EP4045014A1 - Controlled release formulations of highly lipophilic physiologically active substances - Google Patents

Controlled release formulations of highly lipophilic physiologically active substances

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Publication number
EP4045014A1
EP4045014A1 EP20800800.3A EP20800800A EP4045014A1 EP 4045014 A1 EP4045014 A1 EP 4045014A1 EP 20800800 A EP20800800 A EP 20800800A EP 4045014 A1 EP4045014 A1 EP 4045014A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
physiologically active
form according
active substances
highly lipophilic
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.)
Pending
Application number
EP20800800.3A
Other languages
German (de)
French (fr)
Inventor
Mirko Nowak
Jay Jesko NOWAK
Annette Grave
Monika Wentzlaff
Sarah Barthold
Christian Geugelin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ADD Advanced Drug Delivery Technologies AG
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ADD Advanced Drug Delivery Technologies AG
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Filing date
Publication date
Application filed by ADD Advanced Drug Delivery Technologies AG filed Critical ADD Advanced Drug Delivery Technologies AG
Publication of EP4045014A1 publication Critical patent/EP4045014A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to formulations for highly lipophilic physiologically active substances, in particular formulations with controlled release, and to their production.
  • the highly lipophilic physiologically active substances are, for example, active pharmaceutical ingredients.
  • An example of highly lipophilic pharmaceutical active ingredients are cannabinoids.
  • a number of physiologically active substances have highly lipophilic properties, i.e. they have a relatively high log P, for example a log P of 4 or more, where the log P is the logarithm of the n-octanol / water partition coefficient.
  • formulations in particular oral formulations, with such physiologically active substances represents a particular challenge, in particular if a controlled release of the physiologically active substances is to be achieved.
  • the physiologically active substances with strong lipophilic properties include cannabinoids.
  • Cannabinoids are a heterogeneous group of pharmacologically active substances that have an affinity for the so-called cannabinoid receptors.
  • the cannabinoids include, for example, tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD).
  • Cannabinoids have found considerable interest as drugs. There is evidence that cannabinoid administration can be beneficial in a number of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia, and schizophrenia (N. Bruni et al., Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478). The provision of suitable dosage forms is associated with difficulties, however, since cannabinoids are highly lipophilic molecules (log P 6-7) with very low water solubility (2-10 pg / ml).
  • WO 2015/065179 A1 describes compressed tablets which, in addition to cannabidiol, contain lactose and sucrose fatty acid monoesters.
  • Dronabinol (A9-THC) is marketed in capsule form (Marinol ® ) and as an oral solution (Syndros ®). Marinol ® capsules are soft gelatine capsules that contain the active ingredient in sesame oil.
  • the finished drug Sativex ® which contains nabiximols, is an oral spray that is sprayed onto the inside of the cheek.
  • Epidiolex for the treatment of certain forms of epilepsy is made available in the form of an oral solution which, in addition to the active ingredient cannabidiol, contains the auxiliary substances absolute ethanol, sesame oil, strawberry aroma and sucralose.
  • One object of the invention is to provide solid dosage forms, in particular oral solid dosage forms, for highly lipophilic physiologically active substances such as Cannabinoids, which release the physiologically active substance (s) and which can be produced in a simple manner.
  • physiologically active substances such as Cannabinoids
  • This object is achieved by providing a solid dosage form which has a matrix with one or more highly lipophilic physiologically active substances; one or more water-soluble binders and not more than 20% by weight, based on the weight of all components, of further auxiliaries, a physiologically active substance being highly lipophilic if it has a log P of 4 or more.
  • solid forms of administration in particular oral solid forms of administration, of highly lipophilic physiologically active substances can be provided, the release being determined via the amount of water-soluble binder (s), based on the amount of strongly lipophilic substance / substances can be controlled.
  • the use of one or more water-soluble binders not only allows the formation of a matrix with the physiologically active substance (s), but also serves to control the release.
  • a water-soluble binder promotes the release of the highly lipophilic substances, which are only very slightly soluble in water. These are only released in sufficient quantity and speed by the binding agent.
  • Fig. 1 shows the in vitro release from three pellet products containing 2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol as Contains active ingredient and low viscosity hydroxypropylmethyl cellulose.
  • the dosage forms provided according to the invention contain one or more highly lipophilic physiologically active substances.
  • a substance is highly lipophilic if it has a log P of 4 or more.
  • the log P is the decadic logarithm of the n-octanol / water partition coefficient.
  • the distribution coefficient can be determined experimentally. Values typically refer to room temperature (25 ° C). The distribution coefficient can also be calculated approximately from the molecular structure.
  • the pellets according to the invention are particularly suitable for physiologically active substances with a log P of 5 or more and very particularly for those with a log P of 6 or more.
  • physiologically active substance refers to a substance that is administered to a human or an animal in order to develop an effect in the human or animal body.
  • the physiologically active substance can, for example, be a pharmaceutical active ingredient of a human or veterinary medicinal product or a food supplement.
  • An example of highly lipophilic pharmaceutical active ingredients that can be used according to the invention are cannabinoids.
  • the cannabinoids can be both phytocannabinoids and synthetic cannabinoids.
  • the phytocannabinoids are a group of about 70 terpenophenolic compounds (V.R. Preedy (Ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene residue attached to a phenolic ring and having a Cs-Cs alkyl chain that is in the meta position to the phenolic hydroxyl group.
  • a preferred group of cannabinoids are tetrahydrocannabinols of the following general formula (1): wherein R is selected from C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl and optionally has one or more substituents.
  • R is selected from C 1 -C 10 -alkyl or C 2 -C 10 -alkenyl and optionally has one or more substituents.
  • R in the formula (1) is an alkyl radical of the formula CsHu.
  • Compounds of the general formula (1) can exist in the form of stereoisomers.
  • the centers 6a and 10a preferably each have the R configuration.
  • the tetrahydrocannabinol is in particular A9-THC with the chemical name (6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8, 10a-tetrahydro-6H-benzo [c] chromene-1-ol.
  • the structure is represented by the following formula (2):
  • cannabinoids are cannabidiols of the following general formula (3): wherein R is selected from Ci-C2o-alkyl, C2-C2o-alkenyl or C2-C2o-alkynyl and optionally has one or more substituents.
  • R is selected from C 1 -C 10 -alkyl or C 2 -C 10 -alkenyl and optionally has one or more substituents.
  • R in the formula (3) is an alkyl radical of the formula CsHu.
  • the cannabidiol is in particular 2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol.
  • A9-THC (6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo [c] chromene-1 -ol) and CBD (2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol) can be used.
  • cannabinoids are cannabinols of the following general formula (4): wherein R is selected from C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl and optionally has one or more substituents.
  • R is selected from C1-Cio-alkyl or C2-Cio-alkenyl and optionally has one or more substituents.
  • R in the formula (4) is an alkyl radical of the formula CsHu.
  • the cannabinol is in particular 6,6,9-trimethyl-3-pentyl-6 / - / - dibenzo [b, c] pyran-1-ol.
  • cannabinoids or cannabinoid mixtures from hemp extracts can also be used.
  • Nabiximols is a plant extract mixture used as a medicinal substance from the leaves and flowers of the hemp plant (Cannabis sativa L.) with standardized levels of tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • Synthetic cannabinoids can also be used.
  • This includes 3- (1,1-dimethylheptyl) -6,6a, 7,8, 10, 10a-hexahydro-1-hydroxy-6,6-dimethyl- 9 / - / - dibenzo [ö, c (] pyran- 9-one.
  • This compound contains two stereogenic centers.
  • the drug nabilone is a 1: 1 mixture (racemate) of the (6aR, 10aR) form and the (6aS, 10aS) form.
  • Nabilone is a cannabinoid which is preferred according to the invention.
  • JWH-018 (1-naphthyl- (1-pentylindol-3-yl) methanone.
  • one or more highly lipophilic physiologically active substances such as one or more pharmaceutical active ingredients such as cannabinoids, are contained in a matrix.
  • the matrix preferably does not contain any further physiologically active substances.
  • the matrix contains one or more water-soluble binders.
  • These binders are polymeric film-forming substances.
  • suitable water-soluble binders are methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (Na-CMC) and polyvinylpyrrolidone (PVP).
  • HPMC Hydroxypropylmethylcellulose
  • low-viscosity HPMC such as HPMC with a viscosity of a 2% (w / w) aqueous solution at 20 ° C. of 6 mPa ⁇ s or less.
  • the matrix of one or more highly lipophilic physiologically active substances and one or more water-soluble binders can contain other customary auxiliaries, such as one or more fillers or carriers.
  • the amount of further auxiliaries is limited to not more than 20% by weight, based on the weight of all components. It preferably does not contain more than 10% by weight, based on the weight of all components, of further auxiliaries.
  • the matrix consists of strongly lipophilic physiologically active substance / strongly lipophilic physiologically active substances and binding agent (s), for example cannabinoid (s) and binding agent (s).
  • binding agent for example cannabinoid (s) and binding agent (s).
  • the matrix contains one or more water-soluble binders, based on the total amount of highly lipophilic physiologically active substances, in a total proportion of 0.1-10% by weight, preferably in a total proportion of 0.5-8% by weight and in particular contains in a total proportion of 1 - 6 wt .-%.
  • the release of the physiologically active substance can be adjusted by choosing the proportion in the specified ranges. For example, the release from an oral dosage form can be adjusted so that the physiologically active substance is released over the usual time of gastrointestinal passage.
  • the solid oral dosage form according to the invention which has a matrix with one or more highly lipophilic physiologically active substances, can be provided and used in any form.
  • the dosage form can be provided in the form of granules, matrix pellets or matrix tablets or contain one of these forms.
  • the production can take place in a manner known per se.
  • the dosage form contains matrix pellets.
  • the matrix pellets typically have a size in the range from 30 to 1800 ⁇ m, and the size can be determined by sieve analysis.
  • the matrix pellets can be used as an oral dosage form, e.g. being offered in sachets, or they can be further processed.
  • the matrix pellets can be provided with one or more additional coatings. This enables additional control of the release.
  • no coating is provided that controls the release.
  • the matrix pellets can also be used to obtain multiparticulate dosage forms. They can be filled into capsules or incorporated into tablets.
  • Matrix pellets with different release profiles can be combined in one dosage form (capsule / tablet / sachet).
  • the oral dosage forms according to the invention release the strongly lipophilic physiologically active substance contained therein or, if more than one strongly lipophilic physiologically active substance is contained, release all the strongly lipophilic physiologically active substances contained in the digestive tract after ingestion.
  • the dosage forms are used in particular for controlled release. In particular, they release more than 30% by weight and less than 80% by weight of the physiologically active substance contained within two hours. Furthermore, they release in particular more than 40% by weight and less than 90% by weight of the physiologically active substance contained within three hours. In addition, they release more than 50% by weight and less than 95% by weight of the physiologically active substance contained within four hours. If it contains more than one physiologically active substance, the information relates to all substances contained.
  • HPMC solution was then gradually added to the cannabidiol solution.
  • amorphous silica (Syloid ® 244 FP) was added.
  • the spray liquid obtained was sprayed onto starter cores made of microcrystalline cellulose (Cellets ® 500).
  • Example 1 pellet products The release from the results obtained in Example 1 pellet products is examined using a blade stirrer apparatus in 1000 ml phosphate buffer pH 6.8 with an addition of 0.4% Tween ® 80, namely at 37 ° C. The results obtained 1 are shown in Fig..

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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

The invention relates to a solid dosage form that comprises a matrix with one or more highly lipophilic physiologically active substances, one or more water-soluble binders and, relative to the weight of all components, not more than 20 wt% of other auxiliary substances.

Description

Kontrolliert freisetzende Formulierungen stark lipophiler physiologisch aktiver Substanzen Controlled release formulations of highly lipophilic physiologically active substances
Beschreibung description
Gebiet der Erfindung Field of the invention
Die Erfindung betrifft Formulierungen für stark lipophile physiologisch aktive Substanzen, insbesondere kontrolliert freisetzende Formulierungen, sowie deren Herstellung. Bei den stark lipophilen physiologisch aktiven Substanzen handelt es sich beispielsweise um pharmazeutische Wirkstoffe. Ein Beispiel für stark lipophile pharmazeutische Wrkstoffe sind Cannabinoide. The invention relates to formulations for highly lipophilic physiologically active substances, in particular formulations with controlled release, and to their production. The highly lipophilic physiologically active substances are, for example, active pharmaceutical ingredients. An example of highly lipophilic pharmaceutical active ingredients are cannabinoids.
Hintergrund der Erfindung Background of the invention
Eine Reihe von physiologisch aktiven Substanzen haben stark lipophile Eigenschaften, d.h., sie weisen einen relativ hohen log P auf, beispielsweise einen log P von 4 oder mehr auf, wobei der log P der dekadische Logarithmus des n-Octanol/Wasser- Verteilungskoeffizienten ist. A number of physiologically active substances have highly lipophilic properties, i.e. they have a relatively high log P, for example a log P of 4 or more, where the log P is the logarithm of the n-octanol / water partition coefficient.
Die Bereitstellung von Formulierungen, insbesondere oralen Formulierungen, mit solchen physiologisch aktiven Substanzen stellt eine besondere Herausforderung dar, insbesondere wenn eine kontrollierte Freisetzung der physiologisch aktiven Substanzen erzielt werden soll. The provision of formulations, in particular oral formulations, with such physiologically active substances represents a particular challenge, in particular if a controlled release of the physiologically active substances is to be achieved.
Zu den physiologisch aktiven Substanzen mit stark lipophilen Eigenschaften gehören Cannabinoide. The physiologically active substances with strong lipophilic properties include cannabinoids.
Cannabinoide sind eine heterogene Gruppe pharmakologisch aktiver Substanzen, die eine Affinität zu den sogenannten Cannabinoid-Rezeptoren aufweisen. Zu den Cannabinoiden gehören beispielsweise Tetrahydrocannabinol (THC) und das nicht psychoaktive Cannabidiol (CBD). Cannabinoids are a heterogeneous group of pharmacologically active substances that have an affinity for the so-called cannabinoid receptors. The cannabinoids include, for example, tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD).
Cannabinoide haben erhebliches Interesse als Arzneistoffe gefunden. So gibt es Hinweise darauf, dass die Verabreichung von Cannabinoiden bei einer Reihe von klinischen Zuständen von Vorteil sein kann, darunter Schmerzen, Entzündungen, Epilepsie, Schlafstörungen, Symptome von Multipler Sklerose, Anorexie und Schizophrenie (N. Bruni et al. , Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478). Die Bereitstellung geeigneter Darreichungsformen ist allerdings mit Schwierigkeiten verbunden, da Cannabinoide stark lipophile Moleküle (log P 6-7) mit sehr geringer Wasserlöslichkeit (2-10 pg / ml) sind. Cannabinoids have found considerable interest as drugs. There is evidence that cannabinoid administration can be beneficial in a number of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia, and schizophrenia (N. Bruni et al., Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478). The provision of suitable dosage forms is associated with difficulties, however, since cannabinoids are highly lipophilic molecules (log P 6-7) with very low water solubility (2-10 pg / ml).
So hat die geringe orale Bioverfügbarkeit von Cannabinoiden dazu geführt, dass transdermale, intranasale und transmukosale Verabreichung vorgeschlagen wurden.For example, the low oral bioavailability of cannabinoids has led to transdermal, intranasal and transmucosal administration being proposed.
Daneben gehören aufgrund der hohen Lipophilie von Cannabinoiden Salzbildung (d.h. pH-Einstellung), Cosolvenz (z. B. Ethanol, Propylenglykol, PEG400), Mizellisierung (z. B. Polysorbat 80, Cremophor-ELP), Emulgierung einschließlich Mikro- und Nano- Emulgierung, Komplexierung (z. B. Cyclodextrine) und Einkapselung in Formulierungen auf Lipidbasis (z. B. Liposomen) zu den Formulierungsstrategien, die im Stand der Technik in Betracht gezogen wurden. Zudem wurden Nanopartikel-Systeme vorgeschlagen (N. Bruni et al. , a.a.O.). In addition, due to the high lipophilicity of cannabinoids, salt formation (i.e. pH adjustment), cosolvency (e.g. ethanol, propylene glycol, PEG400), micellization (e.g. polysorbate 80, Cremophor-ELP), emulsification including micro and nano- Emulsification, complexing (e.g. cyclodextrins) and encapsulation in lipid-based formulations (e.g. liposomes) are among the formulation strategies considered in the prior art. In addition, nanoparticle systems have been proposed (N. Bruni et al., Op. Cit.).
In der Patentliteratur sind verschiedene feste orale Darreichungsformen vorgeschlagen worden, so in WO 2008/024490 A2 und in WO 2018/035030 A1. Diese Dokumente enthalten keine Daten zum Freisetzungsverhalten, so dass die praktische Eignung der vorgeschlagenen Formen für die Verabreichung von Cannabinoiden unklar bleibt. Various solid oral administration forms have been proposed in the patent literature, for example in WO 2008/024490 A2 and in WO 2018/035030 A1. These documents do not contain any data on release behavior, so the practical suitability of the proposed forms for the administration of cannabinoids remains unclear.
WO 2015/065179 A1 beschreibt komprimierte Tabletten, die neben Cannabidiol Lactose und Saccharosefettsäuremonoester enthalten. WO 2015/065179 A1 describes compressed tablets which, in addition to cannabidiol, contain lactose and sucrose fatty acid monoesters.
Dronabinol (A9-THC) wird in Form von Kapseln (Marinol®) und als orale Lösung (Syndros®) vermarktet. Bei den Marinol®-Kapseln handelt es sich um Weichgelatinekapseln, die den Wirkstoff in Sesamöl enthalten. Dronabinol (A9-THC) is marketed in capsule form (Marinol ® ) and as an oral solution (Syndros ®). Marinol ® capsules are soft gelatine capsules that contain the active ingredient in sesame oil.
Das Nabiximols-haltige Fertigarzneimittel Sativex® ist ein Mundspray, das auf die Innenseite der Wange gesprüht wird. The finished drug Sativex ® , which contains nabiximols, is an oral spray that is sprayed onto the inside of the cheek.
Das unlängst zugelassene Präparat Epidiolex zur Behandlung bestimmter Formen der Epilepsie wird in Form einer oralen Lösung zur Verfügung gestellt, die neben dem Wirkstoff Cannabidiol die Hilfsstoffe absolutes Ethanol, Sesamöl, Erdbeeraroma und Sucralose enthält. The recently approved preparation Epidiolex for the treatment of certain forms of epilepsy is made available in the form of an oral solution which, in addition to the active ingredient cannabidiol, contains the auxiliary substances absolute ethanol, sesame oil, strawberry aroma and sucralose.
Ungeachtet all dieser Vorschläge besteht aber weiterhin ein Bedarf an verbesserten Darreichungsformen für stark lipophile physiologisch aktive Substanzen, beispielsweise pharmazeutische Wirkstoffe wie Cannabinoide, insbesondere an oralen festen Darreichungsformen. Regardless of all these proposals, there is still a need for improved forms of administration for highly lipophilic physiologically active substances, for example active pharmaceutical ingredients such as cannabinoids, in particular for oral solid forms of administration.
Aufgaben und Kurzdarstellung der Erfindung Objects and summary of the invention
Eine Aufgabe der Erfindung besteht darin, feste Darreichungsformen, insbesondere orale feste Darreichungsformen, für stark lipophile physiologisch aktive Substanzen, wie Cannabinoide, bereitzustellen, die die physiologisch aktive Substanz/die physiologisch aktiven Substanzen freisetzen und die in einfacher Weise hergestellt werden können.One object of the invention is to provide solid dosage forms, in particular oral solid dosage forms, for highly lipophilic physiologically active substances such as Cannabinoids, which release the physiologically active substance (s) and which can be produced in a simple manner.
Diese Aufgabe wird durch die Bereitstellung einer festen Darreichungsform gelöst, die eine Matrix mit einer oder mehreren stark lipophilen physiologisch aktiven Substanzen; einem oder mehreren wasserlöslichen Bindemitteln und nicht mehr als 20 Gew.-%, bezogen auf das Gewicht aller Komponenten, an weiteren Hilfsstoffen aufweist, wobei eine physiologisch aktive Substanz stark lipophil ist, wenn sie einen log P von 4 oder mehr hat. This object is achieved by providing a solid dosage form which has a matrix with one or more highly lipophilic physiologically active substances; one or more water-soluble binders and not more than 20% by weight, based on the weight of all components, of further auxiliaries, a physiologically active substance being highly lipophilic if it has a log P of 4 or more.
Überraschend wurde festgestellt, dass sich so feste Darreichungsformen, insbesondere orale feste Darreichungsformen, von stark lipophilen physiologisch aktiven Substanzen bereitstellen lassen, wobei über die Menge an wasserlöslichen Bindemittel(n), bezogen auf die Menge an stark lipophiler Substanz/stark lipophilen Substanzen, die Freisetzung gesteuert werden kann. Der Einsatz eines oder mehrerer wasserlöslicher Bindemittel erlaubt nicht nur die Ausbildung einer Matrix mit der physiologisch aktiven Substanz/den physiologisch aktiven Substanzen, sondern dient auch der Steuerung der Freisetzung. Insbesondere fördert ein wasserlösliches Bindemittel die Freisetzung der nur sehr wenig in Wasser löslichen stark lipophilen Substanzen. Erst durch das Bindemittel werden diese in ausreichender Menge und Geschwindigkeit freigesetzt. Surprisingly, it was found that solid forms of administration, in particular oral solid forms of administration, of highly lipophilic physiologically active substances can be provided, the release being determined via the amount of water-soluble binder (s), based on the amount of strongly lipophilic substance / substances can be controlled. The use of one or more water-soluble binders not only allows the formation of a matrix with the physiologically active substance (s), but also serves to control the release. In particular, a water-soluble binder promotes the release of the highly lipophilic substances, which are only very slightly soluble in water. These are only released in sufficient quantity and speed by the binding agent.
Weitere Aufgaben und deren Lösung ergeben sich aus der nachstehenden ausführlichen Darstellung der Erfindung. Further objects and their solution emerge from the detailed description of the invention below.
Kurze Beschreibung der Figuren Brief description of the figures
Die Erfindung wird nachstehend unter Bezugnahme auf die Figur näher erläutert. The invention is explained in more detail below with reference to the figure.
Fig. 1 zeigt die in vitro-Freisetzung aus drei Pelletprodukten, die 2-[1R-3-Methyl-6R-(1- methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol als Wirkstoff und niedrigviskose Hydroxypropylmethylcellulose enthalten. Fig. 1 shows the in vitro release from three pellet products containing 2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol as Contains active ingredient and low viscosity hydroxypropylmethyl cellulose.
Ausführliche Darstellung der Erfindung Detailed description of the invention
Die erfindungsgemäß bereitgestellten Darreichungsformen enthalten eine oder mehrere stark lipophile physiologisch aktive Substanzen. The dosage forms provided according to the invention contain one or more highly lipophilic physiologically active substances.
Eine Substanz ist stark lipophil, wenn sie einen log P von 4 oder mehr aufweist. Der log P ist der dekadische Logarithmus des n-Octanol/Wasser-Verteilungskoeffizienten. Der Verteilungskoeffizient kann experimentell ermittelt werden. Werte beziehen sich typischerweise auf Raumtemperatur (25°C). Der Verteilungskoeffizient kann auch näherungsweise aus der Molekülstruktur errechnet werden. Die erfindungsgemäßen Pellets eignen sich besonders für physiologisch aktive Substanzen mit einem log P von 5 oder mehr und ganz besonders für solche mit einem log P von 6 oder mehr. A substance is highly lipophilic if it has a log P of 4 or more. The log P is the decadic logarithm of the n-octanol / water partition coefficient. The distribution coefficient can be determined experimentally. Values typically refer to room temperature (25 ° C). The distribution coefficient can also be calculated approximately from the molecular structure. The pellets according to the invention are particularly suitable for physiologically active substances with a log P of 5 or more and very particularly for those with a log P of 6 or more.
Der Begriff „physiologisch aktive Substanz“ bezieht sich auf eine Substanz, die einem Menschen oder einem Tier verabreicht wird, um eine Wirkung im menschlichen oder tierischen Körper zu entfalten. Die physiologisch aktive Substanz kann beispielsweise ein pharmazeutischer Wrkstoff eines Human- oder Tierarzneimittels oder ein Nahrungsergänzungsmittel sein. The term “physiologically active substance” refers to a substance that is administered to a human or an animal in order to develop an effect in the human or animal body. The physiologically active substance can, for example, be a pharmaceutical active ingredient of a human or veterinary medicinal product or a food supplement.
Ein Beispiel für stark lipophile pharmazeutische Wrkstoffe, die erfindungsgemäß verwendet werden können, sind Cannabinoide. An example of highly lipophilic pharmaceutical active ingredients that can be used according to the invention are cannabinoids.
Bei den Cannabinoiden kann es sich sowohl um Phytocannabinoide als auch um synthetische Cannabinoide handeln. The cannabinoids can be both phytocannabinoids and synthetic cannabinoids.
Die Phytocannabinoide sind eine Gruppe von etwa 70 terpenophenolischen Verbindungen (V.R. Preedy (Hrsg.), Handbook of Cannabis and Related Pathologies (1997)). Diese Verbindungen enthalten typischerweise einen Monoterpenrest, der an einen Phenolring gebunden ist und eine Cs-Cs-Alkylkette aufweist, die sich in der meta- Position zur phenolischen Hydroxylgruppe befindet. The phytocannabinoids are a group of about 70 terpenophenolic compounds (V.R. Preedy (Ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene residue attached to a phenolic ring and having a Cs-Cs alkyl chain that is in the meta position to the phenolic hydroxyl group.
Eine bevorzugte Gruppe von Cannabinoiden sind Tetrahydrocannabinole der folgenden allgemeinen Formel (1): worin R ausgewählt ist aus CrC2o-Alkyl, C2-C2o-Alkenyl oder C2-C2o-Alkinyl und optional einen oder mehrere Substituenten aufweist. A preferred group of cannabinoids are tetrahydrocannabinols of the following general formula (1): wherein R is selected from C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl and optionally has one or more substituents.
In einerweiter bevorzugten Gruppe von Verbindungen der vorstehenden allgemeinen Formel (1) ist R ausgewählt aus CrCio-Alkyl oder C2-Cio-Alkenyl und weist optional einen oder mehrere Substituenten auf. In a further preferred group of compounds of the general formula (1) above, R is selected from C 1 -C 10 -alkyl or C 2 -C 10 -alkenyl and optionally has one or more substituents.
Insbesondere ist R in der Formel (1) ein Alkylrest der Formel CsHu. In particular, R in the formula (1) is an alkyl radical of the formula CsHu.
Verbindungen der allgemeinen Formel (1) können in Form von Stereoisomeren vorliegen. Vorzugsweise weisen die Zentren 6a und 10a jeweils die R-Konfiguration auf. Bei dem Tetrahydrocannabinol handelt es sich insbesondere um A9-THC mit dem chemischen Namen (6aR, 10aR)-6,6,9-T rimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H- benzo[c]chromen-1-ol. Die Struktur wird durch die nachstehende Formel (2) wiedergegeben: Compounds of the general formula (1) can exist in the form of stereoisomers. The centers 6a and 10a preferably each have the R configuration. The tetrahydrocannabinol is in particular A9-THC with the chemical name (6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8, 10a-tetrahydro-6H-benzo [c] chromene-1-ol. The structure is represented by the following formula (2):
Eine weitere bevorzugte Gruppe von Cannabinoiden sind Cannabidiole der folgenden allgemeinen Formel (3): worin R ausgewählt ist aus Ci-C2o-Alkyl, C2-C2o-Alkenyl oder C2-C2o-Alkinyl und optional einen oder mehrere Substituenten aufweist. Another preferred group of cannabinoids are cannabidiols of the following general formula (3): wherein R is selected from Ci-C2o-alkyl, C2-C2o-alkenyl or C2-C2o-alkynyl and optionally has one or more substituents.
In einerweiter bevorzugten Gruppe von Verbindungen der vorstehenden allgemeinen Formel (3) ist R ausgewählt aus CrCio-Alkyl oder C2-Cio-Alkenyl und weist optional einen oder mehrere Substituenten auf. In a further preferred group of compounds of the general formula (3) above, R is selected from C 1 -C 10 -alkyl or C 2 -C 10 -alkenyl and optionally has one or more substituents.
Insbesondere ist R in der Formel (3) ein Alkylrest der Formel CsHu. In particular, R in the formula (3) is an alkyl radical of the formula CsHu.
Bei dem Cannabidiol handelt es sich insbesondere um 2-[1R-3-Methyl-6R-(1- methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol. The cannabidiol is in particular 2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol.
Erfindungsgemäß kann als Wirkstoff auch eine Kombination aus um A9-THC ((6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol) und CBD (2-[1R-3-Methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3- benzenediol) verwendet werden. According to the invention, a combination of A9-THC ((6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo [c] chromene-1 -ol) and CBD (2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol) can be used.
Eine weitere bevorzugte Gruppe von Cannabinoiden sind Cannabinole der folgenden allgemeinen Formel (4): worin R ausgewählt ist aus CrC2o-Alkyl, C2-C2o-Alkenyl oder C2-C2o-Alkinyl und optional einen oder mehrere Substituenten aufweist. Another preferred group of cannabinoids are cannabinols of the following general formula (4): wherein R is selected from C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl and optionally has one or more substituents.
In einerweiter bevorzugten Gruppe von Verbindungen der vorstehenden allgemeinen Formel (4) ist R ausgewählt aus CrCio-Alkyl oder C2-Cio-Alkenyl und weist optional einen oder mehrere Substituenten auf. In a further preferred group of compounds of the general formula (4) above, R is selected from C1-Cio-alkyl or C2-Cio-alkenyl and optionally has one or more substituents.
Insbesondere ist R in der Formel (4) ein Alkylrest der Formel CsHu. In particular, R in the formula (4) is an alkyl radical of the formula CsHu.
Bei dem Cannabinol handelt es sich insbesondere um 6,6,9-Trimethyl-3-pentyl-6/-/- dibenzo[b,c]pyran-1-ol. The cannabinol is in particular 6,6,9-trimethyl-3-pentyl-6 / - / - dibenzo [b, c] pyran-1-ol.
Erfindungsgemäß können auch Cannabinoide oder Cannabinoid-Gemische aus Hanfextrakten verwendet werden. According to the invention, cannabinoids or cannabinoid mixtures from hemp extracts can also be used.
Beispielsweise ist Nabiximols eine als Arzneistoff verwendete Pflanzenextraktmischung aus den Blättern und Blüten der Hanfpflanze (Cannabis sativa L.) mit standardisierten Gehalten an Tetrahydrocannabinol (THC) und Cannabidiol (CBD). For example, Nabiximols is a plant extract mixture used as a medicinal substance from the leaves and flowers of the hemp plant (Cannabis sativa L.) with standardized levels of tetrahydrocannabinol (THC) and cannabidiol (CBD).
Es können auch synthetische Cannabinoide verwendet werden. Synthetic cannabinoids can also be used.
Dazu gehört 3-(1 , 1-Dimethylheptyl)-6,6a,7,8, 10, 10a-hexahydro-1 -hydroxy-6,6-dimethyl- 9/-/-dibenzo[ö,c(]pyran-9-on. Diese Verbindung enthält zwei stereogene Zentren. Der Arzneistoff Nabilon ist ein 1:1-Gemisch (Racemat) aus der (6aR,10aR)-Form und der (6aS,10aS)-Form. Nabilon ist ein erfindungsgemäß bevorzugtes Cannabinoid. This includes 3- (1,1-dimethylheptyl) -6,6a, 7,8, 10, 10a-hexahydro-1-hydroxy-6,6-dimethyl- 9 / - / - dibenzo [ö, c (] pyran- 9-one. This compound contains two stereogenic centers. The drug nabilone is a 1: 1 mixture (racemate) of the (6aR, 10aR) form and the (6aS, 10aS) form. Nabilone is a cannabinoid which is preferred according to the invention.
Ein weiteres Beispiel für ein synthetisches Cannabinoid ist JWH-018 (1-Naphthyl-(1- pentylindol-3-yl)methanon. Another example of a synthetic cannabinoid is JWH-018 (1-naphthyl- (1-pentylindol-3-yl) methanone.
Eine oder mehrere stark lipophile physiologisch aktive Substanzen, wie ein oder mehrere pharmazeutische Wirkstoffe, wie Cannabinoide, sind erfindungsgemäß in einer Matrix enthalten. Die Matrix enthält vorzugsweise keine weiteren physiologisch aktiven Substanzen. According to the invention, one or more highly lipophilic physiologically active substances, such as one or more pharmaceutical active ingredients such as cannabinoids, are contained in a matrix. The matrix preferably does not contain any further physiologically active substances.
Die Matrix enthält ein oder mehrere wasserlösliche Bindemittel. Bei diesen Bindemitteln handelt es sich um polymere filmbildende Substanzen. Beispiele für geeignete wasserlösliche Bindemittel sind Methylcellulose (MC), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), Hydroxyethylcellulose (HEC), Natrium-Carboxymethylcellulose (Na-CMC) und Polyvinylpyrrolidon (PVP). The matrix contains one or more water-soluble binders. These binders are polymeric film-forming substances. Examples of suitable water-soluble binders are methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (Na-CMC) and polyvinylpyrrolidone (PVP).
Bevorzugt ist Hydroxypropylmethylcellulose (HPMC), insbesondere niedrigviskose HPMC, wie HPMC mit einer Viskosität einer 2% (Gew./Gew.) wässrigen Lösung bei 20°C von 6 mPa-s oder weniger. Hydroxypropylmethylcellulose (HPMC) is preferred, in particular low-viscosity HPMC, such as HPMC with a viscosity of a 2% (w / w) aqueous solution at 20 ° C. of 6 mPa · s or less.
Eine HPMC mit einer Viskosität einer 2% (Gew./Gew.) wässrigen Lösung bei 20°C von 3 mPa s, wie sie unter der Handelsbezeichnung Pharmacoat® 603 verfügbar ist, ist besonders bevorzugt. A HPMC with a viscosity of a 2% (wt./wt.) Aqueous solution at 20 ° C of 3 mPa s, as it is available under the trade name Pharmacoat ® 603 is especially preferred.
Die Matrix aus einer oder mehreren stark lipophilen physiologisch aktiven Substanzen und einem oder mehreren wasserlöslichen Bindemitteln kann weitere übliche Hilfsstoffe, wie einen oder mehrere Füll- oder Trägerstoffe, enthalten. Die Menge der weiteren Hilfsstoffe ist erfindungsgemäß auf nicht mehr als 20 Gew.-%, bezogen auf das Gewicht aller Komponenten, begrenzt. Vorzugsweise sind nicht mehr als 10 Gew.-%, bezogen auf das Gewicht aller Komponenten, an weiteren Hilfsstoffen enthalten. The matrix of one or more highly lipophilic physiologically active substances and one or more water-soluble binders can contain other customary auxiliaries, such as one or more fillers or carriers. According to the invention, the amount of further auxiliaries is limited to not more than 20% by weight, based on the weight of all components. It preferably does not contain more than 10% by weight, based on the weight of all components, of further auxiliaries.
In einer besonders bevorzugten Ausführungsform besteht die Matrix aus stark lipophiler physiologisch aktiver Substanz/stark lipophilen physiologisch aktiven Substanzen und Bindemittel(n), beispielsweise aus Cannabinoid(en) und Bindemittel(n). In a particularly preferred embodiment, the matrix consists of strongly lipophilic physiologically active substance / strongly lipophilic physiologically active substances and binding agent (s), for example cannabinoid (s) and binding agent (s).
Die Matrix enthält ein oder mehrere wasserlösliche Bindemittel, bezogen auf die Gesamtmenge an stark lipophilen physiologisch aktiven Substanzen, in einem Gesamtanteil von 0,1 - 10 Gew.-%, vorzugsweise in einem Gesamtanteil von 0,5 - 8 Gew.-% und insbesondere in einem Gesamtanteil von 1 - 6 Gew.-% enthält. The matrix contains one or more water-soluble binders, based on the total amount of highly lipophilic physiologically active substances, in a total proportion of 0.1-10% by weight, preferably in a total proportion of 0.5-8% by weight and in particular contains in a total proportion of 1 - 6 wt .-%.
Es wird angenommen, dass bei einer zu geringen Menge an wasserlöslichem Bindemittel die Freisetzung nur sehr langsam und unvollständig erfolgt. Durch Wahl des Anteils in den angegebenen Bereichen kann die Freisetzung der physiologisch aktiven Substanz eingestellt werden. Beispielsweise kann die Freisetzung aus einer oralen Darreichungsform so eingestellt werden, dass die physiologisch aktive Substanz über die übliche Zeit der Magen-Darm-Passage abgegeben wird. It is assumed that if the amount of water-soluble binder is too small, the release takes place only very slowly and incompletely. The release of the physiologically active substance can be adjusted by choosing the proportion in the specified ranges. For example, the release from an oral dosage form can be adjusted so that the physiologically active substance is released over the usual time of gastrointestinal passage.
Die erfindungsgemäße feste orale Darreichungsform, die eine Matrix mit einer oder mehreren stark lipophilen physiologisch aktiven Substanzen aufweist, kann in beliebiger Form bereitgestellt und verwendet werden. Beispielsweise kann die Darreichungsform in Form eines Granulats, von Matrixpellets oder von Matrixtabletten bereitgestellt werden oder eine dieser Formen enthalten. The solid oral dosage form according to the invention, which has a matrix with one or more highly lipophilic physiologically active substances, can be provided and used in any form. For example, the dosage form can be provided in the form of granules, matrix pellets or matrix tablets or contain one of these forms.
Die Herstellung kann auf an sich bekannte Weise erfolgen. In einer bevorzugten Ausführungsform enthält die Darreichungsform Matrixpellets. The production can take place in a manner known per se. In a preferred embodiment, the dosage form contains matrix pellets.
Die Matrixpellets haben typischerweise eine Größe im Bereich von 30 bis 1800 pm, wobei die Größe durch Siebanalyse bestimmt werden kann. The matrix pellets typically have a size in the range from 30 to 1800 μm, and the size can be determined by sieve analysis.
Die Matrixellets können als orale Darreichungsform verwendet werden, wobei sie z.B. in Sachets angeboten werden, oder sie können weiterverarbeitet werden. The matrix pellets can be used as an oral dosage form, e.g. being offered in sachets, or they can be further processed.
Beispielsweise können die Matrixpellets mit einem oder mehreren weiteren Überzügen versehen werden. Damit ist eine zusätzliche Steuerung der Freisetzung möglich. For example, the matrix pellets can be provided with one or more additional coatings. This enables additional control of the release.
In einer bevorzugten Ausführungsform ist kein Überzug vorgesehen, der die Freisetzung steuert. In a preferred embodiment, no coating is provided that controls the release.
Die Matrixpellets können auch verwendet werden, um multipartikuläre Darreichungsformen zu erhalten. Sie können in Kapseln gefüllt oder in Tabletten eingearbeitet werden. The matrix pellets can also be used to obtain multiparticulate dosage forms. They can be filled into capsules or incorporated into tablets.
Matrixpellets mit unterschiedlichen Freisetzungsprofilen können in einer Darreichungsform (Kapsel/Tablette/Sachet) kombiniert werden. Matrix pellets with different release profiles can be combined in one dosage form (capsule / tablet / sachet).
Die erfindungsgemäßen oralen Darreichungsformen setzen die enthaltene stark lipophile physiologisch aktive Substanz oder, falls mehr als eine stark lipophile physiologisch aktive Substanz enthalten ist, sämtliche enthaltenen stark lipophilen physiologisch aktiven Substanzen nach Einnahme im Verdauungstrakt frei. Die Darreichungsformen dienen insbesondere der kontrollierten Freisetzung. Insbesondere setzen sie mehr als 30 Gew.-% und weniger als 80 Gew.-% der enthaltenen physiologisch aktiven Substanz innerhalb von zwei Stunden frei. Weiterhin setzen sie insbesondere mehr als 40 Gew.-% und weniger als 90 Gew.-% der enthaltenen physiologisch aktiven Substanz innerhalb von drei Stunden frei. Darüber hinaus setzen sie mehr als 50 Gew.-% und weniger als 95 Gew.-% der enthaltenen physiologisch aktiven Substanz innerhalb von vier Stunden frei. Falls mehr als eine physiologisch aktive Substanz enthalten ist, beziehen sich die Angaben auf sämtliche enthaltenen Substanzen. The oral dosage forms according to the invention release the strongly lipophilic physiologically active substance contained therein or, if more than one strongly lipophilic physiologically active substance is contained, release all the strongly lipophilic physiologically active substances contained in the digestive tract after ingestion. The dosage forms are used in particular for controlled release. In particular, they release more than 30% by weight and less than 80% by weight of the physiologically active substance contained within two hours. Furthermore, they release in particular more than 40% by weight and less than 90% by weight of the physiologically active substance contained within three hours. In addition, they release more than 50% by weight and less than 95% by weight of the physiologically active substance contained within four hours. If it contains more than one physiologically active substance, the information relates to all substances contained.
Die Bestimmung der Freisetzung erfolgt dabei jeweils in einer Blattrührer- Apparatur in 1000 ml Phosphatpuffer pH 6.8 mit einem Zusatz an 0.4 % Tween® 80 bei 37° C. The determination of the release takes place in each case in a Blattrührer- apparatus in 1000 ml phosphate buffer pH 6.8 with an addition of 0.4% Tween ® 80 at 37 ° C.
Beispiele Die nachstehenden Beispiele zeigen, wie durch Einsatz einer wasserlöslichen filmbildenden Substanz die Freisetzung einer stark lipophilen physiologisch aktiven Substanz gesteuert werden kann. Examples The following examples show how the release of a highly lipophilic physiologically active substance can be controlled by using a water-soluble film-forming substance.
Beispiel 1 - Herstellung von Pellets Example 1 - Making Pellets
Es wurden Pellets unter Verwendung der in der nachstehenden Tabelle 1 angegebenen Mengen an Inhaltsstoffen hergestellt. Pellets were made using the amounts of ingredients shown in Table 1 below.
Dazu wurde 2-[1 R-3-Methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1 ,3- benzenediol (Canapure PH) in Ethanol 96% gelöst. Dieser Wirkstoff weist einen log P von etwa 6,1 auf. For this purpose, 2- [1 R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol (Canapure PH) was dissolved in 96% ethanol. This active ingredient has a log P of about 6.1.
Eine weitere Lösung wurde hergestellt, indem HPMC (Pharmacoat® 603) in Wasser gelöst wurde. Another solution was made by dissolving HPMC (Pharmacoat ® 603) in water.
Anschließend wurde die HPMC-Lösung schrittweise zu der Cannabidiol-Lösung gegeben. The HPMC solution was then gradually added to the cannabidiol solution.
Dann wurde amorphes Siliciumdioxid (Syloid® 244 FP) zugefügt. Then, amorphous silica (Syloid ® 244 FP) was added.
Es wurde jeweils mit einem Propellerrüher gerührt. It was stirred with a propeller stirrer in each case.
Die erhaltene Sprühflüssigkeit wurde auf Starterkerne aus mikrokristalliner Cellulose (Cellets® 500) aufgesprüht. The spray liquid obtained was sprayed onto starter cores made of microcrystalline cellulose (Cellets ® 500).
Dies erfolgte in einer Wirbelschichtanlage vom Typ Mini-Glatt mit einem Wurster-Einsatz. Dabei betrug die Lufteinlasslufttemperatur 40°C. Die mittlere Sprührate betrug 0,5 g/min. This took place in a fluidized bed system of the Mini-Glatt type with a Wurster insert. At this time, the air inlet air temperature was 40 ° C. The mean spray rate was 0.5 g / min.
Tabelle 1 - Eingesetzte Stoffe und Mengen Tabelle 2 - Produkte Table 1 - Substances and quantities used Table 2 - Products
Beispiel 2 - Freisetzung Example 2 - release
Die Freisetzung aus den in Beispiel 1 erhaltenen Pelletprodukten wird unter Verwendung einer Blattrührer-Apparatur in 1000 ml Phosphatpuffer pH 6.8 mit einem Zusatz an 0.4 % Tween® 80 untersucht, und zwar bei 37° C. Die erhaltenen Ergebnisse sind in Fig. 1 gezeigt. The release from the results obtained in Example 1 pellet products is examined using a blade stirrer apparatus in 1000 ml phosphate buffer pH 6.8 with an addition of 0.4% Tween ® 80, namely at 37 ° C. The results obtained 1 are shown in Fig..

Claims

Patentansprüche Claims
1. Feste Darreichungsform, die eine Matrix mit einer oder mehreren stark lipophilen physiologisch aktiven Substanzen, einem oder mehreren wasserlöslichen Bindemitteln und nicht mehr als 20 Gew.-%, bezogen auf das Gewicht aller Komponenten, an weiteren Hilfsstoffen aufweist, wobei eine physiologisch aktive Substanz stark lipophil ist, wenn sie einen log P von 4 oder mehr hat. 1. Solid dosage form which has a matrix with one or more highly lipophilic physiologically active substances, one or more water-soluble binders and not more than 20% by weight, based on the weight of all components, of further excipients, one physiologically active substance is highly lipophilic if it has a log P of 4 or more.
2. Darreichungsform nach Anspruch 1, wobei als stark lipophile physiologisch aktive Substanzen ein oder mehrere stark lipophile pharmazeutische Wirkstoffe enthalten sind. 2. Dosage form according to claim 1, wherein the highly lipophilic physiologically active substances contain one or more highly lipophilic pharmaceutical active ingredients.
3. Darreichungsform nach Anspruch 2, wobei als stark lipophile Wirkstoffe ein oder mehrere Cannabinoide enthalten sind. 3. Dosage form according to claim 2, wherein one or more cannabinoids are contained as highly lipophilic active ingredients.
4. Darreichungsform nach Anspruch 3, wobei ein oder mehrere Cannabinoide enthalten sind, die ausgewählt sind aus Verbindungen einer der folgenden allgemeinen Formeln (1), (3) oder (4): worin R jeweils ausgewählt ist aus CrC2o-Alkyl, C2-C2o-Alkenyl oder C2-C2o-Alkinyl und optional einen oder mehrere Substituenten aufweist; 4. Dosage form according to claim 3, wherein one or more cannabinoids are included, which are selected from compounds of one of the following general formulas (1), (3) or (4): wherein R is in each case selected from C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl and optionally has one or more substituents;
Cannabinoiden oder Cannabinoid-Gemischen aus Hanfextrakten, wie Nabiximols; und synthetischen Cannabinoiden, wie Nabilon oder 1-Naphthyl-(1-pentylindol-3- yl)methanon. Cannabinoids or cannabinoid mixtures from hemp extracts, such as nabiximols; and synthetic cannabinoids such as nabilone or 1-naphthyl- (1-pentylindol-3-yl) methanone.
5. Darreichungsform nach Anspruch 4, wobei es sich bei dem Cannabinoid um 2- [1R-3-Methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; 5. Dosage form according to claim 4, wherein the cannabinoid is 2- [1R-3-methyl-6R- (1-methylethenyl) -2-cyclohexen-1-yl] -5-pentyl-1,3-benzenediol;
(6aR, 10aR)-6,6,9-T rimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H-benzo[c]chromen-1-ol oder ein Gemisch davon handelt. (6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8, 10a-tetrahydro-6H-benzo [c] chromen-1-ol or a mixture thereof.
6. Darreichungsform nach einem der vorstehenden Ansprüche, wobei als wasserlösliches Bindemittel Hydroxypropylmethylcellulose (HPMC) eingesetzt wird. 6. Dosage form according to one of the preceding claims, wherein hydroxypropylmethylcellulose (HPMC) is used as the water-soluble binder.
7. Darreichungsform nach Anspruch 6, wobei die HPMC eine Viskosität von 6 mPa-s oder weniger in einer 2% (Gew./Gew.) wässrigen Lösung bei 20°C aufweist. 7. Dosage form according to claim 6, wherein the HPMC has a viscosity of 6 mPa · s or less in a 2% (w / w) aqueous solution at 20 ° C.
8. Darreichungsform nach einem der vorstehenden Ansprüche, wobei das Bindemittel/die Bindemittel, bezogen auf die Gesamtmenge an stark lipophilen physiologisch aktiven Substanzen, in einem Gesamtanteil von 0,3 - 10 Gew.-%, vorzugsweise in einem Gesamtanteil von 0,5 - 8 Gew.-% und insbesondere in einem Gesamtanteil von 1 - 6 Gew.-%, enthalten ist/sind. 8. Dosage form according to one of the preceding claims, wherein the binder (s), based on the total amount of highly lipophilic physiologically active substances, in a total proportion of 0.3-10% by weight, preferably in a total proportion of 0.5- 8% by weight and in particular in a total proportion of 1 to 6% by weight.
9. Darreichungsform nach einem der vorstehenden Ansprüche, die in Form eines Granulats, von Matrixpellets oder von Matrixtabletten bereitgestellt wird oder eine dieser Formen enthält. 9. Dosage form according to one of the preceding claims, which is provided in the form of granules, matrix pellets or matrix tablets or contains one of these forms.
10. Darreichungsform nach Anspruch 9, wobei die Darreichungsform Matrixpellets enthält. 10. The dosage form according to claim 9, wherein the dosage form contains matrix pellets.
11. Darreichungsform nach Anspruch 10, wobei die Matrixpellets eine Größe im Bereich von 30 bis 1800 pm, bestimmt durch Siebanalyse, aufweisen. 11. Dosage form according to claim 10, wherein the matrix pellets have a size in the range from 30 to 1800 μm, determined by sieve analysis.
12. Darreichungsform nach einem der vorstehenden Ansprüche, die mehr als 30 Gew.-% und weniger als 80 Gew.-% der enthaltenen physiologisch aktiven Substanz/der enthaltenen physiologisch aktiven Substanzen innerhalb von zwei Stunden freisetzen. 12. Dosage form according to one of the preceding claims, which release more than 30 wt .-% and less than 80 wt .-% of the contained physiologically active substance / the contained physiologically active substances within two hours.
13. Darreichungsform nach Anspruch 12, die mehr als 40 Gew.-% und weniger als 90 Gew.-% der enthaltenen physiologisch aktiven Substanz/der enthaltenen physiologisch aktiven Substanzen innerhalb von drei Stunden freisetzen. 13. Dosage form according to claim 12, which release more than 40 wt .-% and less than 90 wt .-% of the contained physiologically active substance / the contained physiologically active substances within three hours.
14. Darreichungsform nach Anspruch 13, die mehr als 50 Gew.-% und weniger als 95 Gew.-% der enthaltenen physiologisch aktiven Substanz/der enthaltenen physiologisch aktiven Substanzen innerhalb von vier Stunden freisetzen. 14. Dosage form according to claim 13, which release more than 50 wt .-% and less than 95 wt .-% of the contained physiologically active substance / the contained physiologically active substances within four hours.
EP20800800.3A 2019-10-16 2020-10-16 Controlled release formulations of highly lipophilic physiologically active substances Pending EP4045014A1 (en)

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