Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
  • C07C67/62—Use of additives, e.g. for stabilisation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/14—All rings being cycloaliphatic
  • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms

Definitions

• the invention relates to a method for slowing the speed of the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S- petasin, especially in extracts from plants of the genus Petasites, preferably Petasites hybridus (L.) Gaertner, Meyer & Scherb, by the addition of at least one suitable stabilizer and/or the removal of at least one destabilizing substance, and to stabilized extracts, and stabilized pharmaceutical formulations comprising said stabilized extracts or their active ingredients.
• Extracts from plants of the genus Petasites are well-known drugs for the treatment of various diseases (cf. e.g. EP0281656B1) including allergic and/or inflammatory diseases, e.g. seasonal allergic rhinitis (hay fever), perennial allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease (COPD), asthma, and gastrointestinal diseases; and migraine.
• diseases e.g. seasonal allergic rhinitis (hay fever), perennial allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease (COPD), asthma, and gastrointestinal diseases; and migraine.
• COPD chronic obstructive pulmonary disease
• asthma chronic obstructive pulmonary disease
• migraine migraine
• Tesalin® which is obtained by extraction with carbon dioxide (CO 2 ) in a subcritical state as described in European patent EP 1023079B 1.
• the main active ingredients of said drugs are petasin of the below formula I, neopeta
• said drugs comprise low amounts of sulfur-containing petasins (S-petasins), wherein the sulfur atom is incorporated in the ester moiety of the petasins, i.e. S-petasin of the below formula IV, neo-S-petasin and iso-S-petasin.
• S-petasins sulfur-containing petasins
• freshly prepared extracts from Petasites hybridus contain petasin as main active ingredient besides about one third to one fourth - relative to the amount of petasin - of neopetasin and isopetasin, together with minor amounts of S-, neo-S-, and iso- S-petasins.
• the extent of stabilization is linked to the amount of stabilizer relative to the amount of native extract, as has been shown in case of the stabilizer n-hexadecanol.
• the best stabilization is achieved when the amount by weight of the stabilizer is 1 to lOfold, especially 2-8fold, preferably 3-6fold, e.g. about 4fold the amount by weight of the native extract.
• some stabilization effect although usually not the best stabilization effect, occurs also when the amount by weight of the stabilizer is inferior, e.g. down to about one fourth, to the amount by weight of the native extract.
• the invention relates to a method for slowing the speed of the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S- petasin by the addition of at least one suitable stabilizer, preferably a stabilizer described herein above or below, and/or the complete or partial removal of at least one destabilizing substance, like preferably a fatty acid in free or bound form, especially in free form.
• suitable stabilizer preferably a stabilizer described herein above or below
• at least one destabilizing substance like preferably a fatty acid in free or bound form, especially in free form.
• the fatty acids those in free form are considered to have the main destabilizing effect. However, it can not be excluded that free fatty acids are generated by hydrolysis of bound fatty acids.
• the speed of the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S-petasin in extracts from plants of the genus Petasites can not only be slowed down by the addition of at least one suitable stabilizer, but also by the removal of at least one destabilizing substance.
• At least 50 %, especially more than 60, 70, 80 or 90 %, preferably more than 95 % and most preferably essentially all of the destabilizing substances are removed.
• Fatty acids have been identified as destabilizing substances as shown in Examples 7 and 8 of the present application. In contrast thereto, acetic acid does not appear to have a significant destabilizing effect.
• Fatty acids are aliphatic monocarboxylic acids which are present, including the presence in a bound form, e.g. an esterified form, e.g. in the form of triglycerides or phospholipids, in an animal or vegetable fat, oil, or wax.
• Natural fatty acids commonly have a chain of four to 28, especially 8 to 28 carbons (usually unbranched and even numbered), which may be saturated or unsaturated.
• the presence of fatty acids, like especially palmitic acid, in free form in the CO 2 extract from Petasites hybridus plants has been verified for the purposes of the present patent application by means of qualitative thin layer chromatography.
• the invention relates also to a method wherein at least one destabilizing substance is removed from an extract from plants of the genus Petasites, and to a process for removing from an extract from plants of the genus Petasites at least one substance promoting the isomerisation of petasin and neopetasin to isopetasin, by adding to said extract a suitable organic solvent which is immiscible or at most slightly miscible with water, like a suitable ether, e.g. diisopropylether, and a diluted aqueous solution of a suitable base, e.g.
• the fatty acids may be removed as follows:
• the native carbon dioxide extract is dissolved in a suitable solvent, e.g. an inert hydrophobic solvent, like especially a suitable hydrocarbon solvent, like a saturated aliphatic hydrocarbon solvent, like especially hexane, e.g. n-hexane.
• a suitable anion exchanger especially a slightly alkaline/weakly basic anion exchanger, like Lewatit® MP 62 (supplied by LANXESS Germany GmbH, Leverkusen, Germany).
• Lewatit® MP 62 supplied by LANXESS Germany GmbH, Leverkusen, Germany.
• the ion exchanger removes all organic, but not anorganic acids.
• the present invention relates also to a process for at least partial, but preferably essentially complete removal of all fatty acids from an extract from plants of the genus Petasites, especially Petasites hybridus, in a manner known known to a person skilled in the art, i.e. preferably by means of a suitable ion exchanger.
• the present invention relates also to a process for removing from an extract from plants of the genus Petasites at least one fatty acid, i.e.
• fatty acids preferably all fatty acids, promoting the isomerisation of petasin and neopetasin to isopetasin by passing a solution comprising said extract through a suitable weakly alkaline ion exchanger, or by neutralizing said fatty acid with a suitable base and extracting it with water.
• the extract may be dissolved in a solvent which is immiscible or at most slightly miscible with water, like a suitable ether, e.g. diisopropylether.
• a suitable ether e.g. diisopropylether.
• a diluted aqueous solution of a suitable base e.g. 0.1 molar aqueous sodium hydroxide solution, is added in an amount sufficient to neutralize the fatty acids present in said extract.
• the present invention relates also to an extract from plants of of the genus Petasites, especially Petasites hybridus, which contains a stabilizer as defined herein and/or wherein the amount of fatty acids has been reduced below 50 % of the natural occurrence in the extract.
• the present invention relates also to an extract from plants of the genus Petasites, especially Petasites hybridus, obtainable by the above purification process, to an extract from plants of the genus Petasites stabilized by a stabilizer, preferably a stabilizer as defined below, slowing the speed of the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S-petasin, and to a method for slowing the speed of the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S-petasin, preferably in an extract from plants of the genus Petasites, by the addition of at least one suitable stabilizer and/or the removal of at least one destabilizing substance.
• a suitable stabilizer is preferably selected from a) a compound of formula I
• Alkyl having up to 30 carbon atoms is straight-chain or branched alkyl having 1 to 30, preferably 1-22, especially 3-22 carbon atoms.
• Alkyl wherein one or more non-adjacent carbon atoms may be replaced by oxygen is e.g. ethoxyethyl.
• a compound of the formula I wherein R 1 represents cycloalkyl is e.g. cyclohexanol.
• a compound of the formula I wherein R 1 represents phenyl is e.g. phenol or benzylalcohol.
• a compound of the formula I wherein R 1 represents phenoxymethyl is e.g. 2- phenoxyethanol.
• a glycol of the formula HO-[CHR 2 -CH 2 -O] m -H, wherein R 2 is hydrogen is e.g. polyethylene glycol wherein m is the number of ethylene oxide units.
• polyethylene glycols the term "PEG” is used in combination with a numerical value (e.g. PEG 4000) which, within the pharmaceutical industry, indicates the mean molecular weight.
• PEG 4000 a numerical value
• the various pharmacopeias use different nomenclature for some PEG molecular weights.
• the molecular weights cited herein are in accordance with the European (2002) and US pharmacopeias. PEGs can be obtained for example from the company Clariant, Basle, Switzerland.
• the invention relates also to the use of an above-mentioned stabilizer for slowing down the isomerisation of petasin and neopetasin to isopetasin, and the isomerisation of S-petasin and neo-S-petasin to iso-S-petasin, preferably in an extract from plants of the genus Petasites, especially Petasites hybridus.
• the invention relates also to a pharmaceutical formulation comprising an effective dose of an extract from plants of the genus Petasites, especially from Petasites hybridus, together with an above-mentioned stabilizer and a pharmaceutical excipient, preferably to such a pharmaceutical formulation wherein at least one destabilizing substance, like especially a fatty acid, has been removed, e.g. as described above, from said extract from plants of the genus Petasites.
• at least 50, 60, 70, 80, 90 or 95 % of the fatty acids, especially those present in free, i.e. non-bound, e.g. non-esterified, form are removed.
• Said formulation may be in liquid or especially in non-liquid form.
• the invention relates especially to such pharmaceutical formulation comprising propylene glycol and/or a hydrogenated plant oil, like hydrogenated ricinus oil.
• the invention relates also to a pharmaceutical formulation comprising an effective dose of petasin, neopetasin, isopetasin or any mixture of those, an above-mentioned stabilizer and a pharmaceutical excipient.
• This kind of formulation is manufactured using pure petasin, pure neopetasin and/or pure isopetasin. Even in this case, the addition of an above- mentioned stabilizer may be meaningful, especially if the pharmaceutical excipient comprises fatty acids in free or bound form, e.g. fatty acid triglycerides.
• the invention relates also to a pharmaceutical formulation comprising petasin, neopetasin and/or isopetasin and a pharmaceutical excipient substantially free from free fatty acids.
• the native extract obtained by extraction with carbon dioxide (CO 2 ) in a subcritical state contains about 25-35%, usually about 30% by weight of petasins.
• the native CO 2 -extract is a very viscous oil. Therefore, in order to enable easier handling, substances like microcrystalline cellulose are added, preferably in a 3 to 4fold excess by weight whereupon a powder is obtained. As has been shown in the Examples the effect of microcrystalline cellulose on the speed of isomerisation is negligibly small.
• the invention relates especially to an above-mentioned pharmaceutical formulation wherein the stabilizer is selected from a) a compound of formula I
• the present invention relates also to pharmaceutical formulations, especially non-liquid formulations, comprising 5-80 %, especially 10-70 %, preferably 15-60%, more preferably 20-50%, e.g. about 25 % by weight of a (optionally purified) Petasites extract together with an above-mentioned stabilizer and a pharmaceutical excipient.
• the pharmaceutical formulations are those for enteral or parenteral administration comprising especially the usual pharmaceutical excipients, and, if desired, a suitable cyclodextrin, e.g. ⁇ - cyclodextrin.
• the daily dose of native extract to be administered to a human adult having about 70 kg of body weight is about 40-100 mg, e.g. about 55 mg.
• the Petasites extract used in the following Examples may be prepared from Petasites hybridus as described in German Offenlegungsschrift DE 19702168Al or preferably by extraction with carbon dioxide in a subcritical state as described in European patent EP 1023079Bl .
• the dry extract obtained from Petasites hybridus after evaporation of the carbon dioxide is designated herein as "native extract”. It contains about 30% by weight of petasins.
• stabilizers In order to assess the effect of certain substances (designated herein as "stabilizers") concerning their ability to hinder or slow the isomerisation to isopetasin said substances may be either added to the native extract (two component mixture) or to a mixture of native extract and microcrystalline cellulose (MCC; three component mixture).
• one part of said two or three component mixtures is frozen at -20 °C and serves for comparison purposes while the other part (“heated part”) is heated at 80 °C for 15 hours and, thereafter, analyzed by gas chromatography (GC) in order to determine the content of the various petasins contained therein expressed as percentage of the respective content (set as 100 %) in the above-mentioned comparison part which has been kept at -20 °C.
• GC gas chromatography
• the gas chromatography (GC) is conducted using a Hewlett Packard 5890 Series 2 or Agilent 6890N instrument, equipped with a flame ionisation detector and a DB - 1 GC- column [i.e. a fused silica capillary GC column supplied by J&W Scientific (Agilent) comprising an amber-brown polyimide exterior coating which protects the tubing from breakage, the fused silica tubing and a stationary phase (consisting of dimethylpoly- siloxane, bonded and crosslinked) which is evenly coated (film thickness: 0.52 ⁇ m) onto the inner wall of the tubing], said column having a length of 25 m and an inside diameter of 0.32 mm, using hydrogen (purity 99.999 %) as carrier gas at a flow of 3 ml/minute at 180°C (pressure: about 70 kPa), and (-)- ⁇ -Santonin as internal standard.
• a fused silica capillary GC column
• the ratio by weight of native extract, microcrystalline cellulose and stabilizer is 1 : 3.75 : 3.75.
• the mixtures are prepared in a mortar, into which first MCC, then the stabilizer and finally the native extract are added, followed by mixing during 5 minutes.
• the thus obtained mixture is separated into two parts, one part (“comparison part") of which is frozen at -20°C and serves for comparison purposes, while the second part is kept at 80°C during 15 hours.
• Poloxamer 188 is a synthetic copolymer of ethyleneoxide and propyleneoxide, i.e. a polyoxyethylene-polyoxypropylene-triblock copolymer.
• the approximate lengths of the two polyethylene glycol blocks is 75 repeat units while the approximate length of the propylene gycol block is 30 repeat units.
• **Poloxamer 407 also known by the BASF trade name Pluronic F 127) is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol.
• the approximate lengths of the two polyethylene glycol blocks is 101 repeat units while the approximate length of the propylene gycol block is 56 repeat units.
• ***Hydrogenated castor oil contains about 80 - 90 % of the triglyceride of ricinolic acid (a linear hydroxy fatty acid)
• the stabilizing effect of stearyl alcohol, i.e. n-octadecanol, and n-hexadecanol is determined analogously as described in Example 1 , by combining the native extract with these stabilizers, but, in contrast to Example 1, without addition of microcrystalline cellulose (MCC), and with the ratio by weight of native extract and stabilizer being 1 :7, i.e. the relative amount by weight of the stabilizer is doubled in comparison to Example 1 in order to "compensate" for the absence of MCC (twice 3.75 is 7).
• MCC microcrystalline cellulose
• Example 3a 1 : 3.75 : 3.75
• Example 3b 1 : 4.69 : 2.81
• Example 3c 1 : 5.63 : 1.88
• Example 3d 1 : 6.56 : 0.94
• Example 3e 1 : 7.00 : 0.50
• Example 3f 1 : 7.25 : 0.25
• Example 3g 1 : 7.50 : 0.00
• the ratio of native extract to stabilizer is varied stepwise very roughly from 1 : 4 to 1 : 0.
• the content by weight of the native extract in the total three component mixtures is kept constant at about 11.8 %.
• Example 4a The stabilizing effect of n-hexadecanol is determined analogously as described in Example 1 with the following exception: Whereas in Example 1 the ratio by weight of native extract, microcrystalline cellulose (MCC) and stabilizer is 1 : 3.75 : 3.75, said ratio is varied in the present Example as follows: Example 4a) 1 : 5.63 : 1.88 Example 4b) 1 : 2.79 : 1.88 Example 4c) 1 : 1.38 : 1.88 Example 4d) 1 : 0.53 : 1.88
• Example 1 The stabilizing effect of various stabilizers is determined analogously as described in Example 1 with the following exception: Whereas in Example 1 the ratio by weight of native extract, microcrystalline cellulose (MCC) and stabilizer is 1 : 3.75 : 3.75, said ratio is used only in Example 6a, but varied in Examples 6b and 6c as follows: Example 6b) 1 : 3.75 : 0.71 Example 6c) 1 : 3.75 : 1.67
• the molar amount of the stabilizers is the same in Examples 6a to 6c.
• Example 6 As evident by comparison with Table 1 (where the stabilizers are used in the same absolute amounts) the stabilizing effect of ethanol is considerably reduced when using the same molar amounts as the other stabilizers. However, this might, in part, be due to the fact that in Example 6 a relatively higher amount of the ethanol is evaporating within the closed vessel into the gaseous phase than for hexadecanol or benzylalcohol in Example 6 and also for ethanol in Example 1.
• Example 7 purification of native extract (inter alia by removal of fatty acids)
• the native extract from Petasites hybridus is split into three parts.
• the first part is kept at - 20 0 C and later serves for comparison purposes.
• the second part (“heated part") is heated at 80 0 C for 15 hours and, thereafter analyzed by gas chromatography (GC) in order to determine the content of neopetasin, petasin, and isopetasin contained therein expressed as percentage of the respective content in the first part (taken as 100 %) which has been kept at -20 0 C.
• GC gas chromatography
• To the third part consisting of 3.0 g of native extract are added 15.6 ml of 0.1 molar aqueous sodium hydroxide solution (i.e.
• a part of the purified extract (comparison part) is frozen, the other part ("heated part") is heated at 80 °C for 15 hours and, thereafter analyzed by gas chromatography (GC) in order to determine the content of neopetasin, petasin, and isopetasin contained therein expressed as percentage of the respective content in the above-mentioned comparison part which has been kept at - 20 °C.
• GC gas chromatography
• the fatty acids may be removed as follows:
• One part by volume of native CO2 extract is dissolved in 3 parts by volume of n-hexane.
• the ion exchanger removes all organic, but not anorganic acids.
• a Stephan mixer i.e. a mixer supplied by the German company Stephan Machinery GmbH.
• Lutrol®F68 (Poloxamer 188; supplied by the German company BASF ; surface active compound; solubilizer; readily water soluble; block polymer of the type ABA, consisting of a central, hydrophobic block of polypropylene oxide, which is edged by two hydrophilic blocks of polyethylene oxide.
• Lutrol®F68 has an average molecular weight of about 8600.
• the polyoxyethylene units represent about 81% of the molecular weight whereas that one of polyoxypropylene stands for about 19 %.) and 360 parts by weight of Lutrol®F127 (Poloxamer 407; supplied by the German company BASF ; surface active compound; solubilizer; readily water soluble; block polymer of the type ABA, consisting of a central, hydrophobic block of polypropylene oxide, which is edged by two hydrophilic blocks of polyethylene oxide.
• Lutrol®F127 has an average molecular weight of about 12200.
• the polyoxyethylene units represent about 73% of the molecular weight whereas that one of polyoxypropylene stands for about 27 %.) are melted at about 75°C and added in portions, i.e. portion-wise, under stirring to the obtained mixture.
• the resulting white granulate is sieved and pressed in a tabletting machine to tablets each of which is weighing 500 mg.

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• 2009
  • 2009-05-23 EP EP09765497A patent/EP2285767A2/en not_active Withdrawn
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