ABSTRACT
Abstract
A medical product is disclosed. The medical product contains an accurately metered dose of at least one GLP medicament intended for pulmonary inhalation put into a moisture-tight, high barrier seal container. The medical product optionally also contains a dose of insulin. The container is adapted for application into a dry powder inhaler. The dose loaded in 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 may comprise at least one biologically acceptable excipient.
Description
PRIOR APPLICATION
This application claims priority to Swedish Patent Application 0402976-5 filed Dec. 3, 2004 and U.S. patent application Ser. No. 11/049696 filed Feb. 4, 2005, both incorporated herein by reference.
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 m 2 ) 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 μm. 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 (AD) of a particle is defined as the diameter of a spherical particle having a density of 1 g/cm 3 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 μm 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, âlightâ, porous particles. See e.g. âMicron-Size Drug Particles: Common and Novel Micronization techniquesâ by Rasenack and Muller in Pharmaceutical development and technology, 2004, 9(1):1-13. See also âUnit Operation-Micronizationâ prepared by Lee Siang Hua, dept. of Chemical & Biomolecular Engineering, National University of Singapore. In these documents the term âfinely divided powderâ 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 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 B1.
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 lung and dissolve, thereby ensuring rapid absorption from the lung into the system before enzymatic inactivation sets in. See for instance U.S. Pat. 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 OF THE INVENTION
The present invention discloses a medical product comprising an accurately metered dose of at least one 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. 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 at least one GLP agent including GLP analogues and derivates.
The active GLP agent 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 at least one 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-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.
BRIEF 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;
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 OF THE PREFERRED EMBODIMENTS
The present invention discloses an improved medical product comprising: an accurately metered medication dose of at least one 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 one 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.
In the present invention âGLP analoguesâ are analogues of naturally occurring GLPs
PRIOR APPLICATION
This application claims priority to Swedish Patent Application 0402976-5 filed Dec. 3, 2004 and U.S. patent application Ser. No. 11/049696 filed Feb. 4, 2005, both incorporated herein by reference.
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 m 2 ) 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 μm. 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 (AD) of a particle is defined as the diameter of a spherical particle having a density of 1 g/cm 3 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 μm 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, âlightâ, porous particles. See e.g. âMicron-Size Drug Particles: Common and Novel Micronization techniquesâ by Rasenack and Muller in Pharmaceutical development and technology, 2004, 9(1):1-13. See also âUnit Operation-Micronizationâ prepared by Lee Siang Hua, dept. of Chemical & Biomolecular Engineering, National University of Singapore. In these documents the term âfinely divided powderâ 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 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 B1.
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 lung and dissolve, thereby ensuring rapid absorption from the lung into the system before enzymatic inactivation sets in. See for instance U.S. Pat. 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 OF THE INVENTION
The present invention discloses a medical product comprising an accurately metered dose of at least one 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. 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 at least one GLP agent including GLP analogues and derivates.
The active GLP agent 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 at least one 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-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.
BRIEF 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;
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 OF THE PREFERRED EMBODIMENTS
The present invention discloses an improved medical product comprising: an accurately metered medication dose of at least one 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 one 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.
In the present invention âGLP analoguesâ are analogues of naturally occurring GLPs (or recombinant versions), preferably human GLPs, such as GLP-1 and GLP-2, which differ by substitution of at least one naturally occurring amino acid residue with one or more other amino acid residues and/or addition/removal of at least one amino acid residue from the corresponding, otherwise identical, naturally occurring GLP. The added and/or replaced amino acid residue(s) can also be those which do not occur naturally. In this context, the number of amino acids that can be substituted, removed and/or added to the GLP sequence can non-inventively be determined by the person skilled in the art. In a preferred implementation, 1-20 amino acids of the naturally occurring GLP sequences can be replaced and/or removed, more preferably 1-10 amino acids, e.g. 1-5 amino acids. Correspondingly, in a preferred implementation, 1-20 amino acids can be added to any of the naturally occurring GLP sequences, more preferably 1-10 amino acids, e.g. 1-5 amino acids. A resulting GLP analogue is, thus, preferably a polypeptide sequence which exhibit at least about 50% sequence identity, e.g. at least 60% sequence identity, preferably at least about 70% sequence identity, more preferably at least 80%, e.g. at least 85%, 90%, 95% or 98% sequence identity the polypeptide sequence of a naturally occurring GLP. The sequence identity of two polynucleotides may be determined by several different methods known to the person skilled in the art including, but not limited to, BLAST program of Altschul et al. (J. Mol. Biol., 215: 403-410, 1990).
The important concept here is that the GLP analogue has or retains at least some of the functions of naturally occurring GLP in stimulating insulin release and biosynthesis, suppressing glucagon release and/or inhibiting gastric emptying. Any amino acid substitutions, removals or additions to the polypeptide sequence of a naturally occurring GLP that fulfils this preferred requirement of at least partly retained âGLP functionâ, as defined above, can be used to produce a GLP analogue useful according to the present invention.
âGLP derivatesâ are derivates of naturally occurring GLP or of a GLP analogue which are obtained by chemical modification. The chemical modification can consist, for example, in the addition, substitution or deletion of one or more specific chemical groups to one or more amino acids. It can also involve the addition, substitution or deletion of one or more chemical groups of the peptide backbone, such as, the amino and/or carboxyl terminus. Typical examples of such chemical modifications to amino acides include, without limitation, acylation of lysine ε-amino groups, N-aculation of arginine, histidine or lysine, alkylation of glutamic or aspartic carboxylic acid groups and deamidation of glutamine or asparagines. Modifications of the terminal amino include, without limitation, the des-amino, N-lower alkyl, N-di-lower alkyl and N-acyl modifications. Modification fo the terminal carboxy group include, without limitation, the amide, lower alkyl amide, dialkyl amide and lower alkyl ester modifications. Lower alkyl is C 1 -C 6 , and more preferably C 1 -C 4 alkyl. In this context, the number of amino acids that can be modified in the GLP (analogue) sequence can non-inventively be determined by the person skilled in the art. In a preferred implementation, 1-20 amino acids can be modified, more preferably 1-10 amino acids, e.g. 1-5 amino acids.
The important concept here is that the GLP derivate has or retains at least some of the functions of naturally occurring GLP in stimulating insulin release and biosynthesis, suppressing glucagon release and/or inhibiting gastric emptying. Any amino acid modifications that fulfil this preferred requirement of at least partly retained âGLP functionâ, as defined above, can be used to produce a GLP derivate useful according to the present invention.
The GLP analogues and derivates useful according to the present invention can have desired new improved properties including, without limitation, improved stability, longer or shorter half-life, increased pulmonary absorption, properties that make them particular suitable for powder preparation.
Examples of suitable GLP analogues and derivates that are useful as GLP agent according to the present invention are given here below.
One particular peptide agonist acting as a GLP agent useful in the present invention is described in U.S. Pat. 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:
R 1 -Gly-Glu-Gly-Thr-Phe-Thr-Ser- (SEQ ID NOs:1-9)
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-R 2,
wherein
R 1 â is selected from a group consisting of His- (see SEQ ID NOs: 1-3), (Lys) 6 -His- (see SEQ ID NOs: 4-6) and Asn-(Glu) 5 -His- (see SEQ ID NOs: 7-9) âR 2 is selected from a group consisting of -Pro-Pro-Ser-(Lys) 6 (see SEQ ID NOs: 1, 4, and 7), -Ser (see SEQ ID NOs: 2, 5, and 8) and -Ser-(Lys) 6 (see SEQ ID NOs: 3, 6, and 9).
Another particular GLP derivate, which may be used in the present invention is described in U.S. Pat. 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-R 3 -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly (SEQ ID NO: 10) wherein R 3 is selected from a group consisting of Lys and Lys in which the ε-amino group is substituted with a lipophilic substituent, optionally via a spacer. Preferred lipophilic substituents include CH 3 (CH 2 ) n COâ, wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22, HOOC(CH 2 ) m COâ, wherein m is 10, 12, 14, 16, 18, 20 or 22, and lithochoyl. Preferred optional spacers include an unbranched alkane α,Ï-dicarboxylic acid group having from 1 to 7 methylene groups, an amino acid residue except Cys, and γ-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-R 4 (SEQ ID NOs: 11 and 12) wherein âR 4 is selected from a group consisting of -Arg (see SEQ ID NO: 11), -Arg-Gly (see SEQ ID NO: 12);
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser- (SEQ ID NO:13)
Asp-Tyr-Ala-Lys-Tyr-Leu-Asp-Ala-
Arg-Arg-Ala-Lys-Glu-Phe-Ile-Ala-
Trp-Leu-Val-Lys-Cys-Arg-Gly;
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser- (SEQ ID NO:14)
Asp-Tyr-Ala-Lys-Tyr-Leu-Asp-Ala-
Arg-Arg-Ala-Lys-Glu-Phe-Ile-Ala-
Trp-Leu-Val-Lys-Gly-Cys-Gly;
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser- (SEQ ID NOs:15-18)
Asp-Tyr-Ala-R 5 -Tyr-Leu-Asp-Ala-
R 6 -R 7 -Ala-R 8 -Glu-Phe-Ile-R 9 -Trp-
Leu-Val-R 10 -Gly-R 11
wherein
R 5 is selected from a group consisting of Lys, Arg, Ala
R 6 is selected from a group consisting of Arg, Lys, Ala
R 7 is selected from a group consisting of Arg, Lys
R 8 is selected from a group consisting of Lys, Ala
R 9 is selected from a group consisting of Ala, Lys
R 10 is selected from a group consisting of Lys, Cys, Arg
âR 11 is selected from a group consisting of -Arg (see SEQ ID NO: 15), -Arg-Gly (see SEQ ID NO: 16), -Arg-Cys (see SEQ ID NO: 17), -Arg-Gly-Lys (see SEQ ID NO: 18)
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), [Val 8 ]-GLP-1 (7-36) amide, [Val 8 ]-GLP-1 (7-37); [Lys 26 , ε-NH{γ-Glu(N-α-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-R 12 -Glu-Gly-R 13 âR 14 -Thr-Ser-Asp-R 15 -Ser-Ser-Tyr-Leu-Glu-R 16 âR 17 âR 18 -Ala-R 19 âR 20 -Phe-Ile-R 21 -Trp-Leu-R 22 âR 23 âR 24 âR 25 âR 26 (SEQ ID NOs: 19 and 20)
wherein
R 12 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Ser, Thr
R 13 is selected from a group consisting of Asp, Glu, Arg, Thr, Ala, Lys, His
R 14 is selected from a group consisting of His, Trp, Phe, Tyr
R 15 is selected from a group consisting of Leu, Ser, Thr, Trp, His, Phe, Asp, Val, Tyr, Glu, Ala
R 16 is selected from a group consisting of Gly, Asp, Glu, Gln, Asn, Lys, Arg, Cys, cysteic acid
R 17 is selected from a group consisting of His, Asp, Lys, Glu, Gln, Arg
R 18 is selected from a group consisting of Glu, Arg, Ala, Lys
R 19 selected from a group consisting of Trp, Tyr, Phe, Asp, Lys, Glu, His
R 20 is selected from a group consisting of Ala, Glu, His, Phe, Tyr, Trp, Arg, Lys
R 21 is selected from a group consisting of Ala, Glu, Asp, Ser, His
R 22 is selected from a group consisting of Asp, Arg, Val, Lys, Ala, Gly, Glu
R 23 is selected from a group consisting of Glu, Lys, Asp
R 24 is selected from a group consisting of Thr, Ser, Lys, Arg, Trp, Tyr, Phe, Asp, Gly, Pro, His, Glu
R 25 is selected from a group consisting of Thr, Ser, Asp, Trp, Tyr, Phe, Arg, Glu, His
âR 26 is selected from a group consisting of -Lys, -Arg, -Thr, -Ser, -Glu, -Asp, -Trp, -Tyr, -Phe, -His, -NH 2 , -Gly, -Gly-Pro (see SEQ ID NO: 20), -Gly-Pro-NH 2 (see SEQ ID NO: 20) or is deleted.
A particular peptide agonist acting as a GLP agent useful 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-R 27 -R 28 -Gly-R 29 -Phe-Thr-R 30 -Asp- (SEQ ID NO:21)
R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -
R 40 -R 41 -R 42 -Phe-Ile-R 43 -R 44 -R 45 -R 46 -
R 47 -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -
R 56 -R 57 -R 58
wherein
R 27 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 28 is selected from a group consisting of Glu, Asp, Lys
R 29 is selected from a group consisting of Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, Lys
R 30 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 31 is selected from a group consisting of Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, Lys
R 32 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 33 is selected from a group consisting of Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 34 is selected from a group consisting of Tyr, Phe, Trp, Glu, Asp, Lys
R 35 is selected from a group consisting of Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 36 is selected from a group consisting of Glu, Asp, Lys
R 37 is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 38 is selected from a group consisting of Gln, Asn, Arg, Glu, Asp, Lys
R 39 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Gln, Asp, Lys
R 40 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 41 is selected from a group consisting of Lys, Arg, Gln, Asp, His
R 42 is selected from a group consisting of Gln, Asp, Lys
R 43 is selected from a group consisting of Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 44 is selected from a group consisting of Trp, Phe, Tyr, Glu, Asp, Lys
R 45 is selected from a group consisting of Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, Lys
R 46 is selected from a group consisting of Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, Lys
R 47 is selected from a group consisting of Lys, Arg, Glu, Asp, His
R 48 is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys
R 49 is selected from a group consisting of Arg, Lys, Glu, Asp, His
R 50 is selected from a group consisting of Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys or is deleted
R 51 is selected from a group consisting of Arg, Lys, Glu, Asp, His or is deleted
R 52 is selected from a group consisting of Arg, Lys, Glu, Asp, His or is deleted
R 53 is selected from a group consisting of Asp, Glu, Lys or is deleted
R 54 is selected from a group consisting of Phe, Trp, Tyr, Glu, Asp, Lys or is deleted
R 55 is selected from a group consisting of Pro, Lys, Glu, Asp or is deleted
R 56 is selected from a group consisting of Glu, Asp, Lys or is deleted
R 57 is selected from a group consisting of Glu, Asp, Lys or is deleted
âR 58 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. WO2005/066207. This GLP agent embodiment has any one of the following sequences:
R 59 -His-R 60 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-R 61 -Glu-Gly-Gln-Ala-Ala-Lys-R 62 -Phe-Ile-R 63 -Trp-Leu-R 64 (SEQ ID NOs: 22-26)
wherein
R 59 is selected from a group consisting of H, a linear or branched unsaturated C 1 -C 6 acyl group, an optionally substituted arylcarbonyl, an optionally cycloalkylcarbonyl, an optionally substituted arylalkylcarbonyl
R 60 is selected from a group consisting of Ala, 1-aminoisobutyric acid (Aib), Val, Gly
R 61 selected from a group consisting of Leu and Gly having a C 6 -C 20 alkyl side chain
R 62 is selected from a group consisting of Ala, Leu, Val, Ile, Glu
R 63 is selected from a group consisting of Glu, Asp, Asn, Gln, Ala
âR 64 is selected from a group consisting of -Lys-Asn-Aib-OH (see SEQ ID NO: 22), -Lys-Asn-Aib-NH 2 (see SEQ ID NO: 22), -Val-Lys-Asn-OH (see SEQ ID NO: 23), -Val-Lys-Asn-NH 2 (see SEQ ID NO: 23), -Lys-Asn-OH (see SEQ ID NO: 24), -Lys-Asn-NH 2 (see SEQ ID NO: 24), -Val-Lys-Gly-Arg-NH 2 (see SEQ ID NO: 25), -Val-Lys-Aib-Arg-OH (see SEQ ID NO: 26), -Val-Lys-Aib-Arg-NH 2 (see SEQ ID NO: 26), -Lys-Asn-Gly-OH (see SEQ ID NO: 22), -Lys-Asn-Gly-NH 2 (see SEQ ID NO: 22)
Another particular GLP-1 sequence, which may be used in the present invention is described in PCT Application No. WO2004/029081. This GLP agent embodiment has any one of the following sequences:
R 65 -His-Ala-Glu-Gly-Thr-Phe-Thr-Ser- (SEQ ID NO:27)
Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-
Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-
Val-Lys-Gly-Arg-R 66
wherein
R 65 is a rigidifying hydrophobic moiety selected from the group consisting of
C 1 -C 10 alkenoic acid, optionally substituted by at least one substituent selected from the group consisting of straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl and substituted aryl;
C 1 -C 10 alkynoic acid;
C 3 -C 10 cycloalkanoic acid, or heterocycloalkanoic acid comprising an heteroatom selected from O, S and N;
C 5 -C 14 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, âNH(lower alkyl), âN(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;
C 5 -C 14 heteroarylcarboxylic or heteroarylalkanoic acid comprising a heteoatom selected from O, 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, âNH(lower alkyl), âN(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
âR 66 is selected from a group consisting of âOH, âNH 2 , -Gly-OH.
In a particular aspect of the present invention a GLP agent is selected, which is long-acting following pulmonary delivery. In all embodiments herein, more than one GLP agent can be used.
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 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 times 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 FIG. 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 μg to 25 mg. Both doses are then administered in a single inhalation. See FIGS. 7 a and 7 b 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 FIGS. 6 a, 6 b and 6 c. 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 FIG. 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 <figure-callout id="1" label="diabetes" filenames="US20060239933A1-20061026-D00002.png,US20060239933A1-20061026-D00003.png
CLAIMS
Claims ( 20 )
1 . A medical product comprising a sealed dose container, said container comprising therein:
a metered, dry powder medicament dose of at least one active, glucagon-like peptide (GLP) agent; the medicament dose optionally further comprising an active insulin agent, the insulin agent comprising at least one peptide of recombinant, human insulin or insulin analogue; the medicament dose optionally further comprising at least one biologically acceptable excipient; the medical product being adapted for a pulmonary delivery of the medicament dose by inhalation from a dry powder inhaler, and the medicament dose of the medical product being arranged to be aerosolized and entrained into inspiration air directly from the container when opened by the inhaler, the medicament dose being further arranged to be aerosolized exclusively by the inhalation power of a user for the pulmonary delivery, whereby more than 50% by mass of each of the respective active agents of the medicament dose leaves the inhaler as a fine particle dose (FPD).
2 . The medical product according to claim 1 , wherein the medicament dose comprises the active insulin agent.
3 . The medical product according to claim 2 , wherein the active agents of the medicament dose are provided as an inter-mixture in the container.
4 . The medical product according to claim 2 , wherein the active agents of the medicament dose are provided separately in the container, each active agent optionally further comprising at least one biologically acceptable excipient.
5 . The medical product according to claim 2 , wherein the medical product comprises an amount of insulin agent in a range from 100 μg to 25 mg in the medicament dose.
6 . The medical product according to claim 1 , wherein the GLP agent is selected from a GLP sequence or a pharmaceutically acceptable analogue or derivate thereof.
7 . The medical product according to claim 1 , wherein the GLP agent comprises. GLP-1 or a pharmaceutically acceptable analogue or derivate thereof.
8 . The medical product according to claim 1 , wherein the GLP agent comprises GLP-2 or a pharmaceutically acceptable analogue or derivate thereof.
9 . The medical product according to claim 1 , wherein the prolonged pulmonary delivery of a dose of the medical product takes place in a period of not less than 0.1 s and not more than 5 s.
10 . The medical product according to claim 1 , wherein the required inhalation power for de-aggregating and aerosolizing a dose of the medical product is not less than 2 kPa and not more than 6 kPa of air pressure resulting in an inspiration air flow of not less than 20 l/min and not more than 60 l/min.
11 . The medical product according to claim 1 , wherein more than 60% by mass of the active agent or each of the respective active agents of the medicament dose leaves the inhaler as a FPD.
12 . The medical product according to claim 1 , wherein a total mass of the GLP agent in the medicament dose of the medical product is in a range from 10 μg to 25 mg of a total dose mass in a range from 1 mg to 50 mg.
13 . The medical product according to claim 1 , wherein the dry powder medicament dose has a mass median aerodynamic diameter in a range from 1 to 3 μm.
14 . The medical product according to claim 1 , wherein the at least one, optional dry excipient of the medical product is present and comprises particles having a diameter of 25 μm or more in an amount of more than 40% by mass based on total mass of excipient, and the at least one, optional dry excipient further comprises an excipient selected from a group consisting of monosaccarides, disaccarides, polylactides, oligo- and polysaccarides, polyalcohols, polymers, salts or mixtures thereof.
15 . The medical product according to claim 1 , wherein the container of the medical product constitutes a high barrier seal container protecting the medicament dose from ingress of moisture, whereby the integrity of the medicament dose is fully protected for the shelf-life of the medical product.
16 . A dry powder inhaler comprising a medical product according to claim 1 .
17 . A method of producing a medical product, said method comprising the steps of
providing a dry powder medicament dose of at least one active, glucagon-like peptide (GLP) agent, optionally an active insulin agent, the insulin agent comprising at least one peptide of recombinant, human insulin or insulin analogue, and optionally at least one biologically acceptable excipient in a dose container; and sealing the dose container, wherein the medical product is adapted for a pulmonary delivery of the medicament dose by inhalation from a dry powder inhaler, and the medicament dose of the medical product is adapted to be aerosolized and entrained into inspiration air exclusively by the inhalation power of a user directly from the container when opened by the inhaler.
18 . The method according to claim 17 , wherein the medicament dose comprises the active insulin agent.
19 . A method of emitting a dry powder medicament dose of a medical product according to claim 1 comprising the steps of:
arranging the medical product in a dry powder inhaler in such a way that the medicament dose of the medical product is aerosolized and entrained into inspiration air directly from the container when opened by the inhaler; and applying a suction effort to the inhaler, whereby the medicament dose is aerosolized exclusively by the inhalation power provided by the suction effort for a prolonged pulmonary delivery, whereby more than 50% by mass of each of the respective active agents of the medicament dose leaves the inhaler as a fine particle dose, FPD.
20 . The method according to claim 19 comprising the further steps of
providing the suction effort by machine operated means, and mimicking pulmonary delivery by a mechanical in-vitro means.
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Cited By (44)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US20080260838A1
( en )
*
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US20090110647A1
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US11446127B2
( en )
2013-08-05
2022-09-20
Mannkind Corporation
Insufflation apparatus and methods
Families Citing this family (13)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
EP2280004B1
( en )
1999-06-29
2016-04-20
MannKind Corporation
Pharmaceutical formulations comprising insulin complexed with a diketopiperazine
SE0402976L
( en )
*
2004-12-03
2006-06-04
Mederio Ag
Medical product
US20130172274A1
( en )
2005-12-20
2013-07-04
Duke University
Methods and compositions for delivering active agents with enhanced pharmacological properties
US8178495B2
( en )
2008-06-27
2012-05-15
Duke University
Therapeutic agents comprising a GLP-1 receptor agonist and elastin-like peptide
DE102006031962A1
( en )
*
2006-07-11
2008-01-17
Sanofi-Aventis Deutschland Gmbh
Amidated insulin glargine
US8785396B2
( en )
2007-10-24
2014-07-22
Mannkind Corporation
Method and composition for treating migraines
KR20100090692A
( en )
*
2007-10-24
2010-08-16
맨카ì¸ë ì½í¬ë ì´ì
Delivery of active agents
KR101853606B1
( en )
2009-07-06
2018-05-03
ì¬ë ¸í¼-ì벤í°ì¤ ëì´ì¹ ëí¸ ê²ì ë² í
Aqueous insulin preparations containing methionine
JP5801997B2
( en )
*
2009-07-07
2015-10-28
ãã¡ã¤ã¶ã¼ã»ãªããããï¼°ï½ï½ï½ï½ ï½ ï¼¬ï½ï½ï½ï½ï½ ï½
Dosing unit, dosing unit pack, and inhaler for inhaling a combination of drugs
RU2012138909A
( en )
*
2010-03-31
2014-05-10
ÐленмаÑк ФаÑмаÑÑÑÑÐ¸ÐºÐ°Ð»Ñ ÐимиÑед
PHARMACEUTICAL POWDER COMPOSITION FOR INHALATIONS
CN120586220A
( en )
2016-01-11
2025-09-05
Syqeå»è¯æéå ¬å¸
Personal evaporation device
WO2023224577A1
( en )
*
2022-05-18
2023-11-23
Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Inhalation compositions comprising micronized human insulin
CN115192554A
( en )
*
2022-08-08
2022-10-18
æµæ±ä»çèæ³½å»è¯ç§ææéå ¬å¸
Propellant-free peptide-containing inhalation solution and preparation method thereof
Citations (9)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US20010012829A1
( en )
*
2000-01-11
2001-08-09
Keith Anderson
Transepithelial delivery GLP-1 derivatives
US20020160008A1
( en )
*
1994-02-12
2002-10-31
John Dupre
Treatment of diabetes
US6526969B2
( en )
*
2001-04-05
2003-03-04
Microdrug Ag
Method and device for releasing powder
US6528486B1
( en )
*
1999-07-12
2003-03-04
Zealand Pharma A/S
Peptide agonists of GLP-1 activity
US20030192540A1
( en )
*
2002-04-12
2003-10-16
Mattias Myrman
Therapeutic dry powder preparation
US20040052862A1
( en )
*
2000-09-18
2004-03-18
Henriksen Dennis B.
Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US6720407B1
( en )
*
1998-08-28
2004-04-13
Eli Lilly And Company
Method for administering insulinotropic peptides
US6810873B1
( en )
*
1999-04-23
2004-11-02
Innovata Biomed Limited
Powder inhaler for combined medicament
US20060120969A1
( en )
*
2004-12-03
2006-06-08
Microdrug Ag
Medical product for inhalation containing glucagon-like peptide-1 (GLP-1)
2004
2004-12-03
SE
SE0402976A
patent/SE0402976L/en
not_active
Application Discontinuation
2005
2005-02-04
US
US11/049,696
patent/US20060120969A1/en
not_active
Abandoned
2005-11-02
BR
BRPI0518600-5A
patent/BRPI0518600A2/en
not_active
Application Discontinuation
2005-11-02
CN
CNA2005800476483A
patent/CN101111226A/en
active
Pending
2005-11-02
JP
JP2007544302A
patent/JP2008521893A/en
active
Pending
2005-11-02
ZA
ZA200705376A
patent/ZA200705376B/en
unknown
2005-11-02
RU
RU2007124795/15A
patent/RU2007124795A/en
not_active
Application Discontinuation
2005-11-02
MX
MX2007006533A
patent/MX2007006533A/en
unknown
2005-11-15
US
US11/272,859
patent/US20060239933A1/en
not_active
Abandoned
2007
2007-06-03
IL
IL183623A
patent/IL183623A0/en
unknown
Patent Citations (10)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US20020160008A1
( en )
*
1994-02-12
2002-10-31
John Dupre
Treatment of diabetes
US6720407B1
( en )
*
1998-08-28
2004-04-13
Eli Lilly And Company
Method for administering insulinotropic peptides
US20040120897A1
( en )
*
1998-08-28
2004-06-24
Hughes Benjamin Lee
Method for administering insulinotropic peptides
US6810873B1
( en )
*
1999-04-23
2004-11-02
Innovata Biomed Limited
Powder inhaler for combined medicament
US6528486B1
( en )
*
1999-07-12
2003-03-04
Zealand Pharma A/S
Peptide agonists of GLP-1 activity
US20010012829A1
( en )
*
2000-01-11
2001-08-09
Keith Anderson
Transepithelial delivery GLP-1 derivatives
US20040052862A1
( en )
*
2000-09-18
2004-03-18
Henriksen Dennis B.
Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US6526969B2
( en )
*
2001-04-05
2003-03-04
Microdrug Ag
Method and device for releasing powder
US20030192540A1
( en )
*
2002-04-12
2003-10-16
Mattias Myrman
Therapeutic dry powder preparation
US20060120969A1
( en )
*
2004-12-03
2006-06-08
Microdrug Ag
Medical product for inhalation containing glucagon-like peptide-1 (GLP-1)
Cited By (76)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US9801925B2
( en )
1999-06-29
2017-10-31
Mannkind Corporation
Potentiation of glucose elimination
US9700690B2
( en )
2002-03-20
2017-07-11
Mannkind Corporation
Inhalation apparatus
US20080260838A1
( en )
*
2003-08-01
2008-10-23
Mannkind Corporation
Glucagon-like peptide 1 (glp-1) pharmaceutical formulations
US9078866B2
( en )
2003-08-01
2015-07-14
Mannkind Corporation
Method for treating hyperglycemia with GLP-1
US8921311B2
( en )
2003-08-01
2014-12-30
Mannkind Corporation
Method for treating hyperglycemia
US9796688B2
( en )
2004-08-20
2017-10-24
Mannkind Corporation
Catalysis of diketopiperazine synthesis
US9675674B2
( en )
2004-08-23
2017-06-13
Mannkind Corporation
Diketopiperazine salts for drug delivery and related methods
US10130685B2
( en )
2004-08-23
2018-11-20
Mannkind Corporation
Diketopiperazine salts for drug delivery and related methods
US9717689B2
( en )
2005-09-14
2017-08-01
Mannkind Corporation
Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US10143655B2
( en )
2005-09-14
2018-12-04
Mannkind Corporation
Method of drug formulation
US9446001B2
( en )
2005-09-14
2016-09-20
Mannkind Corporation
Increasing drug affinity for crystalline microparticle surfaces
US9283193B2
( en )
2005-09-14
2016-03-15
Mannkind Corporation
Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US9241903B2
( en )
2006-02-22
2016-01-26
Mannkind Corporation
Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US10130581B2
( en )
2006-02-22
2018-11-20
Mannkind Corporation
Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US8377869B2
( en )
2007-10-24
2013-02-19
Mannkind Corporation
Method of preventing adverse effects by GLP-1
US20090110647A1
( en )
*
2007-10-24
2009-04-30
Peter Richardson
Method of preventing adverse effects by glp-1
US9358352B2
( en )
2008-06-13
2016-06-07
Mannkind Corporation
Dry powder drug delivery system and methods
US10342938B2
( en )
2008-06-13
2019-07-09
Mannkind Corporation
Dry powder drug delivery system
US9339615B2
( en )
2008-06-13
2016-05-17
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US8485180B2
( en )
2008-06-13
2013-07-16
Mannkind Corporation
Dry powder drug delivery system
US10201672B2
( en )
2008-06-13
2019-02-12
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US12447293B2
( en )
2008-06-13
2025-10-21
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US8424518B2
( en )
2008-06-13
2013-04-23
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US9393372B2
( en )
2008-06-13
2016-07-19
Mannkind Corporation
Dry powder drug delivery system
US10751488B2
( en )
2008-06-13
2020-08-25
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US9192675B2
( en )
2008-06-13
2015-11-24
Mankind Corporation
Dry powder inhaler and system for drug delivery
US9446133B2
( en )
2008-06-13
2016-09-20
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US9511198B2
( en )
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2016-12-06
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Dry powder inhaler and system for drug delivery
US8499757B2
( en )
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US8636001B2
( en )
2008-06-13
2014-01-28
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US8912193B2
( en )
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2014-12-16
Mannkind Corporation
Dry powder inhaler and system for drug delivery
US9662461B2
( en )
2008-06-13
2017-05-30
Mannkind Corporation
Dry powder drug delivery system and methods
US9364619B2
( en )
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Interactive apparatus and method for real-time profiling of inhalation efforts
US10675421B2
( en )
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US9943571B2
( en )
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Use of ultrarapid acting insulin
US9526764B2
( en )
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( en )
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( en )
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Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol
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