EP1250126A2 - Distribution transepitheliale de derives de glp-1 - Google Patents

Distribution transepitheliale de derives de glp-1

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Publication number
EP1250126A2
EP1250126A2 EP01900109A EP01900109A EP1250126A2 EP 1250126 A2 EP1250126 A2 EP 1250126A2 EP 01900109 A EP01900109 A EP 01900109A EP 01900109 A EP01900109 A EP 01900109A EP 1250126 A2 EP1250126 A2 EP 1250126A2
Authority
EP
European Patent Office
Prior art keywords
glp
lys
arg
xaa
spacer
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Withdrawn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
EP01900109A
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German (de)
English (en)
Inventor
Keith Anderson
Henrik Agerso
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1250126A2 publication Critical patent/EP1250126A2/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Withdrawn legal-status Critical Current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
    • A61K9/0012—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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • GLP-1 and analogues have been well- characterised over recent years. There is little doubt that the development of a pharmaceutically useful form of GLP-1 , or an analogue thereof, would result in a valuable addition to the available chemotherapeutic products for the treatment of diabetes and other metabolic disorders. It has been made clear that certain fatty-acyl derivatives of GLP-1 are prone to non- covalent self-association, which can lead to clinical failure (cf. Clodfelter DK et al. Effects of non-covalent self-association on the subcutaneous absorption of a therapeutic peptide. Pharm Res 15(2) (1998) 254-262).
  • the present invention relates to a new formulation comprising a stabilized GLP-1 compound, such as an analog, fragment or derivative thereof for delivery across pulmonary tissue in vivo.
  • a family of fatty-acylated GLP-1 compounds can be solubi- lized to a very high degree in water without formation of insoluble physical aggregates (> 5 mg/mL), are stable in solution without the requirement of additional stabilizing excipients in the formulation (eg. surfactants, cyclodextrins, etc.), are physically stable in solution in the presence of external stresses such as during exposure to high shear encountered during jet or ultrasonic nebulisation and are physically stable without forming insoluble aggregates or fibrillated products over time, and are metabolicly stable. Further, the solution structure of these candidates allow for simple formulation design changes to control pulmonary absorp- tion rates, thus having features which allow optimisation of drug delivery.
  • a pulmonary dosage form of a GLP-1 compound whereto is attached a lipo- philic substituent optionally via a spacer represents a non-invasive means of protein drug de- livery without the inconvenience and health/environmental risks associated with traditional injectable, needle-based medications.
  • permeability enhancers or absorption promoters are viewed as potentially toxic agents and will require much documentation to prove that they represent no potential harm to human subjects, especially when concerning such sensitive tissues as in the lung.
  • One class of potentially approvable enhancers are the protease inhibitors, however they are often required in excessive amounts to improve the delivery efficiency (cf. Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Del Rev 35 (1999) 235-247).
  • Gly 8 -GLP-1 (7-37) designates a peptide which relates to GLP-1 (1-37) by the deletion of the amino acid residues at positions 1 to 6 and the substitution of the naturally occurring amino acid residue in position 8 (Ala) with Gly.
  • Lys 34 (N ⁇ -tetradecanoyl)-GLP-1(7-37) designates GLP-1 (7-37) wherein the ⁇ -amino group of the Lys residue in position 34 has been tetradecanoylated.
  • the present invention relates to a new formulation for use in a pulmonary device, comprising a soluble and, solution stabilized, metabolic stabilized, and/or stress stabilized GLP-1 compound for delivery across pulmonary tissue in vivo.
  • the present invention relates to a method for preparing a formulation for use in a pulmonary device, said formulation comprising a soluble and, solution stabilized, metabolic stabilized, and/or stress stabilized GLP-1 compound for delivery across pulmonary tissue in vivo.
  • Typical, soluble GLP-1 compounds are compounds that, within the pH range of 4-9, within a temperature range of 0-50°C, in isotonic buffered solutions, at concentrations in solution representing no less than a 1 :1 potency:bioavailable dose ratio when compared to na- tive GLP-1 , demonstrate no formation of insoluble aggregates (or insoluble material), according to techniques acceptable in the art.
  • Typical, solution stabilized GLP-1 compounds are compounds, which, in the presence of no stabilizing excipients (e.g. surfactants, cyclodextrins, etc.), within the pH range of 4-9, within a temperature range of 0-50°C, in isotonic buffered solutions, after storage of at least 3 months, demonstrate the presence of:
  • no stabilizing excipients e.g. surfactants, cyclodextrins, etc.
  • Typical, metabolic stabilized GLP-1 compounds are compounds, which demonstrate, after introduction into mammals within the therapeutic window, terminal plasma half-lives of greater than 1 hour, as measured by techniques acceptable in the art.
  • Typical, stress stabilized GLP-1 compounds are compounds which maintain > 75% of initial bioactivity after exposure to conditions associated with manufacturing processes, de- livery processes, handling or storage conditions, as measured by techniques acceptable in the art.
  • the therapeutic window is a range of drug concentrations within which the probability of the desired clinical response is relatively high and the probability of unacceptable toxicity is relatively low. Evans, WE ed., Applied Pharmacokinetics : Principles of Therapeutic Drug Monitoring, 3 rd ed, Ch 1-3, 1992.
  • a way of preparing a soluble and, solution stabilized, metabolic stabilized, and/or stress stabilized GLP-1 compound ideal for delivery across pulmonary tissue in vivo is by modifying the structure of a GLP-1 analogue by introducing a lipophilic substituent optionally via a spacer.
  • a spacer is present.
  • the present invention relates to a pulmonary liquid or dry formulation comprising a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • the present invention relates to a method for preparing a pulmonary liquid or dry formulation for use in a pulmonary device, said formulation comprising a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • the present invention relates to a pulmonary delivery device comprising a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • the present invention relates to a method for preparing a pulmonary delivery device, said device comprising a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • the present invention relates to a method of reducing blood glu- cose levels, treating diabetes type I, diabetes type II or obesity, or inhibiting gastric acid secretion, or inhibiting apoptosis of ⁇ -cells, comprising administering to a patient in need thereof an effective amount of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer, by inhalation so as to deposit said GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer in the lungs of the patient.
  • the present invention relates to a method of treating gastric ulcers comprising administering to a patient in need thereof an effective amount of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer, by inhalation so as to deposit said GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer in the lungs of the patient.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for reducing blood glucose levels.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for treating diabetes type I.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for treating diabetes type II.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for treating obesity.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for treating gastric ulcers.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary liquid or dry formulation for inhibition of apoptosis of ⁇ -cells.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for reducing blood glucose levels.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for treating diabetes type I.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for treating diabetes type II.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for treating obesity. In a further aspect the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for treating gastric ulcers.
  • the present invention relates to use of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer for the preparation of a pulmonary delivery device for inhibition of apoptosis of ⁇ -cells.
  • the lipophilic substituent may be attached to an amino group of the GLP-1 compound by means of a carboxyl group of the lipophilic substituent which forms an amide bond with an amino group of the amino acid residue to which it is attached.
  • the lipophilic substituent may be attached to said amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue.
  • the lipophilic substituent may be linked to the GLP-1 compound via an ester bond.
  • the ester can be formed either by reaction between a carboxyl group of the GLP-1 compound and a hydroxyl group of the substituent-to-be or by reaction between a hydroxyl group of the GLP-1 compound and a carboxyl group of the substituent- to-be.
  • the lipophilic substituent can be an alkyl group which is introduced into a primary amino group of the GLP-1 compound.
  • the lipophilic substituent may be attached to the GLP-1 compound by means of a spacer in such a way that a carboxyl group of the spacer forms an amide bond with an amino group of the GLP-1 compound.
  • a spacer must contain at least two functional groups, one to attach to a functional group of the lipophilic substituent and the other to a functional group of the parent GLP-1 peptide. Examples of suitable spacers are succinic acid, lysyl, glutamyl, asparagyl, glycyl, beta-alanyl and gamma-aminobutanoyl, or a dipeptide such as Gly-Lys, each of which constitutes an individual embodiment.
  • one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may form an amide bond with an amino group of the lipophilic substituent.
  • the spacer is lysyl, glutamyl, asparagyl, glycyl, beta-alanyl or gamma-aminobutanoyl
  • the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue
  • the amino group thereof may form an amide bond with a carboxyl group of the lipophilic substituent.
  • a further spacer may in some instances be inserted between the ⁇ -amino group of Lys and the lipophilic substituent.
  • a further spacer is succinic acid which forms an amide bond with the ⁇ -amino group of Lys and with an amino group present in the lipophilic substituent.
  • such a further spacer is Glu or Asp which forms an amide bond with the ⁇ -amino group of Lys and another amide bond with a carboxyl group present in the lipophilic substituent, that is, the lipophilic substituent is a N ⁇ -acylated lysine residue.
  • the spacer is an amino acid residue except Cys or Met, or a dipeptide such as Gly-Lys.
  • a dipeptide such as Gly-Lys means any combination of two amino acids except Cys or Met, preferably a dipeptide wherein the C-terminal amino acid residue is Lys, His or Trp, preferably Lys, and the N-terminal amino acid residue is Ala, Arg, Asp, Asn, Gly, Glu, Gin, lie, Leu, Val, Phe, Pro, Ser, Tyr, Thr, Lys, His and Trp.
  • an amino group of the GLP-1 compound forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer
  • an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.
  • Examples of such GLP-1 compounds whereto is attached one or more lipophilic substituents optionally via a spacer have been disclosed in e.g EP 0708179, WO 98/08871 , WO 99/43705, WO 99/43706, WO 99/43707, WO 99/43708, WO 99/43341 , which are incorporated herein by reference.
  • the GLP-1 compounds whereto is attached one or more lipophilic substituents optionally via a spacer are useful in treatment of diabetes mellitus (types I or II) and prevention of hyperglycaemia, as well as in treatment of obesity, or gastric ulcers, or in inhibition of apoptosis of ⁇ -cells, upon administering to a patient in need thereof an effective amount of a pulmonary formulation comprising a stabilized GLP-1 compound by inhalation so as to deposit said stabilized GLP-1 compound in the lungs of the patient.
  • exendin-3 and -4 and fragments are useful in treatment of diabetes mellitus (types I or II) and prevention of hyperglycaemia. They normalise hyperglycaemia through glucose-dependent, insulin-independent and insulin- dependent mechanisms.
  • Exendin-4 is specific for exendin receptors, i.e. it does not interact with vasoactive intestinal peptide receptors.
  • WO 9746584 describes truncated versions of exendin peptide(s) for treating diabetes. The disclosed peptides increase secretion and biosynthesis of insulin, but reduce those of glucagon. The truncated peptides can be made more economically than full length versions.
  • the GLP-1 compound is GLP-1 (7-37) or GLP-1 (7- 36) amide.
  • the GLP-1 compound is exendin or an ana- log thereof.
  • the GLP-1 compound whereto is attached a lipophilic substituent via a spacer is Arg 34 Lys 26 (N ⁇ -( ⁇ -glutamyl(N ⁇ -hexadecanoyl)))-GLP-1(7- 37)-OH.
  • the GLP-1 compound whereto is attached a lipophilic substituent via a spacer is Arg 18 , Leu 20 , Gin 34 , Lys 33 (N ⁇ -( ⁇ -aminobutyroyl(N ⁇ - hexadecanoyl))) Exendin-4-(7-45)-NH 2 .
  • the GLP-1 compound whereto is attached a lipophilic substituent via a spacer is Arg 33 , Leu 20 , Gin 34 , Lys 18 (N ⁇ -( ⁇ -aminobutyroyl(N ⁇ - hexadecanoyl))) Exendin-4-(7-45)-NH 2 .
  • the GLP-1 compound is a GLP-1 analogue.
  • the GLP-1 analogue is selected from the Thr 8 , Met 8 , Gly 8 and Val 8 analogues of GLP-1 (7-37) and GLP-1 (7-36) amide, more preferred the Gly 8 and Val 8 analogues of GLP-1 (7-37) and GLP-1 (7-36) amide, most preferred the Val 8 analogues of GLP-1 (7-37) and GLP-1 (7-36) amide.
  • the GLP-1 analogue has the formula II:
  • Xaa at posit on 8 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, Met, or Lys
  • Xaa at posit on 9 is Glu, Asp, or Lys
  • Xaa at posit on 11 is Thr, Ala, Gly, Ser, Leu, lie, Val, Glu, Asp, or Lys
  • Xaa at positi on 18 Ser, Ala, Gly, Thr, Leu, lie,
  • the amino acids at positions 37-45 are absent.
  • the amino acids at positions 38-45 are absent. In another embodiment of the GLP-1 analogue of formula II, the amino acids at posi- tions 39-45 are absent.
  • Xaa at position 8 is Ala, Gly, Ser, Thr, Met, or Val.
  • Xaa at position 8 is Gly, Thr, Met, or Val.
  • Xaa at position 8 is Val.
  • Xaa at position 9 is Glu.
  • Xaa at position 11 is Thr.
  • Xaa at position 14 is Ser.
  • Xaa at position 16 is Val.
  • Xaa at position 17 is Ser.
  • Xaa at position 18 is Ser, Lys, Glu, or Asp.
  • Xaa at position 19 is Tyr, Lys, Glu, or Asp.
  • Xaa at position 20 is Leu, Lys, Glu, or Asp.
  • Xaa at position 21 is Glu, Lys, or Asp.
  • Xaa at position 22 is Gly,
  • Xaa at position 23 is Gin, Glu, Asp, or Lys.
  • Xaa at position 24 is Ala, Glu, Asp, or Lys.
  • Xaa at position 25 is Ala, Glu, Asp, or Lys.
  • Xaa at position 26 is Lys, Glu, Asp, or Arg.
  • Xaa at position 27 is Glu
  • Xaa at position 30 is Ala, Glu, Asp, or Lys.
  • Xaa at position 31 is Trp, Glu, Asp, or Lys.
  • GLP-1 analogue of formula Xaa at position 32 is Leu, Glu, Asp, or Lys.
  • Xaa at position 33 is Val, Glu, Asp, or Lys.
  • Xaa at position 34 is Lys,
  • Xaa at position 35 is Gly, Glu, Asp, or Lys.
  • Xaa at position 36 is Arg, Lys, Glu, or Asp.
  • Xaa at position 37 is Gly, Glu, Asp, or Lys.
  • Xaa at position 38 is Arg, or Lys, or is deleted. In another embodiment of the GLP-1 analogue of formula I, Xaa at position 39 is de- leted.
  • Xaa at position 40 is de- leted.
  • Xaa at position 42 is de- leted.
  • Xaa at position 43 is de- leted.
  • Xaa at position 44 is deleted.
  • Xaa at position 45 is deleted.
  • Xaa at position 26 is Arg, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1 (7-36).
  • Xaa at position 26 is Arg
  • each of Xaa at positions 38-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-37).
  • Xaa at position 26 is Arg
  • each of Xaa at positions 39-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at position 34 is Arg
  • each of Xaa at positions 37-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-36).
  • Xaa at position 34 is Arg, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1 (7-37).
  • Xaa at position 34 is Arg, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at positions 26 and 34 is Arg
  • Xaa at position 36 is Lys
  • each of Xaa at positions 37-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-36).
  • Xaa at positions 26 and 34 is Arg
  • Xaa at position 36 is Lys
  • each of Xaa at positions 38-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-37).
  • Xaa at positions 26 and 34 is Arg
  • Xaa at position 36 is Lys
  • each of Xaa at positions 39-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at positions 26 and 34 is Arg
  • Xaa at position 38 is Lys
  • each of Xaa at positions 39-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at position 8 is Thr, Ser, Gly, or Val
  • Xaa at position 37 is Glu
  • Xaa at position 36 is Lys
  • each of Xaa at positions 38- 45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-37).
  • Xaa at position 8 is Thr, Ser, Gly, or Val
  • Xaa at position 37 is Glu
  • Xaa at position 36 is Lys
  • each of Xaa at positions 39- 45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at position 8 is Thr, Ser, Gly or Val
  • Xaa at position 37 is Glu
  • Xaa at position 38 is Lys
  • each of Xaa at positions 39- 45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-38).
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at positions 26 and 34 is Arg
  • each of Xaa at positions 38-45 is deleted
  • each of the other Xaa is the amino acid in native GLP-1 (7-37).
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at positions 26 and 34 is Arg
  • each of Xaa at positions 39-45 is deleted
  • each of the other Xaa is the amino acid, in native GLP-1 (7-38).
  • Xaa at position 8 is Thr, Ser, Gly, or Val
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at position 26 and 34 is Arg
  • each of Xaa at positions 37-45 is deleted
  • each of the other Xaa is the amino acid in native GLP- 1(7-36).
  • Xaa at position 8 is Thr, Ser, Gly, or Val
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at position 26 and 34 is Arg
  • each of Xaa at positions 38-45 is deleted
  • each of the other Xaa is the amino acid in native GLP- 1(7-37).
  • Xaa at position 8 is Thr, Ser, Gly, or Val
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at position 26 and 34 is Arg
  • each of Xaa at positions 39-45 is deleted
  • each of the other Xaa is the amino acid in native GLP- 1(7-38).
  • Such GLP-1 analogues of formula II includes, but is not limited to, Arg 26 -GLP- 1(7-37); Arg 34 -GLP-1(7-37); Lys 36 -GLP-1(7-37); Arg 2634 Lys 36 -GLP-1 (7-37); Arg 2634 Lys 38 GLP-1(7-38); Arg 263 Lys 39 -GLP-1 (7-39); Arg 2634 Lys 40 -GLP-1(7-40); Arg 26 Lys 36 -GLP-1 (7-37); Arg ⁇ Lys ⁇ -GLP- 1(7-37); Arg 26 Lys 39 -GLP-1(7-39); Arg 34 Lys 40 -GLP-1(7-40); Arg 263 Lys 36 ' 39 -GLP-1(7-39); Arg ⁇ Lys ⁇ -GLP-l (7-40); Gly 8 Arg26-GLP-1 (7-37); Gly' ⁇ rg ⁇ -GLP-l (7-37); Val 8 -
  • R 1 , R 2 and R 3 are independently H, lower alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, NH 2 , NH-CO-(lower alkyl), -OH, lower alkoxy having 1 to 6 carbon atoms, halogen, SO 2 -(lower alkyl) or CF 3 , said phenyl is optionally substituted with at least one group selected from NH 2 , -OH, lower alkyl or lower alkoxy having 1-6 carbon atoms, halogen, SO 2 - (lower alkyl), NH-CO-(lower alkyl) or CF 3 , or R and R 2 may together form a bond;
  • Y is a five or six membered ring system selected from the group consisting of:
  • Z is N, O or S
  • said ring system is optionally substituted with one or more functional groups selected from the group consisting of NH 2 , NO 2 , OH, C 1-6 alkyl, C 1-6 alkoxy, halogen (Cl,
  • B is an integer in the range of 35-45;
  • X is -OH, -NH 2 , or a C 1-6 alkyl amide or C 1-6 dialkyl amide group; or an analogue thereof.
  • GLP-1 analogues of formula III includes, but is not limited to
  • Each one of these specific GLP-1 analogues constitutes an alternative embodiment of the invention.
  • the GLP-1 analogue has the formula IV
  • A is a peptide comprising the amino acid residues of GLP-1 (8-18) or a fragment thereof;
  • B is an integer in the range of 35-45;
  • X is -OH, -NH 2 , or a C 1-6 alkyl amide or C ⁇ dialkyl amide group; or an analogue thereof.
  • A is a peptide selected from the group consisting of GLP-1 (8-18), GLP-1 (9-18), GLP-1 (10-18), GLP-1 (11-18), GLP-1 (12-18),
  • A is GLP-1 (8-18), GLP-1 (9-18), GLP-1 (10-18), GLP-1 (11 -18) or GLP-1 (12-18), and
  • B is 36, 37 or 38. Most preferably, A is GLP-1 (8-18). In a further embodiment of the GLP-1 analogue of formula IV, B is 35, 36, 37, 38, 39,
  • B is 36. In another more preferred embodiment. B is 37. In another more preferred embodiment, B is 38.
  • Such GLP-1 analogues of formula IV includes, but is not limited to
  • the lipophilic substituent comprises 4-40 carbon atoms. In a further embodiment of the present invention the lipophilic substituent comprises 8-30 carbon atoms. In a further embodiment of the present invention the lipophilic substituent comprises 8-25 carbon atoms. In a further embodiment of the present invention the lipophilic substituent comprises 12-25 carbon atoms. In a further embodiment of the present invention the lipophilic substituent comprises 14-18 carbon atoms.
  • the lipophilic substituent(s) contain a functional group which can be attached to one of the following functional groups of an amino acid of the parent GLP-1 compound:
  • a lipophilic substituent is attached to the carboxy group of the R group of any Asp and Glu residue. In another embodiment, a lipophilic substituent is attached to the carboxy group attached to the alpha-carbon of the C-terminal amino acid.
  • a lipophilic substituent is attached to the epsilon- amino group of any Lys residue.
  • Each lipophilic substituent contains a functional group which may be attached to a functional group of an amino acid of the parent GLP-1 compound.
  • a lipophilic substituent may contain a carboxyl group which can be attached to an amino group of the parent GLP-1 peptide by means of an amide bond.
  • the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton. In another embodiment, the lipophilic substituent is a straight-chain or branched alkyl group.
  • the lipophilic substituent is an acyl group of a straight-chain or branched fatty acid. In a further embodiment the lipophilic substituent is an acyl group having the formula
  • the lipophilic substituent is selected from the following individual embodiments CH 3 (CH 2 ) ⁇ 2 CO-, CH 3 (CH 2 ) 14 CO-, CH 3 (CH 2 ) ⁇ 6 CO-, CH 3 (CH 2 ) 18 CO-, CH 3 (CH 2 ) 2 oCO- and CH 3 (CH ) 22 CO-.
  • the lipophilic substituent is tetradecanoyl.
  • the lipophilic substituent is hexadecanoyl.
  • the lipophilic substituent has a group which is negatively charged such as a carboxylic acid group.
  • the lipophilic substituent may be an acyl group of a straight-chain or branched alkane ⁇ , ⁇ -dicarboxylic acid of the formula HOOC(CH 2 ) m CO-, wherein m is an integer from 4 to 38, preferably an integer from 12 to 38, and most preferably is HOOC(CH 2 ) ⁇ 4 CO-, HOOC(CH 2 ) 16 CO-, HOOC(CH 2 ) ⁇ 8 CO-, HOOC(CH 2 ) 20 CO- or HOOC(CH 2 ) 22 CO-.
  • the lipophilic substituent is attached to the parent GLP-1 compound by means of a spacer.
  • a spacer must contain at least two functional groups, one to attach to a functional group of the lipophilic substituent and the other to a functional group of the parent GLP-1 compound.
  • the spacer is an amino acid residue except Cys or Met. In another embodiment, the spacer is a dipeptide such as Gly-Lys.
  • the spacer is selected from lysyl, glutamyl, asparagyl, glycyl, beta-alanyl and gamma-aminobutanoyl, each of which constitutes an individual embodiment. Most preferred spacers are glutamyl and beta-alanyl.
  • the spacer is an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, which spacer forms a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.
  • the spacer is succinic acid.
  • the lipophilic substituent with the attached spacer is a group of the formula CH 3 (CH 2 )pNH-CO(CH 2 ) q CO-, wherein p is an integer from 8 to 33, such as from 12 to 28 and q is an integer from 1 to 6, such as 2.
  • the lipophilic substituent with the attached spacer is a group of the formula CH3(CH 2 ) r CO-NHCH(COOH)(CH 2 ) 2 CO-, wherein r is an integer from 4 to 24, such as from 10 to 24.
  • the lipophilic substituent with the attached spacer is a group of the formula CH 3 (CH 2 )sCO-NHCH((CH 2 ) 2 COOH)CO-, wherein s is an integer from 4 to 24, preferably from 10 to 24.
  • the lipophilic substituent is a group of the formula COOH(CH 2 ) t CO- wherein t is an integer from 6 to 24.
  • the lipophilic substituent with the attached spacer is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) u CH 3 , wherein u is an integer from 8 to 18.
  • the lipophilic substituent with the attached spacer is a group of the formula CH 3 (CH 2 ) v CO-NH-(CH 2 ) z -CO, wherein v is an integer from 4 to 24 and z is an integer from 1 to 6.
  • the lipophilic substituent with the attached spacer is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-COCH((CH 2 ) 2 COOH)NH-CO(CH 2 ) w CH 3 , wherein w is an integer from 10 to 16.
  • the lipophilic substituent with the attached spacer is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) 2 CH(COOH)NHCO(CH 2 ) ⁇ CH3, wherein x is zero or an integer from 1 to 22, such as from 10 to 16.
  • GLP-1 means GLP-1 (7-37) or GLP-1 (7-36) amide.
  • the amino acid sequence of GLP-1 is given La. by Schmidt et al. (Diabetologia 28 704-707 (1985).
  • treatment is defined as the management and care of a patient, e.g. a mammal, in particular a human, for the purpose of combating the disease, condition, or disorder and includes the administration of a GLP-1 compound to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • a GLP-1 compound is intended to indicate GLP-1 or an ana- logue or a derivative thereof, or exendin or an analogue or a derivative thereof, which binds to a GLP-1 receptor, preferably with an affinity constant, K D , below 1 ⁇ M, e.g. below 100 nM.
  • GLP-1 compounds are described in WO 93/19175 (Novo Nordisk A/S). Suitable GLP-1 compounds have been disclosed in e.g. WO 87/06941 , WO 90/11296, WO 93/25579, WO 91/11457, EP 0699686, WO 98/43658, EP 0619322, which are incorporated herein by reference.
  • a GLP-1 compound is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and prodrugs of GLP-1 or an analogue or a derivative thereof, or exendin or an analogue or a derivative thereof.
  • a “metabolite” is an active derivative of a GLP-1 compound produced when the GLP-1 compound is metabolized.
  • a “prodrug” is a compound which is either metabolized to a GLP-1 compound or is metabolized to the same metabolite(s) as a GLP-1 compound.
  • an analogue is used to designate a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide.
  • Such addition can take place either in the peptide, at the N-terminal end or at the C- terminal end of the parent peptide, or any combination thereof.
  • derivative is used in the present text to designate a peptide in which one or more of the amino acid residues of the parent peptide have been chemically modified, e.g. by alkylation, acylation, ester formation or amide formation.
  • lipophilic substituent is characterised by comprising 4-40 carbon atoms and having a solubility in water at 20°C in the range from about 0.1 mg/100 ml water to about 250 mg/100 ml water, preferable in the range from about 0.3 mg/100 ml water to about 75 mg/100 ml water.
  • octanoic acid (C8) has a solubility in water at 20°C of 68 mg/100 ml
  • decanoic acid (C10) has a solubility in water at 20°C of 15 mg/100 ml
  • octa- decanoic acid (C18) has a solubility in water at 20°C of 0.3 mg/100 ml.
  • spacer is used in the present text to designate a bivalent moiety which contain at least two functional groups, one to attach to a functional group of the lipophilic substituent and the other to a functional group of the GLP-1 compound.
  • suitable spacers are succinic acid, lysyl, glutamyl, asparagyl, glycyl, beta-alanyl and gamma- aminobutanoyl, or a dipeptide such as Gly-Lys.
  • an effective amount is the effective dose to be determined by a qualified practitioner, who may titrate dosages to achieve the desired response.
  • Factors for considera- tion of dose will include potency, bioavailability, desired pharmacokinetic/pharmacodynamic profiles, condition of treatment (e.g. diabetes, obesity, gastric ulcers), patient-related factors (e.g. weight, health, age, etc.), presence of co-administered medications (e.g. insulin), time of administration, or other factors known to a medical practitioner.
  • an effective amount of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer will range from 0.01 - 1000.0 ⁇ g/kg, more preferably from 0.05 - 500 ⁇ g/kg, even more preferably from 0.1 - 100 ⁇ g/kg, such as from 0.5 - 50 ⁇ g/kg .
  • Ranges of required daily doses would typically include the equivalent of about 0.1- 4.0 inhalations/day.
  • the inhaled GLP-1 compound whereto is at- tached a lipophilic substituent optionally via a spacer is administered once daily and demonstrate bioequivalence to a sub-cutaneous dosage form.
  • the pulmonary formulation is a liquid formulation, such as a solution or a suspension.
  • the pulmonary formulation is a dry formulation.
  • the pulmonary delivery device is selected from nebulizers, such as jet or ultrasonic nebulizers, metered-dose inhalers, or dry powder inhalers. Each of said devices is considered an individual embodiment.
  • aerosol formulations for pulmonary delivery of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer could be designed which minimise the excipient requirements and maximise bioactive delivery of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer to the deep lung (i.e. alveolar tissue), where compounds are known to be predominantly absorbed (cf. Yu J, Chien YW. Pulmonary drug delivery: Physiologic and mechanistic aspects. Crit Rev Ther Drug Carr Sys 14(4) (1997) 395-453).
  • formulations should also be designed in accordance with common pharmaceutical development goals and have features such as, long-term stability and preservation from bacterial or fungal contamination during defined shelf-lives. Additionally, formulations should allow for controlled delivery profiles in order to optimise the pharmacokinetic/pharmacodynamic profile following in vivo pulmonary delivery of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer may be produced by any recognised peptide / protein synthetic, semi-synthetic and/or recombinant DNA techniques.
  • the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer can be delivered in a vehicle, as a solution, suspension, or dry powder and can be administered by any of the known devices suitable for pulmonary drug delivery known in the art.
  • a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer can be administered by any of three general types of aerosol-generating systems for pulmonary drug delivery, and include jet or ultrasonic nebulizers, metered-dose inhalers, or dry powder inhalers (Cf. Yu J, Chien YW. Pulmonary drug delivery: Physiologic and mechanistic aspects. Crit Rev Ther Drug Carr Sys 14(4) (1997) 395-453).
  • MMAD mass median aerodynamic diameter
  • MMEAD mass median effective aerodynamic diameter
  • the aerodynamic diameter (d a ) of a particle is defined as the geometric equivalent diameter of a reference standard spherical particle of unit density (1 g/cm 3 ).
  • d a is related to a reference diameter (d) as a function of the square root of the density ratio as described by:
  • MMAD is normally measured by cascade impactors, which estimate the particle size based on the particle behavior in a high velocity airstream. It is commonly accepted that a MMAD window between 1-3 ⁇ m is optimal for deposition of particles in the deep lung.
  • stable liquid formulations of GLP-1 compounds whereto is attached a lipophilic substituent optionally via a spacer can be designed for nebulisation.
  • Such liquid formulations may contain preservative agents, isotonicty agents, buffering agents, antioxidants, flavorants, or delivery modifying agents so as to improve the shelf-life and performance of formulated products.
  • Preservatives may be required to develop a commercial product for multiple-use.
  • Preservatives may include, but are not limited to, phenolics, such as phenol or m-cresol, benzyl alcohol, chlorobutanol, parabens, quaternary ammonium compounds, thirmerosal, or phenylmercuric salts or combinations thereof. Phenol or m-cresol at concentrations between 2 - 5 mg/mL is preferred as a preservative agent.
  • Pharmaceutically acceptable isotonicity agents may include NaCI, dextrose, manni- tol, lactose, or glycerin.
  • Pharmaceutically acceptable buffering agents for controlling formulation pH may include, but are not limited to, phosphates, citrates, acetates, TRIS, amino acids, or amino acid based salts (e.g. glycylglycine).
  • Pharmaceutically acceptable antioxidants may be included to improve the chemical stability profile of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer. Suitable antioxidants may include, but are not limited to, phenolic compounds (e.g.BHT, BHA, popyl gallate, ⁇ -tocopherol), reducing agents (e.g. methionine, ascorbic acid, sodium sulfite, thioglycerol, thioglycolic acid), or chelating agents (e.g. EDTA, citric acid, or thioglycolic acid).
  • phenolic compounds e.g.BHT, BHA, popyl gallate, ⁇ -tocopherol
  • reducing agents e.g.
  • delivery modifying agents in this context, can include substances which can be added to the formulation in order to improve delivery efficiency of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer to the lower lung, or modify the permeation of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer across the pulmonary epithelium.
  • the added ingredient may: 1) on exposure to an aerosol-generating device, facilitate nebulisation of liquids to achieve particle sizes within the optimum window of 1-3 ⁇ m MMAD, which has been defined as being optimal for deep lung deposition (cf. Edwards DA, Ben-Jebria A, Langer R.
  • Typical formulations for nebulisation would normally include between 0.1 - 100 mg of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer per mL solution. More preferably between 1 - 50 mg protein per mL solution.
  • One liquid formulation for nebulization could include a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer at 5mg/mL, phenol at 5.0 mg/mL, mannitol at 38 mg/mL, and phosphate- buffer adjusted to about pH 7.4 in bacteriostatic water for injection.
  • the liquid formulation could be nebulised by any known nebulisation technology, such as jet or ultrasonic nebulisation, to achieve a MMAD of aerosol particles less than 10 ⁇ m, more preferably between 1-5 ⁇ m, and most preferably between 1-3 ⁇ m.
  • nebulisation technology such as jet or ultrasonic nebulisation
  • An example of a clinically useful nebuliser could be the Maxin® nebuliser developed by Clinova Medical AB (Malmo, Swe).
  • the particle distribution is substantially narrow so as to provide an optimal, reproducible delivery of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer to the lung.
  • the preferred particle size range is based on the most effective size range for delivery of drug to the deep lung, where protein is optimally absorbed.
  • advanced nebulisation techniques such as those provided for by Aradigm Corp. (AERx® system) could be utilised (cf. US 5,934,272; US 5,855,564).
  • the GLP-1 compound whereto is attached a lipophilic sub- stituent optionally via a spacer could be formulated as a dry powder for inhalation.
  • Dry powders have the advantages of room-temperature stability, and high drug payload (e.g. dry powder aerosols contain between 50-95% pure drug) when compared to aqueous formulations for nebulisation, or metered dose inhalers (MDIs), an additional advantage is that DPIs (dry powder inhalers) do not require the co-ordination necessary to operate traditional MDIs (metered dose inhalers) since most are breath activated and are optimally designed to deliver consistent doses independent of inspiratory flow rates over a wide range.
  • MDIs dry powder inhalers
  • Dry powder formulations can be designed to be highly soluble in pulmonary fluid.
  • controlled pulmonary delivery may be achieved by modifying the solubility of the dry powder formulation, modifying the aggregation state of the solubilized GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer, or the dry powder particle size.
  • Additives may be included to facilitate controlled pulmonary delivery, processing and filling of powders, aersoli- sation efficiency of the powder, chemical stabilization, or to provide cosmetic appeal (e.g. flavorants).
  • Examples of processing, filling, and metering methods for developing dry powders for inhalation are provided for in e.g. US 5,874,064, US 5,855,913, WO9829096, WO9829098, WO9829140, WO9829141 , WO9816205, WO9741833, WO 97/41833, US 5,780,014, WO 99/16419, US 5,699,649, US 5,654,007, WO 97/47286, WO 98/13031 , US 5725841 , WO 98/34596, WO 99/36334, WO 98/35888, WO 98/30262.
  • excipients can include, but are not limited to, substances which can be added to the formulation in order to improve dry powder processing, metering, and filling, de- livery efficiency of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer to the lower lung, or modify the permeation of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer across the pulmonary epithelium.
  • the added ingredient may: 1) facilitate processing of dry powders to achieve particle sizes within the optimum window of 1-3 ⁇ m MMAD, which has been defined as being optimal for deep lung deposition (cf. Edwards DA, Ben-Jebria A, Langer R.
  • excipients include, but are not limited to, complexing agents (e.g. divalent metals, cyclodextrins, pro- teins/polypeptides (e.g. albumin, protamine)), phospholipids, glycolipids, glycerides, carbohydrates, surfactants, biocompatible polymers (polyethylene glycols, PLGA derivatives, plu- ronics, methylcellulose derivatives, etc.), salts, amino acids, or, alternatively, small organic molecules as described by Emisphere Technologies (cf. WO 98/25589).
  • Choice and amount of excipients in the formulation would depend primarily on the excipients safety record (i.e. toxicological profile). This safety record would be based on relative systemic and local pulmonary toxicity determinations.
  • no added excipient will adversely affect the airways of a patient.
  • antioxidants may be added to prevent chemical degradation of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer.
  • Suitable antioxidants may include, but are not limited to, phenolic compounds (e.g.BHT, BHA, popyl gallate, ⁇ -tocopherol), reducing agents (e.g. methionine, ascorbic acid, sodium sulfite, thioglycerol, thioglycolic acid), or chelating agents (e.g. EDTA, citric acid, or thioglycolic acid).
  • phenolic compounds e.g.BHT, BHA, popyl gallate, ⁇ -tocopherol
  • reducing agents e.g. methionine, ascorbic acid, sodium sulfite, thioglycerol, thioglycolic acid
  • chelating agents e.g. EDTA, citric acid, or thioglycolic acid.
  • dry powders for inhalation would contain between 50 - 100 %, more preferably between 75-100%, and most preferably between 90 - 100% GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer on a w/w basis.
  • the dry powder formulation should be designed to contain a MMAD of aerosol particles less than 10 ⁇ m, more preferably between 1-5 ⁇ m, and most preferably between 1-3 ⁇ m.
  • the particle distribution is substantially narrow so as to provide an optimal, reproducible delivery of GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer to the lung.
  • the preferred particle size range is based on the most effective size range for delivery of drug to the deep lung, where protein is optimally absorbed.
  • the defined optimal particle size range of the protein powders may be obtained by any conventional method know to those skilled in the art, such as spray-drying, spray-coating, jet-milling, extrusion, micronization, lyophilisation, solution condensation, or the like
  • the above particles may be supplied to the aerosol-generating device as redisper- sable aggregates or agglomerates in order to improve the powder handling characteristics, for example during filling of unit dose blister packs.
  • Aggregates, agglomerates, or granules may be formed by techniques known in the art, for example formation of a wetted particle mass with a binding solvent, extrusion of wetted mass through fine mesh screens (ca. 40 - 650 ⁇ m), and subsequent drying, sieving, and optional spheronization steps. Examples of such processes used in protein formulations are provided for in e.g. WO 99/48476, US 5,780,014 and US 5,654,007, and are recognised in the art.
  • Formation of aggregates, agglomerates, granules or the like may include the use of non aqueous solvents such as, a flu- rocarbon (e.g. perfluorodecalin, perfluorooctylbromide), toluene, xylene, benzene, acetone, hexane, octane, chloroform and methylene chloride.
  • a flu- rocarbon e.g. perfluorodecalin, perfluorooctylbromide
  • toluene xylene
  • benzene benzene
  • acetone hexane
  • octane chloroform
  • methylene chloride e.g. perfluorodecalin, perfluorooctylbromide
  • Packaging of drug product is typically done in unit dose blisters or cartridges, and is completed by techniques know in the art.
  • Embodiments of devices suitable for dry powder pulmonary delivery of a GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer include, but are not limited to, devices provided for by 3M, Inhale Therapeutic Systems, Advanced Inhalation Technology Corp., Dura Pharmaceuticals (e.g. Spiros® device), Astra Pharmaceuticals (e.g Turbuhaler® device), Glaxo (e.g. rotahaler® or diskhaler® device), Fisons (e.g. spinhaler® device) or MicroDose Technologies, of which some examples are provided for in e.g. WO 96/32149, US 5,655,523, US 5,645,051 , US 5,622,166, US 5,577,497, US 5,492,112, US 5,327,883, US 5,277,195 and US 5,694,920.
  • 3M Inhale Therapeutic Systems, Advanced Inhalation Technology Corp.
  • Dura Pharmaceuticals e.g. Spiros® device
  • Astra Pharmaceuticals e
  • the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer may be formulated for use with conventional metered dose inhalers (MDIs).
  • MDIs can usually deliver higher concentrations of active over shorter periods of time when compared to nebulised solutions.
  • Formulations prepared for MDIs are typically finely dispersed powders, which are suspended in non-aqueous propellant solutions.
  • a solution aerosol can be made by including organic co-solvents, such as ethanol.
  • Propellents used can be chosen from common materials such as, chlorofluorcarbons, hydrochlorofluorocarbons, hydrofluro- carbons, or hydrocarbons.
  • the propellant is chosen to be more environmentally friendly, such as the hydrofluorocarbons.
  • additional excipients may be necessary to stabilise the dispersed powder suspension, to prevent chemical degradation, or to optimise the delivery of the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer in a finely dispersed form.
  • the particle size fractions delivered from the MDI device will ideally have an MMAD of ⁇ 10 ⁇ m, more preferably between 1-5 ⁇ m, and most preferably between 1-3 ⁇ m.
  • Examples of formulations and devices for MDIs are provided for in WO 97/47286, WO 98/13031 , US 5725841 , WO 98/34596, WO 99/36334, WO 98/35888, WO 98/30262.
  • Pigs Loaded x Yorkshire x Duroc, mean weight ca. 20kg
  • the nebulizer was attached in line on the inspiratory side of the ventilation circuit using a T-piece.
  • MMAD of aerosol particles were between 4.3 - 4.8 ⁇ m.
  • Plasma GLP-1 levels were assessed using a validated immunoassay. The results showed that the GLP-1 compound whereto is attached a lipophilic substituent optionally via a spacer (e.g. Arg 34 Lys 26 (N ⁇ -( ⁇ -glutamyl(N ⁇ -hexadecanoyl)))-GLP-1 (7- 37)-OH, referred to as Acyl-GLP-1) was absorbed in vivo via pulmonary delivery.
  • a spacer e.g. Arg 34 Lys 26 (N ⁇ -( ⁇ -glutamyl(N ⁇ -hexadecanoyl))

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Abstract

L'invention concerne une nouvelle formulation comprenant un composé stabilisé de GLP-1, tel qu'un analogue, un fragment ou un dérivé de celui-ci, destiné à être distribué in vivo à travers un tissu pulmonaire.
EP01900109A 2000-01-11 2001-01-11 Distribution transepitheliale de derives de glp-1 Withdrawn EP1250126A2 (fr)

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