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BE1006872A6 - Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE) - Google Patents

Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE) Download PDF

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Publication number
BE1006872A6
BE1006872A6 BE9300299A BE9300299A BE1006872A6 BE 1006872 A6 BE1006872 A6 BE 1006872A6 BE 9300299 A BE9300299 A BE 9300299A BE 9300299 A BE9300299 A BE 9300299A BE 1006872 A6 BE1006872 A6 BE 1006872A6
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BE
Belgium
Prior art keywords
nasal
dhe
dihydroergotamine
ergotamine
hydro
Prior art date
Application number
BE9300299A
Other languages
Dutch (nl)
Original Assignee
Merkus Franciscus W H M
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
Priority to BE9300299A priority Critical patent/BE1006872A6/en
Application filed by Merkus Franciscus W H M filed Critical Merkus Franciscus W H M
Priority to AT94911944T priority patent/ATE241984T1/en
Priority to US08/525,771 priority patent/US5756483A/en
Priority to DE69432789T priority patent/DE69432789T2/en
Priority to JP6521631A priority patent/JPH08508472A/en
Priority to EP94911944A priority patent/EP0689438B1/en
Priority to AU64288/94A priority patent/AU6428894A/en
Priority to ES98109002T priority patent/ES2239369T3/en
Priority to PT94911944T priority patent/PT689438E/en
Priority to PT98109002T priority patent/PT865789E/en
Priority to EP98109002A priority patent/EP0865789B1/en
Priority to DK98109002T priority patent/DK0865789T3/en
Priority to AT98109002T priority patent/ATE290864T1/en
Priority to ES94911944T priority patent/ES2194867T3/en
Priority to DE69434304T priority patent/DE69434304T2/en
Priority to PCT/EP1994/000891 priority patent/WO1994022445A2/en
Priority to DK94911944T priority patent/DK0689438T3/en
Application granted granted Critical
Publication of BE1006872A6 publication Critical patent/BE1006872A6/en
Priority to US09/062,633 priority patent/US5942251A/en
Priority to JP2004293322A priority patent/JP2005041884A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Otolaryngology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to nasal pharmaceutical preparations in a compositionand form that is suitable for nasal application of di-hydro-ergotamine (DHE),such as nose drops, nasal spray, suspension, gel, ointment or powder.Consistent with the invention, in addition to the di-hydro-ergotamine ordi-hydro-ergotamine salt, the nasal pharmaceutical preparation also containsa cyclodextrine, for example a methylated beta-cyclodextrine with a CH3substitution factor between 0.5 and 3.0. Moreover, the preparation may alsocontain a preservative and/or viscosity increasing matter and/or anisotonicity substances and/or a complexing agent, such as sodium edetateand/or pH controlling substances.

Description

       

   <Desc/Clms Page number 1> 
 



  NASALE FARMACEUTISCHE PREPARATEN MET DIHYDROERGOTAMINE (DHE) De uitvinding heeft betrekking op nasale farmaceutische preparaten met een voor nasale toediening van dihydroergotamine (DHE) geschikte samenstelling en vorm, zoals neusdruppels, neusspray, suspensie, gel, zalf of poeder. 



  Dihydroergotamine mesylaat wordt reeds lang in de therapie van migraine toegepast. Bij patiënten met migraine-aanvallen is DHE geschikt voor interval behandeling in de vorm van tabletten of een oplossing, die oraal worden ingenomen. Bij acute aanvallen wordt DHE per intraveneuze of intramusculaire injectie toegediend. 



  DHE is recent op de markt geintroduceerd als nasale spray ter vermijding van de orale of injectie-therapie (o. a. Dihydergot nasal spray en Diergo-spray). De nasale toediening van DHE zou een goed alternatief kunnen zijn, omdat het minder pijn-   lijk,   minder duur en veel gemakkelijker voor de patiënt is dan een injectie. Ook is de nasale spray een meer efficiënte wijze van behandelen dan de orale toediening, omdat veel migraine patiënten last hebben van misselijkheid en vooral braken. 



  Een nasale spray, die DHE 4 mg/ml bevat, is in de afgelopen jaren uitvoerig bestudeerd door een aantal researchgroepen. 



  Door sommigen hiervan wordt gerapporteerd dat de DHE 4 mg/ml spray tevens 5% glucose en 1% coffeine bevat. Het bleek dat 1 mg DHE nasaal toegediend, equivalent was aan 10 mg oraal en dat de biologische beschikbaarheid bijna 40% bedroeg ten 
 EMI1.1 
 opzichte van de intramusculaire toediening (P. en L. Jespersen, Cephalalgia 1986 De maximale venoconstrictie veroorzaakt door 1 mg DHE nasaal, bedroeg ongeveer 40%, en die van 0, 5 mg i. m. DHE ongeveer 

 <Desc/Clms Page number 2> 

 50%, beide gemeten ten opzichte van de initiële veneuze diameter   (W. H. Aellig   en J. Rosenthaler, Eur. J. Clin. Pharm. 



  1986 ; 30 : 581-584). 



  Nasaal DHE bleek een gelijke effectiviteit te hebben in het verlichten van migraine aanvallen als een orale toediening van ergotamine en   coffeine   (D. Hirt et al., Cephalalgia   1989 ;   9, suppl   10 : 410-411).   In een andere studie werd de effectiviteit van nasaal DHE 4 mg/ml bevestigd bij 904 patiënten. 



  Bij 18, 4% van deze patiënten werden bijwerkingen gerapporteerd : nasale irritatie, braken, misselijkheid, vermoeidheid, duizeligheid, ademnood, tachycardie en transpiratie. Slechts 3, 9 % van de patiënten weigerde verdere behandeling met nasaal DHE (G. Jenzer en M. F. Bremgartner, Schweiz. Rundsch. 



  Med. Prax. 1990 ; 79 ; 914-917). Lataste et al. (Cephalalgia   1989 ;   9, suppl. 10 : 342-343) en Di Serio et al. (Cephalalgia   1989 ;   9, suppl. 10 : 344-345) bevestigen de effectiviteit van nasaal DHE bij de acute behandeling van migraine. In tegenstelling hiermee zijn de resultaten van Tulunay et al. (Cephalalgia   1987 ; 7 :   131-133) die geen verschil konden aantonen tussen nasaal DHE en placebo. 



  De meeste van de hierboven genoemde studies leveren dus een bemoedigend resultaat en het lijkt dat nasaal DHE toegediend in de samenstelling van 4 mg/ml, tezamen met 5% glucose en 1% coffeine, een interessant alternatief is voor de orale en parenterale preparaten. DHE in deze samenstelling is op recept verkrijgbaar in verschillende landen (o. a. Zwitserland). 



  Een groot probleem is echter dat de bekende samenstelling van het preparaat weinig stabiel is. Een producent   brengt'DHE-   nasaal'op de markt in een glazen ampul, die door de patiënt eerst gebroken moet worden en   daarna   in de neus wordt gespoten met een aparte spray-unit. 



  De uitvinding beoogt een nasaal farmaceutisch preparaat met 

 <Desc/Clms Page number 3> 

 een voor nasale toediening geschikte samenstelling en vorm voor de toediening van dihydroergotamine, dat efficiënt door de neus wordt geabsorbeerd en dat een hoge mate van stabiliteit bezit. 



  Hiertoe bevat volgens de uitvinding het nasaal farmaceutisch preparaat naast het dihydroergotamine, of het dihydroergotamine-zout, cyclodextrine.. 



  Hoewel in de afgelopen jaren nasale toediening van DHE is beschreven, is er nimmer een preparaat gepubliceerd, waarin dit geneesmiddel was gecombineerd met een cyclodextrine. De onderzoekingen die tot de uitvinding hebben geleid, hadden het doel om de biologische beschikbaarheid, de toxiciteit en de stabiliteit van dit geneesmiddel te verbeteren. 



  Bij die onderzoekingen is verrassenderwijs gevonden dat DHE als base (dihydroergotamine) en als zout (dihydroergotamine mesylaat), toegediend in combinatie met een cyclodextrine, in het bijzonder een gemethyleerde ss-cyclodextrine met een graad van   CH3-substitutie   ('degree of   substitution'ofwel D. S.)   tussen 0, 5-3, 0, onverwacht efficiënt door de neus wordt geabsorbeerd. In vrijwilligers is een uitermate hoge mate van absorptie gebleken. Bovendien is gebleken dat het preparaat een, ten opzichte van de bekende preparaten, superieure stabiliteit heeft. 



  Deze nasale toediening kan plaatsvinden in de vorm van een neusspray, neusdruppels, gel, zalf of poeder en kan de gebruikelijke conserveermiddelen en viscositeitsverhogende stoffen bevatten. 



  Het preparaat kan nasaal worden toegediend door middel van een dispenser die een bepaalde hoeveelheid ervan bevat. De dispenser kan een   pompje   omvatten om het preparaat als neusspray in het neusgat te spuiten. Het kan ook een pompje of een ander middel omvatten om een suspensie, een gel, een 

 <Desc/Clms Page number 4> 

 zalf, een poeder of neusdruppels in een afgepaste hoeveelheid af te geven. De afgepaste hoeveelheid kan zieh ook bevinden in een capsule die wordt geopend voor of tijdens het toedienen. De dispenser kan ook een vloeistof opzuigend en/of vasthoudend element omvatten zoals een tampon of een sponsje. 



  VOORBEELD 1
Dihydroergotamine mesylaat 0, 25 g
Methyl-ss-cyclodextrine D. S. 1, 8 2, 5 g 
 EMI4.1 
 Benzalkoniumchloride 0, % 
NA-EDTA 0, 05-0, 1 %
Sorbitol 5 %
Gedestilleerd water tot 100 ml
1 puff = 100   lil =   250   jig   DHE VOORBEELD 2
Dihydroergotamine mesylaat 0, 5 g 
 EMI4.2 
 Methyl-ss-cyclodextrine D. 5 g Benzalkoniumchloride 0, 01 % Na-EDTA   0, 05 %   Sorbitol 5 % Hydroxypropylmethylcellulose 1-2 % Gedestilleerd water tot 100 ml 100   lil gel   = 500   jig   DHE



   <Desc / Clms Page number 1>
 



  The invention relates to nasal pharmaceutical preparations of a composition and form suitable for nasal administration of dihydroergotamine (DHE), such as nasal drops, nasal spray, suspension, gel, ointment or powder. NASAL PHARMACEUTICAL PREPARATIONS WITH DIHYDROERGOTAMINE (DHE)



  Dihydroergotamine mesylate has long been used in migraine therapy. In patients with migraine attacks, DHE is suitable for interval treatment in the form of tablets or a solution, which are taken orally. In acute attacks, DHE is administered by intravenous or intramuscular injection.



  DHE has recently been introduced to the market as a nasal spray to avoid oral or injection therapy (eg a. Dihydergot nasal spray and Diergo spray). The nasal administration of DHE could be a good alternative, because it is less painful, less expensive and much easier for the patient than an injection. The nasal spray is also a more efficient method of treatment than the oral administration, because many migraine sufferers suffer from nausea and especially vomiting.



  A nasal spray containing DHE 4 mg / ml has been extensively studied in recent years by a number of research groups.



  Some of these report that the DHE 4 mg / ml spray also contains 5% glucose and 1% caffeine. It was found that 1 mg DHE administered nasally was equivalent to 10 mg orally and the bioavailability was nearly 40%
 EMI1.1
 relative to intramuscular administration (P. and L. Jespersen, Cephalalgia 1986) The maximum venoconstriction caused by 1 mg DHE nasal was about 40%, and that of 0.5 mg i. m DHE about

 <Desc / Clms Page number 2>

 50%, both measured relative to the initial venous diameter (W.H. Aellig and J. Rosenthaler, Eur. J. Clin. Pharm.



  1986; 30: 581-584).



  Nasal DHE was found to have similar effectiveness in relieving migraine attacks as an oral administration of ergotamine and caffeine (D. Hirt et al., Cephalalgia 1989; 9, suppl 10: 410-411). In another study, the effectiveness of nasal DHE 4 mg / ml was confirmed in 904 patients.



  Adverse reactions were reported in 18.4% of these patients: nasal irritation, vomiting, nausea, fatigue, dizziness, breathlessness, tachycardia, and perspiration. Only 3.9% of patients refused further treatment with nasal DHE (G. Jenzer and M. F. Bremgartner, Schweiz. Rundsch.



  Med. Prax. 1990; 79; 914-917). Lataste et al. (Cephalalgia 1989; 9, suppl. 10: 342-343) and Di Serio et al. (Cephalalgia 1989; 9, suppl. 10: 344-345) confirm the effectiveness of nasal DHE in the acute treatment of migraine . In contrast, the results of Tulunay et al. (Cephalalgia 1987; 7: 131-133) were unable to demonstrate a difference between nasal DHE and placebo.



  Thus, most of the above studies provide encouraging results and it seems that nasal DHE administered in the 4 mg / ml formulation, together with 5% glucose and 1% caffeine, is an interesting alternative to the oral and parenteral preparations. DHE in this composition is available by prescription in various countries (including Switzerland).



  A major problem, however, is that the known composition of the preparation is not very stable. A manufacturer markets 'DHE nasal' in a glass ampoule, which must first be broken by the patient and then injected into the nose with a separate spray unit.



  The invention contemplates a nasal pharmaceutical composition containing

 <Desc / Clms Page number 3>

 a composition and form suitable for nasal administration for the administration of dihydroergotamine, which is efficiently absorbed through the nose and which has a high degree of stability.



  For this purpose, according to the invention, the nasal pharmaceutical preparation contains, in addition to the dihydroergotamine, or the dihydroergotamine salt, cyclodextrin.



  Although nasal administration of DHE has been described in recent years, no formulation has ever been published in which this drug has been combined with a cyclodextrin. The studies that led to the invention aimed to improve the bioavailability, toxicity and stability of this drug.



  In those studies, it has surprisingly been found that DHE administered as a base (dihydroergotamine) and as a salt (dihydroergotamine mesylate) in combination with a cyclodextrin, in particular a methylated ss-cyclodextrin with a degree of substitution (degree of substitution) DS) between 0.5-3.0, is absorbed through the nose unexpectedly efficiently. An extremely high degree of absorption has been found in volunteers. In addition, it has been found that the preparation has superior stability compared to the known preparations.



  This nasal administration may take the form of a nasal spray, nasal drops, gel, ointment or powder and may contain the usual preservatives and viscosity enhancers.



  The preparation can be administered nasally by means of a dispenser containing a certain amount of it. The dispenser may include a pump to inject the preparation into the nostril as a nasal spray. It may also include a pump or other means to dissolve a suspension, a gel, a

 <Desc / Clms Page number 4>

 deliver ointment, powder, or nose drops in a measured amount. The metered amount may also be contained in a capsule that is opened before or during administration. The dispenser may also include a liquid aspirating and / or retaining element such as a tampon or a sponge.



  EXAMPLE 1
Dihydroergotamine mesylate 0.25 g
Methyl-ss-cyclodextrin D. S. 1.8 2.5 g
 EMI4.1
 Benzalkonium chloride 0.1%
NA-EDTA 0.05-0.1%
Sorbitol 5%
Distilled water to 100 ml
1 puff = 100 lil = 250 jig DHE EXAMPLE 2
Dihydroergotamine mesylate 0.5 g
 EMI4.2
 Methyl-ss-cyclodextrin D. 5 g Benzalkonium chloride 0.01% Na-EDTA 0.05% Sorbitol 5% Hydroxypropylmethylcellulose 1-2% Distilled water to 100 ml 100 µl gel = 500 jig DHE

Claims (8)

CONCLUSIES : 1. Nasaal farmaceutisch preparaat met een voor nasale toe- diening geschikte samenstelling en vorm, dat dihydroer- gotamine of dihydroergotamine-zout en cyclodextrine bevat. CONCLUSIONS: 1. Nasal pharmaceutical composition with a composition and form suitable for nasal administration, which contains dihydroergotamine or dihydroergotamine salt and cyclodextrin. 2. Nasaal farmaceutisch preparaat volgens conclusie 1, met het kenmerk dat het dihydroergotamine base bevat. Nasal pharmaceutical preparation according to claim 1, characterized in that it contains dihydroergotamine base. 3. Nasaal farmaceutisch preparaat volgens conclusie 1, met het kenmerk dat het dihydroergotamine mesylaat bevat. Nasal pharmaceutical preparation according to claim 1, characterized in that the dihydroergotamine contains mesylate. 4. Nasaal farmaceutisch preparaat volgens conclusie 1-3, met het kenmerk dat het als cyclodextrine bevat, methyl- ss-cyclodextrine met een graad van substitutie tussen 0, 5-3, 0.   Nasal pharmaceutical preparation according to claims 1-3, characterized in that it contains as cyclodextrin, methyl ss-cyclodextrin with a degree of substitution between 0.5-3.0. 5. Nasaal farmaceutisch preparaat volgens een der voorgaan- de conclusies met het kenmerk dat het tevens bevat een conserveermiddel en/of een viscositeitsverhogende stof en/of een isotoniciteitsmiddel en/of een complexerende stof, zoals natriumedetaat en/of stoffen om de pH in te stellen. Nasal pharmaceutical preparation according to any one of the preceding claims, characterized in that it also contains a preservative and / or a viscosity-increasing substance and / or an isotonicity agent and / or a complexing agent, such as sodium edate and / or substances to adjust the pH set. 6. Inrichting omvattende een dispenser voor nasale toedie- ning welke een bepaalde hoeveelheid van een farmaceu- tisch preparaat volgens een der voorgaande conclusies bevat. A device comprising a nasal administration dispenser containing a specified amount of a pharmaceutical composition according to any one of the preceding claims. 7. Inrichting volgens conclusie 6, met het kenmerk, dat de dispenser een nasale tampon, spons of dergelijk element omvat, waarin de nasale compositie is verwerkt. Device according to claim 6, characterized in that the dispenser comprises a nasal tampon, sponge or the like, in which the nasal composition is incorporated. 8. Capsule voor nasale toediening van dihydroergotamine, inhoudende een preparaat volgens een der voorgaande con- cluses. 8. Capsule for nasal administration of dihydroergotamine, comprising a composition according to any one of the preceding claims.
BE9300299A 1993-03-26 1993-03-26 Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE) BE1006872A6 (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
BE9300299A BE1006872A6 (en) 1993-03-26 1993-03-26 Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE)
EP98109002A EP0865789B1 (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for intranasal administration of dihydroergotamine
DE69432789T DE69432789T2 (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR THE INTRANASAL ADMINISTRATION OF APOMORPHINE
JP6521631A JPH08508472A (en) 1993-03-26 1994-03-18 Drugs for intranasal administration of dihydroergotamine, apomorphine and morphine
EP94911944A EP0689438B1 (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for intranasal administration of apomorphine
AU64288/94A AU6428894A (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for intranasal administration of dihydroergotamine, apomorphine and morphine
ES98109002T ES2239369T3 (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL ADMINISTRATION OF DIHYDROERGOTAMINE.
PT94911944T PT689438E (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR INTROMASSAL ADMINISTRATION OF APOMORPHINE
AT94911944T ATE241984T1 (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL ADMINISTRATION OF APOMORPHINE
US08/525,771 US5756483A (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for intranasal administration of apomorphine
DK98109002T DK0865789T3 (en) 1993-03-26 1994-03-18 Pharmaceuticals for intranasal administration of dihydroergotamine
AT98109002T ATE290864T1 (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL ADMINISTRATION OF DIHYDROERGOTAMIN
ES94911944T ES2194867T3 (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR THE INTRANASAL ADMINISTRATION OF APOMORPHINE.
DE69434304T DE69434304T2 (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for the intranasal administration of dihydroergotamine
PCT/EP1994/000891 WO1994022445A2 (en) 1993-03-26 1994-03-18 Pharmaceutical compositions for intranasal administration of dihydroergotamine, apomorphine and morphine
DK94911944T DK0689438T3 (en) 1993-03-26 1994-03-18 Pharmaceuticals for intranasal administration of apomorphine
PT98109002T PT865789E (en) 1993-03-26 1994-03-18 PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL ADMINISTRATION OF DI-HYDROERGOTAMINE
US09/062,633 US5942251A (en) 1993-03-26 1998-04-17 Pharmaceutical compositions for intranasal administration of dihydroergotamine
JP2004293322A JP2005041884A (en) 1993-03-26 2004-10-06 Intranasal medicine composition and production method therefor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
BE9300299A BE1006872A6 (en) 1993-03-26 1993-03-26 Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE)

Publications (1)

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BE1006872A6 true BE1006872A6 (en) 1995-01-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994197B2 (en) 2007-02-11 2011-08-09 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US11185497B2 (en) 2018-01-05 2021-11-30 Impel Neuropharma, Inc. Intranasal delivery of dihydroergotamine by precision olfactory device
US11266799B2 (en) 2015-09-10 2022-03-08 Impel Neuropharma, Inc. In-line nasal delivery device

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994197B2 (en) 2007-02-11 2011-08-09 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US8119639B2 (en) 2007-02-11 2012-02-21 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
EP2425819A1 (en) 2007-02-11 2012-03-07 MAP Pharmaceuticals Inc Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
EP2425820A1 (en) 2007-02-11 2012-03-07 MAP Pharmaceuticals Inc Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
US8148377B2 (en) 2007-02-11 2012-04-03 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US9833451B2 (en) 2007-02-11 2017-12-05 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
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