peptide, or an analog thereof. In another embodiment, the active
agent is an endocrine hormone or an analog thereof. The endocrine
hormone is a hormone associated with diabetes, hyperglycemia and/or
obesity. In another embodiment, the diabetes is type 2 diabetes
mellitus.
[0128] In another embodiment of the disclosed method, the step of
administering the composition to the patient comprises pulmonary
administration of the composition using a dry powder inhaler
comprising a cartridge, such as a unit dosing cartridge.
[0129] The methods of delivery presented in various embodiments
herein can provide a more direct path to an active agent's site of
action. Thus in addition to the avoidance of degradation, though in
some instances still in part due to it, the biodistribution of the
active agent delivered by inhalation can differ from that achieved
with modes of delivery that entail absorption into, and travel
through, the venous circulation prior to reaching sites of action
in the body. For active agents such as GLP-1 and analogs thereof,
with multiple effects and sites of action, a different
constellation of effects may be observed when administered via
inhalation as the relative concentrations at different sites of
action will differ from that achieved using other modes of
administration. This can further contribute to greater effective
bioavailability, avoidance of unwanted effects, and the like.
[0130] In one embodiment, the dry powder formulation for use with
the methods disclosed herein comprises particles comprising a GLP-1
analog molecule, preferably ROSE-010, and a diketopiperazine or a
pharmaceutically acceptable salt thereof.
[0131] In one embodiment, the inhalable formulation comprises a dry
powder formulation comprising the above-mentioned active ingredient
with a diketopiperazine, including
2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected
from the group consisting of succinyl, glutaryl, maleyl, and
fumaryl, or a salt of the diketopiperazine. In this embodiment, the
inhalable formulation can comprise microparticles for inhalation
comprising the active ingredient with the aerodynamic
characteristics as described above. In one embodiment, the amount
of active ingredient can be determined by one of ordinary skill in
the art, however, the present microparticles can be loaded with
various amounts of active ingredient as needed by the patient. For
example, for oxyntomodulin, the microparticles can comprise from
about 1% (w/w) to about 75% (w/w) of the active ingredient in the
formulation. In certain embodiments, the inhalable formulations can
comprise from about 10% (w/w) to about 30% (w/w) of the
pharmaceutical composition and can also comprise a pharmaceutically
acceptable carrier, or excipient, such as a surfactant, such as
polysorbate 80. In this embodiment, oxyntomodulin can be
administered to the patient from once to about four times a day or
as needed by the patient with doses ranging from about 0.05 mg up
to about 5 mg in the formulation. In particular embodiments, the
dosage to be administered to a subject can range from about 0.1 mg
to about 3.0 mg of oxyntomodulin. In one embodiment, the inhalable
formulation can comprise from about 50 pmol to about 700 pmol of
oxyntomodulin in the formulation.
[0132] In one embodiment, the formulation comprising the active
ingredient can be administered to the patient in a dry powder
formulation by inhalation using a dry powder inhaler such as the
inhaler disclosed, for example, in U.S. Pat. No. 7,305,986 and U.S.
patent application Ser. No. 10/655,153 (US 2004/0182387), which
disclosures are incorporated herein by reference. Repeat inhalation
of dry powder formulation comprising the active ingredient can also
be administered between meals and daily as needed. In some
embodiments, the formulation can be administered once, twice, three
or four times a day.
[0133] In this embodiment, the carrier can be associated with one
or more active agents to form a drug/carrier complex which can be
administered as a composition that avoids rapid degradation of the
active agent in the peripheral and vascular venous tissue of the
lung. In one embodiment, the carrier is a diketopiperazine.
[0134] The method described herein utilizes a drug delivery system
that effectively delivers a therapeutic amount of an active agent,
including peptide hormones, rapidly into the arterial circulation.
In one embodiment, the active agent include, but are not limited to
peptides such as ROSE-010 and other GLP-1 analogs, which are
sensitive to degradation or deactivation, formulating the active
agent into a dry powder composition comprising a diketopiperazine,
and delivering the active agent(s) into the systemic circulation by
pulmonary inhalation using a cartridge and a dry powder inhaler. In
one embodiment, the method comprises selecting a peptide that is
sensitive to enzymes in the local vascular or peripheral tissue of,
for example, the dermis, or lungs. The present method allows the
active agent to avoid or reduce contact with peripheral tissue,
venous or liver metabolism/degradation. In another embodiment, for
systemic delivery of the active agent should not have specific
receptors in the lungs.
[0135] The ROSE-010 formulation is administered by inhalation such
as by pulmonary administration. In this embodiment, pulmonary
administration can be accomplished by providing ROSE-010 in a dry
powder formulation for inhalation. The dry powder formulation is a
stable composition and can comprise microparticles which are
suitable for inhalation and which dissolve rapidly in the lung and
rapidly deliver ROSE-010 to the pulmonary circulation. Depending on
the particle size, the ROSE-010 pharmaceutical composition can be
delivered by inhalation to specific areas of the respiratory
system. Suitable particle sizes for pulmonary administration can be
less than 10 .mu.m in diameter, and preferably less than 5 .mu.m.
Exemplary particle sizes that can reach the pulmonary alveoli range
from about 0.5 .mu.m to about 5.8 .mu.m in diameter. Such sizes
refer particularly to aerodynamic diameter, but often also
correspond to actually physical diameter as well. Such particles
can reach the pulmonary capillaries, and can avoid extensive
contact with the peripheral tissue in the lung. In this embodiment,
the drug can be delivered to the arterial circulation in a rapid
manner and avoid degradation of the active ingredient by enzymes or
other mechanisms prior to reaching its target or site of action in
the body. In one embodiment, dry powder compositions for pulmonary
inhalation comprising ROSE-010 and DKP can comprise microparticles
wherein from about 35% to about 75% of the microparticles have an
aerodynamic diameter of less than 5.8 .mu.m. Additionally the
ROSE-010/DKP particles can be made small enough for incorporation
into a intravenous suspension dosage form. For oral delivery, the
particles can be incorporated into a suspension, tablets or
capsules.
[0136] Dosage
[0137] In one aspect, the GLP-1 analog is resistant to degradation
and can have a longer life than native GLP-1 in the circulation. In
this and other embodiments, the GLP-1 analog is administered in
dosages ranging from about 0.01 mg to about 3 mg in the formulation
and the dosing regimen can be daily, or more than once a day. In
administering a ROSE-010/DKP composition of the present invention
to a subject in need thereof, the actual dosage amount of the
composition can be determined on the basis of physical and
physiological factors such as body weight, severity of condition,
the type of disease being treated, previous or concurrent
therapeutic interventions, idiopathy of the patient and the route
of administration. A skilled artisan would be able to determine
actual dosages based on one or more of these factors.
[0138] The ROSE-010/DKP formulation can be administered once or
more than once, depending the disease or condition to be treated.
In particular in relation to treatment of diabetes the formulation
may be administered several times per day, such as before the
meals. In relation to treatment of irritable bowel syndrome, the
formulation may be administered when there is a need for treating
pain spasms.
[0139] In one embodiment, the method of treatment comprises
administering ROSE-010 in therapeutically effective amounts that
can produce a bioavailability of greater than 50 pMol/L, or greater
than 100 pMol/L by pulmonary inhalation. In one embodiment, the
DKP-ROSE-010 formulation delivered by pulmonary inhalation can
produce plasma concentration of the ROSE-010 analog greater than
500 pMol/L. In this embodiment, the GLP-1 analog has the amino acid
sequence:
His-Val-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-A-
la-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-OH(ROSE-010; SEQ
ID NO: 1). In this and other embodiments, the formulation
comprising ROSE-010 can decrease pain and inhibit gastric motility
in patients suffering with irritable bowel syndrome.
[0140] In one embodiment, a patient is administered an inhalable
GLP-1 formulation in a dosing range wherein the amount of GLP-1 is
from about 0.01 mg to about 3 mg, or from about 0.02 mg to about
2.5 mg, or from about 0.2 mg to about 2 mg of the formulation. In
one embodiment, a patient with type 2 diabetes can be given a GLP-1
dose greater than 3 mg. In this embodiment, the GLP-1 can be
formulated with inhalation particles such as a diketopiperazines
with or without pharmaceutical carriers and excipients. In one
embodiment, pulmonary administration of the GLP-1 formulation can
provide plasma concentrations of GLP-1 greater than 100 pmol/L
without inducing unwanted adverse side effects, such as profuse
sweating, nausea and vomiting to the patient.
EXAMPLES
[0141] The following examples are included to demonstrate certain
embodiments of the methods and compositions disclosed herein. It
should be appreciated by those of skill in the art that the
techniques disclosed in the examples elucidate representative
techniques that function well in the practice of the methods
disclosed herein. However, those of skill in the art should, in
light of the present disclosure, appreciate that many changes can
be made in the specific embodiments that are disclosed and still
obtain a like or similar result without departing from the spirit
and scope of the disclosure.
Example 1
Preparation of Diketopiperazine Formulation Comprising a GLP-1
Analog, ROSE-010
[0142] Protein Adsorption onto TECHNOSPHERE.RTM. Particles
[0143] Diketopiperazine particles were prepared using procedures as
disclosed in U.S. patent application Ser. No. 11/735,957, which
disclosure is incorporated by reference as it pertains herein.
[0144] Effect of pH: A solution of ROSE-010 (5 mg/mL) in 7% acetic
acid was mixed with a TECHNOSPHERE.RTM. particle suspension.
Quantities were selected to provide a final dry powder containing
10% ROSE-010 by weight. The pH of the resulting suspension was
adjusted to ensure complete adsorption of ROSE-010 onto the
TECHNOSPHERE.RTM. particles (FIG. 1). Essentially all of the
peptide was adsorbed at pH 4.5.
[0145] Constant pH
[0146] In a second adsorption experiment, a solution of ROSE-010 (5
mg/mL) was prepared at pH 3.0 and added to a TECHNOSPHERE.RTM.
particle suspension at pH 3.0. Quantities were selected to provide
a final dry powder containing 10% ROSE-010 by weight. The mixed
suspension was maintained at pH 3.0 to reduce potential aggregation
of the ROSE-010 peptide. Under these conditions, only 2.4% of the
ROSE-010 was adsorbed to the TECHNOSPHERE.RTM. particles.
[0147] Preparation of Prototype ROSE-010 TECHNOSPHERE.RTM.
Powders
[0148] Powder Preparation: Fumaryl diketopiperazine-ROSE-010
particles in suspension were suspended in water. Water was removed
from the final suspensions from each adsorption experiment by
lyophilization to give 200-300 mg of each powder.
[0149] Determination of ROSE-010 Content in Prototype Powders by
HPLC
[0150] HPLC Method Development
[0151] Several HPLC methods previously developed by MannKind
Corporation (Valencia, Calif.) for quantifying peptides in the
presence of FDKP (primary component of TECHNOSPHERE.RTM. powders)
were used to evaluate ROSE-010 TECHNOSPHERE.RTM. powders. The first
method was a rapid assessment method to quantify ROSE-010 in the
initial prototype powders. This method showed no interference
between FDKP and ROSE-010 (FIG. 2). A more refined assay method was
used to quantitative ROSE-010 in test articles, dosing solutions,
and stability samples (FIG. 3). A third method was evaluated to
monitor related substances in stability samples (FIG. 4). Comparing
chromatograms of ROSE-010 alone and ROSE-010 in the
TECHNOSPHERE.RTM. powder (FIG. 5) using the related substances
method showed no significant increase in related compounds due to
the formulation process. All of these methods are suitable for
analyzing ROSE-010 TECHNOSPHERE.RTM. powders during these
studies.
[0152] The ROSE-010 TECHNOSPHERE.RTM. powders were analyzed by
HPLC. The target and measured ROSE-010 content for the prototype
powders are comparable (Table 1). This formulation process
facilitates quantitative recovery of the peptide.
TABLE-US-00002 TABLE 1 Percent ROSE-010 in prototype powders.
Target Assayed ROSE-010 ROSE-010 Powder content (%) content (%)
Powder prepared 10.0 10.1 at pH 4.5 Powder prepared 10.0 9.2 at pH
3.0
[0153] Aerodynamic Characterization by Cascade Impaction
[0154] The prototype ROSE-010 TECHNOSPHERE.RTM. powders were filled
into inhaler cartridges (5 mg into each of 5 cartridges) and
analyzed by discharge through MannKind Corporation's next
generation inhaler into an Andersen cascade impactor. Aerodynamic
performance was measured as respirable fraction of fill contents (%
RF/fill) and cartridge emptying. The particle size distribution of
the powders was also analyzed by laser diffraction analysis using a
SYMPATEC.TM. RODOS system and the results are shown in FIGS. 6 and
7, and Table 2. The data show the performance of the powder
prepared at pH 3.0 was better than the performance of the powder
prepared by pH adjustment (Table 2). Cartridge emptying was >98%
for both powders. FIGS. 6 and 7, and Table 2 show that of the
powder that emptied from the cartridge, 34% of the powder prepared
at pH 4.5 was in the respirable range and 47% of the powder
prepared at pH 3.0 was in the respirable range.
TABLE-US-00003 TABLE 2 Aerodynamic data for prototype powders.
Cascade impactor SYMPATEC .TM. RODOS % Median Cartridge diameter %
<5.8 .mu.m Powder % RF/fill Emptying (.mu.m) by RODOS Powder
prepared 34 100 4.35 55 at pH 4.5 Powder prepared 47 98 3.42 79 at
pH 3.0
[0155] The RODOS results show that powder prepared at pH 4.5 has a
bimodal particle size distribution as illustrated by the scan shown
at FIG. 6. One particle size population was centered on 2.5 .mu.m
and the other at 60-70 .mu.m (FIG. 6). Only about 55% of the
particles were in the respirable range (<5.8 .mu.m). The powder
prepared at pH 3.0 (FIG. 7) exhibits a single mode at about 4 .mu.m
and more of the particles are sized in the respirable range (below
5.8 .mu.m).
Example 2
Pulmonary Insufflation of ROSE-010 (GLP-1 Peptide Analog)
Completely Suppresses The Migrating Myoelectric/Motor Complex in
the Conscious Rat: Comparison with the Intravenous and Subcutaneous
Administrations
[0156] The aim of these studies were to compare ROSE-010 in the MMC
model pulmonary insufflation of ROSE-010 TECHNOSPHERE.RTM. powder
compared to ROSE-010 administered by subcutaneous (SC) or
intravenous (IV) injection. Studies were carried out in 10 rats
with a jugular vein catheter and bipolar electrodes implanted at 5,
15, and 25 cm distal to the pylorus. Myoelectric activity was
continuously recorded over 6-8 hours. After a control period of
four MMC cycles, animals were briefly (4 min) anesthetized with
Isoflurane 3-4% and rapidly insufflated with air or ROSE-010
TECHNOSPHERE.RTM. powder at doses of 0.2 and 0.1 mg/kg ROSE-010.
Alternatively, ROSE-010 was administered by IV or SC injection at
0.1 mg/kg. Recording was continued until four MMC cycles were
resumed.
[0157] Formulations for Pharmacodynamic (PD) Studies
[0158] Based on the rat pharmacokinetic study, the pH 4.5
formulation process was selected to prepare powder for a subsequent
pharmacodynamic study. This powder was characterized (Table 3). An
SEM micrograph (FIG. 8) shows the agglomerates previously observed
for ROSE-010 TECHNOSPHERE.RTM. powder prepared at pH 4.5. The
scanning electronmicrograph of the sample powder showing the
particle composition of the powder is shown in FIG. 8. The
particles appear somewhat spherical with numerous plate-like
structures
TABLE-US-00004 TABLE 3 Analytical results for the pharmacodynamic
10% ROSE-010 TECHNOSPHERE.RTM. powder. Target ROSE-010 % ROSE- %
Cartridge content (%) 010 % RF/Fill Emptying 10.0 9.1 24 98
[0159] Stability: The ROSE-010 TECHNOSPHERE.RTM. powder used for
the PD study was placed on a three month open dish stability
evaluation at -20.degree. C. and at 25.degree. C./60% relative
humidity (RH). Sampling time points were selected at 2 weeks, 1
month, 2 months and 3 months after initiation of the studies. The
ROSE-010 stability was unchanged after one month at freezer
conditions (Table 4). At 25.degree. C./60% RH, the ROSE-010
stability decreased slightly over a period of three months (Table
5). A review of ROSE-010 assay calculations identified an error for
the value at release (t.sub.0).
TABLE-US-00005 TABLE 4 Stability data (-20.degree. C.) for 10%
ROSE-010 TECHNOSPHERE .RTM. powder. Storage Condition: -20.degree.
C. Parameter (Unit) release (t.sub.0) 2 weeks 1 month 2 months 3
months Appearance White White White White White powder powder
powder powder powder Wt % ROSE-010 (Relative to t.sub.0) 8.6 9.0
9.1 9.2 9.1 (100%) (104%) (106%) (107%) (105%) RRT % RRT % RRT %
RRT % RRT % Related 0.59 0.21 0.63 0.20 0.64 0.29 0.63 0.18 0.59
0.19 Substances 0.62 0.30 0.65 0.33 0.94 0.21 0.66 0.26 0.62 0.31
0.87 0.18 0.95 0.25 0.95 0.23 0.85 0.15 0.83 0.18 0.94 0.23 0.96
0.30 1.03 1.72 0.89 0.19 0.87 0.17 0.95 0.30 1.03 1.07 1.05 0.25
0.95 0.22 0.94 0.23 1.03 1.48 1.05 0.16 1.13 0.16 0.96 0.22 0.95
0.28 1.05 0.16 1.10 0.17 1.15 0.23 1.03 1.28 0.97 0.16 1.11 0.17
1.13 0.23 1.26 0.21 1.05 0.17 1.03 1.24 1.14 0.15 1.13 0.16 1.15
0.17 1.15 0.24 1.14 0.31 1.17 0.25 1.26 0.21 1.30 0.29
TABLE-US-00006 TABLE 5 Stability data (25.degree. C./60% RH) for
10% ROSE-010 TECHNOSPHERE .RTM. powder. Storage Condition:
25.degree. C./60% RH Parameter (Unit) release (t.sub.0) 2 weeks 1
month 2 months 3 months Appearance White White White White White
powder powder powder powder powder Wt % ROSE-010 (Relative to
t.sub.0) 8.6 8.5 8.4 8.3 8.2 (100%) (99%) (98%) (97%) (95%) RRT %
RRT % RRT % RRT % RRT % Related 0.59 0.21 0.63 0.22 0.60 0.22 0.63
0.27 0.59 0.31 Substances 0.62 0.30 0.66 0.34 0.63 0.31 0.66 0.28
0.61 0.37 0.87 0.18 0.69 0.15 0.88 0.17 0.85 0.15 0.65 0.17 0.94
0.23 0.95 0.24 0.94 0.21 0.86 0.18 0.80 0.15 0.95 0.30 0.96 0.38
0.96 0.44 0.89 0.23 0.84 0.21 1.03 1.48 1.03 1.65 1.03 2.51 0.95
0.23 0.87 0.23 1.05 0.16 1.10 0.22 1.05 0.31 0.96 0.48 0.94 0.19
1.11 0.17 1.12 0.36 1.07 0.24 1.03 1.75 0.95 0.57 1.14 0.15 1.13
0.41 1.11 0.26 1.05 0.36 0.97 0.15 1.15 0.24 1.18 0.17 1.13 0.69
1.07 0.19 1.03 1.05 1.15 0.53 1.11 0.23 1.04 2.06 1.20 0.18 1.12
0.15 1.06 0.49 1.26 0.26 1.13 0.74 1.08 0.26 1.14 0.55 1.13 0.35
1.16 0.16 1.15 0.93 1.19 0.18 1.17 0.52 1.25 0.16 1.21 0.19 1.37
0.15 1.30 0.31 1.48 0.16 1.44 0.22 1.53 0.21 1.56 0.21
[0160] ROSE-010 Pharmacokinetics in Rats
[0161] The PK profile of ROSE-010 administered as ROSE-010
TECHNOSPHERE.RTM. prototype powders was evaluated in female Sprague
Dawley rats (n=10/group) by pulmonary insufflation and compared to
ROSE-010 administered by intravenous (IV) and subcutaneous (SC)
injection (Table 6).
TABLE-US-00007 TABLE 6 ROSE-010 PK study design. Dose (mg ROSE-
Route of Group Test Article 010) Administration 1 ROSE-010 0.1 IV 2
ROSE-010 0.1 SC 3 ROSE-010 TECHNOSPHERE.RTM. 0.1 Insufflation
powder pH 4.5 4 ROSE-010 TECHNOSPHERE.RTM. 0.2 Insufflation powder
pH 4.5 5 ROSE-010 TECHNOSPHERE.RTM. 0.3 Insufflation powder pH 4.5
6 ROSE-010 TECHNOSPHERE.RTM. 0.3 Insufflation powder pH 3
[0162] Blood samples for ROSE-010 analysis were collected before
dosing and at 2, 4, 6, 8, 10, 12, 15, 20, 30, 40, 60 and 90 minutes
after dosing. ROSE-010 in plasma was analyzed using enzyme-linked
immunosorbent assay (ELISA) against a GLP-1 standard (n=5 rats/time
point). Subsequently, ROSE-010 was found to be significantly less
sensitive than GLP-1 in the ELISA assay, so a conversion factor was
used to correct for this difference. The PK profiles of ROSE-010
insufflated as ROSE-010 TECHNOSPHERE.RTM. powders were dose-related
and comparable to ROSE-010 administered by subcutaneous injection.
ROSE-010 administered by IV injection demonstrated a faster time to
peak circulating concentrations (FIG. 9).
[0163] ROSE-010 was well tolerated across all treatment groups.
Pharmacokinetic parameters corrected for administered dose were
calculated using noncompartmental methods and the nonlinear
regression program WinNonlin (Table 7) corrected for administered
doses.
TABLE-US-00008 TABLE 7 ROSE-010 PK parameters. Half Test Article
(ROSE- life T.sub.max C.sub.max AUC.sub.all AUC.sub.all-D
Bioavailability Group 010 dose in mg) (min) (min) (pM) (min * pM)
(min * pM/mg) (%) 1 ROSE-010 (0.1) 71 2 231,108 1,475,765
14,757,650 100 2 ROSE-010 (0.1) 35 8 20,314 708,706 7,087,064 48 3
ROSE-010 48 6 9,966 886,160 8,861,600 60 TECHNOSPHERE .RTM. (0.1) 4
ROSE-010 59 10 25,760 1,543,529 7,717,645 52 TECHNOSPHERE .RTM.
(0.2) 5 ROSE-010 65 10 21,894 2,022,256 6,740,853 46 TECHNOSPHERE
.RTM. (0.3) 6 ROSE-010 47 8 15,179 871,523 2,905,077 20
TECHNOSPHERE .RTM. (0.3) *T.sub.max and C.sub.max were defined as
the initial point in the concentration curve plateau.
[0164] Overall, ROSE-010 was systemically bioavailable following
pulmonary insufflation with ROSE-010 TECHNOSPHERE.RTM. powder.
Absolute ROSE-010 bioavailability was between 46 and 60% with
powder prepared at pH 4.5; and 20% with powder prepared at pH 3.
ROSE-010 was absorbed rapidly after pulmonary insufflation with
Cmax occurring approximately 6 minutes after administration.
[0165] ROSE-010 Pharmacodynamics Results
[0166] ROSE-010 TECHNOSPHERE.RTM. powder was tested in the rat
migrating myoelectric/motor complex (MMC) model and compared to
intravenous or subcutaneous injection of ROSE-010. Animals received
either ROSE-010 (0.03 mg) by IV or SC injection or ROSE-010
TECHNOSPHERE.RTM. powder (0.03 or 0.06 mg ROSE-010) by pulmonary
insufflation.
[0167] Myoelectric activity was continuously recorded over 6-8
hours. The animals were fasted with a stable MMC pattern. After a
control period of four MMC cycles, animals were briefly (.about.4
min) anesthetized with 3-4% isoflurane and rapidly insufflated with
air or ROSE-010 TECHNOSPHERE.RTM. powder at doses of 0.06 and 0.03
mg ROSE-010. Alternatively 0.03 mg ROSE-010 was given IV or SC.
Recording was continued until four MMC cycles were resumed.
[0168] Pulmonary insufflation of ROSE-010 TECHNOSPHERE.RTM. powder
(0.06 mg ROSE-010) increased MMC cycle length from 18.7.+-.7.3 to
105.9.+-.9.5 min (n=6), and 0.03 mg ROSE-010 increased MMC cycle
length from 19.4.+-.2.9 to 102.6.+-.18.3 min (n=3). IV or SC
ROSE-010 (0.03 mg) prolonged the MMC cycle from 18.3.+-.2.5 and
14.8.+-.2.0 min to 124.1.+-.27.3 and 148.1.+-.49.4 min,
respectively (n=6/group). There was no increase in MMC cycle length
in animals administered air by insufflation (FIG. 10). This study
demonstrated that MMC inhibition following pulmonary insufflation
of ROSE-010 TECHNOSPHERE.RTM. powder is comparable to inhibition
following intravenous or subcutaneous injection of ROSE-010 at
similar doses.
[0169] FIG. 10 illustrates the duration of MMC suppression in male
Sprague Dawley Rats administered ROSE-010 by intravenous injection
or subcutaneous injection or ROSE-010 TECHNOSPHERE.RTM. powder by
pulmonary insufflation.
[0170] The data indicate that the ROSE-010 TECHNOSPHERE.RTM. powder
formulation administered to rats by the pulmonary route show
measurable levels of ROSE-010 in blood. In these studies, ROSE-010
insufflated as a ROSE-010 TECHNOSPHERE.RTM. powder demonstrated
dose dependent increases in exposure, bioavailability of 60%
relative to IV injection (greater than SC administration), and
inhibition of the MMC comparable to SC and IV administration. The
data obtained demonstrate that pulmonary insufflation of ROSE-010
TECHNOSPHERE.RTM. powder (0.2 mg/kg ROSE-010) increased MMC cycle
length from 18.7.+-.7.3 to 105.9.+-.9.5 min (n=6), and 0.1 mg/kg
ROSE-010 from 19.4.+-.2.9 to 102.6.+-.18.3 min (n=3). IV or SC
ROSE-010 (0.1 mg/kg) prolonged the MMC cycle from 18.3.+-.2.5 and
14.8.+-.2.0 min to 124.1.+-.27.3 and 148.1.+-.49.4 min,
respectively (n=6/group). There was no increase in MMC cycle length
in animals administered air by insufflation.
[0171] In summary, MMC inhibition following pulmonary insufflation
of ROSE-010 TECHNOSPHERE.RTM. powder is comparable to inhibition
following IV or SC injection of ROSE-010 at similar doses
(p>0.05).
Example 3
Administration of GLP-1 in an Inhalable Dry Powder to Healthy Adult
Males
[0172] GLP-1 has been shown to control elevated blood glucose in
humans when given by intravenous (IV) or subcutaneous (SC)
infusions or by multiple subcutaneous injections. Due to the
extremely short half-life of the hormone, continuous subcutaneous
infusion or multiple daily subcutaneous injections would be
required to achieve clinical efficacy. Neither of these routes is
practical for prolonged clinical use. Applicants have found in
animal experiments that when GLP-1 was administered by inhalation,
therapeutic levels could be achieved. The results of these studies
can be found, for example, in U.S. patent application Ser. No.
11/735,957, the disclosure of which is incorporated by reference
herein.
[0173] In healthy individuals, several of the actions of native
GLP-1, including reduction in gastric emptying, increased satiety,
and suppression of inappropriate glucagon secretion appear to be
linked to the burst of GLP-1 released as meals begin. By
supplementing this early surge in GLP-1 with a formulation of GLP-1
and 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine (FDKP) as an
inhalation powder, a pharmacodynamic response, including endogenous
insulin production, reduction in glucagon and glucose levels, in
diabetic animals can be elicited. In addition, the late surge in
native GLP-1 linked to increased insulin secretion can be mimicked
by postprandial administration of GLP-1/FDKP inhalation powder.
[0174] A Phase 1a clinical trials of GLP-1/FDKP inhalation powder
was designed to test the safety and tolerability of selected doses
of a new inhaled glycemic control therapeutic product for the first
time in human subjects. GLP-1/FDKP inhalation powder was
administered using the MEDTONE.RTM. Inhaler device, previously
tested. The experiments were designed to identify the safety and
tolerability of various doses of GLP-1/FDKP inhalation powder by
pulmonary inhalation. Doses were selected for human use based on
animal safety study results from non-clinical studies in rats and
primates using GLP-1/FDKP administered by inhalation as described
in U.S. application Ser. No. 11/735,957, which is incorporated
herein by reference.
[0175] Twenty-six subjects were enrolled into 5 cohorts to provide
up to 4 evaluable subjects in each of cohorts 1 and 2 and up to 6
evaluable subjects in each of cohorts 3 to 5 who met eligibility
criteria and completed the study. Each subject was dosed once with
GLP-1 as GLP-1/FDKP inhalation powder at the following dose levels:
cohort 1: 0.05 mg; cohort 2: 0.45 mg; cohort 3: 0.75 mg; cohort 4:
1.05 mg and cohort 5: 1.5 mg of GLP-1. Dropouts were not replaced.
These dosages assumed a body mass of 70 kg. Persons of ordinary
skill in the art can determine additional dosage levels based on
the studies disclosed herein.
[0176] In these experiments, the safety and tolerability of
ascending doses of GLP-1/FDKP inhalation powder in healthy adult
male subjects were determined. The tolerability of ascending doses
of GLP-1/FDKP inhalation powder were determined by monitoring
pharmacological or adverse effects on variables including reported
adverse events (AE), vital signs, physical examinations, clinical
laboratory tests and electrocardiograms (ECG).
[0177] Additional pulmonary safety and pharmacokinetic parameters
were also evaluated. Pulmonary safety as expressed by the incidence
of pulmonary and other adverse events and changes in pulmonary
function between Visit 1 (Screening) and Visit 3 (Follow-up) was
studied. Pharmacokinetic (PK) parameters of plasma GLP-1 and serum
FDKP following dosing with GLP-1/FDKP inhalation powder were
measured as AUC.sub.0-120 min plasma GLP-1 and AUC.sub.0-480 min
serum FDKP. Additional PK parameters of plasma GLP-1 included the
time to reach maximal plasma GLP-1 concentration, T.sub.max plasma
GLP-1; the maximal concentration of GLP-1 in plasma, C.sub.max
plasma GLP-1, and the half of total time to reach maximal
concentration of GLP-1 in plasma, T.sub.1/2 plasma GLP-1.
Additional PK parameters of serum FDKP included T.sub.max serum
FDKP, C.sub.max serum FDKP, and T.sub.1/2 serum FDKP. Clinical
trial endpoints were based on a comparison of the following
pharmacological and safety parameters determined in the trial
subject population. Primary endpoints included the incidence and
severity of reported AEs, including cough and dyspnea, nausea
and/or vomiting, as well as changes from screening in vital signs,
clinical laboratory tests and physical examinations. Secondary
endpoints included pharmacokinetic disposition of plasma GLP-1 and
serum FDKP (AUC.sub.0-120 min plasma GLP-1 and AUC.sub.0-480 min
serum FDKP), plasma GLP-1 (T.sub.max plasma GLP-1, C.sub.max plasma
GLP-1 T.sub.1/2 plasma GLP-1); serum FDKP (T.sub.max serum FDKP,
C.sub.max serum FDKP); pulmonary function tests (PFTs), and
ECG.
[0178] The clinical trial consisted of 3 clinic visits: 1) One
screening visit (Visit 1); 2) One treatment visit (Visit 2); and 3)
One follow-up visit (Visit 3) 8-14 days after Visit 2. A single
dose of GLP-1/FDKP inhalation powder was administered at Visit
2.
[0179] Five doses of GLP-1/FDKP inhalation powder (0.05, 0.45,
0.75, 1.05 and 1.5 mg of GLP-1) were assessed. To accommodate all
doses, formulated GLP-1/FDKP was mixed with FDKP inhalation powder
containing particles without active agent. Single-dose cartridges
containing 10 mg dry powder consisting of GLP-1/FDKP inhalation
powder (15% weight to weight GLP-1/FDKP) as is or mixed with the
appropriate amount of FDKP inhalation powder was used to obtain the
desired dose of GLP-1 (0.05 mg, 0.45 mg, 0.75 mg, 1.05 mg and 1.5
mg). The first 2 lowest dose levels were evaluated in 2 cohorts of
4 subjects each and the 3 higher dose levels were evaluated in 3
cohorts of 6 subjects each. Each subject received only 1 dose at 1
of the 5 dose levels assessed. In addition to blood drawn for GLP-1
(active and total) and FDKP measurements, samples were drawn for
glucagon, glucose, insulin, and C-peptide determination. The
results from these experiments are described with reference to the
following figures and tables.
[0180] FIG. 11 depicts the active GLP-1 plasma concentration in
cohort 5 after pulmonary administration of 1.5 mg of GLP-1 dose.
The data showed that the peak GLP-1 concentration occurred prior to
the first sampling point at 3 min, closely resembling IV bolus
administration. GLP-1 plasma concentrations in some subjects were
greater than 500 pmol/L, the assay limit. Peak active GLP-1 plasma
concentrations range from about 150 pmol/L to about 500 pmol/L.
Intravenous bolus administration of GLP-1 as reported in the
literature (Vilsboll et al. 2000) results in ratios of total:active
GLP-1 of 3.0-5.0 compared to a ratio of 1.5 in cohort 5 of this
study. At comparable active concentrations the metabolite peaks
were 8-9 fold greater following intravenous administration compared
to pulmonary administration, suggesting that pulmonary delivery
results in rapid delivery and less degradation of GLP-1.
TABLE-US-00009 TABLE 8 Treatment 0.05 mg 0.45 mg 0.75 mg 1.05 mg
1.5 mg Parameter.sup.a (n = 4) (n = 4) (n = 6) (n = 6) (n = 6)
GLP-1.sup.a AUC.sub.0-120 ND n = 1 n = 6 n = 4 n = 4 (min * pmol/L)
355.33 880.12 1377.88 AULQ (195.656) (634.054) C.sub.max (pmol/L) n
= 4 n = 4 n = 6 n = 6 n = 6 2.828 24.630 81.172 147.613 310.700
(2.4507) (8.7291) (63.3601) (122.7014 (54.2431) t.sub.max (min) n =
4 n = 4 n = 6 n = 6 n = 6 3.00 3.00 3.00 3.00 3.00 (3.00, (3.00,
(3.00, (3.00, (3.00, 3.00) 4.02) 6.00) 4.98) 3.00) T.sub.1/2 (min)
n = 1 n = 3 n = 6 n = 4 n = 6 6.1507 3.0018 5.5000 3.6489 3.9410
(0.83511) (2.96928) (1.88281) (1.79028) FDKP AUC.sub.0-120 n = 6 n
= 6 (min * pmol/L) 22169.2 25594.7 (4766.858) (5923.689) C.sub.max
(pmol/L) n = 6 n = 6 184.21 210.36 (56.893) (53.832) t.sub.max
(min) n = 6 n = 6 4.50 6.00 (3.00, (3.00, 25.02) 19.98) T.sub.1/2
(min) n = 6 n = 6 126.71 123.82 (11.578) (15.640) .sup.aAll
parameters are mean (SD) except tmax, which is median (range) AULQ
- Two or more subjects in the dose group had plasma concentrations
of the analyte that were AULQ; NA = The pharmacokinetic profile did
not meet the specifications for this profile because of the short
sampling time (20 minutes); ND = Parameter could not be calculated
because of insufficient data is some subjects.
[0181] In healthy individuals, physiological post-prandial venous
plasma concentrations of GLP-1 typically range from 10-20 pmol/L
(Vilsboll et al. J. Clin. Endocr. & Metabolism. 88(6):2706-13,
June 2003). These levels were achieved with some subjects in cohort
2, who received 0.45 mg GLP-1. Higher doses of GLP-1 produced peak
plasma GLP-1 concentrations substantially higher than physiological
peak venous concentrations. However, because the half-life of GLP-1
is short (about 1-2 min), plasma concentrations of active GLP-1
fell to the physiological range by 9 min after administration.
Although the peak concentrations are much higher than those seen
physiologically in the venous circulation, there is evidence that
local concentrations of GLP-1 may be much higher than those seen
systemically.
[0182] Table 8 shows the pharmacokinetic profile of GLP-1 in a
formulation comprising FDKP from this study.
[0183] FDKP pharmacokinetic parameters are also represented in
Table 8 for cohorts 4 and 5. Other cohorts were not analyzed. The
data also shows that mean plasma concentration of FDKP for the 1.05
mg and the 1.5 mg GLP-1 treated subjects were about 184 and 211
pmol/L, respectively. Maximal plasma FDKP concentrations were
attained at about 4.5 and 6 min after administration for the
respective dose with a half-life about 2 hr (127 and 123 min).
[0184] FIG. 12 depicts the GLP-1 plasma concentration of subjects
treated with the 1.5 mg dose of GLP-1 administered by pulmonary
inhalation compared to subcutaneous administration of a GLP-1 dose.
The data illustrates that pulmononary administration of GLP-1
occurs relatively fast and peak plasma concentration of GLP-1 occur
faster than with subcutaneous administration. Additionally,
pulmonary inhalation of GLP-1 leads to GLP-1 plasma concentrations
returning to basal levels much faster than with subcutaneous
administration. Thus the exposure of the patient to GLP-1 provided
by pulmonary inhalation using the present drug delivery system is
shorter in time than by subcutaneous administration and the total
exposure to GLP-1 as measured by AUC is less for the inhaled
insulin.
[0185] Tables 9 and 10 report the adverse events or side effect
symptoms recorded for the patient population in the study. The list
of adverse events reported in the literature for GLP-1 administered
by injection is not extensive; and those reported have been
described as mild or moderate, and tolerable. The primary adverse
events reported have been profuse sweating, nausea and vomiting
when active GLP-1 concentrations exceed 100 pmol/L. As shown in
Tables 8 and 10, and FIG. 12, pulmonary administration at doses of
1.05 mg and 1.5 mg resulted in active GLP-1 concentrations greatly
exceeding 100 pmol/L without the side effects normally observed
with parenteral (subcutaneous, intravenous [either bolus or
infusion]) GLP-1. None of the subjects in this study reported
symptoms of nausea, profuse sweating or vomiting. Subjects in
Cohort 5 reached C.sub.max comparable to that observed with a 50
.mu.g/kg IV bolus data (reported by Vilsboll et al. 2000), where
the majority of subjects reported significant adverse events.
TABLE-US-00010 TABLE 9 Adverse Events 0.05 mg 0.45 mg 0.75 mg 1.05
mg 1.5 mg Adverse Event (n = 4) (n = 4) (n = 6) (n = 6) (n = 6)
Cough 3 1 3 5 5 Dysphonia 2 -- 2 3 3 Productive Cough -- -- 1 -- --
Throat Irritation -- -- -- 1 -- Headache 1 1 -- 1 1 Dizziness -- --
-- -- 2 Dysgeusia -- -- 1 -- -- Fatigue -- -- 1 1 1 Seasonal
Allergy -- -- -- 1 -- Rhinitis -- -- -- 1 -- Increased Appetite --
-- -- -- 1
TABLE-US-00011 TABLE 10 Comparative Adverse Events of GLP-1: IV vs.
Pulmonary Administration IV.sup..dagger. IV.sup..dagger.*
Pulmonary* Adverse Events (16.7 .mu.g) (50 .mu.g) (1.5 mg) Reduced
well-being 42% 100% 17% Nausea 33% 83% 0% Profuse sweating 17% 67%
0% .sup..dagger.Vilsboll et al. Diabetes Care, June 2000;
*Comparable C.sub.max
[0186] Tables 9 and 10 show there were no serious or severe adverse
events reported by any subjects in the study who received GLP-1 by
pulmonary inhalation. The most commonly reported adverse events
were those associated with inhalation of a dry powder, cough and
throat irritation. Surprisingly, in the patients treated by
pulmonary inhalation, no subject reported nausea or dysphoria, and
there was no vomiting associated with any of these subjects. The
inventors also found that pulmonary administration of GLP-1 in a
dry powder formulation lack inhibition of gastric emptying in the
above subjects (data not shown). Inhibition of gastric emptying is
a commonly encountered unwanted side effect associated with
injected standard formulations of GLP-1.
[0187] In summary, the clinical GLP-1/FDKP powder contained up to
15 wt % GLP-1 providing a maximum dose of 1.5 mg GLP-1 in 10 mg of
powder. Andersen cascade measurements indicated that 35-70% of the
particles had aerodynamic diameters<5.8 .mu.m. A dose of 1.5 mg
GLP-1 produced mean peak concentrations>300 pmol/L of active
GLP-1 at the first sampling time (3 min); resulted in mean peak
insulin concentrations of 375 pmol/L at the first measured time
point (6 min); reduced mean fasting plasma glucose from 85 to 70
mg/dL 20 min after dosing; and was well tolerated and did not cause
nausea or vomiting.
[0188] The data above are representative illustrations of the
distribution of GLP-1 to specific tissues of the body after
degradation of GLP-1 by endogenous enzymes. Based on the above
determinations, the amounts of GLP-1 in brain and liver after
pulmonary administration are about 1.82 to about 1.86 times higher
than the amounts of GLP-1 after intravenous bolus administration.
Therefore, the data indicate that pulmonary delivery of GLP-1 can
be a more effective route of delivery when compared to intravenous
administration of GLP-1, as the amount of GLP-1 at various times
after administration would be about double the amount obtained with
intravenous administration. Therefore, treatment of a disease or
disorder comprising GLP-1 by pulmonary administration would require
smaller total amounts, or almost half of an intravenous GLP-1 dose
that is required to yield the same or similar effects.
[0189] While the invention has been particularly shown and
described with reference to particular embodiments, it will be
appreciated that variations of the above-disclosed and other
features and functions, or alternatives thereof, may be desirably
combined into many other different systems or applications. Also
that various presently unforeseen or unanticipated alternatives,
modifications, variations or improvements therein may be
subsequently made by those skilled in the art which are also
intended to be encompassed by the following claims.
[0190] 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 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.
[0191] The terms "a," "an," "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.
[0192] 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 deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0193] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described 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.
[0194] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
[0195] 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.
Sequence CWU 1
1
3131PRThomo sapiens 1His Val Glu Gly Thr Phe Thr Ser Asp Val Ser
Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp
Leu Val Lys Gly Arg Gly 20 25 30 237PRThomo sapiens 2His Asp Glu
Phe Glu Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val 1 5 10 15 Ser
Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu 20 25
30 Val Lys Gly Arg Gly 35 331PRThomo sapiensVARIANT(1)..(1)Xaa =
L-histidine, D-histidine, desaminohistidine, 2-amino-histidine,
beta-hydroxy-histidine, homohistidine, alpha-fluoromethylhistidine,
or alpha-methyl-histidine 3Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Val
Ser Ser Tyr Leu Xaa Gly 1 5 10 15 Gln Ala Ala Lys Xaa Phe Ile Ala
Trp Leu Val Lys Gly Arg Xaa 20 25 30
* * * * *