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WO1999047161A1 - Regulation de l'appetit chez les humains par un compose se liant a un recepteur de peptide de type glucagon - Google Patents

Regulation de l'appetit chez les humains par un compose se liant a un recepteur de peptide de type glucagon Download PDF

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Publication number
WO1999047161A1
WO1999047161A1 PCT/US1999/005571 US9905571W WO9947161A1 WO 1999047161 A1 WO1999047161 A1 WO 1999047161A1 US 9905571 W US9905571 W US 9905571W WO 9947161 A1 WO9947161 A1 WO 9947161A1
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Prior art keywords
receptor
peptide
glucagon
glp
binding compound
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PCT/US1999/005571
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English (en)
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Burkhard Goke
Christoph Beglinger
Thomas R. Coolidge
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Bionebraska, Inc.
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Publication date
Application filed by Bionebraska, Inc. filed Critical Bionebraska, Inc.
Priority to AU30875/99A priority Critical patent/AU3087599A/en
Priority to US09/646,433 priority patent/US6998387B1/en
Publication of WO1999047161A1 publication Critical patent/WO1999047161A1/fr
Priority to US11/348,148 priority patent/US20060128627A1/en

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    • 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
    • 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
    • C07K14/605—Glucagons

Definitions

  • TITLE HUMAN APPETITE CONTROL BY GLUCAGON-LIKE
  • the present invention relates to the field of appetite control, and more particularly to compositions and methods where a glucagon-like peptide affects appetite suppression in humans, especially in humans with diabetes.
  • CCK the first gut peptide proposed to act as a satiety signal (Gutzwiller, J.P. (1994)), has received the major share of interest in human studies reported in the literature.
  • GLP-1 Glucagon-like peptide- 1 (7-36) amide
  • GLP-1 distal gut in response to food intake.
  • GLP-1 has been shown to reduce food intake in rats when administered mtracerebrovent ⁇ cularly, whereas intraperitoneal application of the peptide did not have any effect (Turton M.D. et al., Nature 379:69-72, (1996)).
  • a GLP-1 receptor-specific antagonist was infused mtracerebroventncularly, it blocked endogenous peptide, and thus affected only physiologically active circuits. Blocking endogenous GLP-1 causes healthy, already satiated animals to eat more. Turton and co-workers have, therefore, suggested that intracerebroventicular GLP-1 inhibits feeding in fasted rats (Turton, et al.
  • GLP-1 receptors In animals, expression of GLP-1 receptors has been found m the hypothalamus, the bramstem and in the periventricular area, but not in the cortex. GLP-1 receptors were found m the endocrine pancreas (Horsch, D. et al. Pancreas 14(3):290-294 (1997)), the adipose tissue (Valverde I. et al., Endocrinology 132:75-79 (1993)) and the stomach (Uttenthal, L.O.
  • GLP-1 receptor is present at sites where administration of exogenous GLP-1 appears to cause satiety; however, whether it is a satiety factor has not been confirmed.
  • GLP-1 controls appetite m normal humans
  • the use of GLP-1 to control appetite m diabetics is surprising for several reasons: first, diabetics normally have hyperinsulmemia, which is a
  • GLP-1 major appetite stimulant. Accordingly, there would be an expected major uncertainty whether GLP-1 could counteract this stimulation and deliver appetite control.
  • diabetics are characterized by having hyperglycemia, which in many causes a functional deterioration of the autonomous neural control systems for the GI tract, and in later stages causes structural damage to these systems. Accordingly, there would be an expected major uncertainty whether GLP-1 could have an appetite control function in such diabetics.
  • Another objective of the present invention is to combine GLP-1 or its biologically active analogues with a pharmaceutically acceptable carrier to provide an effective treatment composition for humans for use in appetite control, including in diabetics.
  • a yet further objective of the present invention is to provide a method, means and composition userful by humans to reduce the spontaneous urge for food intake without significant adverse side effect consequences to the person's metabolic balance.
  • a composition comprising a compound which binds to a receptor for glucagon-like peptide- 1, said composition containing an amount of said compound effective to control appetite in a human in combination with a pharmaceutical carrier.
  • a composition comprising a compound which binds to the receptor for glucagon-like peptide- 1 and a pharmaceutical carrier, said composition containing an amount of said compound effective to control appetite in a human. It is especially userful in humans with diabetes.
  • Figure 1 is a graph of daily time course of procedures (see Example 1) carried out in a randomized, double-blind study with 16 healthy men aged 23.6 ⁇ -/5 years/ Dosage treatments of 0.375, 0.75 and 1.5 pmol/kg of GLP-1, separated by at least 7 days, were administered to the 16 subjects for 120 minutes with an intravenous infusion of 5% glucose used as a placebo control.
  • Figure 2 is a graph of subjective sensations of hunger (see Example 1)
  • upper panel 2A and fullness (lower panel 2B) experienced by healthy male subjects before and after food intake during intravenous infusion of 5% glucose or one dose at various dose levels of human GLP-1.
  • Figure 3 is a graph of immunoreactive GLP-1 (IR-GLP-1) measured in the plasma (pmol/1) in response to .graded doses of intravenous GLP-1 (see Example 1).
  • Figure 4 is a graph of plasma CCK levels (pmol/1) (top panel 4A) and insulinogenic index (insulin/glucose) (lower panel 4B) in response to graded doses of GLP-1 (see Example 1).
  • Figure 5 is a graph of plasma leptin concentrations (ng/ml) in response to graded doses of intravenous GLP-1 (see Example 1).
  • Figures 6(A) and (B) show appetite scores (hunger and fullness) for the twelve patients of Example 2.
  • Figures 7(A)-(D) show the plasma glucose, plasma glucagon, and plasma GLP-1 concentrations, as well as insulinogenic index for the 12 patients of Example 2.
  • the inventors have discovered that the administration of graded doses of human GLP-1 produced plasma glucagon-like peptide- 1 concentrations within physiological ranges and resulted in the reduction of intake of food in non-obese, healthy male subjects. Accordingly, the composition of the present invention is useful in therapeutic treatment for reducing food consumption.
  • the present invention provides a composition comprising a compound which binds to a receptor for glucagon-like peptide- 1 which is effective to control appetite and spontaneous food uptake in humans.
  • the receptor-binding compound is glucagon-like peptide- 1.
  • the receptor-binding compound is a variant peptide in which the combination of the substitutions, deletions and variants does not differ by more than five amino acids from glucagon-like peptide- 1.
  • the receptor-binding compound can further comprise a polynucleotide, or an organic molecule having a molecular weight of not greater than about 5000.
  • glucagon-like peptide- 1 includes glucagon-like peptide- 1 related peptides and peptides which result from natural or synthetic enzymatic or chemical processing of glucagon-like peptide-1 related peptides. These peptides include peptides derived from enzymatic or chemical processing of GLP-1 (1-37), GLP-1 (7-37) and GLP-1 (7-36) amide.
  • the composition comprises a receptor-binding compound selected from the group consisting of a peptide which comprises the amino acid sequence of glucagon- like peptide- 1 described above, or a variant peptide comprising an amino acid sequence that varies from the sequence thereof by one or more substitutions, deletions or insertions.
  • the receptor-binding compound is glucagon-like peptide- 1.
  • the receptor-binding compound is a variant peptide in which the combination of the substitutions, deletions and variants does not differ by more than five amino acids from glucagon-like peptide- 1.
  • the receptor-binding compound can also be a polynucleotide or an organic molecule having a molecular weight of not greater
  • the composition preferably comprises a receptor-binding compound selected from the group consisting of a peptide comprising the amino acid sequence of glucagon-like peptide-1, which includes GLP-1 (7-37) and GLP-1 (7-36) amide, and a variant peptide comprising an amino acid sequence that varies from the sequence thereof by one or more substitutions, deletions or insertions.
  • a receptor-binding compound selected from the group consisting of a peptide comprising the amino acid sequence of glucagon-like peptide-1, which includes GLP-1 (7-37) and GLP-1 (7-36) amide, and a variant peptide comprising an amino acid sequence that varies from the sequence thereof by one or more substitutions, deletions or insertions.
  • the preferred embodiments described for the composition are applicable to the method.
  • the step of administering is preferably selected from the group consisting of a regimen of multiple subcutaneous injections, micropressure injection system, ambulatory pump, depot sustained-release injection, implant, deep lung sustained-release insufflation, skin patch, buccal patch or a sustained-release oral delivery dose form.
  • the step of administering preferably comprises providing graded dose regimen of doses in the range of from about 0.5 to about 2.0 pmol/kg per minute for intravenous delivery and to about 1-10 pmol/kg per minute for subcutaneous continuous delivery.
  • the inventors have demonstrated herein that short-term satiety effects can be induced by peripherally infused GLP-1.
  • the results suggest that GLP-1 can act as an endogenous signal involved in the control of food intake in man.
  • the present composition can comprise glucagon-like peptides and related peptides and biologically active analogs of glucagon-like peptide- 1 that bind to a glucagon-like peptide- 1 receptor protein.
  • the GLP-1 receptors are cell-surface proteins particularly including those present on insulin-producing beta cells.
  • Glucagon-like peptides and analogs can include species that have insulinotropic activity and are agonists of, i.e., activate, the GLP-1 receptor molecule and its second messenger activity on inter alia insulin producing beta cells.
  • Such agonists of glucagon-like peptide that exhibit activity through this receptor have been described: EP 0708179A2; Hjorth, S.A. et al., J. Biol. Chem. 269, (48):30121-30124 (1994); Siegel, E.G. et al. Amer. Diabetes Assoc. 57th Scientific Sessions, Boston (1997); Hareter, A. et al. Amer. Diabetes Assoc. 57th Scientific Sessions, Boston (1997); Adelhorst, K. et al. J. Biol.
  • Polynucleotides also include numerous species that are agonists of, i.e., activate, the GLP-1 receptor molecule and its second messenger activity on inter alia insulin producing beta cells, and include exendin-4 (see WO97/46584).
  • GLP-1 mimetics that also are agonists of beta cells include, for example, enkephalin motif compounds.
  • Glucagon-like peptide-1 antagonists are also know, for example see e.g.
  • inventions include such proteins that are chemically synthesized, as well as any proteins or fragments thereof that are substantially homologous.
  • substantially homologous which can refer both to nucleic acid and amino acid sequences, means that a particular subject sequence, for example, a mutant sequence, varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between reference and subject sequences.
  • sequences having greater than 90 percent homology, equivalent biological activity, and equivalent expression characteristics are considered substantially homologous.
  • truncation of the mature sequence should be disregarded. Sequences having lesser degrees of homology, comparable bioactivity, and equivalent expression characteristics are considered equivalents.
  • GLP-1 Mammalian GLP peptides and glucagon are encoded by the same gene. In the ileum the phenotype is processed into two major classes of GLP-peptide hormones, namely GLP-1 and GLP-2. There are four GLP-1 related peptides known which are processed from the phenotypic peptides. GLP-1 (1-37) has the sequence His Asp Glu Phe Glu Arg His Ala Glu Cly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly (SEQ. ID NO:l).
  • GLP-1 (1-37) is amidated by post translational processing to yield GLP-1 (1-36) NH, which has the sequence His Asp Glu Phe Glu Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg (NH 2 (SEQ. ID NO:2); or is enzymatically processed to yield GLP-1 (7-37) which has the sequence His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly (SEQ. ID NO:3).
  • GLP-1 (7-37) can also be amidated to yield GLP-1 (7-36) amide which has the sequence His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg (NH 2 (SEQ. ID NO:4).
  • GLP-1 (7-37) SEQ. ID NO:3
  • GLP-1 (7-36) NH 2 SEQ. ID NO:4
  • These truncated forms of GLP-1 in situ have short half- lives, i.e., less than 10 minutes, and are inactivated by an aminodipeptidase IV to yield Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys
  • Gly Arg Gly (SEQ. ID NO:5); and Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg (NH 2 ) (SEQ. ID NO: 6), respectively.
  • the peptides Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly (SEQ. ID NO: 5) and Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly (SEQ. ID NO: 5) and Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Ser Ser
  • peptides c and h are derived form b and g respectively. All 6 naturally occurring peptides (a, b, d, e, f and g) are homologous in positions 1, 7, 11 and 18. GLP-1 and exendins 3 and 4 (a, b and d) are further homologous in positions 4, 5, 6, 8, 9, 15, 22, 23, 25, 26 and 29. In position 2, A, S and G are structurally similar. In position 3, residues D arid E (Asp and Glu) are
  • exendins 3 and 4 are identical in 15 positions and equivalent in 5 additional positions. The only positions where radical structural changes are evident are at residues 16, 17, 19, 21, 24, 27, 28 and 30. Exendins also have 9 extra residues at the carboxyl terminus.
  • the GLP-1 like proteins or peptides can be made by solid state direct amino acid synthesis. GLP-1 can also be made by conventional recombinant techniques described in detail for example in Sambrook and Maniaitis. "Recombinant”, as used herein, means that a protein is derived from recombinant (e.g., microbial or mammalian) expression systems.
  • the GLP-1 like proteins or peptides can be recovered and purified from recombinant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography (HPLC) can be employed for final purification steps.
  • the polypeptides of the present invention may be a naturally purified product, or a product of chemical synthetic procedures, or produced by recombinant techniques from prokaryotic or cukaryotic hosts (for example by bacterial, yeast, higher plant, insect and mammalian cells in culture).
  • polypeptides of the present invention may be glycosylated or may be non- glycosylated.
  • Polypeptides of the invention may also include an initial methionine amino acid residue.
  • GLP-1 activity can be determined by standard methods, in general, by receptor-binding activity screening procedures involve providing appropriate cells which express the receptor on the surface thereof, for example insulinoma cell lines such as RINmSF cells or INS-1 cells. See also Mosjov, S. (1992) and
  • cAMP activity or glucose dependent insulin production can also be measured.
  • a polynucleotide encoding the receptor of the present invention is employed to transfect cells to thereby express the GLP-1 receptor protein.
  • such assay may be employed for screening for a receptor agonist by contacting such cells with compounds to be screened and determining whether such compounds generate a signal, i.e. activate the receptor.
  • GLP-1 protein receptor for example, transfected CHO cells
  • Other screening techniques include the use of cells which express the GLP-1 protein receptor, for example, transfected CHO cells, in a system which measures extracellular pH or ionic changes caused by receptor activation.
  • potential agonists may be contacted with a cell which expresses the GLP-1 protein receptor and a second messenger response, e.g. signal transduction or ionic or pH changes, may be measured to determine whether the potential agonist is effective.
  • a second messenger response e.g. signal transduction or ionic or pH changes
  • compositions comprise a therapeutically effective appetite suppression control amount of the polypeptide, and a pharmaceutically acceptable carrier or excipient.
  • a carrier includes, but is not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, lactose, phosphate, mannitol, arginine, trehalose and combinations thereof.
  • the formulations should be pharmaceutically elegant and suit the mode of administration.
  • suggested dose ranges for various applications are 0.1 to 5.0 x 10 12 mol/kg min for intravenous administration; 0.1 to 5.0 nmol/kg GLP-1 in any form as a single subcutaneous shot; continuous subcutaneous administration in a range from about 0.2 to 20 x 10 12 mol/kg min. It is believed that the subcutaneous amounts may be up to or at least 10 times higher than those for intravenous application.
  • the quantity of food eaten and volume of fluid drunk was measured. The time for each subject to complete his meal was also measured. From these observations, the average rate of food and fluid intake, as well as the calorie intake, could be calculated.
  • EDTA ethylenediaminetetraacetic acid
  • the GLP-1 infusions were prepared from a freeze-dried synthetic powder, GLP-1 (7-36) amide purchased from Bachem (Bubendorf, Switzerland). The peptide was dissolved in 0.9% saline containing 0.5% human serum albumin, and prepared under aseptic conditions. .Aliquots of 50 ⁇ g/5ml were stored at -20°C. Infusion solutions were prepared by diluting appropriate amounts of GLP-1 with 5% glucose containing 0.1% human serum albumin. Control solutions contained albumin in 5% glucose alone; and were
  • Glucose concentrations were measured by the hexokinase method. Plasma hormone concentrations of insulin, cholecystokinin, GLP-1 and leptin were measured as depicted in Figure 1. All hormone concentrations were determined by specific radioimmunoassay systems. For insulin and leptin concentrations commercially available test kits were used. Plasma immunoreactive CCK concentrations were measured by a sensitive radioimmunoassay based on the antiserum GAL656 which recognizes the sulfated tyrosine residue of CCK8, but has no relevant cross-reactivity with sulfated gastrin ( ⁇ 1%) and does not cross-react with unrelated gastrointestinal peptides (Hashimura, E.
  • GLP- 1 was measured as previously described (Schirra, J. et al. Proc. Assoc. Am. Phys. 109(1):84-971 (1997)).
  • the detection limit of the GLP-1 assay was 2 fmol/tube. The assay does not have any significant cross-reactivity with GIP, pancreatic glucagon, glicentin, oxyntomodulin or GLP-2. Intra-assay and inter-assay coefficients of variation were 3.4% and 10.4%, respectively.
  • GLP-1 induced changes in plasma hormone concentrations using area under the curve (AUC) analysis. Scores for hunger and fullness were compared at the different time points before and after meals between the different treatments using multiple paired t-tests with Bonferroni correction (Sachs, L. Angewandte Statizing. Berlin, Springer, (1984)).
  • Meal duration for subjects during GLP-1 infusions was also dose- dependently decreased compared to subjects infused with placebo and reached statistical significance at the highest dose (p ⁇ 0.05). None of the participants reported any abdominal discomfort or side effects during any infusions. Furthermore, when questioned at the end of each experiment, none of the participants experienced or reported any adverse reactions.
  • Graded doses of exogenous GLP-1 produced dose-dependent increases in plasma GLP-1 concentrations (Figure 3).
  • the lower two doses produced plasma levels of 3.7 ⁇ 0.6 pmol/1 and 5.0 ⁇ 0.6 pmol/1, respectively, which can be considered physiological postprandial plasma levels, whereas the highest dose of GLP- 1 resulted in supraphysiological plasma concentrations (Byrne, M.M. and Goke, B. Diabetes. Basel, Karger (13):219-233 (1997).
  • the results are depicted as an insulinogenic index in Figure 4.
  • the insulinogenic index calculated as the quotient insulin/glucose, more appropriately reflects insulin release (Schirra, J. et al. Proc. Assoc. Am. Phys. 109(l):84-9 (1997)) than changes of plasma glucose which invariably are associated with changes in plasma insulin.
  • Graded GLP-1 infusions resulted in a dose-dependent reduction in food intake (maximal inhibition 35%; p ⁇ 0.001 vs control) and a similar reduction in calorie intake (32%; p ⁇ 0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p ⁇ 0.01). There were no overt side effects produced by GLP-1, but subjects experienced less hunger and early fullness in the pre-meal period during GLP-1 infusion at the highest dose (p ⁇ 0.05).
  • EXAMPLE 2 Twelve male patients were recruited for the study who had diabetes mellitus type 2 for at least one year. Patients were admitted to a Research
  • VAS visual analogue scales
  • Figure 7 shows blood glucose, plasma insulin, and glucagon levels.
  • blood glucose concentrations were slightly hyperglycemic, but similar in both experiments.
  • the GLP- 1 infusion increased the plasma concentrations of GLP- 1 ( Figure 7).
  • Example 2 demonstrates that peripherally administered GLP-1 significantly reduces energy intake by inhibiting hunger sensations in patients with diabetes mellitus type 2. The marked effect on appetite is clearly illustrated by each of the food parameters, and accompanied with lower fasting as well as meal-stimulated plasma glucose concentrations. These data extend previous findings (Examples) in healthy volunteers that exogenous GLP-1 acts as a physiological regulator of food intake and appetite sensations.

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Abstract

La présente invention concerne une composition renfermant un composé qui se lie à un récepteur de peptide-1 de type glucagon et un porteur pharmaceutique. La quantité de ce composé présente est capable de réguler l'appétit d'un sujet. Par ailleurs, cette invention concerne un procédé de régulation de l'appétit et de réduction de la ration alimentaire d'un sujet par l'administration d'une composition renfermant un composé qui se lie à un récepteur de peptide-1 de type glucagon et un porteur pharmaceutique.
PCT/US1999/005571 1998-03-19 1999-03-16 Regulation de l'appetit chez les humains par un compose se liant a un recepteur de peptide de type glucagon WO1999047161A1 (fr)

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AU30875/99A AU3087599A (en) 1998-03-19 1999-03-16 Human appetite control by glucagon-like peptide receptor binding compounds
US09/646,433 US6998387B1 (en) 1998-03-19 1999-03-16 Human appetite control by glucagon-like peptide receptor binding compounds
US11/348,148 US20060128627A1 (en) 1998-03-19 2006-02-06 Human appetite control by glucagon-like peptide receptor binding compounds

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US60/078,544 1998-03-19

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WO2001083558A1 (fr) * 2000-05-03 2001-11-08 Astrazeneca Ab Agonistes/antagonistes du recepteur gpr56 utilises comme agents de regulation de l'appetit
US7056701B2 (en) 1992-01-31 2006-06-06 Aventis Behring L.L.C. Hormone and albumin fusion protein
US7141547B2 (en) 2001-12-21 2006-11-28 Human Genome Sciences, Inc. Albumin fusion proteins comprising GLP-1 polypeptides
US7507414B2 (en) 2000-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
US7521424B2 (en) 2003-01-22 2009-04-21 Human Genome Sciences, Inc. Albumin fusion proteins
US7914499B2 (en) 2006-03-30 2011-03-29 Valeritas, Inc. Multi-cartridge fluid delivery device
US8070726B2 (en) 2003-04-23 2011-12-06 Valeritas, Inc. Hydraulically actuated pump for long duration medicament administration
US9089636B2 (en) 2004-07-02 2015-07-28 Valeritas, Inc. Methods and devices for delivering GLP-1 and uses thereof
US9200051B2 (en) 2013-05-28 2015-12-01 Takeda Pharmaceutical Company Limited Peptide compound
CN110251662A (zh) * 2018-12-12 2019-09-20 四川利通科创生物医药科技有限公司 一种具有减肥作用的药物
US10501516B2 (en) 2016-05-24 2019-12-10 Takeda Pharmaceutical Company Limited Peptide compound

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