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WO1992016196A1 - Composition renfermant un peptide pour administration nasale - Google Patents

Composition renfermant un peptide pour administration nasale Download PDF

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Publication number
WO1992016196A1
WO1992016196A1 PCT/DK1992/000084 DK9200084W WO9216196A1 WO 1992016196 A1 WO1992016196 A1 WO 1992016196A1 DK 9200084 W DK9200084 W DK 9200084W WO 9216196 A1 WO9216196 A1 WO 9216196A1
Authority
WO
WIPO (PCT)
Prior art keywords
cellulose
preparation
cyclodextrin
phospholipid
growth hormone
Prior art date
Application number
PCT/DK1992/000084
Other languages
English (en)
Inventor
Annie Rassing Hoelgaard
Brigitte Smedemark Dath
Linda Mindeholm
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of WO1992016196A1 publication Critical patent/WO1992016196A1/fr

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Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0043—Nose

Definitions

  • the present invention relates to novel pharmaceutical preparations adapted for intranasal administration and to a process for preparing such preparations.
  • non-invasive medication such as oral or rectal administration of a drug
  • parenteral drug delivery is usualluy regarded as being the most effective.
  • drugs which are inactivated in or poorly absorbed by the gastrointestinal tract and drugs which are subject to extensive first pass hepatic metabolism following oral administration are usually administered parenterally.
  • progesterone and propranolol are absorbed from the nasal cavity in a manner providing blood levels almost equal to interveneous administration.
  • intranasal formulations of pharmaceutically active agents with molecular weights up to about 1 kD are known, for example compositions containing ergopeptide alkaloids dissolved in aqueous ethanol administered as aerosols (Swiss Patent No. 636,011), salts of pharmaceutically active amines with fatty acids (Canadian Patent No. 988,852) and catecholamine suspended in a fatty acid (or ester) emulsified with polyoxyethylene (European Patent Publication No. 0160501 A).
  • polypeptides have been administered parenterally due to incomplete absorption from a digestive instability in the alimentary canal. This is probably the reason why in particular studies of the nasal delivery of polypeptides have been intensified during recent years. It has been found that while some smaller polypeptides (op to about 10 amino acids residues) may be reasonably well absorbed intranassally from simple aqueous formulations, generally the nasal bioavailability of larger polypeptides becomes both incomplete and variable, and increasingly so with increasing molecular weight (for review, see L. Illum: Archiv for Pharmaci og Chemi 94 (1987), 127-135.
  • Nasal formulations adapted to growth hormone delivery would naturally be highly preferred by the patient who has to be given growth hormone by many administrations to the presently available preparations for parenteral administration, provided that the growth hormone is absorbed to a reasonably effective and constant extent from the nasal cavity.
  • absorp tion enhancing agents mainly surfactants, have been devised for nasal formulations.
  • Ionic as well as non-ionic surfactant enhancers such as bile acid salts and polyoxyethylene higher alcohol ethers are disclosed in British Patent No. 1,527,605 while the use of a specific polyoxyethylene higher alcohol ether, namely polyoxyethylene-9 lauryl ether is described in: R. Salzman et al., New England J. of Med. 312 (1985), 1078-1084.
  • Other enhancers for example salts of taurodihydrofusidic acid, are disclosed in U.S. Patent No. 4,548,922.
  • phospholipids such as phosphatidylcholines (lecitins) as an enhancer for nasal administration of in particular insulin is disclosed in International Patent Publication No. WO88/04556.
  • a powdery nasal pharmaceutical preparation which is suitable for systemic treatment using larger polypeptide pharmaceuticals such as insulin and insulin derivatives.
  • the present invention relates to a powdery preparation for intranasal administration of a physiologically active agent, said preparation being characterized by containing
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R''' is 2-(trimethylammonio)ethyl, and optionally excipients such as a buffer and/or a binder.
  • the preparation of the invention preferably contains, as the lower alkyl ether of cellulose, hydroxymethylpropyl cellulose (HPMC) or methyl cellulose (MC).
  • HPMC hydroxymethylpropyl cellulose
  • MC methyl cellulose
  • the contents of lower alkyl ether of cellulose is normally in the range from 25% w/w to 80% w/w, e.g. 30-80% w/w, especially 30-75% w/w of the preparation.
  • a cyclodextrin or a derivative thereof may e.g. be ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropylated, hydroxyethylated, ethylated or methylated derivatives thereof, branched cyclodextrins or cyclodextrin polymers.
  • the preparation of the invention preferably contains ⁇ -cyclodextrin.
  • the contents of a cyclodextrin is normally in the range from 2% w/w to 60% w/w, preferably in the range 5-45% w/w of the preparation.
  • alkyl or “alkylcarbonyl” containing from 4 to 12 carbon atoms are considered to comprise linear and branched alkyl and alkylcarbonyl such as n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1-, 2-, or 3-ethyl-butyl, 1- or 2-propyl-propyl- and 1-butyl-ethyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, isononyl, n-decyl, n-undecyl or n-dodecyl, or the corresponding n-propylcarbonyl, isopropylcarbonyl, sec.
  • the phospholipid contained in the preparation of the invention is preferably a lecitin, more preferred didecanoyl L- ⁇ -phosphatidylcholine.
  • the contents of phospholipid is normally in the range from 2% w/w to 20% w/w, e.g. in the range 4-20% w/w, preferably in the range 6-18% w/w of the preparation.
  • the physiologically active agent to be administered in the preparation of the invention is preferably a polypeptide.
  • the preferred polypeptides to be incorporated in the preparations of the invention are growth hormone, preferably human growth hormone, or a derivative or an analogue thereof, insulin or a derivative or an analogue thereof, calcitonin or glucagon or a derivative or an analogue thereof.
  • growth hormone preferably human growth hormone, or a derivative or an analogue thereof, insulin or a derivative or an analogue thereof, calcitonin or glucagon or a derivative or an analogue thereof.
  • These polypeptides may be derived from a natural source, e.g. by extraction from pancreas or pituitary glands, or be prepared by chemical synthesis or by recombinant techniques.
  • More preferred preparations of the invention comprise human growth hormone, insulin, calcitonin or glucagon, or a derivative or an analogue thereof such as methionyl growth hormone.
  • a preparation of the invention comprising human growth hormone as is enables a reliable nasal administration in a preparation in which the human growth hormone is stable.
  • the buffer may for example be an amino acid such as glycine or glycylglycine, phosphate buffer, citrate buffer, or acetate buffer.
  • Preferred buffers are glycine and citrate buffer.
  • the most preferred buffer is a combination of glycine and citric acid.
  • a further preferred aspect of the invention is a preparation comprising human growth hormone, a) a lower alkyl ether of cellulose selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, b) a cyclodextrin or a derivative thereof, and
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R'" is 2-(trimethylammonio)ethyl
  • the cyclodextrin is a-cyclodextrin, and further comprising glycine and citric acid.
  • glycine and citrat together with ⁇ -CD allows for the omission of mannitol normally necessary for lyophilization but giving rise to significantly lower nasal absorption.
  • ⁇ -CD and glycine and citrate give a good stability. Still further, this formulation is fully acceptable for the patients having no adverse effects from nasal administration thereof.
  • the contents of buffer is normally in the range of from 0.1 to 5% w/w of the preparation.
  • the preparation of the invention may optionally comprise a separate bulking agent for the lyophilization.
  • a separate bulking agent may be a water soluble macromolecular substance such as hydrolysed gelatine or dextran.
  • a binder optionally being present in the preparation may for example be ethyl cellulose or polyvinylpyrrolidone.
  • the present invention also relates to a method for preparing a powdery preparation for intranasal administraion of a physiologically active agent containing
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R''' is 2-(trimethylammonio)ethyl, and optionally excipients such as a buffer or a binder comprising:
  • an additional conventional bulking agent may optionally be added before the lyophilization in step a) above.
  • the invention relates to the use of a combination of
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R'" is 2-(trimethylammonio)ethyl for the preparation of a pharmaceutical preparation for intranasal administration of a physiologically active agent.
  • Such use is of particular interest for the preparation of nasal preparations comprising a peptide as stated above, preferably for the preparation of powdery nasal preparations comprising human growth hormone or a derivative thereof.
  • the preparations of the invention may be used to treat all conditions for which human growth hormone is indicated, e.g. dwarfism, short stature. Turner's syndrome, intoxicated individuals, individuals suffering from subnormal or absent fertility, or substitution therapy for adults, e.g. adult dwarfs, or individuals having had hypophysectomy or suffering from chronic renal illness or failure.
  • human growth hormone e.g. dwarfism, short stature.
  • Turner's syndrome intoxicated individuals, individuals suffering from subnormal or absent fertility, or substitution therapy for adults, e.g. adult dwarfs, or individuals having had hypophysectomy or suffering from chronic renal illness or failure.
  • the Invention also relates to a process for treating growth hormone deficiency in higher mammals comprising administering to the individual, via the nasal route, a sufficient amount of growth hormone in the form of a powdery preparation for intranasal administration of a physiologically active agent containing
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R''' is 2-(trimethylammonio)ethyl, and optionally excipients such as a buffer or a binder.
  • the invention relates to a process for normalizing the growth hormone blood levels in a higher mammal suffering from growth hormone deficiency comprising administering to the mammal via the nasal route a sufficient amount of growth hormone in the form of a powdery preparation for intranasal administration of a physiologically active agent containing
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R''' is 2-(trimethylammonio)ethyl, and optionally excipients such as a buffer or a binder.
  • the invention related to a method of administering human growth hormone comprising the steps of: administering a formulation with an aerosol device wherein the formulation comprises
  • a lower alkyl ether of cellulose selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, c) a cyclodextrin or a derivative thereof, and d) a phospholipid of the general formula
  • R' and R'' are each alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms and R''' is 2-(trimethylammonio)ethyl, and optionally excipients such as a buffer or a binder.
  • Fig. 1 shows the improved plasma levels of hGH in rabbits after administration of a preparation of the invention
  • Fig. 2 shows the serum profiles of the same preparations as in Fig. 1, administered to human beings,
  • Fig. 3 shows the improved serum profiles of another product of the invention in human beings
  • Fig. 4 shows the serum profiles of hGH after administration of various preparations of the invention to human beings
  • Fig. 5 shows the serum profiles of hGH after administration of a preparation of the invention to growth hormone deficient human beings.
  • DDPC Didecanoylphosphatidylcholine
  • ⁇ -CD ⁇ -cyclodextrin
  • Parafilm ® American Can Company
  • DDPC was dissolved in 275 ⁇ l ethanol 96%.
  • Methocel ® E4M hydroxypropylmethylcellulose 7.9 mg
  • Citric acid 0.2 mg a) 479 mg ⁇ -CD was dissolved in 4.0 mg sterile water and mixed with 12.95 g of a solution containing 10.9 mg hGH/ml in glycine/citrate buffer pH 7.2. The solution was lyophilized. (b) 115 mg DDPC was dissolved in 275 ⁇ l ethanol 96%. (c) In a mortar 551 mg lyophilized powder was mixed with 439 mg Methocel ® E4M and granulated with b). The further procedure was analogous to that of preparation B.
  • Blood samples for determination of hGH were taken at ⁇ 5, 0, 5, 10, 15, 20, 25, 30, 45, 75, 90, 105, 120, 150, and 180 min.
  • the blood samples were assayed for GH using a RIA method.
  • the preparations were compared with respect to C max , and AUC of the plasma profiles by means of analysis of variance.
  • Powder C gave significantly larger AUC and C max than powder A and B not containing HPMC. The highest absorption was found for the composition (nasal powder C) containing both ⁇ -CD and HPMC.
  • B-hGH 2.05 mg ⁇ 6 IU Didecanoylphosphatidylcholine (DDPC) 1.6 mg ⁇ -cyclodextrin ( ⁇ -CD) 4.0 mg
  • Methocel ® E4M hydroxypropylmethylcellulose 12.4 mg
  • Citric acid 0.2 mg 240 mg ⁇ -CD was dissolved in 2.0 g sterile water and mixed with 8.2 g of a solution containing 16.27 mg hGH/ml in glycine/citrate buffer pH 7.2. The solution was lyophilized. (b) 93 mg DDPC was dissolved in 275 ⁇ l ethanol 96%. (c) In a mortar 333 mg lyophilized powder was mixed with 683 mg Methocel ® E4M. The procedure was similar to that of preparing nasal powder B.
  • Citric acid 0.2 mg 240 mg Avice l® PH 101 was suspended for 2 hours in 2.5 mg sterile water and mixed with 8.2 g of a solution containing 16.27 mg hGH/ml in glycine/citrate buffer pH 7.2. The mixture was lyophilized. The subsequent procedure was similar to the preparation of nasal powder D.
  • Example 5
  • Powder D gave larger AUC and C max than powder E, which contained no ⁇ -CD. Again the highest absorption was found from the powder containing both ⁇ -CD and HPMC.
  • DDPC Didecanoylphosphatidylcholine
  • ⁇ -CD ⁇ -cyclodextrin
  • DDPC Didecanoylphosphatidylcholine
  • ⁇ -CD ⁇ -cyclodextrin
  • Methocel ® A4M methylcellulose 8. 2 mg
  • Methocel ® E4M hydroxypropylmethylcellulose
  • the method of preparation was analogous to the preparation Nasal powder A.
  • hGH was freeze dried in a solution containing ⁇ -CD, citrate and glycine.
  • the derived powder was granulated with an ethanol solution of DDPC.
  • citric acid 0.2 mg hGH was freeze dried in a solution of mannitol, glycine and citrate.
  • the freeze dried powder were mixed with ⁇ -CD and granulated with an ethanol solution of DDPC.
  • Example 9 3 IU hGH in nasal powder I and J were dosed in male rabbits. The absorption of hGH was measured by the same procedure as described in example 2. The results are shown in Table V
  • Powder I comprising ⁇ -CD as bulking agent for lyophilization gave significantly larger AUC and C max than powder J comprising mannitol as bulking agent for the lyophilization.
  • the preparation is made in an analogous manner as nasal powder H.
  • the Ethocel was added to the ethanol containing DDPC.
  • the capsules were stored at 4oC and at 30oC.
  • the chemical stability of hGH in the preparation was studied by HPLC-methods.
  • the two nasal powders L and M were tested in an amount corresponding to 12 IU in 16 healthy volunteers in the same manner as described in Example 3.
  • Powder L comprising DDPC gave a clearly higher AUC and C max than powder M where DDPC was omitted.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
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  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation pulvérulente pour administration intranasale d'un agent physiologiquement actif contenant: a) un éther alkyle inférieur de cellulose choisi parmi le groupe composé de cellulose méthylique, cellulose hydroxyéthyle, cellulose hydroxypropyle et cellulose hydroxypropylméthyle; b) une cyclodextrine ou un dérivé de celle-ci; et c) un phospholipide de formule générale (I) où R' et R'' sont chacun alkyle ou alkylcarbonyle contenant de 4 à 12 atomes de carbone et R''' est 2-(triméthylammonio)éthyle, et éventuellement des excipients comme par exemple un tampon ou un liant. Ladite préparation présente une absorption accrue.
PCT/DK1992/000084 1991-03-20 1992-03-18 Composition renfermant un peptide pour administration nasale WO1992016196A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK91497A DK49791D0 (da) 1991-03-20 1991-03-20 Nasalt pulverpraeparat
DK0497/91 1991-03-20

Publications (1)

Publication Number Publication Date
WO1992016196A1 true WO1992016196A1 (fr) 1992-10-01

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AU (1) AU1468792A (fr)
DK (1) DK49791D0 (fr)
MX (1) MX9203615A (fr)
WO (1) WO1992016196A1 (fr)
ZA (1) ZA922006B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022461A1 (fr) * 1993-03-26 1994-10-13 Merkus Franciscus W H M Formulation servant a administrer de l'insuline par voie nasale
FR2736547A1 (fr) * 1995-07-12 1997-01-17 Ltt Inst Co Ltd Medicament pour administration nasale
WO2004022100A1 (fr) * 2002-08-15 2004-03-18 Yunqing Liu Formulation nanopharmaceutique et son procede de preparation
WO2005004895A3 (fr) * 2003-06-09 2005-09-15 Nastech Pharm Co Compositions et procedes d'une meilleure administration d'hormone de croissance par voie muqueuse
GB2419528A (en) * 2004-10-11 2006-05-03 Nasaleze Patents Ltd Cellulose powder and signalling agent composition suitable for nasal administration
WO2006040596A3 (fr) * 2004-10-11 2006-06-01 Nasaleze Patents Ltd Compositions pour administration intranasale
WO2008016729A1 (fr) * 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions pour administration intranasale d'insuline humaine et leurs utilisations
US8202550B2 (en) 2004-10-11 2012-06-19 Nasaleze Ppm Limited Compositions for intranasal administration
WO2016133863A1 (fr) * 2015-02-17 2016-08-25 Eli Lilly And Company Formulation de poudre nasale pour le traitement de l'hypoglycémie
CN113727700A (zh) * 2019-04-26 2021-11-30 伊莱利利公司 稳定的肽制剂的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
EP0200383A2 (fr) * 1985-04-15 1986-11-05 Eli Lilly And Company Procédé pour administrer l'insuline
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion
WO1992001440A1 (fr) * 1990-07-24 1992-02-06 Rijksuniversiteit Te Leiden Preparations medicamenteuses transmuqueuses et administration de telles preparations par voie transmuqueuse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
EP0200383A2 (fr) * 1985-04-15 1986-11-05 Eli Lilly And Company Procédé pour administrer l'insuline
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion
WO1992001440A1 (fr) * 1990-07-24 1992-02-06 Rijksuniversiteit Te Leiden Preparations medicamenteuses transmuqueuses et administration de telles preparations par voie transmuqueuse

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022461A1 (fr) * 1993-03-26 1994-10-13 Merkus Franciscus W H M Formulation servant a administrer de l'insuline par voie nasale
FR2736547A1 (fr) * 1995-07-12 1997-01-17 Ltt Inst Co Ltd Medicament pour administration nasale
GB2303064A (en) * 1995-07-12 1997-02-12 Ltt Inst Co Ltd Ion-exchange resin particles for nasal administration of vaccines and peptides
GB2303064B (en) * 1995-07-12 1999-10-06 Ltt Inst Co Ltd Medicament for nasal administration
WO2004022100A1 (fr) * 2002-08-15 2004-03-18 Yunqing Liu Formulation nanopharmaceutique et son procede de preparation
WO2005004895A3 (fr) * 2003-06-09 2005-09-15 Nastech Pharm Co Compositions et procedes d'une meilleure administration d'hormone de croissance par voie muqueuse
GB2419528A (en) * 2004-10-11 2006-05-03 Nasaleze Patents Ltd Cellulose powder and signalling agent composition suitable for nasal administration
WO2006040596A3 (fr) * 2004-10-11 2006-06-01 Nasaleze Patents Ltd Compositions pour administration intranasale
JP2008515870A (ja) * 2004-10-11 2008-05-15 ナサリーズ・ピーピーエム・リミテッド 経鼻投与用組成物
US8202550B2 (en) 2004-10-11 2012-06-19 Nasaleze Ppm Limited Compositions for intranasal administration
WO2008016729A1 (fr) * 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions pour administration intranasale d'insuline humaine et leurs utilisations
US9993425B2 (en) 2006-08-04 2018-06-12 Marina Biotech, Inc. Compositions for intranasal delivery of human insulin and uses thereof
US20180000904A1 (en) * 2015-02-17 2018-01-04 Eli Lilly And Company Nasal powder formulation for treatment of hypoglycemia
KR102121443B1 (ko) * 2015-02-17 2020-06-10 일라이 릴리 앤드 캄파니 저혈당증의 치료를 위한 비강 분말 제제
KR20170103934A (ko) * 2015-02-17 2017-09-13 일라이 릴리 앤드 캄파니 저혈당증의 치료를 위한 비강 분말 제제
JP2018507852A (ja) * 2015-02-17 2018-03-22 イーライ リリー アンド カンパニー 低血糖症の治療用経鼻粉末製剤
WO2016133863A1 (fr) * 2015-02-17 2016-08-25 Eli Lilly And Company Formulation de poudre nasale pour le traitement de l'hypoglycémie
US10213487B2 (en) 2015-02-17 2019-02-26 Eli Lilly And Company Nasal powder formulation for treatment of hypoglycemia
JP2019147817A (ja) * 2015-02-17 2019-09-05 イーライ リリー アンド カンパニー 低血糖症の治療用経鼻粉末製剤
EP3258919B1 (fr) 2015-02-17 2020-01-15 Eli Lilly and Company Formulation de poudre nasale pour le traitement de l'hypoglycémie
EA034820B1 (ru) * 2015-02-17 2020-03-25 Эли Лилли Энд Компани Порошковый состав для интраназального введения для лечения гипогликемии
CN107278154A (zh) * 2015-02-17 2017-10-20 伊莱利利公司 用于治疗低血糖的鼻粉末制剂
EP3673900A1 (fr) * 2015-02-17 2020-07-01 Eli Lilly And Co. Formulation de poudre nasale pour le traitement de l'hypoglycémie
EP3673899A1 (fr) * 2015-02-17 2020-07-01 Eli Lilly And Co. Formulation de poudre nasale pour le traitement de l'hypoglycémie
CN107278154B (zh) * 2015-02-17 2021-04-09 伊莱利利公司 用于治疗低血糖的鼻粉末制剂
JP2021107418A (ja) * 2015-02-17 2021-07-29 イーライ リリー アンド カンパニー 低血糖症の治療用経鼻粉末製剤
US12226456B2 (en) * 2015-02-17 2025-02-18 Amphastar Pharmaceuticals, Inc. Nasal powder formulation for treatment of hypoglycemia
JP7094242B2 (ja) 2015-02-17 2022-07-01 イーライ リリー アンド カンパニー 低血糖症の治療用経鼻粉末製剤
CN113727700A (zh) * 2019-04-26 2021-11-30 伊莱利利公司 稳定的肽制剂的制备方法

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Publication number Publication date
MX9203615A (es) 1992-09-01
DK49791D0 (da) 1991-03-20
AU1468792A (en) 1992-10-21
ZA922006B (en) 1992-11-25

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