WO2002028412A1 - Novel use of peptide - Google Patents
Novel use of peptide Download PDFInfo
- Publication number
- WO2002028412A1 WO2002028412A1 PCT/US2001/041008 US0141008W WO0228412A1 WO 2002028412 A1 WO2002028412 A1 WO 2002028412A1 US 0141008 W US0141008 W US 0141008W WO 0228412 A1 WO0228412 A1 WO 0228412A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- use according
- hexapeptide
- amino acid
- Prior art date
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to novel medical uses of the hexapeptide having the amino acid sequence (I) X-Hexapeptide-Y and the use of the hexapeptide for the preparation of a medicament.
- nociceptin also referred to as orphanin FQ
- Nociceptin binds to a specific receptor named opioid receptor-like one (ORL1) with much greater affinity than to the three classical subtypes of opioid receptors. Effects of nociceptin in the CNS include: hyperalgesia/hypoalgesia, stimulation of appetite and gnawing, increased (low doses) or decreased (high doses) locomotion, impaired learning, and dysphoria.
- nociceptin also exerts important effects outside the CNS.
- nociceptin When administered centrally (i.c.v.) or at high doses peripherally (i.v. bolus or infusion), nociceptin decreases blood pressure, heart rate and peripheral sympathetic nerve activity.
- hexapeptide having the amino acid sequence Ac-RYY(RK)(WI)(RK)-NH2, where the brackets show allowable variation of amino acid residue acts as a partial agonist of the nociceptin receptor ORL1.
- Said hexapeptide was identified from a combinatorial peptide library and the sequence is unique without homology or similarity to the nociceptin heptadecapeptide.
- WO 99/44627 discloses the use of hexapeptides including the hexapeptides discovered by Dooley et al.
- a pharmaceutical composition for the treatment of the following conditions Migraine, type II diabetes, septic shock, inflammation and vasomotor disturbances.
- the pharmacological rationale for using said hexapeptides in the treatment of said conditions is the shown inhibition of depressor response to spinal cord stimulation by the hexapeptide Ac-Arg-Tyr- Tyr-Arg-Trp-Lys-NH 2 .
- the present inventors have shown that the hexapeptides disclosed by Dooley et al. exhibit a peripheral effect that is distinctly different from the effect shown in WO 99/44627 and which is useful in the treatment of disease states, such as hyponatremia, acute renal failure and medical conditions that can be ameliorated by treatment with a selective water diuretic agent.
- the present invention relates to the use of a compound having the general formula I (I) X-Hexapeptide-Y
- X represents H or acyl
- Y represents OH or NH2
- Hexapeptide represents an amino acid sequence of the formula II
- A1 represents Arg, Lys or His
- A2 represents Tyr, Trp, or Phe
- A3 represents Tyr, Asn, Trp or Phe
- A4 represents Lys, Arg or His
- A5 represents Phe, Tyr, Trp or lie
- A6 represents Arg, Lys or His and wherein each amino acid residue in said hexapeptide may be in the L or D form;
- the group X of formula I represents acetyl (Ac) or trifluoroacetyl (Tfa), most preferably X represents acetyl; Y represents NH2, and Hexapeptide represents the amino acid sequence (RK)YY(RK)(WI)(RK) wherein alternative amino acid residues at positions 4, 5 and 6 are shown in brackets.
- (RK)YY(RK)(WI)(RK) is selected form the group consisting of RYYRWR, RYYRWK, RYYRIK, RYYRIR, RYYKIK, RYYKIR, RYYKWR, and RYYKWK, more preferably from the group consisting of RYYRWR, RYYRWK, RYYRIK, RYYKWR, and RYYKWK; and most preferably (RK)YY(RK)(WI)(RK) represents RYYRWK.
- all amino acid residues of the compounds of formula I and II are in the L-form.
- a specific compound of formula I to be used in the present invention is Compound 1 Ac-RYYRWK-NH2, and pharmaceutically acceptable salts, hydrates and solvates thereof.
- the invention also concerns a pharmacologically active compound of formula I or II or a derivative thereof including C-terminally esterified derivatives or C-terminal secondary and tertiary amidated derivatives or a salt, hydrate or solvate thereof for use in the treatment and/or prevention of hyponatremia and acute renal failure and for use in the manufacture of a medicament or pharmaceutical composition for selective water diuresis and/or treatment and/or prevention of hyponatremia and/or acute renal failure.
- a hexapeptide according to the present invention may be used for the manufacture of a medicament for treatment and/or prevention of hyponatremia.
- hyponatremia includes but is not necessarily limited to the following medical conditions:
- Primary Na+ loss secondary water gain associated with, e.g., integumentary loss: sweating, burns; gastrointestinal loss: vomiting, tube drainage, fistula, obstruction, diarrhea; renal loss: diuretics, osmotic diuresis, hypoaldosteronism, salt-wasting nephropathy, postobstructive diuresis, nonoligouric acute tubular necrosis;
- Primary water gain secondary Na+ loss associated with, e.g. primary polydipsia; decreased solute intake (e.g., beer potomania); AVP release due to pain, nausea, drugs; syndrome of inappropriate AVP secretion; glucocorticoid deficiency; hypothyroidism and chronic renal insufficiency; and Primary Na+ gain (exceeded by secondary water gain) associated with, e.g. heart failure, hepatic cirrhosis and nephrotic syndrome; or drug induced.
- a hexapeptide according to the present invention may be used for the manufacture of a medicament for the treatment and prevention of sodium and water retaining conditions as well as acute renal failure and multiple organ failure.
- Sodium and water retaining conditions include diseases, such as
- Congestive heart failure in which the heart failure may be described as systolic or diastolic, high-output or low-output, acute or chronic, right-sided or left-sided, and forward or backward.
- Hypertension in which the hypertension may be primary (idiopathic) or secondary to other eliciting causes, such as drugs, toxins or diseases in endocrine glands, kidneys, or in the central nervous system.
- Acute renal failure include: Prerenal azotemia, such as the following conditions:
- Gastrointestinal fluid loss vomiting, surgical drainage, diarrhea
- Renal fluid loss diuretics, osmotic diuresis (e.g., diabetes mellitus), hypoadrenalism
- Cyclooxygenase inhibitors angiotensin-converting enzyme inhibitors
- Acute renal failure further include:
- Intrinsic renal azotemia such as the following conditions:
- Renovascular obstruction bilateral or unilateral with one functioning kidney
- Ischemia as for prerenal azotemia (hypovolemia, low cardiac output, renal vasoconstriction, systemic vasodilatation), obstetric complications (abruptio placentae, postpartum hemorrhage)
- prerenal azotemia hypervolemia, low cardiac output, renal vasoconstriction, systemic vasodilatation, obstetric complications (abruptio placentae, postpartum hemorrhage)
- Toxins as for prerenal azotemia (hypovolemia, low cardiac output, renal vasoconstriction, systemic vasodilatation), obstetric complications (abruptio placentae, postpartum hemorrhage)
- Allergic antibiotics (e.g., -lactams, sulfonamides, trimethoprim, rifampicin), nonsteroidal anti-inflammatory agents, diuretics, captopril
- Infection bacterial (e.g., acute pyelonephritis, leptospirosis), viral (e.g., cytomegalovirus), fungal (e.g., candidiasis)
- hypokalemia is a major predisposing mechanism for the development of arrhythmias and the prognosis of chronic heart failure (CHF) is poor when serum potassium levels fall below 3.3 mM. Furthermore, in CHF patients treated with digoxin, hypokalemia is the most common precipitating cause of digitalis intoxication, which is a serious and potentially fatal complication.
- a hexapeptide according to the present invention may be used for the manufacture of a medicament for treatment and/or prevention of hypokalemia.
- compositions of the invention comprise a pharmacologically active hexapeptide of formula I or II as defined herein in combination with a pharmaceutically acceptable carrier and/or diluent.
- Such compositions may be in a form adapted to oral, subcutaneous, parenteral (intravenous, intraperitoneal), intramuscular, rectal, epidural, intratracheal, intranasal, dermal, vaginal, buccal, ocularly, or pulmonary administration, preferably in a form adapted for administration by a peripheral route, or is suitable for oral administration or suitable for parenteral administration.
- compositions may be prepared in a manner well-known to the person skilled in the art, e.g., as generally described in "Remington's Pharmaceutical Sciences", 17. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions and in the monographs in the "Drugs and the Pharmaceutical Sciences” series, Marcel Dekker.
- the compositions may appear in conventional forms, for example, solutions and suspensions for injection, capsules and tablets, preferably in the form of enteric formulations, e.g. as disclosed in US 5,350,741 , for oral administration.
- the pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
- liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- the preparation When a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
- the preparation When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
- the composition may also be in a form suited for local or systemic injection or infusion and may, as such, be formulated with sterile water or an isotonic saline or glucose solution. Administration forms which exclude direct delivery into the central nervous system are preferred.
- the compositions may be sterilized by conventional sterilization techniques which are well known in the art.
- the resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with the sterile aqueous solution prior to administration.
- the composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as buffering agents, tonicity adjusting agents and the like, for instance sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
- the preparation may contain a compound of the present invention dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application.
- a liquid carrier in particular, an aqueous carrier
- the carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants such as bile acid salts or polyoxyethylene higher alcohol ethers, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabines.
- the compound of formula I or II is administered as a dose in the range from about 0.001 to about 10 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, more preferably from about 10 to about 100 mg per patient per day, about 50 mg per patient per day.
- the invention relates to a method for providing selective water diuresis in a patient, a method for treatment and/or prevention of hyponatremia, e.g. as defined above, a method for the treatment and/or prevention of sodium and water retaining conditions, e.g. as defined above, and a method for the treatment and/or prevention of acute renal failure, e.g. as defined above, comprising administering an effective dose of a pharmacologically active compound having the formula I or II.
- the one letter code for natural amino acids is used as well as the three letter code for natural amino acids and generally accepted three letter codes for other ⁇ -amino acids, such as Ornithine (Orn), 2,4-Diaminobutanoic acid (Dab) and 2,3-Diaminopropanoic acid (Dapa), Sarcosin (Sar), ⁇ -Amino-iso-butanoic acid (Aib), and
- salt denotes acidic and/or basic salts, formed with inorganic or organic acids and/or bases, preferably basic salts. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in processing these compounds, or where non- medicament-type uses are contemplated. Salts of these compounds may be prepared by art-recognized techniques.
- salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well.
- inorganic and organic addition salts such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or
- Acyl radicals can formally be represented by canonical forms having an unpaired electron or a positive charge on the acid-generating element of the oxoacid.
- acylated indicates that the compound in question carries an acyl group.
- an unspecified acyl group is commonly a carboxylic acyl group.
- Antagonist refers to an endogenous substance or a drug that can interact with a receptor and initiate a physiological or a pharmacological response characteristic of that receptor (contraction, relaxation, secretion, enzyme activation, etc.).
- Partial agonist refers to an agonist which is unable to induce maximal activation of a receptor population, regardless of the amount of drug applied.
- a “partial agonist” may also be termed "agonist with intermediate intrinsic efficacy" in a given tissue.
- a partial agonist may antagonize the effect of a full agonist that acts on the same receptor.
- Antagonist refers to a drug or a compound that opposes the physiological effects of another. At the receptor level, it is a chemical entity that opposes the receptor-associated responses normally induced by another bioactive agent.
- Receptor refers to a molecule or a polymeric structure in or on a cell that specifically recognizes and binds a compound acting as a molecular messenger (neurotransmitter, hormone, lymphokine, lectin, drug, etc.).
- compositions of the present invention are useful as nociceptin agonists or partial agonists as described below.
- Figure 1 shows cardiovascular and renal responses produced by the i.v. bolus injection of isotonic saline vehicle (100 ml) or Compound 1 as the trifluoroacetate dissolved in isotonic saline (100 nmol/kg) in conscious Sprague-Dawley rats with intact renal nerves.
- concious rats were continuously infused i.v. (55 ml/min) with isotonic saline for the duration of the study.
- * indicates P ⁇ 0.05 versus control (C) value.
- a stock solution of Compound 1 (10 mg/ml distilled deionized water) was prepared, divided into aliquots, and frozen until use in each animal.
- Figure 2 shows Cardiovascular and renal responses produced by the i.v. infusion of Compound 1 (1 nmol/kg/min) or nociceptin (0.11 nmol/kg/min) in concious Sprague-Dawley rats. * indicates P ⁇ 0.05 versus control (C) value within group of animals treated with Compound 1. 1 indicates P ⁇ 0.05 versus control (C) value within group of animals treated with nociceptin.
- This figure shows the cardiovascular and renal responses produced by the i.v. infusion of Compound 1 and low dose nociceptin. The i.v. infusion of nociceptin (0.11 nmol/kg/min) produced a significant increase in V without altering HR, MAP or UNaV.
- the invention also concerns a pharmacologically active compound of formula I or II or a derivative thereof including C-terminally esterified derivatives or C-terminal secondary and tertiary amidated derivatives or a salt thereof as disclosed herein for use in therapy, and the use thereof as defined herein for the manufacture of a medicament or pharmaceutical composition for use in therapy.
- a pharmaceutical composition is suitable for oral administration or injection.
- Therapeutic uses of the compounds of formula I or II herein are to increase the renal excretion of water and to decrease urinary sodium excretion (i.e., a selective water diuresis).
- a pharmaceutical composition according to the present invention may be used to treat and/or prevent acute renal failure.
- Additional causes of acute renal failure include renal failure due to trauma, or anaesthesia and surgery induced impairment of renal function. Severe trauma may be associated with hemorrhage, ischemia, and release of toxic substances that may result in acute renal failure as well as multiple organ failure. The present inventors believe that the hexapeptides of the invention may exert their organ protective action through a protection against ischemia.
- Fernandez-Llama P. et al. J Am Soc Nephrol 1999 Aug ; 10(8): 1658- 68) describe an animal model of ischemic acute renal failure suitable for showing the protective effects of the hexapeptide of the invention against ischemic acute renal failure
- Examples of predictive in vivo models of prerenal azotemia for the study of therapeutic actions of peptides of the present invention are the norepinephrine and renal artery clamp rat ischemic acute renal failure models, that may be accelerated by hemorrhage (J. D. Conger, M. F. Schultz, F. Miller, J. B. Robinette, Kidney Int. 1994, 46318-323) which is incorporated by reference.
- An example of a predictive in vivo model of intrinsic renal azotemia for the study of therapeutic actions of peptides of the present invention is the gentamicin-induced acute renal failure model (D. de Rougemont, A.
- a model of organ failure elicited by hemorrhage during anesthesia and surgery will be used.
- rats are infused with isotonic saline or compounds of the present invention for 15 min prior to anesthesia.
- the animals are anestetized with isoflurane (3% in 0 2 /N 2 0 mixture) and subjected to periods of surgery (chronic bladder catheterization + femoral vein and artery; 30 min); hemorrhage (20 cc/kg b.w.; 45 min), and recovery (blood replacement; 120 min).
- Consecutive 10 min urine samples are collected throughout, and rats are allowed to recover for 7 days.
- the peptides of the invention may be prepared by methods known per se in the art including recombinant techniques. It is preferred to prepare the peptide sequences of formula I herein by standard peptide-preparation techniques such as solution synthesis or Merrifield-type solid phase synthesis. Both the Boc (tert.butyloxycarbonyl) as well as the Fmoc (9- fluorenylmethyloxycarbonyl) strategies are applicable.
- Apparatus and synthetic strategy Peptides were synthesized batchwise in a polyethylene vessel equipped with a polypropylene filter for filtration using 9- fluorenylmethyloxycarbonyl (Fmoc) as N- ⁇ -amino protecting group and suitable common protection groups for side-chain functionalities.
- Fmoc 9- fluorenylmethyloxycarbonyl
- Solvent DMF N,N-dimethylformamide, Riedel de-Haen, Germany
- a strong cation exchange resin Lewatit S 100 MB/H strong acid, Bayer AG Leverkusen, Germany
- Dhbt-OH 3,4-dihydro-3-hydroxy-4- oxo-1 ,2,3-benzotriazine
- Solvent DCM diichloromethane, analytical grade, Riedel de-Haen, Germany
- Acetonitril HPLC-grade, Lab-Scan, Dublin Ireland
- Fmoc-protected amino acids were purchased from Advanced ChemTech (ACT) in suitabel side-chain protected forms.
- Coupling reagent diisopropylcarbodiimide was purchased from Riedel de-Haen, Germany. Solid supports
- DIEA Diisopropylethylamine
- Ethandithiol was purchased from Riedel-de Haen, Frankfurt, Germany.
- 3,4-dihydro-3- hydroxy-4-oxo-1,2,3-benzotriazine (Dhbt-OH), 1-hydroxybenzotriazole (HOBt) (HOAt) were obtained from Fluka, Switzerland.
- Acetic anhydride was obtained from Fluka.
- the amino acids were coupled as in situ generated HObt or HOAt esters made from appropriate N-a-protected amino acids and HObt or HOAt by means of DIC in DMF. Acylations were checked by the ninhydrin test performed at 80 oC in order to prevent Fmoc deprotection during the test (Larsen, B. D. and Holm, A., Int. J. Peptide Protein Res. 43, 1994, 1-9).
- Deprotection of the Fmoc group was performed by treatment with 20% piperidine in DMF (1x5 and 1x10 min.), followed by wash with DMF (5 x 15 ml, 5 min. each) until no yellow color could be detected after addition of Dhbt-OH to the drained DMF.
- the acylation was checked by the ninhydrin test as described above.
- Peptides were cleaved from the resins by treatment with 95% triflouroacetic acid (TFA, Riedel-de Haen, Frankfurt, Germany)-water v/v or with 95% TFA and 5% ethandithiol v/v at r.t. for 2 h.
- TFA triflouroacetic acid
- the filtered resins were washed with 95% TFA-water and filtrates and washings evaporated under reduced pressure.
- the residue was washed with ether and freeze dried from acetic acid-water.
- the crude freeze dried product was analyzed by high- performance liquid chromatography (HPLC) and identified by mass spectrometry (MS).
- TentaGel resin (1g, 0.23-0.24 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration.
- the resin was swelled in DMF (15ml), and treated with 20% piperidine in DMF in order to remove the initial Fmoc group either on the linker TentaGel S RAM or on the first amino acid on the resin TentaGel S RAM-Lys(Boc)Fmoc.
- the resin was drained and washed with DMF until no yellow color could be detected after addition of Dhbt-OH to the drained DMF.
- the amino acids according to the sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) as described above. The couplings were continued for 2 h, unless otherwise specified.
- the resin was drained and washed with DMF (5 x 15 ml, 5 min each) in order to remove excess reagent. All acylations were checked by the ninhydrin test as described above.
- the peptide-resin was washed with DMF (3x15 ml, 5 min each), DCM (3x15 ml, 1 min each) and finally diethyl ether (3x15 ml, 1 min each) and dried in vacuo.
- the peptide was cleaved from the resin as described earlier and the crude peptide product was analysed and purified as described below.
- the crude peptide products were purified PerSeptive Biosystems VISION Workstation. VISION 3.0 software was used for instrument control and data acquisition. The following column and HPLC buffer system was used:
- Buffer system Buffers: A: 0,1% TFA in MQV; B: 0,085% TFA, 10% MQV, 90% MeCN. Gradient: 0-37 min. 0-40% B
- the peptides were dissolved in super gradient methanol (Labscan, Dublin, Ireland), milli-Q water (Millipore, Bedford, MA) and formic acid (Merck, Damstadt, Germany) (50:50:0.1 v/v/v) to give concentrations between 1 and 10 mg/ml.
- the peptide solutions (20 ml) were analysed in positive polarity mode by ESI-TOF-MS using a LCT mass spectrometer (Micromass, Manchester, UK).
- a tablet prepared by conventional tabletting techniques may contain:
- Compound 1 (as the trifluoroacetate) 100 mg; colloidal silicon dioxide (Aerosil) 1.5 mg; cellulose, microcryst. (Avicel) 70 mg; modified cellulose gum (Ac-Di-Sol) 7.5 mg; magnesium stearate.
- Coating HPMC approx. 9 mg; acylated monoglyceride used as plasticizer for film coating
- a multi-dose formulation is prepared as a solution of a compound of the invention in sterile, isotonic saline, stored in capped vials, and if necessary a preservative is added (e.g. benzoates).
- Fixed dose formulations are prepared as a solution of the compound in sterile, isotonic saline, stored in glass ampoules, and if necessary filled with an inert gas. Each dose of the compound is stored dry in ampoules or capped vials, if necessary filled with inert gas.
- the multi-dose formulation demands the highest degree of stability of the compound.
- a fixed dose formulation may be preferred when the stability of the active compound is low.
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Abstract
Description
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60144561T DE60144561D1 (en) | 2000-06-16 | 2001-06-15 | N AND / OR C TERMINAL WITH SHORT-LOADED PEPTIDE SEQUENCES MODIFIED PEPTIDES |
AU2001267093A AU2001267093A1 (en) | 2000-10-05 | 2001-06-15 | Novel use of peptide |
CA2410224A CA2410224C (en) | 2000-06-16 | 2001-06-15 | Peptide conjugates modified n- and/or c-terminally by short charged peptide chains |
EP01952155A EP1294746B1 (en) | 2000-06-16 | 2001-06-15 | Peptide conjugates modified n- and/or c-terminally by short charged peptide chains |
PCT/US2001/019113 WO2001098324A1 (en) | 2000-06-16 | 2001-06-15 | Peptide conjugates modified n- and/or c-terminally by short charged peptide chains |
DK01952155.8T DK1294746T3 (en) | 2000-06-16 | 2001-06-15 | Peptide conjugates with modified N- and / or C-termini at short charged peptide chains |
JP2002504279A JP4624639B2 (en) | 2000-06-16 | 2001-06-15 | Peptides modified at the N- and / or C-terminus by short charged peptide chains |
AT01952155T ATE508138T1 (en) | 2000-06-16 | 2001-06-15 | N- AND/OR C-TERMINAL PEPTIDES MODIFIED WITH SHORT CHARGED PEPTIDE SEQUENCES |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DKDKPA200001486 | 2000-10-05 | ||
US25166500P | 2000-12-06 | 2000-12-06 | |
US60/251,665 | 2000-12-06 |
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WO2002028412A1 true WO2002028412A1 (en) | 2002-04-11 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2001/041008 WO2002028412A1 (en) | 2000-06-16 | 2001-06-15 | Novel use of peptide |
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WO (1) | WO2002028412A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7550425B2 (en) | 2000-06-16 | 2009-06-23 | Zealand Pharma A/S | Diuretic peptide conjugates |
US7786119B2 (en) | 2004-04-01 | 2010-08-31 | Cardiome Pharma Corp. | Drug conjugates of ion channel modulating compounds |
EP2895186A4 (en) * | 2012-09-04 | 2016-05-18 | Univ Leland Stanford Junior | Therapeutic compositions and related methods |
WO2016166291A1 (en) * | 2015-04-15 | 2016-10-20 | Serodus Asa | Materials and methods for treatment of pulmonary hypertension |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6228840B1 (en) * | 1998-02-27 | 2001-05-08 | Edward T. Wei | Melanocortin receptor antagonists and modulations of melanocortin receptor activity |
-
2001
- 2001-06-15 WO PCT/US2001/041008 patent/WO2002028412A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6228840B1 (en) * | 1998-02-27 | 2001-05-08 | Edward T. Wei | Melanocortin receptor antagonists and modulations of melanocortin receptor activity |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7550425B2 (en) | 2000-06-16 | 2009-06-23 | Zealand Pharma A/S | Diuretic peptide conjugates |
US7786119B2 (en) | 2004-04-01 | 2010-08-31 | Cardiome Pharma Corp. | Drug conjugates of ion channel modulating compounds |
EP2895186A4 (en) * | 2012-09-04 | 2016-05-18 | Univ Leland Stanford Junior | Therapeutic compositions and related methods |
WO2016166291A1 (en) * | 2015-04-15 | 2016-10-20 | Serodus Asa | Materials and methods for treatment of pulmonary hypertension |
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