Extruded depots for controlled release of active substances - Patent Application 20070122997

Abstract

The present invention relates to an extruded depot for sustained release of an active agent comprising at least one active agent and at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid.

Description

[Technical Field]

[0001] The present invention relates to extruded depots comprising at least one active substance and at least one first compound from the class of biodegradable organic polymers. The invention further relates to a method for producing the extruded depots and to the use of the extruded depots.

[0002] Subcutaneous dosage forms generally include liquid or solid formulations that can be administered into the subcutaneous tissue by injection or surgical procedure. In this case, the solid formulations are usually administered as cylindrical polymer rods with the active substance embedded therein. Dosage forms that provide the active substance in this manner over a period of, for example, several days to 24 months are called depot dosage forms.

[0003] Active substances released from depot dosage forms do not experience the problem known as the first-pass effect and do not pass through the digestive tract and liver, which in turn ensures sustained delivery of the active substance over a sustained period of time. In this manner, the large variations in the concentration of the active substance and the accompanying side effects that often occur, for example, in the case of intravenous administration, can be avoided. The controlled, sustained release of the active substance from depot dosage forms (hereinafter also referred to as "depot forms") can further extend the interval between administrations. Furthermore, depot dosage forms that are biodegradable no longer need to be removed after the intended administration period. These properties make subcutaneous depot forms easy to use pharmaceuticals. Summary of the Invention [Problem to be solved by the invention]

[0004] The release rate and duration of the active substance from the depot can be affected by the additives contained in the formulation, and for formulations with long application periods there are high demands on the biocompatibility of the components to minimize harm to the patient's health.

[0005] Therefore, the formulation is required to have good properties in terms of sustained, controlled delivery over a long application period, high biocompatibility, and biodegradability.

[0006] The dosage forms described in the prior art only have a short application period and / or do not even provide the therapeutic dose of the active substance required by the user.

[0007] It is therefore an object of the present invention to provide a biodegradable depot for parenteral administration of an active agent that allows for sustained, controlled release of the active agent in therapeutically relevant doses. [Means for solving the problem]

[0008] According to the present invention, this object is achieved by an extruded depot comprising at least one active substance and at least one compound from the class of biodegradable organic polymers as defined in claim 1, as well as by a method for producing the depot of the invention as defined in claim 11. Furthermore, this object is achieved by the use of a composition as defined in claim 14. DETAILED DESCRIPTION OF THE INVENTION

[0009] Therefore, the present invention provides (a) at least one active substance; (b) at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid; The present invention relates to an extruded depot for sustained release of an active substance comprising:

[0010] The term "depot formulation" as used herein should be understood to mean a pharmaceutical product in which the release of an active substance occurs in a delayed manner over an extended period of time. In the present invention, a depot formulation is administered parenterally and preferably forms a subcutaneous retention mass.

[0011] The term "biodegradable" should be understood to mean that the substances contained in the formulation are capable of breaking down or eroding in vivo in small amounts, for example by enzymatic, chemical, or physical processes.

[0012] In its simplest embodiment, the depot according to the invention comprises at least one active substance and at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid.

[0013] According to the present invention, the controlled release of at least one active substance from an extruded depot can be significantly improved by combining it with a biodegradable organic polymer based on lactic acid and / or glycolic acid. In this manner, the extruded depot of the present invention exhibits a controlled release of the active substance for a period of one week to one year, with high biocompatibility and good biodegradability.

[0014] When placed subcutaneously, the extruded depot of the present invention releases at least one active agent from the active agent-containing depot into the surrounding tissue, and preferably a substantial amount of the active agent is taken up systemically. To the extent that the extruded depot is provided for localized treatment, a substantial amount of the active agent is preferentially delivered to the tissue surrounding the site of administration.

[0015] Generally, the absolute amount of active agent contained in the depot determines the time interval over which a continuous supply of the active agent into or on the tissue is maintained. Thus, for long-term application of the depot, i.e., from several weeks to 12 months, the highest possible loading of the depot containing at least one active agent is preferred.

[0016] The extruded depot of the present invention is preferably used for an application period of at least 1 week and up to 12 months, preferably 1 week to 6 months, especially 2 weeks to 3 months.

[0017] The present invention therefore relates to the medical, veterinary and / or cosmetic use of the depot of the invention for delivering active substances to the bloodstream of the human or animal body.

[0018] Furthermore, the present invention relates to a method for the preparation of the depot of the present invention, said method comprising the following steps: (i) providing a preferably homogeneous mixture comprising at least one active substance and at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid, (ii) extruding the core at a temperature above the melting point of at least one first compound, preferably from the class of at least one biodegradable organic polymer based on lactic acid and / or glycolic acid, in particular by melt extrusion, (iii) optionally applying a coating mixture or composition to the extrudate obtained above, preferably simultaneously with step (ii); (iv) cutting the extrudate into pieces of suitable size; (v) optionally rounding the pieces, in particular by spheronization; (vi) optionally sterilizing and / or packaging the depot; Includes:

[0019] The term "providing" as used herein should be understood to mean both on-site production and the provision of a homogeneous mixture. In this regard, a homogeneous mixture can be produced by a suitable mixing method, preferably without the addition of a solvent. In addition, mixing a mixture may include two or more steps, such as forming a mixture of biodegradable polymers in a first step, and then separately forming a mixture of one or more optional excipients and at least one active substance, which is then mixed with a polymer and lipid in a second step.

[0020] The preferably homogeneous mixture obtained in this way is then heated to a temperature preferably higher than the melting point temperature of the compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid applied and finally extruded by an extrusion method, in particular by a melt extrusion method.

[0021] Simultaneously with or after extrusion of the core (i.e., extrusion without a coating mixture), a preferably homogeneous coating mixture or composition comprising at least one compound of the depot described in step (i) above of the present invention is applied, if desired. Preferably, the coating mixture is applied simultaneously with extrusion of the core.

[0022] Preferably and advantageously in this regard, the component of step (i) comprises at least about 50% by weight of the dry weight of the depot of the invention, preferably at least about 55% by weight of the total weight of the depot of the invention, particularly preferably at least about 60% by weight, and more particularly preferably at least about 62% by weight.

[0023] If the active substance is a heat-sensitive substance, extrusion can be carried out at a temperature that allows the heat-sensitive active substance to be processed without adverse effects. In this case, at least one compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid is preferably selected so that its melting point is lower than the temperature at which the active substance is thermally damaged. This is particularly important for active substances such as proteins, nucleic acids, etc.

[0024] If manufacturing is not already carried out under sterile conditions, advantageous manufacturing methods may provide a step for sterilization of the extruded depot of the invention prior to any possible packaging step, however, the depot of the invention may also be manufactured without any sterilization procedures and may even be carried out under non-sterile conditions.

[0025] Furthermore, the extruded depot of the present invention may undergo a packaging step in which the depot is directly packaged in a packaging unit after any possible sterilization step. Alternatively, the extruded depot may also be first introduced into an applicator provided for application of the depot of the present invention and then packaged together with the applicator in a packaging unit.

[0026] Finally, the present invention includes an extruded depot obtainable by the above method.

[0027] Further particularly advantageous embodiments and further developments of the present invention will become apparent from the dependent claims and from the following description, whereby certain types of patent claims may also be refined by other types of dependent claims and features from various exemplary embodiments may be incorporated into new exemplary embodiments.

[0028] In a preferred embodiment, the at least one first compound is 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(meso-lactide-co-epsilon-caprolactone), poly(glycolide-co-trimethylene carbonate), poly(glycolide-co-epsilon-caprolactone) and / or poly(glycolide-co-caprolactone), preferably selected from the class of organic polymers based on lactic acid and / or glycolic acid 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).

[0029] Particularly preferred compounds from the class of organic polymers based on lactic acid and / or glycolic acid that are suitable in this respect are poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA), which can be obtained, for example, from Evonik Industries AG (Germany) under the product name R 202H (poly(D,L-lactide)) or under the product names RG 502 H and RG 752 H (PLGA).

[0030] The term "polylactide" (synonymous with polylactic acid (PLA)) should primarily be understood to mean polymers of lactic acid. Polymers that are optically active due to their asymmetric carbon atoms are in the D- or L-lactide structure.

[0031] The term "Polyglycolid (PGA)" should primarily be understood to mean a polymer of glycolic acid (synonymous with Hydroxyacetic acid).

[0032] The term "Poly(D,L-lactide-co-glycolide) (PLGA)" should be understood primarily to mean a copolymer of lactide and glycolide monomers, which can be applied in various ratios, which then form a polyester of D,L-lactic and glycolic acid, which is biodegradable.

[0033] The molecular weight of the organic polymers based on lactic acid and / or glycolic acid, in particular PLA or PLGA, can vary over a broad range. Preferably, however, the molecular weight is at least about 5 kDa and / or at most about 100 kDa. Particularly preferably, the molecular weight is 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, and more particularly preferably at least about 10 kDa and / or at most about 30 kDa.

[0034] The depot of the present invention comprises at least one active substance, which may be selected from the following non-limiting examples: antibiotics, antibacterial agents, antifungals, disinfectants, chemotherapeutic agents, cytostatics, metastasis inhibitors, antiallergic agents, anticoagulants, sex hormones, sex hormone inhibitors, hematopoietic agents, hormones, peptide hormones, fusion proteins, antidepressants, vaccines, gonadotropin-releasing hormone analogs, growth factor inhibitors, hormone mimetics, multiple sclerosis therapeutic agents, programmed cell death receptor 1 antagonists, neuroleptics, complement activation pathway inhibitors, vitamins, antihistamines, antibodies, antibody fragments, nucleic acids, DNA, plasmid DNA, cationic DNA complexes, RNA, siRNA, mRNA, and antidiabetic agents.

[0035] Useful active agents include, but are not limited to, heparin, heparin derivatives, hirudin, acetylsalicylic acid, enoxaparin, liraglutide, albiglutide, dulaglutide, lixisenatide, exenatide, insulin, insulin analogs, acarbose, glatiramella acetate, octreotide, pasireotide, lanreotide and / or vapreotide, desmopressin, oxytocin, zafirlukast, buserelin, somatostatin, glibenclamide, gliclazide, glimepiride, gliquidone, pioglitazone, miglitol, nateglinide, mitiglinide, repaglinide, sitagliptin, vildagliptin, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine , mesalazine, risperidone, paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilone, endostatin, angiostatin, D-Phe-Pro-Arg-chloromethylketone, aflibercept, as well as monoclonal antibodies, such as adalimumab, aducanumab, benralizumab, bevacizumab, certolizumab, dextromethorphan, thiazolinone ... These include nosumab, dupilumab, efalizumab, erenumab, infliximab, ipilimumab, mepolizumab, natalizumab, nemolizumab, ocrelizumab, omalizumab, pembrolizumab, pertuzumab, ranibizumab, reslizumab, rituximab, solanezumab, tocilizumab, tralokinumab, trastuzumab, ustekinumab, and vedolizumab.

[0036] Preferred extruded depot formulations containing at least one active substance are used in the treatment of acromegaly; the treatment of symptoms associated with gastroenteropancreatic endocrine tumors, such as carcinoids with features of the carcinoid syndrome; advanced neuroendocrine tumors; and thyroid-stimulating hormone (TSH)-producing pituitary adenomas; cancers such as multiple myeloma, e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia, cancer of the breast, lung, endometrium, ovary, stomach, cervix, or prostate, pancreatic cancer, glioblastoma, kidney cancer, etc.; hepatocellular carcinoma, colon cancer, neuroendocrine tumors, head and neck tumors, sarcomas; tumor syndromes resulting directly or indirectly from genetic defects in tumor suppressor genes, such as p53, PTEN, or VHL, endometrial cancer, lymphangioleiomyomatosis, neurofibromatosis 1, Hippel-Lindau disease; and rheumatoid arthritis; ankylosing spondylitis (Morbus Bechterew); psoriatic arthritis; psoriasis; osteoarthritis; gout; asthma; bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; chronic inflammatory bowel diseases such as irritable bowel disease, mucosal colitis, ulcerative colitis, and Crohn's disease, Huntington's chorea; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; lupus erythematosus; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic damage to the heart, lungs, intestines, kidneys, liver, pancreas, spleen, and brain; acute or chronic It may be used in the treatment of: sex organ transplant rejection; macular degeneration; diabetic macular edema; hyposomatotropinemia; anemia; fertility disorders; obesity; precocious puberty; endometriosis; breast pain; Tourette's syndrome; depression; personality disorders; obsessive-compulsive disorder; ADHS in children; irritability in fetal alcohol syndrome and autism; delusions; hallucinations; epilepsy; Alzheimer's disease; Parkinson's disease; paroxysmal nocturnal hemoglobinuria; as a sedative; for sex reassignment surgery; and in the treatment of multiple sclerosis and diabetes.

[0037] In a preferred embodiment, the preferred extruded depot contains at least one active substance from the class of peptide hormones. Particularly preferably, the at least one active substance is selected from octreotide, pasireotide, lanreotide and / or vapreotide. In particular, the at least one active substance is selected from octreotide.

[0038] Particularly preferably, at least one active substance is selected from nucleic acids, preferably from DNA, plasmid DNA, cationic DNA complexes, and / or RNA, siRNA, and / or mRNA.In particular, at least one active substance is selected from RNA, siRNA, and / or mRNA, particularly preferably from self-replicating RNA and / or mRNA.This kind of self-replicating RNA is known in the prior art and can be obtained, for example, from viruses.

[0039] The preferred (self-replicating) RNA or mRNA can be preferably used for vaccines and / or cancer treatments.In this regard, the RNA or mRNA encodes a desired antigen, such as a pathogen.Therefore, the vaccine also stimulates the immune response to, for example, tumor-associated antigens, and stimulates defense cells to fight tumor cells.

[0040] A further application area is the use of RNA and / or mRNA as active substances in a preferred depot for the formation of endogenous proteins and / or enzymes. In this manner, non-functional endogenous proteins and enzymes can be replaced by RNA and / or mRNA encoding the corresponding functional proteins or enzymes, with the functional proteins or enzymes encoded by these RNAs or mRNAs.

[0041] Preferably, delivery of RNA or mRNA to a specific organ or tissue is effective. In particular, delivery of RNA or mRNA from a depot is performed to the eye. Particularly preferably, this type of application is used to treat macular degeneration and / or glaucoma, diabetes-related ophthalmic diseases, and tumor-related ophthalmic diseases.

[0042] Advantageously, the immunostimulatory or therapeutic properties or the effect of RNA or mRNA can be further enhanced by adding adjuvants. Such adjuvants are known in the prior art. For example, it is known that the already widespread RNA vaccines are more effective when formulated in cationic oil-in-water nanoemulsions based on squalane and polysorbate (Tween 80) and sorbitan trioleate (Span 85), sodium citrate and citric acid, such as Adjuvans MF59 (Novatris). For example, when combined with mRNA, the effect can be enhanced by combining the molecule with Trimix (mRNAs encoding three proteins that activate the immune system: caTLR4, CD40L, and CD70).

[0043] In a further preferred embodiment, the depot comprises at least one second compound from the lipid class.

[0044] In this regard, 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 accounts for more than about 50% by weight, preferably more than 55% by weight, particularly preferably more than about 60% by weight, and even more particularly preferably more than about 62% by weight of the total weight of the depot.

[0045] However, the dry weight of the at least one first compound from the type of biodegradable organic polymers based on lactic acid and / or glycolic acid and the at least one second compound from the type of lipids may account for a maximum of about 99% by weight, preferably about 97.5% by weight, particularly preferably about 95% by weight, and more particularly preferably about 90% by weight of the total weight of the depot.

[0046] The term "about" means that a particular measurement, such as, for example, the amount in a composition, can vary from the stated measurement within the measurement error of the appropriate measurement method.

[0047] The "dry weight" of a depot herein is the weight of the administrable formulation that contains no water or only a negligible amount of water, in particular less than about 3 wt.

[0048] Therefore, the total content of at least one compound from the biodegradable organic polymer type includes the content of all compounds from the biodegradable organic polymer type and from the lipid type in the depot containing the active substance.

[0049] In the depot of the present invention, at least one second compound from the lipid class has a melting point above room temperature, i.e. above a temperature of about 25° C. Preferably, at least one lipid has a melting point above about 40° C., particularly preferably above about 50° C., particularly preferably above about 60° C., and more particularly preferably above about 70° C. However, the melting point of the lipid in the depot of the present invention does not exceed 100° C.

[0050] In a further preferred embodiment, the lipid contained in the extruded depot has a melting point of at least about 60° C. and / or at most about 80° C. Particularly preferred is a lipid melting point of at least about 62° C., especially at least about 69° C. Particularly preferred is a melting point of at most about 77° C., especially about 73° C.

[0051] In further preferred embodiments, the at least one lipid is selected from mono-, di-, and / or triglycerides, such as esters of saturated and / or unsaturated fatty acids at least 5 and / or at most 26 carbon atoms in length with glycerin, phosphatidic acid, lecithin, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, diphosphatidylglycerin, ceramide, cerebroside, ganglioside, sphingophospholipid, sphingomyelin, sphingosulfatides, glycosphingosides, acylaminosugars, acylaminosugar glycans, acyltrehalose, acyltrehalose glycans, sorbitol fatty acid esters, squalene, steroids, polyketides, sterol lipids, prenol lipids, cholesterol, hard fats, waxes, and salts and derivatives thereof.

[0052] Examples of preferred lipids are hard fats composed of mono-, di-, and triglycerides, which can be obtained, for example, by esterifying natural fatty acids with glycerol or by transesterifying natural fats. Particularly preferred lipids contain fatty acids with at least 12 and / or at most 22 carbon atoms, particularly at least 18 and / or at most 22 carbon atoms. More particularly preferred lipids are selected from glycerol tristearates. This type of hard fat is described in Pharmacopoea Europaea (Ph. Eur. 8. Ausgabe, Grundwerk, 2014) and may be selected, for example, from those with the product names Dynasan 112, Dynasan 116, and / or Dynasan 118. These can be obtained, for example, from IOI Oleo GmbH (Germany). If heat-sensitive active substances are to be used, lipids with a melting point below 50°C are preferred, such as Witepsol E85, Witepsol H5, Witepsol H12, Witepsol H37 and / or Witepsol H15, which may be obtained from, for example, IOI Oleo GmbH (Germany).

[0053] Additionally, the extruded depot may also contain more than one compound from the lipid class, however, preferably the extruded depot contains only one compound from the lipid class.

[0054] In a preferred embodiment, the ratio of at least one first compound from the polymer type to at least one second compound from the lipid type is at most about 25: 1, preferably at most about 20: 1, particularly preferably at most about 19: 1. However, the ratio of at least one first compound from the polymer type to at least one second compound from the lipid type is at least 5: 1, preferably at least about 10: 1, particularly preferably at least about 12: 1.

[0055] Exemplary combinations of at least one compound from the class of organic polymers based on lactic acid and / or glycolic acid and at least one compound from the class of lipids are shown in Table 1.

[0056] [Table 1]

[0057] Further preferred depot formulations are used for the treatment of acromegaly; conditions associated with (functionally active) gastrointestinal and pancreatic endocrine tumors, such as carcinoids with features of the carcinoid syndrome; advanced neuroendocrine tumors; and thyroid-stimulating hormone (TSH)-producing pituitary adenomas.

[0058] In this regard, the particularly preferred active substance octreotide comprises a polypeptide formed advantageously from amino acids of the following sequence: FCFWKTCT(Phe-Cys-Phe-Trp-Lys-Thr-Cys-Thr).

[0059] The at least one active substance may be contained in various forms in the depot, depending on which form provides optimal delivery of the active substance from the depot. Amino acid-based active substances may generally be present as cyclic peptides, oligopeptides, or polypeptides, or other pharmaceutically acceptable derivatives, or as components of molecular complexes. In this regard, amino acids may be bonded to each other via α-peptide bonds as well as ω-peptide bonds. The at least one active substance may be in the form of a salt, such as an acetate salt, or in the form of a free base or acid.

[0060] Additionally, at least one of the amino acids of the amino acid-based active agents described above as preferred active agents may be post-translationally modified, and in this regard, these post-translational modifications advantageously do not affect the properties of the active agent, particularly those related to release and action.

[0061] In principle, the content of active substance in the depot according to the invention can vary within a wide range.

[0062] In a preferred embodiment, the predominant active substance comprises nucleic acids, preferably DNA, plasmid DNA, cationic DNA complexes, and / or nucleic acids from the RNA, siRNA, and mRNA classes, particularly preferably RNA, siRNA, and / or mRNA, especially self-replicating RNA and / or mRNA, in an amount of at least about 1% by weight, preferably about 5% by weight, and particularly preferably about 8% by weight, in the depot. The amount of such active substances in the depot is up to about 40% by weight, preferably up to about 30% by weight, and particularly preferably up to about 20% by weight. In particular, such active substances are present in an amount of up to about 10% by weight and / or up to about 15% by weight.

[0063] The predominant amount of active substance, preferably peptide hormone, particularly preferably octreotide, pasireotide, lanreotide and / or vapreotide, in particular octreotide, is from about 0.3% to about 50% by weight, preferably from about 3% to about 45% by weight, particularly preferably from about 4% to about 40% by weight, in particular from about 7% to about 35% by weight.

[0064] For effective treatment, the concentration of active agent found in the bloodstream of a user receiving the depot is significant. Advantageously, preferred extruded depots, preferably containing a peptide hormone, particularly octreotide, exhibit an in vitro active agent release of at least about 20% by weight after 7 days and / or at least about 60% by weight after 28 days, based on the total amount of active agent contained in the implant.

[0065] Furthermore, the extrusion-type depot of the present invention is suitable for cosmetic applications.In particular, the preferred depot can be used for cosmetic wrinkle treatment.In this regard, the composition of the present invention is used topically, particularly for targeted wrinkle treatment, particularly preferably for wrinkle prevention, to tighten skin and protect against aging.Examples of active substances in this regard can be selected from hyaluronic acid, collagen and / or Botox.

[0066] Advantageous depots may further comprise at least one excipient that is routinely used in the form of subcutaneous application and that can affect the release of the active substance from the depot, the stability of the active substance, the half-life and / or bioavailability of at least one active substance. Advantageously, preferred excipients support the controlled delivery of at least one active substance from the depot. In particular, this type of excipient contributes to long-term, sustained delivery of the active substance without affecting bioavailability. Alternatively or additionally, the addition of such excipients can improve the stability of the active substance contained in the depot. This is particularly important when the depot is provided for long-term, sustained application, from several weeks to up to one year.

[0067] In this regard, substances that are used in the manufacture of subcutaneous implants and that are physiologically harmless can be disclosed. Advantageously, the excipients have high biocompatibility, so that the excipients and their degradation products are not harmful to the user and do not cause any undesirable side effects.

[0068] It is known that the addition of a pore-forming agent can significantly improve the delivery of at least one active substance from a subcutaneous depot.This type of pore-forming agent can be selected from the group formed by hydrophilic materials such as calcium sulfate, calcium hydrogen phosphate, sugars such as glucose, lactose, fructose, mannitol, trehalose, dextrin, maltodextrin, saccharose, sorbitol, xylitol, starch or its derivatives such as hydroxyethyl starch, polyvinylpyrrolidone, polyethylene glycols (PEG) such as PEG6000 or PEG8000, sodium chloride, sodium citrate, citric acid, hyaluronic acid, polyvinyl alcohol, polyacrylic acid and its derivatives, polymethacrylic acid and its derivatives, polymethyl methacrylate, polystyrene, copolymers of methyl methacrylate and styrene monomers, and mixtures thereof.

[0069] Particularly preferred pore formers are trehalose and / or hydroxyethyl starch and / or polyethylene glycol, available from, for example, Clariant or Sigma-Aldrich (Austria).

[0070] In this regard, the molecular weight of the pore-forming agent, particularly PEG, is preferably at least about 3 kDa, especially at least about 4 kDa. Preferred molecular weights for PEG are up to about 10 kDa, especially up to about 8 kDa.

[0071] In a further preferred embodiment, the advantageous depot formulation comprises an excipient that inhibits any acylation of the polypeptide, preferably octreotide, pasireotide, lanreotide and / or vapreotide, particularly preferably octreotide. In this regard, divalent salts or salts of divalent metal ions, such as calcium chloride, are preferred.

[0072] In a further preferred embodiment, the excipient comprises at least one enzyme. This enzyme can favorably influence the delivery of at least one active substance from the preferred depot without adversely affecting the stability and / or biodegradability of the depot. Advantageously, this enzyme improves the biodegradability of the depot. Particularly preferably, this enzyme is selected from the group formed by lipases. This lipase may be available, for example, from Sigma-Aldrich.

[0073] The delivery rate of active substance can be further increased by adding a swellable polymer, which is preferably selected from collagen, gelatin and its derivatives, starch and its derivatives (preferably hydroxyethyl starch, hydroxypropyl starch, carboxymethyl starch), cellulose derivatives, chitin, chitosan and their derivatives, polyamides, polyhydroxy acids, polyhydroxybutyrate, polyhydroxyvalerate, polycaprolactone and polydioxanone.This is particularly relevant for depot preparations containing active substances that require higher dosages and / or have shorter application periods, such as application periods of several weeks to several months.A particularly preferred swellable polymer in this regard is hydroxyethyl starch (HES), which can be obtained from Sigma-Aldrich (Austria).

[0074] Preferably, the molecular weight of the swellable polymer, especially HES, is at least about 50 kDa, preferably at least about 70 kDa, in particular at least about 100 kDa, more particularly preferably at least about 120 kDa. The maximum molecular weight of the swellable polymer, especially HES, is about 400 kDa, particularly preferably at most about 300 kDa, in particular at most about 200 kDa, more particularly preferably at most 150 kDa.

[0075] The degree of substitution of HES, i.e., the ratio of the number of glucose units modified with hydroxyalkyl groups to the total number of monomeric units, is at least about 0.1, preferably at least about 0.2, and particularly at least about 0.3. The highest degree of substitution is about 1, preferably about 0.7, and particularly about 0.5.

[0076] Additionally, the depot preparation of the present invention may further comprise conventional excipients known to those skilled in the art, such as tocopherols, e.g., α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof (vitamin E), which are used in particular as antioxidants.

[0077] In advantageous embodiments, such antioxidants inactivate reactive oxygen species in the depot, thereby slowing or completely preventing oxidation of the active substance and therefore improving the stability of the active substance and extending the shelf life of the depot of the invention both during storage and during use.

[0078] Advantageously, the inclusion of one or more preferred excipients results in controlled and sustained delivery of the active substance from the preferred extruded depot.

[0079] A preferred composition of the extruded depot consists of: (i) 0.1 to 50% by weight of active substance, preferably 1 to 50% by weight of active substance, in particular 2.5 to 40% by weight of active substance, (ii) 1 to 95% by weight of an organic polymer based on lactic acid and / or glycolic acid, preferably 10 to 89% by weight of an organic polymer based on lactic acid and / or glycolic acid, (iii) optionally, 1 to 25% by weight of trehalose, preferably 5 to 20% by weight of trehalose; (iv) optionally, 1 to 25% by weight PEG, preferably 5 to 20% by weight PEG.

[0080] Particularly preferably, the composition of the extruded depot is (i) 5 to 45% by weight of the active substance, in particular 10 to 40% by weight of the active substance, (ii) 30 to 85% by weight of an organic polymer based on lactic acid and / or glycolic acid, preferably PLGA and / or PLA; (iii) 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 (iv) optionally, 3 to 17.5 wt. % PEG Includes:

[0081] More particularly preferably, the components of the extruded depot are: (i) 15 to 35% by weight of an active substance; (ii) 40 to 75% by weight of an organic polymer based on lactic acid and / or glycolic acid, preferably PLGA and / or PLA; (iii) 1 to 10% by weight of lipid; (iv) optionally, 5 to 10% by weight of trehalose, and (v) optionally, 5 to 15 wt. % PEG is selected from.

[0082] More preferably, the components of the extruded depot are: (i) 0.1 to 50% by weight of active substance, preferably 1 to 50% by weight of active substance, in particular 2.5 to 40% by weight of active substance, more particularly preferably 5 to 20% by weight of active substance, (ii) 40 to 75% by weight of an organic polymer based on lactic acid and / or glycolic acid, preferably PLGA and / or PLA; (iii) optionally, 1 to 10% by weight of lipid; (iv) optionally, 0.1 to 2% by weight of a lipase, preferably 0.2 to 1% by weight of a lipase; (v) optionally, 5 to 10% by weight of trehalose, and (vi) optionally, 5 to 15 wt. % PEG; is selected from.

[0083] In particular, the content of the predominant active substance is about 5-30% by weight, the content of the biodegradable organic polymer is about 50-70% by weight, and the content of the optional lipid is about 5% by weight.

[0084] In a further preferred embodiment, trehalose may be completely or partially replaced by HES.

[0085] As already mentioned, the extruded depot of the present invention is produced by extrusion. In this manner, it has been shown that the properties of a mixture of at least two compounds from the type of organic polymers based on lactic acid and / or glycolic acid and the type of lipids with at least one active substance prepared for extrusion are improved when the active substance is mixed with at least two compounds as a dry powder, preferably a spray-dried or freeze-dried powder or a freeze-dried product.

[0086] When dissolved active substances are used, a drying step, preferably a freeze-drying step, is preferably carried out before mixing the substances to prepare the depot of the invention.

[0087] Thus, in principle, several substances can be added to the active substance, advantageously to ensure the maintenance of the biological activity of the active substance. Substances of this type are described as cryoprotectants or cryoprotectants, in this context, cryoprotectants act to protect the substance during drying, and cryoprotectants perform a similar function during freezing.

[0088] Furthermore, it has been shown that the release period of the active substance after subcutaneous application can be influenced by cooling the extrudates immediately after extrusion, for example, by storing them at elevated temperatures, rather than at ambient temperature, for example, in a drying cabinet or incubator for a specific time. In this regard, a period ranging from about 0.5 to about 5 hours is appropriate. The optional storage at elevated temperatures, also referred to as a tempering step, is essentially based on the melting point of at least one lipid and ranges, for example, from about 40°C to 80°C, preferably from about 55°C to about 75°C, and particularly preferably from about 65°C to 70°C. Obviously, the preferred storage temperature will always be a function of the temperature stability of at least one active substance.

[0089] Preferred depots can also be produced by a rounding process, in particular by spheronization. In this regard, cylindrical extrudates are advantageously rounded in such a way that shapes formed by extrusion, such as corners and edges, which may adversely affect application properties, are eliminated. Furthermore, spheronization can be used to produce microparticles that are then administered subcutaneously and thus constitute biodegradable depots.

[0090] Advantageously, the depot is composed of at least one layer applied to the core and preferably has a uniform coating that defines the initial release of the active substance from the depot and ensures a therapeutic concentration of at least one active substance over a sustained period of time. A preferred coating comprises a mixture of substances or compositions selected from at least one of the components (a) to (c) of the depot of the present invention. As long as the coating contains an active substance, its amount may be the same as or different from the amount of active substance in the core. However, in a particularly preferred embodiment, the coating does not contain any active substance.

[0091] In principle, the appropriate weight of the depot is within the range commonly used for subcutaneous implants. In this regard, the weight of the extruded depot also depends on the desired application period and / or application site. However, the preferred weight of the extruded depot is in the range of 1 to 1000 mg, particularly preferably at least about 20 mg and / or at most about 180 mg, in particular about 50 mg and / or at most about 150 mg, and more particularly preferably at least about 80 mg and / or at most about 120 mg.

[0092] The depot of the present invention in this regard may be formed in the shape of a rod, ball, cube, oval, rectangular parallelepiped, cushion, cylinder, tablet, pellet, plate, or briquette.

[0093] The depot of the present invention is preferably of an injectable size, but may be introduced to the administration site by surgical intervention if desired. In this regard, preferred depots have a diameter of at least 0.1 to 10 mm and a length of at least 0.15 to 50 mm. In particular, the depot has a diameter of at least 0.15 to 7.5 mm and a length of at least 0.2 to 45 mm, and particularly preferably a diameter of at least 0.2 to 5 mm and a length of at least 0.3 to 40 mm.

[0094] In this context, the term "diameter" means the longest dimension perpendicular to the axis of rotation that connects two points on the outer edge of the object in question. The term "axis of rotation" is the straight line about which a rotating object can be rotated.

[0095] The term "length" means the portion of an object or axis of rotation that is inside the axis of rotation.

[0096] The diameter to length ratio of the preferred depot is advantageously in the range of 1:30 to 10:1, preferably in the range of 1:15 to 5:1, more particularly preferably in the range of 1:13 to 1:1.

[0097] When the extruded depot preparation is a microparticle, the diameter of the circular or nearly circular particle may be about 1 to about 100 μm, preferably about 5 to about 90 μm, and more particularly preferably about 10 to about 80 μm.

[0098] As described above, the method of the present invention for the preparation of an extruded depot comprises mixing (a) at least one active substance and (b) at least one compound from the class of organic polymers based on lactic acid and / or glycolic acid, and optionally (c) at least one compound from the class of lipids, thereby obtaining a homogeneous powder mixture.

[0099] The term "powder mixture" as used in the present specification should be understood to mean a mixture of multiple solid components, where the components may have particles with a size of less than 1 nm. Furthermore, the powder mixture may also have particles with a size ranging from 1 nm to 1 μm and / or particles with a size greater than 1 μm. If at least one of the components to be mixed is not in a solid form before mixing, it can be converted to a solid state, for example by spray drying or freeze drying, before forming the powder mixture.

[0100] In principle, any application device known to those skilled in the art can be used to apply the extruded depot of the present invention to the subcutaneous tissue. Thus, the depot of the present invention can be administered, for example, by syringe, cannula, applicator and injection, in particular by applicator.

[0101] Finally, the present invention also relates to a kit comprising the extruded depot of the present invention and an applicator suitable for subcutaneous administration of the extruded depot. In this regard, the extruded depot of the present invention does not necessarily have to be sterilized before being received in the applicator; the sterilization procedure may be carried out inside the applicator. Furthermore, this type of applicator is capable of accommodating extruded depots of various lengths. In this regard, it is clear that depots that are not cylindrical in shape, but are, for example, cubic or circular, may also be used.

[0102] Advantageously, this type of applicator comprises a hollow needle for receiving the extrudate having the dimensions mentioned above, and a protective cap that must be removed before application but can be reattached after use. In this way, the extrudate can be advantageously protected from external influences that may have certain negative effects on the preferred use.

[0103] Further features of the present invention will become apparent from the following description of exemplary embodiments in conjunction with the claims and drawings. It should be noted that the present invention is not limited to the embodiments in the described exemplary embodiments, but is defined by the scope of the appended claims. In particular, the individual features of the embodiments of the present invention may be formed in combinations other than those in the examples shown below. The following description of some exemplary embodiments of the present invention refers to the accompanying drawings. [Brief explanation of the drawings]

[0104] [Figure 1]Figure 1 shows the release profile of an octreotide-containing depot according to the invention (Example 2, see below) compared to an octreotide-containing depot not according to the invention. The depot has a diameter of approximately 2 mm. Solid line (inventive example): 33% by weight octreotide, 32% by weight polylactic-co-glycolic acid polymer, 32% by weight polylactic acid, 3% by weight triglyceride. Dotted line (comparative example): 33% by weight octreotide, 33.5% by weight polylactic-co-glycolic acid polymer, 33.5% by weight polylactic acid. [Example]

[0105] Example 1 Example according to the present invention To prepare the depot preparation of the present invention, a powder mixture consisting of equal parts by weight of 34% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 34% polylactic acid (Resomer® R202H, Evonik Industries, Germany), and 32% octreotide lyophilisate (Bachem, Bubendorf, Switzerland) was weighed out and homogeneously mixed by cryo-milling (Freezer / Mill, C3 Prozess-und Analysentechnik GmbH, Haar, Munich, Germany).

[0106] Subsequent extrusion was carried out using a counter-rotating screw melt-kneading extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 85-92 °C and a screw rotation speed of 8 rpm (revolutions per minute). The diameter of the extrudate was set to 2.0 mm using a nozzle. The extruded rod was cut into extrudates of appropriate length (2 cm in length in this example). Alternatively, the extrudate could be shaped into microparticles by spheronization.

[0107] Example 2 Example according to the present invention To prepare the depot formulation of the present invention, a powder mixture consisting of 32 wt% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 32 wt% polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3 wt% triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), and 33 wt% octreotide lyophilizate (Bachem, Bubendorf, Switzerland) was weighed out. This powder mixture was homogeneously mixed by cryo-milling (Freezer / Mill, C3 Prozess-und Analysentechnik GmbH, Haar, Munich, Germany). Subsequent extrusion was carried out using a counter-rotating screw melt-kneading extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 85°C to 92°C and a shaft rotation speed of 8 rpm (revolutions per minute). The diameter of the extrudate was set to 2.0 mm using a nozzle. The extruded rod was cut into extrudates of appropriate length (2 cm length in this example). Alternatively, the extrudates could be shaped into microparticles by spheronization.

[0108] Example 3 Example according to the present invention The preparation was as described in the Examples, but the depot composition of the invention was supplemented with calcium chloride (Sigma-Aldrich, Vienna, Austria). The powder mixture consisted of 31.75 wt.% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 31.75 wt.% polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3.5 wt.% calcium chloride, and 33 wt.% octreotide lyophilisate.

[0109] Example 4 Example according to the present invention The preparation was as described in the Examples, but the composition of the depot of the invention was supplemented with triglycerides and trehalose (Sigma-Aldrich, Vienna, Austria). The powder mixture consisted of 30% by weight of polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 30% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3.5% by weight of triglycerides (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), 3.5% by weight of trehalose, and 33% by weight of octreotide lyophilisate.

[0110] Example 5 Example according to the present invention To prepare the depot formulation according to the present invention, a powder mixture consisting of 38 wt. % polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 10 wt. % glyceryl behenate (Compritol® 888 ATO, Gattefosse), and 33 wt. % octreotide lyophilizate was prepared. The components of this powder mixture were homogeneously mixed by cryo-milling (Freezer / Mill, C3 Prozess- und Analysentechnik GmbH, Haar, Munich, Germany). Subsequent extrusion was carried out using a co-rotating screw melt-kneading extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 83°C to 90°C and a screw rotation speed of 8 rpm.

[0111] Example 6 Example according to the present invention To prepare the depot formulations according to the invention, a powder mixture consisting of 28.5 wt. % polylactic-co-glycolic acid (Resomer® R502H, Evonik Industries, Germany), 28.5 wt. % polylactic acid (Resomer® R203H, Evonik Industries, Germany), 3 wt. % triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), and 40 wt. % lanreotide was processed into a homogeneous mixture by cryo-grinding. To test the release of the active substance, exemplary depot formulations of the invention of each appropriate shape and size (e.g., cut into cylindrical shapes with a length of 1.5-2 cm and a diameter of 1.8 mm) were first weighed out separately.

[0112] Example 7 Example according to the present invention To prepare the depot preparation according to the present invention, a powder mixture consisting of 38 wt.% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 26 wt.% polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3 wt.% triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), and 33 wt.% octreotide lyophilizate (Bachem, Bubendorf, Switzerland) was weighed out and homogenized by cryo-milling (Freezer / Mill, C3 Prozess- und Analysentechnik GmbH, Haar, Munich, Germany). Subsequent coextrusion was performed using a two-component nozzle, in which the actual powder mixture plus a uniform coating made of 100 wt. % polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany) was extruded using a structurally identical second extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany). Using the two-component nozzle, the diameter of the core extrudate was set to 2.0 mm, and the layer thickness of the coating was set to 0.1 mm. The extruded rod was then cut into extrudates of appropriate length.

[0113] Comparative Example For the preparation of a depot to serve as a comparative example: A powder mixture consisting of 33.5 wt% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 33.5 wt% polylactic acid (Resomer® R202H, Evonik Industries, Germany), and 33 wt% octreotide lyophilisate (Bachem, Bubendorf, Switzerland) was prepared and homogenized by cryo-milling (Freezer / Mill, C3 Prozess- und Analysentechnik GmbH, Haar, Munich, Germany).

[0114] Subsequent extrusion was carried out using a counter-rotating melt-kneading extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 85-92°C and a shaft rotation speed of 5-15 rpm (revolutions per minute). The diameter of the extrudate was set to 2.0 mm using a nozzle. The extruded rod was cut into extrudates of appropriate length (2.0 cm in length in this example).

[0115] Measurement of in vitro release of active substance from depot preparations (Examples 1 to 7 and Comparative Example)

[0116] To study the in vitro release of the active substance from the depot, the depot (according to Examples 1-6) was added to a release cell and supplemented with 50 mL of release medium (disodium hydrogen phosphate, pH 7.4). The depot was then placed in an incubator shaker (IKA®-Werke GmbH & Co. KG, Germany) at 37°C for the desired application period.

[0117] At each sampling time, approximately 1 mL of sample solution was removed using a disposable pipette and placed directly on the HPLC column. After each sampling time, the release solvent was replaced in its entirety.

[0118] Example 8 Example according to the present invention To prepare the depot of the present invention, a powder mixture consisting of 44 wt% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 44 wt% polylactic acid (Resomer® R202H, Evonik Industries, Germany), and 12 wt% mRNA (CleanCap® EGFP mRNA, TriLink Biotechnologies, Inc., USA) was weighed out.

[0119] Subsequent extrusion was carried out using a coaxial melt-kneading extruder (Mini Extruder ZE-5, Three-Tec GmbH, Birren, Switzerland) at 85-90°C and a shaft rotation speed of 10 rpm (revolutions per minute). The diameter of the extrudate was set to 0.5 mm using a nozzle. The extruded rod was cut into extrudates of appropriate length (0.5 cm in length in this example).

[0120] Expression (GFP activity assay) was measured using the GFP Assay System (Arbor Assays LLC, USA), where the following protocol was used: the depot of the present invention was added to human cell cultures. Release from the depot and activity of the encoded protein were detected by a fluorescence assay. Upon excitation with light at a wavelength of 395 nm, cells that had taken up mRNA and expressed the GFP gene emitted significant light at a wavelength of 509 nm. Virtually no fluorescence was measured in cell cultures to which a negative control (no mRNA) was added.

[0121] Example 9 Example according to the present invention The preparation was as described in Example 1, but the composition of the depot of the present invention was supplemented with glyceryl behenate. The powder mixture consisted of 40% by weight of polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany), 40% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 5% by weight of triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), 4.5% by weight of glyceryl behenate (Compritol® 888 ATO, Gattefosse), 10% by weight of mRNA (CleanCap® EGFP mRNA, TriLink Biotechnologies, Inc., USA), and 0.5% by weight of lipase (triacylglycerol lipase from Pseudomonas sp., Merck KGaA, Darmstadt). Expression was assayed in the same manner as in Example 8.

[0122] Example 10: Example according to the present invention To prepare the depot preparation of the present invention, a powder mixture consisting of 86 wt% polylactic-co-glycolic acid polymer (Resomer® R752H, Evonik Industries, Germany) and 14 wt% mRNA (CleanCap® EGFP mRNA, TriLink Biotechnologies, Inc., USA) was weighed out. This powder mixture was homogeneously mixed by cryo-milling (Freezer / Mill, C3 Prozess-und Analysentechnik GmbH, Haar, Munich, Germany). Subsequent extrusion was carried out using a co-axial melt-kneading extruder (Mini Extruder ZE-5, Three-Tec GmbH, Birren, Switzerland) at 83°C to 92°C and a shaft rotation speed of 10 rpm.

[0123] Expression (assay of luciferase activity) was measured using the Luciferase Assay System (Promega Corporation, USA). The following protocol was used: the depot of the present invention was added to human cell cultures. Release from the depot and activity of the encoded protein were detected by luciferase assay. Upon addition of the substrate (luciferase), cells that had taken up mRNA and expressed the luciferase enzyme emitted significant light. Virtually no fluorescence was measured in cell cultures to which a negative control (no mRNA) was added.

Claims

1. a. at least one active agent, and b. at least one first compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid 1. An extruded depot for sustained release of an active agent comprising: the at least one active agent is selected from a nucleic acid and is present in the extruded depot in an amount of at least 5% by weight and up to 30% by weight; the extruded depot has a length of at least 0.1 cm and / or at most 5 cm; The biodegradable organic polymer based on lactic acid and / or glycolic acid is selected from the group consisting of 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 and / or poly(glycolide-co-caprolactone).

2. 2. The extrusion-type depot according to claim 1, wherein the biodegradable organic polymer 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), and poly(D,L-lactide-co-glycolide).

3. 2. The extrusion-type depot according to claim 1, wherein the biodegradable organic polymer based on lactic acid and / or glycolic acid is selected from poly(D,L-lactide-co-glycolide) and poly(D,L-lactide).

4. 4. The extruded depot according to claim 1, wherein the at least one active substance is selected from the following types: DNA, plasmid DNA, cationic DNA complexes, and / or RNA, siRNA, and mRNA.

5. The extruded depot according to any one of claims 1 to 3, wherein the at least one active substance is selected from RNA, siRNA, and / or mRNA.

6. 4. The extruded depot according to claim 1, wherein the at least one active substance is selected from self-replicating RNA and / or mRNA.

7. The extruded depot according to any one of claims 1 to 6, further comprising one or more excipients selected from the group consisting of enzymes; polyethylene oxide; salts of divalent metal ions; disaccharides; oligosaccharides; and polysaccharides.

8. 8. The extrusion-type depot according to claim 7, wherein the enzyme is a lipase.

9. 8. The extrusion-type depot according to claim 7, wherein said polyethylene oxide is polyethylene glycol.

10. 8. The extrusion-type depot preparation according to claim 7, wherein the salt of the divalent metal ion is calcium chloride.

11. 8. The extrusion-type depot according to claim 7, wherein the disaccharide is trehalose.

12. 8. The extrusion-type depot according to claim 7, wherein the oligosaccharide is a cyclodextrin.

13. 8. The extrusion-type depot according to claim 7, wherein the polysaccharide is cellulose.

14. 14. The extruded depot of any one of claims 1 to 13, wherein the extruded depot comprises a homogeneous core coating comprising a homogeneous composition of components as defined in claim 1a and / or b.

15. 15. The extruded depot of any one of claims 1 to 14, wherein the extruded depot has a diameter to length ratio of at least 1:30 and / or at most 10:

1.

16. 15. The extruded depot of any one of claims 1 to 14, wherein the extruded depot has a diameter to length ratio of at least 1:15 and / or at most 5:

1.

17. A method for producing the extrusion-type depot preparation according to any one of claims 1 to 16, comprising the following steps: (i) providing a mixture comprising the component a and the component b according to any one of claims 1 to 16; (ii) extruding a core of said mixture at a temperature above the melting point of at least one compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid; (iii) optionally applying a coating mixture or composition to the extrudate obtained above; (iv) cutting the extrudate into pieces of suitable size; (v) optionally rounding the pieces by spheronization; (vi) optionally sterilizing and / or packaging the depot. A method comprising:

18. 18. The method of claim 17, wherein the mixture provided in step (i) is a homogeneous mixture.

19. 18. The method according to claim 17, wherein the step of extruding the core of at least one compound from the class of biodegradable organic polymers based on lactic acid and / or glycolic acid is carried out by melt extrusion.

20. 18. The method of claim 17, wherein the step of applying the coating mixture or composition occurs simultaneously with step (ii).

21. 17. The extruded depot of any one of claims 1 to 16 for medical, veterinary or cosmetic applications.

22. An extruded depot formulation described in any one of claims 1 to 16 and 21 for use in the treatment of acromegaly; in the treatment of symptoms associated with gastrointestinal and pancreatic endocrine tumors; in the treatment of advanced neuroendocrine tumors; in the treatment of thyroid-stimulating hormone (TSH)-producing pituitary adenomas; for vaccines and / or cancer treatment; in the treatment of non-functional expression of proteins and / or enzymes; for the treatment of macular degeneration and / or glaucoma; for the treatment of diabetes-related ophthalmic diseases and tumor-related ophthalmic diseases.

23. 23. The extruded depot according to claim 22, wherein the condition associated with gastrointestinal / pancreatic endocrine tumors is carcinoid with characteristics of carcinoid syndrome.

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