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WO1994018996A1 - Procede d'administration de peptides liberant l'hormone de croissance - Google Patents

Procede d'administration de peptides liberant l'hormone de croissance Download PDF

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Publication number
WO1994018996A1
WO1994018996A1 PCT/US1994/001751 US9401751W WO9418996A1 WO 1994018996 A1 WO1994018996 A1 WO 1994018996A1 US 9401751 W US9401751 W US 9401751W WO 9418996 A1 WO9418996 A1 WO 9418996A1
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WO
WIPO (PCT)
Prior art keywords
growth hormone
peptide
trp
phe
hormone releasing
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.)
Ceased
Application number
PCT/US1994/001751
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English (en)
Inventor
Philip Lawrence Smith
Glynn Wilson
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO1994018996A1 publication Critical patent/WO1994018996A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Definitions

  • This invention relates to a method of administering growth hormone releasing peptides to cause the systemic release of growth hormone in a mammal.
  • GH Growth Hormone
  • a mediator released from the pituitary causes physiologic and metabolic changes in the tissues of the body. Effects such as tissue growth, increased rate of protein synthesis, increased mobilization and use of fatty acids for energy, and decreased use of carbohydrates, have been attributed to growth hormone secretion.
  • a deficiency of growth hormone has been associated with certain types of medical disorders, such as certain instances of dwarfism.
  • the current therapy for growth hormone deficiency requires subcutaneous administration of growth hormone because of the limited absorption of growth hormone when administered by other routes. Daugherty et al . , Int . J. Pharmac , 45, 197 (1988); O'Hagen et al . , Pharm . Res .
  • growth hormone is also released in vitro and in vivo by certain small exogenous peptides generically called growth hormone releasing peptides.
  • growth hormone releasing peptides are described, fo instance, in U.S. Patents 4,410,513; 4,839,344; 4,411,890; 4,880,777; and PCT patent application WO 88/09780 (PCT/US88/01947) .
  • These peptides are characterized by specific binding sites in the pituitary and the hypothalamus, and their mechanism of action is distinct from other secretagogues. See Codd et al . , Neuropharmacol., 28, 1139 (1989); Malozowski et al . , J. Clin . Endocrin . Metab . , 73, 31 (1991) .
  • An object of this invention is to provide a method for administering growth hormone releasing peptides to a mammal.
  • a feature of this invention is the systemic delivery of a growth hormone releasing peptide to a mammal by contacting the peptide with lung tissue.
  • this invention is a method for causing the systemic release of growth hormone by contacting a growth hormone releasing peptide with lung tissue. The method of this invention results in enhanced bioavailability of the peptides relative to other nonparenteral routes, and therapeutic blood levels.
  • growth hormone releasin peptides may be conveniently administered by contacting the peptide with lung tissue.
  • His-D-Trp-Ala-Trp-D Phe-Lys-NH 2 GHRP-6
  • GHRP-6 His-D-Trp-Ala-Trp-D Phe-Lys-NH 2
  • pulmonary delivery may circumvent first pass hepatic clearance, and thereby provide a higher initial concentration of the drug in the plasma.
  • pulmonary delivery of growth hormone releasing peptides provide a convenient alternative to subcutaneous administration of growth hormone, and parenteral, oral or nasal administration of growth hormone releasing peptides.
  • the method may be practiced by contacting the growth hormone releasing peptide with lung tissue, optionally in a pharmaceutical carrier.
  • the lung tissue advantageously provides a large epithelial surface area for absorption of the peptide, and provides exceptional systemic absorption of the peptide relative to the nasal or oral routes of administration.
  • the term lung tissue refers to the pulmonary tract, which for the purpose of this invention includes the trachea, bronchioles and alveoli. It is preferred to deliver the peptide to the smaller airways, such as the bronchioles and alveoli.
  • systemic absorption of the growth hormone releasing peptide means that the peptide is translocated to the circulating blood which nourishes the various tissues of the body. Upon reaching the pituitary, the peptide then stimulates the systemic release of growth hormone, e . g. , into the circulating blood.
  • the peptide may be delivered optionally in a pharmaceutical carrier, such as a sterile solution, suspension or emulsion.
  • Suitable carriers include diluents, such as aqueous solutions, which may include excipients such as stabilizers, permeability enhancers and solubilizing agents.
  • Suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Suitable excipients are found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, Gennaro, A. (ed.). Mack Publishing Co., Easton, Pennsylvania, 1985.
  • Illustrative of such excipients are methanol, ethanol, ascorbic acid, oleic acid, sorbitan trioleate and cetyl pyridinium.
  • Such liquid solutions, suspensions and emulsions may be delivered to the lung tissue by instillation spray or, particularly by a nebulized mist.
  • a metered dose inhaler may be used to deliver the peptide by mouth during inspiration.
  • the peptide may be delivered by aerosol.
  • the peptide may be suspended or dissolved in a suitable halocarbon and propelled into the lung via the mouth.
  • suitable halocarbon propellants are trichlorofluoromethane (Freon 11) , dichlorodifluoromethane (Freon 12) and dichlorotetrafluoroethane (Freon 114) .
  • the growth hormone releasing peptide may be formulated as a dry powder, such as a micronized powder.
  • the dry powder may be injected into the lung by using a carrier such as a compressed gas, for instance compressed air.
  • a carrier such as a compressed gas, for instance compressed air.
  • Suitable devices for instilling, aerosolizing, nebulizing or propelling the peptide into the lung are well known in the art.
  • the peptide is administered to the mammal, in a manner such that the concentration of growth hormone releasing peptide in the plasma is sufficient to cause the release of growth hormone.
  • the peptide is administered in an amount effective to cause the release of a therapeutic amount of growth hormone.
  • the peptide is administered one to four times daily as is indicated by the effect being sought and the condition of the mammal. The determination of the prope dose will be within the ordinary skill of the practitioner. A dosage near the lower end of the useful r***mge of the particular compound may be employed initially and the dosage increased as indicated from the observed response.
  • the peptide is generally administered at a dose between about 0.01 ⁇ g/kg to about 10 mg/kg in a manner consistent with the condition of the subject, route of administration and specie being treated.
  • 0.1 ⁇ g/kg to 0.5 mg/kg is a typical intrapulmonary dose; and 0.5 to 100 mg/kg is more typical fo a human.
  • cows, pigs and humans require about the same dosages, while rats and dogs require a somewhat higher dose.
  • Growth hormone releasing peptides is intended to mean a peptide of 10 or fewer amino acids which act directly on the pituitary to cause the release of growth hormone via the same mechanism of action as His-D-Trp-Ala- Trp-D-Phe-Lys-NH2-
  • Illustrative growth hormone releasing peptides are disclosed, for instance, in U.S.
  • a particular useful subgenus of growth hormone releasing peptides for use in this invention are peptides of 6-9 amino acids which include the sequence -AA1-Ala-AA2- (D-Phe) -, wherein AAl and AA2 are aromatic amino acids.
  • AAl is D- Trp(R 2 ), D-Nal or D-Phe (R 2 ) ;
  • AA2 is Nal (R 2 ) , Trp(R 2 ) or Phe(R 2 ); and R 2 is H, F, Cl, Br, I or N0 2 .
  • the following peptides are representative:
  • amino acid indicates especially the natural D- or L ⁇ -amino acids, Nal (naphthylalanine; ⁇ -Nal is 2- naphthylalanine) and the synthetically available aromatic ⁇ - amino acids.
  • An aromatic amino acid is one having a phenyl, naphthyl or indole sidechain which may be substituted at any stable position on the aromatic moiety by halogen or nitro.
  • R 2 indicates a substituent on the aromatic moiety of an aromatic amino acid.
  • ImAc refers to 4-imidazole acetic acid. Amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Bioche . , 158, 9 (1984) .
  • the growth hormone releasing peptide is formulated as an acid addition salt, basic addition salt or neutral species, including a zwitterionic species.
  • Typical acid addition salts are acetate, mesylate, hydrochloride, sulfate and the like.
  • Alkali metal salts, ammonium salts an organic amine salts are typical basic addition salts.
  • the peptide is provided in a buffered form, so that it has a solution pH of between about 4.5 to 6.5; more preferably about 5.0 to 6.0.
  • Growth hormone releasing peptides were prepared by standard solid phase peptide techniques, such as those disclosed in U.S. Patent 4,411,890, Stewart and Young, SOLID PHASE PEPTIDE SYNTHESIS, 2nd Ed., Pierce Chemical Co., Rockford, IL, 1984, and Bodansky et al . , PEPTIDE SYNTHESIS, 2nd Ed., John Wiley & Sons, New York, N.Y., 1976. Peptides were dissolved in 7 mM acetate buffer to give a final concentration of 0.05 to 0.6 mg/ml and pH 5.5. Intratracheal dosing of GHRP-6 in dogs
  • GHRP-6 Intravenously (0.5 ml/kg) as a bolus into the cephalic vein.
  • GHRP-6 (1 mg/kg in a volume of 3 ml) was administered intratracheally.
  • Beagles were fasted with free access to water for 18 hr prior to dosing. With each dosing regimen, animals were anesthetized with Diprivan® ( ⁇ 6 mg/kg intravenously, duration of anesthesia 5-15 min) .
  • Blood samples were taken from an indwelling catheter placed in the cephalic vein of the foreleg. Intratracheal dosing was accomplished by intubating animals with an endotracheal tube (7.5 mm). A 10 french stomach catheter was inserted through the endotracheal tube to approximately the bifurcation and dosing solution was administered and followed by 60 cc of ai to clear the catheter and large airways. The catheter and endotracheal tube were removed. Blood samples (3 ml) were collected into heparinized tubes at the following times: 0, 1, 3, 5, 10, 15, 30, 45, 60, 120, 180, 240, 300 and 360 min for intravenous administration and 0, 5, 10, 15, 30, 45, 60, 120, 180, 240, 300 and 360 min for intratracheal administration. Blood samples were immediately placed on ice, centrifuged and plasma stored at -80°C.
  • a suture was placed under the jugular proximal and distal to the clavicle, an incision was made in the vein, Silastic tubing (Dow Corning, Midland, MI, 0.020 i i.d.) was inserted in the proximal section approximately 2.5 cm and secured with a suture.
  • Silastic tubing (Dow Corning, Midland, MI, 0.020 i i.d.) was inserted in the proximal section approximately 2.5 cm and secured with a suture.
  • a trocar was employed to provide a route along the skin to an incision through the nape of the neck through which the catheter was inserted. The trocar was removed leaving the catheter exposed, and the incision was closed with wound clips. The catheter was then filled with 50% dextrose containing heparin (200 units/ml) and plugged with a stainless steel pin. Approximately 18 h prior to experimentation, food was removed (free access to water) .
  • rats were anesthetized with sodium pentobarbital (50 mg/kg) diluted with 0.9% saline to a final volume of 1 ml.
  • Intratracheal administration of pep ⁇ tide solutions was accomplished by spray injection into the trachea via the mouth using a modified gavage needle (miniature sprayer, Pen Century, Philadelphia, PA) for peptides (2) to (5) .
  • a modified gavage needle miniature sprayer, Pen Century, Philadelphia, PA
  • peptide (1) upon verification of loss of pain reflex, the rat was positioned supine, and a 1 cm incision was made on the ventral surface of the neck directly above the sternum. Blunt dissection was employed to clear the connective tissue and the salivary glands were gently separated. The two halves of the sternohyoid muscle exposed were separated and retracted laterally exposing the trachea.
  • the peptide was administered by direct intratracheal injection followed by 2 cc of air. Upon removal of the needle, a drop of surgical glue was placed at the injection site and the incision closed with surgical clips.
  • Plasma growth hormone levels were determined by radioimmunoassay (Nelson et al . , Life Sci . , 48, 2283 (1991)) using reagents obtained from Dr. A.F. Parlow, Pituitary Hormones and Antisera Center, Torrence, CA (anti-rat growth hormone-S-5) and from Chemicon, Temecula, CA (cold growth hormone. No.
  • Plasma concentrations of GHRP-6 in dog were determined by radioimmunoassay using antiserum raised in rabbits to the imidazoleacetic acid analog of GHRP-6 conjugated through the ⁇ -NH of lysine with glutaraldehyde to ovalbumin.
  • a radioiodinated tracer was prepared by reacting GHRP-6 with mono-iodinated Bolton-Hunter reagent (1 mCi, 0.1 M borate buffer, pH 8.5, A ' C for 15 min) and separating the mixture b reverse-phase HPLC (Zorbax RX, 25 cm x 4.6 mm i.d., 5 ⁇ , 28 acetonitrile in aqueous 0.1% trifluoroacetic acid, 1.5 ml/min) with UV and radio-monitoring. A mono-derivatised product, eluting at approximately 3.5 min was used.
  • Results are presented as means ⁇ 1 ⁇ EM. Lines and slope were calculated using multiple linear regression. Area unde the plasma concentration vs time curves (AUC) from time zero to the last measurable time point (AUCo-t) was calculated by the trapezoidal method (M. Gibaldi and D. Perri, PHARMACOKINETICS, 2nd edition. Marcel Dekker, Inc., N.Y. (1982)) . Bioavailability, F, the fraction of dose absorbed, was calculated using the equation:
  • Plasma concentrations of GHRP-6 following intratracheal administration (1 mg/kg) resulted in peak plasma concentrations of -300 ng/ml between 5 and 15 min post dosing. From the AUC values, the absolute bioavailability o GHRP-6 following intratracheal administration was -43%.
  • Intratracheal administration of growth hormone releasin peptides elicited a rapid growth hormone response beginning at 5 min after dosing, with maximal average blood - 12 -

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Procédé d'administration, par voie intrapulmonaire, d'un peptide libérant l'hormone de croissance.
PCT/US1994/001751 1993-02-19 1994-02-18 Procede d'administration de peptides liberant l'hormone de croissance Ceased WO1994018996A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1992293A 1993-02-19 1993-02-19
US08/019,922 1993-02-19

Publications (1)

Publication Number Publication Date
WO1994018996A1 true WO1994018996A1 (fr) 1994-09-01

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PCT/US1994/001751 Ceased WO1994018996A1 (fr) 1993-02-19 1994-02-18 Procede d'administration de peptides liberant l'hormone de croissance

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DIABETES, Volume 20, No. 8, issued August 1971, WIGLEY et al., "Insulin Across Respiratory Mucosae by Aerosol Delivery", pages 552-556. *
JOURNAL OF AEROSOL MEDICINE, Volume 4, issued Fall 1991, LAUBE et al., "Aerosolized Insulin Delivered through the Lungs is Effective in Normalizing Plasma Glucose Levels in Non-Insulin Dependent Diabetic Subjects (NIDD)", page 286. *
LUNG, Supplement, issued 1990, DIETER KOHLER, "Aerosols for Systemic Treatment", pages 677-684. *

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