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WO2000029477A1 - Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same - Google Patents

Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same Download PDF

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Publication number
WO2000029477A1
WO2000029477A1 PCT/EP1999/008474 EP9908474W WO0029477A1 WO 2000029477 A1 WO2000029477 A1 WO 2000029477A1 EP 9908474 W EP9908474 W EP 9908474W WO 0029477 A1 WO0029477 A1 WO 0029477A1
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WO
WIPO (PCT)
Prior art keywords
glucan
poly
starch
thermoplastic
polymer
Prior art date
Application number
PCT/EP1999/008474
Other languages
German (de)
French (fr)
Inventor
Holger Bengs
Arnold Schneller
Anette Brunner
Ivan Tomka
Rolf Müller
Original Assignee
Celanese Ventures Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Celanese Ventures Gmbh filed Critical Celanese Ventures Gmbh
Priority to CA002343946A priority Critical patent/CA2343946A1/en
Priority to JP2000582458A priority patent/JP2002530454A/en
Priority to AU15045/00A priority patent/AU1504500A/en
Priority to EP99957283A priority patent/EP1135439A1/en
Priority to KR1020017003849A priority patent/KR20010075375A/en
Publication of WO2000029477A1 publication Critical patent/WO2000029477A1/en
Priority to NO20012429A priority patent/NO20012429D0/en

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0208—Tissues; Wipes; Patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/732—Starch; Amylose; Amylopectin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8135—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid; Compositions of derivatives of such polymers, e.g. vinyl esters (polyvinylacetate)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof

Definitions

  • the present invention relates to poly ( ⁇ -1,4-D-glucan) with a degree of polymerization of at least 40, preferably 50 and more preferably> 60, a thermoplastic polymer mixture containing at least poly ( ⁇ -1,4-D-glucan), a method for producing a thermoplastic polymer mixture and a use of a thermoplastic polymer mixture, at least containing poly ( ⁇ -1, 4-D-glucan) as a carrier matrix for active substances, such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients , and a method for producing an agrochemical, pharmaceutical and / or cosmetic composition.
  • active substances such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients
  • active substances such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients
  • active substances such as pesticides, fungicides, insecticides, herbicide
  • starch in oral, pharmaceutical forms of administration is documented in the Pharmacopea Helvetica, among others.
  • thermoplastic and destructurized starch is described in EP 118 240, EP 304 401, WO 89/12492, WO 90/14938 and US 5, 095, 054.
  • These publications describe the strand or profile extrusion of thermoplastic formulations or polymer mixtures based on starch, plasticizers which are compatible with oral ingestion, such as water and the like, and preferred administration forms being disclosed.
  • the high shear melt viscosity and the pronounced structural viscosity of the starch formulations lead to shear and heat reduction in the administration forms, in particular tablets.
  • the degradation of the starch is mentioned in order to improve the processability.
  • the breakdown of the starch is controlled by heat, hydrogen ions or chloride ions.
  • the resulting thermoplastic formulations are either too brittle or too sticky, depending on the proportion of low molecular weight plasticizers.
  • thermoplastic starch and its production are described in further publications such as WO90 / 05161 and EP 0 479 964.
  • Thermoplastic starch and polymer mixtures thereof have useful mechanical properties, but the processing temperatures are usually all in one Range of approx. 180 - 230 ° C, which is much too high for the processing of a large number of pharmaceutically active substances.
  • the use of thermoplastic starch in the production of pharmaceutical compositions described in EP 0468 003 has not led to the desired success due to the processing temperature being too high.
  • the thermoplastic starch described is largely amorphous, since the starch loses its crystallization potential as a result of the thermomechanical transformation in the manufacturing process of the thermoplastic starch from native starch. Due to the lack of crystalline components, the thermoplastic starch is much too hygroscopic, ie water is absorbed from a humid ambient atmosphere. This is an important one
  • thermoplastically in particular as a thermoplastic carrier substance for active substances - pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceuticals and / or cosmetic active substances - are suitable.
  • Poly ( ⁇ -1,4-D-glucan) with a degree of polymerization of at least approx. 40, preferably at least approx. 50 and more preferably of at least approx. 60 has proven to be suitable for solving the problem , in particular when used in thermoplastic polymer mixtures containing at least the aforementioned poly ( ⁇ -1, 4-D-glucan).
  • Linear poly (-1, 4-D-glucan) s are polysaccharides consisting of glucose monomers, the latter being largely exclusively connected to one another by ⁇ 1,4-glycosidic bonds. The most naturally occurring ⁇
  • amylose is amylose, a component in vegetable starch.
  • linear ⁇ 1, 4-glucans has become more and more important. Due to its physio-chemical properties, amylose can be used to produce films that are colorless, odorless and tasteless, as well as non-toxic and biodegradable. bar.
  • a number of possible applications are already known today, for example in the food industry, the textile industry, the glass fiber industry and in the production of paper.
  • Water-insoluble linear polysaccharides such as the polyglucan proposed according to the invention, such as poly ( ⁇ -1,4-D-glucan) are preferred.
  • the degree of branching in the 6 position is ⁇ 4%, preferably a maximum of 2%, and in particular a maximum of 0.5%, and the degree of branching in the other position not involved in the linear linkage, e.g. the 2- or 3-position, in the case of the preferred poly ( ⁇ -1,4-D-glucan) preferably in each case at most 2%, and in particular at most 1%.
  • poly ( ⁇ -1,4-D-glucan) s which have no branches or whose degree of branching is so minimal that it can no longer be detected using conventional methods.
  • the prefixes “ ⁇ ” or “D” relate solely to the linkages which form the polymer backbone and not to branches.
  • water-insoluble polysaccharides is understood to mean poly ( ⁇ -1,4-D-glucan) s which, according to the definition of the German pharmaceutical book according to classes 4 to 7, belong to the categories “slightly soluble”, “Hardly soluble”, “very poorly soluble” or “practically insoluble” compounds fall.
  • sparingly soluble to practically insoluble compounds especially very sparingly soluble to practically insoluble compounds are preferred, such as e.g. sparingly soluble to practically insoluble poly ( ⁇ -1,4-D-glucan) s with a degree of polymerization> 40, preferably> 50, and even more preferably> 60.
  • Room temperature and separation by centrifugation can be recovered taking into account the experimental losses at least 66% of the amount used.
  • linear poly ( ⁇ -1,4-D-glucan) The production with regard to the isolation of linear poly ( ⁇ -1,4-D-glucan) is described, for example, in WO95 / 31553. Proteins are described which have an enzymatic activity of an amylosucrase which is encoded by a DNA sequence, characterized in one of claims 1 and 2 of the international patent application mentioned. These proteins are suitable for the production of linear poly ( ⁇ -1, 4-D-glucan) s. Other proteins with activity for the synthesis of poly ( ⁇ -1, 4-D-glucan), such as phosphorylases, glycogen synthetases, glucan transferases, starch sythases, are suitable for the production of polyglucans in the sense of the present invention.
  • polyglucans by means of genetically modified organisms such as bacteria, fungi or algae, or higher plants which contain the proteins mentioned, i.e. Phosphorylases, glycogen synthetases, glucan transferases, starch sythases or amylosucrases with the activity for the synthesis of polyglucans preferably contained, suitable.
  • Phosphorylases i.e. Phosphorylases, glycogen synthetases, glucan transferases, starch sythases or amylosucrases with the activity for the synthesis of polyglucans preferably contained, suitable.
  • poly ( ⁇ -1, 4-D-glucan) or also referred to as polyanhydro-D-glucose (PADG) in a range of the degree of polymerization (DP) of approx. 40-300, such as 60-100, for example is preferred, there is a remarkable tendency towards the formation of regular conformation, double helix molecular morphology and a high crystalline fraction detectable by means of nuclear magnetic resonance spectroscopy and X-ray diffraction.
  • the change in crystal structure due to thermal transformation is analogous to that in potato starch.
  • the kinetics of these transformations is faster than that of potato starch.
  • the formation of molecular complexes with suitable low molecular weight Ren mixed components, such as fatty acids, is coupled with the partial conformational conversion to the monohelical V structure, known in the case of amylose, and partially to a secondary unidentified, unknown structure.
  • the ability to form complexes is approximately 3 times higher than that of amylose.
  • the new poly ( ⁇ -1, 4-D-glucan) s combine the ability of the two starch components - amylose and amylopectin - to optionally form regular conformational characteristics characteristic of these two components.
  • the poly ( ⁇ -1,4-D-glucan) s proposed according to the invention advantageously combine the good processability of degraded starch and the desired properties of crystalline starch.
  • the high crystallinity of poly ( ⁇ -1, 4-D-glucan) paired with the low molecular mass of the poly ( ⁇ -1, 4-D-glucan) lead to a structure in which the compound molecules of the crystallites absence.
  • the linking molecules can be introduced by adding thermoplastic starch to the poly ( ⁇ -1, 4-D-glucan).
  • the desired volume fraction ratio of the crystalline and amorphous phase can be adjusted by mixing poly ( ⁇ -1, 4-D-glucan) and thermoplastic starch.
  • Another aspect is the processability of plasticized starch.
  • the ratio between the average degree of polymerization of starch and of poly ( ⁇ -1,4-D-glucan) is preferably at least a power of 10.
  • the limit value of the shear viscosity at a sufficiently low shear rate is called zero
  • Shear viscosity denotes ( ⁇ ( ⁇ ) o, where ⁇ is the viscosity and ⁇ is the shear rate).
  • the zero shear viscosity is proportional to the 3.4th power of the weight average molecular weight.
  • thermoplastic mixtures of one part of poly ( ⁇ -1,4-D-glucan) with 3 parts of thermoplastic starch show a 6 to 7-fold increase in elongation at break and a 2 to 3-fold increase in energy absorption when broken compared to the corresponding values of pure thermoplastic starch.
  • the shear viscosity of the same mixture which is dependent on the shear rate, is a factor 2 lower at the processing temperature of the thermoplastic starch than that of the thermoplastic starch itself.
  • thermoplastic starch The mixture of one part thermoplastic starch and three parts poly ( ⁇ -1, 4-D-glucan) still shows the same energy absorption at break as with thermoplastic starch, but the shear viscosity dependent on the shear rate is more than 10 times lower than that of thermoplastic starch.
  • thermoplastic processability of poly ( ⁇ -1, 4-D-glucan) is an important one
  • thermoplastic poly ( ⁇ -1, 4-D-glucan) mixture supports the control of the release of active ingredients, e.g. drug release; the swelling time, the disintegration time and the dissolution time of these shaped particles define the release time of the active ingredient.
  • the thermoplastic parts or particles made of it must be small enough so that the kinetic process mentioned has a standard deviation that is smaller than the corresponding mean values.
  • the uniform, homogeneous distribution of the active ingredient in the thermoplastic melt can be simplified by counter-rotating twin-screw extruders provided with suitable mixing elements. In conclusion, it can be said that this is now possible since all the necessary requirements have been met:
  • Plasticized poly ( ⁇ -1,4-D-glucan) can be made, for example, by using glycerin as a plasticizer; - Glycerin is on the list of physiologically safe additives for pharmaceutical / pharmaceutical formulations;
  • thermoplastic starch can be reduced by adding poly ( ⁇ -1, 4-D-glucan), at least by 40 ° C.
  • thermoplastic polymer mixture in which the proportion of starch, such as in particular thermoplastic starch, is between 20-80% by weight, based on the proportion of polymer including polyglucan and optionally other thermoplastically processable polymers.
  • thermoplastic is again used
  • Polymer mixture proposed, the proportion of poly ( ⁇ -1,4-D-glucan) being 20-80% by weight, based on the proportion of polymer including the starch and optionally other thermoplastically processable polymers.
  • poly ( ⁇ -1,4-D-glucan) can be mixed with thermoplastic starch according to the present invention and used in particular for the production of a thermoplastic carrier matrix, for example for agrochemical, pharmaceutical and / or cosmetic active ingredients.
  • any biologically active substance and combination of substances in the broadest sense, is regarded as an active substance, preferably pharmaceutical active substances, agrochemical active substances which can be used in agriculture, horticulture and forestry.
  • agrochemical includes fertilizers, herbicides, fungicides, insecticides, pesticides and other pesticides and pesticides, storage protection agents, plant growth and inhibitors, silage additives, preservatives and soil conditioners. Even feed additives, animal hygiene and pharmaceuticals or flavorings and fragrances cannot be excluded.
  • known active substances can be used, as described, for example, by Weed Research 26, 441-445 (1986) or "The Pesticide Manual", Ist edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 1997 and the literature cited therein.
  • Known herbicides which can be added to the active ingredient carrier according to the invention are, for example, the following active ingredients (note: the compounds are either with the "common name” according to the International Organization for Standardization (ISO) or with the chemical name, if necessary (together with a common code number): atrazine; metotachlor; propiconazole; metalaxyl; dicamba (products, brands and trademarks of Novartis); bensulfuron; nicosulfuron; methomyl; flusilazole; benomyl (Du Pont products, brands and trademarks); glyphosate; alachlor; acetochlor; butachlor; triallate (products, brands and trademarks of Monsanto); paraquat; L-cyhalothrin; fluazifop; cypermethrin; EPTC (Zeneca products, brands and trademarks); fenoxaprop; deltametrin; phenmedipham; endosulfan;
  • Rhone Poulenc brands and trademarks of Rhone Poulenc); bentazone; epoxiconazole; sethoxydim; hormones; metazachlor (products, brands and trademarks of BASF); acetochlor; acifluorfen; aclonifen; AKH 7088, ie [[[1- [5- [2-chloro-4- (trifluoromethyl) phenoxyl-2-nitrophenyll-2-methoxyethylidenel-aminol-oxy] - acetic acid and - acetic acid methyl ester; alachlor; alioxydim; ametryn; amidosulfuron; amitroi; AMS, ie ammonium sulfamate; anilofos; asulam; atrazine; azimsulfurone (DPX-A8947); aziprotryn; azoxystrobin; barban; BAS 516 H, ie 5-fluoro
  • Ester derivatives eg clodinafop-propargyl); clomazone; clomeprop; cloproxydim; copyralid; cumyluron (JC 940); cyanazine; cycloate; cyclosulfamuron (AC 104); cy-cloxydim; cycluron; cyhalofop and its ester derivatives (eg butyl ester, DEH-112); cyperquat; cyprazine; cyprazole; daimuron; 2,4-DB; dalapon; desmedipham; desme- tryn; di-allate; dicamba; dichlobenil; dichlorprop, dicloiop and its esters such as dicl-ofop-methyl; diethatyl; difenoxuron; difenzoquat; diflufenican; dimefuron; dimethachlor; dimethametryn; dimethen
  • NC 31 0, i.e. 4- (2,4-dichlorobenzoyl) -1-methyl-5-benzyloxypyrazole; neburon; nico-sulfuron; nipyraclophen; nitraline; nitrofen; nitrofluorfen; norflurazon; orbencarb; oryzalin; oxadiargyl (RP-020630); oxadiazon; oxyfluorfen; paraquat, pebulate-, pendimethalin; perfluidone; phenisopheme; phenisopharm; phenmedipharm; picloram; piperophos; piributicarb; pirifenop-buty: pretilachlor; primisulfuron-methyl; procayzine; prodiamine, profluraline; proglinazine-ethyl; prometon; prometryn; propachlor; propane; propaquizafop and its esters;
  • propargyl esters quinclorac; quinmerac; quinofop and its ester derivatives, quizalofop and quizalofop-P and their ester derivatives e.g. quizalofop-ethyl; quizalofop-P-tefuryl and ethyl; renriduron; rimsulfuron (DPX-E 9636); S 275, i.e. 2- [4-chloro-2-fluoro-5- (2-propynyloxy) phenyl-4,5,6,7-tetrahydro-2H-indazole; secbumeton; sethoxydim; siduron; simazine; simetryn; SN
  • Suitable pharmaceutical active ingredients include:
  • Estrogen derivatives such as estradiol
  • Progestin derivatives such as levonorge strel or norethisterone acetate
  • testosterone e.g. testosterone
  • non-steroidal anti-inflammatory drugs such as Flurbiprofen, Diciofenac, Ketoprofen, Ketololac,
  • ⁇ -adrenoceptor agonists like clonidine, especially also so-called ⁇ -blockers like propranolol, mepindolol and others.
  • - Peptides such as insulin, leuprolide, enkephalin, oxytocin, Ramorelix, caicitonin, buselrelin and their descendants
  • Cytostatics e.g. 5-fluorouracil
  • Parkinson's therapies in particular monoamine oxidase inhibitors such as selegelin, in particular also dopamine D 2 agonists, in particular also parasympathomimetics, in particular cholinesterase inhibitors such as physostigmine
  • Potential active ingredients for oral use include:
  • ß-receptor blockers such as metoprolol, acebutolol, atenolol and others -
  • Anti-Parkinson agents such as levodopa, benserazide, biperiden or combinations of various anti-Parkinson agents
  • Calcium antagonists e.g. Nifedipine, diltiazem and others
  • ACE inhibitors such as Captopril, lisinopril, perindopril and others
  • narcotic analgesics e.g. Morphine sulfate
  • Antiallergics such as Terfenadine, Loratadine and others
  • Antiarrhythmics e.g. Mexitil
  • Anti-epileptics e.g. Carbamazepine
  • Diuretics e.g. Furosemide, piretanide
  • lipid-lowering agents e.g. Clofibrate, lovastatin
  • Antidepressants such as Amytriptyline
  • thermoplastically processable polymers which are preferably biocompatible , as also preferably physiologically compatible.
  • these can be, for example, vinyl compounds, such as ethylene-vinyl alcohol, or copolymers of vinyl acetate and vinyl acrylate with ethylene.
  • suitable polymers are, for example, polyalkanoates, such as, in particular, aliphatic polyesters.
  • the complexation can optionally also be used to bind pharmaceutical, cosmetic, agricultural and similar active substances to the poly ( ⁇ -1,4-D-glucan) by complexation. It is proposed that between 2 and 20% by weight of a complexing agent be added to the poly ( ⁇ -1,4-D-glucan).
  • thermoplastic starch To investigate the suitability of mixtures of poly ( ⁇ -1, 4-D-glucan) with thermoplastic starch, the entire series of mixtures of poly ( ⁇ -1, 4-D-glucan) and thermoplastic starch has now been examined with regard to crystallinity and mechanical properties examined.
  • Glycerin is used because this material has proven to be very suitable and, as already mentioned above, this material can also be safely used in relation to pharmaceutical and / or cosmetic preparations.
  • Poly ( ⁇ -1,4-D-glucan) is mixed at about 170 ° C. with the plasticizer, such as the glycerin mentioned.
  • the plasticized poly ( ⁇ -1,4-D-glucan) with thermoplastic starch is again mixed in a temperature range of approx. 160 ° to 180 ° C in an extruder, the residence time depending on the composition being between 1 and 5 minutes , at 50 to 200 revolutions per minute, preferably 100 rpm.
  • the plasticizing or mixing work per kg of poly ( ⁇ -1, 4-D-glucan) introduced into the extruder is between 0.2 and 0.4 kWh.
  • thermoplastic starch used for the preparation of the mixtures with poly ( ⁇ -1, 4-D-glucan) was produced by mixing with a plasticizer or plasticizer, such as, for example, with 35% glycerol in a temperature range from approx. 160 ° C. to 180 ° C, which is now an essential feature for the production of the thermoplastic starch during the mixing process in the melt
  • thermoplastic mixtures it is also possible to interpose the thermoplastic mixtures
  • thermoplastic starch Prepare poly ( ⁇ -1, 4-D-glucan) and thermoplastic starch in one step by adding poly ( ⁇ -1, 4-D-glucan) and native starch together with 35% glycerin in an extruder at approx. 170 ° C are melted and deformed, again for the formation of the thermoplastic starch moisture must be removed from the melt, to a value below 5% by weight, based on the amount of native starch and a proportionate amount of plasticizer such as 35% glycerin added to the starch.
  • Poly ( ⁇ -1, 4-D-glucan) therefore does not cause an increase in the crystallinity of the thermoplastic starch phase and conversely the TPS portion does not result in a decrease in the crystallinity of poly ( ⁇ -1, 4-D-glucan).
  • the structure found is a mixture of V-amylose and a structure which has not been identified to date, for which reference is made to FIG. 2.
  • Example 1 1, 00 52.7 +/- 7 2.8 +/- 0.5 11, 7 +/- 2 0.458
  • Example 3 0.75 46.2 +/- 6 5.6 +/- 0.7 26.2 +/- 5 0.382
  • Example 5 0.50 18.1 +/- 2 3.5 +/- 0.2 42.0 +/- 7 0.247
  • Example 6 0.25 24.2 +/- 7 4.6 +/- 0.4 79.0 +/- 6 0.072
  • Example 7 0 184 +/- 34 9.4 +/- 0.5 15.8 +/- 5 0.045
  • TPS and poly ( ⁇ -1, 4-D-glucan) are comparable. 25% poly ( ⁇ -1, 4-D-glucan), however, causes a significant improvement in the elongation at break to 79%.
  • glycerin is a suitable plasticizer for poly ( ⁇ -1,4-D-glucan), whereby, for example, by using 35% glycerol practically identical properties can be achieved as in thermoplastic starch, also softened with 35%. Glycerin. In principle, however, all those materials can be used for plasticizing poly ( ⁇ -1, 4-D-glucan) which are also suitable for plasticizing or plasticizing thermoplastic starch.
  • Glycerin, DMSO, citric acid monohydrate, sorbitol, etc. are suitable, to name but a few.
  • all substances are suitable with a solubility parameter of more than 30 Mpa, whereby these have to be physiologically harmless in the field of pharmaceutical applications.
  • thermoplastic polymer mixture suitable as a carrier matrix for agrochemical, active pharmaceutical and / or cosmetic substances, either mixtures between the plasticized poly ( ⁇ -1, 4-D-glucan) and thermoplastic starch can be used, as well as mixtures between the polyglucan and other suitable polymers, such as vinyl compounds, polyalkanoates, to only a few to call. It is of course essential that these other polymers can be processed thermoplastically, are physiologically compatible and preferably are biologically compatible. Mixtures between polyglucan, thermoplastic starch and other polymers can of course also be used for the production of the carrier matrix mentioned.
  • thermoplastic polymer mixture can also be chosen freely, ie the thermoplastic starch to which the plasticized polyglucan is added or a polymer mixture of another polymer can be used. polymer with the thermoplastic starch to which the polyglucan is added in the extruder, etc.
  • agrochemical or pharmaceutical or cosmetic active substance (s) and further physiologically tolerable additives, fillers and the like are added to the melt to produce the agrochemical, pharmaceutical and / or cosmetic composition for the thermoplastic polymer mixture mentioned. It is essential that the temperature in the extruder or when mixing in the melt is not chosen too high, so that the active pharmaceutical or cosmetic substances cannot be damaged.
  • Example 8 Preparation of a transdermal therapeutic system
  • one part of poly ( ⁇ -1,4-D-glucan) is first mixed with two parts of thermoplastic starch in an extruder at about 170 ° C., where Both materials each contain 35% glycerin as a plasticizer or plasticizer.
  • the polymer melt is then cooled to approx. 140 ° C. and nicotine and approx. 5% water are added as the active pharmaceutical substance, and the pharmaceutical polymer melt obtained is then extruded into films with a layer thickness of 200 ⁇ .
  • the dosage of the nicotine is such that 7 cm 2 , cut out of the extruded film, usually contain about 35 mg of nicotine.
  • the amylose film obtained in this way is not used directly to check the release, but rather so-called nicotine amylose 24-hour patches are produced, which have the following structure:
  • amylose film or reservoir of active ingredient produced according to the invention such as the above-mentioned nicotine, polyglucan / TPS mixture containing 35% glycerol,
  • Release medium citrate phosphate buffer pH 5.9; 900 ml.
  • UV detection 290 nm.
  • FIG. 4 shows the cumulative in vitro release of nicotine from the nicotine amylose 24 hour patch or from the amylose / TPS matrix patch.
  • the release profile is usually based on Higuchi's square root law for matrix patches.
  • Example 9 Extrusion pellets for oral administration of active ingredients
  • a poly ( ⁇ -1,4-D-glucan) / TPS polymer mixture is used as a matrix for extrusion pellets for the oral application of active substances according to the principle of "multiple unit dosage forms".
  • a film is again produced, analogous to the amylose / TPS film, which contained active ingredients for transdermal application as a component.
  • active ingredients for transdermal application as a component.
  • only potential active ingredients, suitable for oral use, are incorporated into the polymer melt and extruded as a film.
  • the film obtained in this way is cut into strips of approximately 1-2 mm in width and then reduced in size so that approximately 1 mm 2 large pieces of film are created.
  • the cutlets thus obtained, containing the pharmaceutical active ingredient are pressed in tablet form or else filled into hard gelatin capsules.
  • pellets that are formulated with a combination of suitable pharmaceutical additives or measures an active ingredient release kinetics with almost zero order can be achieved with the use of pellets (for example Beloc-Zok).
  • poly ( ⁇ -1, 4-D-glucan) in combination with, for example, thermoplastic starch the active ingredient release of pellets can be controlled via their geometry and application form (tablet or capsule). The use of other auxiliary substances is not absolutely necessary.
  • the pellets or schnitzel can be filled into a capsule, which can be provided with an enteric coating.
  • the chips or pellets can also be coated with gastric juice-resistant material in that the extruded film is coated accordingly with gastric juice-resistant materials. This can be done, for example, by coextruding multilayer films, the amylose / TPS layer containing the pharmaceutical active ingredient for oral applications being selected as the central layer. If these pellets or chips are not filled into a capsule, they are usually compressed into a tablet, as already mentioned above. This can in turn be provided with a coating for gastric juice resistance or control of the release of the active ingredient.
  • a part of poly ( ⁇ -1,4-D-glucan) is first mixed with two parts of thermoplastic starch in the melt in an extruder at approximately 170 ° C., both materials each Contain 35% glycerin as plasticizer or plasticizer.
  • the film thus obtained is then shredded by means of pecking to form particles.
  • the particles produced in this way can now be applied outdoors, for example at a dosage of approx. 30-100 g per hectare.
  • the great advantage of using these amylose film particles containing the agrochemical active substance is that good dosing becomes possible and the release is delayed.
  • the delayed release can depend on the drug loading
  • the active substance loading in the present example is only 5%, but higher active substance loads of up to 50% are of course also possible.
  • thermoplastic poly ( ⁇ -1, 4-D-glucan) or the thermoplastic polymer mixtures containing poly ( ⁇ -1, 4-D-glucan) described above are of course only Examples to illustrate the present invention.
  • the invention is of course not limited to the applications mentioned or to the active substances, process parameters, polymer component partners for poly ( ⁇ -1, 4-D-glucan) etc. mentioned in the examples, but can be in any way be added or modified by adding further components, by selecting other process parameters, etc.

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Abstract

The invention relates to poly(α-1,4-D-glucan)s with a degree of polymerisation of at least approx. 40, preferably at least approx. 50 and most preferably at least approx. 60. Plasticised poly(α-1,4-D-glucan)s with the aforementioned degrees of polymerisation or thermoplastic polymer mixtures containing plasticised thermoplastic poly(α-1,4-D-glucan)s, are especially suitable as a support matrix for active substances used in agriculture, pharmaceutical active substances and/or cosmetic active substances.

Description

POLY(ALPHA-l,4-D-GLUCAN) UND DIES ENTHALTENDE THERMOPLASTISCHE POLYMERMISCHUNGENPOLY (ALPHA-l, 4-D-GLUCAN) AND THERMOPLASTIC POLYMER BLENDS CONTAINING THIS
Beschreibungdescription
Die vorliegende Erfindung betrifft Poly(α-1 ,4-D-Glucan) mit einem Polymerisationgrad von mindestens 40, vorzugsweise 50 und noch bevorzugter > 60, eine thermoplastische Polymermischung, mindestens enthaltend Poly(α-1,4-D-Glucan), ein Verfahren zur Herstellung einer thermoplastischen Polymermischung sowie eine Verwendung einer thermoplastischen Polymermischung, mindestens enthaltend Poly(α-1 ,4-D-Glucan) als Trägermatrix für Wirksubstanzen, wie Pestizide, Fungizide, Insektizide, Herbizide, Düngemittel, pharmazeutische und/oder kosmetische Wirkstoffe, und ein Verfahren zur Herstellung einer agrochemischen, pharmazeutischen und/oder kosmetischen Zusammensetzung.The present invention relates to poly (α-1,4-D-glucan) with a degree of polymerization of at least 40, preferably 50 and more preferably> 60, a thermoplastic polymer mixture containing at least poly (α-1,4-D-glucan), a method for producing a thermoplastic polymer mixture and a use of a thermoplastic polymer mixture, at least containing poly (α-1, 4-D-glucan) as a carrier matrix for active substances, such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients , and a method for producing an agrochemical, pharmaceutical and / or cosmetic composition.
Die Verwendung von Stärke in oralen, pharmazeutischen Verabreichungsformen ist unter anderem in der Pharmacopea Helvetica dokumentiert. Neben nativer Stärke in verpreßten Tabletten ist die Verwendung von thermoplastischer und destrukturierter Stärke in EP 118 240, EP 304 401 , WO 89/ 12492, WO 90/ 14938 sowie US 5, 095, 054 beschrieben. In diesen Veröffentlichungen ist die Strang- bzw. Profilextru- sion von thermoplastischen Formulierungen bzw. Polymermischungen, basierend auf Stärke, beschrieben, wobei für das orale Einnehmen verträgliche Plastifiziermit- tel, wie Wasser und ähnliche sowie bevorzugte Verabreichungsformen offenbart sind. Die hohe Scherschmelzviskosität und die ausgesprochene Strukturviskosität der Stärkeformulierungen führt zu Scher- und Hitzeabbau der Verabreichungsformen, wie insbesondere von Tabletten. In den erwähnten Schritten ist der Abbau der Stärke erwähnt, um die Verarbeitbarkeit zu verbessern. Der Abbau der Stärke wird durch Wärme, Wasserstoffionen oder Chloridionen gesteuert. Die resultierenden, thermoplastischen Formulierungen sind entweder zu spröde oder zu klebrig, abhängig vom Anteil von niedermolekularen Plastifiziermitteln.The use of starch in oral, pharmaceutical forms of administration is documented in the Pharmacopea Helvetica, among others. In addition to native starch in compressed tablets, the use of thermoplastic and destructurized starch is described in EP 118 240, EP 304 401, WO 89/12492, WO 90/14938 and US 5, 095, 054. These publications describe the strand or profile extrusion of thermoplastic formulations or polymer mixtures based on starch, plasticizers which are compatible with oral ingestion, such as water and the like, and preferred administration forms being disclosed. The high shear melt viscosity and the pronounced structural viscosity of the starch formulations lead to shear and heat reduction in the administration forms, in particular tablets. In the steps mentioned, the degradation of the starch is mentioned in order to improve the processability. The breakdown of the starch is controlled by heat, hydrogen ions or chloride ions. The resulting thermoplastic formulations are either too brittle or too sticky, depending on the proportion of low molecular weight plasticizers.
In weiteren Druckschriften wie der WO90/05161 sowie der EP 0 479 964 werden thermoplastische Stärke (TPS) und deren Herstellung beschrieben. Thermoplastische Stärke sowie Polymermischungen davon weisen nützliche mechanische Eigenschaften auf, jedoch liegen die Verarbeitungstemperaturen in der Regel in einem Bereich von ca. 180 - 230°C, was wesentlich zu hoch ist für die Verarbeitung von einer großen Anzahl von pharmazeutisch aktiven Wirkstoffen. Insbesondere die in der EP 0468 003 beschriebene Verwendung von thermoplastischer Stärke bei der Herstellung von pharmazeutischen Zusammensetzungen hat aufgrund der zu hohen Verarbeitungstemperatur nicht zum gewünschten Erfolg geführt. Im weiteren ist die beschriebene, thermoplastische Stärke weitgehendst amorph, da die Stärke ihr Kristallisationspotential infolge der thermomechanischen Transformation beim Herstellverfahren der thermoplastischen Stärke aus nativer Stärke verliert. Infolge Fehlens kristalliner Anteile ist die thermoplastische Stärke viel zu hygroskopisch, d.h. Wasser wird aus einer feuchten Umgebungsatmosphäre absorbiert. Dies ist ein wichtigerThermoplastic starch (TPS) and its production are described in further publications such as WO90 / 05161 and EP 0 479 964. Thermoplastic starch and polymer mixtures thereof have useful mechanical properties, but the processing temperatures are usually all in one Range of approx. 180 - 230 ° C, which is much too high for the processing of a large number of pharmaceutically active substances. In particular, the use of thermoplastic starch in the production of pharmaceutical compositions described in EP 0468 003 has not led to the desired success due to the processing temperature being too high. Furthermore, the thermoplastic starch described is largely amorphous, since the starch loses its crystallization potential as a result of the thermomechanical transformation in the manufacturing process of the thermoplastic starch from native starch. Due to the lack of crystalline components, the thermoplastic starch is much too hygroscopic, ie water is absorbed from a humid ambient atmosphere. This is an important one
Nachteil, da die mechanischen Eigenschaften der amorphen thermoplastischen Stärken infolge der Veränderung des Wasseranteils stark variieren.Disadvantage, since the mechanical properties of the amorphous thermoplastic starches vary considerably due to the change in the water content.
Es ist daher eine Aufgabe der vorliegenden Erfindung, ein Material analog der Stärke bereit zuschlagen, welches geeignet ist für die Herstellung von Mischungen, die thermoplastisch verarbeitbar sind und insbesondere als thermoplastische Trägersubstanz für Wirkstoffe - Pestizide, Fungizide, Insektizide, Herbizide, Düngemittel, pharmazeutische und/oder kosmetische Wirksubstanzen - geeignet sind.It is therefore an object of the present invention to prepare a material analogous to starch which is suitable for the production of mixtures which can be processed thermoplastically and in particular as a thermoplastic carrier substance for active substances - pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceuticals and / or cosmetic active substances - are suitable.
Für die Lösung der gestellten Aufgabe hat sich Poly(α-1 ,4-D-Glucan) mit einem Polymerisationsgrad von mind. ca. 40, vorzugsweise mind. ca. 50 und noch bevorzug- ter von mind. ca. 60 als geeignet erwiesen, insbesondere bei Verwendung in thermoplastischen Polymermischungen, enthaltend mindestens das erwähnte Poly(α- 1 ,4-D-Glucan).Poly (α-1,4-D-glucan) with a degree of polymerization of at least approx. 40, preferably at least approx. 50 and more preferably of at least approx. 60 has proven to be suitable for solving the problem , in particular when used in thermoplastic polymer mixtures containing at least the aforementioned poly (α-1, 4-D-glucan).
Lineare Poly( -1 ,4-D-Glucan)e sind Polysacharide, bestehend aus Glucosemono- meren, wobei letztere weitgehendst ausschließlich untereinander durch α 1,4- glycosidische Bindungen verbunden sind. Das am meisten natürlich vorkommende αLinear poly (-1, 4-D-glucan) s are polysaccharides consisting of glucose monomers, the latter being largely exclusively connected to one another by α 1,4-glycosidic bonds. The most naturally occurring α
1 ,4-Glucan ist die Amylose, eine Komponente in pflanzlicher Stärke. In der näheren Vergangenheit wurde der kommerziellen Verwendung von linearen α 1 ,4-Glucanen mehr und mehr Bedeutung beigemessen. Infolge ihrer physio-chemikalischen Eigenschaften kann Amylose verwendet werden für die Herstellung von Folien, welche farblos, geruchlos und geschmacklos sind, sowie nichttoxisch und biologisch abbau- bar. Bereits heute ist eine Reihe von möglichen Anwendungen bekannt, wie beispielsweise in der Lebensmittelindustrie, der Textilindustrie, der Glasfaserindustrie und in der Produktion von Papier.1, 4-glucan is amylose, a component in vegetable starch. In the recent past, the commercial use of linear α 1, 4-glucans has become more and more important. Due to its physio-chemical properties, amylose can be used to produce films that are colorless, odorless and tasteless, as well as non-toxic and biodegradable. bar. A number of possible applications are already known today, for example in the food industry, the textile industry, the glass fiber industry and in the production of paper.
Bevorzugt sind wasserunlösliche lineare Polysaccharide, wie das erfindungsgemäß vorgeschlagene Polyglucan, wie beispielsweise Poly(α-1 ,4-D-Glucan). Dabei ist in der Regel der Verzweigungsgrad in 6-Position < 4 %, vorzugsweise maximal 2 %, und insbesondere maximal 0,5 % und der Verzweigungsgrad in der anderen, nicht an der linearen Verknüpfung beteiligten Position, z.B. der 2- bzw. 3-Position, im Fall des bevorzugten Poly(α-1 ,4-D-Glucan) vorzugsweise jeweils maximal 2 %, und ins- besondere maximal 1 %.Water-insoluble linear polysaccharides, such as the polyglucan proposed according to the invention, such as poly (α-1,4-D-glucan) are preferred. As a rule, the degree of branching in the 6 position is <4%, preferably a maximum of 2%, and in particular a maximum of 0.5%, and the degree of branching in the other position not involved in the linear linkage, e.g. the 2- or 3-position, in the case of the preferred poly (α-1,4-D-glucan) preferably in each case at most 2%, and in particular at most 1%.
Besonders bevorzugt sind Poly(α-1 ,4-D-Glucan)e, die keine Verzweigungen aufweisen, bzw. deren Verzweigungsgrad so minimal ist, daß er mit herkömmlichen Methoden nicht mehr nachweisbar ist. Erfindungsgemäß beziehen sich die Präfixe "α" oder "D" allein auf die Verknüpfungen, die das Polymerrückgrad ausbilden, und nicht auf Verzweigungen.Particularly preferred are poly (α-1,4-D-glucan) s which have no branches or whose degree of branching is so minimal that it can no longer be detected using conventional methods. According to the invention, the prefixes “α” or “D” relate solely to the linkages which form the polymer backbone and not to branches.
Unter dem oben erwähnten Begriff "wasserunlösliche Polysaccharide" werden für die vorliegende Erfindung Poly(α-1 ,4-D-Glucan)e verstanden, die nach der Definition des deutschen Arzneimittelbuches entsprechend den Klassen 4 bis 7 unter die Kategorien "wenig lösliche", "schwer lösliche", "sehr schwer lösliche" bzw. "praktisch unlösliche" Verbindungen fallen. Für die vorliegende Erfindung sind schwer lösliche bis praktisch unlösliche Verbindungen, insbesondere sehr schwer lösliche bis praktisch unlösliche Verbindungen bevorzugt, wie z.B. schwer lösliche bis praktisch unlösliche Poly(α-1 ,4-D-Glucan)e mit einem Polymerisationsgrad > 40, bevorzugt > 50, und noch weiter bevorzugt > 60.For the present invention, the above-mentioned term "water-insoluble polysaccharides" is understood to mean poly (α-1,4-D-glucan) s which, according to the definition of the German pharmaceutical book according to classes 4 to 7, belong to the categories "slightly soluble", "Hardly soluble", "very poorly soluble" or "practically insoluble" compounds fall. For the present invention, sparingly soluble to practically insoluble compounds, especially very sparingly soluble to practically insoluble compounds are preferred, such as e.g. sparingly soluble to practically insoluble poly (α-1,4-D-glucan) s with a degree of polymerization> 40, preferably> 50, and even more preferably> 60.
Im Falle der erfindungsgemäß verwendeten Poly(α-1 ,4-D-Glucan)e bedeutet dies, daß mindestens 98 % der eingesetzten Menge, insbesondere mindestens 99,5 % unter Normalbedingungen (T = 25°C ± 20 %, p = 101*325 Pa ± 20 %) in Wasser unlöslich ist (entsprechend den Klassen 4 bzw. 5). "Sehr schwer löslich" entsprechend Klasse 6 kann durch folgende Versuchsbedingungen veranschaulicht werden: 1 g des zu untersuchenden Polyglucans wird in ein 1 Liter entionisiertem Wasser auf 130°C unter einem Druck von 1 bar erhitzt. Die entstehende Lösung bleibt nur kurzzeitig über wenige Minuten stabil. Beim Erkalten unter Normalbedingungen fällt die Substanz wieder aus. Nach Abkühlung aufIn the case of the poly (α-1,4-D-glucan) s used according to the invention, this means that at least 98% of the amount used, in particular at least 99.5% under normal conditions (T = 25 ° C. ± 20%, p = 101 * 325 Pa ± 20%) is insoluble in water (according to classes 4 and 5). "Very poorly soluble" according to class 6 can be illustrated by the following test conditions: 1 g of the polyglucan to be examined is heated in a 1 liter of deionized water to 130 ° C. under a pressure of 1 bar. The resulting solution only remains stable for a short time over a few minutes. When cooling under normal conditions, the substance precipitates again. After cooling down
Raumtemperatur und Abtrennung mittels Zentrifugieren können unter Berücksichtigung der experimentellen Verluste mindestens 66 % der eingesetzten Menge zurückgewonnen werden.Room temperature and separation by centrifugation can be recovered taking into account the experimental losses at least 66% of the amount used.
Die Herstellung hinsichtlich Isolierung von linearen Poly(α-1 ,4-D-Glucan) ist bei- spielsweise in der WO95/31553 beschrieben. Dabei werden Proteine beschrieben, welche eine enzymatische Wirksamkeit von einer Amylosucrase aufweisen, die codiert ist durch eine DNA-Sequenz, charakterisiert in einem der Ansprüche 1 und 2 der genannten internationalen Patentanmeldung. Diese Proteine sind geeignet für die Herstellung von linearen Poly(α-1 ,4-D-Glucan)en. Weitere Proteine mit Wirksam- keit für die Synthese von Poly(α-1 ,4-D-Glucan), wie Phosphorylasen, Glycogensyn- thetasen, Glucantransferasen, Stärkesythetasen sind für die Herstellung von Polyglucanen im Sinne der vorliegenden Erfindung geeignet. Ebenfalls sind in vivo- Methoden im Sinne der vorliegenden Erfindung für die Herstellung von Polyglucanen mittels genetisch veränderten Lebewesen wie Bakterien, Pilze oder Algen, oder hö- heren Pflanzen, welche die erwähnten Proteine, d.h. Phosphorylasen, Glycogen- synthetasen, Glucantransferasen, Stärkesythetasen oder Amylosucrasen mit der Wirksamkeit für die Synthese von Polyglucanen vorzugsweise enthalten, geeignet.The production with regard to the isolation of linear poly (α-1,4-D-glucan) is described, for example, in WO95 / 31553. Proteins are described which have an enzymatic activity of an amylosucrase which is encoded by a DNA sequence, characterized in one of claims 1 and 2 of the international patent application mentioned. These proteins are suitable for the production of linear poly (α-1, 4-D-glucan) s. Other proteins with activity for the synthesis of poly (α-1, 4-D-glucan), such as phosphorylases, glycogen synthetases, glucan transferases, starch sythases, are suitable for the production of polyglucans in the sense of the present invention. Likewise, in vivo methods within the meaning of the present invention for the production of polyglucans by means of genetically modified organisms such as bacteria, fungi or algae, or higher plants which contain the proteins mentioned, i.e. Phosphorylases, glycogen synthetases, glucan transferases, starch sythases or amylosucrases with the activity for the synthesis of polyglucans preferably contained, suitable.
Bei Poly(α-1 ,4-D-Glucan) oder ebenfalls bezeichnet mit Polyanhydro-D-Glukose (PADG) in einem Bereich des Polymerisationsgrades (DP) von ca. 40 - 300, wie bei- spielsweise 60 - 100, das erfindungsgemäß bevorzugt ist, zeigt sich eine bemerkenswerte Tendenz zur Bildung von regulärer Konformation, Doppelhelix- Molekularmorphologie und hohem kristallinen Anteil nachweisbar mittels Nuklearmagnetischer Resonanzspektroskopie und Röntgendiffraktion. Die Änderung der Kristallstruktur infolge thermischer Umwandlung ist analog derjenigen in Kartoffel- stärke. Die Kinetik dieser Umformungen ist jedoch schneller als diejenige in Kartoffelstärke. Die Bildung von molekularen Komplexen mit geeigneten niedermolekula- ren Mischkomponenten, wie Fettsäuren, ist gekoppelt mit der partiellen Konformationsumwandlung zur Monohelikal-V-Struktur, bekannt im Fall von Amylose, und partiell zu einer sekundären unidentifizierten, unbekannten Struktur. Die Fähigkeit der Komplexbildung ist ungefähr 3 x höher als diejenige der Amylose. Die neuen Poly(α- 1 ,4-D-Glucan)e kombinieren die Fähigkeit der zwei Stärkekomponenten - Amylose und Amylopektin, um diese beiden Komponenten kennzeichnende, reguläre Konformationscharakteristiken wahlweise zu bilden. Der Vorteil des niedrigen Polymerisationsgrades von α 1 ,4-Glucanen, verglichen mit demjenigen der Stärke (DP > 1000) verbunden mit der Fähigkeit der Bildung ähnlicher regulärer Konformationen, wie Stärke, führt zur erfindungsgemäß vorteilhaften Verwendung als Trägersubstanz bzw. Trägermatrix bei der Herstellung von agrochemischen, pharmazeutischen und kosmetischen Formulierungen auf thermoplastischer Basis.In the case of poly (α-1, 4-D-glucan) or also referred to as polyanhydro-D-glucose (PADG) in a range of the degree of polymerization (DP) of approx. 40-300, such as 60-100, for example is preferred, there is a remarkable tendency towards the formation of regular conformation, double helix molecular morphology and a high crystalline fraction detectable by means of nuclear magnetic resonance spectroscopy and X-ray diffraction. The change in crystal structure due to thermal transformation is analogous to that in potato starch. However, the kinetics of these transformations is faster than that of potato starch. The formation of molecular complexes with suitable low molecular weight Ren mixed components, such as fatty acids, is coupled with the partial conformational conversion to the monohelical V structure, known in the case of amylose, and partially to a secondary unidentified, unknown structure. The ability to form complexes is approximately 3 times higher than that of amylose. The new poly (α-1, 4-D-glucan) s combine the ability of the two starch components - amylose and amylopectin - to optionally form regular conformational characteristics characteristic of these two components. The advantage of the low degree of polymerization of α 1,4-glucans compared to that of starch (DP> 1000) combined with the ability to form similar regular conformations, such as starch, leads to the use according to the invention as a carrier substance or carrier matrix in the production of agrochemical, pharmaceutical and cosmetic formulations on thermoplastic basis.
Mit anderen Worten kombinieren die erfindungsgemäß vorgeschlagenen Poly(α-1 ,4- D-Glucan)e in vorteilhafter Art und Weise die gute Verarbeitbarkeit von abgebauter Stärke und den erwünschten Eigenschaften von kristalliner Stärke. Die hohe Kristal- linität von Poly(α-1 ,4-D-Glucan) gepaart mit der niedrigen Molekularmasse der Po- ly(α-1 ,4-D-Glucan)e führen zu einer Struktur, bei welcher die Verbindungsmoleküle der Kristallite fehlen. Die Verbindungsmoleküle können eingeführt werden durch Hinzufügen von thermoplastischer Stärke zum Poly(α-1 ,4-D-Glucan). Das ge- wünschte Volumenfraktionsverhältnis der kristallinen und amorphen Phase kann durch Mischen von Poly(α-1 ,4-D-Glucan) und thermoplastischer Stärke eingestellt werden. Ein weiterer Aspekt liegt in der Verarbeitbarkeit von plastifizierter Stärke. Das Verhältnis zwischen dem mittleren Polymerisationsgrad von Stärke und von Poly(α-1 ,4-D-Glucan) beträgt vorzugsweise mindestens eine 10er Potenz. Der Grenzwert der Scherviskosität bei ausreichend niedriger Scherrate wird als Null-In other words, the poly (α-1,4-D-glucan) s proposed according to the invention advantageously combine the good processability of degraded starch and the desired properties of crystalline starch. The high crystallinity of poly (α-1, 4-D-glucan) paired with the low molecular mass of the poly (α-1, 4-D-glucan) lead to a structure in which the compound molecules of the crystallites absence. The linking molecules can be introduced by adding thermoplastic starch to the poly (α-1, 4-D-glucan). The desired volume fraction ratio of the crystalline and amorphous phase can be adjusted by mixing poly (α-1, 4-D-glucan) and thermoplastic starch. Another aspect is the processability of plasticized starch. The ratio between the average degree of polymerization of starch and of poly (α-1,4-D-glucan) is preferably at least a power of 10. The limit value of the shear viscosity at a sufficiently low shear rate is called zero
Scherviskosität bezeichnet (η(γ)o, wobei η die Viskosität und γ die Scherrate bedeuten). Die Null-Scherviskosität ist proportional der 3.4ten Potenz des Gewichtsmittels der Molmasse. Bei identischen Parametern in bezug auf Scherrate, Weichmachergehalt und Temperatur ist die Scherviskosität der thermoplastischen Stärke mehr als 1000 mal höher als diejenige von Poly(α-1 ,4-D-Glucan). Als Konsequenz ergibt sich ein weiterer wesentlicher Aspekt der vorliegenden Erfindung, indem Mischungen von thermoplastischer Stärke mit plastifiziertem Poly(α-1 ,4-D-Glucan) eine wesentliche Verbesserung der Verarbeitbarkeit mit sich bringt. Im weiteren weisen derartige Mischungen vorteilhafte mechanische Eigenschaften auf.Shear viscosity denotes (η (γ) o, where η is the viscosity and γ is the shear rate). The zero shear viscosity is proportional to the 3.4th power of the weight average molecular weight. With identical parameters in terms of shear rate, plasticizer content and temperature, the shear viscosity of the thermoplastic starch is more than 1000 times higher than that of poly (α-1, 4-D-glucan). As a consequence, another essential aspect of the present invention results from mixtures of thermoplastic starch with plasticized poly (α-1, 4-D-glucan) brings a significant improvement in processability. Mixtures of this type also have advantageous mechanical properties.
So zeigen beispielsweise thermoplastische Mischungen von einem Teil Poly(α-1 ,4- D-Glucan) mit 3 Teilen thermoplastischer Stärke 6- bis 7-fach erhöhte Bruchdehnung und 2- bis 3-fach erhöhte Energieaufnahme bei Bruch im Vergleich zu den entsprechenden Werten von reiner thermoplastischer Stärke. Die von der Scherrate abhängige Scherviskosität derselben Mischung ist um einen Faktor 2 tiefer bei der Verarbeitungstemperatur der thermoplastischen Stärke als diejenige der thermoplasti- sehen Stärke selbst.For example, thermoplastic mixtures of one part of poly (α-1,4-D-glucan) with 3 parts of thermoplastic starch show a 6 to 7-fold increase in elongation at break and a 2 to 3-fold increase in energy absorption when broken compared to the corresponding values of pure thermoplastic starch. The shear viscosity of the same mixture, which is dependent on the shear rate, is a factor 2 lower at the processing temperature of the thermoplastic starch than that of the thermoplastic starch itself.
Die Mischung von einem Teil thermoplastischer Stärke und drei Teilen Poly(α-1 ,4-D- Glucan) zeigt immer noch dieselbe Energieaufnahme bei Bruch, wie bei thermoplastischer Stärke, aber die von der Scherrate abhängige Scherviskosität ist mehr als um ein Faktor 10 tiefer als diejenige von thermoplastischer Stärke.The mixture of one part thermoplastic starch and three parts poly (α-1, 4-D-glucan) still shows the same energy absorption at break as with thermoplastic starch, but the shear viscosity dependent on the shear rate is more than 10 times lower than that of thermoplastic starch.
Die thermoplastische Verarbeitbarkeit von Poly(α-1 ,4-D-Glucan) ist ein wichtigesThe thermoplastic processability of poly (α-1, 4-D-glucan) is an important one
Merkmal der vorliegenden Erfindung. Die regelmäßige Geometrie von geformten Teilen, hergestellt mittels Strangextrusion resp. Strangpressen der Wirkstoff/thermoplastische Poly(α-1 ,4-D-Glucan)Mischung unterstützt die Steuerung der Freigabe von Wirksubstanzen, z.B. der Medikamentenfreigabe; die Quellzeit, die Desintegrati- onszeit und die Auflösungszeit dieser geformten Partikel definieren die Freigabezeit des Wirkstoffes. Die thermoplastisch geformten Teile oder Partikel daraus müssen klein genug sein, damit der erwähnte kinetische Ablauf eine Standardabweichung aufweist, die kleiner ist als die entsprechenden Mittelwerte. Die gleichmäßige homogene Verteilung des Wirkstoffes in der thermoplastischen Schmelze kann vereinfacht werden durch gegenläufige Doppelschneckenextruder, versehen mit geeigneten Mischelementen. Abschließend kann festgestellt werden, daß dies nun möglich ist, da alle notwendigen Voraussetzungen ausreichend erfüllt sind:Feature of the present invention. The regular geometry of molded parts, manufactured by extrusion or. Extrusion of the active ingredient / thermoplastic poly (α-1, 4-D-glucan) mixture supports the control of the release of active ingredients, e.g. drug release; the swelling time, the disintegration time and the dissolution time of these shaped particles define the release time of the active ingredient. The thermoplastic parts or particles made of it must be small enough so that the kinetic process mentioned has a standard deviation that is smaller than the corresponding mean values. The uniform, homogeneous distribution of the active ingredient in the thermoplastic melt can be simplified by counter-rotating twin-screw extruders provided with suitable mixing elements. In conclusion, it can be said that this is now possible since all the necessary requirements have been met:
- Plastifiziertes Poly(α-1 ,4-D-Glucan) kann hergestellt werden, beispielsweise durch die Verwendung von Glyzerin als Weichmacher; - Glyzerin ist auf der Liste von physiologisch unbedenklichen Additiven für pharma- zeutische/galenische Formulierungen;- Plasticized poly (α-1,4-D-glucan) can be made, for example, by using glycerin as a plasticizer; - Glycerin is on the list of physiologically safe additives for pharmaceutical / pharmaceutical formulations;
- Die Verarbeitungstemperatur von thermoplastischer Stärke kann erniedrigt werden durch das Hinzufügen von Poly(α-1 ,4-D-Glucan), mindestens um 40°C.- The processing temperature of thermoplastic starch can be reduced by adding poly (α-1, 4-D-glucan), at least by 40 ° C.
5 Gemäß einer Ausführungsvariante der vorliegenden Erfindung wird eine thermoplastische Polymermischung vorgeschlagen, bei welcher der Anteil Stärke, wie insbesondere thermoplastischer Stärke, zwischen 20 - 80 Gew% beträgt, bezogen auf den Anteil Polymer inklusive Polyglucan und gegebenenfalls weitere thermoplastisch verarbeitbare Polymere.5 According to one embodiment variant of the present invention, a thermoplastic polymer mixture is proposed in which the proportion of starch, such as in particular thermoplastic starch, is between 20-80% by weight, based on the proportion of polymer including polyglucan and optionally other thermoplastically processable polymers.
l o Gemäß einer weiteren Ausführungsvariante wird wiederum eine thermoplastischeAccording to a further embodiment variant, a thermoplastic is again used
Polymermischung vorgeschlagen, wobei der Anteil Poly(α-1 ,4-D-Glucan) 20 - 80 Gew% beträgt, bezogen auf den Anteil Polymer inklusive der Stärke und gegebenenfalls weiterer thermoplastisch verarbeitbarer Polymere.Polymer mixture proposed, the proportion of poly (α-1,4-D-glucan) being 20-80% by weight, based on the proportion of polymer including the starch and optionally other thermoplastically processable polymers.
Aufgrund der oben geschilderten Voraussetzungen kann gemäß der vorliegenden 15 Erfindung Poly(α-1 ,4-D-Glucan) mit thermoplastischer Stärke gemischt und insbesondere zur Herstellung von einer thermoplastischen Trägermatrix beispielsweise für agrochemische, pharmazeutische und/oder kosmetische Wirkstoffe eingesetzt werden.Based on the above-described requirements, poly (α-1,4-D-glucan) can be mixed with thermoplastic starch according to the present invention and used in particular for the production of a thermoplastic carrier matrix, for example for agrochemical, pharmaceutical and / or cosmetic active ingredients.
Als Wirkstoff wird im Rahmen dieser Erfindung jede biologisch aktive Substanz und 20 Substanzkombination, im weitesten Sinne angesehen, vorzugsweise pharmazeutische Wirkstoffe, agrochemische Wirkstoffe, die in Landwirtschaft, Gartenbau und Forstwirtschaft eingesetzt werden können.In the context of this invention, any biologically active substance and combination of substances, in the broadest sense, is regarded as an active substance, preferably pharmaceutical active substances, agrochemical active substances which can be used in agriculture, horticulture and forestry.
Unter dem Begriff Agrochemikalie fallen Düngemittel, Herbizide, Fungizide, Insektizi- 25 de, Pestizide und andere Pflanzenschutz- und Schädlingsbekämpfungsmittel, Vorratsschutzmittel, Pflanzenwuchs- und -hemmstoffe, Silierungs-, Konservierungsmittel sowie Bodenverbesserungsmittel. Selbst Futtermittelzusätze, Tierhygiene- und Arzneimittel oder Aroma- und Duftstoffe sind nicht auszuschließen. Beispielsweise sind bekannte Wirkstoffe einsetzbar, wie sie z.B. aus Weed Research 26, 441-445 (1986) oder "The Pesticide Manual", Ist edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 1997 und dort zitierter Literatur beschrieben sind. Als bekannte Herbizide, die in den erfindungsgemäßen Wirkstoff- träger eingetragen werden können, sind z.B. folgende Wirkstoffe zu nennen (Anmerkung: Die Verbindungen sind entweder mit dem "common name" nach der International Organization for Standardization (ISO) oder mit dem chemischen Namen, ggf. zusammen mit einer üblichen Codenummer bezeichnet): atrazine; metotachlor; pro- piconazole; metalaxyl; dicamba (Produkte, Marken und Warenzeichen der Firma Novartis); bensulfuron; nicosulfuron; methomyl; flusilazole; benomyl (Produkte, Marken und Warenzeichen der Firma Du Pont); glyphosate; alachlor; acetochlor; but- achlor; triallate (Produkte, Marken und Warenzeichen der Firma Monsanto); pa- raquat; L-cyhalothrin; fluazifop; cypermethrin; EPTC (Produkte, Marken und Warenzeichen der Firma Zeneca); fenoxaprop; deltametrin; phenmedipham; endosulfan; glufosinate (Produkte, Marken und Warenzeichen der Firma AgrEvo); imidaciloprid; tebuconazole; metamitron; metribuzin; methamidophos (Produkte, Marken und Warenzeichen der Firma Bayer); imazethapyr; pendimethalin; imazaquin; terbufos; irna- zapyr (Produkte, Marken und Warenzeichen der Firma Cyanamid); chlorpyrifos; trifu- ralin; fluroxypyr; clopyralid; haloxyfop (Produkte, Marken und Warenzeichen der Fir- ma DowElanco); aldicarb; iprodione; dinufenican; bromoxynil; fosethyl-AI (Produkte,The term agrochemical includes fertilizers, herbicides, fungicides, insecticides, pesticides and other pesticides and pesticides, storage protection agents, plant growth and inhibitors, silage additives, preservatives and soil conditioners. Even feed additives, animal hygiene and pharmaceuticals or flavorings and fragrances cannot be excluded. For example, known active substances can be used, as described, for example, by Weed Research 26, 441-445 (1986) or "The Pesticide Manual", Ist edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 1997 and the literature cited therein. Known herbicides which can be added to the active ingredient carrier according to the invention are, for example, the following active ingredients (note: the compounds are either with the "common name" according to the International Organization for Standardization (ISO) or with the chemical name, if necessary (together with a common code number): atrazine; metotachlor; propiconazole; metalaxyl; dicamba (products, brands and trademarks of Novartis); bensulfuron; nicosulfuron; methomyl; flusilazole; benomyl (Du Pont products, brands and trademarks); glyphosate; alachlor; acetochlor; butachlor; triallate (products, brands and trademarks of Monsanto); paraquat; L-cyhalothrin; fluazifop; cypermethrin; EPTC (Zeneca products, brands and trademarks); fenoxaprop; deltametrin; phenmedipham; endosulfan; glufosinate (products, brands and trademarks of AgrEvo); imidaciloprid; tebuconazole; metamitron; metribuzin; methamidophos (products, brands and trademarks of Bayer); imazethapyr; pendimethalin; imazaquin; terbufos; irnazapyr (products, brands and trademarks of the company Cyanamid); chlorpyrifos; trifuralin; fluroxypyr; clopyralid; haloxyfop (products, brands and trademarks of DowElanco); aldicarb; iprodione; dinufenican; bromoxynil; fosethyl-AI (products,
Marken und Warenzeichen der Firma Rhone Poulenc); bentazone; epoxiconazole; sethoxydim; hormones; metazachlor (Produkte, Marken und Warenzeichen der Firma BASF); acetochlor; acifluorfen; aclonifen; AKH 7088, d.h. [[[1-[5-[2-Chloro-4-(trifluoromethyl)- phenoxyl-2-nitrophenyll-2-methoxyethylidenel-aminol-oxy]- essigsaure und - essigsäuremethylester; alachlor; alioxydim; ametryn; amidosulfuron; amitroi; AMS, d.h. Ammoniumsulfamat; anilofos; asulam; atrazin; azimsulfurone (DPX-A8947); azi- protryn; azoxystrobin; barban; BAS 516 H, d.h. 5-Fluor-2-phenyl-4H-3,1-benzoxazin- 4-on; benazolin; benfluralin; benfuresate; bensulfuron-methyl; bensulide; bentazone; benzofenap; benzofluor; benzoylpropethyl; benzthiazuron; bialaphos; bifenox; bro- macil; bromobutide; bromofenoxim; bromoxynil; bromuron; buminafos; busoxinone; butachlor; butamifos; butenachlor; buthidazole; butralin; butylate; cafenstrole (CH- 900); carbetamide; cafentrazone (ICI-A0051); CDAA, d.h. 2-Chlor-N,N-di-2- propenylacetamid; CDEC, d.h. Diethyldithiocarbaminsäure-2-chlorallylester; chlo- methoxyfen; chloramben; chlorazifop-butyl, chlormesulon (ICI-A0051); chlorbromu- ron; chlorbufam; chlorfenac; chlorflurecol-methyl; chloridazon; chlorimuron ethyl; chlornitrofen; chlorotoluron; chloroxuron; chlorpropham; chlorsulfuron; chlorthaldi- methyl; chlorthiamid; cinmethylin; cinosulfuron; clethodim; clodinafop und dessenBrands and trademarks of Rhone Poulenc); bentazone; epoxiconazole; sethoxydim; hormones; metazachlor (products, brands and trademarks of BASF); acetochlor; acifluorfen; aclonifen; AKH 7088, ie [[[1- [5- [2-chloro-4- (trifluoromethyl) phenoxyl-2-nitrophenyll-2-methoxyethylidenel-aminol-oxy] - acetic acid and - acetic acid methyl ester; alachlor; alioxydim; ametryn; amidosulfuron; amitroi; AMS, ie ammonium sulfamate; anilofos; asulam; atrazine; azimsulfurone (DPX-A8947); aziprotryn; azoxystrobin; barban; BAS 516 H, ie 5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one; benazolin; benfluralin; benfuresate; bensulfuron-methyl; bensulide; bentazone; benzofenap; benzofluor; benzoylpropethyl; benzthiazuron; bialaphos; bifenox; bro-macil; bromobutide; bromofenoxim; bromoxynil; bromuron; buminafos; busoxinone; butachlor; butamifos; butenachlor; buthidazole; butralin; butylates; cafenstrole (CH-900); carbetamide; cafentrazone (ICI-A0051); CDAA, ie 2-chloro-N, N-di-2- propenylacetamide; CDEC, ie 2-chloroallyl ester of diethyldithiocarbamic acid; chlo methoxyfen; chloramben; chlorazifop-butyl, chloromesulone (ICI-A0051); chlorobromon; chlorobufam; chlorfenac; chlorflurecol-methyl; chloridazon; chlorimuron ethyl; chloronitrofen; chlorotoluron; chloroxuron; chlorpropham; chlorsulfuron; chlorthaldi-methyl; chlorothiamide; cinmethylin; cinosulfuron; clethodim; clodinafop and its
Esterderivate (z.B. clodinafop-propargyl); clomazone; clomeprop; cloproxydim; clo- pyralid; cumyluron (JC 940); cyanazine; cycloate; cyclosulfamuron (AC 104); cy- cloxydim; cycluron; cyhalofop und dessen Esterderivate (z.B. Butylester, DEH-112); cyperquat; cyprazine; cyprazole; daimuron; 2,4-DB; dalapon; desmedipham; desme- tryn; di-allate; dicamba; dichlobenil; dichlorprop, dicloiop und dessen Ester wie dicl- ofop-methyl; diethatyl; difenoxuron; difenzoquat; diflufenican; dimefuron; di- methachlor; dimethametryn; dimethenamid (SAN-582H); dimethazone, clomazon; dimethipin; dimetrasulfuron, dinitramine; dinoseb; dinoterb; diphenamid; dipropetryn; diquat; dithiopyr; diuron; DNOC; eglinazine-ethyl; EL 77, d.h. 5-Cyano-1 -(1 , 1 - dimethylethyl)-N-methyl-1 H-pyrazole-4-carboxamid; endothal; EPTC; esprocarb; ethalfluralin; eihametsulfuron-methyl; ethidimuron; ethiozin; ethofumesate; F5231 , d.h. N-[2-Chlor-4-fluor-5-[4-(3-fluorpropyl)-4,5-dihydro-5-oxo-l H-tetrazol-1 -yll- phe- nyl)-ethansulfonamid; ethoxyfen und dessen Ester (z.B. Ethylester, HN-252); etobanzanid (HW 52); fenoprop; fenoxan, fenoxaprop und fenoxaprop-P sowie deren Ester, z.B. fenoxaprop-P-ethyl und fenoxaprop-ethyl; fenoxydim; fenuron; flamprop- methyl; flazasulfuron, fluazifop; fluazifop-P und deren Ester, z.B. fluazifop-butyl und fluazifop-P-butyl; fluchloralin; flumetsulam; flumeturon; flumiclorac und dessen Ester (z.B. Pentylester, S-23031); flumioxazin (S-482); flumipropyn; flupoxam (KNW-739); fluorodifen; fluoroglycofen-ethyl, flupropacil (USIC-4243); fluridone; flurochloridone; fluroxypyr; flurtamone; fomesafen; fosamine; furyloxyfen; glufosinate; glyphosate, halosafen; halosulfuron und dessen Ester (z.B. Methylester, NC-31 9); haloxyfop und dessen Ester; haloxyfop- P (= R-haloxyfop) und dessen Ester; hexazinone; imaza- methabenz-methyl; imazapyr; imazaquin und Salze wie das Ammoniumsalz; ima- zethamethapyr; imazethapyr; imazosulfuron; imidacloprid; ioxynil; isocarbamid; iso- propalin; isoproturon; isouron; isocaben; isoxapyrifop; karbutilate, kresoxim; kre- soxim-methyl; KTU 3616; lacofen; lenacil; linuron; MCPA; MCPB; mecoprop; me- fenacet; mefluidid; metamitron; metazachlor-, methabenzthiazuron; metham; metha- zole; methoxyphenone; methyldymron; metabenzuron; methobenzuron; metobromu- ron; metolachlor; metosulam (XRD 511); metoxuron; metribuzin; metsulfuron-mathyl; MH; molinate; monalide; monocarbarnide dihydrogensulfate; monolinuron; monuron; MT 1 28, d.h. 6-Chlor-N- (3-chlor-2-propenyl)-5-methyl-N-phenyl-3-pyridazinamin; MT-5950, d.h. N-[3-Chlor-4- (1-methylethyi)-phenyll-2-methylpentanamid; naproanilide; napropamide; naptalam;Ester derivatives (eg clodinafop-propargyl); clomazone; clomeprop; cloproxydim; copyralid; cumyluron (JC 940); cyanazine; cycloate; cyclosulfamuron (AC 104); cy-cloxydim; cycluron; cyhalofop and its ester derivatives (eg butyl ester, DEH-112); cyperquat; cyprazine; cyprazole; daimuron; 2,4-DB; dalapon; desmedipham; desme- tryn; di-allate; dicamba; dichlobenil; dichlorprop, dicloiop and its esters such as dicl-ofop-methyl; diethatyl; difenoxuron; difenzoquat; diflufenican; dimefuron; dimethachlor; dimethametryn; dimethenamid (SAN-582H); dimethazone, clomazone; dimethipin; dimetrasulfuron, dinitramine; dinoseb; dinoterb; diphenamide; dipropetryn; diquat; dithiopyr; diuron; DNOC; eglinazine-ethyl; EL 77, ie 5-cyano-1 - (1, 1-dimethylethyl) -N-methyl-1 H-pyrazole-4-carboxamide; endothal; EPTC; esprocarb; ethalfluralin; egg hametsulfuron-methyl; ethidimuron; ethiozin; ethofumesate; F5231, ie N- [2-chloro-4-fluoro-5- [4- (3-fluoropropyl) -4,5-dihydro-5-oxo-1H-tetrazole-1-yl-phenyl) -ethanesulfonamide ; ethoxyfen and its esters (eg ethyl ester, HN-252); etobanzanide (HW 52); fenoprop; fenoxan, fenoxaprop and fenoxaprop-P and their esters, for example fenoxaprop-P-ethyl and fenoxaprop-ethyl; fenoxydim; fenuron; flamprop-methyl; flazasulfuron, fluazifop; fluazifop-P and their esters, for example fluazifop-butyl and fluazifop-P-butyl; fluchloralin; flumetsulam; flumeturon; flumiclorac and its esters (eg pentyl ester, S-23031); flumioxazin (S-482); flumipropyn; flupoxam (KNW-739); fluorodifen; fluoroglycofen-ethyl, flupropacil (USIC-4243); fluridone; flurochloridone; fluroxypyr; flurtamone; fomesafen; fosamine; furyloxyfen; glufosinate; glyphosate, halosafen; halosulfuron and its esters (eg methyl ester, NC-31 9); haloxyfop and its esters; haloxyfop-P (= R-haloxyfop) and its esters; hexazinone; imazamethabenz-methyl; imazapyr; imazaquin and salts such as the ammonium salt; imazethamethapyr; imazethapyr; imazosulfuron; imidacloprid; ioxynil; isocarbamide; iso-propalin; isoproturon; isouron; isocaben; isoxapyrifop; carbutilates, cresoxime; cre- soxim-methyl; KTU 3616; lacofen; lenacil; linuron; MCPA; MCPB; mecoprop; mefenacet; mefluidide; metamitron; metazachloro-, methabenzthiazuron; metham; methazole; methoxyphenone; methyldymron; metabenzuron; methobenzuron; metobromu- ron; metolachlor; metosulam (XRD 511); metoxuron; metribuzin; metsulfuron-mathyl; MH; molinate; monalide; monocarbarnide dihydrogen sulfates; monolinuron; monuron; MT 1 28, ie 6-chloro-N- (3-chloro-2-propenyl) -5-methyl-N-phenyl-3-pyridazinamine; MT-5950, ie N- [3-chloro-4- (1-methylethyl) phenyl-2-methylpentanamide; naproanilide; napropamide; naptalam;
NC 31 0, d.h. 4-(2,4-dichlorbenzoyl)-1 -methyl-5- benzyloxypyrazol; neburon; nico- sulfuron; nipyraclophen; nitralin; nitrofen; nitrofluorfen; norflurazon; orbencarb; ory- zalin; oxadiargyl (RP-020630); oxadiazon; oxyfluorfen; paraquat, pebulate-, pendi- methalin; perfluidone; phenisophem; phenisopharm; phenmedipharm; picloram; pi- perophos; piributicarb; pirifenop-buty: pretilachlor; primisulfuron-methyl; procayzine; prodiamine, profluraline; proglinazine-ethyl; prometon; prometryn; propachlor; pro- panil; propaquizafop und dessen Ester; propazine; propham; propisochlor; propyza- mide; prosulfalin; prosulfocarb; prosulfuron (CGA-152005); prynachlor; pyrazolinate, pyrazon; pyrazosulfuron-ethyl; pyrazoxyfen; pyridate; pyrithiobac (KIH-2031); pyroxofop und dessen Ester (z.B. Propargylester); quinclorac; quinmerac; quinofop und dessen Esterderivate, quizalofop und quizalofop-P und deren Esterderivate z.B. quizalofop- ethyl; quizalofop-P-tefuryl und -ethyl; renriduron; rimsulfuron (DPX-E 9636); S 275, d.h. 2-[4-Chlor-2-fluor-5-(2-propynyloxy)-phenyll-4,5,6,7-tetrahydro-2H-indazol; secbumeton; sethoxydim; siduron; simazine; simetryn; SNNC 31 0, i.e. 4- (2,4-dichlorobenzoyl) -1-methyl-5-benzyloxypyrazole; neburon; nico-sulfuron; nipyraclophen; nitraline; nitrofen; nitrofluorfen; norflurazon; orbencarb; oryzalin; oxadiargyl (RP-020630); oxadiazon; oxyfluorfen; paraquat, pebulate-, pendimethalin; perfluidone; phenisopheme; phenisopharm; phenmedipharm; picloram; piperophos; piributicarb; pirifenop-buty: pretilachlor; primisulfuron-methyl; procayzine; prodiamine, profluraline; proglinazine-ethyl; prometon; prometryn; propachlor; propane; propaquizafop and its esters; propazine; propham; propisochlor; propyzamide; prosulfalin; prosulfocarb; prosulfuron (CGA-152005); prynachlor; pyrazolinates, pyrazone; pyrazosulfuron-ethyl; pyrazoxyfen; pyridate; pyrithiobac (KIH-2031); pyroxofop and its esters (e.g. propargyl esters); quinclorac; quinmerac; quinofop and its ester derivatives, quizalofop and quizalofop-P and their ester derivatives e.g. quizalofop-ethyl; quizalofop-P-tefuryl and ethyl; renriduron; rimsulfuron (DPX-E 9636); S 275, i.e. 2- [4-chloro-2-fluoro-5- (2-propynyloxy) phenyl-4,5,6,7-tetrahydro-2H-indazole; secbumeton; sethoxydim; siduron; simazine; simetryn; SN
106279, d.h. 2-[[7-[2-Chlor-4-(trifluor-methyl)-phenoxyl-2-naphthalenyll-Oxyl- pro- pansäure und -methylester; sulfentrazon (FMC-97285, F-6285); sulfazuron; sulfo- meturon-mothyl; sulfosate (ICI-A0224); TCA; tebutam (GCP-5544); tebuthiuron; ler- bacil; terbucarb; terbuchlor; terbumeton; terbuthylazine; terbutryn; TFH 450, d.h. N,N-Diethyl-3-[(2-ethyl-6-methylphenyl)-sulfonyll-1 H- 1 ,2,4-triazol-l-carboxamid; thenylchlor (NSK-850); thiazafluron; thiazopyr (Mon-13200); thidiazimin (SN-24085) thifensulfuron-methyl; thiobencarb; tiocarbazil; tralkoxydim; tri-allate; triasulfuron; triazofenamide; tribenuron-methyl; triclopyr; tridiphane; trietazine; trifluralin; triflusul- furon und Ester (z.B. Methylester, DPX-66037); trimeturon; tsitodef; vernolate; WL 1 1 0547, d.h. 5-Phenoxy-1 -[3-(trifluormethyl)-phenyll-1 H-tetrazol; UBH-509; D-489;106279, i.e. 2 - [[7- [2-chloro-4- (trifluoromethyl) phenoxyl-2-naphthalenylloxylpropanoic acid and methyl ester; sulfentrazone (FMC-97285, F-6285); sulfazuron; sulfometuron-mothyl; sulfosate (ICI-A0224); TCA; tebutam (GCP-5544); tebuthiuron; ler-bacil; terbucarb; terbuchlor; terbumeton; terbuthylazine; terbutryn; TFH 450, i.e. N, N-Diethyl-3 - [(2-ethyl-6-methylphenyl) sulfonyll-1 H-1, 2,4-triazole-l-carboxamide; thenylchlor (NSK-850); thiazafluron; thiazopyr (Mon-13200); thidiazimin (SN-24085) thifensulfuron-methyl; thiobencarb; tiocarbazil; tralkoxydim; tri-allate; triasulfuron; triazofenamide; tribenuron-methyl; triclopyr; tridiphane; trietazine; trifluralin; triflusul furon and esters (e.g. methyl ester, DPX-66037); trimeturon; tsitodef; vernolate; WL 1 1 0547, i.e. 5-phenoxy-1 - [3- (trifluoromethyl) phenyl-1 H-tetrazole; UBH-509; D-489;
LS 82-556; KPP-300; NC-324; NC-330; KH-21 8; DPX-N81 89; SC-0774; DOWCO- 535; DK-8910; V-53482; PP-600, MBH-001; KIH-9201; ET-75 1; KIH-61 27 und KIH- 2023. Als pharmazeutische Wirkstoffe geeignet sind u.a.:LS 82-556; KPP-300; NC-324; NC-330; KH-21 8; DPX-N81 89; SC-0774; DOWCO-535; DK-8910; V-53482; PP-600, MBH-001; KIH-9201; ET-75 1; KIH-61 27 and KIH-2023. Suitable pharmaceutical active ingredients include:
- Nikotin,- nicotine,
- Scopoiamin bzw. L-Hyoscin- Scopoiamin or L-hyoscin
- Hormone, z.B. Östrogenderivate wie Estradiol; Gestagenderivate wie Levonorge- strel oder Norethisteronacetat; TestosteronHormones, e.g. Estrogen derivatives such as estradiol; Progestin derivatives such as levonorge strel or norethisterone acetate; testosterone
- Glyceroltrinitrat- glycerol trinitrate
- synthetische Opoidanalgetika wie z.B. Fentanyl- synthetic opoid analgesics such as Fentanyl
- nichtsteroidale Antiphlogistika wie z.B. Flurbiprofen, Diciofenac, Ketoprofen, Keto- rolac,- non-steroidal anti-inflammatory drugs such as Flurbiprofen, Diciofenac, Ketoprofen, Ketololac,
- blutdrucksenkende Wirkstoffe, insbesondere α-Adrenozeptor-Agonisten wie Clo- nidin, insbesondere auch sogenannte ß-Blocker wie Propranolol, Mepindolol u.a.- Blood pressure lowering agents, especially α-adrenoceptor agonists like clonidine, especially also so-called β-blockers like propranolol, mepindolol and others.
- Peptide wie Insulin, Leuprolid, Enkephalin, Oxytocin, Ramorelix, Caicitonin, Buse- relin und deren Abkömmlinge- Peptides such as insulin, leuprolide, enkephalin, oxytocin, Ramorelix, caicitonin, buselrelin and their descendants
- Campher- Camphor
- Ethanol- ethanol
- Zytostatika, wie z.B. 5-FluorouracilCytostatics, e.g. 5-fluorouracil
- Parkinsonstherapeutika, insbesondere Monoaminooxidasehemmer wie Selegelin, insbesondere auch Dopamin-D2-Agonisten, insbesondere auch Parasympatho- mimetika, im speziellen Cholinesterasehemmstoffe wie Physostigmin- Parkinson's therapies, in particular monoamine oxidase inhibitors such as selegelin, in particular also dopamine D 2 agonists, in particular also parasympathomimetics, in particular cholinesterase inhibitors such as physostigmine
- Neuroleptika- neuroleptics
Potentielle Wirkstoffe für eine orale Anwendung sind beispielsweise:Potential active ingredients for oral use include:
- ß-Rezeptorenblocker, wie z.B. Metoprolol, Acebutolol, Atenolol u.a. - Anti-Parkinsonmittel, wie z.B. Levodopa, Benserazid, Biperiden oder Kombinationen verschiedener Anti-Parkinsonmittel- ß-receptor blockers, such as metoprolol, acebutolol, atenolol and others - Anti-Parkinson agents, such as levodopa, benserazide, biperiden or combinations of various anti-Parkinson agents
- Calciumantagonisten, wie z.B. Nifedipin, Diltiazem u.a.Calcium antagonists, e.g. Nifedipine, diltiazem and others
- ACE-Hemmer, wie z.B. Captopril, Lisinopril, Perindopril u.a.ACE inhibitors, such as Captopril, lisinopril, perindopril and others
- Opoide und Narkoanalgetika, wie z.B. Morphinsulfat- opoids and narcotic analgesics, e.g. Morphine sulfate
- Antiallergika, wie z.B. Terfenadin, Loratadin u.a.Antiallergics, such as Terfenadine, Loratadine and others
- Antiarrhytmika, wie z.B. MexitilAntiarrhythmics, e.g. Mexitil
- Antiepileptika, wie z.B. CarbamazepinAnti-epileptics, e.g. Carbamazepine
- Antiphlogistika, wie z.B. Piroxicam, Indomethacin- anti-inflammatory drugs, e.g. Piroxicam, indomethacin
- Theophyllin und Derivate als Broncholytikum- Theophylline and derivatives as a broncholytic
- Diuretika, wie z.B. Furosemid, PiretanidDiuretics, e.g. Furosemide, piretanide
- Gichtmittel, wie z.B. Allopurinol- gout agents, e.g. Allopurinol
- Lipidsenker, wie z.B. Clofibrat, Lovastatin- lipid-lowering agents, e.g. Clofibrate, lovastatin
- Antidepressiva, wie z.B. AmytriptylinAntidepressants, such as Amytriptyline
Bei den in obiger Liste angeführten Wirkstoffen handelt es sich selbstverständlich nur um Beispiele zur näheren Erläuterung der vorliegenden Erfindung.The active substances listed in the above list are of course only examples for a more detailed explanation of the present invention.
Sowohl Poly(α-1 ,4-D-Glucan) wie auch die vorab erwähnten thermoplastischen Mischungen von Poly(α-1 ,4-D-Glucan) mit thermoplastischer Stärke können selbstverständlich mit weiteren thermoplastisch verarbeitbaren Polymeren gemischt werden, welche bevorzugt biokompatibel sind, wie auch vorzugsweise physiologisch verträglich. Dabei kann es sich beispielsweise um Vinylverbindungen handeln, wie Äthylen- vinylalkohol, bzw. Copolymere von Vinylacetat und Vinylacrylat mit Äthylen. Weitere geeignete Polymere sind beispielsweise Polyalkanoate, wie insbesondere aliphati- sche Polyester. Im weiteren ist es auch möglich, α 1 ,4-Glucan zu komplexieren, wie beispielsweise mit Palmitinsäure. Die Komplexierung kann gegebenenfalls auch dazu verwendet werden, um pharmazeutische, kosmetische, landwirtschaftliche und ähnliche Wirkstoffe am Poly(α-1 ,4-D-Glucan) durch Komplexierung zu binden. Dabei wird vorgeschlagen, daß dem Poly(α-1 ,4-D-Glucan) zwischen 2 - 20 Gew% eines Komplexbildners beigemengt werden.Both poly (α-1, 4-D-glucan) and the aforementioned thermoplastic mixtures of poly (α-1, 4-D-glucan) with thermoplastic starch can of course be mixed with other thermoplastically processable polymers, which are preferably biocompatible , as also preferably physiologically compatible. These can be, for example, vinyl compounds, such as ethylene-vinyl alcohol, or copolymers of vinyl acetate and vinyl acrylate with ethylene. Other suitable polymers are, for example, polyalkanoates, such as, in particular, aliphatic polyesters. Furthermore, it is also possible to complex α 1,4-glucan, for example with palmitic acid. The complexation can optionally also be used to bind pharmaceutical, cosmetic, agricultural and similar active substances to the poly (α-1,4-D-glucan) by complexation. It is proposed that between 2 and 20% by weight of a complexing agent be added to the poly (α-1,4-D-glucan).
Die Erfindung wird nun nachfolgend anhand von Beispielen näher erläutert, wobei selbstverständlich die vorliegende Erfindung nicht auf die angeführten Beispiele beschränkt bleibt. The invention will now be explained in more detail below with the aid of examples, the present invention of course not being restricted to the examples given.
Beispiele 1 bis 7:Examples 1 to 7:
Zur Untersuchung der Eignung von Mischungen von Poly(α-1 ,4-D-Glucan) mit thermoplastischer Stärke wurde nun die ganze Mischungsreihe von Poly(α-1 ,4-D- Glucan) und thermoplastischer Stärke bezüglich Kristallinität und mechanischer Ei- genschaften untersucht. Als Weichmacher für Poly( -1 ,4-D-Glucan) wurden 35%To investigate the suitability of mixtures of poly (α-1, 4-D-glucan) with thermoplastic starch, the entire series of mixtures of poly (α-1, 4-D-glucan) and thermoplastic starch has now been examined with regard to crystallinity and mechanical properties examined. As a plasticizer for poly (-1, 4-D-glucan) 35%
Glyzerin verwendet, da sich dieses Material als sehr geeignet erwiesen hat und zudem, wie bereits oben erwähnt, dieses Material in bezug auf pharmazeutische und/oder kosmetische Präparationen unbedenklich einsetzbar ist. Poly(α-1 ,4-D- Glucan) wird dabei bei ca. 170°C mit dem Weichmacher, wie dem erwähnten Glyze- rin gemischt. Anschließend wird das so weichgemachte Poly(α-1 ,4-D-Glucan) mit thermoplastischer Stärke wiederum in einem Temperaturbereich von ca. 160° bis 180°C in einem Extruder gemischt, wobei die Verweilzeit je nach Zusammensetzung zwischen 1 bis 5 Minuten beträgt, bei 50 bis 200 Umdrehungen pro Minute, vorzugsweise 100 U/min. Die beim Extruder eingebrachte Plastifizier- bzw. Mischarbeit pro Kg Poly(α-1 ,4-D-Glucan) beträgt zwischen 0,2 bis 0,4 kWh.Glycerin is used because this material has proven to be very suitable and, as already mentioned above, this material can also be safely used in relation to pharmaceutical and / or cosmetic preparations. Poly (α-1,4-D-glucan) is mixed at about 170 ° C. with the plasticizer, such as the glycerin mentioned. Subsequently, the plasticized poly (α-1,4-D-glucan) with thermoplastic starch is again mixed in a temperature range of approx. 160 ° to 180 ° C in an extruder, the residence time depending on the composition being between 1 and 5 minutes , at 50 to 200 revolutions per minute, preferably 100 rpm. The plasticizing or mixing work per kg of poly (α-1, 4-D-glucan) introduced into the extruder is between 0.2 and 0.4 kWh.
Die für die Herstellung der Mischungen mit Poly(α-1 ,4-D-Glucan) verwendete thermoplastische Stärke wurde hergestellt durch Mischen mit einem Plastifiziermittel bzw. Weichmacher, wie beispielsweise mit 35% Glyzerin in einem Temperaturbereich von ca. 160°C bis 180°C, wobei nun als wesentliches Merkmal für die Herstel- lung der thermoplastischen Stärke während des Mischvorgangs in der Schmelze derThe thermoplastic starch used for the preparation of the mixtures with poly (α-1, 4-D-glucan) was produced by mixing with a plasticizer or plasticizer, such as, for example, with 35% glycerol in a temperature range from approx. 160 ° C. to 180 ° C, which is now an essential feature for the production of the thermoplastic starch during the mixing process in the melt
Wassergehalt auf mindestens weniger als 5 Gew% bezogen auf die Mischung Stär- ke/Plastifiziermittel reduziert wurde. Im übrigen wird für die Herstellung der thermoplastischen Stärke auf das europäische Patent EP 0 397 819 verwiesen, welches aus der eingangserwähnten WO90/05161 hervorgegangen ist.Water content was reduced to at least less than 5% by weight based on the starch / plasticizer mixture. For the rest, reference is made to the European patent EP 0 397 819 for the production of the thermoplastic starch, which was derived from the aforementioned WO90 / 05161.
Alternativ ist es aber auch möglich, die thermoplastischen Mischungen zwischenAlternatively, it is also possible to interpose the thermoplastic mixtures
Poly(α-1 ,4-D-Glucan) und thermoplastischer Stärke in einem Schritt herzustellen, indem Poly(α-1 ,4-D-Glucan) und native Stärke zusammen mit 35% Glyzerin in einem Extruder bei ca. 170°C aufgeschmolzen und verformt werden, wobei wiederum für das Entstehen der thermoplastischen Stärke Feuchtigkeit der Schmelze entzogen werden muß, auf einen Wert unter 5 Gew%, bezogen auf die Menge native Stärke und anteilsmäßig zur Stärke beigefügte Menge Plastifiziermittel wie beispielsweise 35% Glyzerin.Prepare poly (α-1, 4-D-glucan) and thermoplastic starch in one step by adding poly (α-1, 4-D-glucan) and native starch together with 35% glycerin in an extruder at approx. 170 ° C are melted and deformed, again for the formation of the thermoplastic starch moisture must be removed from the melt, to a value below 5% by weight, based on the amount of native starch and a proportionate amount of plasticizer such as 35% glycerin added to the starch.
Zur Bestimmung der Kristallinität wurden verschiedene Proben mit unterschiedlicher Zusammensetzung drei Tage nach der Herstellung mit Röntgend iffraktion unter- sucht, wobei in den erhaltenen Spektren dann der kristalline Anteil AR im Röntgenspektrum vom amorphen Halo Aa separiert und der Kristallinitätsgrad K in Prozent entsprechend der nachfolgenden FormelTo determine the crystallinity, different samples with different compositions were examined with X-ray fraction three days after production, the crystalline fraction AR in the X-ray spectrum being separated from the amorphous halo A a in the spectra obtained and the degree of crystallinity K in percent according to the following formula
K = 100 x Ak /(Aa + Aκ) berechnet wurde.K = 100 x A k / (A a + A κ ) was calculated.
Die Kristallinität für die Mischungsreihe, bezogen auf Gewichtsanteil Poly( -1 ,4-D- Glucan) mit jeweils 0,35 Gewichtsanteil Glyzerin als Weichmacher ist in Tabelle 1 angeführt.The crystallinity for the series of mixtures, based on the proportion by weight of poly (-1, 4-D-glucan), each with 0.35 part by weight of glycerol as plasticizer, is shown in Table 1.
Wird die Kristallinität von 45,8% von reinem Poly(α-1 ,4-D-Glucan) gleich 1 gesetzt und die Kristallinität der anderen Proben darauf bezogen, so ergibt sich ein nahezu linearer Zusammenhang zwischen der relativen Kristallinität und dem Anteil von Po- ly(α-1 ,4-D-Glucan). Die oben angeführte Zahlenreihe ist im übrigen in Figur 1 der beigefügten Figuren dargestellt.If the crystallinity of 45.8% of pure poly (α-1, 4-D-glucan) is set to 1 and the crystallinity of the other samples is based on this, there is an almost linear relationship between the relative crystallinity and the proportion of Po - ly (α-1,4-D-glucan). The series of numbers mentioned above is otherwise shown in Figure 1 of the accompanying figures.
Poly(α-1 ,4-D-Glucan) bewirkt also keine Zunahme der Kristallinität der thermoplastischen Stärkephase und umgekehrt bringt der TPS-Anteil keine Abnahme der Kristallinität von Poly(α-1 ,4-D-Glucan). Die festgestellte Struktur ist eine Mischung aus V- Amylose und einer bisher nicht identifizierten Struktur, wozu auf Figur 2 verwiesen wird.Poly (α-1, 4-D-glucan) therefore does not cause an increase in the crystallinity of the thermoplastic starch phase and conversely the TPS portion does not result in a decrease in the crystallinity of poly (α-1, 4-D-glucan). The structure found is a mixture of V-amylose and a structure which has not been identified to date, for which reference is made to FIG. 2.
Von der Mischungsreihe zwischen Poly(α-1,4-D-Glucan), weichgemacht mit 35% Glyzerin und thermoplastischer Stärke wurden im weiteren die mechanischen Eigenschaften gemessen, wobei sich die nachfolgenden Werte ergaben: Tabelle 1The mechanical properties of the mixture series between poly (α-1,4-D-glucan), plasticized with 35% glycerin and thermoplastic starch were measured further, giving the following values: Table 1
Poly(α 1 ,4-D-Glucan) E δ b KPoly (α 1, 4-D-glucan) E δ b K
Gew.Anteile MPa MPa % %Parts by weight MPa MPa%%
Beispiel 1 1 ,00 52,7+/-7 2.8+/-0.5 11 ,7+/-2 0,458Example 1 1, 00 52.7 +/- 7 2.8 +/- 0.5 11, 7 +/- 2 0.458
Beispiel 2 0,875 55,3+/-9 4.5+/-0.5 21.1+/-3 0,386Example 2 0.875 55.3 +/- 9 4.5 +/- 0.5 21.1 +/- 3 0.386
Beispiel 3 0,75 46,2+/-6 5,6+/-0,7 26,2+/-5 0,382Example 3 0.75 46.2 +/- 6 5.6 +/- 0.7 26.2 +/- 5 0.382
Beispiel 4 0,62 31 ,3+ 4.0+/-0.1 23.8+/-1 0,285Example 4 0.62 31, 3 + 4.0 +/- 0.1 23.8 +/- 1 0.285
Beispiel 5 0,50 18.1+/-2 3.5+/-0.2 42.0+/-7 0,247Example 5 0.50 18.1 +/- 2 3.5 +/- 0.2 42.0 +/- 7 0.247
Beispiel 6 0,25 24,2+/-7 4.6+/-0.4 79,0+/-6 0,072Example 6 0.25 24.2 +/- 7 4.6 +/- 0.4 79.0 +/- 6 0.072
Beispiel 7 0 184 +/-34 9.4+/-0.5 15.8+/-5 0,045Example 7 0 184 +/- 34 9.4 +/- 0.5 15.8 +/- 5 0.045
Für jede Probe wurden jeweils fünf Zugversuche durchgeführt. Der Verlauf der Festigkeit und der Bruchdehnung unter Angabe des Gehaltes an Poly(α-1 ,4-D-Glucan) ist in Figur 3 dargestellt. Die Festigkeit hat innerhalb der Mischungsreihe bei reiner thermoplastischer Stärke mit 9,4 MPa das Maximum, wonach sie schnell abnimmt und bei 50% α 1 ,4-Glucan mit 3,5 MPa zu einem Minimum kommt, welches nur wenig über der Festigkeit von 2,8 MPa von reinem Poly(α-1 ,4-D-Glucan) liegt. Nach diesem Minimum steigt die Festigkeit wieder an und erreicht bei 75% Poly(α-1 ,4-D- Glucan) ein Zwischenmaximum, um danach bis zu 100% Poly(α-1 ,4-D-Glucan) wieder abzunehmen. Ein solcher S-förmiger Verlauf der Festigkeit ist üblich, dieses Verhalten kann innerhalb vieler Mischungsreihen beobachtet werden. Die Bruchenergie bei einem TPS-Gehalt von 25% ist vergleichbar mit reiner thermoplastischer Stärke. Der E-Modul beträgt für 100% TPS mit 35% Glyzerin 184 MPa und fällt dann knapp auf 20 MPa bei 50% Poly(α-1 ,4-D-Glucan), um danach wieder auf rund 50Five tensile tests were carried out for each sample. The course of the strength and the elongation at break, indicating the content of poly (α-1,4-D-glucan), is shown in FIG. 3. The strength has the maximum within the series of mixtures with pure thermoplastic starch at 9.4 MPa, after which it decreases rapidly and at 50% α 1, 4-glucan with 3.5 MPa comes to a minimum, which is only slightly above the strength of 2 , 8 MPa of pure poly (α-1,4-D-glucan). After this minimum, the strength increases again and reaches an intermediate maximum at 75% poly (α-1, 4-D-glucan) and then decreases again up to 100% poly (α-1, 4-D-glucan). Such an S-shaped course of strength is common, this behavior can be observed in many mixture series. The breaking energy at a TPS content of 25% is comparable to pure thermoplastic starch. For 100% TPS with 35% glycerol, the modulus of elasticity is 184 MPa and then falls just below 20 MPa at 50% poly (α-1, 4-D-glucan) and then again to around 50
MPa von reinem anzusteigen. Bezüglich der Bruchdehnung sind TPS und Poly(α- 1 ,4-D-Glucan) vergleichbar. 25% Anteil Poly(α-1 ,4-D-Glucan) jedoch bewirkt eine deutliche Verbesserung der Bruchdehnung auf 79%. Wie bereits oben erwähnt, ist Glyzerin ein geeigneter Weichmacher für Poly(α-1 ,4-D- Glucan), wobei beispielsweise durch Verwendung von 35% Glyzerin praktisch identische Eigenschaften erreicht werden können, wie in thermoplastischer Stärke, ebenfalls weich gemacht mit 35% Glyzerin. Allerdings können grundsätzlich alle diejenigen Materialien zur Weichmachung von Poly(α-1 ,4-D-Glucan) verwendet werden, welche ebenfalls geeignet sind für die Plastifizierung bzw. Weichmachung von thermoplastischer Stärke. Geeignet sind beispielsweise Glycerin, DMSO, Zitronen- säure-Monohydrat, Sorbitol, etc. um nur einige zu nennen. Generell sind alle Substanzen geeignet mit einem Löslichkeitsparameter von größer 30 Mpa, wobei diese im Bereich von Pharmaanwendungen physiologisch unbedenklich zu sein haben.To increase MPa from pure. In terms of elongation at break, TPS and poly (α-1, 4-D-glucan) are comparable. 25% poly (α-1, 4-D-glucan), however, causes a significant improvement in the elongation at break to 79%. As already mentioned above, glycerin is a suitable plasticizer for poly (α-1,4-D-glucan), whereby, for example, by using 35% glycerol practically identical properties can be achieved as in thermoplastic starch, also softened with 35%. Glycerin. In principle, however, all those materials can be used for plasticizing poly (α-1, 4-D-glucan) which are also suitable for plasticizing or plasticizing thermoplastic starch. Glycerin, DMSO, citric acid monohydrate, sorbitol, etc. are suitable, to name but a few. In general, all substances are suitable with a solubility parameter of more than 30 Mpa, whereby these have to be physiologically harmless in the field of pharmaceutical applications.
Insbesondere die Verwendung von 35% Zitronensäure-Monohydrat ergab ein Material mit erstaunlichen mechanischen Eigenschaften. So wurde beispielsweise ein E- Modul von 550 MPa und eine Festigkeit von 15 MPa bei einer Bruchdehnung von 15% gefunden.In particular, the use of 35% citric acid monohydrate resulted in a material with astonishing mechanical properties. For example, an elastic modulus of 550 MPa and a strength of 15 MPa with an elongation at break of 15% were found.
Herstellung von pharmazeutischen bzw. kosmetischen Zusammensetzungen:Manufacture of pharmaceutical or cosmetic compositions:
Zunächst wird erneut als Basis von weichgemachtem Poly(α-1 ,4-D-Glucan) ausgegangen, wie bereits hergestellt gemäß dem Verfahren, beschrieben im Zusammenhang mit den Beispielen 1 bis 7. Zum Herstellen einer thermoplastischen Polymermischung, geeignet als Trägermatrix für agrochemische, pharmazeutische und/oder kosmetische Wirksubstanzen, können entweder Mischungen zwischen den weichgemachten Poly(α-1 ,4-D-Glucan) und thermoplastischer Stärke verwendet werden, wie auch Mischungen zwischen dem Polyglucan und anderen geeigneten Polymeren, wie Vinylverbindungen, Polyalkanoate, um nur einige zu nennen. Wesentlich dabei ist natürlich, daß diese weiteren Polymere thermoplastisch verarbeitbar sind, physiologisch verträglich sowie vorzugsweise biologisch kompatibel sind. Natürlich können auch Mischungen zwischen Polyglucan, thermoplastischer Stärke und weiteren Polymeren für die Herstellung der erwähnten Trägermatrix verwendet werden. Auch die Reihenfolge des Mischens der Komponenten für die Herstellung zur thermoplastischen Polymermischung ist an sich frei wählbar, d.h. es kann von der ther- moplastischen Stärke ausgegangen werden, welcher das weichgemachte Polyglucan beigemischt wird, oder aber von einer Polymermischung eines weiteren Po- lymeren mit der thermoplastischen Stärke, welcher das Polyglucan im Extruder beigefügt wird, etc.First, the basis of plasticized poly (α-1, 4-D-glucan) is again used, as already prepared according to the process described in connection with Examples 1 to 7. For producing a thermoplastic polymer mixture, suitable as a carrier matrix for agrochemical, active pharmaceutical and / or cosmetic substances, either mixtures between the plasticized poly (α-1, 4-D-glucan) and thermoplastic starch can be used, as well as mixtures between the polyglucan and other suitable polymers, such as vinyl compounds, polyalkanoates, to only a few to call. It is of course essential that these other polymers can be processed thermoplastically, are physiologically compatible and preferably are biologically compatible. Mixtures between polyglucan, thermoplastic starch and other polymers can of course also be used for the production of the carrier matrix mentioned. The order in which the components are mixed for manufacture to form the thermoplastic polymer mixture can also be chosen freely, ie the thermoplastic starch to which the plasticized polyglucan is added or a polymer mixture of another polymer can be used. polymer with the thermoplastic starch to which the polyglucan is added in the extruder, etc.
Schlußendlich wird zur Herstellung der agrochemischen, pharmazeutischen und/oder kosmetischen Zusammensetzung zur erwähnten thermoplastischen Poly- mermischung eine oder mehrere agrochemische bzw. pharmazeutische bzw. kosmetische Wirksubstanz(en) sowie weitere physiologisch verträgliche Additive, Füllstoffe und dergleichen in der Schmelze beigefügt. Dabei ist es wesentlich, daß die Temperatur im Extruder bzw. beim Mischen in der Schmelze nicht zu hoch gewählt ist, damit nicht eine Schädigung der pharmazeutischen oder kosmetischen Wirksub- stanzen erfolgen kann.Finally, one or more agrochemical or pharmaceutical or cosmetic active substance (s) and further physiologically tolerable additives, fillers and the like are added to the melt to produce the agrochemical, pharmaceutical and / or cosmetic composition for the thermoplastic polymer mixture mentioned. It is essential that the temperature in the extruder or when mixing in the melt is not chosen too high, so that the active pharmaceutical or cosmetic substances cannot be damaged.
Beispiel 8: Herstellung eines transdermalen therapeutischen SystemsExample 8: Preparation of a transdermal therapeutic system
Zur Herstellung eines Amylosefilms, welcher als Bestandteil ein transdermales therapeutisches System aufweist, werden zunächst in einem Extruder bei ca. 170°C ein Teil Poly(α-1 ,4-D-Glucan) mit zwei Teilen thermoplastischer Stärke in der Schmelze gemischt, wobei beide Materialien je 35 % Glyzerin als Weichmacher bzw. Plastifi- ziermittel enthalten. Anschließend wird die Polymerschmelze auf ca. 140°C abgekühlt und als pharmazeutische Wirksubstanz Nikotin sowie ca. 5 % Wasser hinzugefügt und anschließend die erhaltene pharmazeutische Polymerschmelze zu Folien mit einer Schichtdicke von 200 μ extrudiert. Die Dosierung des Nikotins ist derart, daß 7 cm2, ausgeschnitten aus dem extrudierten Film, üblicherweise ca. 35 mg Nikotin enthalten. In der Regel wird der so erhaltene Amylosefilm nicht direkt zur Prüfung der Freigabe verwendet, sondern vielmehr werden sogenannte Nikotinamylose- 24-Std-Patches hergestellt, welche den nachfolgenden Aufbau aufweisen:To produce an amylose film which has a transdermal therapeutic system as a component, one part of poly (α-1,4-D-glucan) is first mixed with two parts of thermoplastic starch in an extruder at about 170 ° C., where Both materials each contain 35% glycerin as a plasticizer or plasticizer. The polymer melt is then cooled to approx. 140 ° C. and nicotine and approx. 5% water are added as the active pharmaceutical substance, and the pharmaceutical polymer melt obtained is then extruded into films with a layer thickness of 200 μ. The dosage of the nicotine is such that 7 cm 2 , cut out of the extruded film, usually contain about 35 mg of nicotine. As a rule, the amylose film obtained in this way is not used directly to check the release, but rather so-called nicotine amylose 24-hour patches are produced, which have the following structure:
- transparente Abdeckfolie aus einem Polymerlaminat,- transparent cover film made of a polymer laminate,
- erfindungsgemäß hergestellter Amylosefilm bzw. Reservoir aus Wirkstoff, wie das erwähnte Nikotin, Polyglucan/TPS-Gemisch enthaltend 35 % Glyzerin,amylose film or reservoir of active ingredient produced according to the invention, such as the above-mentioned nicotine, polyglucan / TPS mixture containing 35% glycerol,
- ringförmige Haftschicht, sowie- annular adhesive layer, as well
- mehrschichtige Laminatschutzschicht. Materialien für die Herstellung des Polymerlaminates, der Haftschicht sowie der Laminatschutzschicht sind allgemein bekannt.- multi-layer laminate protective layer. Materials for the production of the polymer laminate, the adhesive layer and the laminate protective layer are generally known.
Aus dem erwähnten Schichtaufbau werden üblicherweise 7 cm2 große Versuchs- "Pflaster" herausgeschnitten und für den Freigabeversuch verwendet.7 cm 2 large trial “plasters” are usually cut out of the layer structure mentioned and used for the release trial.
Versuchsaufbau:Experiment setup:
Sotax-Auflösungsgerät AT7 mit Extraktionszellen (entspricht USP IV)Sotax AT7 resolution device with extraction cells (corresponds to USP IV)
Freigabemedium: Citratphosphat-Puffer pH 5,9; 900 ml.Release medium: citrate phosphate buffer pH 5.9; 900 ml.
Freigabetemperatur 32°CRelease temperature 32 ° C
Online-Detektion über ein Perkin-Elmer-UV/VIS-Spektrophotometer Lambda 20.Online detection using a Perkin-Elmer UV / VIS spectrophotometer Lambda 20.
UV-Detektion: 290 nm.UV detection: 290 nm.
In der beigefügten Fig. 4 ist die kumulative in vitro-Freigabe von Nikotin aus dem Nikotinamylose-24-Std-Patch bzw. aus dem Amylose/TPS-Matrix-Patch aufgezeichnet bzw. dargestellt. Das Freigabeprofil erfolgt üblicherweise annähernd nach dem Quadratwurzel-Gesetz von Higuchi bei Matrix-Patches.The attached FIG. 4 shows the cumulative in vitro release of nicotine from the nicotine amylose 24 hour patch or from the amylose / TPS matrix patch. The release profile is usually based on Higuchi's square root law for matrix patches.
Anstelle von Nikotin können für transdermale Applikationen in Form beispielsweise von Folien bzw. von sogenannten Pflastern eine Reihe weiterer pharmazeutischer Wirkstoffe verwendet werden.Instead of nicotine, a number of other active pharmaceutical ingredients can be used for transdermal applications in the form of, for example, films or so-called plasters.
Beispiel 9: Extrusionspellets zur oralen Applikation von WirkstoffenExample 9: Extrusion pellets for oral administration of active ingredients
Wiederum wird eine Poly(α-1 ,4-D-Glucan)/TPS-Polymermischung als Matrix für Ex- trusionspellets zur oralen Applikation von Wirkstoffen nach dem Prinzip der "multiple unit dosage forms" verwendet.Again, a poly (α-1,4-D-glucan) / TPS polymer mixture is used as a matrix for extrusion pellets for the oral application of active substances according to the principle of "multiple unit dosage forms".
Zunächst wird wiederum eine Folie hergestellt, analog des Amylose/TPS-Film, welcher als Bestandteil Wirkstoffe für eine transdermale Applikation enthielt. Allerdings werden nur potentielle Wirkstoff, geeignet für eine orale Anwendung, in die Polymer- schmelze eingearbeitet und als Folie extrudiert. Die so erhaltene Folie wird in Streifen von ca. 1 - 2 mm Breite geschnitten und anschließend verkleinert, so daß ca. 1 mm2 große Folienschnitzel entstehen. Diese so erhaltenen Schnitzel, enthaltend den pharmazeutischen Wirkstoff, werden in Tablettenform eingepreßt oder aber in Hartgelatinekapseln eingefüllt.First, a film is again produced, analogous to the amylose / TPS film, which contained active ingredients for transdermal application as a component. However, only potential active ingredients, suitable for oral use, are incorporated into the polymer melt and extruded as a film. The film obtained in this way is cut into strips of approximately 1-2 mm in width and then reduced in size so that approximately 1 mm 2 large pieces of film are created. The cutlets thus obtained, containing the pharmaceutical active ingredient, are pressed in tablet form or else filled into hard gelatin capsules.
Der Vorteil dieser sogenannten "multiple unit dosage forms" liegt darin, daß so Arz- neistoff-Formulierungen erhalten werden, die in vivo rasch in viele Untereinheiten zerfallen. Wird eine "Single unit dosage form", wie z.B. eine herkömmliche Tablette eingesetzt, ist der Zerfall und damit die Wirkstofffreigabe nicht so gut reproduzierbar. Durch Einsatz von Pellets, die mit einer Kombination geeigneter galenischer Hilfsstoffe oder Maßnahmen formuliert werden, ist eine Wirkstofffreigabekinetik mit an- nähernd nullter Ordnung mit dem Einsatz von Pellets (beispielsweise Beloc-Zok) erreichbar. Durch Einsatz von Poly(α-1 ,4-D-Glucan) in Kombination beispielsweise mit thermoplastischer Stärke kann die Wirkstofffreigabe von Pellets über ihre Geometrie und Applikationsform (Tablette oder Kapsel) gesteuert werden. Der Einsatz weiterer Hilfsstoffe ist nicht unbedingt notwendig.The advantage of these so-called "multiple unit dosage forms" is that drug formulations are obtained which rapidly disintegrate into many subunits in vivo. If a "Single unit dosage form", such as If a conventional tablet is used, the disintegration and thus the release of the active ingredient are not so reproducible. By using pellets that are formulated with a combination of suitable pharmaceutical additives or measures, an active ingredient release kinetics with almost zero order can be achieved with the use of pellets (for example Beloc-Zok). By using poly (α-1, 4-D-glucan) in combination with, for example, thermoplastic starch, the active ingredient release of pellets can be controlled via their geometry and application form (tablet or capsule). The use of other auxiliary substances is not absolutely necessary.
Die Pellets oder Schnitzel können in eine Kapsel gefüllt sein, die mit magensaftresi- stentem Überzug versehen sein kann. Die Schnitzel oder Pellets können aber auch selbst magensaftresistent überzogen sein, indem die extrudierte Folie entsprechend mit magensaftresistenten Materialien beschichtet wird. Dies kann beispielsweise durch Koextrudion von Mehrschichtfolien erfolgen, wobei als mittige Schicht die Amylose/TPS-Schicht gewählt wird, enthaltend den pharmazeutischen Wirkstoff für orale Anwendungen. Werden diese Pellets oder Schnitzel nicht in eine Kapsel gefüllt, werden sie üblicherweise, wie bereits oben erwähnt, zu einer Tablette verpreßt. Diese kann wiederum mit einem Überzug zur Magensaftresistenz oder Kontrolle der Wirkstofffreigabe versehen sein.The pellets or schnitzel can be filled into a capsule, which can be provided with an enteric coating. However, the chips or pellets can also be coated with gastric juice-resistant material in that the extruded film is coated accordingly with gastric juice-resistant materials. This can be done, for example, by coextruding multilayer films, the amylose / TPS layer containing the pharmaceutical active ingredient for oral applications being selected as the central layer. If these pellets or chips are not filled into a capsule, they are usually compressed into a tablet, as already mentioned above. This can in turn be provided with a coating for gastric juice resistance or control of the release of the active ingredient.
Beispiel 10: Herstellung einer agrochemischen FormulierungExample 10: Preparation of an agrochemical formulation
Analog der Herstellung eines transdermalen therapeutischen Systems gemäß Beispiel 8 werden zunächst wiederum in einem Extruder bei ca. 170°C ein Teil Poly(α- 1 ,4-D-Glucan) mit zwei Teilen thermoplastischer Stärke in der Schmelze gemischt, wobei beide Materialien je 35 % Glyzerin als Weichmacher bzw. Plastifiziermittel enthalten. Anschließend wird die Polymerschmelze auf ca. 140°C abgekühlt und als agrochemische Wirksubstanz beispielsweise Bensulforonmethyl (Mw = 396,4) sowie ca. 5 % Wasser hinzugefügt und anschließend die erhaltene agrochemische Polymerschmelze mittels Profilextrusion zu breiten Folien extrudiert.Analogous to the production of a transdermal therapeutic system according to Example 8, a part of poly (α-1,4-D-glucan) is first mixed with two parts of thermoplastic starch in the melt in an extruder at approximately 170 ° C., both materials each Contain 35% glycerin as plasticizer or plasticizer. The polymer melt is then cooled to approx. 140 ° C. and as agrochemical active substance, for example bensulforonmethyl (Mw = 396.4) and about 5% water, and then the agrochemical polymer melt obtained is extruded into wide films by means of profile extrusion.
Anschließend wird die so erhaltene Folie mittels Hechsein zur Partikelbildung zer- kleinert.The film thus obtained is then shredded by means of pecking to form particles.
Die so hergestellten Partikel können nun im Freien appliziert werden, beispielsweise mit einer Dosierung von ca. 30 - 100 g pro Hektar. Der große Vorteil der Verwendung dieser Amylosefilm-Partikel, enthaltend die agrochemische Wirksubstanz, besteht darin, daß eine gute Dosierung möglich wird und die Freisetzung verzögert er- folgt. Dabei kann die verzögerte Freisetzung über die Wirkstoffbeladung je nachThe particles produced in this way can now be applied outdoors, for example at a dosage of approx. 30-100 g per hectare. The great advantage of using these amylose film particles containing the agrochemical active substance is that good dosing becomes possible and the release is delayed. The delayed release can depend on the drug loading
Verwendungszweck angepaßt werden. Wohl beträgt die Wirkstoffbeladung im vorliegenden Beispiel lediglich 5 %, doch sind selbstverständlich auch höhere Wirk- stoffbeladungen von bis zu 50 % durchaus möglich.Purpose to be adjusted. The active substance loading in the present example is only 5%, but higher active substance loads of up to 50% are of course also possible.
Bei den vorab beschriebenen, möglichen Anwendungen bzw. Verwendungen des thermoplastischen Poly(α-1 ,4-D-Glucan) bzw. der thermoplastischen Polymermischungen, enthaltend Poly(α-1 ,4-D-Glucan), handelt es sich selbstverständlich lediglich um Beispiele, um die vorliegende Erfindung zu erläutern. Die Erfindung ist selbstverständlich nicht auf die angeführten Anwendungen bzw. auf die in den Beispielen angeführten Wirksubstanzen, Verfahrensparameter, Polymerkomponenten- partner zum Poly(α-1 ,4-D-Glucan) etc. beschränkt, sondern kann auf x-beliebige Art und Weise durch das Hinzufügen weiterer Komponenten, durch Wahl anderer Verfahrensparameter etc. ergänzt bzw. modifiziert werden. The possible applications or uses of the thermoplastic poly (α-1, 4-D-glucan) or the thermoplastic polymer mixtures containing poly (α-1, 4-D-glucan) described above are of course only Examples to illustrate the present invention. The invention is of course not limited to the applications mentioned or to the active substances, process parameters, polymer component partners for poly (α-1, 4-D-glucan) etc. mentioned in the examples, but can be in any way be added or modified by adding further components, by selecting other process parameters, etc.

Claims

Patentansprüche claims
1. Poly(α-1 ,4-D-Glucan) mit einem Polymerisationsgrad von mindestens ca. 40.1. Poly (α-1,4-D-glucan) with a degree of polymerization of at least about 40.
2. Poly(α-1 ,4-D-Glucan) nach Anspruch 1 mit einem Polymerisationsgrad von > ca. 50.2. poly (α-1, 4-D-glucan) according to claim 1 with a degree of polymerization of> about 50.
3. Poly(α-1 ,4-D-Glucan) nach einem der Ansprüche 1 oder 2 mit einem Polymerisationsgrad von ca. 50 bis ca. 56.3. poly (α-1, 4-D-glucan) according to one of claims 1 or 2 with a degree of polymerization of about 50 to about 56.
4. Poly(α-1 ,4-D-Glucan) nach einem der Ansprüche 1 oder 2 mit eine Polymerisationsgrad von > ca. 60.4. poly (α-1, 4-D-glucan) according to one of claims 1 or 2 with a degree of polymerization of> about 60.
5. Poly(α-1 ,4-D-Glucan) nach einem der Ansprüche 1 , 2 oder 4 mit einem Poly- merisationsgrad von maximal ca. 300.5. poly (α-1, 4-D-glucan) according to one of claims 1, 2 or 4 with a degree of polymerization of at most about 300.
6. Thermoplastische Polymermischung, mindestens enthaltend Poly(α-1 ,4-D- Glucan) nach einem der Ansprüche 1 bis 5 sowie einen Weichmacher.6. Thermoplastic polymer mixture containing at least poly (α-1, 4-D-glucan) according to any one of claims 1 to 5 and a plasticizer.
7. Polymermischung nach Anspruch 6, enthaltend mindestens ein weiteres Polymer, welches thermoplastisch verarbeitbar ist, vorzugsweise physiologisch verträglich und/oder biologisch kompatibel.7. Polymer mixture according to claim 6, comprising at least one further polymer which can be processed thermoplastically, preferably physiologically compatible and / or biologically compatible.
8. Polymermischung, insbesondere nach einem der Ansprüche 6 oder 7, dadurch gekennzeichnet, daß als weiteres Polymer eine Vinylverbindung wie beispielsweise ein Copolymer von Vinylacetat oder Vinylacrylat mit Ethylen bzw. Polyethylen-Vinylalkohol und/oder ein Polyalkanoat, wie beispielsweise ein aliphatischer Polyester, enthalten ist.8. Polymer mixture, in particular according to one of claims 6 or 7, characterized in that contain as a further polymer a vinyl compound such as a copolymer of vinyl acetate or vinyl acrylate with ethylene or polyethylene-vinyl alcohol and / or a polyalkanoate, such as an aliphatic polyester is.
9. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 8, weiter mindestens enthaltend native Stärke, chemisch oder physikalisch modifizierte Stärke, wie insbesondere thermoplastische Stärke.9. polymer mixture, in particular according to one of claims 6 to 8, further at least containing native starch, chemically or physically modified starch, such as in particular thermoplastic starch.
10. Polymermischung, insbesondere nach Anspruch 9, dadurch gekennzeichnet, daß die Mischung thermoplastische Stärke enthält, welche erhältlich ist durch10. polymer mixture, in particular according to claim 9, characterized in that the mixture contains thermoplastic starch, which is obtainable by
Mischen von nativer Stärke oder einem Stärkederivat mit einem Weichmacher bzw. Plastifiziermittel in der Schmelze bei einem Wassergehalt von < 5 Gew%, bezogen auf die Mischung Stärke Weichmacher.Mixing native starch or a starch derivative with a plasticizer or plasticizers in the melt with a water content of <5% by weight, based on the mixture of starch and plasticizer.
11. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 10, dadurch gekennzeichnet, daß als Weichmacher für Poly(α-1 ,4-D-Glucan) und/oder des weiteren Polymeres und/oder der Stärke mindestens eine Substanz der nachfolgenden Liste enthalten ist:11. Polymer mixture, in particular according to one of claims 6 to 10, characterized in that as a plasticizer for poly (α-1, 4-D-glucan) and / or the further polymer and / or the starch contain at least one substance from the list below is:
Sorbitol, Glyzerin sowie deren Oligomere und Kondensationsprodukte, DMSO, Bernsteinsäure, Citronensäure-Monohydrat, Apfelsäure und/oder Weinsäure.Sorbitol, glycerin and their oligomers and condensation products, DMSO, succinic acid, citric acid monohydrate, malic acid and / or tartaric acid.
12. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 11 , dadurch gekennzeichnet, daß der Anteil Stärke, wie insbesondere thermoplastische Stärke, zwischen 20 - 80 Gew% beträgt, bezogen auf den Anteil Polymer inklusive Polyglucan und gegebenenfalls weitere thermoplastisch verarbeitbare Polymere.12. Polymer mixture, in particular according to one of claims 6 to 11, characterized in that the proportion of starch, such as in particular thermoplastic starch, is between 20-80% by weight, based on the proportion of polymer including polyglucan and optionally further thermoplastically processable polymers.
13. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 12, dadurch gekennzeichnet, daß der Anteil Poly(α-1 ,4-D-Glucan) 20 bis 80 Gew.% beträgt, bezogen auf den Anteil Polymer inklusive der Stärke und gegebenenfalls weitere thermoplastisch verarbeitbare Polymere.13. Polymer mixture, in particular according to one of claims 6 to 12, characterized in that the proportion of poly (α-1, 4-D-glucan) is 20 to 80 wt.%, Based on the proportion of polymer including the starch and optionally further thermoplastically processable polymers.
14. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 13, weiter enthaltend zwischen 2 bis 20 Gew.% eines Komplexbildners für Poly(α-1 ,4-D-14. Polymer mixture, in particular according to one of claims 6 to 13, further containing between 2 to 20 wt.% Of a complexing agent for poly (α-1, 4-D-
Glucan).Glucan).
15. Polymermischung, insbesondere nach einem der Ansprüche 6 bis 14, weiter enthaltend Wirksubstanzen, wie Pestizide, Fungizide, Insektizide, Herbizide, Düngemittel, pharmazeutische und/oder kosmetische Wirkstoffe.15. Polymer mixture, in particular according to one of claims 6 to 14, further containing active substances, such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients.
16. Verwendung der Polymermischung nach einem der Ansprüche 6 bis 15 als thermoplastische Trägermatrix für die Aufnahme mindestens einer Wirksubstanz, wie Pestizide, Fungizide, Insektizide, Herbizide, Düngemittel, pharmazeutische und/oder kosmetische Wirkstoffe. 16. Use of the polymer mixture according to one of claims 6 to 15 as a thermoplastic carrier matrix for the inclusion of at least one active substance, such as pesticides, fungicides, insecticides, herbicides, fertilizers, pharmaceutical and / or cosmetic active ingredients.
17. Verfahren zur Herstellung einer thermoplastischen Polymermischung nach einem der Ansprüche 6 bis 15, dadurch gekennzeichnet, daß zunächst Po- ly(α-1 ,4-D-Glucan) aufgeschmolzen wird und diesem mindestens 20 Gew%, vorzugsweise mindestens 30 Gew%, eines Weichemachers bei ca. 170°C zu- gefügt werden.17. A method for producing a thermoplastic polymer mixture according to one of claims 6 to 15, characterized in that first poly (α-1, 4-D-glucan) is melted and this at least 20% by weight, preferably at least 30% by weight, of a softener at approx. 170 ° C.
18. Verfahren, insbesondere nach Anspruch 17, dadurch gekennzeichnet, daß das aufgeschmolzene und weichgemachte Poly(α-1 ,4-D-Glucan) mit mindestens einem weiteren thermoplastisch verarbeitbaren Polymer in der Schmelze in einem Temperaturbereich von ca. 140 bis 180°C gemischt wird, wobei vorzugsweise das Mischen in der Schmelze in einem Extruder erfolgt, wobei die Verweilzeit im Extruder 1 bis 5 Min. beträgt bei 50 bis 200 Umdrehungen pro Minute, vorzugsweise 100 U/min. und einer eingebrachten Plastifizier- bzw. Mischarbeit pro Kg Poly(α-1 ,4-D-Glucan) von 0,2 bis 0,4 kWh.18. The method, in particular according to claim 17, characterized in that the melted and plasticized poly (α-1, 4-D-glucan) with at least one further thermoplastically processable polymer in the melt in a temperature range from about 140 to 180 ° C. is mixed, the mixing preferably taking place in the melt in an extruder, the residence time in the extruder being 1 to 5 minutes at 50 to 200 revolutions per minute, preferably 100 rpm. and a plasticizing or mixing work per kg poly (α-1, 4-D-glucan) of 0.2 to 0.4 kWh.
19. Verfahren zur Herstellung einer pharmazeutischen und/oder kosmetischen Zusammensetzung, dadurch gekennzeichnet, daß mit einem Weichmacher versetztes, thermoplastisches Poly(α-1 ,4-D-Glucan) mit einem weiteren Polymer, wie insbesondere thermoplastischer Stärke, in der Schmelze in einem Temperaturbereich von ca. 140 - 180°C gemischt wird und anschließend die Schmelze auf einen Temperaturbereich von < 150°C abgekühlt und mit einem landwirtschaftlich nutzbaren oder kosmetischen und/oder pharmazeutischen19. A process for the preparation of a pharmaceutical and / or cosmetic composition, characterized in that a thermoplastic poly (α-1,4-D-glucan) mixed with a plasticizer and another polymer, such as in particular thermoplastic starch, in the melt in one Temperature range of about 140 - 180 ° C is mixed and then the melt is cooled to a temperature range of <150 ° C and with an agricultural or cosmetic and / or pharmaceutical
Wirkstoff wiederum in der Schmelze gemischt wird, wobei vorzugsweise das Mischen in einem Extruder erfolgt und anschließend die so erhaltene Schmelze zu einer Folie extrudiert oder zu einem thermoplastischen Formkörper gespritzt wird, in welcher Folie oder in welchem Formkörper die thermoplasti- sehe Polymermischung, enthaltend Poly(α-1 ,4-D-Glucan) sowie das weitereActive ingredient is in turn mixed in the melt, the mixing preferably being carried out in an extruder and then the melt obtained in this way being extruded into a film or injected into a thermoplastic molded article, in which film or in which molded article the thermoplastic polymer mixture containing poly ( α-1, 4-D-glucan) and the other
Polymer, als Trägermatrix dient und der landwirtschaftlich nutzbare, kosmetische und/oder pharmazeutische Wirkstoff im Sinne eines Füllstoffes enthalten ist.Polymer, serves as a carrier matrix and contains the agricultural, cosmetic and / or pharmaceutical active ingredient in the sense of a filler.
20. Verfahren, insbesondere nach Anspruch 19, dadurch gekennzeichnet, daß die extrudierte Folie zu beispielsweise transdermalen oder landwirtschaftlich nutzbaren Systemen weiterverarbeitet wird oder zerkleinert in Tablettenform oder eingefüllt in Kapseln in eine verabreichbare Form gebracht wird.20. The method, in particular according to claim 19, characterized in that the extruded film, for example transdermal or agricultural usable systems is processed or crushed in tablet form or filled into capsules in an administrable form.
21. Verfahren, insbesondere nach einem der Ansprüche 19 oder 20, dadurch gekennzeichnet, daß der thermoplastische Formkörper in eine subcutane Verarbeitungsform weiterverarbeitet wird. 21. The method, in particular according to one of claims 19 or 20, characterized in that the thermoplastic molded body is further processed into a subcutaneous processing mold.
PCT/EP1999/008474 1998-11-17 1999-11-05 Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same WO2000029477A1 (en)

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CA002343946A CA2343946A1 (en) 1998-11-17 1999-11-05 Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same
JP2000582458A JP2002530454A (en) 1998-11-17 1999-11-05 Poly (α-1,4-D-glucan) and thermoplastic polymer mixture containing it
AU15045/00A AU1504500A (en) 1998-11-17 1999-11-05 Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same
EP99957283A EP1135439A1 (en) 1998-11-17 1999-11-05 Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same
KR1020017003849A KR20010075375A (en) 1998-11-17 1999-11-05 Poly(alpha-1,4-d-glucan) and thermoplastic polymer mixtures containing the same
NO20012429A NO20012429D0 (en) 1998-11-17 2001-05-16 Poly (<alpha> -1,4-glucan) and thermoplastic polymer blends of the same

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JP4885408B2 (en) * 2000-07-17 2012-02-29 江崎グリコ株式会社 Biodegradable articles obtained from enzymatically synthesized amylose
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CN114316424A (en) * 2021-11-22 2022-04-12 金发科技股份有限公司 Transparent weather-resistant PP/PS composite material and preparation method thereof
CN114316424B (en) * 2021-11-22 2023-08-25 金发科技股份有限公司 Transparent weather-proof PP/PS composite material and preparation method thereof

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