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WO2000000199A1 - Administration intranasale de citrate de sildenafil - Google Patents

Administration intranasale de citrate de sildenafil Download PDF

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Publication number
WO2000000199A1
WO2000000199A1 PCT/US1999/014352 US9914352W WO0000199A1 WO 2000000199 A1 WO2000000199 A1 WO 2000000199A1 US 9914352 W US9914352 W US 9914352W WO 0000199 A1 WO0000199 A1 WO 0000199A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
pharmaceutical composition
mammal
surfactant
buffer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/014352
Other languages
English (en)
Inventor
Vincent D. Romeo
Charanjit R. Behl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Marina Biotech Inc
Original Assignee
MDRNA Inc
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 MDRNA Inc filed Critical MDRNA Inc
Priority to AU47172/99A priority Critical patent/AU4717299A/en
Publication of WO2000000199A1 publication Critical patent/WO2000000199A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates generally to the intranasal delivery of cyclic guanosine monophosphate-specific phosphodiesterase inhibitors to a mammal. More particularly, pharmaceutical compositions for the treatment of various diseases, including impotence, are disclosed which compositions are dispersed in nasal delivery vehicles. Methods of treatment via various nasal delivery systems are also provided.
  • PDE PDE
  • a variety of cardiovascular disorders including angina, hypertension, heart failure and atherosclerosis
  • U.S. Patent Nos. 5,250,534, 5,272,147 and 5,426,107 assigned to Pfizer Inc. which are hereby incorporated by reference reportedly describe a series of pyrazolo[4,3-d]- pyrimidin-7-ones which are potent and selective inhibitors of cGMP PDE.
  • cGMP PDE inhibitors block the action of endogenous cGMP PDE and allows for the relaxation of the corpus cavernosum tissue of a penis which in turn allows blood to flow into the penis and subsequent erection.
  • These compositions are reported to have therapeutic activity when administered orally, intravenously, buccally or sublingually.
  • These traditional methods of delivery suffer from a variety of draw backs.
  • drugs administered orally suffer from the well know "first pass effect" in which the environment of the stomach denatures and/or degrades large amounts of the drug before a therapeutically effective amount is absorbed.
  • Intravenous delivery of such drugs is painful and is not tolerated well by certain patients.
  • Buccal and sublingual delivery of such drugs is often slow and can lead to degradation of the drug by enzymes in the oral cavity.
  • each of these traditional delivery mechanisms take an hour or longer before peak plasma concentration of the inhibitor is reached.
  • the relatively long lag time between administration of such inhibitors and their physiologic effect is thus not optimal because of the time it takes to achieve peak plasma concentrations.
  • one hour lag between administration of the inhibitor and its desired effect is inconvenient.
  • the present invention relates to pharmaceutical compositions for the treatment of sexual dysfunction in a mammal.
  • This composition includes a cyclic guanosine monophosphate-specific phosphodiesterase type V inhibitor in combination with a nasal delivery vehicle.
  • a method is provided for treating impotence in humans that includes nasally administering the above-referenced composition.
  • a nasally administered pharmaceutical composition that includes a therapeutically effective amount of a cyclic guanosine monophosphate- specific phosphodiesterase type V inhibitor dispersed in a buffer to maintain the pH of the inhibitor, a pharmaceutically acceptable thickening agent, a humectant and a pharmaceutically acceptable surfactant.
  • a method of treating impotence, angina, hypertension, pulmonary hypertension, heart failure, atherosclerosis and glaucoma in a human in need of such treatment includes administering to a nasal membrane of the human an effective amount of this pharmaceutical composition.
  • a method of treating impotence in a mammal includes administering into a nasal cavity of the mammal a therapeutically effective dosage of a cyclic guanosine monophosphate specific phosphodiesterase inhibitor in combination with a nasal delivery vehicle that includes a pharmaceutically acceptable buffer, thickening agent, humectant and surfactant.
  • a method of administering a therapeutically effective amount of a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor to a mammal through a nasal membrane includes delivering to a nasal membrane of the mammal the inhibitor dispersed in a nasal delivery vehicle that includes a pharmaceutically acceptable buffer, thickening agent, humectant and surfactant.
  • an intranasal dosage unit for treating impotency in a mammal.
  • This dosage unit includes an effective amount of a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor in combination with an intranasal delivery formulation.
  • This delivery formulation includes a buffer and an effective amount of a surfactant. The pH of the buffer and the concentration of the surfactant are selected to facilitate the abso ⁇ tion of the inhibitor so that a peak plasma concentration of the inhibitor is achieved in less than one hour, desirably in less than 45 minutes, such as for example, in about 10 to about 20 minutes of administering the dosage unit to a nasal mucosa of the mammal.
  • the present invention is directed to pharmaceutical compositions and methods for treating sexual dysfunction in a mammal which composition includes a cyclic guanosine monophosphate-specific inhibitor in combination with a nasal delivery vehicle.
  • the phrase "sexual dysfunction" is intended to encompass medically related symptoms resulting in the inability of a male or female to perform sexually, including male impotence.
  • the term "sexual dysfunction" is intended to encompass medically related symptoms resulting in the inability of a male or female to perform sexually, including male impotence.
  • impotence is intended to mean the inability of a male to achieve and/or sustain a penile erection sufficient for vaginal penetration and intercourse.
  • cyclic guanosine monophosphate-specific phosphodiesterase inhibitors of the present invention are well known in the art and are set forth in U.S. Patent Nos.
  • cGMP PDE inhibitors include compounds of the formula (I):
  • R is H; C,-C 3 alkyl; C 3 -C 5 perfluoroalkyl; or C 3 -C 5 cycloalkyl
  • R 2 is H; C,-C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl; C r C 3 perfluoroalkyl or C 3 -C 6 cycloalkyl
  • R 3 is C r C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl; C,-C 6 perfluoroalkyl; C 3 -C 5 cycloalkyl; C 3 -C 6 alkenyl; or C 3 -C 6 alkynyl
  • R, is C r C 4 alkyl optionally substituted with OH, NR ⁇ , CN, CONRjR ⁇ or CO 2 R 7 ; C 2 -C 4 alkenyl optionally substituted with CN, CONRjR,; or CO 2 R 7 ; C 2 -C
  • R 5 and Rg are each independently H or C,-C 4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R n )-piperazinyl or imidazolyl group wherein this group is optionally substituted with methyl or OH;
  • R 7 is H or C ⁇ -C 4 alkyl;
  • R g is C r C 3 alkyl optionally substituted with NRjRg; Rg and R 10 together with the nitrogen atom to which they are attached form a pyrrolidiny
  • compositions also include all classes of PDE inhibitors including the type II, III and V inhibitors identified in International Publication No. WO 94/28902, as well as all pyrazolopyrimidinones which are effective for treating sexual dysfunction in a mammal, including impotence.
  • composition set forth in formula I above is l-[[3-(6,7-dihydro-
  • cGMP PDE inhibitors of the present invention can also include chemically modified equivalents of Sildenafil Citrate.
  • chemically modified equivalents includes pharmaceutical salts, derivatives, analogs, homologs, free bases and other chemical variations of the compositions set forth above which do not significantly alter the structure or function thereof.
  • nasal delivery vehicles that can be used with the present invention can take various forms including for example, powders, powder microspheres, solutions, gels, nano-particle suspensions, suspensions, liposomes, emulsions and microemulsions.
  • nano-particle suspensions are made by milling powders of the present pharmaceutical compositions to a micronized size. Delivery vehicles made from such nano-particles provide superior absorbability for compositions having generally poor solubility.
  • the various forms of the delivery vehicle set forth above can include a buffer to maintain the pH of the inhibitor, a pharmaceutically acceptable thickening agent, humectant and surfactant.
  • the pH of the buffer is selected to maintain the inhibitor in an un-ionized form.
  • the pH of the buffer is selected to optimize the absorption of the inhibitor across the nasal mucosa.
  • the particular pH of the buffer can vary depending upon the particular nasal delivery formulation, as well as the specific inhibitor composition selected.
  • Buffers that are suitable for use in the present invention include, for example, acetate, citrate and phosphate buffers.
  • the pH of the compositions should be maintained from about 3 to about 10. Compositions having a pH of less than about 3 or greater than about 10 can increase the risk of irritating the nasal mucosa of a recipient.
  • the viscosity of the compositions of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.
  • Thickening agents that can be used in accordance with the present invention include for example, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer and mixtures thereof.
  • concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agents will also be used in the particulate formulations of the present invention.
  • compositions of the present invention also include a humectant or a soothing/moisturizing agent to reduce or prevent drying of the mucus membrane and to prevent irritation thereof.
  • Suitable humectants that can be used in the present invention include, for example, sorbitol, propylene glycol and glycerol.
  • concentration of the humectant or soothing/moisturizing agent(s) in the present compositions will also vary with the agent selected.
  • a therapeutically acceptable surfactant is added to the nasal delivery vehicle.
  • Suitable surfactants that can be used in accordance with the present invention include, for example, polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides, such as for example, Tween 80, Polyoxyl 40 Stearate, Polyoxy ethylene 50 Stearate, fusieates, bile salts and Octoxynol.
  • Suitable surfactants include non- ionic, anionic and cationic surfactants. These surfactants can be present in the delivery vehicle in a concentration ranging from about 0.001% to about 20% by weight.
  • Particulate formulations may also contain suitable surfactants.
  • ingredients may also be inco ⁇ orated into the nasal delivery vehicle provided they do not interfere with the action of the inhibitor or significantly decrease the abso ⁇ tion of the inhibitor across the nasal mucosa.
  • Such ingredients can include, for example, pharmaceutically acceptable excipients and preservatives.
  • the excipients that can be used in accordance with the present invention include, for example, bio-adhesives and/or swelling/thickening agents.
  • any other suitable abso ⁇ tion enhancers as known in the art may also be used in both the non-particulate and particulate formulations set forth herein.
  • preservatives can be added to the present compositions.
  • Suitable preservatives that can be used with the present compositions include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium, with benzalkonium chloride being preferred.
  • the preservative will be present in the present compositions in a concentration of up to about 2% by weight. The exact concentration of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skilled in the art.
  • compositions as described above are administered nasally to a mammal to treat impotence.
  • administered nasally or “nasal administration” is intended to mean that the cGMP PDEs are combined with a suitable delivery vehicle for abso ⁇ tion across the nasal mucosa of a mammal, desirably a human.
  • Another embodiment of the present invention is a nasally administered pharmaceutical composition that includes a therapeutically effective amount of a cyclic monophosphate-specific phosphodiesterase inhibitor dispersed in a buffer to maintain the pH of the inhibitor, a pharmaceutically acceptable thickening agent, a humectant and a pharmaceutically acceptable surfactant.
  • therapeutically effective amount means a unit dosage of the present inhibitors which is able to be combined with a pharmaceutically acceptable nasal delivery vehicle and absorbed through the nasal mucosa of a mammal to provide a peak plasma concentration within the mammal of the inhibitor in less than 1 hour, desirably in less than about 45 minutes, such as for example, from about 20 to about 30 minutes, and which renders the intended physiological effect, such as for example to allow an erection in an impotent mammal.
  • the cGMP PDE inhibitor is a cyclic guanosine monophosphate- specific phosphodiesterase type V inhibitor. More desirably, the inhibitor is l-[[3- (6,7-dihydro-l-methyl-7-oxo-3-propyl-l-H-pyrazolo [4,3-d]pyrimidin-5-yl)-4- ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate.
  • the present nasally administered pharmaceutical compositions can be used to treat a wide variety of disorders including for example, stable, unstable and variant angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, such as for example, post- percutaneous transluminal coronary angioplasty, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of gut motility, e.g., irritable bowel syndrome, as well as sexual dysfunction, including for example impotence.
  • disorders of gut motility e.g., irritable bowel syndrome
  • sexual dysfunction including for example impotence.
  • a method of treating impotence includes administering into a nasal cavity of a mammal for abso ⁇ tion through the nasal mucosa thereof a therapeutically effective dosage of a cGMP PDE inhibitor as previously set forth in combination with a nasal delivery vehicle.
  • the inhibitor is a cGMP PDE inhibitor and includes sildenafil citrate and chemically modified equivalents thereof.
  • the nasal delivery vehicle can include, for example, a pharmaceutically acceptable buffer, a thickening agent a humectant and a surfactant.
  • a method for administering a therapeutically effective amount of a cGMP PDE inhibitor to a mammal through a nasal membrane.
  • This method includes delivering to a nasal membrane of a mammal the inhibitor dispersed in a nasal delivery vehicle that includes a pharmaceutically acceptable buffer, thickening agent, humectant and surfactant.
  • the cGMP PDE inhibitor is effective for the treatment of a sexual dysfunction in a mammal, particularly impotence in man.
  • the method is also suitable for treating for example, angina, hypertension, pulmonary hypertension, heart failure, atherosclerosis and glaucoma.
  • a further embodiment of the present invention includes an intranasal dosage unit for treating impotency in a mammal.
  • This intranasal dosage unit includes an effective amount of a cGMP PDE inhibitor in combination with a pharmaceutically acceptable intranasal carrier.
  • This carrier includes a buffer and an effective amount of a surfactant. The pH of the buffer and the concentration of the surfactant are selected as set forth above to facilitate cGMP PDE inhibitor abso ⁇ tion through the nasal mucosa so that peak plasma concentrations of the inhibitor is achieved in less than 45 minutes, desirably in less than 30 minutes, and most desirably in less than 20 minutes after administration.
  • the pharmaceutically acceptable carrier of the present invention will vary depending upon the exact nature of the particular dosage form required. Suitable dosage forms that can be used with the present cGMP PDE inhibitors are found in Remington's Pharmaceutical Sciences, 18th. ed. (1995) which is hereby inco ⁇ orated by reference, and include for example, nano-particle suspensions, suspensions, ointments, gels, solutions, simple powders, powder microspheres, liposomes, emulsions or microemulsions.
  • the powder microspheres according to the present invention can be formed from, for example, various polysaccharides and celluloses including starch, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, alginate and chitosan.
  • the intranasal dosage form of the present invention can include an abso ⁇ tion enhancer and/or an excipient as previously described.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des unités galéniques à usage intranasal. Ces unités comprennent des inhibiteurs des phosphodiestérases spécifiques de la guanosine monophosphate cyclique, associés à des excipients adaptés à une administration intranasale qui contiennent un tampon, des tensioactifs et des agents facilitant l'absorption. Le pH du tampon et la concentration du tensioactif sont choisis de façon à faciliter la passage de l'inhibiteur à travers la muqueuse nasale afin d'obtenir un pic de concentration plasmatique de l'inhibiteur en moins d'une heure et de préférence en moins de 30 minutes après administration.
PCT/US1999/014352 1998-06-26 1999-06-24 Administration intranasale de citrate de sildenafil Ceased WO2000000199A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47172/99A AU4717299A (en) 1998-06-26 1999-06-24 Nasal delivery of sildenafil citrate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9094198P 1998-06-26 1998-06-26
US60/090,941 1998-06-26

Publications (1)

Publication Number Publication Date
WO2000000199A1 true WO2000000199A1 (fr) 2000-01-06

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1074258A3 (fr) * 1999-07-28 2001-04-18 Pfizer Products Inc. Méthodes et compositions pour le traitement des maladies et des affections oculaires
WO2002083674A3 (fr) * 2001-04-12 2003-01-09 Bayer Ag Compositions contenant des imidazotriazinones pour application nasale
WO2003020720A1 (fr) * 2001-09-05 2003-03-13 PALACIO BARBERÁN, John, Luis Maleate de sildenafil
US7148350B2 (en) 2000-08-08 2006-12-12 Cristalia Prod.Qui.Farm. Ltda Compounds in the form of homodimeric or heterodimeric pro-drugs; process for obtaining these pro-drugs and their acceptable pharmaceutical salts and use of compounds in the treatment of phosphodiesterases-mediated diseases or dysfunction
WO2008019106A1 (fr) * 2006-08-04 2008-02-14 Artesian Therapeutics, Inc. Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase
WO2012048685A1 (fr) 2010-06-02 2012-04-19 Thinxxs Microtechnology Ag Cellule à circulation
WO2012103881A2 (fr) 2011-04-20 2012-08-09 Bernhard Hildebrandt Prothèse articulaire biologique implantable
WO2013153035A2 (fr) 2012-04-10 2013-10-17 Bernhard Spindler Blindage de volet roulant utilisable en jalousie
DE102010056126A1 (de) 2010-02-09 2014-05-08 Vladimir Volchkov Boxermotor
DE102010056125A1 (de) 2010-03-01 2014-05-15 Vladimir Volchkov Gegenkolbenmotor
DE102013112255A1 (de) 2013-11-07 2015-05-07 Agraferm Technologies Ag Rührwerksgestell und Rührwerksanordnung für Fermenter, Fermenter, Biogasanlage, Verfahren zum Erzeugen von Biogas und Verfahren zum Umrüsten eines Fermenters
DE102013226122A1 (de) 2013-12-16 2015-06-18 Bayerische Motoren Werke Aktiengesellschaft Armlehne für einen Innenraum eines Kraftwagens sowie Bedienverfahren für eine Armlehne für einen Innenraum eines Kraftwagens
DE102016002803A1 (de) 2016-03-08 2016-08-18 Daimler Ag Befestigungseinrichtung für ein Lastenträgersystem an einem Fahrzeugdach eines Kraftfahrzeuges
WO2016131939A1 (fr) 2015-02-19 2016-08-25 Sirona Dental Systems Gmbh Insert passif de ponts et de nervures d'implant au moyen d'un outil cad/fao pour la création sans modèle de restaurations portées par implant
DE102015204186A1 (de) 2015-03-09 2016-09-15 Michael Schmidt Stoffgemisch, Verfahren zur Herstellung einer dentalen Restauration und Dentalrestauration
DE202016106728U1 (de) 2016-12-02 2016-12-14 Vetter Gmbh Flugzeug-Hebekissen mit einem Oberkissen und einem Basiskissen
DE102015014130A1 (de) 2015-10-28 2017-05-04 Frank Müller Schlägel für Schlag- und Perkussionsinstrumente in der Art eines Schlagzeugbesens (Brushes / Rods) mit zusätzlichem Schlagpolster
DE102015119438A1 (de) 2015-11-11 2017-05-11 Kmb Produktions Ag Vorrichtung zum Herstellen von Verzehrgütern
DE202017004282U1 (de) 2017-03-15 2017-10-25 Jörg Schmidt Lichtrichtende Abdeckung
DE202017005377U1 (de) 2017-10-18 2017-12-20 Nora Weber Schale zur Aufbewahrung von Mikro-/Führungsdrähten, Kathetern und ähnlichen aufwickelbaren Operationsgeräten

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE HCAPLUS ON STN, AMERICAN CHEMICAL SOCIETY, AN 1995:412879; & WO 9428902 A1 (ELLIS et al.). *
DATABASE MEDLINE ON STN, US NATIONAL LIBRARY OF MEDICINE, (Bethesda, MD, USA), AN 95159287, HEATON J.P. et al., "Recovery of Erectile Function by the Oral Administration of Apomorphine"; & UROLOGY, Feb. 1995. *
MURRAY K J: "PHOSPHODIESTERASE VA INHIBITORS", DRUG NEWS AND PERSPECTIVES., PROUS SCIENCE, ES, vol. 06, no. 03, 1 April 1993 (1993-04-01), ES, pages 150 - 156, XP002924954, ISSN: 0214-0934 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1074258A3 (fr) * 1999-07-28 2001-04-18 Pfizer Products Inc. Méthodes et compositions pour le traitement des maladies et des affections oculaires
US7148350B2 (en) 2000-08-08 2006-12-12 Cristalia Prod.Qui.Farm. Ltda Compounds in the form of homodimeric or heterodimeric pro-drugs; process for obtaining these pro-drugs and their acceptable pharmaceutical salts and use of compounds in the treatment of phosphodiesterases-mediated diseases or dysfunction
WO2002083674A3 (fr) * 2001-04-12 2003-01-09 Bayer Ag Compositions contenant des imidazotriazinones pour application nasale
US6740306B2 (en) 2001-04-12 2004-05-25 Bayer Aktiengesellschaft Imidazotriazinone-containing compositions for nasal administration
WO2003020720A1 (fr) * 2001-09-05 2003-03-13 PALACIO BARBERÁN, John, Luis Maleate de sildenafil
WO2008019106A1 (fr) * 2006-08-04 2008-02-14 Artesian Therapeutics, Inc. Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase
DE102010056126A1 (de) 2010-02-09 2014-05-08 Vladimir Volchkov Boxermotor
DE102010056125A1 (de) 2010-03-01 2014-05-15 Vladimir Volchkov Gegenkolbenmotor
WO2012048685A1 (fr) 2010-06-02 2012-04-19 Thinxxs Microtechnology Ag Cellule à circulation
WO2012103881A2 (fr) 2011-04-20 2012-08-09 Bernhard Hildebrandt Prothèse articulaire biologique implantable
WO2013153035A2 (fr) 2012-04-10 2013-10-17 Bernhard Spindler Blindage de volet roulant utilisable en jalousie
DE102013112255A1 (de) 2013-11-07 2015-05-07 Agraferm Technologies Ag Rührwerksgestell und Rührwerksanordnung für Fermenter, Fermenter, Biogasanlage, Verfahren zum Erzeugen von Biogas und Verfahren zum Umrüsten eines Fermenters
DE102013226122A1 (de) 2013-12-16 2015-06-18 Bayerische Motoren Werke Aktiengesellschaft Armlehne für einen Innenraum eines Kraftwagens sowie Bedienverfahren für eine Armlehne für einen Innenraum eines Kraftwagens
WO2016131939A1 (fr) 2015-02-19 2016-08-25 Sirona Dental Systems Gmbh Insert passif de ponts et de nervures d'implant au moyen d'un outil cad/fao pour la création sans modèle de restaurations portées par implant
DE102015203031A1 (de) 2015-02-19 2016-08-25 Sirona Dental Systems Gmbh Passive fit von Implantatbrücken und -stegen mittels eines CAD/CAM Tools für die modellfreie Erstellung von implantatgetragenen Restaurationen
DE102015204186A1 (de) 2015-03-09 2016-09-15 Michael Schmidt Stoffgemisch, Verfahren zur Herstellung einer dentalen Restauration und Dentalrestauration
DE102015014130A1 (de) 2015-10-28 2017-05-04 Frank Müller Schlägel für Schlag- und Perkussionsinstrumente in der Art eines Schlagzeugbesens (Brushes / Rods) mit zusätzlichem Schlagpolster
DE102015119438A1 (de) 2015-11-11 2017-05-11 Kmb Produktions Ag Vorrichtung zum Herstellen von Verzehrgütern
DE102016002803A1 (de) 2016-03-08 2016-08-18 Daimler Ag Befestigungseinrichtung für ein Lastenträgersystem an einem Fahrzeugdach eines Kraftfahrzeuges
DE202016106728U1 (de) 2016-12-02 2016-12-14 Vetter Gmbh Flugzeug-Hebekissen mit einem Oberkissen und einem Basiskissen
EP3330213A1 (fr) 2016-12-02 2018-06-06 Vetter GmbH Coussin de levage d'avion pourvu d'un coussin supérieur et d'un coussin de base
DE202017004282U1 (de) 2017-03-15 2017-10-25 Jörg Schmidt Lichtrichtende Abdeckung
DE202017005377U1 (de) 2017-10-18 2017-12-20 Nora Weber Schale zur Aufbewahrung von Mikro-/Führungsdrähten, Kathetern und ähnlichen aufwickelbaren Operationsgeräten

Also Published As

Publication number Publication date
AU4717299A (en) 2000-01-17

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