WO2004091589A1 - Transdermally administerable tranquilizing and sedating agent - Google Patents
Transdermally administerable tranquilizing and sedating agent Download PDFInfo
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- WO2004091589A1 WO2004091589A1 PCT/DE2004/000766 DE2004000766W WO2004091589A1 WO 2004091589 A1 WO2004091589 A1 WO 2004091589A1 DE 2004000766 W DE2004000766 W DE 2004000766W WO 2004091589 A1 WO2004091589 A1 WO 2004091589A1
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- 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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
Definitions
- psychotropic drugs e.g. Benzodiazepines, in particular tetracyclic benzodiazepines such as midazolam, furthermore propofol, ketamine, and the long-established barbituric acid derivatives such as thiopental sodium (“trapanal”).
- Benzodiazepines in particular tetracyclic benzodiazepines such as midazolam, furthermore propofol, ketamine, and the long-established barbituric acid derivatives such as thiopental sodium (“trapanal”).
- a transdermally effective system is known, with which an ACE inhibitor can be administered and with which a depot effect should also be achievable, and which consists of an impermeable backing layer, a layer-like one Element with a cavity, an agent that controls the release of the active ingredient and a removable cover layer (release liner) on a paper basis.
- EP-A2-0 439 430 (reservoir- ⁇ S) and EP-A2-0 468 875 (Matrix-TTS), according to EP-A2-0 468 875 Silicone elastomers as Matrix material (ie as an adhesive containing active ingredient) can be used.
- EP-A3-0 452 837 describes a transdermal system with a matrix based, inter alia, on polyisobutylene rubber and containing, inter alia, ACE inhibitors. In addition to polyisobutylene rubbers, polymers of the acrylic resin type iWS and silicone rubbers are also listed as other possible matrices.
- Acetylsalicylic acid (2-acetoxybenzoic acid; aspirin) has also already been proposed as a transdermally applicable medicament (WO 00/76315) and also dextromethorphan [(+) - 3-methoxy-17-methyl-9a, 13a, 14a-morphinan] and its pharmacologically acceptable Compounds as a remedy for coughing fits. It is known from Anesthesia Analgesia 2000/91 1479-82 that racemic ketamine can be administered transdermally, but not alone, but as support for pain-relieving postoperative treatment after gynecological abdominal surgery.
- a further object of the invention is to propose a system for the transdermal supply of an anti-conscious medication with a sedative, sedative and / or short anesthetic function, with which a prolonged
- Effectiveness of this agent can be achieved, for example, for up to about a week, so that a therapeutically effective plasma level can be achieved for a corresponding period of time by continuous release of active ingredient.
- Benzodiazepines but also classic agents such as barbiturates and agents from various other families.
- Examples include propofol, etomidate, midazolam, 4-hydroxybutyric acid and their pharmaceutically acceptable salts and / or derivatives, S-ketamine, triazolam, temazepam, tetrazepam, lorazepam, nitrazepam, flunitrazepam, lormetazepam, diazepam, melperidol, zperpidem zopiclone,
- a pharmacologically effective amount of propofol with a matrix, for. B. mixed on the basis of polyisobutylene or butyl rubber and, if necessary, one or more emulsifiers of the type and applied to a neutral plaster base.
- Immediate subject matter of the invention is a layered arrangement in the form of a plaster, which contains an effective amount of propofol in at least one layer and is preferably composed of: (1) a first backing layer
- matrix which contains at least the active substance and agents which control the delivery and mode of action of the active substance
- a release liner to be removed before use based on a plastic film or a coated paper.
- Another object of the invention is an arrangement of the above type, which contains the active ingredient directly embedded in the adhesive layer (4), with the proviso that in this case a special layer (2) and the carrier layer having a cavity for receiving the layer (3) eliminated.
- a release rate of the active ingredient from 0.01 to 0.1 mg active ingredient / cm2 / 24 hours and in particular from 0.025 to 0.050 mg of active ingredient / cm2 / 24 hr can be achieved, for example, from a polymer matrix, such that a transdermal system according to Inventions offers a plasma concentration of active ingredient in a therapeutically effective amount.
- a therapeutically effective concentration in the blood of more than about 0.5 ng / ml can be achieved for propofol. aim.
- the propofol in the transdermal system according to the invention, can be present in a concentration of at least 0.1%, preferably at least 5% by weight and in particular in a concentration of 10 to 20% by weight (based on the matrix). It is surprising that the propofol hitherto used as a short anesthetic is suitable as a long-term active ingredient in the application according to the invention without the need for a further injection or administration of another active ingredient.
- Propofol can be in substance or as a therapeutically active salt.
- the active ingredient can likewise be embedded in a body which delays the release of the active ingredient, that is to say a carrier. It is preferably a surface-rich body of the type of an ion exchanger or a silica gel with a large inner surface. Because of the purely external application, no particular consideration needs to be given to the physiological tolerance of this vehicle.
- the transdermal system according to the invention can comprise a permeation enhancer, for example 2-octyldodecanol and in particular DMSO (dimethyl sulfoxide).
- a permeation enhancer for example 2-octyldodecanol and in particular DMSO (dimethyl sulfoxide).
- transdermal systems for example matrix- or membrane-controlled systems.
- Matrix-controlled means that the rate of release essentially depends on the rate of diffusion of the active substance within the matrix body becomes.
- Membrane-controlled means that the rate of drug release is mainly determined by a membrane upstream of the matrix, in the sense that the drug first (relatively quickly) travels through the matrix and then according to the specific rate of diffusion through the film.
- Cellulose and its derivatives such as ethyl cellulose, are preferably suitable as film material.
- Microporous or semipermeable membranes are also obtained from certain inert polymers which can be provided with pores of different widths during the manufacturing process, for example polypropylene, polyvinyl acetate or silicone. If such a membrane is provided, it can, depending on the pore size, have an effect which controls the release of the active substance or also no influence on the active substance release from the system.
- the transdermal system according to the invention can be characterized by
- a self-adhesive polyisobutylene adhesive can be used as the matrix.
- the covering layer can be formed, for example, from polyester, polypropylene, polyethylene or polyurethane.
- a fabric or fleece-reinforced film is used, such as that which is available from Beiersdorf under the trade name "Fixomull® Stretch".
- a measured amount of a preparation according to the invention can be applied to the skin and with the correspondingly tailored one Foil are covered.
- the doctor in charge has the ability to dose the intended amount of active ingredient himself.
- the peelable cover layer can be formed from polyester, polypropylene or coated paper (paper with coating), in particular with a silicone and / or polyethylene coating.
- the transdermal system according to the invention can have a covering layer (backing foil) and / or a removable covering layer (release liner) with a thickness in the range from 5 to 100 ⁇ m.
- Placebo approach 2ml gel containing a base of, among others, macrogol-glycerol-hydroxystearate, propylene glycol, polyacrylic acid, trometamol, isopropyl alcohol, purified water and as active ingredients: 0.075 g DMSO 75 IU heparin-Na; 0.0125 g dexpanthe nol.
- TTS in vivo comparative study of a TTS according to the invention with an oral administration of trandolapril (capsule)
- trandolapril capsule
- the TTS were applied in an open 2-period cross-over design over a period of 7 days (1 TTS 4 days, then 1 TTS 3 days) and 1 capsule of 2 mg trandolapril was applied daily for 7 days.
- Blood samples were taken after application after the following times: 0.5 - 1 - 2 - 4 - 6 - 8 - 10 - 12 - 24 - 48 - 72 - 96 - 98 - 100 - 102 - 104 - 106 - 108 - 120 - 132 - 144 - 156 - 168 h.
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Abstract
Description
Transdermal applizierbares Beruhigungs- und Sedierungsmittel Sedative and sedative that can be applied transdermally
Beschreibungdescription
Zur Behandlung von Erregungszuständen, zur präoperativen oder sonst gebotenen Ruhigstellung von Patienten ist die Gabe von bewusstseinsdämpfenden, d.h. leicht narkotisierenden/sedierenden Medikamenten allgemein üblich.For the treatment of arousal, for preoperative or otherwise necessary immobilization of patients, the administration of consciousness-reducing, i.e. slightly anesthetic / sedative medication common.
Die gebräuchlichen Mittel sind in erster Linie Psychopharmaka, z.B. Benzodiaze- pine, insbesondere tetrazyklische Benzodiazepine wie Midazolam, ferner Propofol, Ketamin, sowie die seit langem bewährten Barbitursäure-Derivate wie Thiopen- tal-Natrium ("Trapanal").The most common means are psychotropic drugs, e.g. Benzodiazepines, in particular tetracyclic benzodiazepines such as midazolam, furthermore propofol, ketamine, and the long-established barbituric acid derivatives such as thiopental sodium (“trapanal”).
Der Nachteil der üblichen Sedierungsmaßnahmen, die meistens durch i.m. oder i.v. Injektion, Suppositorien usw. erfolgen, ist der häufig zu beobachtende Widerwillen des Patienten gegen diese Behandlung. Auch die perorale Gabe, die überdies manchmal objektiv schwer vertragen und gelegentlich auch durch unwillkürliches Erbrechen des Patienten vereitelt wird, ist nicht immer anwendbar. Methoden der Sedierung sind u.a. beschrieben von Dietmar Weixler, Klaus Pau- litsch in PRAXIS DER SEDIERUNG, Vademecum Praxis der Sedierung, Facultas 2003 (ISBN 3-85076-584-9).The disadvantage of the usual sedation measures, which are mostly caused by i.m. or i.v. Injection, suppositories, etc. is the patient's reluctance to use this treatment. Oral administration, which is sometimes also objectively difficult to tolerate and occasionally thwarted by the patient's involuntary vomiting, is not always applicable. Methods of sedation include described by Dietmar Weixler, Klaus Pallitsch in PRACTICE OF SEDATION, Vademecum Praxis der Sedierung, Facultas 2003 (ISBN 3-85076-584-9).
Aus WO-Al-9 323 019 ist ein transdermal wirksames System bekannt, mit dem ein ACE-Hemmer administriert werden kann und mit dem auch eine Depotwir- kung erzielbar sein soll, und das besteht aus einer undurchlässigen Abdeckschicht (Backing Layer), einem schichtartigen Element mit Hohlraum, einem die Wirkstoffabgabe steuernden Mittel und einer abziehbaren Deckschicht (Release Liner) auf Papierbasis.From WO-Al-9 323 019 a transdermally effective system is known, with which an ACE inhibitor can be administered and with which a depot effect should also be achievable, and which consists of an impermeable backing layer, a layer-like one Element with a cavity, an agent that controls the release of the active ingredient and a removable cover layer (release liner) on a paper basis.
Transdermal applizierbare Systeme mit einem Gehalt an einem ACE-Hemmer werden ferner in EP-A2-0 439 430 (Reservoir-πS) und EP-A2-0 468 875 (Matrix-TTS) beschrieben, wobei nach EP-A2-0 468 875 Silikon-Elastomere als Matrixmaterial (d.h. als wirkstoffhaltiger Kleber) verwendet werden. EP-A3-0 452 837 beschreibt ein transdermales System mit einer Matrix auf der Grundlage von u. a. Polyisobutylenkautsch.uk und mit einem Gehalt, u. a. an ACE-Inhibitoren. Neben Polyisobutylen-Kautschuken werden als weitere mögli- ehe Matrices auch Polymere vom Typus der Acrylharze i.w.S. und Silikon- Kautschuke angeführt. Als transdermal applizierbares Medikament wurde auch schon Acetylsalicylsäure (2-Acetoxybenzoesäure; Aspirin) vorgeschlagen (WO 00/76315) und ferner Dextromethorphan [(+)-3-methoxy-17-methyl- 9a,13a,14a-morphinan] und dessen pharmakologisch akzeptable Verbindungen als Mittel gegen Hustenanfälle. Aus Anesthesia Analgesia 2000/91 1479-82 ist bekannt, dass racemisches Ketamin transdermal appliziert werden kann, jedoch nicht allein, sondern unterstützend bei schmerzlindernder postoperativer Behandlung nach gynäkologischen Unterleibsoperationen.Systems which can be applied transdermally and contain an ACE inhibitor are also described in EP-A2-0 439 430 (reservoir-πS) and EP-A2-0 468 875 (Matrix-TTS), according to EP-A2-0 468 875 Silicone elastomers as Matrix material (ie as an adhesive containing active ingredient) can be used. EP-A3-0 452 837 describes a transdermal system with a matrix based, inter alia, on polyisobutylene rubber and containing, inter alia, ACE inhibitors. In addition to polyisobutylene rubbers, polymers of the acrylic resin type iWS and silicone rubbers are also listed as other possible matrices. Acetylsalicylic acid (2-acetoxybenzoic acid; aspirin) has also already been proposed as a transdermally applicable medicament (WO 00/76315) and also dextromethorphan [(+) - 3-methoxy-17-methyl-9a, 13a, 14a-morphinan] and its pharmacologically acceptable Compounds as a remedy for coughing fits. It is known from Anesthesia Analgesia 2000/91 1479-82 that racemic ketamine can be administered transdermally, but not alone, but as support for pain-relieving postoperative treatment after gynecological abdominal surgery.
In den vorstehenden Dokumenten sind weitere Fundstellen für transdermale Anwendungen von Pharmazeutika angegeben.Further references for transdermal applications of pharmaceuticals are given in the above documents.
Es ist eine Aufgabe der Erfindung, eine Zubereitung für die Administrierung eines bewusstseinsdämpfenden Medikaments anzugeben, das auch Beruhigungs- und/oder Sedierungswirkung aufweist und das die oben angegebenen Nachteile nicht oder nur in geringerem Maße aufweist.It is an object of the invention to provide a preparation for the administration of an anti-conscious medication which also has a sedative and / or sedative effect and which does not or only has the disadvantages mentioned above to a lesser extent.
Eine weitere Aufgabe der Erfindung ist es, ein System für die transdermale Zufuhr eines bewusstseinsdämpfenden Medikaments mit Beruhigungs-, Sedierungs- und/oder Kurznarkosefunktion vorzuschlagen, mit dem sich eine verlängerteA further object of the invention is to propose a system for the transdermal supply of an anti-conscious medication with a sedative, sedative and / or short anesthetic function, with which a prolonged
Wirksamkeit dieses Mittel, beispielsweise bis zu etwa einer Woche erreichen lässt, so dass für eine etwa entsprechende Dauer durch eine kontinuierliche Abgabe an Wirkstoff ein therapeutisch wirksamer Plasmaspiegel erreicht werden kann.Effectiveness of this agent can be achieved, for example, for up to about a week, so that a therapeutically effective plasma level can be achieved for a corresponding period of time by continuous release of active ingredient.
Es wurde nun gefunden, dass sich für die transdermale Zufuhr eines bewusstseinsdämpfenden Medikaments mit Beruhigungs-, Sedierungs- und/oder Kurznarkosefunktion, d.h. durch Aufbringen einer vorzugsweise mit permeationsför- dernden Mitteln versetzten Zubereitung auf die Haut im besonderen Maße Propo- fol eignet.It has now been found that for the transdermal supply of an anti-consciousness medication with a sedative, sedative and / or short anesthetic function, ie by applying a preparation which is preferably admixed with permeation-promoting agents to the skin to a particular extent. fol is suitable.
Als bewusstseinsdämpfende Mittel mit Beruhigungs-, Sedierungs- und/oder Kurznarkosefunktion eignen sich für die angegebene Methode ferner z.B. Benzo- diazepine, aber auch klassische Mittel wie Barbiturate und Mittel aus verschiedenen anderen Familien. Genannt seien beispielsweise Propofol, Etomidat, Midazo- lam, 4-Hydroxybuttersäure und deren phamazeutisch annehmbare Salze und/oder Derivate, S-Ketamin, Triazolam, Temazepam, Tetrazepam, Lorazepam, Nitrazepam, Flunitrazepam, Lormetazepam, Diazepam, Zolpidem, Melperon, Phenobarbital, Zopiclon,As an awareness-reducing agent with a sedative, sedative and / or short anesthetic function, the following methods are also suitable e.g. Benzodiazepines, but also classic agents such as barbiturates and agents from various other families. Examples include propofol, etomidate, midazolam, 4-hydroxybutyric acid and their pharmaceutically acceptable salts and / or derivatives, S-ketamine, triazolam, temazepam, tetrazepam, lorazepam, nitrazepam, flunitrazepam, lormetazepam, diazepam, melperidol, zperpidem zopiclone,
Propofol (= 2,6-Di-isopropyl-phenol) ist ein vom Isopropylphenol abgeleitetes Dialkylphenol. Wegen der Einfachheit der Struktur ist keine Strukturformel beigefügt. Es handelt sich um ein relativ junges Narkotikum, das bisher intravenös angewendet wird. Seine chemische Struktur erinnert an Thymol. Es besitzt bei i.v. Applikation eine kurze Wirkungsdauer und wahrscheinlich einen physikoche- mischen Wirkungsmechanismus. Zur Einleitung einer Narkose werden bisher 1,0-2,5 mg/kg i.v. als wässrige Emulsion gegeben (Hilfsstoffe: Sojaöl, Ei- Phosphatid, Glycerin). Aufgrund der schnellen Verteilung tritt der Effekt in ca. 1 Minute ein. Propofol wird nach i.v. Gabe mit einer Halbwertszeit von ca. 2 Stunden vollständig metabolisch abgebaut. Eine längere Narkose mit Propofol muss daher bei Bedarf durch Nachinjektion unterhalten werden. Die Kopplungsprodukte werden renal ausgeschieden. Es werden jedoch Nebenwirkungen wie u.a. Venenreizungen an der Injektionsstelle beobachtet. Dies lässt eine andere Administrierung als die intravenöse Gabe wünschenswert erscheinen.Propofol (= 2,6-di-isopropylphenol) is a dialkylphenol derived from isopropylphenol. Because of the simplicity of the structure, no structural formula is included. It is a relatively young anesthetic that has so far been used intravenously. Its chemical structure is reminiscent of thymol. At i.v. Application a short duration of action and probably a physico-chemical mechanism of action. To initiate anesthesia, 1.0-2.5 mg / kg i.v. given as an aqueous emulsion (auxiliary substances: soybean oil, egg phosphatide, glycerin). Due to the quick distribution, the effect occurs in about 1 minute. Propofol is used after i.v. Administration completely metabolically degraded with a half-life of approx. 2 hours. Prolonged anesthesia with propofol must therefore be maintained by re-injection if necessary. The coupling products are excreted renally. However, side effects such as Vein irritation observed at the injection site. This makes administration other than intravenous administration appear desirable.
Zur Herstellung einer erfindungsgemäßen Zubereitung eines transdermal appli- zierbarenen Systems auf der Grundlage von Propofol wird eine pharmakologisch wirksame Menge von Propofol mit einer Matrix z. B. auf Basis von Polyisobutylen oder Butylkautschuk sowie bedarfsweise einem oder mehreren Emulgatoren vom Typ gemischt und auf eine neutrale Pflastergrundlage aufgebracht. Überraschenderweise wurde festgestellt, dass Propofol in dieser Zubereitung anders als andere Sedierungsmittel oder deren Wirkformen, die die menschliche Haut nur schwer permeieren können, mit Hilfe eines transdermal applizierbaren Arzneimittels die Haut gut durchdringen kann und einen zuverlässigen, kontinu- ierlichen Blutspiegel erzeugt.To produce a preparation according to the invention of a transdermally applicable system based on propofol, a pharmacologically effective amount of propofol with a matrix, for. B. mixed on the basis of polyisobutylene or butyl rubber and, if necessary, one or more emulsifiers of the type and applied to a neutral plaster base. Surprisingly, it was found that, unlike other sedation agents or their active forms, which are difficult for the human skin to permeate, propofol in this preparation can penetrate the skin well with the aid of a transdermally applicable medicinal product and produces a reliable, continuous blood level.
Unmittelbarer Erfindungsgegenstand ist eine geschichtete Anordnung in Form eines Pflasters, die in mindestens einer Schicht eine wirksame Menge Propofol enthält und vorzugsweise aufgebaut ist aus: (1) einer ersten Abdeckschicht (Backing Layer)Immediate subject matter of the invention is a layered arrangement in the form of a plaster, which contains an effective amount of propofol in at least one layer and is preferably composed of: (1) a first backing layer
(2) einer gegebenenfalls begrenzten Schicht ("Matrix"), die mindestens den Wirkstoff sowie Mittel enthält, die Abgabe und Wirkungsweise des Wirkstoffs steuern,(2) an optionally delimited layer (“matrix”) which contains at least the active substance and agents which control the delivery and mode of action of the active substance,
(3) gegebenenfalls einer einen Hohlraum zur Aufnahme der Schicht (2) aufwei- senden Trägerschicht,(3) optionally a carrier layer having a cavity for receiving the layer (2),
(4) einer Klebstoffschicht, die die Wirkstoffschicht und gegebenenfalls den sie enthaltenden Hohlraum der Trägerschicht freilässt,(4) an adhesive layer which leaves the active substance layer and, if appropriate, the cavity of the carrier layer containing it,
(5) gegebenenfalls einer vor der Anwendung abzuziehenden Deckschicht (Release Liner) auf der Grundlage einer Kunststofffolie oder eines beschich- teten Papiers.(5) if necessary, a release liner to be removed before use, based on a plastic film or a coated paper.
Ein weiterer Erfindungsgegenstand ist eine Anordnung der vorstehenden Art, die den Wirkstoff unmittelbar eingebettet in die Kleberschicht (4) enthält, mit der Maßgabe, dass in diesem Fall eine besondere Schicht (2) und die einen Hohlraum zur Aufnahme der Schicht (3) aufweisende Trägerschicht entfällt.Another object of the invention is an arrangement of the above type, which contains the active ingredient directly embedded in the adhesive layer (4), with the proviso that in this case a special layer (2) and the carrier layer having a cavity for receiving the layer (3) eliminated.
Erfindungsgemäß kann eine Abgaberate des Wirkstoffs von 0,01 bis 0,1 mg Wirkstoff/cm2/24 h und insbesondere 0,025 bis 0,050 mg Wirkstoff/cm2/24 h aus beispielsweise einer Polymermatrix erreicht werden, so dass ein erfindungs- gemäßes transdermales System eine Plasmakonzentration an Wirkstoff in einer therapeutisch wirksamen Menge bietet. Beispielsweise lässt sich für Propofol eine therapeutisch wirksame Konzentration im Blut von mehr als etwa 0,5 ng/ml er- zielen.According to the invention a release rate of the active ingredient from 0.01 to 0.1 mg active ingredient / cm2 / 24 hours and in particular from 0.025 to 0.050 mg of active ingredient / cm2 / 24 hr can be achieved, for example, from a polymer matrix, such that a transdermal system according to Inventions offers a plasma concentration of active ingredient in a therapeutically effective amount. For example, a therapeutically effective concentration in the blood of more than about 0.5 ng / ml can be achieved for propofol. aim.
Der Fachmann ist mit geeigneten Matrizes aus Polyisobutylen oder Butylkautschuk vertraut; vgl. beispielsweise Higgins et al. in Satas, Handbook of Pressure Sensitive Adhesive Technology, 14 : 374 etc., Butyl Rubber and Polyisobutylene; Van Nostrand Reinhold, New York.The person skilled in the art is familiar with suitable matrices made of polyisobutylene or butyl rubber; see. for example Higgins et al. in Satas, Handbook of Pressure Sensitive Adhesive Technology, 14: 374 etc., Butyl Rubber and Polyisobutylene; Van Nostrand Reinhold, New York.
Bei dem erfindungsgemäßen transdermalen System kann das Propofol in einer Konzentration von mindestens 0,1 %, bevorzugt mindestens 5 Gew.-% und ins- besondere in einer Konzentration von 10 bis 20 Gew.-% (bezogen auf die Matrix) vorliegen. Es ist überraschend, dass das bisher als Kurznarkotikum eingesetzte Propofol bei der erfindungsgemäßen Anwendung sich als Langzeitwirkstoff eignet, ohne dass eine Nachinjektion oder Gabe eines weiteren Wirkstoffs erforderlich wird.In the transdermal system according to the invention, the propofol can be present in a concentration of at least 0.1%, preferably at least 5% by weight and in particular in a concentration of 10 to 20% by weight (based on the matrix). It is surprising that the propofol hitherto used as a short anesthetic is suitable as a long-term active ingredient in the application according to the invention without the need for a further injection or administration of another active ingredient.
Propofol kann in Substanz oder als therapeutisch wirksames Salz vorliegen. Ebenso kann der Wirkstoff eingebettet sein in einen Körper, der die Wirkstoffabgabe verzögert, also einen Träger. Dabei handelt es sich vorzugsweise um einen Oberflächen reichen Körper vom Typ eines Ionenaustauschers oder ein Kieselgel mit großer innerer Oberfläche. Wegen der rein äußerlichen Anwendung muss keine besondere Rücksicht auf die physiologische Verträglichkeit dieses Trägers genommen werden.Propofol can be in substance or as a therapeutically active salt. The active ingredient can likewise be embedded in a body which delays the release of the active ingredient, that is to say a carrier. It is preferably a surface-rich body of the type of an ion exchanger or a silica gel with a large inner surface. Because of the purely external application, no particular consideration needs to be given to the physiological tolerance of this vehicle.
Das erfindungsgemäße transdermale System kann einem Permeationsförderer umfassen, beispielsweise 2-Octyldodecanol und insbesondere DMSO (Dimethylsulfoxid).The transdermal system according to the invention can comprise a permeation enhancer, for example 2-octyldodecanol and in particular DMSO (dimethyl sulfoxide).
Bei den erfindungsgemäßen Transdermalsystemen können unterschiedliche Formen Anwendung finden, beispielsweise matrix- oder membrankontrollierte Sy- steme. \Different forms can be used in the transdermal systems according to the invention, for example matrix- or membrane-controlled systems. \
Matrixkontrolliert heißt, dass die Abgabegeschwindigkeit wesentlich von der Diffusionsgeschwindigkeit des Wirkstoffs innerhalb des Matrixkörpers bestimmt wird. Membrankontrolliert heißt, dass die Geschwindigkeit der Wirkstoffabgabe überwiegend durch eine Membran bestimmt wird, die der Matrix vorgeschaltet ist, in dem Sinne, dass der Wirkstoff zunächst (relativ schnell) die Matrix, und dann nach Maßgabe der spezifischen Diffusionsgeschwindigkeit die Folie durch- wandert. Als Folienmaterial eignen sich vorzugsweise Cellulose und deren Derivate, wie Ethylcellulose. Mikroporöse oder semipermeable Membranen erhält man auch aus gewissen inerten Polymeren, die während des Herstell Prozesses mit Poren unterschiedlicher Weite versehen werden können, beispielsweise Polypropylen, Polyvinylacetat oder Silikon. Wenn eine solche Membran vorgesehen ist, kann sie je nach Porenweite eine die Freisetzung des Wirkstoffs kontrollierende Wirkung oder auch keinen Einfluss auf die Wirkstofffreisetzung aus dem System haben.Matrix-controlled means that the rate of release essentially depends on the rate of diffusion of the active substance within the matrix body becomes. Membrane-controlled means that the rate of drug release is mainly determined by a membrane upstream of the matrix, in the sense that the drug first (relatively quickly) travels through the matrix and then according to the specific rate of diffusion through the film. Cellulose and its derivatives, such as ethyl cellulose, are preferably suitable as film material. Microporous or semipermeable membranes are also obtained from certain inert polymers which can be provided with pores of different widths during the manufacturing process, for example polypropylene, polyvinyl acetate or silicone. If such a membrane is provided, it can, depending on the pore size, have an effect which controls the release of the active substance or also no influence on the active substance release from the system.
Gemäß einer speziellen Ausführungsform kann das erfindungsgemäße transder- male System gekennzeichnet sein durchAccording to a special embodiment, the transdermal system according to the invention can be characterized by
- eine undurchlässige Abdeckschicht (Backing Foil),- an impermeable covering layer (backing foil),
- eine Matrixschicht für den Wirkstoff,a matrix layer for the active ingredient,
- (sofern die Schicht gemäß (b) nicht selbstklebend ist) eine wirkstoffdurchlässige Haftklebeschicht und - gegebenenfalls eine abziehbare Deckschicht (Release Liner).- (if the layer according to (b) is not self-adhesive) an active ingredient-permeable PSA layer and - if necessary a removable cover layer (release liner).
Als Matrix kann erfindungsgemäß ein selbstklebender Polyisobutylenkleber verwendet werden.According to the invention, a self-adhesive polyisobutylene adhesive can be used as the matrix.
Bei dem erfindungsgemäßen transdermalen System kann die Abdeckschicht (Backing Foil) z.B.. aus Polyester, Polypropylen, Polyethylen oder Polyurethan gebildet sein.In the transdermal system according to the invention, the covering layer (backing foil) can be formed, for example, from polyester, polypropylene, polyethylene or polyurethane.
Nach einer weiteren, besonders einfach applizierbaren Ausführungsform der Er- findung wird eine gewebe- oder vliesverstärkte Folie verwendet, wie sie z.B. unter der Handelsbezeichnung "Fixomull® Stretch" von der Firma Beiersdorf im Handel ist. Dabei kann eine abgemessene Menge einer erfindungsgemäßen Zubereitung auf die Haut aufgetragen und mit der entsprechend zugeschnittenen Folie abgedeckt werden. In diesem Falle hat es der behandelnde Arzt in der Hand, die vorgesehene Wirkstoffmenge selbst zu dosieren.According to a further embodiment of the invention that is particularly easy to apply, a fabric or fleece-reinforced film is used, such as that which is available from Beiersdorf under the trade name "Fixomull® Stretch". A measured amount of a preparation according to the invention can be applied to the skin and with the correspondingly tailored one Foil are covered. In this case, the doctor in charge has the ability to dose the intended amount of active ingredient himself.
Ferner kann bei dem erfindungsgemäßen transdermalen System die abziehbare Deckschicht (Release Liner) aus Polyester, Polypropylen oder beschichtetem Papier (Papier mit Beschichtung) gebildet sein, insbesondere mit einer Silikon- und/oder Polyethylen-Beschichtung.Furthermore, in the transdermal system according to the invention, the peelable cover layer (release liner) can be formed from polyester, polypropylene or coated paper (paper with coating), in particular with a silicone and / or polyethylene coating.
Schließlich kann das erfindungsgemäße transdermale System eine Abdeckschicht (Backing Foil) und/oder abziehbare Deckschicht (Release Liner) mit einer Dicke im Bereich von 5 bis 100 μm aufweisen.Finally, the transdermal system according to the invention can have a covering layer (backing foil) and / or a removable covering layer (release liner) with a thickness in the range from 5 to 100 μm.
Beispiel 1example 1
Versuchsanordnung zur Ermittlung des Verlaufs einer transdermalen Applikation von Propofol zu Sedationszwecken beim MenschenExperimental set-up to determine the course of a transdermal application of propofol for sedation purposes in humans
1 männliche Versuchsperson 38 3 182 cm, 78kg;1 male subject 38 3 182 cm, 78kg;
1 weibliche Versuchsperson 36 3 160 cm, 51 kg. Die Versuchspersonen waren im Hinblick auf die applizierte Substanz geblindet.1 female subject 36 3 160 cm, 51 kg. The test subjects were blinded to the substance applied.
2 ml Gel in der für den Placebo- bzw. in der für den Verum-Ansatz beschriebenen Zusammensetzung wurde volarseitig auf den rechten Unterarm aufgebracht, durch einen Okklusivverband aus Kunststoff-Verbandfolie (Tegaderm®) abgedeckt und 45 Minuten auf der Applikationsstelle belassen.2 ml of gel in the composition described for the placebo or for the verum approach was applied to the right forearm on the volar side, covered by an occlusive bandage made of plastic bandage film (Tegaderm®) and left on the application site for 45 minutes.
Es wurde an zwei verschiedenen Tagen jeweils ein Ansatz durchgeführt, beide Versuchspersonen also crossover getestet.One approach was carried out on two different days, i.e. both test subjects were crossover tested.
Placebo-Ansatz: 2ml Gel enthaltend eine Grundlage aus u.a. Macrogol-Glycerol-Hydroxystearat, Propylenglycol, Polyacrylsäure, Trometamol, Isopropylalkohol, gereinigtem Wasser und als Wirkstoffen: 0,075 g DMSO 75 IE Heparin-Na; 0,0125 g Dexpanthe- nol.Placebo approach: 2ml gel containing a base of, among others, macrogol-glycerol-hydroxystearate, propylene glycol, polyacrylic acid, trometamol, isopropyl alcohol, purified water and as active ingredients: 0.075 g DMSO 75 IU heparin-Na; 0.0125 g dexpanthe nol.
Verum -Ansatz:Verum approach:
2ml Gel enthaltend eine Grundlage aus u.a. Macrogol-Glycerol-Hydroxystearat, Propylenglycol. Polyacrylsäure, Trometamol, Isopropylalkohol, gereinigtem Wasser und als Wirkstoffen: 0,0375g DMSO; 37,5 IE Heparin-Na; 0,00625 g Dexpan- thenol; 20mg Propofol, zugesetzt als 1 ml 2%ige Sojaöl/Wasser-Emulsion.2ml gel containing a base of i.a. Macrogol glycerol hydroxystearate, propylene glycol. Polyacrylic acid, trometamol, isopropyl alcohol, purified water and as active ingredients: 0.0375g DMSO; 37.5 IU heparin-Na; 0.00625 g dexpanethanol; 20mg propofol, added as 1 ml 2% soybean oil / water emulsion.
Es konnte ein leichter sedierender Effekt durch die Verum-Zusammensetzung beobachtet werden, während die Placebo-Formulierung wirkungslos blieb.A slight sedative effect was observed due to the verum composition, while the placebo formulation remained ineffective.
Beispiel 2Example 2
In einer in-vivo-Vergleichsstudie eines erfindungsgemäßen TTS mit einer oralen Gabe von Trandolapril (Kapsel) wurde bei 6 gesunden Probanden das pharma- kokinetische Verhalten für TTS-Applikation geprüft. Dabei wurden im offenen 2-Perioden-cross-over-design die TTS über einen Zeitraum von 7 Tagen (1 TTS 4 Tage, anschließend 1 TTS 3 Tage) appliziert und im Vergleich 7 Tage lang 1 Kapsel ä 2 mg Trandolapril täglich appliziert. Blutproben wurden nach Applikation nach folgenden Zeiten genommen: 0,5 - 1 - 2 - 4 - 6 - 8 - 10 - 12 - 24 - 48 - 72 - 96 - 98 - 100 - 102 - 104 - 106 - 108 - 120 - 132 - 144 - 156 - 168 h. In an in vivo comparative study of a TTS according to the invention with an oral administration of trandolapril (capsule), the pharmacokinetic behavior for TTS application was tested in 6 healthy volunteers. The TTS were applied in an open 2-period cross-over design over a period of 7 days (1 TTS 4 days, then 1 TTS 3 days) and 1 capsule of 2 mg trandolapril was applied daily for 7 days. Blood samples were taken after application after the following times: 0.5 - 1 - 2 - 4 - 6 - 8 - 10 - 12 - 24 - 48 - 72 - 96 - 98 - 100 - 102 - 104 - 106 - 108 - 120 - 132 - 144 - 156 - 168 h.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10317108.8 | 2003-04-14 | ||
| DE10317108A DE10317108A1 (en) | 2003-04-14 | 2003-04-14 | Sedative and sedative that can be applied transdermally |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004091589A1 true WO2004091589A1 (en) | 2004-10-28 |
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ID=33154204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DE2004/000766 Ceased WO2004091589A1 (en) | 2003-04-14 | 2004-04-14 | Transdermally administerable tranquilizing and sedating agent |
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| Country | Link |
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| DE (1) | DE10317108A1 (en) |
| WO (1) | WO2004091589A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7989475B2 (en) | 2003-01-27 | 2011-08-02 | Merck Sharp & Dohme Corp. | Substituted pyrazoles, compositions containing such compounds and methods of use |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4710497A (en) * | 1983-05-20 | 1987-12-01 | Nitto Electric Industrial Co., Ltd. | Method for percutaneously administering physiologically active agents |
| WO1993023019A1 (en) * | 1992-05-11 | 1993-11-25 | Sri International | Transdermal drug delivery systems and related compositions and methods of use |
| US5372819A (en) * | 1992-08-07 | 1994-12-13 | Minnesota Mining And Manufacturing Company | Tramsdermal drug delivery device |
| US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
| WO2002087642A2 (en) * | 2001-05-01 | 2002-11-07 | A.V. Topchiev Institute Of Petrochemical Synthesis | Two-phase, water-absorbent bioadhesive composition |
-
2003
- 2003-04-14 DE DE10317108A patent/DE10317108A1/en not_active Withdrawn
-
2004
- 2004-04-14 WO PCT/DE2004/000766 patent/WO2004091589A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4710497A (en) * | 1983-05-20 | 1987-12-01 | Nitto Electric Industrial Co., Ltd. | Method for percutaneously administering physiologically active agents |
| US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
| WO1993023019A1 (en) * | 1992-05-11 | 1993-11-25 | Sri International | Transdermal drug delivery systems and related compositions and methods of use |
| US5372819A (en) * | 1992-08-07 | 1994-12-13 | Minnesota Mining And Manufacturing Company | Tramsdermal drug delivery device |
| WO2002087642A2 (en) * | 2001-05-01 | 2002-11-07 | A.V. Topchiev Institute Of Petrochemical Synthesis | Two-phase, water-absorbent bioadhesive composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7989475B2 (en) | 2003-01-27 | 2011-08-02 | Merck Sharp & Dohme Corp. | Substituted pyrazoles, compositions containing such compounds and methods of use |
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| Publication number | Publication date |
|---|---|
| DE10317108A1 (en) | 2004-11-11 |
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