DE19834505A1 - Transdermal therapeutic system useful for treating male sexual impotence contains sildenafil - Google Patents
Transdermal therapeutic system useful for treating male sexual impotence contains sildenafilInfo
- Publication number
- DE19834505A1 DE19834505A1 DE1998134505 DE19834505A DE19834505A1 DE 19834505 A1 DE19834505 A1 DE 19834505A1 DE 1998134505 DE1998134505 DE 1998134505 DE 19834505 A DE19834505 A DE 19834505A DE 19834505 A1 DE19834505 A1 DE 19834505A1
- Authority
- DE
- Germany
- Prior art keywords
- transdermal therapeutic
- therapeutic system
- sildenafil
- active ingredient
- layer
- 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.)
- Withdrawn
Links
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 30
- 229960003310 sildenafil Drugs 0.000 title claims abstract description 25
- 201000001881 impotence Diseases 0.000 title description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 title 1
- -1 Viagra (RTM)) Chemical compound 0.000 claims abstract description 21
- 239000010410 layer Substances 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000011159 matrix material Substances 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 11
- 229920001296 polysiloxane Polymers 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 8
- 239000011241 protective layer Substances 0.000 claims description 8
- 239000006071 cream Substances 0.000 claims description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 6
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- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 3
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 3
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- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 3
- 229960001380 cimetidine Drugs 0.000 claims description 3
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- 150000002148 esters Chemical class 0.000 claims description 3
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- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
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- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 claims description 2
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003883 ointment base Substances 0.000 claims 1
- 229960002639 sildenafil citrate Drugs 0.000 claims 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims 1
- 229940094720 viagra Drugs 0.000 abstract description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 11
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 7
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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
- A61K31/495—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
-
- 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
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft ein wirkstoffhaltiges transdermales System zur Anwendung von Sildenafil und dessen pharmazeutisch unbedenklichen Salzen.The invention relates to a drug-containing transdermal system for the application of Sildenafil and its pharmaceutically acceptable salts.
Sildenafil [1-(4-ethoxy-3-(6,7-dihydro 1-methyl-7-oxo-3-propyl 1H-pyazolo(4,3-d)pyrimidin- 5-yl)phenylsulfonyl)-4-methyl piperazin], besser bekannt unter dem Markennamen VIAGRA, stellt einen sehr selektiven cyclischen-Guanosinmonophosphat (cGMP)-spezifischen Phosphodiesterase (PDE)-Typ-5-Hemmer dar, der zur Behandlung sowohl von organisch als auch von psychisch bedingter Impotenz entwickelt wurde.Sildenafil [1- (4-ethoxy-3- (6,7-dihydro 1-methyl-7-oxo-3-propyl 1H-pyazolo (4,3-d) pyrimidine- 5-yl) phenylsulfonyl) -4-methyl piperazine], better known under the brand name VIAGRA, represents a very selective cyclic guanosine monophosphate (cGMP) specific Phosphodiesterase (PDE) type 5 inhibitor, which is used to treat both organically and was also developed from psychological impotence.
Der physiologische Mechanismus der Erektion des Penis beinhaltet die Freisetzung von Stickoxid (NO) in den Schwellkörpern während der sexuellen Stimulation. NO aktiviert das Enzym Guanylatcyclase, welches für einen erhöhten Spiegel an cyclischem Guanosinmonophosphat (cGMP) sorgt. Dieses cGMP ist dafür verantwortlich, daß sich die glatte Muskulatur der Schwellkörper entspannt und somit das Blut in die Schwellkörper eindringen kann, so daß eine Erektion (Gliedsteife) zustande kommt. Sildenafil hat keinen direkten entspannenden Effekt auf die Schwellkörpermuskulatur, sondern es verstärkt die Wirkung des Stickoxides durch eine Hemmung der Phosphodiesterase-Typ-5 (PDE 5), welche für den Abbau von cGMP in den Schwellkörpern verantwortlich ist. Falls durch sexuelle Stimulation eine Freisetzung von NO erfolgt, steigt aufgrund der Hemmung der PDE 5 durch Sildenafil der cGMP-Spiegel in den Schwellkörpern, so daß sich die glatte Muskulatur entspannt und das Blut in die Schwellkörper eindringen kann. Die Wirkung von Sildenafil bleibt bei empfohlener Dosierung aber fehlender sexueller Stimulierung aus. The physiological mechanism of penile erection involves the release of Nitric oxide (NO) in the erectile tissue during sexual stimulation. NO activates this Enzyme guanylate cyclase, which is responsible for an increased level of cyclic Guanosine monophosphate (cGMP) provides. This cGMP is responsible for ensuring that the smooth muscle of the erectile tissue relaxes and thus the blood in the erectile tissue can penetrate so that an erection (limb stiffness) occurs. Sildenafil has none direct relaxing effect on the cavernous muscles, but it strengthens the Effect of nitrogen oxide by inhibiting phosphodiesterase type 5 (PDE 5), which is responsible for the breakdown of cGMP in the erectile tissue. If through sexual Stimulation of NO release increases due to the inhibition of PDE 5 Sildenafil the cGMP level in the erectile tissue, so that the smooth muscles relaxed and the blood can penetrate the erectile tissue. The effect of sildenafil does not occur at the recommended dosage but lacks sexual stimulation.
Bisher erfolgt die Verabreichung von Sildenafil oral in Form einer Tablette mit einem Wirkstoffgehalt von 25mg, 50 mg oder 100 mg/Tag, wobei die Bioverfügbarkeit bei nur 40% liegt. Der im Normalfall verabreichte Wirkstoffgehalt beträgt 50 mg/Tag. Die Tablette sollte, um ihre volle Wirkung zu zeigen, mindestens eine Stunde, bei vorherigem Verzehr von fetten Lebensmitteln 1,5 Stunden vor Bedarf eingenommen werden. Das sexuelle Verhalten der Patienten entbehrt somit einer gewissen Spontaneität, was eine doch sehr beträchtliche Einschränkung für diese darstellt.So far, sildenafil has been administered orally in the form of a tablet with a Active substance content of 25 mg, 50 mg or 100 mg / day, the bioavailability being only 40% lies. The active substance content normally administered is 50 mg / day. The tablet should to show their full effect, at least an hour, with previous consumption of fats Food to be taken 1.5 hours before need. The sexual behavior of the Patients are therefore somewhat spontaneous, which is very considerable Represents restriction for this.
Der größte Teil des oral verabreichten Sildenafils wird sofort in der Leber metabolisiert (first path-effect), wobei der entstandene N-demethylierter Metabolit, der eine Aktivität von 50% im Vergleich zur Muttersubstanz aufweist, weiter zu inaktiven Metaboliten umgewandelt wird. Die Metabolite werden hauptsächlich über den Kot und in geringem Maße über den Urin ausgeschieden.Most of the oral sildenafil is immediately metabolized in the liver (first path-effect), the resulting N-demethylated metabolite, which has an activity of 50% compared to the parent compound, further converted to inactive metabolites becomes. The metabolites are mainly via the faeces and to a lesser extent via the Urine excreted.
Als Nebenwirkungen werden häufig Kopfschmerzen, Durchfall, Gesichtsrötungen oder verstopfte Nasen beklagt. Ebenfalls treten teilweise Sehstörungen auf, die dadurch bedingt werden, daß Sildenafil eine gewisse Affinität für die Phosphodiesterase-Typ 6 (PDE 6) aufweist, welche in der Retina für das Farbsehen mitverantwortlich ist. Der Patient sieht, als Folge davon, alles vorübergehend mit einem Blaustich, der nach Abklingen der Wirkung wieder verschwindet. Bei langfristiger Einnahme oder bei erhöhter Dosis ist allerdings zu befürchten, daß das Auge dauerhaft Schaden nimmt.Side effects are often headache, diarrhea, facial flushing or nasal congestion complained. Visual disturbances also partially occur, which is caused by this that sildenafil has some affinity for phosphodiesterase type 6 (PDE 6) which is responsible for color vision in the retina. The patient sees when As a result, everything temporarily with a bluish tinge after the effect has subsided disappears again. With long-term use or with an increased dose, however, is too fear that the eye will suffer permanent damage.
Die Aufgabe der Erfindung ist es nun, ein transdermales therapeutisches System zur Anwendung von Sildenafil oder dessen pharmazeutisch unbedenklichen Salzen bereitzustellen, wobei die Nachteile der oralen Darreichungsform vermieden und die Patienten-Compliance verbessert werden sollen.The object of the invention is now to provide a transdermal therapeutic system Use of sildenafil or its pharmaceutically acceptable salts provide, the disadvantages of the oral dosage form avoided and the Patient compliance should be improved.
Es wurde nun überraschenderweise getunden, daß Sildenafil oder dessen pharmazeutisch wirksame Salze derart hautgängig sind, daß sehr schnell ein therapeutisch wirksamer Blutplasmaspiegel erreicht werden kann, obwohl die klassische Medizin bisher davon ausging, daß hochmolekulare Pharmaka wegen ihrer Molekülgröße und ihrer elektrischen Ladung nicht die Zellschichten des Oberflächenepithels passieren können, da dieses nur eine gewisse Porengröße und Eigenladung aufweist, die die Permeabilität für derartige Mittel begrenzt.It has now surprisingly been found that sildenafil or its pharmaceutical effective salts are so accessible to the skin that a therapeutically effective very quickly Blood plasma levels can be reached, although traditional medicine has so far been used assumed that high molecular weight pharmaceuticals because of their molecular size and their electrical Charge cannot pass through the cell layers of the surface epithelium, as this is only one has certain pore size and intrinsic charge, which is the permeability for such agents limited.
Es besteht somit die Möglichkeit relativ kurzfristig das transdermale therapeutische System aufzutragen, um die gewünschte Wirkung zu erreichen.The transdermal therapeutic system is therefore available at relatively short notice apply to achieve the desired effect.
Liegt das transdermale therapeutische System in Form einer Creme oder Lotion vor, kann innerhalb kürzester Zeit nach dem Auftragen auf die Haut ein Erfolg verzeichnet werden. Die Flexibilität der betroffenen Personen wird somit wesentlich verbessert und eine gewisse Spontaneität wird ermöglicht, so daß eine freie Gestaltung des Liebesleben kein Problem mehr darstellt, da das Auftragen der Creme oder Lotion in das Liebesspiel mit eingebaut werden kann. Bei dieser Darreichungsform wird die Wirkung durch eine zuvor eingenommene Mahlzeit zudem nicht verzögert. Das transdermale therapeutische System in Form eines Pflasters hat gegenüber der Creme oder Lotion noch zusätzlich den Vorteil, daß ein Verschmieren vermieden und ein höherer bzw. kontrollierter Wirkstoffgehalt eingesetzt werden kann, so daß die Patienten-Compliance gegenüber der oralen Darreichungsform stark verbessert wird. Zudem ist es bei Verwendung des Pflasters möglich, nach Vollendung des Liebesaktes durch das Entfernen des Pflasters die Wirkung zu beenden. Dieser Vorteil kommt ganz besonders bei der Frage der Medikamentensicherheit zum Tragen, da gerade dieses Arzneimittel aufgrund des Irrglaubens, durch Einnahme des Präparates eine besondere Liebesfähigkeit erlangen zu können, eine sehr hohe Mißbrauchsrate vorzuweisen hat. Der Gebrauch des Präparates von gesunden Personen führt zu einer verlängerten Erektion. Eine Erektion, die langer als 4 Stunden andauert, kann dazu führen, daß das Blut in den Schwellkörpern gerinnt und somit eine dauerhafte Impotenz durch entstehende Verklebungen zur Folge hat (Priapismus). Durch die Möglichkeit, das Pflaster rechtzeitig zu entfernen, können schwere gesundheitliche Schäden vermieden werden.If the transdermal therapeutic system is in the form of a cream or lotion, can Success can be seen within a very short time after application to the skin. The The flexibility of the data subjects is thus significantly improved and a certain one Spontaneity is made possible, so that a free design of love life is not a problem represents more because the application of the cream or lotion built into the lovemaking can be. With this pharmaceutical form, the effect is by a previously meal not delayed. The transdermal therapeutic system in The shape of a plaster has the additional advantage over the cream or lotion that smearing avoided and a higher or controlled active ingredient content used can be so that patient compliance is strong compared to the oral dosage form is improved. In addition, when using the patch, it is possible after the completion of the Love act by removing the plaster to end the effect. This advantage comes especially important when it comes to the question of drug safety, since this is precisely the one Medicines due to misconception, taking the preparation a special one Being able to attain the ability to love has a very high rate of abuse. The Use of the preparation by healthy people leads to a prolonged erection. A Erection that lasts longer than 4 hours can cause the blood to go into the The erectile tissue curdles and thus permanent impotence due to adhesive bonds results in (priapism). The ability to remove the patch in time serious health damage can be avoided.
Die Verwendung von Sildenafil als transdermales therapeutisches System führt, neben den oben erwähnten Vorzügen, zu einer stark verbesserten Bioverfügbarkeit, so daß wesentlich geringere Wirkstoffmengen eingesetzt werden müssen. Das hat zum einen eine gesteigerte Wirtschaftlichkeit zur Folge und zum anderen wird das doch ganz beträchtliche Nebenwirkungspotential verringert, so daß ein ungehindertes Liebesleben möglich ist. Die Belastung des Organismus und die Beeinträchtigung der Leber durch die First-Path- Metabolisierung kann zudem verringert werden. The use of sildenafil as a transdermal therapeutic system leads, in addition to the advantages mentioned above, to a greatly improved bioavailability, so essential smaller amounts of active ingredient must be used. On the one hand, this has increased Profitability and on the other hand it becomes quite considerable Side effect potential reduced, so that an unhindered love life is possible. The Stress on the organism and the impairment of the liver through the first-path Metabolism can also be reduced.
Für Personen, denen die orale Einnahme von Tabletten Schwierigkeiten bereitet, wird durch das transdermale therapeutische System eine angenehme Alternative geschaffen.For people who have difficulty taking oral tablets, through the transdermal therapeutic system created a pleasant alternative.
Die der Erfindung zugrundeliegende Aufgabe wird nun durch ein transdermales therapeutisches System mit einem Gehalt an Sildenafil oder einem seiner pharmazeutisch unbedenklichen Salze gelöst. Als mögliche Salze kommen die Säureadditionssalze wie die Hydrochloride oder die Halogenide, Sulfate, Phosphate, Citrate sowie Carbonate in Frage.The object on which the invention is based is now achieved by a transdermal therapeutic system containing sildenafil or one of its pharmaceutical harmless salts dissolved. Possible addition salts are acid addition salts such as Hydrochloride or the halides, sulfates, phosphates, citrates and carbonates in question.
Sildenafil oder dessen pharmazeutisch unbedenkliche Salze können ferner in Kombination mit weiteren bekannten Wirkstoffen, vor allem spezifischen und unspezifischen Cytochrom P450 (CYP) Inhibitoren, angewendet werden.Sildenafil or its pharmaceutically acceptable salts can also be used in combination with other known active ingredients, especially specific and non-specific cytochrome P450 (CYP) inhibitors.
Durch Kombination von Sildenafil mit einem CYP-Inhibitor wie Erythromycin, Cimetidin, Ketoconazol, Itraconazol oder Mibefradil wird die Konzentration im Blutplasma stark gesteigert und der Abbau bzw. die Ausscheidung verzögert. Die schnelle Anflutung wird somit bei einer stark verringerten Sildenafilmenge trotzdem beibehalten bzw. beschleunigt.By combining sildenafil with a CYP inhibitor such as erythromycin, cimetidine, Ketoconazole, itraconazole or mibefradil, the concentration in the blood plasma becomes strong increased and the degradation or excretion delayed. The rapid flooding will thus maintained or accelerated with a greatly reduced amount of sildenafil.
Das transdermale therapeutische System kann als Pflaster, Creme, Salbe, Paste oder Liniment vorliegen.The transdermal therapeutic system can be used as a plaster, cream, ointment, paste or liniment available.
Als Permeationsförderer lassen sich ein- und/oder mehrwertige aliphatische, cycloaliphatische und/oder aromatisch- aliphatische Alkohole mit jeweils bis zu acht C-Atomen, z. B. Ethanol, 1,2-Propandiol, Dexpanthenol und/oder Polyethylenglykol; Alkohol/Wasser- Gemische; gesättigte und/oder ungesättigte Fettalkohole mit jeweils 8-18 C-Atomen; Terpene; Teebaumöl; gesättigte und/oder ungesättigte cyclisch Ketone; Alkyl- Methylsulfoxide; gesättigte und/oder ungesättigte Fettsäuren mit jeweils 8-18 C-Atomen; deren Ester; natürliches Vitamin E (α-Tocopherol); synthetisches Vitamin E und/oder Vitamin E- Derivate, insbesondere Ethanol, α-Tocopherol, Polyethylenglycol, Isopropylmyristat oder Dexpanthenol verwenden.Mono- and / or polyvalent aliphatic, cycloaliphatic can be used as permeation promoters and / or aromatic-aliphatic alcohols, each with up to eight carbon atoms, e.g. B. ethanol, 1,2-propanediol, dexpanthenol and / or polyethylene glycol; Alcohol / water mixtures; saturated and / or unsaturated fatty alcohols, each with 8-18 C atoms; Terpenes; Tea tree oil; saturated and / or unsaturated cyclic ketones; Alkyl methyl sulfoxides; saturated and / or unsaturated fatty acids, each with 8-18 C atoms; their esters; natural vitamin E (α-tocopherol); synthetic vitamin E and / or vitamin E Derivatives, especially ethanol, α-tocopherol, polyethylene glycol, isopropyl myristate or Use dexpanthenol.
Zur Herstellung der Salben, Pasten, Cremes oder Linimenten können als Salbengrundlage die bekannten Substanzen wie beispielsweise Triglyceride enthaltende Lipogele, anorganische und organische Hydrogele, Emulsionsgele oder Polyethylengele verwendet werden. For the production of the ointments, pastes, creams or liniments, the known substances such as lipogels containing triglycerides, inorganic and organic hydrogels, emulsion gels or polyethylene gels can be used.
Bei einem transdermalen therapeutischen System in der Form eines Pflasters kann es sich um ein Matrix- oder Membransystem handeln, welches eine undurchlässige Deckschicht und eine abziehbare Schutzschicht aufweist. Als Bestandteil der undurchlässigen Deckschicht kommen Polyester, Polypropylen, Polyurethan oder Polyethylen in Frage, die bei Bedarf metallisiert oder pigmentiert werden können. Für die abziehbare Schutzschicht kommen Polyester, Polypropylen, Polysiloxan, Polyacrylat, Ethylenvinylacetat, Polyurethan, Polyisobuten oder Papier mit Silikon- und/oder Polyethylenbeschichtung in Betracht.A transdermal therapeutic system in the form of a patch may be act a matrix or membrane system, which has an impermeable cover layer and peelable protective layer. As part of the impermeable top layer polyester, polypropylene, polyurethane or polyethylene can be used if necessary can be metallized or pigmented. For the peelable protective layer come Polyester, polypropylene, polysiloxane, polyacrylate, ethylene vinyl acetate, polyurethane, Polyisobutene or paper with silicone and / or polyethylene coating into consideration.
Dieses transdermale therapeutische System kann in Form eines Matrixpflasters vorliegen. Das Matrixpflaster besteht aus einer undurchlässigen Deckschicht, aus einer oder mehreren den Wirkstoff oder einer seiner pharmazeutisch unbedenklichen Ester oder Salze und gegebenenfalls weiteren Wirkstoffen und/oder Permeationsförderer und/oder Aminosäuren enthaltenden, selbstklebenden Matrixschicht oder einer Matrixschicht, die mit einem Haftkleber beschichtet ist und einer abziehbaren Schutzschicht. Bei dem in der Matrix enthaltenen Wirkstoff handelt es sich um Sildenafil oder um dessen pharmazeutisch unbedenkliche Salze, sowie bei der Kombination zudem um weitere Wirkstoffe wie spezifische und unspezifische CYP-Inhibitoren z. B. Erythromycin, Cimetidin, Ketoconazol, Itraconazol oder Mibefradil.This transdermal therapeutic system can be in the form of a matrix patch. The matrix patch consists of an impermeable cover layer, one or more the active substance or one of its pharmaceutically acceptable esters or salts and optionally further active ingredients and / or permeation promoters and / or amino acids containing, self-adhesive matrix layer or a matrix layer with a Pressure sensitive adhesive is coated and a removable protective layer. The one in the matrix contained active ingredient is sildenafil or its pharmaceutical harmless salts, as well as in combination with other active ingredients such as specific and non-specific CYP inhibitors e.g. B. erythromycin, cimetidine, ketoconazole, Itraconazole or mibefradil.
Für die Matrix werden die medizinisch üblichen Matrixbildner wie Polyacrylat, Silikon, Polyisobutylen, Kautschuk, kautschukähnliche synthetische Homo-, Co- oder Blockpolymere, Butylkautschuk, Styrol/Isopren-Copolymerisat, Polyurethane, Copolymere des Ethylens, Polysiloxane oder Styrol/Butadien-Copolymerisat, wie sie im Stand der Technik vorgesehen werden, verwendet. Als Kleber kann Polydimethylsiloxan, Polyacrylat mit C4-C10 Alkylalkoholestern, amminrestistentes Silikon in Trichlorofluoroethan und Polyisobutylen/ Mineralöl verwendet werden.For the matrix, the medically customary matrix formers, such as polyacrylate, silicone, polyisobutylene, rubber, rubber-like synthetic homo-, co- or block polymers, butyl rubber, styrene / isoprene copolymer, polyurethanes, copolymers of ethylene, polysiloxanes or styrene / butadiene copolymer, such as they are provided in the prior art used. Polydimethylsiloxane, polyacrylate with C 4 -C 10 alkyl alcohol esters, amine-resistant silicone in trichlorofluoroethane and polyisobutylene / mineral oil can be used as the adhesive.
Eine weitere Ausführungsform der Erfindung stellt ein Membransystem dar. Dieses besteht aus einer undurchlässigen Deckschicht, einem wirkstoffhaltigen Reservoir oder einer Reservoirschicht, einer semipermeablen Membran, einer fakultativen Haftklebeschicht und einer abziehbaren Schutzschicht. Das Reservoir enthält Sildenafil oder eines seiner pharmazeutisch unbedenklichen Salze, gegebenenfalls weitere Wirkstoffe und/oder Permeationsförderer, Stabilisatoren, Emulgatoren, Verdickungsmittel und/oder übliche Membransystem- bzw. Reservoirpflaster-Hilfsmittel. Das Reservoir bzw. die Reservoirschicht liegt zwischen der Deckschicht und der Membran. Als Gelbildner können bei Bedarf Methylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose, Carboxyvinylpolymer, Natrium-Plyoxilat, Carboxymethylcellulose oder ein Gemisch aus diesen verwendet werden. Die Membran, die üblicherweise aus inerten Polymeren, insbesondere auf Basis von Polypropylen, Polyvinylacetat, Polyamid, Ethylen- Vinylacetat- Copolymeren oder Silikon, besteht, kann je nach Porengröße eine die Wirkstofffreisetzung kontrollierende Wirkung haben.Another embodiment of the invention is a membrane system. This exists from an impermeable cover layer, an active substance-containing reservoir or one Reservoir layer, a semipermeable membrane, an optional pressure sensitive adhesive layer and a peelable protective layer. The reservoir contains sildenafil or one of its pharmaceutically acceptable salts, optionally other active ingredients and / or Permeation promoters, stabilizers, emulsifiers, thickeners and / or conventional ones Membrane system or reservoir plaster aids. The reservoir or the The reservoir layer lies between the cover layer and the membrane. Can as a gelling agent if necessary methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, Carboxyvinylpolymer, sodium plyoxylate, carboxymethyl cellulose or a mixture of these are used. The membrane, which is usually made of inert polymers, especially based on Polypropylene, polyvinyl acetate, polyamide, ethylene-vinyl acetate copolymers or silicone, Depending on the pore size, there may be an effect controlling the release of the active ingredient to have.
Claims (17)
- - einer undurchlässigen Deckschicht,
- - einer oder mehreren wirkstoffhaltigen selbstklebenden Matrixschicht(en) oder einer oder mehreren wirkstoffhaltigen Matrixschicht(en), die mit einem Haftkleber beschichtet sind,
- - einer abziehbaren Schutzschicht und
- - Sildenafil oder einem seiner pharmazeutisch verträglichen Salze
- - an impermeable top layer,
- one or more active substance-containing self-adhesive matrix layer (s) or one or more active substance-containing matrix layer (s) which are coated with a pressure sensitive adhesive,
- - a peelable protective layer and
- - Sildenafil or one of its pharmaceutically acceptable salts
- - einer undurchlässigen Deckschicht,
- - einem wirkstoffhaltigen Reservoir oder einer wirkstoffhaltigen Reservoirschicht,
- - einer mikroporösen oder semipermeablen Membran,
- - einer fakultativen Haftklebeschicht,
- - einer abziehbaren Schutzschicht und
- - Sildenafil oder einem seiner pharmazeutisch verträglichen Salze
- - an impermeable top layer,
- an active substance-containing reservoir or an active substance-containing reservoir layer,
- - a microporous or semi-permeable membrane,
- - an optional pressure-sensitive adhesive layer,
- - a peelable protective layer and
- - Sildenafil or one of its pharmaceutically acceptable salts
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998134505 DE19834505A1 (en) | 1998-07-31 | 1998-07-31 | Transdermal therapeutic system useful for treating male sexual impotence contains sildenafil |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998134505 DE19834505A1 (en) | 1998-07-31 | 1998-07-31 | Transdermal therapeutic system useful for treating male sexual impotence contains sildenafil |
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| DE19834505A1 true DE19834505A1 (en) | 2000-02-03 |
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| DE1998134505 Withdrawn DE19834505A1 (en) | 1998-07-31 | 1998-07-31 | Transdermal therapeutic system useful for treating male sexual impotence contains sildenafil |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10012908A1 (en) * | 2000-03-16 | 2001-10-04 | Lohmann Therapie Syst Lts | Stabilized supersaturated transdermal therapeutic matrix systems |
| DE10114382A1 (en) * | 2001-03-23 | 2002-09-26 | Beiersdorf Ag | Moisture-absorbing material used for plasters, medical fixings, wound coverings and bandages comprises adhesive matrix of silicon, gel former and optionally silicone resin |
| WO2002102385A1 (en) * | 2001-06-14 | 2002-12-27 | Sampad Bhattacharya | Compositions comprising cgmppde5 inhibitor for transdermal delivery to the erectile tissue of the penis |
| WO2006018088A1 (en) * | 2004-08-19 | 2006-02-23 | Switch Biotech Ag | Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders |
| 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 |
| EP1759700A1 (en) * | 2004-08-19 | 2007-03-07 | Switch Biotech Aktiengesellschaft | Use of a PDE5 inhibitor for treating and preventing hypopigmentary disorders |
| WO2009064071A1 (en) * | 2007-11-14 | 2009-05-22 | Kyungpook National University Industry Academic Cooperation Foundation | Controlled drug carrier for deliverying sildenafil citrate transdermally and patch containing the same |
| EP2399607A4 (en) * | 2009-02-18 | 2013-08-21 | Hisamitsu Pharmaceutical Co | TRANSDERMAL PREPARATION |
-
1998
- 1998-07-31 DE DE1998134505 patent/DE19834505A1/en not_active Withdrawn
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10012908B4 (en) * | 2000-03-16 | 2005-03-17 | Lts Lohmann Therapie-Systeme Ag | Stabilized supersaturated transdermal therapeutic matrix systems and methods for their preparation |
| DE10012908A1 (en) * | 2000-03-16 | 2001-10-04 | Lohmann Therapie Syst Lts | Stabilized supersaturated transdermal therapeutic matrix systems |
| 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 |
| DE10114382A1 (en) * | 2001-03-23 | 2002-09-26 | Beiersdorf Ag | Moisture-absorbing material used for plasters, medical fixings, wound coverings and bandages comprises adhesive matrix of silicon, gel former and optionally silicone resin |
| WO2002102385A1 (en) * | 2001-06-14 | 2002-12-27 | Sampad Bhattacharya | Compositions comprising cgmppde5 inhibitor for transdermal delivery to the erectile tissue of the penis |
| EP1759700A1 (en) * | 2004-08-19 | 2007-03-07 | Switch Biotech Aktiengesellschaft | Use of a PDE5 inhibitor for treating and preventing hypopigmentary disorders |
| WO2006018088A1 (en) * | 2004-08-19 | 2006-02-23 | Switch Biotech Ag | Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders |
| JP2008509944A (en) * | 2004-08-19 | 2008-04-03 | スイッチ ビオテッヒ アーゲー | Use of PDE5 inhibitors, isomers, and salts to treat and prevent hypopigmentary disorders |
| AU2005274546B2 (en) * | 2004-08-19 | 2011-02-03 | Switch Biotech, Llc | Use of a PDE5 inhibitor for treating and preventing hypopigmentary disorders |
| US8268785B2 (en) | 2004-08-19 | 2012-09-18 | Switch Biotech Ag | Use of a Pde 5 inhibitor for treating and preventing hypopigmentary disorders |
| US8329656B2 (en) | 2004-08-19 | 2012-12-11 | Switch Biotech Ag | Use of a PDE5 inhibitor for treating and preventing hypopigmentary disorders |
| WO2009064071A1 (en) * | 2007-11-14 | 2009-05-22 | Kyungpook National University Industry Academic Cooperation Foundation | Controlled drug carrier for deliverying sildenafil citrate transdermally and patch containing the same |
| EP2399607A4 (en) * | 2009-02-18 | 2013-08-21 | Hisamitsu Pharmaceutical Co | TRANSDERMAL PREPARATION |
| US8702664B2 (en) | 2009-02-18 | 2014-04-22 | Hisamitsu Pharmaceutical Co., Inc. | Transdermal preparation |
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