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CA 02589118 2007-06-01
WO 2006/059939 1 PCT/SE2005/001648
A MEDICAL PRODUCT COMPRISING A
GLUCAGON-LIKE PEPTIDE MEDICAMENT
INTENDED FOR PULMONARY INHALATION
TECHNICAL FIELD
The present invention relates to a medical product comprising a metered
medication dose of a glucagon-like peptide (GLP) in dry powder form and
more particularly to a metered GLP dose enclosed in a sealed container
adapted for use in a dry powder inhaler, capable of systemic dose delivery.
BACKGROUND
Administering systemically acting drugs directly to the lungs of a patient by
means of an inhaler is an effective, quick and user-friendly method of drug
delivery, especially compared to administration by injections. A number of
different inhaler devices have been developed in order to deliver drugs to the
lung, e.g. pressurized aerosol inhalers (pMDIs), nebulizers and dry powder
inhalers (DPIs).
The lung is an appealing site for systemic delivery of drugs as it offers a
large
surface area (about 100 m2) for the absorption of the molecules across a thin
epithelium, thus having a potential for rapid drug absorption. Pulmonary
delivery of drugs has the potential of attaining a high, rapid systemic drug
concentration often without the need of penetration enhancers. The
feasibility of this route of administration for a particular drug depends on,
for example, dose size and extent and ease of systemic absorption through
the alveols of the particular drug. The critical factors for the deposition of
inhaled particles in the lung are inspiration/expiration pattern and the
particle aerodynamic size distribution. The aerodynamic particle size (AD) of
the drug particles is important if an acceptable deposition of the drug within
the lung is to be obtained. In order for a particle to reach into the deep
lung
the aerodynamic particle size should typically be between 1 and 3 m. Larger
particle sizes will easily stick in the mouth and throat and will be
swallowed.
Thus, it is important to keep the aerodynamic particle size distribution of
the
dose within tight limits to ensure that a high percentage of the dose is
actually deposited where it will be most effective. The aerodynamic diameter
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(AD) of a particle is defined as the diameter of a spherical particle having a
density of 1 g/ cm3 that has the same inertial properties in air as the
particle
of interest. If primary particles form aggregates, the aggregates will
aerodynamically behave like one big particle in air.
However, finely divided powders, suitable for inhalation, are rarely free
flowing but tend to stick to all surfaces they come in contact with and the
small particles tend to aggregate into lumps. This is due to van der Waal
forces generally being stronger than the force of gravity acting on small
particles having diameters of 10 m or less. There are several micronization
technologies known in the art. Two major categories dominate in prior art:
breaking of large particles using milling process such as jet milling, pearl-
ball milling or high-pressure homogenization and the production of small
particles using controlled production processes such as spray drying,
lyophilization, precipitation from supercritical fluid and controlled
crystallization. The former category produces predominantly crystalline,
homogenous particles, the latter more amorphous, 'light', porous particles.
See e.g. "Micron-Size Drug Particles: Common and Novel Micronization
techniques" by Rasenack and Muller in Pharmaceutical development and
technology, 2004, 9(1):1-13. See also "Unit Operation-Micronization"
prepared by Lee Siang Hua, dept. of Chemical & Biomolecular Engineering,
National University of Singapore. In these documents the term 'finely divided
powder' refers to inhalable particles in general and does not limit or
preclude
any method of producing such particles.
Glucagon
Glucagon is a 29 amino acid peptide hormone liberated in the alpha-cells of
the islets of Langerhans. It has been established that glucagon opposes the
action of insulin in peripheral tissues, particularly the liver, in order to
maintain the levels of blood glucose, especially if a state of hypoglycemia
threatens. At mealtime, glucagon secretion is generally suppressed in
healthy subjects. However, diabetics often exhibit disordered control of
glucagon secretion, leading to failure to suppress hepatic glucose production
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and fasting hyperglycemia. Thus, it is important to determine what
mechanisms are at work in relation to glucagon, so that adequate, new
drugs may be produced to help the human body to function normally.
Glucagon-like peptide (GLP- 1 and GLP-2)
GLP-1 and GLP-2 are synthesized in intestinal endocrine cells and liberated,
following posttranslational processing of a single proglucagone precursor.
The complex functions of these substances are not fully understood at this
point and much research remains before glucagon-like peptides (GLPs) and
analogues or derivates thereof can be used e.g. in the treatment of diabetes
or obesity. As small and medium-sized molecules, GLPs are suitable for
pulmonary delivery to' the system by a dry powder inhaler, provided suitable
formulations can be produced, preferably in finely divided, dry powder form.
GLP-1 exists in two principal major molecular forms, as GLP-1(7-36),; amide
and GLP-1(7-37). These molecules are secreted in response to nutrient
ingestion and play multiple roles in metabolic homeostasis following nutrient
absorption. Biological activities include stimulation of glucose-dependent
insulin secretion and insulin biosynthesis, inhibition of glucagon secretion
and gastric emptying and inhibition of food intake. The substance plays an
important role in lowering blood glucose levels in diabetics by stimulating
the beta-cells in pancreas to produce insulin. A very interesting effect of
GLP-1 is that it normalizes blood glucose levels in response to hyperglycemic
conditions without the risk of ending up in a hypoglycemic condition. Also,
GLP-1 helps control satiety and food intake. The substance therefore
constitutes an interesting pharmacological drug, particularly so for
treatment of diabetes, preferably in combination with insulin or even as an
alternative to a regimen of insulin. See European Patent EP 0 762 890 B 1.
GLP-1 is a relatively small peptide molecule with a great potential for
inhalation therapy. Fortunately, provided that the GLP-1 powder formulation
is constituted of particles of the right size to sediment in the deep lung
after
inhalation, GLP-1 has been shown to be soluble in the fluid layer in the deep
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lung and dissolve, thereby ensuring rapid absorption from the lung into the
system before enzymatic inactivation sets in. See for instance U.S. Patent No.
6,720,407.
From a stability point of view, a solid formulation stored under dry
conditions is normally the best choice. In the solid state, GLP molecules are
normally relatively stable in the absence of moisture or elevated
temperatures. GLP and analogues or derivatives thereof in dry powder form
are more or less sensitive to moisture depending on the powder formulation.
GLP may be administered to humans by any available route, but oral or
parenteral administration may be the most common methods in the art.
Frequent injections, necessary for the management of a disease, is of course
not an ideal method of drug delivery and often leads to a low patient
compliance as they infringe on the freedom of the patient as well as, because
of psychological factors. Tablets or capsules given orally have a fairly long
onset and may suffer from low efficacy because of metabolic degradation of
the GLP substance before it passes into the system. Pulmonary absorption is
therefore an interesting alternative, which potentially offers a fast onset,
less
degradation and higher efficacy. Tests have shown that users, given a choice,
prefer inhalation of medicaments to self-injection.
Hence, there is a demand for precisely matched, therapeutic pulmonary
dosages of GLP-based medicaments, especially in dry powder formulations
and optionally in combination with insulin, and high efficacy devices for
delivering dosages to the system by inhalation.
SUMMARY
The present invention discloses a medical product comprising an accurately
metered dose of a GLP medicament intended for pulmonary inhalation filled
in a dose container, which is effectively sealed against ingress of moisture
for
a specified in-use time. The medical product optionally also comprises a dose
of insulin. The container is adapted for application in a dry powder inhaler.
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The dose loaded into the container, is intended for a prolonged delivery by
inhalation to the deep lung where the active ingredients are absorbed into
the system. Optionally the medical product also comprises at least one
biologically acceptable excipient.
In a preferred embodiment, the present invention presents a medicament
containing as active ingredient a therapeutically effective amount of a
physiologically acceptable salt of a GLP agent including GLP analogues and
derivates.
The active GLP agerit exists in dry powder form suitable for administration
by inhalation, optionally comprising at least one biologically acceptable
excipient.
In a further aspect of the present invention the GLP agent or medicament is
combined with an active insulin agent, whereby the dry powder medication
combination of a GLP dosage and an insulin dosage are administered by
inhalation as dry powder(s) in a regimen of therapeutically effective dosages
to a user in need thereof. Particularly, the combined dosages may be
administered together as a single formulation, a single preparation, an inter-
mixture of powders or administered separately as part-doses in a single
inhalation or administered separately by separate inhalation of each part-
dose.
The present invention offers the following advantages:
- provides a medical product comprising an active GLP agent that is
prepared in a dry powder dose for a prolonged, pulmonary delivery of the
active agent by inhalation;
- provides a medical product in which a well-defined dosage of an active
GLP agent and optionally an insulin agent is efficiently delivered to the deep
lung by a user-driven suction effort in a single inhalation process;
- provides a medical product that is intended for application in a single
dose inhaler, which entirely relies on the power of the inhalation for de-
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aggregating and aerosolizing the dose, with no further external source of
power necessary; and
- provides a medical product that protects the active GLP and optional
insulin agents from deteriorating during a specified in-use time period.
Other advantages offered by the present invention will be appreciated upon
reading of the below description of the embodiments of the invention.
SHORT DESCRIPTION OF THE DRAWINGS
The invention together with further objects and advantages thereof, may best
be understood by making reference to the following description taken
together with the accompanying drawings, in which:
FIG. 1 illustrates in a timing diagram the concentration of GLP in the
system of a diabetic user after inhalation of a small dose in
connection with meals during a day, compared to a big dose once
a day
FIG. 2 illustrates in a timing diagram the concentration of insulin in the
system of a diabetic user after inhalation of a combined dose of
GLP and insulin in connection with meals during a day;
FIG. 3 illustrates in two timing diagrams a typical inhalation and dose
delivery of the medical product according to the present invention;
FIG. 4 illustrates in perspective, top and side views a first embodiment of
a medical product comprising a dose loaded into a high barrier
seal container;
FIG. 5 illustrates in top and side views a second embodiment of a
medical product comprising a dose loaded into a high barrier seal
container, here illustrated in an opened state;
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FIG. 6 illustrates in a top view a third embodiment of several similar
medical products comprising differently sized doses loaded into
identical high barrier seal containers; and
FIG. 7 illustrates in top and side views a second embodiment of a
medical product comprising a combined dose loaded into two
separate high barrier seal containers, adapted for insertion
together into a DPI.
DETAILED DESCRIPTION
The present invention discloses an improved medical product comprising: an
accurately metered medication dose of an active glucagon-like peptide (GLP)
agent filled in a sealed container. The GLP dose is adequately protected by
the sealed container from ingress of moisture for a specified in-use time
period. The active GLP agent may optionally include at least one biologically
acceptable excipient. The dose is intended for systemic delivery by oral
inhalation and pulmonary absorption. The improved medical product is
preferably adapted for a prolonged pulmonary dose delivery using a dry
powder inhaler device. An objective of the present invention is to deliver an
exact, high efficacy powder dosage of an active GLP agent to the system of a
user via the deep lung.
The pharmacological actions of glucagon-like peptide or analogues and
derivates thereof, in this document generically denoted GLP, include
stimulation of insulin release, suppression of glucagon release and inhibition
of gastric emptying. These actions provide the basis for this invention, where
we have surprisingly found that it is possible to treat type 1 as well as type
2
diabetes by pulmonary administration of therapeutically effective amounts of
GLP alone or preferably in combination with a regimen of inhalable insulin.
It will be understood by a person skilled in the art that various
modifications
and changes may be made to the present invention without departure from
the scope thereof, which is defined by the appended claims.
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A particular peptide agonist acting as a GLP agent to be used in the present
invention is described in U.S. Patent No. 6,528,486, which hereby is
included in this document in its entirety as a reference. This GLP agent
embodiment has any one of the following sequences:
R1-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-
Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-
Ala-R2 (SEQ ID NO: 1),
wherein
R1- is selected from a group consisting of His-, (Lys)6-His- and Asn-(Glu)5-
His-
-R2 is selected from a group consisting of -Pro-Pro-Ser-(Lys)6, -Ser and -Ser-
(Lys)6.
Another particular GLP derivate, which may be used in the present invention
is described in U.S. Patent No. 6,268,343, which hereby is included: in. this
document in its entirety as a reference. This GLP agent embodiment has any
one of the following sequences:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-
Gln-Ala-Ala-Rs-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly (SEQ ID NO: 2)
wherein R3 is selected from a group consisting of Lys and Lys in which the E-
amino group is substituted with a lipophilic substituent, optionally via a
spacer. Preferred lipophilic substituents include CH3(CH2)nCO-, wherein n is
6, 8, 10, 12, 14, 16, 18, 20 or 22, HOOC(CH2)mCO-, wherein m is 10, 12, 14,
16, 18, 20 or 22, and lithochoyl. Preferred optional spacers include an
unbranched alkane a,co-dicarboxylic acid group having from 1 to 7
methylene groups, an amino acid residue except Cys, and y-aminobutanoyl.
Another particular GLP derivate, a GLP-1 antagonist, which may be used in
the present invention is described in US Application No. 2005/0153890,
which hereby is included in this document in its entirety as a reference. This
GLP agent embodiment has any one of the following sequences:
His-Ala-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-R4 (SEQ ID NO: 3)
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wherein -R4 is selected from a group consisting of -Arg, -Arg-Gly;
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ala-Lys-Tyr-Leu-Asp-Ala-Arg-
Arg-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Cys-Arg-Gly (SEQ ID NO: 4);
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ala-Lys-Tyr-Leu-Asp-Ala-Arg-
Arg-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Cys-G1y (SEQ ID NO: 5);
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ala-R5-Tyr-Leu-Asp-Ala-R6-
R7-Ala-Rs-Glu-Phe-Ile-Rg-Trp-Leu-Val-Rlo-Gly-R11 (SEQ ID NO: 6)
wherein
Rs is selected from a group consisting of Lys, Arg, Ala
R6 is selected from a group consisting of Arg, Lys, Ala
R7 is selected from a group consisting of Arg, Lys
R8 is selected from a group consisting of Lys, Ala
R9 is selected from a group consisting of Ala, Lys
Rio is selected from a group consisting of Lys, Cys, Arg
-R11 is selected from a group consisting of -Arg, -Arg-Gly, -Arg-Cys, -Arg,-
Gly-
Lys
Other particular GLP derivates and -analogues, which may be used in the
present invention are described in US2005/0014681, which hereby is
included in this document in its entirety as a reference. This GLP agent
embodiment is selected from a group consisting of: GLP-1, GLP-1 amide,
GLP-1 (7-36) amide, GLP-1 (7-37), [Val8]-GLP-1 (7-36) amide, [Val8]-GLP-1
(7-37); [Lys26, s-NH{y-Glu(N-a-palmitoyl)}]-GLP-1 (7-37), GLP-1 (9-36) amide,
GLP-1 (9-37) and GLP-2.
Another particular GLP-1 sequence, which may be used in the present
invention is described in US Application No.2003/0220243, which hereby is
included in this document in its entirety as a reference. This GLP agent
embodiment has any one of the following sequences:
His-R12-Glu-Gly-R13-Rla.-Thr-Ser-Asp-R15-Ser-Ser-Tyr-Leu-Glu-R16-R17-
Rls-Ala-Rlg-R2o-Phe-Ile-R21-Trp-Leu-R22-R23-R24-R25-R26 (SEQ ID NO: 7)
wherein
R12 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Ser, Thr
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R13 is selected from a group consisting of Asp, Glu, Arg, Thr, Ala, Lys, His
R14 is selected from a group consisting of His, Trp, Phe, Tyr
R15 is selected from a group consisting of Leu, Ser, Thr, Trp, His, Phe, Asp,
Val, Tyr, Glu, Ala
R16 is selected from a group consisting of Gly, Asp, Glu, Gln, Asn, Lys, Arg,
Cys, cysteic acid
R17 is selected from a group consisting of His, Asp, Lys, Glu, Gln, Arg
R18 is selected from a group consisting of Glu, Arg, Ala, Lys
R19 is selected from a group consisting of Trp, Tyr, Phe, Asp, Lys, Glu, His
R20 is selected from a group consisting of Ala, Glu, His, Phe, Tyr, Trp, Arg,
Lys
R21 is selected from a group consisting of Ala, Glu, Asp, Ser, His
R22 is selected from a group consisting of Asp, Arg, Val, Lys, Ala, Gly, Glu
R23 is selected from a group consisting of Glu, Lys, Asp
R24 is selected from a group consisting of Thr, Ser, Lys, Arg, Trp, Tyr',.
Phe,
Asp, Gly, Pro, His, Glu
R25 is selected from a group consisting of Thr, Ser, Asp, Trp, Tyr, Phe, Arg,
Glu, His
-R26 is selected from a group consisting of -Lys, -Arg, -Thr, -Ser, -Glu, -
Asp, -
Trp, -Tyr, -Phe, -His, -NH2, -Gly, -Gly-Pro, -Gly-Pro-NH2 or is deleted.
A particular peptide agonist acting as a GLP agent to be used in the present
invention is described in U.S. Application No. 2003/0199672. This GLP
agent embodiment has any one of the following sequences:
His-R27-R28-Gly-R29-Phe-Thr-R3o-Asp-R31-R32-R33-R34-R35-R36-R37-R38-
R39-R40-R41-R42-Phe-Ile-R43-R44-R45-R46-R47-R48-R49-R50-R51-R52-R53-R54-R55-
R56-R57-R58 (SEQ ID NO: 8)
wherein
R27 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R28 is selected from a group consisting of Glu, Asp, Lys
R29 is selected from a group consisting of Thr, Ala, Gly, Ser, Leu, Ile, Val,
Glu, Asp, Lys
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R30 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R31 is selected from a group consisting of Val, Ala, Gly, Ser, Thr, Leu, Ile,
Tyr, Glu, Asp, Lys
R32 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R33 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R34 is selected from a group consisting of Tyr, Phe, Trp, Glu, Asp, Lys
1 o R35 is selected from a group consisting of Leu, Ala, Gly, Ser, Thr, Leu,
Ile,
Val, Glu, Asp, Lys
R36 is selected from a group consisting of Glu, Asp, Lys
R37 is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R3$ is selected from a group consisting of Gln, Asn, Arg, Glu, Asp, Lys
R39 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val,
Arg, Gln, Asp, Lys
R40 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val,,
Glu, Asp, Lys
R41 is selected from a group consisting of Lys, Arg, Gln, Asp, His
R42 is selected from a group consisting of Gln, Asp, Lys
R43 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R44 is selected from a group consisting of Trp, Phe, Tyr, Glu, Asp, Lys
R45 is selected from a group consisting of Leu, Gly, Ala, Ser, Thr, Ile, Val,
Glu, Asp, Lys
R46 is selected from a group consisting of Val, Gly, Ala, Ser, Thr, Leu, Ile,
Glu, Asp, Lys
R47 is selected from a group consisting of Lys, Arg, Glu, Asp, His
R48 is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val,
Glu, Asp, Lys
R49 is selected from a group consisting of Arg, Lys, Glu, Asp, His
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Rso is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val,
Glu, Asp, Lys or is deleted
Rs1 is selected from a group consisting of Arg, Lys, Glu, Asp, His or is
deleted
R52 is selected from a group consisting of Arg, Lys, Glu, Asp, His or is
deleted
R53 is selected from a group consisting of Asp, Glu, Lys or is deleted
R54 is selected from a group consisting of Phe, Trp, Tyr, Glu, Asp, Lys or is
deleted
R55 is selected from a group consisting of Pro, Lys, Glu, Asp or is deleted
R56 is selected from a group consisting of Glu, Asp, Lys or is deleted
R57 is selected from a group consisting of Glu, Asp, Lys or is deleted
-R58 is selected from a group consisting of -Val, -Glu, -Asp, -Lys or is
deleted
Another particular GLP-1 sequence, which may be used in the present
invention is described in PCT Application No. W02005/066207. This GLP
agent embodiment has any one of the following sequences:
Rs9-His-R6o-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-R61-Glu-Gly-
Gln-Ala-Ala-Lys-R62-Phe-Ile-R63-Trp-Leu-R64 (SEQ ID NO: 9)
wherein
R5g is selected from a group consisting of H, a linear or branched
unsaturated Cl-C6 acyl group, an optionally substituted arylcarbonyl, an
optionally cycloalkylcarbonyl, an optionally substituted arylalkylcarbony1
R60 is selected from a group consisting of Ala, 1-aminoisobutyric acid (Aib),
Val, Gly
R61 is selected from a group consisting of Leu and Gly having a C6-C2o alkyl
side chain
R62 is selected from a group consisting of Ala, Leu, Val, Ile, Glu
R63 is selected from a group consisting of Glu, Asp, Asn, Gln, Ala
-R64 is selected from a group consisting of -Lys-Asn-Aib-OH, -Lys-Asn-Aib-
NH2, -Val-Lys-Asn-OH, -Val-Lys-Asn-NH2, -Lys-Asn-OH, -Lys-Asn-NH2, -Val-
Lys-Gly-Arg-NH2, -Val-Lys-Aib-Arg-OH, -Va1-Lys-Aib-Arg-NH2, -Lys-Asn-Gly-
OH, -Lys-Asn-Gly-NH2
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Another particular GLP-1 sequence, which may be used in the present
invention is described in PCT Application No.W02004/029081. This GLP
agent embodiment has any one of the following sequences:
R65-His-Ala-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-R66 (SEQ ID NO:
10)
wherein
R65 is a rigidifying hydrophobic moiety selected from the group consisting of
C1-Clo alkenoic acid, optionally substituted by at least one substituent
selected from the group consisting of straight or branched C1-C6 alkyl, C3-C6
cycloalkyl, aryl and substituted aryl;
C1-Clo alkynoic acid;
C3-C1o cycloalkanoic acid, or heterocycloalkanoic acid comprising an
heteroatom selected from 0, S and N;
C5-C14 arylcarboxylic or arylalkanoic acid optionally substituted,; by at
least one substituent selected from the group consisting of lower alkyl, lower
alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, -NH(lower
alkyl), -N(lower alkyl)2, di- and tri-substituted phenyl, 1-naphtyl and 2-
naphtyl substituted with a substituent selected from the group consisting of
methyl, methoxy, methylthio, halo, hydroxy and amino;
C5-C14 heteroarylcarboxylic or heteroarylalkanoic acid comprising a
-heteoatom selected from 0, S and N, and being optionally substituted by at
least one substituent selected from the group consisting of lower alkyl, lower
alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, -NH(lower
alkyl), -N(lower alkyl)2, di- and tri-substituted phenyl, 1-naphtyl and 2-
naphtyl substituted with a substituent selected from the group consisting of
methyl, methoxy, methylthio, halo, hydroxy and amino
-R66 is selected from a group consisting of -OH, -NH2, -Gly-OH.
In a particular aspect of the present invention a GLP agent is selected, which
is long-acting following pulmonary delivery.
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In a particular aspect of the present invention a GLP medicament is used as
an alternative to subcutaneous insulin in the treatment of early diabetes
type 2, where a regimen of the GLP medicament, optionally in combination
with insulin, through a pulmonary route of administration eliminates the
use of subcutaneous insulin to a user.
In a further aspect of the present invention a GLP medicament is used in
combination with insulin in the treatment of diabetes type 1 and 2, such
that a regimen of inhaled GLP and insulin for instance in connection with
meals three or four times per day is well adapted to the needs of a diabetic
user with the objective of improving glycemic control for the user and
eliminating subcutaneous insulin altogether.
Self-administration of peptides, such as insulin, by subcutaneous injection
is part of everyday life for many patients with diabetes. Normally,, the. user
needs to administer insulin several times daily based on close monitoring of
the glucose level. Incorrect timing of the administration or incorrect. dosing
may lead to hyperglycemia or hypoglycemia. Also, there are pharmacokinetic
limitations when using the subcutaneous route. Absorption of insulin after a
subcutaneous injection is slow. It sometimes takes up to an hour before the,
glucose level in the blood begins to be significantly reduced. This inherent
problem with subcutaneous insulin delivery cannot be solved with a more
frequent administration. In order to obtain plasma insulin concentrations
that are physiologically correct over time it is advantageous to choose
another route of administration, such as inhalation.
In yet another particular aspect of the present invention GLP, administered
by inhalation for pulmonary absorption into the system, optionally in
combination with insulin, improves user quality of life and user compliance
with a prescribed dosing regimen based on inhalation of medicaments,
compared to injections or a mixture of oral administration and injections.
Systemic delivery by pulmonary absorption is faster and more accurate than
by subcutaneous injection, partly because of the difficulty in the latter
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WO 2006/059939 15 PCT/SE2005/001648
method to control exactly where the dose will be located in the subcutaneous
tissue and as a consequence the systemic concentration over time will vary
considerably from one injection to the next. Furthermore, GLP has a rather
small therapeutic window, i.e. a too small dose will have no effect at all
whereas a too big dose will often cause the user to feel sick and even cause
the user to vomit. The pulmonary route for GLP is thus to be preferred
because of fast on-set, exactness, user comfort and reduced adverse side
effects.
Advantageously, GLP is inhaled several tiines daily in connection with meals,
so that the GLP effect on the pancreatic insulin production is not too small
nor leading to too high concentration in the blood, but so that the GLP
concentration is kept within the optimal therapeutic window, thereby leading
to a better control of glucose concentration in the blood. See Figure 1,
showing two curves, A and B over time T, representing plasma concentration
of GLP, where curve A is the result of a single, high dose administered in the
morning compared to 3 smaller doses administered in direct connection with
meals during the day as in curve B. Curve A shoots over the permitted
maximum level L, which causes unwanted adverse effects in a subject, such
as nausea or inducing vomiting attacks. Clearly, a better way to achieving
glycemic control is to administer GLP in relatively small doses in connection
with meals.
In a particular embodiment of the present invention the medical product is
arranged such that a selected, effective dose of GLP is combined with a dose
of insulin, where the size of the insulin dose is selected before each
administration by a diabetic user based on an estimation or actual
measurement of the present level of glucose in the blood and with a regard
for the imminent meal. A dry powder inhaler is thus to be loaded by the said
user with a sealed container carrying a dose of GLP and the same or a
similar container carrying a titratable dose of insulin, e.g. containing the
equivalence of from 1 to 100 insulin units (IU). Thus, a therapeutically
effective insulin dose mass is normally in a range from 100 g to 25 mg.
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Both doses are then administered in a single inhalation. See Figures 7a and
7b illustrating two carriers, 41 and 42, each carrying a sealed container 33
(seal 31) containing a dose 21 of GLP and a dose 22 of insulin respectively.
The doses are hidden from view by the respective sealed container, but
nevertheless indicated in the illustration for the benefit of the reader. For
instance, the user has been supplied with a number of identical GLP dose
containers and a collection of insulin dose containers representing three
different dose sizes, low, medium and high, plus empty dose containers. For
example, differently sized doses 21 may be loaded into identical or similar
sealed containers 33 (seal 31) and fitted to carriers 41 as illustrated in
Figures 6a, 6b and 6c. Based on the need of the user in the course of a day,
he or she decides, e.g. based on a measurement of blood sugar level, what
combination is required at each instance of administration and composes an
adequate combination of GLP and insulin, where the GLP dose is fixed but
the insulin dose is variable. The flexibility of the medical product will
permit
GLP to stimulate the self production of insulin and only add a minimum of
exogenous insulin to help control blood sugar. See Figure 2 for graphic
representations of insulin plasma concentration partly from GLP stimulated
endogenous insulin 1, exogenous insulin 2 and the combined insulin
concentration 3 over time during a day, if a combined dose of GLP and
insulin is administered in connection with meals.
In another embodiment of the invention a GLP dose is loaded in the same
dose container as a dose of insulin, and the combined doses are then
delivered by a dry powder inhaler in a single inhalation from the single dose
container. This embodiment is possible providing the GLP and the insulin do
not detrimentally affect each other during transport and storage. See our
U.S. Application No. 2004/0258625, which is hereby included by reference.
There are many advantages in combining GLP and insulin in a medical
product intended for administration by inhalation in the treatment of
diabetes 1 and 2, such as:
0 Substantial reduction of insulin doses is possible
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WO 2006/059939 17 PCT/SE2005/001648
= Big improvement in glycemic control
= Endogenous insulin secretion is stimulated
= Risk of hyperglycemia is substantially reduced
= Partial or complete inhibition of insulin injections is possible
= Less adverse side effects
= Big improvement in user quality of life
= Better user compliance
In short, a combined therapy comprising GLP and insulin results in better
medical status and higher quality of life for the user.
Besides diabetes 1 and 2, other important and interesting therapeutic'areas,
where GLP may be a highly effective drug, especially in combination with
other medicaments, such as insulin, are cardiovascular disorders, conditions
of obesity, dyslipidemia and lipodystrophy.
From the disclosure herein, however, it is clear that the quality of a
delivered
GLP dose, as well as an insulin dose, to the lung needs to be very high in
terms of fine particle fraction. As has been pointed out in the foregoing,.
particles need to be 5}a.m or less in aerodynamic diameter (AD) to have a
reasonable chance of reaching into the deep lung when inhaled. Large
particles may impact and stick in the mouth or further down in the airways
before they reach the deep lung. In the deep lung, small particles may be
absorbed by the alveoli and delivered to the system. AD of particles should
preferably be in a range from 0.5 to 5 pm and more preferably in a range 1
to 3 pm for a rapid and successful delivery to the system through the lung.
Particles of this size sediment in the lung provided that the inhalation is
deep and not too short. For maximum lung deposition, the inspiration must
take place in a calm manner to decrease air speed and thereby reduce
deposition by impaction in the upper respiratory tracts. Small particles are
more easily absorbed by the alveoli, which is a further reason for the
delivered dose, according to the disclosure, to present a high fine particle
fraction (FPF), i.e. the fine particle dose (FPD) of the delivered dose mass
should be as high as possible.
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The advantages of using the inhalation power of the user to full potential in
a
prolonged, continuous dose delivery interval within the inhalation cycle is
disclosed in our US Patent No. US 6,622,723 (WO 01/34233 Al), which is
hereby incorporated herein by reference in its entirety. An objective of a
prolonged dose delivery is to achieve a very high level of particle de-
aggregation when the dose is in the process of being released from the
container where it is deposited. In a preferred embodiment of the present
invention, the medical product is optimized for a prolonged dose delivery.
Prior art dry powder inhalers begin aerosolizing a dose by uncontrolled
spreading of energy to the powder in the dose. In prior art the supplied
energy may be of different kinds, e.g. mechanical, electric or pneumatic to
name a few and combinations of different kinds are common, e.g. where the
inhalation energy provided by the user is re-enforced by external sources of
power to accomplish particle de-aggregation and aerosolization of the dose.
But the energy thus provided is directed to the whole dose for a short time.
Surprisingly, we have found that the energy thus provided becomes unevenly
distributed onto and in the dose, i.e. the energy density (Ws/m3) is too low
in
parts of the dose for de-aggregation to come about. Thus, significant parts of
the dose are aerosolized as aggregated particles and delivered as aggregates
to a user. However, these aggregates are aerodynamically too big to reach the
deep lung. This is why the delivered fine particle doses (FPD) out of blisters
or capsules or aerosolizing chambers of prior art inhalers are too low,
representing only 20 - 30 % of the metered dose mass.
According to the present invention, a particular solution to this problem of
individually releasing all particles of the dose, is to optimize the use of
available inhalation energy over time. An initial build-up of suction power
establishes an airflow, which is then directed onto the dose in a piecemeal
fashion. The particles in the dose are thus released and aerosolized by the
high level of energy density (Ws/m3) supplied to the dose in a gradual
manner. Thus, a preferred embodiment of the medical product is adjusted to
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accommodate and facilitate a gradual release of the enclosed GLP dose and
an optional dose of insulin by a dry powder inhaler. Surprisingly, we have
found that if the inhalation power of a user is first allowed to build up to a
certain level and then applied for a prolonged period to a single or combined
dose, no other external source of power is necessary for a complete release
and aerosolization of the dose(s). A minimum level of power has been
determined to be 2 kPa of suction and a normal range of suction power is 2
to 6 kPa, but typically a suction not less than 2 kPa and not greater than 4
kPa is quite satisfactory for complete particle by particle release of a
single or
combined dose. Preferably, the suction produces an inspiration air stream in
a range 20 to 60 1/min and more preferably in a range 20 to 40 1/min.
Arranging the medical product, according to the invention, for a prolonged
delivery in this way results in an FPD value several times higher than in
prior art. Since the dose is aerosolized gradually, the dose is delivered over
an interval, thereby resulting in a prolonged pulmonary dose delivery.
Typically, a prolonged pulmonary dose delivery lasts from 0,1 s to 5 s,
depending on dose mass in the medical product and design and efficiency of
the dry powder inhaler that is used. Two typical inhalation sequences are
illustrated in Figures 3a and 3b, carried out by two subjects. Diagram curve
Y represents the suction power in kPa provided by the respective subject
over time X and curve Z represents dose delivery from 0 to 100 % from a
DPI. As can be seen, delivery of the dose does not begin until the suction is
near the peak at about 4 to 5 kPa. The respective dose is fully delivered
before the suction power has dropped below 4 kPa. In one embodiment of the
invention the medicament dose is made available in a dry powder inhaler
and a user provides the suction effort to the inhaler, whereby the dose is
released in a resulting single inhalation operation. In another embodiment of
the invention the medicament dose is made available in a dry powder inhaler
and a machine operated means provides the suction effort to the inhalation
operation whereby the dose is released and pulmonary delivery is mimicked
by a mechanical in-vitro means.
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WO 2006/059939 20 PCT/SE2005/001648
In a preferred embodiment of the present invention the prolonged delivery is
accomplished within a time period of not less than 0.1 second and not more
than 5 seconds by the inhaler device.
In another embodiment of the present invention the prolonged delivery is
accomplished within a time period of not less than 0.2 second and not more
than 2 seconds by the inhaler device.
In a different embodiment of the present invention the prolonged delivery is
accomplished within a time period of not less than 0.2 seconds and not more
than 5 seconds and the dose is delivered in a manner where at least 50 % of
the dose by mass is emitted within a time frame of 0.2 - 1 seconds by the
inhaler device.
In yet another embodiment of the present invention the prolonged delivery is
accomplished within a time period of not less than 0.2 seconds and not more
than 5 seconds and the dose is delivered in a manner where at least 75 % of
the dose by mass is emitted within a time frame of 0.2 - 2 seconds by the
inhaler device.
Surprisingly, we have found that aerosolizing the dose gradually leads to less
irritation of the mucous membranes and airways of the user, with a reduced
risk of coughing or choking during an inhalation. This beneficial effect is
due
to a reduced concentration of particles per liter inspiration air, compared to
prior art combinations of dose packages and inhalers. In a further aspect of
the present invention the medical product is intended for application in a
single dose inhaler, which entirely relies on the power of the inhalation for
de-aggregating and aerosolizing the dose, with no further external source of
power necessary. See Figures 7a and 7b for an example of a medical product
comprising a combination of GLP and selectable insulin doses.
The disclosure herein is by way of example and a person of ordinary skill in
the art may of course find alternative methods of energy optimization,
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whereby de-aggregation power of sufficient strength may be distributed
evenly and efficiently onto the dose, which methods, however, are still within
the scope of the present invention. See our US Patent Nos. 6,571,793,
6,881,398, 6,840,239 and 6,892,727, which are hereby incorporated herein
by reference.
In another aspect of the invention it is important to protect a moisture-
sensitive dose, such as GLP or insulin, up to the very point of delivery to a
user. Therefore, the medical product of the present invention must be
protected from ingress of moisture for a specified in-use period. Preferably,
the container of the medical product of the present invention is not opened
until a user performs an inhalation. In such case the time of exposing the
dose powder to the atmosphere is approximately the time it takes for the
delivery to take place. Any adverse effect, which depends on exposing the
dose to the ambient atmosphere is thereby minimized and in practice
negligible. A particular embodiment of the present invention is illustrated in
Figure 4a, 4b and 4c. Figure 4a shows a sealed container 33 (seal 31) put
into a protective carrier 41 adapted for insertion into a dry powder inhaler.
Figure 4b shows a top view of the carrier/container and indicates
depositions of dry powder making up a metered dose inside the container 33
under a seal 31, for the benefit of the reader. Figure 4c illustrates a side
view
of the carrier/ container in Figure 4b. Figure 5a and 5b illustrate the
container 33 in an opened state, where the seal 31 has been slit open and
folded upwards, away from the dose 21 inside the container 33. Dose 21 is
in the embodiment made up of four separate depositions 22 of dry powder.
Depositions 22 may comprise same or different powders, such that the
combined depositions either represent a single, metered GLP dose or a
combined dose of GLP and insulin. A skilled person would realize that the
number of depositions depends, inter alia, on the total dose mass and the
relation between masses of different powders together making up a
combined dose.
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The fine particle fraction (FPF) of the finely divided active peptide agent,
GLP
and optionally insulin, if present, in the metered medicament dose is to be
as high as possible, having a mass median aerodynamic diameter (MMAD)
below 3}a.m and a particle size distribution having at least 70 % and
preferably more than 80 % and most preferably more than 90 % by mass
with AD between 1 and 3 pm. After forming a metered dose, it is very
important to protect the dose from negative influences, which may otherwise
detrimentally affect FPF of GLP as well as insulin. Moisture constitutes a
particular risk in this respect, because moisture increases the tendency of
powders to form agglomerates, which reduces the FPF of the powder. So, in
order to protect the dose according to the present invention against
moisture, the medical product either comprises a primary dose package
constituting a high barrier seal container, or the medical product is put in a
suitable secondary, õ package, whereby the FPF of GLP as well as optional
insulin is protected from ingress of moisture from the point of manufacture
to the point of administering a dose, through the steps of transporting,
storing, distributing and consuming.
Methods of dose forming of peptide powder formulations, e.g. GLP and
insulin according to the present invention, include conventional mass,
gravimetric or volumetric metering and devices and machine equipment well
known to the pharmaceutical industry for filling blister packs, for example.
Electrostatic forming methods may also be used, or combinations of methods
mentioned. A most suitable method of depositing microgram and milligram
quantities of dry powders uses electric field technology (ELFID) as disclosed
in our U.S. Patent No. 6,592,930 B2, which is hereby incorporated in this
document in its entirety as a reference.
Insulin according to the present invention is defined as insulin, insulin
analogue and insulin derivates, preferably recombinant, human insulin.
Prior art methods of producing a powder formulation of a medicament
intended for inhalation, such as insulin or GLP, generally involves
micronizing e.g. by jet milling or spray-drying, freeze-drying, vacuum drying
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or open drying. Prior art methods include the addition of excipients, e.g.
surfactants, stabilizers and penetration enhancers, in the manufacturing
process with the object of improving the bioavailability, speed of systemic
absorption and efficacy of the medicament, for instance insulin. Methods
also include making porous or hollow particles, preferably spherical in shape
and geometrically bigger than 10 gm in diameter, but with AD less than 5
gm. The objectives are to get a flowable powder, which makes handling and
dose forming and metering easier and yet to provide a powder, which is easy
to de-aggregate when inhaled and which offers a high delivered FPD.
A particular method of preparing a dry, crystalline medicament powder
before an optional mixing step, is to jet mill or otherwise micronize the
ingredients of the medicament at least once and preferably twice in order to
get a small mass median aerodynamic diameter (MMAD) for the finely
divided powder in a range 1- 3 pm with as small tails of particles, outside
this range as possible. The powder is then optionally mixed with one or more
excipients, for example in order to dilute the potency of the active
ingredient(s) to get a final powder preparation well adapted to chosen
methods of metering and forming doses.
In another aspect of the present invention of combining GLP and insulin in
treatment of diabetes, it is advantageous to include more than one
formulation of recombinant, human insulin, or human insulin analogue,
powder in the insulin dose, e.g. in order to improve the insulin delivery into
the blood circulation, such that the natural course of insulin production in a
healthy person is mimicked more closely than would be possible when using
only one insulin formulation. Different formulations of recombinant insulin
and insulin analogue present different absorption delays and blood
concentrations over time, e.g. Lantus from Sanofy-Aventis, which is slow-
acting but long duration and insulin lispro Humalog from Eli Lilly, the latter
having fast on-set. Therefore, a use of two or more insulin analogues in a
combined dose with GLP is well suited with the objective of adjusting the
systemic concentration of insulin in the blood of a diabetic user over time by
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WO 2006/059939 24 PCT/SE2005/001648
the combined action of the active ingredients. This treatment comes very
close to bringing about the natural concentration curve in a healthy subject.
When insulin is combined with administration of GLP, the choice of suitable
insulin formulations and dosage sizes must be carefully adjusted by a
person skilled in the art for best possible combination result. A typical
combined therapy and dosing regimen of GLP and insulin lets the diabetic
user take a combined dose by inhalation just before or in connection with
each meal, such as breakfast, lunch and dinner. The insulin and the GLP
ingredients are within minutes of inhalation absorbed into the system. The
insulin helps reduce the spike of glucose following intake of food and the
GLP stimulates the beta-cells in pancreas to produce insulin and helps the
body to keep a normal level of glucose in the blood until it is time for the
next meal. In this therapy the objective of controlling a normal glucose level
in the user during the day is fulfilled. Optionally, depending on the diabetic
status of the user, additional doses of GLP and/or insulin may be required
in order to control the level of glucose during the day and night.
According to the present invention, mixing of two or more active agents into
a homogenous powder mixture, optionally including one or more excipients,
may be done in any order of all possible permutations, before the resulting
powder mixture is used in a method of metering and forming doses. For
instance, insulin may be mixed with GLP first and then this mixture may be
added to a mixture of excipients, if needed, but any permutation of the
mixing steps may be used. The properties of the final powder mixture are
decisive for the choice of mixing method, such that e.g. peptide stability is
maintained, risk of particle segregation by size is eliminated and dose to
dose relative standard deviation (RSD) is kept within specified limits,
usually
within 5 %. Naturally, the ingredients must not adversely affect each other in
the mixture. If there is any risk of degradation or other adverse effect in a
component resulting from the mixing, then that component must not be
included in the mixture, but separately administered, although preferably in
a single inhalation operation, if technically possible.
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In another aspect of the present invention separate dry powder dosages of
GLP and insulin respectively, each optionally comprising excipients, may be
arranged onto a common dose carrier for insertion into an adapted inhaler
and delivered to the lungs of a user, preferably in the course of a single
inhalation. In a particular embodiment the separated dosages are separately
enclosed onto the dose carrier in individually sealed enclosures, such as
compartments, containers, capsules or blisters, known in the art. In another
embodiment the separated dosages share a common enclosure onto the dose
carrier. A cbmmon, sealed enclosure may be used to simplify the
manufacturing process if the dosages of GLP and insulin have no adverse
effect on each other after deposition and sealing onto the carrier for the
shelf-life of the product. The combined dosages according to the disclosure
may be advantageously used in the treatment of diabetes type 1 and type 2,
providing at least one of the advantages listed in the foregoing.
It is a further objective of the present invention to deliver a fine particle
dose
(FPD) of the at least one GLP powder and optionally insulin powder if
included in a combined dose, where the delivered fine particle dose amounts
to at least 50 % by mass, preferably at least 60 % by mass, more preferably
at least 70 % by mass and most preferably at least 80 % by mass of the
active GLP ingredient and optional insulin ingredient of the respective
ingredients of the metered dose.
In another aspect of the invention at least one excipient is in a formulation
where the MMAD of the particles is 10 }.tm or more, such that the at least
one excipient acts as a carrier for the finely divided particles of the at
least
one active GLP agent of the metered dose. Besides diluting the potency of the
active GLP ingredient(s), excipients contribute to acceptable metering and
dose forming properties of the powder mixture. When the metered dose is
delivered to a user by means of a dry powder inhaler device (DPI), almost all
of the excipient particle mass is deposited in the mouth and upper airways,
because the AD of excipient particles are generally too big to follow the
inspiration air into the lung. Therefore, excipients acting as carriers and J
or
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diluents are selected inter alia with a view to being harmless when deposited
in these areas.
Suitable carrier or diluent excipients for inclusion in a GLP formulation are
to be found among the groups of monosaccarides, disaccarides, oligo- and
polysaccarides, polylactides, polyalcohols, polymers, salts or mixtures from
these groups, e.g. glucose, arabinose, lactose, lactose monohydrate, lactose
anhydrous [i.e., no crystalline water present in lactose molecule],
saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride,
calcium carbonate. A particular excipient is lactose.
In our experience many dry powder peptides are sensitive to moisture. Thus,
the moisture properties of any proposed excipient must be checked before it
is chosen to be included in a formulation comprising GLP and/or insulin,
regardless of the intended function of the proposed excipient. If an excipient
gives off much water, after dose forming, it will negatively affect the active
ingredients in the dose, such that the FPD deteriorates rapidly after dose
forming. Therefore, excipients are to be selected among acceptable
excipients, which have good moisture properties in the sense that the
excipient will not adversely affect the FPD of the active ingredients for the
shelf life of the product, regardless of normal changes in ambient conditions
during transportation and storage. Suitable "dry" excipients are to be found
in the above-mentioned groups. In a particular embodiment of a GLP dose,
optionally also comprising insulin, lactose is selected as the preferred dry
excipient and preferably lactose monohydrate. A reason for selecting lactose
as excipient, is its inherent property of having a low and constant water
sorption isotherm. Excipients having a similar or lower sorption isotherm
can also be considered for use, provided other required qualities are met.
The dose size depends on the type of disorder and the selected GLP agent for
adequate therapy, but naturally age, weight, gender and severity of the
medical condition of the subject undergoing therapy are important factors.
According to the present invention, a delivered fine particle dose (FPD) of
the
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active ingredient administered by inhalation herein is not limited, and may
generally be in a range from 10 pg to 25 mg. Normally, of course, a physician
prescribes a proper dose size. Depending on the potency of the active
substance, such as GLP and human insulin agents, the active dose mass is
optionally diluted by adding a pharmacologically acceptable excipient to the
formulation to suit a particular method of dose forming and to achieve a pre-
metered dose in the inhaler, preferably exceeding 100 g. Besides acting as a
diluent, the excipient may optionally be selected to give desired electrical
qualities to the powder mixture constituting the drug. A method for
preparing a powder or powder mixture to bring about suitable electrostatic
properties of the prepared powder to make the powder apt for a filling
process is described in our US Patent No. US 6,696,090, which is hereby
incorporated in this document in its entirety by reference.
Further, the correct metered dose loaded into an inhaler for administration
must be adjusted for predicted losses such as retention and fine particle
fraction (FPF) of the inhaled dose. A practical lower limit for volumetric
dose
forming is in a range 0.5 to 1 mg. Doses smaller than an order of 1 mg are
difficult to produce while maintaining a low relative standard deviation
between doses of the order of at least 5 %. Typically, though, dose masses for
inhalation are in a range from 1 to 50 mg.
Ambient conditions during dose forming, metering and container sealing
should be closely controlled. The ambient temperature is preferably limited
to 25 C maximum and relative humidity preferably limited to 15 % Rh
maximum, although some drug formulations must be filled in very dry
conditions of only a few percent relative humidity. As already mentioned in
the foregoing it is very important to control the electric properties of the
powder and thereby controlling the use of electric charging and discharging
of particles, regardless of which method of dose forming is to be used. Fine
powders pick up static electric charges extremely easily, which can be
advantageously used in dose forming, if the charging and discharging is
under proper control.
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"High barrier seal" means a dry packaging construction or material or
combinations of materials. A high barrier seal is wherein it represents a high
barrier against moisture and that the seal itself is 'dry', i.e. it cannot
give off
measurable amounts of water to the load of powder. A high barrier seal may
for instance be made up of one or more layers of materials, i.e. technical
polymers, aluminum or other metals, glass, silicon oxides etc that together
constitutes the high barrier seal. If the high barrier seal is a foil, a 50 pm
PCTFE/PVC pharmaceutical foil is the minimum required high barrier foil if
a two-week in-use stability for a moisture sensitive medicament shall be
achieved. For longer in-use stabilities metal foils like aluminum foils from
Alcan Singen can be used.
The medical product disclosed comprises a dose container as primary
package, which may be a "high barrier seal container". The disclosed. dose
container is a mechanical construction made to harbor and enclose a dose of
e.g. GLP or insulin or a dose combination or a mixture thereof, which may be
sensitive to humidity. The design of the dose container and the materials
used must be adequate for the drug considering the sensitivity to humidity
and the specified in-use time for the container as primary package. A sealed
dose container can be made up of one or more layers of materials, i.e.
technical polymers, aluminum or other metals, glass, silicon oxides etc and
may exist in many different shapes, e.g. completely or partly spherical,
cylindrical, box-like etc. However, the volume of the container is preferably
not bigger than necessary for loading and enclosing a metered dose or dose
combination, thereby minimizing the amount of moisture enclosed in the
atmosphere. Another requirement is that the container is designed to
facilitate opening thereof, preferably in a way that makes the enclosed dose
accessible for direct release, aerosolization and entrainment of the powder in
inspiration air during an inhalation. The time the dose is exposed to ambient
air is thereby minimized. A high barrier seal container is built using high
barrier seals constituting the enclosing, i.e. walls of the container.
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The sealed, dry container of the present invention that is directly loaded
with
a GLP dose may be in the form of a blister and it may e.g. comprise a flat
dose bed or a formed cavity in aluminum foil or a molded cavity in a polymer
material, using a seal foil against ingress of moisture, e.g. of plastic or
aluminum or a combination of aluminum and polymer materials. The sealed,
dry, container may form a part of an inhaler device or it may form a part of a
separate item intended for insertion into an inhaler device for administration
of pre-metered doses. A particular embodiment of a sealed high barrier
container used in an adapted DPI has the following data:
= Container internal volume: 100 mm3
= Effective diffusion area: 46 mm2
= Diffusion constant: 0.044 g/m2 for 24 hours at 23 C and differential Rh =
50 % Rh
In a further aspect of the present invention the medical product comprises at
least one GLP agent and at least one insulin agent in a combined metered
dose, optionally including at least one biologically acceptable excipient,
loaded and sealed into a dose container. A GLP dosage and an insulin
dosage, which together constitute a combined dose, may be sharing the
same dose container or the dosages may be separated into separate dose
containers. Methods of producing the combined dose are known in the art
and include spray-drying, lyophilizing, vacuum drying, open drying, jet
milling and mixing. Each ingredient may be produced as separate
formulations or may be introduced into a selected process producing a
combined formulation of the ingredients, if safe with regard to chemical and
biological stability and toxicology. It is further possible, according to the
disclosure herein, to make the resulting formulation(s) as powder, optionally
powder inter-mixtures, of finely divided particles, or large-sized porous
particles. The sealed dose container of the medical product is thus protecting
the combined dose from ingress of moisture and other foreign matter,
thereby preserving the FPD of the combined peptide medicament for the
specified in-use time period. Deterioration of the FPD is further protected by
enclosing only an insignificant quantity of moisture inside the container
CA 02589118 2007-06-01
WO 2006/059939 30 PCT/SE2005/001648 _
together with the dose by keeping the humidity in the atmosphere during
dose metering and forming to a sufficiently low level, and optionally by
choosing the biologically acceptable excipient with as low sorption
coefficient
as possible. For instance, the humidity in the atmosphere where the powder
is handled immediately prior to metering and forming should be kept below
% Rh and preferably below 10 % Rh, more preferably below 5 % Rh and
most preferably below 1 % Rh. The disclosed medical product warrants that
the quality of the delivered dose is high and intact over the full shelf life
period and the in-use period of the product.
In Figures , 4, 5, 6 and 7 reference numbers 11 - 42 of the drawings same
numbers indicate like elements throughout the different embodiments of the
medical product, presented here as non-limiting examples.
As used herein, the phrases "selected from the group consisting of," "chosen
from," and the like include mixtures of the specified materials. All
references,
patents, applications, tests, standards, documents, publications, brochures,
texts, articles, instructions, etc. mentioned herein are incorporated herein
by
reference. Where a numerical limit or range is stated, the endpoints are
included. Also, all values and sub-ranges within a numerical limit or range
are specifically included as if explicitly written out.
In the context of this document all references to ratios, including ratios
given
as percentage numbers, are related to mass, if not explicitly said to be
otherwise.
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