EP2029100A2 - Ache-nmda combination wafer - Google Patents
Ache-nmda combination waferInfo
- Publication number
- EP2029100A2 EP2029100A2 EP07725819A EP07725819A EP2029100A2 EP 2029100 A2 EP2029100 A2 EP 2029100A2 EP 07725819 A EP07725819 A EP 07725819A EP 07725819 A EP07725819 A EP 07725819A EP 2029100 A2 EP2029100 A2 EP 2029100A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- preparation according
- dementia
- active
- active ingredients
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Definitions
- the present invention relates to a sheet-like, quickly disintegrating on contact with moisture, pharmaceutical preparation based on hydrophilic polymers for the treatment of dementia, wherein the dosage form contains a drug combination of at least two active ingredients which are suitable for the treatment of dementias (anti-dementia).
- the invention further relates to the use of such an active substance combination for the production of an orally administrable medicament for the treatment of dementia diseases such as Alzheimer's disease, and to a process for the symptomatic treatment of Alzheimer's disease by oral administration of one of the medicament formulations mentioned.
- Alzheimer's is currently the most common form of dementia, with dementia being understood as the loss of intellectual functions such as thinking, remembering, and associating mental contents that go so far that actions and processes of daily life can no longer be carried out independently. In the terminal stage, dementia can also lead to death.
- Alzheimer's disease is defined in the literature as a progressive, degenerative disease of the CNS associated with impaired memory, intelligence, and behavior, with memory loss not only personal memories but also elemental actions such as food intake, spatial orientation , basic vocabulary and the like.
- impaired memory is a disorder of the neurotransmitters glutamate and acetylcholine.
- Alzheimer's Disease As with all dementias, Alzheimer's Disease, or Alzheimer's disease for short (Alzheimer's disease), with its increasing average age, causes an increasing number of patients in need of treatment.
- the treatment should improve, or at least stabilize, and delay the decline in mental capacity.
- a corresponding drug therapy is required.
- advanced dementia the preservation of the everyday competence of the patient and a delay in the need for care or home admission are ultimately the focus of therapy.
- NMDA neuroprotective NMDA
- Antagonists N-methyl-D-aspartic acid
- Memantine prevents the absorption of glutamate at the NMDA receptors, so that the permanent irritation overload is reduced and signals in the conduction can be recognized again.
- the cell death of nerve cells due to permanent overload can be prevented or delayed in this way.
- the patients become mentally active again and everyday life is increasing. Visible improvements can also be detected in patients who are already in need of care.
- AchE inhibitors acetylcholinesterase inhibitors
- AchE Ace- tylcholinesterase inhibitors
- the therapy is further complicated by the fact that often not only a drug is given in the therapy, but often a combination of different drugs is used. Each additional drug increases but the Danger that his intake, in addition to often other required drugs that must take the usually older patients, forgotten and omitted. In addition, as the number of tablets to be taken increases, the reluctance to ingest often increases, thus decreasing patient compliance.
- the object underlying the invention was therefore to provide pharmaceutical preparations with which a combination therapy for the symptomatic treatment of Alzheimer's can be carried out in a simple and safe manner, and which make it possible to avoid or reduce the abovementioned disadvantages.
- the invention was also based on the object of demonstrating methods for the drug combination therapy of dementia dementia.
- Typical administration forms for administering active substances in therapy are tablets or capsules.
- buccal or sublingual tablets which release the active ingredient in the oral cavity, so that it can be absorbed directly through the oral mucosa.
- the disadvantage of these tablets is an often unpleasant mouthfeel and, due to their compact form, only a slow disintegration of the tablet and a resulting slow release of the active ingredients.
- the object of the present invention is achieved in that in a hydrophilic polymer film, which rapidly decomposes after application in the oral cavity, at least two active ingredients are included, which belong to the group of anti-dementia drugs.
- An active substance is preferably an acetylcholine nesterase inhibitor (AchE inhibitor) and the second is an NMDA antagonist (n-methyl-D-aspartic acid antagonist).
- the improved therapeutic success of a drug combination in the treatment of dementias is due to the fact that different drugs act through different mechanisms, thereby complementing or potentiating the positive effects on memory performance.
- the dose of the individual active ingredients can thus possibly be lowered or the effect improved.
- the orally administered dosage form as a wafer from a rapidly disintegrating hydrophilic polymer the intake of the drugs is ensured by the patient, as it disintegrates immediately in the mouth, so that the administration and monitoring of the intake are simplified for the nursing staff.
- the dosage form according to the invention there is already a combination of active substances adapted to the therapy, so that the administration of the medicaments in non-independent patients must be monitored only once.
- the absorption of the active ingredients through the oral mucosa offers over other peroral forms of administration further the advantages that even patients with dysphagia patients who refuse to take tablets, or Patients who have lost swallowing due to their dementia can receive medication orally.
- the active ingredients are not subject to the first-pass effect. Since in this way no active ingredient is metabolized before reaching the site of action, the initial dosage can be kept as low as possible. Furthermore, variations in the active substance concentration due to incomplete or delayed absorption and delayed action as a function of the amount of food ingested are suppressed or minimized. The adjustment of the patient to the required treatment dose can thus be made more reliable and the need, for example, an intake on an empty stomach can be omitted.
- active ingredients with different mechanisms of action may be present in a combination of active ingredients which have a synergistic effect, so that smaller amounts of the active ingredients can be dosed as a result of the different physiological action and treatment of various symptoms of dementia than would be the case with single-component formulations.
- a positive enhancing effect of this type is known for drug combinations of memantine with an AchE inhibitor.
- the wafers may contain up to five, preferably up to three, and more preferably two active ingredients, at least one of which is an AchE inhibitor, an NMDA antagonist or a nootropic agent.
- the dosages can be adapted to the respective needs and forms of treatment. If the mental state of the patient changes, it can easily be adjusted to a dosage form with a modified combination of active substances, generally with a higher active ingredient concentration.
- the wafer is made of a laminate, then during production e.g. only the layer thickness of an active substance-containing layer or the concentration of the active substance are changed.
- drugs with different active ingredient content but the same active ingredient ratio can be easily prepared via different area blanks of the dosage form. Due to their flat shape, the wafers containing the active compound combinations according to the invention are easy to carry, for example in the wallet, and are immediately available on the way, easy to take and rapidly effective, which facilitates regular use in still mobile patients.
- Suitable anti-dementia agents for use in a combination wafer include the AchE inhibitors, NMDA antagonists and nootropics.
- the drug combination consists of at least two drugs selected from the group comprising the AchE inhibitors, NMDA antagonists and the nootropics.
- Suitable AchE inhibitors are rivastigmine, galanthamine, and donezepil as well as pharmaceutically acceptable salts of these active substances.
- Memantine can be used as an NMDA antagonist.
- the group of the nootropic agents used according to the invention includes piracetam and naftidrofuryl.
- the preparation may contain further active ingredients which are among the vasodilators, calcium antagonists and generally circulation-promoting agents.
- the total active ingredient content of the wafer is between 5% to 50%, preferably between 10% to 30%, and more preferably between 15% to 25%, based on the total weight of the wafer.
- the ratio of the active substances with one another is freely variable and depends on the potency of the active substance and the desired effect or the required dosage.
- water-soluble or swellable polymers are suitable which form a hydrophilic, water-soluble and / or swellable polymer film.
- the polymers of the matrix of the dosage form are selected from the group consisting of dextran, polysaccharides, including starch and starch derivatives, cellulose derivatives, such as carboxymethylcellulose, ethyl or propylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose (eg. B.
- the polymer film may also consist of a po- lyvinyl alcohol-polyethylene glycol graft copolymer.
- the polymer content of a dosage form according to the invention is preferably from 5 to 95% by weight, more preferably from 15 to 75% by weight, based on the dry weight of the dosage form.
- moisturizers may be added to the film, e.g. Glycerol, propylene glycol, sorbitol, mannitol, polyethylene glycol, polyglycerol esters and the like.
- antioxidants may be added to the wafer to stabilize the film and the active agents, e.g. Vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives.
- active agents e.g. Vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives.
- acidic and basic ion exchangers can also be used as stabilizers.
- flavourings and flavorings can mask the often poor taste or smell of the active ingredients and / or give the dosage form a pleasant taste, so that the willingness to take the medication by the patient is significantly improved.
- the active ingredient (s) of the Preparation may also be bound to an acidic or basic ion exchanger for taste masking.
- buffering systems serves, on the one hand, to stabilize the film and the active ingredients against external influences and during storage and, on the other hand, to adjust the pH of the dosage form to a physiologically acceptable pH, so that mucous membrane irritations are avoided .
- a buffer system can also improve the solubility of acidic or basic drugs in the matrix.
- the administration forms according to the invention are thin, for example in the form of a wafer.
- the thickness of the dosage form is preferably 0.1 to 5 mm, more preferably 0.5 to 1 mm.
- the lower limit for the thickness of the dosage forms is about 50 ⁇ m.
- the area of the dosage form is between 0.09 cm 2 and 12 cm 2 , preferably between 1 cm 2 and 8 cm 2 , and particularly preferably between 3 cm 2 and 6 cm 2 .
- the wafers of the present invention include a disintegrant or wicking agent, e.g. a bicarbonate-acid mixture or an aerosil, which is activated by contact with liquid and accelerates the disintegration of the wafer after application and thus also the release of active ingredient.
- a disintegrant or wicking agent e.g. a bicarbonate-acid mixture or an aerosil
- the wafer is present as a foam, so that the release of active ingredient is even faster due to the increased surface area.
- the active ingredients or auxiliaries it is also possible for one or more of the active ingredients or auxiliaries to be present in liquid form in the cavities of the foam.
- permeation enhancers e.g. Substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan monolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid, or also substances such as DMSO ( Dimethylsulfoxide) and oleic diethanolamine.
- the proportion of these substances, if present, is 0.1% by weight to 25% by weight, preferably from 1% by weight to 10% by weight, in each case based on the total weight of the active substance matrix.
- composition of the wafer may contain compounds that retard drug release (e.g., microencapsulation).
- the wafer has mucoadhesive properties, so that it adheres to the mucous membrane until complete dissolution.
- This embodiment additionally facilitates the monitoring of the administration of the medicaments since the wafer adhering to the mucous membrane can not be spit out.
- At least one of the active ingredients is bound to an ion exchanger, see above that the hydrophilic polymer disintegrates rapidly in the oral cavity, but the release of the active ingredient only delayed or at a changed pH, for example in the gastrointestinal tract, takes place.
- active ingredients having different or higher active and absorption mechanisms can be administered in one dosage form, ie at least one of the released active substances is absorbed at the site of application, eg. B. on the oral mucosa, and the other is transported and resorbed at another location.
- the wafer can also be constructed as a laminate with different layers, wherein the active ingredients are contained in discrete layers, which are spatially separated from each other and differ in their construction.
- the active ingredients can be released at different sites of action or else delayed, if the disintegration time of the different layers of the wafer differs.
- the active ingredients may be arranged in layers which disintegrate at different rates so that the entire preparation has a sustained-release effect.
- only one of the outer layers may be mucoadhesive to promote adherence of the dosage form to the mucosa and to facilitate drug absorption through the mucosa through direct contact.
- Dosage form is preferably in the range of 1 s to 5 minutes, more preferably in the range of 5 seconds to 1 minute, and most preferably in the range of 10 seconds to 30 seconds.
- the dosage forms according to the invention are advantageously suitable for the administration of medicaments in the oral cavity or for rectal, vaginal or intranasal administration.
- the present invention is further directed to the use of one of the active ingredient combination according to the invention for the preparation of an oral dosage form for the treatment of dementia diseases, wherein the dosage form is preferably formulated as a wafer.
- the present invention is directed to a method for the therapeutic treatment of a person suffering from dementia, wherein the administration of a previously described active ingredient combination of anti-dementia agents by means of an orally administered dosage form with at least partial transmucosal absorption of at least one active ingredient.
- the present invention is also directed to a process for the preparation of a sheet-like dosage form which comprises the following steps:
Abstract
The invention relates to wafer-like pharmaceutical products based on hydrophilic polymers, which rapidly disintegrate upon contact with humidity and which are used to treat dementia-related illnesses, wherein the presentation contains an active agent combination of at least two active agents suitable for the treatment of dementia (antidementia agents). Preferably, the antidementia agents should be chosen from the group comprising acetyl cholinesterase inhibitors (AChE inhibitors) and NMDA antagonists (n-methyl-D-asparaginic acid antagonists). The invention further relates to the use of such an active agent combination for the production of an orally administrable pharmaceutical product for the treatment of dementia-related illnesses such as Alzheimer's disease, as well as to a procedure for the symptomatic treatment of Alzheimer's disease by means of the oral administration of one of the above pharmaceutical products.
Description
AchE-NMDA-Kombinationswafer AchE NMDA combination wafer
Die vorliegende Erfindung betrifft eine flächenförmige , bei Kontakt mit Feuchtigkeit schnell zerfallende, Arzneimittelzubereitung auf Basis hydrophiler Polymere zur Behandlung von Demenzerkrankungen, wobei die Darreichungsform eine Wirkstoffkombination aus mindestens zwei Wirkstoffen enthält, die zur Behandlung von Demenzen (Antidementiva) ge- eignet sind.The present invention relates to a sheet-like, quickly disintegrating on contact with moisture, pharmaceutical preparation based on hydrophilic polymers for the treatment of dementia, wherein the dosage form contains a drug combination of at least two active ingredients which are suitable for the treatment of dementias (anti-dementia).
Die Erfindung betrifft ferner die Verwendung einer solchen Wirkstoffkombination zur Herstellung eines oral verabreichbaren Arzneimittels zur Behandlung von Demenzerkrankungen wie Alzheimer, sowie ein Verfahren zur symptomatischen Be- handlung von Alzheimer durch orale Verabreichung einer der genannten Arzneimittelzubereitungen.The invention further relates to the use of such an active substance combination for the production of an orally administrable medicament for the treatment of dementia diseases such as Alzheimer's disease, and to a process for the symptomatic treatment of Alzheimer's disease by oral administration of one of the medicament formulations mentioned.
Derzeit leiden in Deutschland etwa 1,2 Millionen Menschen an einer Demenz, wobei die Tendenz steigend ist. Die Ursa- che hierfür ist in der steigenden Anzahl von Menschen mit höherem Lebensalter und dem mit dem Lebensalter steigenden Risiko, an Demenz zu erkranken, zu sehen. Leidet im Alter zwischen 65 und 69 Jahren "nur" jeder Zwanzigste an einer Demenz, so liegt der Anteil der Betroffenen zwischen 80 und 90 schon bei nahezu einem Drittel.Currently, about 1.2 million people in Germany suffer from dementia, and the trend is rising. The reason for this is the growing number of people of higher age and the increasing risk of developing dementia with age. Suffering between the ages of 65 and 69 "only" every twentieth of a dementia, the proportion of those affected between 80 and 90 is already close to a third.
Mit dem zu erwartenden steigendem Anteil älterer Mitbürger an der Gesamtbevölkerung wird auch mit einer Zunahme der Demenzerkrankungen zu rechnen sein. Experten rechnen bis zum Jahr 2030 mit einer Verdoppelung der Zahl der Krankheitsfälle.
Alzheimer ist die derzeit häufigste Form der Demenz, wobei unter Demenz der Verlust der intellektuellen Funktionen wie Denken, Erinnern und Verknüpfen von Denkinhalten verstanden wird, die so weit gehen, daß Handlungen und Abläufe des täglichen Lebens nicht mehr selbständig ausgeführt werden können. Im Endstadium kann die Demenz auch zum Tode führen.With the expected increasing proportion of older people in the total population, an increase in dementia is expected. Experts expect the number of cases to double by 2030. Alzheimer's is currently the most common form of dementia, with dementia being understood as the loss of intellectual functions such as thinking, remembering, and associating mental contents that go so far that actions and processes of daily life can no longer be carried out independently. In the terminal stage, dementia can also lead to death.
Die Alzheimersche Krankheit wird in der Literatur definiert als eine fortschreitende, degenerative Erkrankung des ZNS, die mit Beeinträchtigungen des Gedächtnisses, der Intelligenz und des Verhaltens einhergeht, wobei der Gedächtnis- verlust nicht nur persönliche Erinnerungen, sondern auch so Elementare Handlungen wie Nahrungsaufnahme, räumliche Orientierung, grundlegendes Vokabular und dergleichen betref- fen kann. Eine der Ursachen für die Beeinträchtigung der Gedächtnisleistung ist dabei eine Störung der Neurotransmitter Glutamat und Acetylcholin.Alzheimer's disease is defined in the literature as a progressive, degenerative disease of the CNS associated with impaired memory, intelligence, and behavior, with memory loss not only personal memories but also elemental actions such as food intake, spatial orientation , basic vocabulary and the like. One of the causes of impaired memory is a disorder of the neurotransmitters glutamate and acetylcholine.
Wie bei allen Demenzerkrankungen bringt auch die Alzheimer- sehe Krankheit oder kurz Alzheimer (Morbus Alzheimer) , mit ansteigendem durchschnittlichen Lebensalter der Bevölkerung eine steigende Zahl von Patienten hervorbringt, die einer Behandlung bedürfen.As with all dementias, Alzheimer's Disease, or Alzheimer's disease for short (Alzheimer's disease), with its increasing average age, causes an increasing number of patients in need of treatment.
Da es sich um eine degenerative, fortschreitende Erkrankung ohne Aussicht auf Heilung handelt, gilt es durch die Behandlung eine Verbesserung oder zumindest Stabilisierung und Verzögerung des Abbaus der geistigen Leistungsfähigkeit zu erzielen. Hierzu ist neben nicht medikamentösen Maßnah- men wie Gedächtnistraining auch eine entsprechende medikamentöse Therapie erforderlich.
Bei einer fortgeschrittener Demenz stehen letztlich der Erhalt der Alltagskompetenz des Patienten und eine Verzögerung der Pflegebedürftigkeit bzw. Heimeinweisung im Vordergrund der Therapie.Because it is a degenerative, progressive disease with no chance of recovery, the treatment should improve, or at least stabilize, and delay the decline in mental capacity. In addition to non-medical measures such as memory training, a corresponding drug therapy is required. In the case of advanced dementia, the preservation of the everyday competence of the patient and a delay in the need for care or home admission are ultimately the focus of therapy.
Wirksame Mittel zur Heilung von Alzheimer sind derzeit, wie dargelegt, nicht verfügbar, dennoch gibt es eine Reihe von Medikamenten, die den Krankheitsverlauf verlangsamen und eine Besserung der Symptome bewirken können.Effective means of curing Alzheimer's are currently unavailable, as outlined, but there are a number of medications that can slow the progression of the disease and improve symptoms.
Insbesondere zwei Arzneimittelgruppen stehen zur medikamentösen Behandlung der Alzheimer-Demenz zur Verfügung, die die bei Demenzen gestörten Botenstoffe Glutamat und Acetyl- cholin positiv beeinflussen. Eine dieser Gruppen sind die neuroprotektiven NMDA-In particular, two groups of drugs are available for the treatment of Alzheimer's dementia, which have a positive effect on the messenger substances glutamate and acetylcholine, which are disturbed in dementia. One of these groups is the neuroprotective NMDA
Antagonisten (N-Methyl-D-Asparaginsäure) , zu denen beispielsweise Memantine gehört.Antagonists (N-methyl-D-aspartic acid), which include, for example, memantine.
Memantine unterbindet die Aufnahme von Glutamat an den NMDA-Rezeptoren, so daß die permanente Reizüberlastung gemindert wird und Signale bei der Reizleitung wieder erkannt werden können. Der Zelltod der Nervenzellen infolge dauernder Überlastung kann auf diese Weise verhindert oder verzögert werden. Die Patienten werden geistig wieder aktiver und die Alltagskomptenz steigt. Auch bei bereits pflegebedürftigen Patienten lassen sich sichtbare Verbesserungen nachweisen.Memantine prevents the absorption of glutamate at the NMDA receptors, so that the permanent irritation overload is reduced and signals in the conduction can be recognized again. The cell death of nerve cells due to permanent overload can be prevented or delayed in this way. The patients become mentally active again and everyday life is increasing. Visible improvements can also be detected in patients who are already in need of care.
Eine weitere Gruppe von Arzneimitteln zur symptomatischen Behandlung von Alzheimer sind die AchE-Hemmer (Acetylcholi- nesterasehemmer) , die den Abbau des Neurotransmitters Ace-
tylcholinesterase (AchE) verhindern und so eine Signalweiterleitung im Gehirn positiv beeinflussen.Another group of medicines for the symptomatic treatment of Alzheimer's are the AchE inhibitors (acetylcholinesterase inhibitors), which inhibit the breakdown of the neurotransmitter Ace- tylcholinesterase (AchE) and thus positively influence a signal transmission in the brain.
Neben den erwähnten vorteilhaften Wirkungen auf den Patien- ten ist eine ausreichende medikamentöse Therapie auch deshalb von besonderer Bedeutung, da sie die Betreuungszeiten und somit die Pflegekosten drastisch senken kann. Hierdurch können nicht nur Kosten eingespart werden, sondern auch die erforderliche Zeit für die nicht medikamentöse Therapie ge- wonnen werden.In addition to the aforementioned beneficial effects on the patient, adequate medical therapy is also of particular importance because it can drastically reduce the time taken to care for and thus the cost of care. As a result, not only can costs be saved, but also the time required for non-drug therapy can be gained.
Bei der Therapie der Alzheimerschen Krankheit im besonderen und der Demenz im allgemeinen stellen sich allerdings häufig folgende Probleme:In the treatment of Alzheimer's disease in particular and dementia in general, however, the following problems often arise:
Aufgrund der fehlenden Gedächtnisleistung des Patienten fehlt die notwendige Compliance, d.h. die Einnahme der Medikamente wird häufig vergessen, was wiederum die Gedächtnisleistung noch weiter herabsetzt, wodurch wiederum die Einnahme der notwendigen Medikamente noch weiter sinkt.Due to the patient's lack of memory, the necessary compliance, i. E. the intake of the drugs is often forgotten, which in turn reduces the memory even further, which in turn decreases the intake of the necessary medication even further.
In extremen Fällen "verlernen" die Patienten das Schlucken oraler Darreichungsformen, so daß diese Patienten einer o- ralen Therapieform nicht mehr zugänglich sind. Bei der oralen Therapie bereitet die Überprüfung der tat- sächlichen Einnahme (Tablette nicht geschluckt, vergessen zu schlucken, etc.) oft Probleme.In extreme cases, the patients "unlearn" the swallowing of oral dosage forms, so that these patients are no longer accessible to an oral form of therapy. In the case of oral therapy, checking the actual intake (tablet not swallowed, forgetting to swallow, etc.) often causes problems.
Die Therapie wird des weiteren dadurch erschwert, daß oft nicht nur ein Medikament in der Therapie gegeben wird, son- dern häufig eine Kombination verschiedener Medikamente eingesetzt wird. Jedes weitere Medikament steigert aber die
Gefahr, das dessen Einnahme, neben oftmals anderen erforderlichen Medikamenten, die die in der Regel älteren Patienten einnehmen müssen, vergessen wird und unterbleibt. Darüber hinaus steigt häufig mit zunehmender Anzahl der einzunehmenden Tabletten der Widerwillen gegen die Einnahme, so daß die Compliance des Patienten sinkt.The therapy is further complicated by the fact that often not only a drug is given in the therapy, but often a combination of different drugs is used. Each additional drug increases but the Danger that his intake, in addition to often other required drugs that must take the usually older patients, forgotten and omitted. In addition, as the number of tablets to be taken increases, the reluctance to ingest often increases, thus decreasing patient compliance.
Die der Erfindung zugrunde liegende Aufgabe bestand daher darin, Arzneimittelzubereitungen bereitzustellen, mit denen eine Kombinationstherapie zur symptomatischen Behandlung von Alzheimer auf einfache und sichere Weise durchführbar ist, und die es ermöglichen, die oben genannten Nachteile zu vermeiden oder zu vermindern. Der Erfindung lag ferner die Aufgabe zugrunde, Verfahren für die medikamentöse Kom- binationstherapie von Demenz -Erkrankungen aufzuzeigen.The object underlying the invention was therefore to provide pharmaceutical preparations with which a combination therapy for the symptomatic treatment of Alzheimer's can be carried out in a simple and safe manner, and which make it possible to avoid or reduce the abovementioned disadvantages. The invention was also based on the object of demonstrating methods for the drug combination therapy of dementia dementia.
Übliche Darreichungsformen zur Verabreichung von Wirkstoffen in der Therapie sind Tabletten oder Kapseln.Typical administration forms for administering active substances in therapy are tablets or capsules.
Tabletten oder Kapseln können zwar leicht eingenommen werden, jedoch ist die Überprüfung der tatsächlichen Einnahme erschwert und die Wirkstoffe unterliegen bei Resorption über den Gastrointestinaltrakt dem "First-Pass-Effekt", so daß hohe initiale Wirkstoffkonzentrationen in der Tablette oder Kapsel erforderlich sind, um die gewünschten therapeutischen Wirkungen zu erreichen.Although tablets or capsules can be taken easily, the review of the actual intake is difficult and the drugs are subject to the "first-pass effect" when absorbed through the gastrointestinal tract, so that high initial drug concentrations in the tablet or capsule are required to to achieve desired therapeutic effects.
Darüber hinaus ist die Anwendung von Buccal- oder Sublingualtabletten bekannt, die den Wirkstoff im Mundraum freiset- zen, so daß dieser direkt über die Mundschleimhaut absorbiert werden kann.
Der Nachteil dieser Tabletten besteht in einem oft unangenehmen Mundgefühl und aufgrund der kompakten Form einem nur langsamen Zerfall der Tablette und einer daraus resultie- renden langsamen Freisetzung der Wirkstoffe. Darüber hinaus besteht bei Patienten, die das Schlucken verlernt haben o- der stark verwirrt sind, die Gefahr, des "sich Verschluk- kens" bei der Gabe von Tabletten oder Kapseln.In addition, the use of buccal or sublingual tablets is known, which release the active ingredient in the oral cavity, so that it can be absorbed directly through the oral mucosa. The disadvantage of these tablets is an often unpleasant mouthfeel and, due to their compact form, only a slow disintegration of the tablet and a resulting slow release of the active ingredients. Moreover, in patients who have forgotten to swallow, or who are highly confused, there is a risk of "swallowing" when taking tablets or capsules.
Die Aufgabe der vorliegenden Erfindung wird dadurch gelöst, daß in einem hydrophilen Polymerfilm, der nach Applikation in der Mundhöhle schnell zerfällt, mindestens zwei Wirkstoffe enthalten sind, die zur Gruppe der Antidementiva zählen. Bevorzugt ist dabei ein Wirkstoff ein Acetylcholi- nesterase-Hemmstoff (AchE-Hemmer) und der zweite ein NMDA- Antagonist (n-Methyl-D-Asparaginsäure-Antagonist) .The object of the present invention is achieved in that in a hydrophilic polymer film, which rapidly decomposes after application in the oral cavity, at least two active ingredients are included, which belong to the group of anti-dementia drugs. An active substance is preferably an acetylcholine nesterase inhibitor (AchE inhibitor) and the second is an NMDA antagonist (n-methyl-D-aspartic acid antagonist).
Der verbesserte Therapieerfolg einer Wirkstoffkombination bei der Behandlung von Demenzen ist darauf zurückzuführen, daß unterschiedliche Wirkstoffe über unterschiedliche Mechanismen wirken, wodurch sich die positiven Effekte auf die Gedächtnisleistungen ergänzen oder potenzieren. Die Dosis der Einzelwirkstoffe kann so gegebenenfalls gesenkt oder der Effekt verbessert werden.The improved therapeutic success of a drug combination in the treatment of dementias is due to the fact that different drugs act through different mechanisms, thereby complementing or potentiating the positive effects on memory performance. The dose of the individual active ingredients can thus possibly be lowered or the effect improved.
Auch bei einer Kombination von Wirkstoffen ist eine konsequente Einnahme und gute Compliance des Medikaments Voraussetzung, um eine optimale Wirksamkeit zu gewährleisten.Even with a combination of active ingredients, a consistent intake and good compliance of the drug is a prerequisite to ensure optimal efficacy.
Die Verabreichung dieser Wirkstoffkombinationen in flächen- förmigen Darreichungsformen (Wafern) ermöglicht dabei nicht
nur eine einfache Einnahme, sondern auch eine exakte Abstimmung der Wirkstoffkomponenten untereinander, so daß Fehldosierungen durch vergessene oder doppelte Einnahme nur eines Wirkstoffs, ein Problem insbesondere bei Demenzer- krankten, und somit eine unzureichende Therapie unterbleiben.The administration of these drug combinations in areal forms (wafers) does not allow only a simple ingestion, but also an exact vote of the active ingredient components with each other, so that misdosing by forgotten or double intake of only one active ingredient, a problem especially in dementia patients, and thus insufficient therapy is omitted.
Durch die oral applizierbare Darreichungsform als Wafer aus einem schnell zerfallenden hydrophilen Polymer wird die Einnahme der Medikamente durch den Patienten gewährleistet, da dieser sofort im Mund zerfällt, so daß die Gabe und Überwachung der Einnahme für das Pflegepersonal vereinfacht werden. Zudem liegt in der erfindungsgemäßen Darreichungsform be- reits eine an die Therapie angepaßte Wirkstoffkombination vor, so daß die Gabe der Medikamente bei nicht selbständigen Patienten nur einmalig überwacht werden muß.The orally administered dosage form as a wafer from a rapidly disintegrating hydrophilic polymer, the intake of the drugs is ensured by the patient, as it disintegrates immediately in the mouth, so that the administration and monitoring of the intake are simplified for the nursing staff. In addition, in the dosage form according to the invention there is already a combination of active substances adapted to the therapy, so that the administration of the medicaments in non-independent patients must be monitored only once.
Für Patienten, die selbst für ihre Medikation verantwort- lieh sind, wird die Einnahme durch den Wafer mit einerFor patients who are themselves responsible for their medication, the ingestion through the wafer with a
Wirkstoffkombination deutlich erleichtert, so daß die notwendige konsequente Einnahme gemäß dem Einnahmeplan gewährleistet ist. Sowohl Compliance als auch der Therapieerfolg werden verbessert und das Risiko fehlerhafter Anwendungen minimiert .Drug combination significantly relieved, so that the necessary consistent intake according to the intake plan is guaranteed. Both compliance and treatment success are improved and the risk of incorrect applications is minimized.
Die Resorption der Wirkstoffe über die Mundschleimhaut bietet gegenüber anderen peroralen Darreichungsformen weiterhin die Vorteile, daß auch Patienten mit Schluckbeschwerden Patienten, die die Einnahme von Tabletten verweigern, oder
Patienten, die aufgrund ihrer Demenz das Schlucken verlernt haben, Medikamente oral verabreicht bekommen können.The absorption of the active ingredients through the oral mucosa offers over other peroral forms of administration further the advantages that even patients with dysphagia patients who refuse to take tablets, or Patients who have lost swallowing due to their dementia can receive medication orally.
Infolge der parenteralen Gabe, d.h. der direkten Resorption des Wirkstoffes über die Schleimhaut, unterliegen die Wirkstoffe auch nicht dem First-Pass-Effekt. Da auf diese Weise kein Wirkstoff vor Erreichen des Wirkortes verstoffwechselt wird, kann die initiale Dosierung so gering wie möglich gehalten werden. Weiterhin werden Schwankungen der Wirk- Stoffkonzentration durch unvollständige oder verzögerte Resorption und Wirkungsverzögerungen in Abhängigkeit von der zuvor aufgenommenen Nahrungsmenge unterdrückt bzw. minimiert. Die Einstellung des Patienten auf die erforderliche Behandlungsdosis kann somit zuverlässiger erfolgen und die Notwendigkeit beispielsweise einer Einnahme auf nüchternen Magen kann entfallen.As a result of parenteral administration, i. the direct absorption of the active ingredient through the mucous membrane, the active ingredients are not subject to the first-pass effect. Since in this way no active ingredient is metabolized before reaching the site of action, the initial dosage can be kept as low as possible. Furthermore, variations in the active substance concentration due to incomplete or delayed absorption and delayed action as a function of the amount of food ingested are suppressed or minimized. The adjustment of the patient to the required treatment dose can thus be made more reliable and the need, for example, an intake on an empty stomach can be omitted.
Ferner können in einer Wirkstoffkombination Wirkstoffe mit unterschiedlichen Wirkmechanismen vorhanden sein, die sy- nergistisch wirken, so daß infolge der unterschiedlichen physiologischen Wirkung und Behandlung verschiedener Symptome der Demenz geringere Mengen der Wirkstoffe dosiert werden können, als dieses bei Einkomponentenzusaxnmensetzun- gen der Fall wäre. Ein positiv verstärkender Effekt dieser Art ist für Wirktstoffkombinationen von Memantine mit einem AchE-Hemmer bekannt.Furthermore, active ingredients with different mechanisms of action may be present in a combination of active ingredients which have a synergistic effect, so that smaller amounts of the active ingredients can be dosed as a result of the different physiological action and treatment of various symptoms of dementia than would be the case with single-component formulations. A positive enhancing effect of this type is known for drug combinations of memantine with an AchE inhibitor.
In den Darreichungsformen der vorliegenden Erfindung finden Kombinationen aus verschiedenen AchE-Hemmern, Nootropika und NMDA-Antagonisten Anwendung, wobei auch mehrere Wirk-
Stoffe einer Gruppe in dem erfindungsgemäßen Arzneimittel vorhanden sein können.In the administration forms of the present invention, combinations of different AchE inhibitors, nootropics and NMDA antagonists are used, whereby several active substances are also used. Substances of a group may be present in the medicament according to the invention.
Die Wafer können bis zu fünf, bevorzugt bis zu drei, und besonders bevorzugt zwei Wirkstoffe enthalten, wobei mindestens einer dieser Wirkstoffe ein AchE-Hemmer, ein NMDA- Antagonist oder ein Nootropikum ist.The wafers may contain up to five, preferably up to three, and more preferably two active ingredients, at least one of which is an AchE inhibitor, an NMDA antagonist or a nootropic agent.
Durch die Variation des Verhältnisses der Wirkstoffe zuein- ander können die Dosierungen an die jeweiligen Bedürfnisse und Behandlungsformen angepaßt werden. Verändert sich der geistige Zustand des Patienten, so kann dieser leicht auf eine Darreichungsform mit geänderter Wirkstoffkombination, in der Regel mit höherer Wirkstoffkonzentration, einge- stellt werden.By varying the ratio of the active substances to one another, the dosages can be adapted to the respective needs and forms of treatment. If the mental state of the patient changes, it can easily be adjusted to a dosage form with a modified combination of active substances, generally with a higher active ingredient concentration.
Aufgrund der einfachen und kostengünstigen Herstellung der Wafer ist es möglich, eine große Anzahl von Arzneimitteln mit unterschiedlichen Wirkstoffkonzentrationen bereitzu- stellen.Due to the simple and inexpensive production of the wafers, it is possible to provide a large number of medicaments with different active ingredient concentrations.
Ist der Wafer aus einem Laminat aufgebaut, so kann bei der Herstellung z.B. nur die Schichtdicke einer Wirkstoffhaltigen Schicht oder die Konzentration des Wirkstoffes verän- dert werden.If the wafer is made of a laminate, then during production e.g. only the layer thickness of an active substance-containing layer or the concentration of the active substance are changed.
Andererseits können Arzneimittel mit unterschiedlichem Wirkstoffgehalt aber gleichem Wirkstoffverhältnis einfach über unterschiedliche Flächenzuschnitte der Darreichungs- form hergestellt werden.
Die erfindungsgemäßen Wafer mit den Wirkstoffkombinationen sind aufgrund ihrer flachen Form leicht mitzuführen, z.B. in der Brieftasche, und sind auch unterwegs sofort verfügbar, einfach einzunehmen und schnell wirksam, was eine re- gelmäßige Einnahme bei noch mobilen Patienten erleichtert.On the other hand, drugs with different active ingredient content but the same active ingredient ratio can be easily prepared via different area blanks of the dosage form. Due to their flat shape, the wafers containing the active compound combinations according to the invention are easy to carry, for example in the wallet, and are immediately available on the way, easy to take and rapidly effective, which facilitates regular use in still mobile patients.
Geeignete Antidementiva zur Verwendung in einem Kombinati- onswafer umfassen die AchE-Hemmer, NMDA-Antagonisten und Nootropika.Suitable anti-dementia agents for use in a combination wafer include the AchE inhibitors, NMDA antagonists and nootropics.
In einer bevorzugten Ausführungsform besteht die Wirkstoffkombination aus mindestens zwei Wirkstoffen, ausgewählt aus der Gruppe, die die AchE-Hemmstoffe, NMDA-Antagonisten und die Nootropika umfaßt .In a preferred embodiment, the drug combination consists of at least two drugs selected from the group comprising the AchE inhibitors, NMDA antagonists and the nootropics.
Geeignete AchE-Hemmer sind dabei Rivastigmin, Galanthamin, und Donezepil sowie pharmazeutisch akzeptable Salze dieser Wirkstoffe. Als NMDA-Antagonist kann Memantine verwendet werden. Die Gruppe der erfindungsgemäß verwendeten Nootro- pika beinhaltet Piracetam und Naftidrofuryl.Suitable AchE inhibitors are rivastigmine, galanthamine, and donezepil as well as pharmaceutically acceptable salts of these active substances. Memantine can be used as an NMDA antagonist. The group of the nootropic agents used according to the invention includes piracetam and naftidrofuryl.
Zusätzlich können in der Zubereitung weitere Wirkstoffe enthalten sein, die zu den Vasodilatoren, Calciumantagonisten und allgemein durchblutungsfördernden Mitteln zählen.In addition, the preparation may contain further active ingredients which are among the vasodilators, calcium antagonists and generally circulation-promoting agents.
Für die Therapie von Demenzerkrankungen sind ferner erfindungsgemäße flächenförmige Darreichungsformen geeignet, die mindestens einen Wirkstoff enthalten, ausgewählt aus der Gruppe, die Nimodipin, Dihydroergotoxin, Piracetam, Pento- xyfyllin, Naftidrofuryl, Ginkgo Biloba Extrakte sowie pharmazeutisch akzeptable Salze dieser Wirkstoffe umfaßt. Be-
vorzugt ist einer dieser Wirkstoffe mit einem AchE-Hemmer und/oder einem NMDA-Antagonisten kombiniert.Also suitable for the therapy of dementia are sheet-like administration forms according to the invention which comprise at least one active substance selected from the group comprising nimodipine, dihydroergotoxine, piracetam, pentoxyfylline, naftidrofuryl, ginkgo biloba extracts and pharmaceutically acceptable salts of these active substances. loading Preferably, one of these agents is combined with an AchE inhibitor and / or an NMDA antagonist.
Der Gesamtwirkstoffgehalt des Wafers liegt zwischen 5 % bis 50 %, bevorzugt zwischen 10 % bis 30 %, und besonders bevorzugt zwischen 15 % bis 25 % bezogen auf das Gesamtgewicht des Wafers.The total active ingredient content of the wafer is between 5% to 50%, preferably between 10% to 30%, and more preferably between 15% to 25%, based on the total weight of the wafer.
Das Verhältnis der Wirkstoffe untereinander ist frei varia- ble und richtet sich nach Potenz des Wirkstoffs und dem gewünschten Effekt bzw. der notwendigen Dosierung.The ratio of the active substances with one another is freely variable and depends on the potency of the active substance and the desired effect or the required dosage.
Zur Herstellung der Darreichungsformen sind wasserlösliche oder quellfähige Polymere geeignet, die einen hydrophilen wasserlöslichen und/oder quellfähigen Polymerfilm bilden. Die Polymere der Matrix der Darreichungsform sind dabei ausgewählt aus der Gruppe, die Dextran, Polysaccharide, einschließlich der Stärke und Stärkederivate, Cellulosede- rivate, wie Carboxymethylcellulose, Ethyl- oder Propylcel- lulose, Hydroxypropylmethylcellulose, Hydroxypropylcellulo- se, Natrium-Carboxymethylcellulose (z. B. Walocel) , Methyl- cellulose, Hydroxyethylcellulose und Hydroxypropylethylcel- lulose, Polyvinylalkohole, Polyethylenglykole, Polyacryl- säuren, Polyacrylate, Polyvinylpyrrolidone, Alginate, Pek- tine, Gelatine, Alginsäure, Kollagen, Chitosan, Arabinoga- lactan, Galactomannan, Agar-Agar, Agarose, Carrageen natürliche Gummen, Tragant, hochdisperses Siliziumdioxid, Bentonit, sowie Derivate der vorgenannten hydrophilen Polymere bzw. Kombinationen aus zwei oder mehreren dieser Polymere umfaßt. Alternativ kann der Polymerfilm auch aus einem Po-
lyvinylalkohol-Polyethylenglycol-Pfropfcopolymer herge- stellt sein.For the preparation of the dosage forms, water-soluble or swellable polymers are suitable which form a hydrophilic, water-soluble and / or swellable polymer film. The polymers of the matrix of the dosage form are selected from the group consisting of dextran, polysaccharides, including starch and starch derivatives, cellulose derivatives, such as carboxymethylcellulose, ethyl or propylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose (eg. B. Walocel), methylcellulose, hydroxyethylcellulose and hydroxypropylethylcellulose, polyvinyl alcohols, polyethylene glycols, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, alginates, pectins, gelatin, alginic acid, collagen, chitosan, arabinogalactan, galactomannan, agar-agar , Agarose, carrageenan natural gums, tragacanth, fumed silica, bentonite, as well as derivatives of the aforementioned hydrophilic polymers or combinations of two or more of these polymers. Alternatively, the polymer film may also consist of a po- lyvinyl alcohol-polyethylene glycol graft copolymer.
Der Polymeranteil an einer erfindungsgemäßen Darreichungs- form beträgt vorzugsweise 5 bis 95 Gew.-%, besonders bevorzugt 15 bis 75 Gew.-%, bezogen auf die Trockenmasse der Darreichungsform.The polymer content of a dosage form according to the invention is preferably from 5 to 95% by weight, more preferably from 15 to 75% by weight, based on the dry weight of the dosage form.
Zur Verbesserung der physiko-chemischen Eigenschaften, z.B. Verringerung der Brüchigkeit oder Versprödung, können dem Film Feuchthaltemittel zugesetzt sein, wie z.B. Glycerin, Propylenglycol , Sorbitol, Mannitol, Polyethylenglycol, Po- lyglycerinester und dergleichen.To improve physicochemical properties, e.g. To reduce brittleness or embrittlement, moisturizers may be added to the film, e.g. Glycerol, propylene glycol, sorbitol, mannitol, polyethylene glycol, polyglycerol esters and the like.
In einer weiteren Ausführungsform können dem Wafer zur Stabilisierung des Films und der Wirkstoffe Antioxidantien zugesetzt sein, z.B. Vitamin C (Ascorbinsäure) , Ascorbylpal- mitat, Vitamin E (Tocopherolacetat) , Hydroxybenzoesäurede- rivate. Weiterhin können auch saure und basische Ionentau- scher als Stabilisatoren verwendet werden.In another embodiment, antioxidants may be added to the wafer to stabilize the film and the active agents, e.g. Vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives. Furthermore, acidic and basic ion exchangers can also be used as stabilizers.
In weiteren Ausführungsformen können dem Film weitere Inhaltsstoffe wie Farbstoffe, Pigmente, Geschmacksstoffe, natürliche und/oder synthetische Aromastoffe, Süßstoffe, puf- fernde Systeme zugesetzt sein. Insbesondere Geschmacks- und Aromastoffe können dabei den oft schlechten Eigengeschmack oder Geruch der Wirkstoffe überdecken und/oder der Darrei- chungsform einen angenehmen Geschmack verleihen, so daß die Bereitschaft zur Einnahme der Medikation durch den Patien- ten deutlich verbessert wird. Der oder die Wirkstoff (e) der
Zubereitung können zur Geschmacksmaskierung auch an einen sauren oder basischen Ionentauscher gebunden sein.In further embodiments, further ingredients such as dyes, pigments, flavorings, natural and / or synthetic flavorings, sweeteners, buffering systems may be added to the film. In particular, flavorings and flavorings can mask the often poor taste or smell of the active ingredients and / or give the dosage form a pleasant taste, so that the willingness to take the medication by the patient is significantly improved. The active ingredient (s) of the Preparation may also be bound to an acidic or basic ion exchanger for taste masking.
Der Zusatz von puffernden Systemen dient zum einen der Sta- bilisierung des Films und der Wirkstoffe gegen äußere Einflüsse und bei der Lagerung, zum anderen kann so der pH- Wert der Darreichungsform auf einen physiologisch akzeptablen pH-Wert eingestellt werden, so daß Schleimhautreizungen vermieden werden. Durch ein PufferSystem kann auch die Löslichkeit von aciden oder basischen Wirkstoffen in der Matrix verbessert werden.The addition of buffering systems serves, on the one hand, to stabilize the film and the active ingredients against external influences and during storage and, on the other hand, to adjust the pH of the dosage form to a physiologically acceptable pH, so that mucous membrane irritations are avoided , A buffer system can also improve the solubility of acidic or basic drugs in the matrix.
Die erfindungsgemäßen Darreichungsformen sind dünn, beispielsweise in Form einer Oblate gestaltet. Die Dicke der Darreichungsform beträgt vorzugsweise 0,1 bis 5 mm, besonders bevorzugt 0,5 bis 1 mm. Die untere Grenze für die Dik- ke der Darreichungsformen liegt bei etwa 50 μm. Die Fläche der Darreichungsform beträgt dabei zwischen 0,09 cm2 und 12 cm2, bevorzugt zwischen 1 cm2 und 8 cm2, und besonders bevorzugt zwischen 3 cm2 und 6 cm2.The administration forms according to the invention are thin, for example in the form of a wafer. The thickness of the dosage form is preferably 0.1 to 5 mm, more preferably 0.5 to 1 mm. The lower limit for the thickness of the dosage forms is about 50 μm. The area of the dosage form is between 0.09 cm 2 and 12 cm 2 , preferably between 1 cm 2 and 8 cm 2 , and particularly preferably between 3 cm 2 and 6 cm 2 .
In einer weiteren Ausführungsform enthalten die Wafer der vorliegenden Erfindung ein Sprengmittel oder ein Dochtmittel, z.B. ein Bicarbonat-Säure-Gemisch oder ein Aerosil, das durch Kontakt mit Flüssigkeit aktiviert wird und den Zerfall des Wafers nach Applikation und somit auch die Wirkstofffreisetzung beschleunigt .In another embodiment, the wafers of the present invention include a disintegrant or wicking agent, e.g. a bicarbonate-acid mixture or an aerosil, which is activated by contact with liquid and accelerates the disintegration of the wafer after application and thus also the release of active ingredient.
In einer weiteren bevorzugten Ausführungsform liegt der Wa- fer als Schaum vor, so daß die Wirkstoffabgäbe aufgrund der vergrößerten Oberfläche noch schneller erfolgt. Hierbei
können in den Hohlräumen des Schaums auch einer oder mehrere der Wirkstoffe oder Hilfsmittel in flüssiger Form vorliegen.In a further preferred embodiment, the wafer is present as a foam, so that the release of active ingredient is even faster due to the increased surface area. in this connection It is also possible for one or more of the active ingredients or auxiliaries to be present in liquid form in the cavities of the foam.
Zur Verbesserung der Resorption der Wirkstoffe durch die Schleimhaut können in dem Film auch Permeationsförderer, z.B. Stoffe aus den Gruppen der Fettalkohole, Fettsäuren, Polyoxyethylenfettalkoholether, Polyoxyethylenfettsäuree- ster, Fettalkoholester und Fettsäureester, insbesondere Sorbitanmonolaurat oder Ester von langkettigen Fettsäuren mit Methyl-, Ethyl- oder Isopropylalkohol, oder Ester von Fettalkoholen mit Essigsäure oder Milchsäure, oder auch Stoffe wie DMSO (Dimethylsulfoxid) und Ölsäurediethanolamin zugesetzt sein. Der Mengenanteil dieser Stoffe beträgt, so- fern vorhanden, 0,1 Gew.-% bis 25 Gew.-%, vorzugsweise von 1 Gew.-% bis 10 Gew.-%, jeweils bezogen auf das Gesamtgewicht der Wirkstoffmatrix.To improve the absorption of the active ingredients through the mucosa, permeation enhancers, e.g. Substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan monolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid, or also substances such as DMSO ( Dimethylsulfoxide) and oleic diethanolamine. The proportion of these substances, if present, is 0.1% by weight to 25% by weight, preferably from 1% by weight to 10% by weight, in each case based on the total weight of the active substance matrix.
Darüber hinaus können in der Zusammensetzung des Wafers Verbindungen enthalten sein, die die Wirkstofffreisetzung verzögern (z.B. Mikroverkapselung) .In addition, the composition of the wafer may contain compounds that retard drug release (e.g., microencapsulation).
In einer weiteren Ausführungsform besitzt der Wafer mukoadhäsive Eigenschaften, so daß dieser an der Schleimhaut bis zur vollständigen Auflösung haftet. Diese Ausführungsform erleichtert zusätzlich die Überwachung der Gabe der Medikamente, da der an der Schleimhaut haftende Wafer nicht ausgespuckt werden kann.In a further embodiment, the wafer has mucoadhesive properties, so that it adheres to the mucous membrane until complete dissolution. This embodiment additionally facilitates the monitoring of the administration of the medicaments since the wafer adhering to the mucous membrane can not be spit out.
In einer anderen bevorzugten Ausführungsform ist mindestens einer der Wirkstoffe an einen Ionentauscher gebunden, so
daß das hydrophile Polymer schnell im Mundraum zerfällt, die Freisetzung des Wirkstoffes aber erst verzögert oder bei verändertem pH-Wert, z.B. im Gastrointestinaltrakt, erfolgt. Auf diese Weise können Wirkstoffe mit unterschiedli- ehern Wirk- und Resorptionsmechanismus in einer Darreichungsform verabreicht werden, d.h. mindestens einer der freigesetzten Wirkstoffe wird am Applikationsort resorbiert, z. B. über die Mundschleimhaut, und der andere wird weitertransportiert und an einem anderen Ort resorbiert.In another preferred embodiment, at least one of the active ingredients is bound to an ion exchanger, see above that the hydrophilic polymer disintegrates rapidly in the oral cavity, but the release of the active ingredient only delayed or at a changed pH, for example in the gastrointestinal tract, takes place. In this way, active ingredients having different or higher active and absorption mechanisms can be administered in one dosage form, ie at least one of the released active substances is absorbed at the site of application, eg. B. on the oral mucosa, and the other is transported and resorbed at another location.
Der Wafer kann auch als Laminat mit unterschiedlichen Schichten aufgebaut sein, wobei die Wirkstoffe in diskreten Schichten enthalten sind, die räumlich voneinander getrennt sind und sich in ihrem Aufbau voneinander unterscheiden. Die Wirkstoffe können so an unterschiedlichen Wirkorten o- der aber auch verzögert freigesetzt werden, wenn sich die Zerfallszeit der unterschiedlichen Schichten das Wafers unterscheidet.The wafer can also be constructed as a laminate with different layers, wherein the active ingredients are contained in discrete layers, which are spatially separated from each other and differ in their construction. The active ingredients can be released at different sites of action or else delayed, if the disintegration time of the different layers of the wafer differs.
Ebenso können die Wirkstoffe in Schichten angeordnet sein, die unterschiedlich schnell zerfallen, so daß die gesamte Zubereitung einen Retardeffekt aufweist.Likewise, the active ingredients may be arranged in layers which disintegrate at different rates so that the entire preparation has a sustained-release effect.
In einer weiteren Ausführungsform kann nur eine der äußeren Schichten mukoadhäsiv sein, um das Anhaften der Darreichungsform auf der Schleimhaut zu begünstigen und die Wirkstoffresorption über die Schleimhaut durch den direkten Kontakt zu vereinfachen.In another embodiment, only one of the outer layers may be mucoadhesive to promote adherence of the dosage form to the mucosa and to facilitate drug absorption through the mucosa through direct contact.
Der Zerfall in wäßrigem Medium der erfindungsgemäßenThe decomposition in aqueous medium of the invention
Darreichungsform erfolgt vorzugsweise im Bereich von 1 s
bis 5 min, stärker bevorzugt im Bereich von 5 s bis 1 min, und am meisten bevorzugt im Bereich von 10 s bis 30 s.Dosage form is preferably in the range of 1 s to 5 minutes, more preferably in the range of 5 seconds to 1 minute, and most preferably in the range of 10 seconds to 30 seconds.
Die erfindungsgemäßen Darreichungsformen eignen sich in vorteilhafter Weise für die Verabreichung von Medikamenten in der Mundhöhle oder zur rektalen, vaginalen oder intranasalen Verabreichung.The dosage forms according to the invention are advantageously suitable for the administration of medicaments in the oral cavity or for rectal, vaginal or intranasal administration.
Die vorliegende Erfindung ist weiterhin auf die Verwendung einer der erfindungsgemäßen Wirkstoffkombination zur Herstellung einer oralen Darreichungsform zur Behandlung von Demenzerkrankungen gerichtet, wobei die Darreichungsform bevorzugt als Wafer formuliert wird.The present invention is further directed to the use of one of the active ingredient combination according to the invention for the preparation of an oral dosage form for the treatment of dementia diseases, wherein the dosage form is preferably formulated as a wafer.
Weiterhin ist die vorliegende Erfindung auf ein Verfahren zur therapeutischen Behandlung einer an Demenz leidenden Person gerichtet, wobei die Verabreichung einer zuvor beschriebenen Wirkstoffkombination von Antidementiva mittels einer oral applizierbaren Darreichungsform mit zumindest teilweiser transmukosaler Resorption mindestens eines Wirkstoffs erfolgt.Furthermore, the present invention is directed to a method for the therapeutic treatment of a person suffering from dementia, wherein the administration of a previously described active ingredient combination of anti-dementia agents by means of an orally administered dosage form with at least partial transmucosal absorption of at least one active ingredient.
Schließlich ist die vorliegende Erfindung auch auf ein Verfahren zur Herstellung einer flächenföπnigen Darreichungs- form gerichtet, das die folgenden Schritte umfaßt:Finally, the present invention is also directed to a process for the preparation of a sheet-like dosage form which comprises the following steps:
- Herstellen einer Lösung, die zumindest ein Polymer und mindestens zwei Wirkstoffe aus der Gruppe der Antidementiva enthält;- Preparing a solution containing at least one polymer and at least two active substances from the group of anti-dementia agents;
- Ausstreichen der Lösung auf eine Beschichtungsunterla- ge und
Verfestigen der ausgestrichenen Lösung durch Trocknen und Entzug des Lösemittels.
Spreading the solution on a coating base and Solidification of the precipitated solution by drying and removal of the solvent.
Claims
1. Flächenförmige, bei Kontakt mit Feuchtigkeit schnell zerfallende, Arzneimittelzubereitung auf Basis hydrophiler Polymere zur Behandlung von Demenzerkrankungen, dadurch gekennzeichnet, daß die Darreichungsform eine Wirkstoffkombination aus mindestens zwei Wirkstoffen enthält, die zur Behandlung von Demenzen geeignet sind.1. A surface-shaped, rapidly disintegrating on contact with moisture, pharmaceutical preparation based on hydrophilic polymers for the treatment of dementia diseases, characterized in that the dosage form contains a combination of active ingredients of at least two active substances which are suitable for the treatment of dementia.
2. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß die Wirkstoffe aus der Gruppe ausgewählt sind, die Acetylcholinesterase-Hemmstoffe (AchE-Hemmer) , NMDA-Antagonisten (N-Methyl-D-Asparaginsäure-Antagonisten) und Nootropika umfaßt.2. Medicament preparation according to claim 1, characterized in that the active ingredients are selected from the group comprising acetylcholinesterase inhibitors (AchE inhibitors), NMDA antagonists (N-methyl-D-aspartic acid antagonists) and nootropics.
3. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß mindestens einer der Wirkstoffe ein AchE-Hemmer und/oder mindestens einer der Wirkstoffe ein NMDA-Antagonist ist.3. Pharmaceutical preparation according to one of the preceding claims, characterized in that at least one of the active ingredients is an AchE inhibitor and / or at least one of the active ingredients is an NMDA antagonist.
4. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß der AchE-Hemmer ausgewählt ist aus der Gruppe, die Rivastigmin, Galanthamin, und Donezepil sowie pharmazeutisch akzeptable Salze dieser Wirkstoffe umfaßt.4. Medicament preparation according to one of the preceding claims, characterized in that the AchE inhibitor is selected from the group comprising rivastigmine, galanthamine, and donezepil and pharmaceutically acceptable salts of these active ingredients.
5. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß der NMDA-Antagonist Memantine ist. 5. Pharmaceutical preparation according to one of the preceding claims, characterized in that the NMDA antagonist is memantine.
6. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das Nootropikum Piracetam oder Naftidrofuryl ist.6. Medicament preparation according to one of the preceding claims, characterized in that the nootropic drug is piracetam or naftidrofuryl.
7. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung mindestens einen weiteren Wirkstoff zur Behandlung von Demenzen enthält, ausgewählt aus der Gruppe der Vasodilatoren, Calciumantagonisten und durchblutungsfördernden Mittel.7. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains at least one further active ingredient for the treatment of dementias, selected from the group of vasodilators, calcium antagonists and circulation-promoting agents.
8. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung mindestens einen Wirkstoff enthält, ausgewählt aus der Gruppe, die Nimodipin, Dihydroergotoxin, Pentoxyfyllin, Naftidrofu- ryl, Ginkgo Biloba Extrakte sowie pharmazeutisch akzeptable Salze dieser Wirkstoffe umfaßt.8. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains at least one active ingredient selected from the group comprising nimodipine, dihydroergotoxin, pentoxyfylline, naftidrofuryl, ginkgo biloba extracts and pharmaceutically acceptable salts of these active ingredients.
9. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das hydrophile PoIy- mer ausgewählt ist aus der Gruppe, die Dextran, Polysaccharide, einschließlich der Stärke und Stärkederivate, Cellu- losederivate, wie Carboxymethylcellulose, Ethyl- oder Pro- pylcellulose, Hydroxypropylmethylcellulose, Hydroxypropyl- cellulose, Natrium-Carboxymethylcellulose (z. B. Walocel) , Methylcellulose, Hydroxyethylcellulose und Hydroxypropy- lethylcellulose, Polyvinylalkohole, Polyethylenglykole, Polyacrylsäuren, Polyacrylate, Polyvinylpyrrolidone, Algi- nate, Pektine, Gelatine, Alginsäure, Kollagen, Chitosan, Arabinogalactan, Galactomannan, Agar-Agar, Agarose, Carra- geen natürliche Gummen, Tragant, hochdisperses Siliziumdioxid, Bentonit, sowie Derivate der vorgenannten hydrophilen Polymere bzw. Kombinationen aus zwei oder mehreren dieser Polymere umfaßt.9. Medicament preparation according to one of the preceding claims, characterized in that the hydrophilic polymer is selected from the group consisting of dextran, polysaccharides, including the starch and starch derivatives, cellulose derivatives, such as carboxymethylcellulose, ethyl or propylcellulose, hydroxypropylmethylcellulose , Hydroxypropylcellulose, sodium carboxymethylcellulose (eg, Walocel), methylcellulose, hydroxyethylcellulose and hydroxypropylethylcellulose, polyvinyl alcohols, polyethylene glycols, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, alginates, pectins, gelatin, alginic acid, collagen, chitosan, arabinogalactan, Galactomannan, agar-agar, agarose, carrageenan natural gums, tragacanth, fumed silica, bentonite, and derivatives of the aforesaid hydrophilic Polymers or combinations of two or more of these polymers.
10. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß der Polymerfilm aus einem Polyvinylalkohol-Polyethylenglycol-Pfropfcopolymer hergestellt ist.10. Medicament preparation according to one of the preceding claims, characterized in that the polymer film is made of a polyvinyl alcohol-polyethylene glycol graft copolymer.
11. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung ein11. Medicament preparation according to one of the preceding claims, characterized in that the preparation is a
Feuchthaltemittel, ausgewählt aus der Gruppe, die Glycerin, Propylenglycol, Sorbitol, Mannitol, Polyethylenglycol und Polyglycerinester umfaßt, enthält.Humectant selected from the group comprising glycerin, propylene glycol, sorbitol, mannitol, polyethylene glycol and polyglycerol ester.
12. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung ein Antioxidans, ausgewählt aus der Gruppe, die Vitamin C (As- corbinsäure) , Ascorbylpalmitat, Vitamin E (Tocopherolace- tat) , Hydroxybenzoesäurederivate umfaßt, enthält.12. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation comprises an antioxidant selected from the group comprising vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives.
13. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff der Zubereitung zur Geschmacksmaskierung an einen sauren oder basischen Ionentauscher gebunden ist.13. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredient of the preparation for taste masking is bound to an acidic or basic ion exchanger.
14. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung Farbstoffe und/oder Pigmente enthält. 14. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains dyes and / or pigments.
15. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung natürliche und/oder synthetische Aromastoffe enthält.15. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains natural and / or synthetic flavorings.
16. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung ein Sprengmittel oder Dochtmittel enthält.16. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains a disintegrant or wicking agent.
17. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß der pH-Wert der Zubereitung über ein Puffersystem eingestellt ist.17. Pharmaceutical preparation according to one of the preceding claims, characterized in that the pH of the preparation is adjusted via a buffer system.
18. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das hydrophile PoIy- mer in weniger als 5 min, bevorzugt in weniger als 3 min, weiter bevorzugt in weniger als 1 min und besonders bevorzugt in weniger als 30 s nach Applikation im Mundraum zerfällt.18. Medicament preparation according to one of the preceding claims, characterized in that the hydrophilic polymer in less than 5 min, preferably in less than 3 min, more preferably in less than 1 min and more preferably in less than 30 s after application in the oral cavity decays.
19. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das hydrophile Polymer schnell im Mundraum zerfällt, der Wirkstoff aber an einen Ionentauscher gebunden bleibt, der den Wirkstoff erst im Gastrointestinaltrakt freisetzt.19. Pharmaceutical preparation according to one of the preceding claims, characterized in that the hydrophilic polymer disintegrates rapidly in the oral cavity, but the active substance remains bound to an ion exchanger, which releases the active substance only in the gastrointestinal tract.
20. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Wirkstoffe in diskreten Schichten enthalten sind, die räumlich voneinander getrennt sind und sich in ihrem Aufbau voneinander un- terscheiden. 20. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active substances are contained in discrete layers, which are spatially separated from each other and differ in their structure from each other.
21. Arzneimittelzubereitung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Zubereitung als Schaum vorliegt und mindestens einer der Wirkstoffe in flüssiger Form in den Hohlräumen des Schaums vorliegt.21. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation is present as a foam and at least one of the active ingredients is present in liquid form in the cavities of the foam.
22. Verwendung einer in den Ansprüchen 1 bis 7 definierten Wirkstoffkombination zur Herstellung eines oral verabreichbaren Arzneimittels in Form eines Wafers zur Behandlung von Demenzerkrankungen.22. Use of a defined in claims 1 to 7 drug combination for the preparation of an orally administrable drug in the form of a wafer for the treatment of dementia.
23. Verfahren zur therapeutischen Behandlung einer an Demenz erkrankten Person, wobei dieser Person eine in den Ansprüchen 1 bis 7 definierte Wirkstoffkombination auf oralem Wege verabreicht wird.23. A method for the therapeutic treatment of a person suffering from dementia, wherein said person is administered a defined in claims 1 to 7 drug combination by oral route.
24. Verfahren nach Anspruch 23, dadurch gekennzeichnet, daß die Verabreichung der Wirkstoffkombination mittels eines schnell zerfallenden Wafers, welcher diese Kombination enthält, erfolgt. 24. The method according to claim 23, characterized in that the administration of the drug combination by means of a rapidly disintegrating wafer containing this combination takes place.
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DE102006027791A DE102006027791A1 (en) | 2006-06-16 | 2006-06-16 | AchE NMDA combination wafer |
PCT/EP2007/004951 WO2007144083A2 (en) | 2006-06-16 | 2007-06-04 | Ache-nmda combination wafer |
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EP07725819A Withdrawn EP2029100A2 (en) | 2006-06-16 | 2007-06-04 | Ache-nmda combination wafer |
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JP (1) | JP2009539895A (en) |
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CA (1) | CA2653030A1 (en) |
DE (1) | DE102006027791A1 (en) |
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DE102017127434A1 (en) * | 2017-11-21 | 2019-05-23 | Lts Lohmann Therapie-Systeme Ag | Pocket-shaped oral-release films with high drug loading |
CN108926549A (en) * | 2018-09-27 | 2018-12-04 | 安徽安科余良卿药业有限公司 | Rivastigmine gel emplastrum and preparation method thereof |
CN109498643A (en) * | 2018-12-06 | 2019-03-22 | 北京斯利安药业有限公司 | A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement |
CN111234323A (en) * | 2020-03-27 | 2020-06-05 | 南京林业大学 | Preparation method of high-strength flame-retardant galactomannan-polysaccharide-based composite membrane |
DE102021100780A1 (en) | 2021-01-15 | 2022-07-21 | Lts Lohmann Therapie-Systeme Ag. | ORAL THIN FILM WITH PVA-TRIS BUFFER LAYER |
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2006
- 2006-06-16 DE DE102006027791A patent/DE102006027791A1/en not_active Withdrawn
-
2007
- 2007-06-04 EP EP07725819A patent/EP2029100A2/en not_active Withdrawn
- 2007-06-04 BR BRPI0711503-2A patent/BRPI0711503A2/en not_active IP Right Cessation
- 2007-06-04 US US12/308,236 patent/US20090202597A1/en not_active Abandoned
- 2007-06-04 JP JP2009514664A patent/JP2009539895A/en not_active Withdrawn
- 2007-06-04 CA CA002653030A patent/CA2653030A1/en not_active Abandoned
- 2007-06-04 WO PCT/EP2007/004951 patent/WO2007144083A2/en active Application Filing
- 2007-06-04 CN CNA2007800205090A patent/CN101460144A/en active Pending
Non-Patent Citations (1)
Title |
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See references of WO2007144083A2 * |
Also Published As
Publication number | Publication date |
---|---|
CA2653030A1 (en) | 2007-12-21 |
CN101460144A (en) | 2009-06-17 |
BRPI0711503A2 (en) | 2011-11-01 |
WO2007144083A2 (en) | 2007-12-21 |
US20090202597A1 (en) | 2009-08-13 |
JP2009539895A (en) | 2009-11-19 |
DE102006027791A1 (en) | 2007-12-20 |
WO2007144083A3 (en) | 2008-04-17 |
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