WO1998026763A1 - Active substance carrier for releasing apomorphine into the buccal cavity - Google Patents
Active substance carrier for releasing apomorphine into the buccal cavity Download PDFInfo
- Publication number
- WO1998026763A1 WO1998026763A1 PCT/EP1997/006529 EP9706529W WO9826763A1 WO 1998026763 A1 WO1998026763 A1 WO 1998026763A1 EP 9706529 W EP9706529 W EP 9706529W WO 9826763 A1 WO9826763 A1 WO 9826763A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- apomorphine
- pharmaceutical preparation
- preparation according
- active ingredient
- active substance
- 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
Links
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the present invention relates to a medicament preparation for the application of active substances in the area of the oral cavity or the oral mucosa. It relates in particular to a preparation that is flat and designed as a film, paper or wafer-like dosage form.
- DE-OS 27 46 414 which describes a film-like band of active substance, binder and other auxiliaries, in which, due to homogeneous thickness and density, there is a direct connection between a unit length of the band and the dose of active substance contained therein, can be regarded as fundamental for this dosage form .
- the advantages of continuous dosing were also recognized by other applicants and described in special individual variants.
- DE-PS 36 30 603 claims a flat carrier material e.g. in the form of a release paper with a coating containing the active substance, the latter being subtracted from the carrier material in doses after being divided up into dose units.
- a flat, film-like or paper-like active ingredient carrier enables a faster onset of action than the application of conventional dosage forms, such as tablets.
- Tablets are usually designed for drug release after swallowing in the gastrointestinal tract. Ordinary, rapidly disintegrating tablets release their active ingredient in the stomach. The disintegration of the dosage form is a prerequisite for the release of the active ingredient.
- the disintegration of a tablet in the fluids of the gastrointestinal tract is often a multi-stage process. If the tablet has a coating, it must first disintegrate and expose the compact.
- the latter are suitable for introducing active substances into the organism more quickly than with tablets, and can advantageously be used when a quick onset of action is necessary or particularly desirable, for example when administering analgesics, antiallergics, antitussives, antiemetics, active substances against Angina, migraines, hypotension, etc.
- the object of the present invention is therefore to create a medicinal preparation based on and with the general advantages of flat, film-like or paper-like active substance carriers, which, however, in addition, through the combination with a special active substance, also have additional economic and / or therapeutic advantages over medicament preparations thereof Active ingredient based on conventional dosage forms such as tablets.
- a medicinal preparation is provided on the basis of a flat, film, paper or wafer-like active ingredient carrier which contains apomorphine or one of its therapeutically suitable salts as the active ingredient.
- a pharmaceutical preparation according to claim 1 is, as will be explained in the following, a conventional oral dosage form for the administration of apomorphine far superior both from an economic as well as from a therapeutic point of view and is particularly suitable for the therapy of Parkinson's disease.
- apomorphine a potent dopamine agonist
- apomorphine must be injected subcutaneously for this purpose, since it is hardly bioavailable after oral administration, i.e. it only appears to a very small extent in the bloodstream of a few percent of the dose taken.
- the reason for the lack of bioavailability probably lies in the extensive breakdown of the substance during the first passage through the liver after gastrointestinal absorption ("first pass effect").
- One way to circumvent the first-pass effect in the case of oral administration is to induce the active ingredient to be absorbed on the oral mucosa.
- Active substance that enters the blood here does not first have to pass through the portal vein system and thus in concentrated form through the liver metabolizing the active substance in order to get into the central body circulation.
- a prerequisite for buccal or sublingual application is the sufficient permeability of the oral mucosa for the active substance, taking into account the necessary dose. The permeability in turn depends to a large extent on the physicochemical properties of the active ingredient.
- buccal or sublingual administration of apomorphine appears to be very desirable for the patients because of the injections to be avoided.
- apomorphine with the aid of a pharmaceutical preparation according to claim 1 is completely different.
- This dosage form can be brought into direct contact with the oral mucosa during application. Due to the flat design, about half of the already large surface of the dosage form is immediately on the mucosa immediately after application.
- the released apomorphine therefore finds two particularly favorable factors for entry into the body, namely a short diffusion distance and a large diffusion area. This reduces the amount of apomorphine that is swallowed, which would not be particularly problematic with other active ingredients. In the case of apomorphine, however, the swallowing of active ingredient should be avoided or reduced as far as possible, since swallowed apomorphine remains ineffective for the reasons set out above.
- test person showed the superiority of an apomorphine-containing film over an apomorphine-containing tablet.
- An improved contact of the pharmaceutical preparation according to the invention with the oral mucosa can be brought about by the selection of the auxiliary substances.
- pharmaceutically customary, orally administrable auxiliaries have mucosal properties.
- mucoadhesive substances are polyacrylic acid, carboxylmethyl cellulose, tragacanth, alginic acid, gelatin, hydroxymethyl cellulose, methyl cellulose and gum arabic.
- various non-mucoadhesive substances are known to also form mucoadhesive properties in certain mixing ratios.
- An example of such a mixture is glycerol monooleate / water in the ratio 84:16 (Engström et al., Pharm. Tech. Eur. 7 [1995], No. 2, pages 14-17).
- a two- or multi-layer structure of the dosage form of the medicinal preparation according to the invention is to be preferred, only one layer, which should come into contact with the mucous membrane when the preparation is applied, to be provided with mucoadhesive properties. This prevents the preparation from sticking together different parts of the mucous membrane, which would lead to considerable discomfort during use.
- the amount of active ingredient or the proportion of the administered active ingredient dose which is absorbed in the preparation according to the invention depends not only on the contact area and the perme bailiness of the mucous membrane, but also on the contact time.
- auxiliaries can be, for example, film-forming polymers with low water solubility, such as ethyl cellulose, cellulose acetate, highly hydrolyzed polyvinyl alcohol and many others.
- apomorphine usually leads to undesirable side effects. First of all there are nausea, vomiting and a drop in blood pressure. These side effects can be seen as serious and therapy-limiting. However, it is known that the simultaneous administration of antiemetic dopamine antagonists such as metoclopramide, but especially domperidone, can prevent or alleviate the occurrence of these side effects without losing the anti-Parkinson effect of apomorphine.
- antiemetic dopamine antagonists such as metoclopramide, but especially domperidone
- a further preferred embodiment of the present invention therefore contains apomorphine in combination with a dopamine antagonist in a combination as active ingredients.
- Production examples of the pharmaceutical preparation according to the invention are given below:
- H 2 0 Place H 2 0 in a heatable, evacuable batch vessel and disperse Ti0 2 in it.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Wirkstoffträger für die Freisetzung von Apomorphin in derDrug carrier for the release of apomorphine in the
MundhöhleOral cavity
Die vorliegende Erfindung betrifft eine Arzneizubereitung zur Applikation von Wirkstoffen im Bereich der Mundhöhle bzw. der Mundschleimhaut. Sie betrifft insbesondere eine Zubereitung, die flach und als folien-, papier- oder oblatenartige Darreichungsform ausgestaltet ist.The present invention relates to a medicament preparation for the application of active substances in the area of the oral cavity or the oral mucosa. It relates in particular to a preparation that is flat and designed as a film, paper or wafer-like dosage form.
Flache Wirkstoffträger wurden bereits für verschiedene Zwecke entwickelt und hergestellt. Als grundlegend für diese Darreichungsform kann die DE-OS 27 46 414 angesehen werden, die ein folienartiges Band aus Wirkstoff, Bindemittel und weiteren Hilfsstoffen beschreibt, bei dem aufgrund homogener Dicke und Dichte ein direkter Zusammenhang zwischen einer Längeneinheit des Bandes und der darin enthaltenen Wirkstoffdosis besteht. Die Vorteile der kontinuierlichen Dosierbarkeit wurden auch von anderen Anmeldern erkannt und in speziellen Einzelvarianten beschrieben. So beansprucht DE-PS 36 30 603 ein flächiges Trägermaterial z.B. in Form eines Trennpapieres mit einer wirkstoffhaltigen Beschichtung, wobei letztere nach Vor- zerteilung in Dosiseinheiten vom Trägermaterial dosisweise abzuziehen ist.Flat active ingredient carriers have already been developed and manufactured for various purposes. DE-OS 27 46 414, which describes a film-like band of active substance, binder and other auxiliaries, in which, due to homogeneous thickness and density, there is a direct connection between a unit length of the band and the dose of active substance contained therein, can be regarded as fundamental for this dosage form . The advantages of continuous dosing were also recognized by other applicants and described in special individual variants. DE-PS 36 30 603 claims a flat carrier material e.g. in the form of a release paper with a coating containing the active substance, the latter being subtracted from the carrier material in doses after being divided up into dose units.
Die Praktikabilität des flachen Formates im allgemeinen sowie die Vorteilhaftigkeit bei der Herstellung der Darreichungsform und bei der Dosierung unter ihrer Anwendung wurden im Stand der Technik erkannt. Darüber hinaus las- sen sich weitere Vorteile solcher Darreichungsformen ableiten, wie etwa die Bedruckbarkeit einer relativ großen Fläche auf der Arzneiform im Verhältnis zu ihrem Gewicht, womit die Einnahmesicherheit erhöht werden kann, wie auch die Möglichkeit der diskreten Einnahme ohne daß Flüssigkeit zur Verfügung steht .The practicability of the flat format in general and the advantageousness in the preparation of the dosage form and in the dosage using it have been recognized in the prior art. In addition, Further advantages of such dosage forms can be derived, such as the printability of a relatively large area on the dosage form in relation to its weight, which can increase the income security, as well as the possibility of discrete intake without liquid being available.
Falls ein Wirkstoff zur Applikation gebracht werden soll, der durch die Mundschleimhaut zur Resorption gebracht werden kann, ermöglicht ein flacher, film- oder papierartiger Wirkstoffträger einen schnelleren Wirkungseintritt als die Applikation konventioneller Darreichungsformen wie etwa Tabletten. Tabletten sind in der Regel für eine Wirkstofffreisetzung nach dem Schlucken im Gastrointe- stinaltrakt konzipiert. Gewöhnliche schnellzerfallende Tabletten geben ihren Wirkstoff im Magen frei. Dabei ist der Zerfall der Arzneiform eine Voraussetzung für die Wirkstofffreisetzung. Der Zerfall einer Tablette in den Flüssigkeiten des Gastrointestinaltraktes ist häufig ein mehrstufiger Prozeß. Besitzt die Tablette eine Umhüllung, so muß diese zunächst zerfallen und den Preßling exponieren. Danach erfolgt ein sogenannter Primärzerfall, bei dem die Tablette in kleine Bruchstücke, z.B. in die Granulatkörner zerfällt, aus denen sie gepreßt wurde, welche wiederum im sogenannten Sekundärzerfall in ihre Pulverkomponenten zerfallen. Während der Primärzerfall makroskopisch sichtbar ist und laut Arzneibuch mit einer speziellen Apparatur geprüft wird, läßt sich der Sekundärzerf ll kaum wahrnehmen oder messen, obwohl er eine unmittelbare Voraussetzung für die Wirkstoffauflösung ist . Selbst wenn also gewöhnliche Tabletten solange im Mund behalten werden, bis sie makroskopisch zerfallen sind, kann nicht davon ausgegangen werden, daß sie deshalb bereits ihren Wirkstoff freigesetzt haben, wohingegen flache, film- oder papierartige Wirkstoffträger hierzu innerhalb von wenigen Sekunden bis Minuten nach ihrer Applikation in der Lage sind. Insofern sind letztere geeignet, Wirkstoffe schneller in den Organismus einzubringen als mit Tabletten, und lassen sich vorteilhafterweise dann einsetzten, wenn ein schneller Wirkungseintritt notwendig oder besonders wünschenswert ist, also etwa bei der Verabreichung von Analgetika, Antiallergika, Antitus- siva, Antiemetika, Wirkstoffen gegen Angina pectoris, Migräne, Hypotonie usw.If an active ingredient is to be applied that can be resorbed through the oral mucosa, a flat, film-like or paper-like active ingredient carrier enables a faster onset of action than the application of conventional dosage forms, such as tablets. Tablets are usually designed for drug release after swallowing in the gastrointestinal tract. Ordinary, rapidly disintegrating tablets release their active ingredient in the stomach. The disintegration of the dosage form is a prerequisite for the release of the active ingredient. The disintegration of a tablet in the fluids of the gastrointestinal tract is often a multi-stage process. If the tablet has a coating, it must first disintegrate and expose the compact. This is followed by a so-called primary disintegration, in which the tablet disintegrates into small fragments, for example into the granules, from which it was pressed, which in turn disintegrates into its powder components in the so-called secondary disintegration. While the primary decay is macroscopically visible and, according to the pharmacopoeia, it is checked with special equipment, the secondary decay can hardly be perceived or measured, although it is an immediate prerequisite for the dissolution of the active substance. So even if ordinary tablets last Shut up until they have macroscopically disintegrated, it can not be assumed that they have already released their active ingredient, whereas flat, film or paper-like active ingredient carriers are able to do this within a few seconds to minutes after their application. In this respect, the latter are suitable for introducing active substances into the organism more quickly than with tablets, and can advantageously be used when a quick onset of action is necessary or particularly desirable, for example when administering analgesics, antiallergics, antitussives, antiemetics, active substances against Angina, migraines, hypotension, etc.
Trotz dieser klaren Vorteile haben sich solche flachen Darreichungsformen bisher kaum durchgesetzt. Offensichtlich reicht für viele Hersteller von Pharmazeutika der Nutzen gegenüber konventionellen Darreichungsformen nicht aus, um Produkte dieser Art mit den gebräuchlichen Wirkstoffen zu entwickeln und deren arzneimittelrechtliche Zulassung zu betreiben, was mit erheblichem Aufwand und hohen Kosten verbunden ist . Darüber hinaus können vorhandene Produktionsmaschinen und existierendes Know-how für diese neuartigen Produkte nicht genutzt werden; ein hoher Investitionsbedarf würde entstehen. Trotz der oben beschriebenen Vorteile von flachen, film- oder papierartigen Darreichungsformen ist der therapeutische und/oder wirtschaftliche Nutzen bei der Verabreichung von gängigen, auch peroral applizierbaren Wirkstoffen im Vergleich zu konventionellen Tabletten nicht so groß, daß er die Kosten der Umstellung auf diese Darreichungsformen rechtfertigen würde.Despite these clear advantages, such flat dosage forms have so far hardly become established. Obviously, for many manufacturers of pharmaceuticals, the benefits compared to conventional dosage forms are not sufficient to develop products of this type with the usual active ingredients and to operate their drug approval, which is associated with considerable effort and high costs. In addition, existing production machines and existing know-how cannot be used for these new products; a high investment requirement would arise. Despite the above-described advantages of flat, film-like or paper-like dosage forms, the therapeutic and / or economic benefit when administering common active ingredients, which can also be administered orally, is not so great compared to conventional tablets that it does Would justify the cost of switching to these dosage forms.
Aufgabe der vorliegenden Erfindung ist daher die Schaffung einer ArzneiZubereitung auf der Basis von und mit den allgemeinen Vorteilen von flachen, film- oder papierartigen Wirkstoffträgem, welche darüber hinaus jedoch durch die Kombination mit einem speziellen Wirkstoff noch zusätzliche wirtschaftliche und/oder therapeutische Vorteile gegenüber Arzneizubereitungen desselben Wirkstoffes auf der Basis konventioneller Darreichungsformen wie etwa Tabletten aufweist.The object of the present invention is therefore to create a medicinal preparation based on and with the general advantages of flat, film-like or paper-like active substance carriers, which, however, in addition, through the combination with a special active substance, also have additional economic and / or therapeutic advantages over medicament preparations thereof Active ingredient based on conventional dosage forms such as tablets.
Die Aufgabe wird nach Anspruch 1 dadurch gelöst, daß eine Arzneizubereitung auf der Basis eines flächigen, folien-, papier- oder oblatenartigen Wirkstoffträgers bereitgestellt wird, welche als Wirkstoff Apomorphin oder eines seiner therapeutisch geeigneten Salze enthält.The object is achieved according to claim 1 in that a medicinal preparation is provided on the basis of a flat, film, paper or wafer-like active ingredient carrier which contains apomorphine or one of its therapeutically suitable salts as the active ingredient.
Eine ArzneiZubereitung nach Anspruch 1 ist, wie im folgenden dargelegt werden soll, einer konventionellen oralen Darreichungsform zur Verabreichung von Apomorphin sowohl unter wirtschaftlichen wie auch unter therapeutischen Gesichtspunkten weit überlegen und eignet sich insbesondere für die Therapie der Parkinson-Krankheit .A pharmaceutical preparation according to claim 1 is, as will be explained in the following, a conventional oral dosage form for the administration of apomorphine far superior both from an economic as well as from a therapeutic point of view and is particularly suitable for the therapy of Parkinson's disease.
Eine nur schwer der Pharmakotherapie zugängliche Symptomatik des Morbus Parkinson ist die fluktuierende Dyskine- se, bekannt unter der Bezeichnung "On-off-Phänomen" . Dabei handelt es sich um den plötzlichen Wechsel zwischen guter Beweglichkeit und Akinese. Zur akuten Therapie der "off-Phasen" eignet sich der Wirkstoff Apomorphin, ein potenter Dopamin-Agonist . Allerdings muß Apomorphin hierzu subcutan injiziert werden, da es nach peroraler Gabe kaum bioverfügbar ist, also nur in einem sehr geringen Ausmaß von wenigen Prozent der eingenommenen Dosis im Blutkreislauf erscheint. Der Grund für die mangelnde Bioverfügbarkeit liegt vermutlich im weitgehenden Abbau der Substanz während der ersten Leberpassage nach der gastro- intestinalen Resorption ("First-pass Effekt").One of the symptoms of Parkinson's disease that is difficult to access in pharmacotherapy is fluctuating dyskinesis, known as the "on-off phenomenon". This is the sudden change between good mobility and akinesia. For acute therapy of The active ingredient apomorphine, a potent dopamine agonist, is suitable for "off phases". However, apomorphine must be injected subcutaneously for this purpose, since it is hardly bioavailable after oral administration, i.e. it only appears to a very small extent in the bloodstream of a few percent of the dose taken. The reason for the lack of bioavailability probably lies in the extensive breakdown of the substance during the first passage through the liver after gastrointestinal absorption ("first pass effect").
Eine Möglichkeit, den First-pass Effekt bei der oralen Verabreichung zu umgehen, besteht darin, den Wirkstoff bereits an der Mundschleimhaut zur Resorption zu bringen. Wirkstoff, welcher hier ins Blut übertritt, muß nicht als erstes das Pfortadersystem und damit in konzentrierter Form die den Wirkstoff metaboliserende Leber passieren, um in den zentralen Körperkreislauf zu gelangen. Voraussetzung für eine buccale oder sublinguale Applikation ist jedoch die ausreichende Permeabilität der oralen Mucosa für den Wirkstoff unter Berücksichtigung der notwendigen Dosis. Die Permeabilität wiederum hängt in hohem Maße von den physikochemischen Eigenschaften des Wirkstoffes ab. Eine buccale oder sublinguale Verabreichung von Apomorphin erscheint wegen der damit zu vermeidenden Injektionen für die Patienten als sehr erstrebenswert.One way to circumvent the first-pass effect in the case of oral administration is to induce the active ingredient to be absorbed on the oral mucosa. Active substance that enters the blood here does not first have to pass through the portal vein system and thus in concentrated form through the liver metabolizing the active substance in order to get into the central body circulation. A prerequisite for buccal or sublingual application, however, is the sufficient permeability of the oral mucosa for the active substance, taking into account the necessary dose. The permeability in turn depends to a large extent on the physicochemical properties of the active ingredient. Buccal or sublingual administration of apomorphine appears to be very desirable for the patients because of the injections to be avoided.
Verschiedene Forschungsgruppen haben daher in den letzten Jahren versucht, Apomorphin über die Mundschleimhaut zu applizieren. Tatsächlich konnte in mehreren voreinander unabhängigen Versuchen eine relevante absolute Bioverfüg- barkeit nach sublingualer Gabe nachgewiesen werden, so etwa von Gancher et al.(Movement Disorders 6 [1991], Seiten 212-216), die Bioverfügbarkeitswerte zwischen 10 und 22 % fanden. Montastruc et al . (Clin.Neuropharmacol .14 [1991], Seiten 432-437) zeigte die Äquivalente von 30 mg Apomorphin sublingual zu 3 mg des Wirkstoffes subcutan. Ähnliche Ergebnisse finden sich bei Hughes et al . (Clin. Neuropharmacol .14 [1991], Seiten 556-561), Durif et al. (Eur. .Clin.Pharmacol.41 [1991], Seiten 493-494) und andere .Various research groups have therefore tried to apply apomorphine through the oral mucosa in recent years. In fact, in several mutually independent experiments, relevant absolute bioavailability after sublingual administration could be demonstrated from Gancher et al. (Movement Disorders 6 [1991], pages 212-216), who found bioavailability values between 10 and 22%. Montastruc et al. (Clin.Neuropharmacol .14 [1991], pages 432-437) showed the equivalents of 30 mg apomorphine sublingually to 3 mg of the active ingredient subcutaneously. Similar results can be found in Hughes et al. (Clin. Neuropharmacol .14 [1991], pages 556-561), Durif et al. (Eur. Clin.Pharmacol.41 [1991], pages 493-494) and others.
Zu diesen Studien ist kritisch anzumerken, daß nirgendwo im Methodenteil der Veröffentlichungen die Parameter der sublingualen Applikation selbst definiert wurden. Die einzigen Angaben hierzu machen Gancher et al . , die die Probanden anwiesen, Apomorphintabletten ä 6 mg bis zu deren Zerfall unter der Zunge zu behalten. Waren die Tabletten nach 5 min nicht zerfallen, durfte ein Schluck Wasser genommen werden, ohne diesen jedoch zu schlucken. In den anderen Arbeiten wurde offensichtlich überhaupt nicht sichergestellt, daß entweder ein möglichst großer oder zumindest ein möglichst gleicher Anteil der Wirkstoffdosis aus der Darreichungsform der Mundschleimhaut zur Resorption zur Verfügung steht . Zumindest die Einwirkungszeit sollte aber ausreichend und konstant gewählt sein, und das Schlucken von Speichel über einen konstanten Zeitraum unterbunden sein, um eine sublinguale Applikation methodisch von einer peroralen abzugrenzen. Darüber hinaus muß die in allen oben genannten Fällen verabreichte Arzneiform, nämlich eine perorale Tablette, wie bereits erwähnt, als völlig ungeeignet für die sublinguale Applikation angesehen werden. Vermutlich verursachte genau diese Problematik auch die hohe Variabilität, die in den oben genannten Studien zu beobachten ist.With regard to these studies, it should be critically noted that the parameters of the sublingual application itself were not defined anywhere in the method part of the publications. The only information on this is provided by Gancher et al. who instructed the subjects to keep apomorphine tablets of 6 mg under their tongue until they disintegrated. If the tablets did not disintegrate after 5 minutes, a sip of water could be taken without swallowing it. In the other works, it was obviously not ensured at all that either as large as possible or at least as equal a proportion of the active substance dose from the dosage form of the oral mucosa is available for absorption. At least the exposure time should be sufficient and constant, and the swallowing of saliva should be prevented for a constant period of time in order to differentiate a sublingual application from a oral one. In addition, the dosage form administered in all of the above cases, namely a oral tablet, as already mentioned, must be regarded as completely unsuitable for sublingual application. Probably caused exactly this problem also the high variability that can be observed in the studies mentioned above.
Völlig anders gestaltet sich die Applikation von Apomorphin mit Hilfe einer Arzneizubereitung nach Anspruch 1. Diese Darreichungsform kann bei der Applikation direkt mit der Mundschleimhaut in Kontakt gebracht werden. Durch die flächige Ausgestaltung befindet sich sofort nach der Applikation etwa die Hälfte der ohnehin großen Oberfläche der Darreichungsform unmittelbar auf der Mucosa. Das freigesetzte Apomorphin findet also für den Eintritt in den Körper zwei besonders günstige Faktoren vor, nämlich eine kurze Diffusionsstreσke und eine große Diffusionsfläche. Hierdurch wird der Anteil an Apomorphin herabgesetzt, der verschluckt wird, was bei anderen Wirkstoffen nicht sonderlich problematisch wäre. Bei Apomorphin jedoch ist das Verschlucken von Wirkstoff möglichst zu vermeiden oder herabzusetzen, da verschlucktes Apomorphin aus den oben dargelegten Gründen unwirksam bleibt.The application of apomorphine with the aid of a pharmaceutical preparation according to claim 1 is completely different. This dosage form can be brought into direct contact with the oral mucosa during application. Due to the flat design, about half of the already large surface of the dosage form is immediately on the mucosa immediately after application. The released apomorphine therefore finds two particularly favorable factors for entry into the body, namely a short diffusion distance and a large diffusion area. This reduces the amount of apomorphine that is swallowed, which would not be particularly problematic with other active ingredients. In the case of apomorphine, however, the swallowing of active ingredient should be avoided or reduced as far as possible, since swallowed apomorphine remains ineffective for the reasons set out above.
Bereits bei der einfachsten erfindungsgemäßen Ausgestaltung als schnellzerfallende Arzneiform, also mit einer Zerfallszeit von bis zu 15 min nach Applikation oder nach dem Einbringen in wässrige Medien, zeigte sich bei einer Versuchsperson die Überlegenheit eines apomorphinhaltigen Filmes gegenüber einer apomorphinhaltigen Tablette.Even in the simplest embodiment according to the invention as a rapidly disintegrating pharmaceutical form, i.e. with a disintegration time of up to 15 min after application or after being introduced into aqueous media, the test person showed the superiority of an apomorphine-containing film over an apomorphine-containing tablet.
Ein verbesserter Kontakt der erfindungsgemäßen Arzneizubereitung mit der Mundschleimhaut läßt sich durch die Auswahl der Hilfsstoffe herbeiführen. Von bestimmten pharmazeutisch gebräuchlichen, oral applizierbaren Hilfs- stoffen ist bekannt, daß sie schleimhauthaftende Eigenschaften besitzen. Beispiele für solche mucoadhäsiven Substanzen sind Polyacrylsäure, Carboxylmethylcellulose, Traganth, Alginsäure, Gelatine, Hydroxymethylcellulose, Methylcellulose und Gummi Arabicum. Darüber hinaus ist von verschiedenen nicht mucoadhäsiven Stoffen bekannt, daß sie in bestimmten Mischungsverhältnissen ebenfalls mucoadhäsive Eigenschaften ausbilden. Ein Beispiel für ein solches Gemisch ist Glycerinmonooleat/Wasser im Verhältnis 84:16 (Engström et al . , Pharm. Tech. Eur. 7 [1995], Nr. 2, Seiten 14-17).An improved contact of the pharmaceutical preparation according to the invention with the oral mucosa can be brought about by the selection of the auxiliary substances. From certain It is known that pharmaceutically customary, orally administrable auxiliaries have mucosal properties. Examples of such mucoadhesive substances are polyacrylic acid, carboxylmethyl cellulose, tragacanth, alginic acid, gelatin, hydroxymethyl cellulose, methyl cellulose and gum arabic. In addition, various non-mucoadhesive substances are known to also form mucoadhesive properties in certain mixing ratios. An example of such a mixture is glycerol monooleate / water in the ratio 84:16 (Engström et al., Pharm. Tech. Eur. 7 [1995], No. 2, pages 14-17).
Im Falle der Verwendung mucoadhasiver Hilfsstoffe ist ein zwei- oder mehrschichtiger Aufbau der Darreichungsform der erfindungsgemäßen ArzneiZubereitung zu bevorzugen, wobei nur eine Schicht, die bei der Applikation der Zubereitung mit der Schleimhaut in Kontakt treten soll, mit mucoadhäsiven Eigenschaften ausgestattet sein sollte. Hierdurch wird vermieden, daß die Zubereitung verschiedene Schleimhautpartien miteinander verklebt, was zu erheblichen Mißempfindungen bei der Anwendung führen würde.If mucoadhesive excipients are used, a two- or multi-layer structure of the dosage form of the medicinal preparation according to the invention is to be preferred, only one layer, which should come into contact with the mucous membrane when the preparation is applied, to be provided with mucoadhesive properties. This prevents the preparation from sticking together different parts of the mucous membrane, which would lead to considerable discomfort during use.
Eine gute Haftung der Darreichungsform auf der Mundschleimhaut führt zu einer optimalen Verfugbarmachung des Wirkstoffs für die Resorption. Sie ist außerdem die Voraussetzung für eine weitere, bevorzugte Ausgestaltung der Erfindung, nämlich als Retardzubereitung. Die Wirkstoff- menge bzw. der Anteil der verabreichten Wirkstoffdosis, der resorbiert wird, hängt bei der erfindungsgemäßen Zubereitung nicht nur von der Kontaktfläche und der Perme bailität der Schleimhaut, sondern auch von der Kontaktzeit ab. Um eine größere Wirkstoffmenge über die relativ geringflächige Mundschleimhaut in den Körper gelangen zu lassen, kann es notwendig sein, eine lange Kontaktzeit zu erlauben, was jedoch voraussetzt, daß die Zubereitung nicht zu rasch zerfällt, sondern durch den Zusatz von in Speichelflüssigkeit schwer- oder langsamlöslichen Hilfsstoffen den Wirkstoff über die gewünschte Zeitdauer freisetzt. Geeignete Hilfsstoffe können beispielsweise filmbildende Polymere mit geringer Wasserlöslichkeit sein wie etwa Ethylcellulose, Celluloseacetat, hochhydrolysierter Polyvinylalkohol und viele andere mehr.Good adhesion of the dosage form to the oral mucosa leads to optimal availability of the active ingredient for absorption. It is also the prerequisite for a further, preferred embodiment of the invention, namely as a sustained-release preparation. The amount of active ingredient or the proportion of the administered active ingredient dose which is absorbed in the preparation according to the invention depends not only on the contact area and the perme bailiness of the mucous membrane, but also on the contact time. In order to allow a larger amount of active substance to enter the body through the relatively small area of the oral mucosa, it may be necessary to allow a long contact time, which, however, presupposes that the preparation does not disintegrate too quickly, but rather through the addition of sparingly or slowly soluble in saliva Excipients releases the active ingredient over the desired period of time. Suitable auxiliaries can be, for example, film-forming polymers with low water solubility, such as ethyl cellulose, cellulose acetate, highly hydrolyzed polyvinyl alcohol and many others.
Die Verabreichung von Apomorphin führt in der Regel zu unerwünschten Nebeneffekten. An erster Stelle sind Übelkeit, Erbrechen und Blutdruckabfall zu nennen. Diese Nebenwirkungen sind als gravierend und therapielimitierend anzusehen. Es ist jedoch bekannt, daß die gleichzeitige Gabe von antiemetisch wirkenden Dopamin-Antagonisten wie Metoclopramid, insbesondere jedoch Domperidon, das Auftreten dieser Nebenwirkungen verhindern oder sie abmildern kann, ohne daß dabei die Anti-Parkinson-Wirkung von Apomorphin verlorengeht .The administration of apomorphine usually leads to undesirable side effects. First of all there are nausea, vomiting and a drop in blood pressure. These side effects can be seen as serious and therapy-limiting. However, it is known that the simultaneous administration of antiemetic dopamine antagonists such as metoclopramide, but especially domperidone, can prevent or alleviate the occurrence of these side effects without losing the anti-Parkinson effect of apomorphine.
Eine weitere bevorzugte Ausführungsform der vorliegenden Erfindung enthält daher als Wirkstoffe Apomorphin in Kombination mit einem Dopamin-Antagonisten in einer Kombination. Nachfolgend werden Herstellungsbeispiele der Arzneizubereitung gemäß der Erfindung angegeben:A further preferred embodiment of the present invention therefore contains apomorphine in combination with a dopamine antagonist in a combination as active ingredients. Production examples of the pharmaceutical preparation according to the invention are given below:
Beispiel 1:Example 1:
73,8 g H2O73.8 g H 2 O
5,5 g τio2 5.5 g τio 2
18,4 g Polyvinylpyrrolidon18.4 g polyvinyl pyrrolidone
18,4 g Kartoffelstärke18.4 g potato starch
23,3 g Ethanol23.3 g ethanol
4,0 g H.04.0 g H. 0
16,6 g Apomorphin HCI16.6 g apomorphine HCI
1,8 g Aroma1.8 g aroma
1,2 g Süßstoff1.2 g sweetener
3,0 g Säuerungsmittel3.0 g acidifier
H20 in einem beheizbaren, evakuierbaren Ansatzgefäß vorlegen. Polyvinylpyrrolidon darin dispergieren und aufquellen lassen. Ti02 in dieser Masse dispergieren. Um den Quellprozeß des Polyvinylpyrrolidons zu beschleunigen kann die Masse erhitzt werden. Bei Raumtemperatur Kartoffelstärke in der homogenen Masse dispergieren. Ethanol, Rest H20 und Apomorphin HCI unter Rühren zugeben. Masse unter Rühren auf 100°C erhitzen. Nach dem Abkühlen auf Raumtemperatur Aroma, Süßstoff und Säuerungsmittel zugeben und Masse unter Vakuum entgasen. Masse mit Hilfe einer Rakel auf geeignetes Trägermaterial ausstreichen und bei 80°C 30 min trocknen. Dosiseinheiten mit einem Hen- kellocheisen ausstanzen. Beispiel 2:Place H 2 0 in a heatable, evacuable batch container. Disperse and swell polyvinylpyrrolidone in it. Disperse Ti0 2 in this mass. The mass can be heated in order to accelerate the swelling process of the polyvinylpyrrolidone. At room temperature, disperse the potato starch in the homogeneous mass. Add ethanol, H 2 0 and apomorphine HCl while stirring. Heat the mass to 100 ° C while stirring. After cooling to room temperature, add the aroma, sweetener and acidifier and degas the mass under vacuum. Spread the mass with a squeegee onto a suitable carrier material and dry at 80 ° C for 30 min. Punch out dose units with a handle punch. Example 2:
135,8 g H20135.8 g H 2 0
35,7 g Polyvinylalkohol35.7 g polyvinyl alcohol
9,9 g Ti02 9.9 g Ti0 2
46,5 g Si02 46.5 g Si0 2
20,0 g Glycerin (85 )20.0 g glycerin (85)
50,0 g Apomorphin HCI50.0 g apomorphine HCI
4,8 g Aroma4.8 g aroma
3,2 g Süßstoff3.2 g sweetener
8,0 g Säuerungsmittel8.0 g of acidulant
H20 in einem beheizbaren, evakuierbaren Ansatzgefäß vorlegen und Ti02 darin dispergieren. Polyvinylalkohol und Apomorphin HCI unter Rühren einstreuen und unter Erwärmen auf ca. 80°C homogenisieren. Masse im Vakuum entgasen. Nach dem Abkühlen auf Raumtemperatur Si02, Glycerol, Aroma, Süßstoff und Säuerungsmittel zugeben und homogenisieren. Masse unter Vakuum entgasen. Masse mit Hilfe einer Rakel auf geeignetes Trägermaterial ausstreichen und bei 80°C 30 min trocknen. Dosiseinheiten mit einem Henkel- locheisen ausstanzen. Place H 2 0 in a heatable, evacuable batch vessel and disperse Ti0 2 in it. Sprinkle in polyvinyl alcohol and Apomorphin HCI while stirring and homogenize while heating to approx. 80 ° C. Degas the mass in a vacuum. After cooling to room temperature, add Si0 2 , glycerol, aroma, sweetener and acidifier and homogenize. Degas the mass under vacuum. Spread the mass with a squeegee onto a suitable carrier material and dry at 80 ° C for 30 min. Punch out dose units with a punch.
Claims
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52593498A JP2001506612A (en) | 1996-12-16 | 1997-11-21 | Active substance carrier for release of apomorphine into the oral cavity |
| EP97952795A EP0959875A1 (en) | 1996-12-16 | 1997-11-21 | Active substance carrier for releasing apomorphine into the buccal cavity |
| AU56547/98A AU746373B2 (en) | 1996-12-16 | 1997-11-21 | Active substance carrier for releasing apomorphine into the buccal cavity |
| CA002274893A CA2274893A1 (en) | 1996-12-16 | 1997-11-21 | Active substance carrier for releasing apomorphine into the buccal cavity |
| NO992944A NO992944D0 (en) | 1996-12-16 | 1999-06-16 | Active ingredient for the delivery of apomorphine in the oral cavity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19652268.4 | 1996-12-16 | ||
| DE19652268A DE19652268C2 (en) | 1996-12-16 | 1996-12-16 | Medicinal preparation for the release of apomorphine in the oral cavity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998026763A1 true WO1998026763A1 (en) | 1998-06-25 |
Family
ID=7814859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1997/006529 Ceased WO1998026763A1 (en) | 1996-12-16 | 1997-11-21 | Active substance carrier for releasing apomorphine into the buccal cavity |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0959875A1 (en) |
| JP (1) | JP2001506612A (en) |
| KR (1) | KR20000057627A (en) |
| AU (1) | AU746373B2 (en) |
| CA (1) | CA2274893A1 (en) |
| DE (1) | DE19652268C2 (en) |
| NO (1) | NO992944D0 (en) |
| WO (1) | WO1998026763A1 (en) |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6291471B1 (en) | 1998-12-17 | 2001-09-18 | Abb Holdings, Inc. | Use of apomorphine for the treatment of organic erectile dysfunction in males |
| US6596298B2 (en) | 1998-09-25 | 2003-07-22 | Warner-Lambert Company | Fast dissolving orally comsumable films |
| US7067116B1 (en) | 2000-03-23 | 2006-06-27 | Warner-Lambert Company Llc | Fast dissolving orally consumable solid film containing a taste masking agent and pharmaceutically active agent at weight ratio of 1:3 to 3:1 |
| US7314716B2 (en) | 1999-11-19 | 2008-01-01 | Mount Sinai School Of Medicine | Gustducin γ subunit materials and methods |
| USRE40594E1 (en) | 1998-12-23 | 2008-12-02 | Mount Sinai School Of Medicine Of New York University | Inhibitors of the bitter taste response |
| WO2010144817A1 (en) | 2009-06-12 | 2010-12-16 | Adagio Pharmaceuticals Ltd. | Sublingual apomorphine |
| US7910132B2 (en) | 1998-09-24 | 2011-03-22 | Orexo Ab | Pharmaceutical composition for the treatment of acute disorders |
| WO2012083269A1 (en) | 2010-12-16 | 2012-06-21 | Cynapsus Therapeutics, Inc. | Sublingual films |
| US8481071B2 (en) | 2001-05-01 | 2013-07-09 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
| US8481059B2 (en) | 2001-05-01 | 2013-07-09 | A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Sciences | Hydrogel compositions |
| US8541021B2 (en) | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
| US8617647B2 (en) | 2001-05-01 | 2013-12-31 | A.V. Topchiev Institutes of Petrochemical Synthesis, Russian Academy of Sciences | Water-absorbent adhesive compositions and associated methods of manufacture and use |
| US8658201B2 (en) * | 2004-01-30 | 2014-02-25 | Corium International, Inc. | Rapidly dissolving film for delivery of an active agent |
| US8784879B2 (en) | 2009-01-14 | 2014-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
| US8840918B2 (en) | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
| USRE45666E1 (en) | 2000-07-07 | 2015-09-08 | A.V. Topchiev Institute Of Petrochemical Synthesis | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
| US10449146B2 (en) | 2015-04-21 | 2019-10-22 | Sunovion Pharmaceuticals Inc. | Methods of treating parkinson's disease by administration of apomorphine to an oral mucosa |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10252726B4 (en) * | 2002-11-13 | 2008-05-08 | Lts Lohmann Therapie-Systeme Ag | Multilayer transmucosal therapeutic system |
| AU2003277788A1 (en) * | 2002-11-14 | 2004-06-03 | Givaudan Sa | Edible film containing food acid |
| KR100945741B1 (en) * | 2003-01-16 | 2010-03-05 | 부광약품 주식회사 | Oral Spray Formulations Containing Apomorphine Hydrochloride |
| US20050281757A1 (en) * | 2004-06-17 | 2005-12-22 | Sayed Ibrahim | Oral care film |
| US10806703B2 (en) | 2012-01-20 | 2020-10-20 | Lts Lohmann Therapie-System Ag | Transmucosal administration system for a pharmaceutical drug |
| EP3524247A1 (en) * | 2013-11-11 | 2019-08-14 | Impax Laboratories, Inc. | Rapidly disintegrating formulations and methods of use |
| US20210369703A1 (en) * | 2018-10-18 | 2021-12-02 | Avior, Inc. | Method and device of treating chronic kidney disease-associated pruritus |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3972995A (en) * | 1975-04-14 | 1976-08-03 | American Home Products Corporation | Dosage form |
| WO1995028930A1 (en) * | 1994-04-22 | 1995-11-02 | Pentech Pharmaceuticals, Inc. | Dosage forms and method for ameliorating male erectile dysfunction |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2746414A1 (en) * | 1977-10-15 | 1979-04-26 | Gerlach Eduard Chem Fab | Foil-like tape for dispensing measured amts. of substance - consisting of the substance, binding agent and adjuvants, tape length being proportional to weight of substance |
| FR2732896B1 (en) * | 1995-04-11 | 1997-06-13 | Prographarm Lab | TRANSDERMAL PHARMACEUTICAL FORM FOR PERCUTANEOUS ADMINISTRATION OF APOMORPHINE |
-
1996
- 1996-12-16 DE DE19652268A patent/DE19652268C2/en not_active Expired - Fee Related
-
1997
- 1997-11-21 AU AU56547/98A patent/AU746373B2/en not_active Ceased
- 1997-11-21 WO PCT/EP1997/006529 patent/WO1998026763A1/en not_active Ceased
- 1997-11-21 JP JP52593498A patent/JP2001506612A/en active Pending
- 1997-11-21 KR KR1019990705422A patent/KR20000057627A/en not_active Ceased
- 1997-11-21 EP EP97952795A patent/EP0959875A1/en not_active Withdrawn
- 1997-11-21 CA CA002274893A patent/CA2274893A1/en not_active Abandoned
-
1999
- 1999-06-16 NO NO992944A patent/NO992944D0/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3972995A (en) * | 1975-04-14 | 1976-08-03 | American Home Products Corporation | Dosage form |
| WO1995028930A1 (en) * | 1994-04-22 | 1995-11-02 | Pentech Pharmaceuticals, Inc. | Dosage forms and method for ameliorating male erectile dysfunction |
Cited By (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8454996B2 (en) | 1998-09-24 | 2013-06-04 | Orexo Ab | Pharmaceutical composition for the treatment of acute disorders |
| US8512747B2 (en) | 1998-09-24 | 2013-08-20 | Orexo Ab | Pharmaceutical composition for the treatment of acute disorders |
| US7910132B2 (en) | 1998-09-24 | 2011-03-22 | Orexo Ab | Pharmaceutical composition for the treatment of acute disorders |
| EP1676557A2 (en) | 1998-09-25 | 2006-07-05 | Warner-Lambert Company LLC | Fast dissolving orally consumable films |
| US7025983B2 (en) | 1998-09-25 | 2006-04-11 | Warner-Lambert Company Llc | Fast dissolving orally consumable films |
| US7491406B2 (en) | 1998-09-25 | 2009-02-17 | Mcneil-Ppc, Inc. | Fast dissolving orally consumable films |
| US6923981B2 (en) | 1998-09-25 | 2005-08-02 | Warner-Lambert Company | Fast dissolving orally consumable films |
| US6596298B2 (en) | 1998-09-25 | 2003-07-22 | Warner-Lambert Company | Fast dissolving orally comsumable films |
| US6291471B1 (en) | 1998-12-17 | 2001-09-18 | Abb Holdings, Inc. | Use of apomorphine for the treatment of organic erectile dysfunction in males |
| USRE40594E1 (en) | 1998-12-23 | 2008-12-02 | Mount Sinai School Of Medicine Of New York University | Inhibitors of the bitter taste response |
| US7314716B2 (en) | 1999-11-19 | 2008-01-01 | Mount Sinai School Of Medicine | Gustducin γ subunit materials and methods |
| US7067116B1 (en) | 2000-03-23 | 2006-06-27 | Warner-Lambert Company Llc | Fast dissolving orally consumable solid film containing a taste masking agent and pharmaceutically active agent at weight ratio of 1:3 to 3:1 |
| EP1674078A2 (en) | 2000-03-23 | 2006-06-28 | Warner-Lambert Company LLC | Fast dissolving orally consumable filsm containing an ion exchange resin as a taste masking agent |
| US7648712B2 (en) | 2000-03-23 | 2010-01-19 | Mcneil-Ppc, Inc. | Fast dissolving orally consumable films containing a taste masking agent |
| USRE45666E1 (en) | 2000-07-07 | 2015-09-08 | A.V. Topchiev Institute Of Petrochemical Synthesis | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
| US9127140B2 (en) | 2001-05-01 | 2015-09-08 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Water-absorbent adhesive compositions and associated methods of manufacture and use |
| US9084723B2 (en) | 2001-05-01 | 2015-07-21 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions with an erodible backing member |
| US8481071B2 (en) | 2001-05-01 | 2013-07-09 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
| US8481059B2 (en) | 2001-05-01 | 2013-07-09 | A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Sciences | Hydrogel compositions |
| US10869947B2 (en) | 2001-05-01 | 2020-12-22 | Corium, Inc. | Hydrogel compositions |
| US8541021B2 (en) | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
| US8617647B2 (en) | 2001-05-01 | 2013-12-31 | A.V. Topchiev Institutes of Petrochemical Synthesis, Russian Academy of Sciences | Water-absorbent adhesive compositions and associated methods of manufacture and use |
| US9532935B2 (en) | 2001-05-01 | 2017-01-03 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
| US8741331B2 (en) | 2001-05-01 | 2014-06-03 | A. V. Topchiev Institute of Petrochemicals Synthesis, Russian Academy of Sciences | Hydrogel compositions with an erodible backing member |
| US9687428B2 (en) | 2001-05-01 | 2017-06-27 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
| US8840918B2 (en) | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
| US10835454B2 (en) | 2001-05-01 | 2020-11-17 | Corium, Inc. | Hydrogel compositions with an erodible backing member |
| US10179096B2 (en) | 2001-05-01 | 2019-01-15 | Corium International, Inc. | Hydrogel compositions for tooth whitening |
| US9259504B2 (en) | 2001-05-01 | 2016-02-16 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Non-electrically conductive hydrogel composition |
| US9089481B2 (en) | 2001-05-01 | 2015-07-28 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
| US8658201B2 (en) * | 2004-01-30 | 2014-02-25 | Corium International, Inc. | Rapidly dissolving film for delivery of an active agent |
| US9144552B2 (en) | 2004-01-30 | 2015-09-29 | A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Sciences | Rapidly dissolving film for delivery of an active agent |
| US10238612B2 (en) | 2009-01-14 | 2019-03-26 | Corium International, Inc. | Transdermal administration of tamsulosin |
| US8784879B2 (en) | 2009-01-14 | 2014-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
| US9610253B2 (en) | 2009-01-14 | 2017-04-04 | Corium International, Inc. | Transdermal administration of tamsulosin |
| EP3434270A1 (en) * | 2009-06-12 | 2019-01-30 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| AU2017200329B2 (en) * | 2009-06-12 | 2018-11-08 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| EP2442650B2 (en) † | 2009-06-12 | 2025-05-14 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| US9326981B2 (en) | 2009-06-12 | 2016-05-03 | Cynapsus Therapeutics, Inc. | Sublingual apomorphine |
| AU2019200308B2 (en) * | 2009-06-12 | 2020-11-26 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| US10420763B2 (en) | 2009-06-12 | 2019-09-24 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| AU2010259971B2 (en) * | 2009-06-12 | 2016-10-27 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| WO2010144817A1 (en) | 2009-06-12 | 2010-12-16 | Adagio Pharmaceuticals Ltd. | Sublingual apomorphine |
| AU2010259971C1 (en) * | 2009-06-12 | 2017-02-16 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| CN102480958A (en) * | 2009-06-12 | 2012-05-30 | Adagio制药有限公司 | Sublingual apomorphine |
| US9669018B2 (en) | 2009-06-12 | 2017-06-06 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| US9669021B2 (en) | 2009-06-12 | 2017-06-06 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| US9669019B2 (en) | 2009-06-12 | 2017-06-06 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| US9669020B2 (en) | 2009-06-12 | 2017-06-06 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| EP2442650B1 (en) | 2009-06-12 | 2015-08-26 | Cynapsus Therapeutics Inc. | Sublingual apomorphine |
| EP2952191A1 (en) * | 2009-06-12 | 2015-12-09 | Cynapsus Therapeutics Inc. | Sublingual apomorphine |
| CN102480958B (en) * | 2009-06-12 | 2015-08-19 | Cynapsus疗法有限公司 | sublingual apomorphine |
| EP2442650A4 (en) * | 2009-06-12 | 2012-11-14 | Adagio Pharmaceuticals Inc | APOMORPHINE SUBLINGUAL |
| US9044475B2 (en) | 2009-06-12 | 2015-06-02 | Cynapsus Therapeutics, Inc. | Sublingual apomorphine |
| US10285953B2 (en) | 2010-12-16 | 2019-05-14 | Sunovion Pharmaceuticals Inc. | Sublingual films |
| US9427412B2 (en) | 2010-12-16 | 2016-08-30 | Cynapsus Therapeutics, Inc. | Sublingual films |
| EP3735988A1 (en) * | 2010-12-16 | 2020-11-11 | Sunovion Pharmaceuticals Inc. | Sublingual films |
| US8846074B2 (en) | 2010-12-16 | 2014-09-30 | Cynapsus Therapeutics, Inc. | Sublingual films |
| EP2651357A4 (en) * | 2010-12-16 | 2016-07-20 | Cynapsus Therapeutics Inc | SUBLINGUAL MOVIES |
| WO2012083269A1 (en) | 2010-12-16 | 2012-06-21 | Cynapsus Therapeutics, Inc. | Sublingual films |
| US11419769B2 (en) | 2010-12-16 | 2022-08-23 | Sunovion Pharmaceuticals Inc. | Sublingual films |
| US9283219B2 (en) | 2010-12-16 | 2016-03-15 | Cynapsus Therapeutics, Inc. | Sublingual films |
| US10449146B2 (en) | 2015-04-21 | 2019-10-22 | Sunovion Pharmaceuticals Inc. | Methods of treating parkinson's disease by administration of apomorphine to an oral mucosa |
| US10959943B2 (en) | 2015-04-21 | 2021-03-30 | Sunovion Pharmaceuticals Inc. | Methods of treating Parkinson's disease by administration of apomorphine to an oral mucosa |
Also Published As
| Publication number | Publication date |
|---|---|
| NO992944L (en) | 1999-06-16 |
| JP2001506612A (en) | 2001-05-22 |
| EP0959875A1 (en) | 1999-12-01 |
| DE19652268A1 (en) | 1998-06-18 |
| NO992944D0 (en) | 1999-06-16 |
| CA2274893A1 (en) | 1998-06-25 |
| AU746373B2 (en) | 2002-04-18 |
| DE19652268C2 (en) | 2000-06-29 |
| KR20000057627A (en) | 2000-09-25 |
| AU5654798A (en) | 1998-07-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0959875A1 (en) | Active substance carrier for releasing apomorphine into the buccal cavity | |
| EP0949925B1 (en) | Flat medicament preparation for the application and release of buprenorphine or a pharmacologically comparable substance in the buccal cavity, and method of producing the same | |
| AT401613B (en) | SPRAY PREPARATIONS CONTAINING NITROGLYCER | |
| DE60212475T2 (en) | Pharmaceutical tablet and a process for its preparation | |
| DE69731847T2 (en) | DOSE FORMULATIONS RELEASING AFTER A DEFINED TIME SPAN AND METHOD FOR THE PRODUCTION THEREOF | |
| DE10207394B4 (en) | Taste-masked oblate medicinal preparation | |
| DE202006018608U1 (en) | Oral administration form useful in the manufacture of medicament to treat pain, and in drug substitution therapy, comprises buprenorphine or its salt | |
| DE69924710T2 (en) | PHARMACEUTICAL PREPARATION FOR APPLICATION IN ANTIASTHMATHERAPY | |
| WO2001043728A1 (en) | Flat medicinal preparation for transmucosal administration of oxycodon or a comparable active ingredient in the oral cavity, for use in pain therapy and in addiction therapy | |
| DE69720055T2 (en) | ADMINISTRATIVE FORM FOR DELIVERING RISING ACTIVE SUBSTANCES | |
| DE69425589T2 (en) | COMBINED ANTIPYRETIC AND ANALGETIC MEDICINAL PRODUCT | |
| EP1850836B1 (en) | Treatment with a medicament combination | |
| DE10215131A1 (en) | Stable pharmaceutical preparation useful for the treatment of pain, especially severe pain, without causing side-effects comprises oxycodone and naxolone in retarded release formulation | |
| EP1656112B1 (en) | Buccal formulations of galanthamine and uses thereof | |
| WO2001007015A2 (en) | Quick-release extrudates, method for preparing the same and compositions obtained from said extrudates | |
| EP4277596B1 (en) | Multi-layer oral thin film | |
| EP1235555A2 (en) | Stable galenic preparations comprising a benzimidazol and method for the production thereof | |
| EP4277597B1 (en) | Oral thin film | |
| DE10354894A1 (en) | Oral formulations of deoxypeganine and their applications | |
| DE202021100039U1 (en) | Ethyl cellulose-coated particles containing a salt of tapentadol and phosphoric acid | |
| EP4301335B1 (en) | Oral thin film | |
| EP4277598B1 (en) | Oral thin film comprising a pva-tris buffer layer | |
| EP4308078B1 (en) | Rolled oral thin films having a high level of active-ingredient loading | |
| EP2116232A1 (en) | Medicine containing galanthamine with controlled release | |
| DE202020103814U1 (en) | Extended release dosage forms of tapentadol phosphoric acid salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR MX NO SI US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 1997952795 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 525934 Kind code of ref document: A Format of ref document f/p: F |
|
| ENP | Entry into the national phase |
Ref document number: 2274893 Country of ref document: CA Ref country code: CA Ref document number: 2274893 Kind code of ref document: A Format of ref document f/p: F |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1999/005556 Country of ref document: MX |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1019997005422 Country of ref document: KR Ref document number: 56547/98 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 09319886 Country of ref document: US |
|
| WWP | Wipo information: published in national office |
Ref document number: 1997952795 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 1019997005422 Country of ref document: KR |
|
| WWG | Wipo information: grant in national office |
Ref document number: 56547/98 Country of ref document: AU |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1997952795 Country of ref document: EP |
|
| WWR | Wipo information: refused in national office |
Ref document number: 1019997005422 Country of ref document: KR |