EP1827381A1 - Produit medical contenant un medicament peptidique de type glucagone a inhaler - Google Patents

Produit medical contenant un medicament peptidique de type glucagone a inhaler

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Publication number
EP1827381A1
EP1827381A1 EP05801482A EP05801482A EP1827381A1 EP 1827381 A1 EP1827381 A1 EP 1827381A1 EP 05801482 A EP05801482 A EP 05801482A EP 05801482 A EP05801482 A EP 05801482A EP 1827381 A1 EP1827381 A1 EP 1827381A1
Authority
EP
European Patent Office
Prior art keywords
dose
medical product
glp
container
medicament dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05801482A
Other languages
German (de)
English (en)
Inventor
Thomas Nilsson
Sven Calander
Alf Niemi
Claes Friberg
Lars Kax
Mattias Myrman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mederio AG
Original Assignee
Mederio AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0402976A external-priority patent/SE0402976L/xx
Application filed by Mederio AG filed Critical Mederio AG
Publication of EP1827381A1 publication Critical patent/EP1827381A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • 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.
  • GLP glucagon-like peptide
  • 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.
  • inhaler devices 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 ⁇ m. Larger particle sizes will easily stick in the mouth and throat and will be swallowed.
  • 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 inertia! properties in air as the particle of interest. If primary particles form aggregates, the aggregates will aerodynamically behave like one big particle in air.
  • 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-I 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.
  • 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-I 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.
  • GLP-I 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 Bl.
  • GLP-I is a relatively small peptide molecule with a great potential for inhalation therapy. Fortunately, provided that the GLP-I 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. Patent No. 6,720,407.
  • 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.
  • 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.
  • 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.
  • the medical product also comprises at least one biologically acceptable excipient.
  • 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 agent exists in dry powder form suitable for administration by inhalation, optionally comprising at least one biologically acceptable excipient.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • GLP active glucagon-like peptide
  • 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.
  • GLP glucagon-like peptide or analogues and derivates thereof
  • stimulation of insulin release suppression of glucagon release and inhibition of gastric emptying.
  • suppression of glucagon release and inhibition of gastric emptying.
  • GLP agent 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: Ri-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-
  • R 1 - is selected from a group consisting of His-, (Lys) ⁇ -His- and Asn-(Glu)s- His-
  • -R 2 is selected from a group consisting of -Pro-Pro-Ser-(Lys)6, -Ser and -Ser- (Lys)e.
  • R3 is selected from a group consisting of Lys and Lys in which the ⁇ - amino group is substituted with a lipophilic substituent, optionally via a spacer.
  • Preferred lipophilic substituents include CH3(CH 2 ) n CO-, wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22, HOOC(CH 2 ) m CO-, wherein m is 10, 12, 14, 16, 18, 20 or 22, and lithochoyl.
  • Preferred optional spacers include an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, an amino acid residue except Cys, and ⁇ -aminobutanoyl.
  • R5 is selected from a group consisting of Lys, Arg, Ala Re is selected from a group consisting of Arg, Lys, Ala
  • R 7 is selected from a group consisting of Arg
  • Lys Rs is selected from a group consisting of Lys
  • Ala Rg is selected from a group consisting of Ala
  • Lys Rio is selected from a group consisting of Lys
  • Gys Arg -Rn is selected from a group consisting of -Arg, -Arg-Gly, -Arg-Cys, -Arg-Gly-
  • GLP agent embodiment is selected from a group consisting of: GLP-I, GLP-I amide, GLP-I (7-36) amide, GLP-I (7-37), [VaF]-GLP-I (7-36) amide, [Val 8 ]-GLP-1 (7-37); [Lys26, ⁇ -NH ⁇ -Glu(N- ⁇ -palmitoyl) ⁇ ] -GLP-I (7-37), GLP-I (9-36) amide, GLP-I (9-37) and GLP-2.
  • GLP-I 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-Ri2-Glu-Gly-Ri3-Ri4-Thr-Ser-Asp-Ri5-Ser-Ser-Tyr-Leu-Glu-Ri6-Ri7-
  • R12 is selected from a group consisting of GIy, Ala, VaI, Leu, He, Ser, Thr ⁇
  • Ri3 is selected from a group consisting of Asp, GIu, Arg, Thr, Ala, Lys, His
  • Ri4 is selected from a group consisting of His, Trp, Phe, Tyr
  • R 1 S is selected from a group consisting of Leu, Ser, Thr, Trp, His, Phe, Asp,
  • VaI, Tyr, GIu, Ala Ri6 is selected from a group consisting of GIy, Asp, GIu, GIn, Asn, Lys, Arg,
  • Rn is selected from a group consisting of His, Asp, Lys, GIu, GIn, Arg
  • Ri8 is selected from a group consisting of GIu, Arg, Ala, Lys
  • Ri9 is selected from a group consisting of Trp, Tyr, Phe, Asp, Lys, GIu, His R20 is selected from a group consisting of Ala, GIu, His, Phe, Tyr, Trp, Arg,
  • R21 is selected from a group consisting of Ala, GIu, Asp, Ser, His
  • R22 is selected from a group consisting of Asp, Arg, VaI, Lys, Ala, GIy, GIu
  • R23 is selected from a group consisting of GIu, Lys, Asp R24 is selected from a group consisting of Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
  • R25 is selected from a group consisting of Thr, Ser, Asp, Trp, Tyr, Phe, Arg,
  • -R26 is selected from a group consisting of -Lys, -Arg, -Thr, -Ser, -GIu, -Asp, - Trp, -Tyr, -Phe, -His, -NH2, -GIy, -Gly-Pro, -Gly-Pro-NH2 or is deleted.
  • GLP agent embodiment has any one of the following sequences: His-R27-R28-Gly-R29-Phe-Thr-R30-Asp-R3i-R32-R33-R34-R35-R36-R37-R38-
  • R39-R40-R41-R42-Phe-Ile-R 4 3-R44-R45-R46-R47-R48-R49-R50-R51-R52-R53-R54-R55-
  • R27 is selected from a group consisting of Ala, GIy, Ser, Thr, Leu, lie, VaI, GIu, Asp, Lys
  • R28 is selected from a group consisting of GIu, Asp, Lys
  • R29 is selected from a group consisting of Thr, Ala, GIy, Ser, Leu, He, VaI,
  • GIu, Asp, Lys R3o is selected from a group consisting of Ser, Ala, GIy, Thr, Leu, He, VaI,
  • R31 is selected from a group consisting of VaI, Ala, GIy, Ser, Thr, Leu, He,
  • Tyr, GIu, Asp, Lys R32 is selected from a group consisting of Ser, Ala, GIy, Thr, Leu, He, VaI,
  • R33 is selected from a group consisting of Ser, Ala, GIy, Thr, Leu, He, VaI,
  • R34 is selected from a group consisting of Tyr, Phe, Trp, GIu, Asp, Lys R35 is selected from a group consisting of Leu, Ala, GIy, Ser, Thr, Leu, He,
  • R36 is selected from a group consisting of GIu, Asp, Lys
  • R37 is selected from a group consisting of GIy, Ala, Ser, Thr, Leu, He, VaI,
  • GIu, Asp, Lys R38 is selected from a group consisting of GIn, Asn, Arg, GIu, Asp, Lys
  • R39 is selected from a group consisting of Ala, GIy, Ser, Thr, Leu, He, VaI,
  • R40 is selected from a group consisting of Ala, GIy, Ser, Thr, Leu, He, VaI,
  • GIu, Asp, Lys R41 is selected from a group consisting of Lys, Arg, GIn, Asp, His
  • R42 is selected from a group consisting of GIn, Asp, Lys
  • R43 is selected from a group consisting of Ala, GIy, Ser, Thr, Leu, He, VaI, GIu, Asp, Lys
  • R44 is selected from a group consisting of Trp, Phe, Tyr, GIu, Asp, Lys R45 is selected from a group consisting of Leu, GIy, Ala, Ser, Thr, He, VaI,
  • R46 is selected from a group consisting of VaI, GIy, Ala, Ser, Thr, Leu, He, GIu, Asp, Lys R47 is selected from a group consisting of Lys, Arg, GIu, Asp, His R48 is selected from a group consisting of GIy, Ala, Ser, Thr, Leu, He, VaI,
  • R49 is selected from a group consisting of Arg, Lys, GIu, Asp, His Rso is selected from a group consisting of GIy, Ala, Ser, Thr, Leu, He, VaI, GIu, Asp, Lys or is deleted
  • R51 is selected from a group consisting of Arg, Lys, GIu, Asp, His or is deleted
  • R52 is selected from a group consisting of Arg, Lys, GIu, Asp, His or is deleted
  • R53 is selected from a group consisting of Asp, GIu, Lys or is deleted
  • R54 is selected from a group consisting of Phe, Trp, Tyr, GIu, Asp, Lys or is deleted
  • R55 is selected from a group consisting of Pro, Lys, GIu, Asp or is deleted
  • R56 is selected from a group consisting of GIu, Asp, Lys or is deleted
  • R57 is selected from a group consisting of GIu, Asp, Lys or is deleted
  • -R58 is selected from a group consisting of -VaI, -GIu, -Asp, -Lys or is deleted
  • GLP-I 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:
  • R59 is selected from a group consisting of H, a linear or branched unsaturated Ci-C ⁇ acyl group, an optionally substituted arylcarbonyl, an optionally cycloalkylcarbonyl, an optionally substituted arylalkylcarbonyl R ⁇ o is selected from a group consisting of Ala, 1-aminoisobutyric acid (Aib), VaI, GIy
  • R ⁇ i is selected from a group consisting of Leu and GIy having a C6-C20 alkyl side chain
  • R ⁇ 2 is selected from a group consisting of Ala, Leu, VaI, He, GIu
  • R ⁇ 3 is selected from a group consisting of GIu, Asp, Asn, GIn, Ala
  • -R ⁇ 4 is selected from a group consisting of -Lys-Asn-Aib-OH, -Lys-Asn-Aib-
  • GLP-I 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 ⁇ 5 is a rigidifying hydrophobic moiety selected from the group consisting of
  • C 1 -CiO alkenoic acid optionally substituted by at least one substituent selected from the group consisting of straight or branched Ci-Ce alkyl, C3-C6 cycloalkyl, aryl and substituted aryl;
  • C5-C14 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, -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 -R ⁇ is selected from a group consisting of -OH, -NH2, -GIy-OH.
  • a GLP agent is selected, which is long-acting following pulmonary delivery.
  • 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.
  • 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.
  • another route of administration such as inhalation.
  • 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.
  • 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.
  • 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.
  • 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.
  • a better way to achieving glycemic control is to administer GLP in relatively small doses in connection with meals.
  • 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).
  • a therapeutically effective insulin dose mass is normally in a range from 100 ⁇ g to 25 mg. Both doses are then administered in a single inhalation.
  • FIGS. 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.
  • 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.
  • 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.
  • 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.
  • a combined therapy comprising GLP and insulin results in better medical status and higher quality of life for the user.
  • 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.
  • AD aerodynamic diameter
  • Particles of this size sediment in the lung provided that the inhalation is deep and not too short.
  • 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.
  • FPF fine particle fraction
  • FPD fine particle dose
  • 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.
  • 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.
  • 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/m 3 ) is too low in parts of the dose for de-aggregation to come about.
  • Ws/m 3 energy density
  • 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/m 3 ) supplied to the dose in a gradual manner.
  • Ws/m 3 energy density
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 medical product of the present invention must be protected from ingress of moisture for a specified in-use period.
  • the container of the medical product of the present invention is not opened until a user performs an inhalation.
  • 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.
  • 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 ⁇ 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 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • 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 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 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.
  • EFID electric field technology
  • 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 generally involves micronizing e.g. by jet milling or spray-drying, freeze-drying, vacuum drying oo
  • 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 ⁇ m in diameter, but with AD less than 5 ⁇ m. 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 ⁇ m 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.
  • MMAD mass median aerodynamic diameter
  • 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.
  • 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 the combined action of the active ingredients.
  • This treatment comes very close to bringing about the natural concentration curve in a healthy subject.
  • 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.
  • additional doses of GLP and/ or insulin may be required in order to control the level of glucose during the day and night.
  • mixing of two or more active agents into a homogenous powder mixture 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.
  • 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 %.
  • RSD dose to dose relative standard deviation
  • separate dry powder dosages of GLP and insulin respectively 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.
  • 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.
  • the separated dosages share a common enclosure onto the dose carrier.
  • a common, 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.
  • FPD fine particle dose
  • At least one excipient is in a formulation where the MMAD of the particles is 10 ⁇ m 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.
  • excipients Besides diluting the potency of the active GLP ingredient(s), excipients contribute to acceptable metering and dose forming properties of the powder mixture.
  • DPI dry powder inhaler device
  • excipients acting as carriers and/ or 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.
  • 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.
  • 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.
  • a delivered fine particle dose (FPD) of the active ingredient administered by inhalation herein is not limited, and may generally be in a range from 10 ⁇ g to 25 mg. Normally, of course, a physician prescribes a proper dose size.
  • 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.
  • 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.
  • 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 0 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.
  • 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.
  • 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 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • a particular embodiment of a sealed high barrier container used in an adapted DPI has the following data: • Container internal volume: 100 mm 3
  • 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.
  • 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 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
  • 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.

Abstract

L'invention concerne un produit médical comprenant pour l'essentiel une dose précise d'un médicament peptidique de type glucagone (GLP) à inhaler, qui est logé dans un récipient étanche à l'humidité hautement hermétique. Ce produit médical peut également renfermer une dose d'insuline. Le récipient est destiné à un inhalateur pour poudre sèche. La dose introduite dans le récipient est conçue pour une administration prolongée par inhalation au fond des poumons, où les principes actifs sont absorbés dans l'organisme. En variante, ce produit médical peut comprendre au moins un excipient acceptable au plan biologique.
EP05801482A 2004-12-03 2005-11-02 Produit medical contenant un medicament peptidique de type glucagone a inhaler Withdrawn EP1827381A1 (fr)

Applications Claiming Priority (3)

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SE0402976A SE0402976L (sv) 2004-12-03 2004-12-03 Medicinsk produkt
US11/049,696 US20060120969A1 (en) 2004-12-03 2005-02-04 Medical product for inhalation containing glucagon-like peptide-1 (GLP-1)
PCT/SE2005/001648 WO2006059939A1 (fr) 2004-12-03 2005-11-02 Produit medical contenant un medicament peptidique de type glucagone a inhaler

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