EP4031116A1 - Forme de dépôt extrudée pour la libération contrôlée de substance active - Google Patents

Forme de dépôt extrudée pour la libération contrôlée de substance active

Info

Publication number
EP4031116A1
EP4031116A1 EP20780972.4A EP20780972A EP4031116A1 EP 4031116 A1 EP4031116 A1 EP 4031116A1 EP 20780972 A EP20780972 A EP 20780972A EP 4031116 A1 EP4031116 A1 EP 4031116A1
Authority
EP
European Patent Office
Prior art keywords
poly
lactide
class
weight
depot form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20780972.4A
Other languages
German (de)
English (en)
Inventor
Elisabeth Ritter
Alexandra Feuersinger
Lukas OLIV
Klaus Raddatz
Dirk BARTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AMW GmbH
Original Assignee
AMW 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 AMW GmbH filed Critical AMW GmbH
Publication of EP4031116A1 publication Critical patent/EP4031116A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K8/0216—Solid or semisolid forms
    • A61K8/022—Powders; Compacted Powders
    • 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
    • A61K8/0216—Solid or semisolid forms
    • A61K8/022—Powders; Compacted Powders
    • A61K8/0225—Granulated powders
    • A—HUMAN NECESSITIES
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    • 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
    • A61K8/11—Encapsulated compositions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • 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
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/805—Corresponding aspects not provided for by any of codes A61K2800/81 - A61K2800/95

Definitions

  • the present invention relates to an extruded depot form, comprising at least one active ingredient and at least one first compound from the class of biodegradable organic polymers.
  • the present invention also relates to a method for producing the extruded depot shape and the use of the extruded depot shape.
  • Subcutaneous dosage forms generally comprise liquid or solid formulations that can be administered by injection or surgery into the subcutaneous tissue. Solid formulations are mostly administered as cylindrical polymer sticks with the active ingredient embedded in them. Dosage forms that release active ingredients over a period of several days up to, for example, 24 months are also referred to as depot medicament forms.
  • Active ingredients released by depot dosage forms are not subject to the so-called first pass effect, i.e. they do not pass through the digestive tract and the liver and can also ensure continuous release of active ingredients over a sustained period of time. In this way, strong fluctuations in the active ingredient concentration and the associated side effects, which, for example, often occur with intravenous dosage forms, are avoided.
  • the controlled, sustained release of active ingredients from depot forms (hereinafter also referred to as “depot forms”) can also extend the application interval.
  • depot dosage forms that are biodegradable do not have to be removed after the intended application time. These properties make subcutaneous depot forms user-friendly drugs.
  • the active ingredient release rate and duration from depot forms can be influenced by additives contained in the formulation, with high demands on the formulations with a long application duration
  • the ingredients are biocompatible in order to minimize adverse health effects for patients. Therefore, formulations are required which have a continuous, controlled release over a long application period and a high level of biocompatibility as well as good properties with regard to their biodegradability.
  • the administration systems described in the prior art have short application times and / or even miss the required therapeutic active substance dose for the user.
  • an extruded depot form which comprises at least one active ingredient and at least one compound from the class of biodegradable organic polymers according to claim 1, as well as by a method for producing the depot form according to the invention according to claim 11. Furthermore, the object is achieved by a Composition according to the invention for use according to claim 14 dissolved.
  • the present invention therefore relates to an extruded depot form for sustained release of active ingredients
  • the term “depot form” is understood to mean a drug form in which the active ingredient is released through retardation over a longer period of time.
  • the depot form is administered parenterally and preferably forms a subcutaneous depot.
  • biodegradable means that substances contained in the formulation are broken down or eroded into smaller units in vivo, for example by enzymatic, chemical or physical processes.
  • the depot forms according to the invention comprise at least one active ingredient and at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid.
  • extruded depot forms can be significantly improved according to the invention by the combination of a biodegradable organic polymer based on lactic acid and / or glycolic acid.
  • extruded depot forms according to the invention advantageously have a controlled release of active ingredient within a period of one week to one year, high biocompatibility and good biodegradability.
  • the extruded depot form according to the invention When used subcutaneously, the extruded depot form according to the invention releases the at least one active ingredient from the active ingredient-containing depot form to the surrounding tissue, a substantial part of the active ingredient preferably being absorbed systemically. If the extruded depot form is intended for local therapy, a substantial proportion of the active ingredient can advantageously be released into the tissue surrounding the application site.
  • the absolute amount of active ingredient contained in the depot form generally determines the period of time in which a continuous supply of the active ingredient in or to the organism is maintained. Therefore, the highest possible loading of the depot form with at least one active ingredient is desirable if the application time of the depot form is long, ie. H. several weeks to twelve months.
  • An extruded depot form according to the invention is preferably preferred for an application period of at least one week to a maximum of 12 months for an application period of one week to 6 months, in particular for an application period of 2 weeks to 3 months.
  • the present invention thus relates to the medical, veterinary and / or cosmetic use of the depot form according to the invention for the delivery of active substances into the bloodstream of a human or animal body.
  • the present invention also relates to a method for producing a depot form according to the invention, the method comprising the following steps:
  • extrusion in particular melt extrusion, of the core, preferably at a temperature above the melting temperature of the at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid,
  • step (iii) optionally applying a coating mixture or composition to the extrudate obtained above, preferably simultaneously with step (ii),
  • a homogeneous mixture can be produced by a suitable mixing process, preferably without the addition of solvents.
  • the mixing process can also include more than one step, for example by first preparing a mixture of the biodegradable polymer and, separately therefrom, a mixture of one or more optional excipients and the at least one active ingredient, which in a second step with the Polymer can be mixed.
  • the preferably homogeneous mixture obtained in this way is then heated to a temperature which is preferably higher than the temperature of the melting point of the compound used from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid, and then by means of extrusion, in particular by means of melt extrusion, extruded.
  • a preferably homogeneous coating mixture or composition is optionally applied, which consists of at least one of the above-mentioned components according to step (i) of the depot form according to the invention.
  • the coating mixture is preferably applied simultaneously with the extrusion of the core.
  • the components according to step (i) preferably comprise at least about 50% by weight of the dry weight of the depot form according to the invention, preferably at least about 55% by weight, particularly preferably at least about 60% by weight, particularly preferably at least about 62% by weight. %, of the total weight of the depot form according to the invention.
  • the active ingredient is a thermosensitive active ingredient
  • extrusion can advantageously take place at temperatures at which thermosensitive active ingredients can also be processed without impairment.
  • the at least one compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid is selected so that its melting point is preferably below the temperature at which the active ingredient is thermally impaired.
  • an advantageous production method can provide for a sterilization of the extruded depot form according to the invention before a possible packaging step.
  • a depot form according to the invention can also be used without a sterilization process or under conditions which are not aseptic.
  • the extruded depot form according to the invention can be subjected to a packaging process in which the depot form, after a possible sterilization process, is packed directly into a packaging unit.
  • the extruded depot form can also first be introduced into an applicator provided for applying the depot form according to the invention and packaged together with this in a packaging unit.
  • the present invention comprises an extruded depot shape which can be obtained by a method described above.
  • the at least one first compound from the class of organic polymers based on lactic acid and / or glycolic acid is selected from poly (L-lactide), poly (D, L-lactide), poly (glycolide), poly (L -lactide-co-D, L-lactide), poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (meso-lactide), poly (D, L-lactide -co-trimethylene carbonate), poly (L-lactide-co-meso-lactide), poly (L-lactide-co-epsilon-caprolactone), poly (D, L-lactide-co-meso-lactide), poly (D , L-lactide-co-epsilon-caprolactone), poly (meso-lactide-co-glycolide), poly (meso-lactide-co-trimethylene carbonate), poly
  • Particularly preferred compounds from the class of organic polymers based on lactic acid and / or glycolic acid are poly (D, L-lactide) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) , which are available, for example, from Evonik Industries AG (Germany) under the names R 202 H (poly (D, L-lactide) or RG 502 H and RG 752 H (PLGA).
  • polylactide (syn. Polylactic acids, PLA) is understood to mean polymers of lactic acid.
  • the polymers which are optically active due to the asymmetric carbon atom occur in the form of D- or L-lactides.
  • polyglycolide PGA
  • polyglycolide PGA
  • polyglycolide PGA
  • polyglycolide PGA
  • PGA polyglycolide
  • PLGA poly (lactide-co-glycolide)
  • a polyester is formed from D, L-lactic acid and glycolic acid, which is biodegradable.
  • the molecular weight of the organic polymer based on lactic acid and / or glycolic acid, in particular PLA or PLGA can in principle vary within a wide range. However, the molecular weight is preferably at least about 5 kDa and / or at most about 100 kDa.
  • the molecular weight is particularly preferably at least about 7 kDa and / or at most about 60 kDa, in particular at least about 9 kDa and / or at most about 40 kDa, particularly preferably at least about 10 kDa and / or at most about 30 kDa.
  • the depot forms according to the invention contain at least one active ingredient.
  • This at least one active ingredient can, without being restrictive, be selected from the class of antibiotics, antimicrobiotics, antimycotics, antiseptics, chemotherapeutics, cytostatics, metastasis inhibitors, antiallergics, anticoagulants, sex hormones, sex hormone inhibitors, hemostatic agents Hormones, peptide hormones, fusion proteins, antidepressants, vaccines, gonadotropin-releasing hormone analogs, growth factor inhibitors,
  • Hormone mimetics multiple sclerosis therapeutics, programmed cell death receptor 1 antagonists, neuroleptics, complement system inhibitors, vitamins, antihistamines, antibodies, antibody fragments, nucleic acids, DNA, plasmid DNA, cationic DNA complexes and RNA, siRNA, mRNA and antidiabetic agents.
  • Useful active ingredients include, but are not limited to, heparin, heparin derivatives, hirudin, acetylsalicylic acid, enoxaparin, liraglutide, albiglutide, dulaglutide, lixisenatide, exenatide, insulin, insulin analogs, acarbose, glatiramer acetate, octreotide, and lanopreotide, lanopreotide, and desicotide , Zafirlukast, buserelin, somatostatin, glibenclamide, gliclazide, glimepiride, gliquidone, pioglitazone, miglitol, nateglinide, mitiglinide, repaglinide, sitagliptin, vildagliptin, dexamethasone, prednisolone, corticosterone, estrogen, mesidazine, 5, corticoster
  • Preferred extruded depot forms containing at least one active ingredient can be used for the treatment of acromegaly; of symptoms associated with (functionally active) gastroenteropancreatic endocrine tumors, such as carcinoids with features of carcinoid syndrome; advanced neuroendocrine tumors; and Thyroid Stimulating Hormone (TSH) - secreting pituitary adenomas; Cancers such as multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia, breast, lung, endometrial, ovarian, stomach, cervical or prostate cancer, pancreatic cancer, glioblastoma, kidney cancer; hepatocellular carcinoma, colon carcinoma, neuroendocrine tumors, head and neck tumors, sarcoma; Tumor syndromes result directly or indirectly from genetic defects in tumor suppressor genes such as P53, PTEN or VHL, end
  • an advantageous extruded depot form contains at least one active ingredient from the class of peptide hormones.
  • the at least one active ingredient is particularly preferably selected from octreotide, pasireotide, lanreotide and / or valpreotide.
  • the at least one active ingredient is selected from octreotide.
  • the at least one active ingredient is particularly preferably selected from nucleic acids, preferably from DNA, plasmid DNA, cationic DNA complexes and / or RNA, siRNA and / or mRNA.
  • a self-replicating RNA is known from the prior art and can be obtained from viruses, for example.
  • RNA or mRNA can preferably be used as a vaccine and / or for cancer therapy.
  • the RNA or mRNA codes for a desired antigen, for example from a pathogen.
  • the vaccines also stimulate immune reactions against tumor-associated antigens and stimulate immune cells to fight the cancer cells.
  • RNA and / or mRNA as an active ingredient in the advantageous depot form for the formation of endogenous proteins and / or enzymes.
  • non-functional endogenous proteins and enzymes can be replaced by these RNA or mRNA-coded functional proteins or enzymes by means of RNA and / or mRNA, which codes for a corresponding functional protein or enzyme.
  • RNA or mRNA in or to a specific organ or tissue is preferably of relevance.
  • RNA and / or mRNA are released from the depot form into the eye.
  • Such an application is particularly preferred for the therapy of macular degeneration and / or glaucoma, eye diseases caused by diabetes and oncologically caused eye diseases.
  • the immune-stimulating or therapeutic properties or an effect of the RNA or mRNA can advantageously be increased by adding an adjuvant.
  • adjuvants are known in the art.
  • the self-replicating RNA vaccine is more effective when it is converted into a cationic oil-in-water nanoemulsion based on squalene and polysorbates (Tween 80) and sorbitan trioleate (Span 85), sodium citrate and citric acid, such as an adjuvant MF59 (Novartis).
  • the effectiveness of mRNA can be enhanced, for example, by adding the molecules with TriMix (mRNAs, which encode three proteins that activate the immune system, caTLFM, CD40L and CD70).
  • the depot form comprises at least one second compound from the class of lipids.
  • the dry weight of the at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid and the at least one second compound from the class of lipids have a proportion of more than about 50% by weight, preferably more than about 55% by weight, particularly preferably more than about 60% by weight, particularly preferably at least about 62% by weight, of the total weight of the depot form.
  • the dry weight of the at least one compound from the class of biodegradable polymers and of the at least one compound from the class of lipids has a maximum proportion of about 99% by weight, preferably of a maximum of about 97.5% by weight, particularly preferably of a maximum of about 95% by weight, particularly preferably about 90% by weight, of the total weight of the depot form.
  • the designation “approximately” means that a specified measured value, such as a content in the composition, may deviate from the specified measured value within the measurement tolerance of a suitable measurement method.
  • the dry weight of the depot form is the weight of a formulation ready for administration which has no or a negligible content, in particular less than about 3% by weight, of water.
  • the total content of the at least one compound from the class of biodegradable polymers includes the content of all compounds from the Class of biodegradable polymers and from the class of lipids in the active ingredient-containing depot form.
  • the at least one second compound from the class of lipids has a melting point which is above room temperature, that is to say a temperature of about 25 ° C.
  • the melting point of the at least one lipid is preferably above about 40.degree. C., particularly preferably above about 50.degree. C., in particular above about 60.degree. C., particularly preferably above about 70.degree.
  • the melting point of the lipid in the depot form according to the invention does not exceed 100.degree.
  • the lipid contained in the extruded depot form has a melting point of at least about 60.degree. C. and / or of at most about 80.degree.
  • the melting point of the lipid is particularly preferably at least about 62.degree. C., in particular at least about 69.degree. At most, the particularly preferred melting point is about 77 ° C, in particular about 73 ° C.
  • the at least one lipid is selected from mono-, di- and / or triglycerides, for example esterifications of glycerol with saturated and / or unsaturated fatty acids with a length of at least 5 and / or at most 26 carbon atoms, phosphatidic acid, lecithin, phosphatidylethanolamine , Phosphatidylinositol, phosphatidylserine, diphosphatidylglycerine, ceramides, cerebrosides, gangliosides, sphingophospholipids, sphingomyelins, sphingosulfatides, glycosphingosides, acylamino sugars, acylamino sugar glycans, acyl trehaloses,
  • Acyl trehalose glycans sorbitan fatty acid esters, squalene, steroids, polyketides, sterol lipids, prenol lipids, cholesterol, hard fats, waxes, and salts and derivatives thereof.
  • preferred lipids are hard fats, which for example consist of a mixture of mono-, di- and triglycerides obtained by esterification of fatty acids of natural origin with glycerol or by transesterification of fats of natural origin can be obtained.
  • Particularly preferred lipids include fatty acids with a number of carbon atoms of at least 12 and / or at most 22, in particular at least 18 and / or at most 22.
  • a very particularly preferred lipid is selected from glyceryl tristearate.
  • Such hard fats are described in the Pharmacopoeia Europaea (Ph. Eur. 8th edition, basic work 2014) and can be selected under the name Dynasan 112, Dynasan 116 and / or Dynasan 118, for example.
  • thermosensitive active ingredients are available, for example, from IOI Oleo GmbH (Germany).
  • lipids with a melting point below 50 ° C. such as Witepsol E85, Witepsol H5, Witepsol H12, Witepsol H37 and / or Witepsol H15, obtained for example from IOI Oleo GmbH (Germany), are preferably suitable can be.
  • extruded depot forms can also comprise more than one compound from the class of the lipids.
  • the extruded depot forms preferably only comprise one compound from the class of lipids.
  • the ratio of the at least one first compound from the class of polymers and the at least one second compound from the class of lipids is at most about 25: 1, preferably at most about 20: 1, particularly preferably at most about 19: 1.
  • the ratio of the at least one first compound from the class of polymers and the at least one second compound from the class of lipids is at least about 5: 1, preferably at least about 10: 1, particularly preferably at least about 12: 1.
  • compositions for the treatment of acromegaly; of symptoms associated with (functionally active) gastroenteropancreatic endocrine tumors, such as for example, carcinoids with features of carcinoid syndrome; advanced neuroendocrine tumors; and Thyroid Stimulating Flormone (TSH) - secreting pituitary adenomas.
  • the particularly preferred active ingredient octreotide can preferably comprise a polypeptide composed of amino acids with the following sequence:
  • FCFWKTCT Phe-Cys-Phe-Trp-Lys-Thr-Cys-Thr
  • the at least one active ingredient can also be contained in the depot form in various forms, depending on which form is optimal
  • Amino acid-based active ingredients can generally be present as a cyclopeptide, oligopeptide or polypeptide or other pharmacologically acceptable derivatives or as components of molecular complexes.
  • the amino acids can be linked to one another via a-peptide bonds as well as via w-peptide bonds.
  • the at least one active ingredient can also be present as a salt such as, for example, acetate, or also in the form of the free base or acid.
  • amino acids of the amino acid-based active ingredients mentioned above as preferred active ingredients can be post-translational
  • an advantageous amount of active ingredient comprises a nucleic acid, preferably from the class of DNA, plasmid DNA, cationic DNA complexes and / or RNA, siRNA, mRNA, particularly preferably from RNA, siRNA and / or mRNA, in particular from self-replicating RNA and / or mRNA, in the depot form of at least about 1% by weight, preferably of at least about 5% by weight, particularly preferably of about 8% by weight. At most, such an active ingredient is present in the depot form in an amount of up to about 40% by weight, preferably up to about 30% by weight, particularly preferably up to about 20% by weight. In particular, such an active ingredient is present in an amount of about 10% by weight and / or up to about 15% by weight.
  • An advantageous amount of active ingredient preferably a peptide hormone, particularly preferably octreotide, pasireotide, lanreotide and / or valpreotide, especially octreotide, is about 0.3% by weight to about 50% by weight, preferably about 3% by weight to about 45% by weight, particularly preferably about 4% by weight to about 40% by weight, in particular about 7% by weight to about 35% by weight.
  • the active ingredient concentration of the active ingredient which prevails in the blood of the user after administration of a depot form, is important.
  • a preferred extruded depot form which preferably contains a peptide hormone, in particular octreotide, therefore advantageously has an in vitro active ingredient release after 7 days of at least about 20% by weight and / or after 28 days of at least about 60% by weight on the total amount of active substance contained in the implant.
  • Extruded depot forms according to the invention are also suitable for cosmetic applications.
  • an advantageous depot form can be used for cosmetic smoothing of wrinkles.
  • the composition according to the invention is used for local, in particular for targeted smoothing of wrinkles, particularly preferably for avoiding wrinkles, for tightening the skin and for protecting against skin aging.
  • Exemplary active ingredients for this can be selected from hyaluronic acid, collagen and / or botox.
  • Advantageous depot forms can also contain at least one auxiliary substance which is customary for subcutaneous administration forms and which can influence the active ingredient release from the depot form, the active ingredient stability, the plasma half-life and / or the bioavailability of the at least one active ingredient.
  • a preferred auxiliary advantageously supports the controlled release of the at least one active ingredient from the depot form.
  • one contributes Such an adjuvant contributes to a long-lasting release of the active substance without, however, adversely affecting the biocompatibility.
  • the addition of such an adjuvant can improve the stability of the active ingredient contained in the depot form. This is of particular interest if the depot form is intended for long-term application of several weeks to a year.
  • the auxiliaries preferably have a high biocompatibility, so that the auxiliaries and any degradation products of the auxiliaries are non-toxic for the user and do not cause any undesired side effects.
  • pore formers can advantageously improve the release of the at least one active ingredient from the subcutaneous depot form.
  • a pore former can, for example, from the group of hydrophilic substances such as calcium sulfate, calcium hydrogen phosphate, sugars such as glucose, lactose, fructose, mannitol, trehalose, dextrins, maltodextrin, sucrose, sorbitol, xylitol, starch or their derivatives such as hydroxyethyl starch, polyvinylpyrrolidone, Polyethylene glycol (PEG) such as PEG 6000 or PEG 8000, sodium chloride, sodium citrate, citric acid, hyaluronic acids, polyvinyl alcohol, polyacrylic acid and its derivatives, polymethacrylic acid and its derivatives, polymethyl methacrylate, polystyrene, copolymers with monomers of methyl methacrylate and styrene and mixtures thereof can
  • PEG polyethylene
  • Particularly preferred pore formers are trehalose and / or hydroxyethyl starch and / or polyethylene glycol, which can be obtained, for example, from Clariant or Sigma-Aldrich (Austria).
  • the molecular weight of a pore former, in particular of PEG is preferably at least about 1 kDa, particularly preferably at least about 3 kDa, in particular at least about 4 kDa. At most there is a preferred one Molecular weight of PEG at about 10 kDa, particularly preferably at most about 8 kDa.
  • an advantageous depot form can comprise auxiliaries which inhibit acylation of polypeptides, preferably octreotide, pasireotide, lanreotide and / or valpreotide, particularly preferably octreotide.
  • Divalent salts or salts of divalent metal ions, such as, for example, calcium chloride, are preferably suitable for this purpose.
  • an adjuvant comprises at least one enzyme.
  • Such an enzyme can favorably influence the release of the at least one active ingredient from the advantageous depot form, without adversely affecting the stability and / or the biodegradability of the depot form.
  • Such an enzyme advantageously brings about improved biodegradability of the depot form.
  • Such an enzyme is particularly preferably selected from the group of lipases. Such a lipase can be obtained, for example, from Sigma-Aldrich.
  • the active ingredient release rate can also be increased by adding a swellable polymer, which is preferably selected from collagen, gelatin and their derivatives, starch and their derivatives (preferably hydroxyethyl starch, hydroxypropyl starch, carboxymethyl starch), cellulose derivatives, chitin, chitosan and their derivatives, polyamides, polyhydroxy acids, Polyhydroxybutyrates, polyhydroxyvalerates, polycaprolactones and polydioxanones.
  • a particularly preferred swellable polymer is hydroxyethyl starch (HES) and can be obtained from Sigma Aldrich (Austria).
  • the molecular weight of a swellable polymer, in particular of HES is preferably at least about 50 kDa, preferably at least about 70 kDa, in particular at at least about 100 kDa, particularly preferably at least about 120 kDa.
  • the molecular weight of a swellable polymer, in particular of HES is at most about 400 kDa, particularly preferably at most about 300 kDa, in particular at most about 200 kDa, particularly preferably at most about 150 kDa.
  • the degree of substitution of HES is at least about 0.1, preferably at least about 0.2, in particular at least about 0.3.
  • the degree of substitution is at most about 1, preferably about 0.7, in particular about 0.5.
  • the depot forms according to the invention can contain other customary auxiliaries known to the person skilled in the art, such as, for example, tocopherols, e.g. B. a-tocopherol, ß-tocopherol, ⁇ -tocopherol, d-tocopherol and mixtures thereof (vitamin E), which are used in particular as antioxidants.
  • tocopherols e.g. B. a-tocopherol, ß-tocopherol, ⁇ -tocopherol, d-tocopherol and mixtures thereof (vitamin E), which are used in particular as antioxidants.
  • such an antioxidant inactivates reactive oxygen species in the depot form, as a result of which oxidation of the active ingredient is slowed down or completely prevented, and thus brings about an improved stability of the active ingredient and thus a longer shelf life of the depot form according to the invention both during storage and during use .
  • a content of one or more of the preferred auxiliaries advantageously brings about a controlled and sustained release of active ingredient from the preferred extruded depot form.
  • a composition particularly preferably comprises an extruded depot shape
  • trehalose optionally 2.5 to 18% by weight of trehalose, preferably 3 to 16% by weight of trehalose, in particular 3.5 to 15% by weight of trehalose, and
  • constituents of an extruded depot shape are particularly preferably selected from
  • the constituents of an extruded depot shape are more preferably selected from (i) 0.1 to 50% by weight of active ingredient, preferably 1 to 50% by weight of active ingredient, in particular 2.5 to 40% by weight of active ingredient, particularly preferably 5 to 20% by weight of active ingredient,
  • an advantageous active ingredient content is around 5 to 30% by weight
  • a content of a biodegradable organic polymer is around 50 to 70% by weight
  • an optional content of a lipid is around 5% by weight.
  • trehalose can be completely or partially replaced by HES.
  • extruded depot forms according to the invention are produced by means of extrusion. It has been shown that the properties of the mixture prepared for extrusion of the at least two compounds from the class of organic polymers based on lactic acid and / or glycolic acid and from the class of lipids with the at least one active ingredient are improved when the active ingredient is used as dried powder, preferably as a spray- or freeze-dried powder or lyophilizate, to which at least two compounds are mixed.
  • a drying step in particular a lyophilization step, preferably takes place before the substances are mixed to produce the depot form according to the invention.
  • a large number of substances can in principle be added to the active ingredient in order to advantageously ensure that the bioactivity of the active ingredient is maintained.
  • Such substances are also called cryoprotectors or lyoprotectors referred to, where lyoprotectors in this context serve to protect the substances during drying and cryoprotectors have a corresponding task during freezing.
  • the length of the active ingredient release after subcutaneous application can be influenced by not cooling the extrudates to ambient temperature immediately after the extrusion, but instead storing them in a drying cabinet or incubator for a certain time at an elevated temperature, for example. A period of time in the range from about 0.5 to about 5 hours is preferably suitable for this.
  • the optional storage at elevated temperature also referred to as the tempering step, depends essentially on the melting point of the at least one lipid and is, for example, in the range from about 40 to about 80 ° C., preferably from about 55 to about 75 ° C., particularly preferred at about 65 to 70 ° C.
  • a preferred storage temperature always depends on the temperature stability of the at least one active ingredient.
  • Preferred depot shapes can moreover be produced by a rounding process, in particular by spheronization.
  • the cylindrical extrudate is advantageously rounded in such a way that any shapes that may have arisen during the extrusion, such as corners and edges, which can adversely affect the application properties, are removed.
  • Spheronization can also be used to produce microparticles, which are then administered subcutaneously and thus also represent a biodegradable depot form.
  • a depot form advantageously has a homogeneous coating which consists of at least one layer applied to the core and preferably limits the initial burst of release of active ingredient from the depot form and ensures therapeutic concentrations of the at least one active ingredient over a sustained period of time.
  • a preferred coating has a mixture of substances or a composition which is selected from at least one of the above-mentioned components a) to c) of the depot form according to the invention or is, and can thus, for example, also be designed to be free of active substances. If the coating contains an active ingredient, its content can be the same or different from the active ingredient content of the core. In a particularly preferred embodiment, however, the coating is designed to be free of active substances.
  • a suitable weight of an extruded depot shape is in a range that is usual for subcutaneous implants.
  • the weight of the extruded depot shape is also dependent on the desired application time and / or the application site.
  • a preferred weight of an extruded depot form is in the range from 1 to 1000 mg, particularly preferably at least about 20 mg and / or at most about 180 mg, in particular at least about 50 mg and / or at most about 150 mg, particularly preferably at least about 80 mg and / or at most about 120 mg.
  • a depot form in the sense of the invention can be designed as a rod, ball, cube, ellipsoid, cuboid, cushion, cylinder, tablet, pellet, plate or briquette.
  • Depot forms according to the invention preferably have an injectable size, but can, if desired, also be introduced at the administration site by means of a surgical intervention.
  • Preferred depot shapes have a diameter of at least 0.1 to 10 mm and a length of at least 0.15 to 50 mm.
  • depot forms have a diameter of at least 0.15 to 7.5 mm and a length of at least 0.2 to 45 mm, particularly preferably a diameter of at least 0.2 to 5 mm and a length of at least 0.3 to 40 mm .
  • the term “diameter” refers to the longest distance running orthogonally to an axis of rotation, which connects two points on the edge of the body in question.
  • the axis of rotation is the straight line around which a body of revolution can be rotated.
  • the term “length” relates to the part of the axis of rotation that is located within the body of revolution.
  • the ratio of diameter to length of preferred depot shapes is advantageously in the range from 1:30 to 10: 1, preferably in the range from 1:15 to 5: 1, particularly preferably in the range from 1:13 to 1: 1.
  • the diameter of the round or almost round particles can be from about 1 to about 100 ⁇ m, preferably from about 5 to about 90 ⁇ m, particularly preferably from about 10 to about 80 ⁇ m.
  • a method for producing the extruded depot form comprises mixing (a) the at least one active ingredient and (b) the at least one compound from the class of organic polymers based on lactic acid and / or glycolic acid, optionally (c) the at least one compound from the class of lipids, whereby a homogeneous powder mixture is obtained.
  • a powder mixture is understood to mean a mixture of several solid constituents of suitable size, wherein the constituents can have particles of a size of less than 1 nm.
  • a powder mixture can also have particles with a size in the range from 1 nm to 1 ⁇ m and / or particles with a size of more than 1 ⁇ m. If at least one of the constituents to be mixed is not in solid form before mixing, it can be converted into the solid state before the powder mixture is created, for example by spray drying or freeze drying.
  • the present invention also relates to a kit comprising an extruded depot form according to the invention and an applicator suitable for application, with which the depot form can be administered subcutaneously.
  • extruded depot forms according to the invention do not necessarily have to be sterilized before they are received in the applicator, but can also be subjected to a sterilization process within the applicator.
  • Such an applicator is also able to accommodate extruded depot shapes of different lengths. It goes without saying that depot forms which are not cylindrical, but are, for example, cuboid or round or the like, can also be applied.
  • Such an applicator expediently has a hollow needle for receiving extruded depot forms with the dimensions explained above and a protective cap, which is to be removed before application and can be fixed again after use.
  • the extruded depot shape is advantageously protected from external influences which can negatively affect the preferred application in any way.
  • FIG. 1 Release profiles of an octreotide-containing depot form according to the invention (according to Example 2, see below) in comparison with an octreotide-containing depot form not according to the invention.
  • the depot forms have a diameter of about 2 mm.
  • Solid line (example according to the invention): 33% by weight Octreotide, 32% by weight polylactic acid-co-glycolic acid polymer, 32% by weight polylactic acid, 3% by weight triglyceride.
  • Dashed line comparativative example: 33% by weight octreotide; 33.5% by weight polylactic acid-co-glycolic acid polymer, 33.5% by weight polylactic acid.
  • a powder mixture was weighed out, which consisted of 34% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany) and 34% by weight of polylactic acid (Resomer® R202H, Evonik Industries Germany) and 32% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland).
  • This powder mixture was mixed homogeneously by means of cryogenic grinding (Freezer / M ill, C3 Roth- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the subsequent extrusion was carried out via counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Düsseldorf, Germany) at 85 ° C. to 92 ° C. and a screw speed of 8 rpm (revolutions per minute).
  • the diameter for the extrudate was adjusted to 2.0 mm with a nozzle.
  • the extrudate strand was cut into extrudates of suitable length (in the present example a length of 2 cm).
  • the extrudate can be formed into microparticles via spheronization.
  • a powder mixture was weighed out, 32% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 32% by weight Polylactic acid (Resomer® R202H, Evonik Industries Germany), 3% by weight from a triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany) and 33% by weight from octreotide lyophilisate (Bachem, Bubendorf, Switzerland) , duration.
  • This powder mixture was mixed homogeneously by means of cryogenic grinding (Freezer / Mill, C3 Saw- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the subsequent extrusion was carried out via counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Düsseldorf, Germany) at 85 ° C. to 92 ° C. and a screw speed of 8 rpm (revolutions per minute).
  • the diameter for the extrudate was adjusted to 2.0 mm with a nozzle.
  • the extrudate strand was cut into extrudates of suitable length (in the present example a length of 2 cm). Alternatively, the extrudate can be formed into microparticles via spheronization.
  • Example 3 according to the invention:
  • Example 2 Production took place as in Example 1, but the composition of the depot forms according to the invention was supplemented with calcium chloride (Sigma Aldrich, Vienna, Austria).
  • the powder mixture consisted of 31.75% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 31.75% by weight of polylactic acid (Resomer® R202H, Evonik Industries Germany), 3.5% by weight Calcium chloride and 33% by weight of octreotide lyophilisate.
  • composition of the depot forms according to the invention was supplemented with a triglyceride and trehalose (Sigma Aldrich, Vienna, Austria).
  • the powder mixture consisted of 30% by weight polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 30% by weight polylactic acid (Resomer® R202H, Evonik Industries Germany), 3.5% by weight triglyceride ( Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), 3.5% by weight of trehalose and 33% by weight of octreotide lyophilisate.
  • a powder mixture of 57% by weight polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 10% by weight glycerol dibehenate (Compritol 888 ATO, Gattefosse) and 33% by weight was used.
  • Octreotide lyophilisate produced.
  • the constituents of this powder mixture were mixed homogeneously by means of cryogenic grinding (Freezer / Mi II, C3 Saw- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the following extrusion was carried out via co-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Düsseldorf, Germany) at 83 ° C. to 90 ° C. and a screw speed of 8 rpm.
  • a powder mixture of 28.5% by weight polylactic acid-co-glycolic acid (Resomer® RG502H, Evonik Industries Germany), 28.5% by weight polylactic acid (Resomer® R203H, Evonik Industries Germany), 3 % By weight triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany) and 40% by weight lanreotide processed into a homogeneous mixture by means of Kroy grinding.
  • exemplary depot forms according to the invention in the appropriate shape and size (e.g. cut into cylinders 1.5 to 2 cm in length and 1.8 mm in diameter) were initially weighed individually.
  • a powder mixture was weighed in, consisting of 38% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany) and 26% by weight of polylactic acid (Resomer® R202H, Evonik Industries Germany), 3% by weight of a triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany) and 33% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland).
  • This powder mixture was mixed homogeneously by means of cryogenic grinding (Freezer / Mi II, C3 Saw- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the following co-extrusion was carried out with the aid of a two-substance nozzle, whereby in addition to the actual powder mixture with the aid of a structurally identical, second extruder (Mini CTW, Thermo Fisher Scientific GmbH, Düsseldorf, Germany) a homogeneous coating of 100% by weight polylactic acid-co- glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany) was extruded.
  • the diameter for the core extrudate was set to 2.0 mm and the application thickness of the coating was set to 0.1 mm with the aid of the two-fluid nozzle.
  • the extrudate strand was then cut into extrudates of suitable length.
  • a powder mixture was produced, which consists of 33.5% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 33.5% by weight. % consisted of polylactic acid (Resomer® R202H, Evonik Industries Germany) and 33% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland).
  • This powder mixture was mixed homogeneously by means of cryogenic grinding (Freezer / M ill, C3 Saw- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the subsequent extrusion was carried out via counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Düsseldorf, Germany) at 85 ° C. to 92 ° C. and a screw speed of 5-15 rpm (revolutions per minute).
  • the diameter for the extrudate was set to 2.0 mm with a nozzle.
  • the extrudate strand was cut into extrudates of suitable length (in the present example a length of 2.0 cm).
  • the depot forms (according to Example 1-6) were placed in release cells and mixed with 50 ml release medium (disodium hydrogen phosphate, pH 7.4). The depot forms were then placed in an incubation shaker (IKA®-Werke GmbH & Co. KG, Germany) at 37 ° C. for the desired application time.
  • 50 ml release medium sodium hydrogen phosphate, pH 7.4
  • a powder mixture was weighed out consisting of 44% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany) and 44% by weight of polylactic acid (Resomer® R202H, Evonik Industries Germany) and 12% by weight mRNA (CleanCap® EGFP mRNA, TriLink Biotechnologies, Inc.
  • the subsequent extrusion was carried out via co-rotating screw melt extrusion (Mini Extruder ZE-5, Three-Tec GmbH, Birnen Switzerland) at 85 ° C. to 90 ° C. and a screw speed of 10 rpm (revolutions per minute).
  • the diameter for the extrudate was adjusted to 0.5 mm with a nozzle.
  • the extrudate strand was cut into extrudates of suitable length (in the present example a length of 0.5 cm).
  • the expression control was carried out with the aid of the GFP Assay System (Arbor Assays LLC, USA).
  • the protocol is used: The depot form according to the invention is added to a human cell culture. The release from the depot form and the activity of the encoded protein were detected using the fluorescence assay. When excited with light with a wavelength of 395 nm, the cells that have absorbed the mRNA and express the GFP gene emit measurable light with a wavelength of 509 nm. In cell cultures that had received a negative control (without mRNA), no significant fluorescence could be measured .
  • the production was carried out according to Example 1, but the composition of the depot forms according to the invention was supplemented with glycerol dibehenate.
  • the powder mixture consisted of 40% by weight polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany), 40% by weight polylactic acid (Resomer® R202H, Evonik Industries Germany), 5% by weight triglyceride (Dynasan 118 , IOI Oleo GmbH, Hamburg, Germany), 4.5% by weight glycerol dibehenate (Compritol 888 ATO, Gattefosse), 10% by weight mRNA (CleanCap® EGFP mRNA, TriLink Biotechnologies, Inc.
  • Example 10 according to the invention:
  • a powder mixture was weighed out, 86% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries Germany) and 14% by weight of mRNA (CleanCap® FLuc mRNA, TriLink Biotechnologies, Inc. USA).
  • This powder mixture was mixed homogeneously by means of cryogenic grinding (Freezer / Mi II, C3 Roth- und Analysentechnik GmbH, Haar near Kunststoff, Germany).
  • the subsequent extrusion was carried out via co-rotating screw melt extrusion (Mini Extruder ZE-5, Three-Tec GmbH, Birnen Switzerland) at 83 ° C. to 92 ° C. and a screw speed of 10 rpm.
  • the expression control (detection of the luciferase activity) was carried out using the Luciferase Assay System E1500 (Promega Corporation, USA). The protocol was used: The depot form according to the invention was added to a human cell culture. The release from the depot form and the activity of the encoded protein were detected using the luciferase assay. When the substrate (luciferin) is added, the cells that have absorbed the mRNA and express the luciferase enzyme emit measurable light. No significant luminescence could be measured in cell cultures which had received a negative control (without mRNA).

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  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
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  • Medicinal Preparation (AREA)
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Abstract

L'invention concerne une forme de dépôt extrudée pour la libération prolongée d'une substance active, comprenant au moins une substance active et au moins un premier composé de la classe des polymères organiques biodégradables à base d'acide lactique et/ou d'acide glycolique.
EP20780972.4A 2019-09-19 2020-09-18 Forme de dépôt extrudée pour la libération contrôlée de substance active Pending EP4031116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102019125208 2019-09-19
PCT/EP2020/076155 WO2021053171A1 (fr) 2019-09-19 2020-09-18 Forme de dépôt extrudée pour la libération contrôlée de substance active

Publications (1)

Publication Number Publication Date
EP4031116A1 true EP4031116A1 (fr) 2022-07-27

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Family Applications (2)

Application Number Title Priority Date Filing Date
EP20780970.8A Pending EP4031108A1 (fr) 2019-09-19 2020-09-18 Forme de dépôt extrudée pour la libération contrôlée de substance active
EP20780972.4A Pending EP4031116A1 (fr) 2019-09-19 2020-09-18 Forme de dépôt extrudée pour la libération contrôlée de substance active

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP20780970.8A Pending EP4031108A1 (fr) 2019-09-19 2020-09-18 Forme de dépôt extrudée pour la libération contrôlée de substance active

Country Status (7)

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US (2) US20230210775A1 (fr)
EP (2) EP4031108A1 (fr)
JP (2) JP2022548554A (fr)
CN (2) CN114340598A (fr)
CA (2) CA3153224A1 (fr)
DE (2) DE102020124430A1 (fr)
WO (2) WO2021053167A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117618322A (zh) * 2022-08-15 2024-03-01 深圳善康医药科技股份有限公司 一种长效缓控释植入剂的制备方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1243390B (it) * 1990-11-22 1994-06-10 Vectorpharma Int Composizioni farmaceutiche in forma di particelle atte al rilascio controllato di sostanze farmacologicamente attive e procedimento per la loro preparazione.
JP2002520120A (ja) * 1998-07-17 2002-07-09 スカイファーマ インコーポレーテッド 封入物質の制御放出のための生分解性組成物
AU2003221497A1 (en) * 2002-03-13 2003-09-22 Novartis Ag Pharmaceutical microparticles
US7074426B2 (en) * 2002-03-27 2006-07-11 Frank Kochinke Methods and drug delivery systems for the treatment of orofacial diseases
US8846073B2 (en) * 2006-12-19 2014-09-30 Allergan, Inc. Low temperature processes for making cyclic lipid implants for intraocular use
EP3685837A1 (fr) * 2008-09-04 2020-07-29 Amylin Pharmaceuticals, LLC Formulations à libération prolongée à base de supports non aqueux
EP2308478A1 (fr) * 2009-10-06 2011-04-13 Abbott GmbH & Co. KG Système de libération prolongée d'agents bloquants des canaux calciques
DE102011114864A1 (de) * 2011-10-05 2013-04-11 Acino Ag Verfahren zur Herstellung einer homogenen Pulvermischung und Verfahren zur Herstellung eines Implantats sowie Implantat
EP3079670A1 (fr) * 2013-11-15 2016-10-19 DSM IP Assets B.V. Formulation de composés modérément solubles obtenue par extrusion à chaud
DE102017106216A1 (de) * 2017-03-22 2018-09-27 Amw Gmbh Extrudierte Depotform zur anhaltenden Wirkstofffreisetzung
SG11202000497VA (en) * 2017-07-25 2020-02-27 PK Med SAS Process for preparing a drug delivery composition

Also Published As

Publication number Publication date
US20230210763A1 (en) 2023-07-06
DE102020124430A1 (de) 2021-03-25
WO2021053171A1 (fr) 2021-03-25
CA3153222A1 (fr) 2021-03-25
EP4031108A1 (fr) 2022-07-27
CN114450000A (zh) 2022-05-06
JP2022548355A (ja) 2022-11-18
CN114340598A (zh) 2022-04-12
WO2021053167A1 (fr) 2021-03-25
DE102020124431A1 (de) 2021-03-25
JP2022548554A (ja) 2022-11-21
CA3153224A1 (fr) 2021-03-25
US20230210775A1 (en) 2023-07-06

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