EXTRUDED DEPOT FORM FOR CONTROLLED ACTIVE SUBSTANCE RELEASE

Abstract

The invention concerns an extruded depot form for sustained active substance release, comprising at least one active substance, at least one first compound from the class of biodegradable organic polymers based on lactic acid and/or glycolic acid and at least one second compound from the class of lipids.

Claims

1. An extruded depot form, comprising at least one active substance; at least one biodegradable organic polymer comprising at least one monomer selected from the group consisting of on lactic acid and glycolic acid; and at least one lipid, wherein the at least one biodegradable organic polymer and the at least one lipid preferably comprise at least 50% by weight of the dry weight of the depot form.

2. The extruded depot form of claim 1, wherein the at least one biodegradable polymer is at least one 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(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 poly(glycolide-co-caprolactone).

3. The extruded depot form of claim 1, wherein the at least one lipid has a melting point in the range of 60° C. to 80° C.

4. The extruded depot form of claim 1, wherein the at least one lipid is at least one selected from the group consisting of mono-, di- and triglycerides and salts thereof.

5. The extruded depot form of claim 1, wherein the at least one lipid is at least one ester of glycerine with saturated and/or unsaturated fatty acids having an alkyl chain of 5 to 26 carbon atoms.

6. The extruded depot form of claim 1, further comprising one or more excipients selected from the group consisting of an enzyme, a polyethylene oxide, a salt with divalent metal ions, a disachharide, an oligosaccharide, and a polysaccharide.

7. The extruded depot form of claim 1, wherein the at least one active substance is at least one selected from the group consisting of a peptide hormone, a growth hormone, a VEGF inhibitor, an antidiabetic, a gonadotropin-releasing hormone analogue (GnRH analogue), an antirheumatic, a breast cancer therapeutic, an MS (multiple sclerosis) therapeutic, a programmed cell death receptor-1 (PD-1) antagonist, a protein medicinal product against paroxysmal nocturnal haemoglobulinuria, and a neuroleptic.

8. The extruded depot form of claim 1, wherein the at least one active substance is at least one selected from the group consisting of DNA, plasmid DNA, cationic DNA complex, RNA, siRNA and mRNA.

9. The extruded depot form of claim 1, wherein the extruded depot form comprises a homogeneous core coating comprising a homogeneous composition of the at least one active substance, the at least one biodegradable organic polymer, and the at least one lipid.

10. The extruded depot form of claim 1, wherein the extruded depot form has a length of 0.1 cm to 5 cm.

11. The extruded depot form of claim 1, wherein the extruded depot form has a ratio of diameter to length of 1:30 to 10:1.

12. A method for production of an extruded depot form of claim 1, comprising: providing a homogeneous mixture of the at least one active substance, the at least one biodegradable organic polymer, and the at least one lipid, extruding the mixture, at a temperature above the melting temperature of the at least one lipid, to obtain an extrudate, optionally, applying a coating composition to the extrudate, cutting the extrudate into pieces, optionally, rounding the pieces, and optionally, sterilizing and/or packaging the depot form.

13. An extruded depot form obtained in accordance with the method of claim 12.

14. The extruded depot form of claim 1, wherein the in vitro release of the peptide hormone is at least 20% by weight after 7 days and/or is at least 60% by weight after 28 days.

15. A medical, veterinary or cosmetic composition, comprising the extruded depot form of claim 1.

16. A method of treating a condition, comprising providing a pharmaceutically effective amount of the extruded depot form of claim 1 to a patient, the condition comprising at least one selected from the group consisting of acromegaly; gastroenteropancreatic endocrinal tumours; advanced neuroendocrinal tumours; thyroid-stimulating hormone (TSH)-secreting pituitary adenomas; vaccination and/or cancer therapy; the non-functional expression of proteins and/or enzymes; macular degeneration and/or glaucoma, diabetes-related eye disease and oncologically-related eye disease.

17. The extruded depot form of claim 6, wherein the one or more excipients is selected from the group consisting of a lipase, polyethylene glycol, calcium chloride, trehalose, a cyclodextrin, and cellulose.

18. The extruded depot form of claim 7, wherein the at least one active substance is at least one selected from the group consisting of octreotide, pasireotide, lanreotide, valpreotide, somatotropin, erythropoetin, bevacizumab, ranibizumab, exenatide, goserelin, leuprorelin, infliximab, etanercept, trastuzumab, natalizumab, pembrolizumab, eculizumab, and risperidone.

19. The method of claim 12, wherein the coating composition is applied to the extrudate simultaneously with extruding the core to obtain the extrudate.

Description

[0132] FIG. 1: shows the release profiles for an octreotide-containing depot form in accordance with the invention (in accordance with Example 1, see below) compared with an octreotide-containing depot form which is not in accordance with the invention. The depot forms have a diameter of approximately 2 mm. Solid line (example in accordance with 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 (comparative example): 33% by weight octreotide; 33.5% by weight polylactic acid-co-glycolic acid polymer, 33.5% by weight polylactic acid.

EXAMPLES

[0133] Example 1, in accordance with the invention:

[0134] In order to produce depot forms in accordance with the invention, a powdered mixture was weighed out which consisted of 32% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 32% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3% by weight of a triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) and 33% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland). This powdered mixture was homogeneously mixed by cryogenic milling (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Munchen, Germany). The subsequent extrusion was carried out by means of counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 85 C to 92° C. and at a screw rotation speed of 8 rpm (revolutions per minute). The diameter of the extrudate was set at 2.0 mm with a nozzle. The extruded rod was cut into extrudates of a suitable length (in the present example to a length of 2 cm). Alternatively, the extrudate could have been shaped into microparticles by spheronisation.

[0135] Example 2, in accordance with the invention:

[0136] Production was as described in Example 1, but the composition of the depot form in accordance with the invention was supplemented with calcium chloride (Sigma Aldrich, Vienna, Austria). The powdered mixture consisted of 30% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 30% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3.5% by weight of triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 3.5% by weight of calcium chloride and 33% by weight of octreotide lyophilisate.

[0137] Example 3, in accordance with the invention:

[0138] Production was as described in Example 1, but the composition of the depot form in accordance with the invention was supplemented with trehalose (Sigma Aldrich, Vienna, Austria). The powdered mixture consisted of 30% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 30% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3.5% by weight of triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 3.5% by weight of trehalose and 33% by weight of octreotide lyophilisate.

[0139] Example 4, in accordance with the invention:

[0140] In order to produce depot forms in accordance with the invention, a powdered mixture was produced which consisted of 57% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 10% by weight of glycerol dibehenate (Compritol 888 ATO, Gattefosse) and 33% by weight of octreotide lyophilisate. The components of this powdered mixture were homogeneously mixed by means of cryogenic milling (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Munchen, Germany). The subsequent extrusion was carried out by means of co-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 83° C. to 90° C. and at a screw rotation speed of 8 rpm.

[0141] Example 5, in accordance with the invention:

[0142] In order to produce depot forms in accordance with the invention, a powdered mixture which consisted of 28.5% by weight of polylactic acid-co-glycolic acid (Resomer® RG502H, Evonik Industries, Germany), 28.5% by weight of polylactic acid (Resomer® R203H, Evonik Industries, Germany), 3% by weight of triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) and 40% by weight of lanreotide was processed into a homogeneous mixture by means of cryogenic milling. To examine the active substance release, exemplary depot forms in accordance with the invention in the respectively suitable shape and sizes (for example cut into cylinders 1.5 to 2 cm in length and with a diameter of 1.8 mm) were initially weighed out separately.

[0143] Example 6, in accordance with the invention:

[0144] In order to produce depot forms in accordance with the invention, a powdered mixture was weighed out which consisted of 38% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 26 by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 3 by weight of a triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) and 33% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland). This powdered mixture was homogeneously mixed by cryogenic milling (Freezer/Mill, C3Prozess—and Analysentechnik GmbH, Haar bei Munchen, Germany). The subsequent co-extrusion was carried out with the aid of a dual-component nozzle wherein, in addition to the actual powdered mixture, a homogeneous coating produced from 100% by weight polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany) was extruded with the aid of a structurally identical second extruder (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany). The diameter for the core extrudate was set at 2.0 mm and the layer thickness of the coating was set to 0.1 mm with the aid of the dual-component nozzle. The extruded rod was then cut into extrudates of a suitable length.

COMPARATIVE EXAMPLE

[0145] For the production of a depot form which acted as a comparative example, a powdered mixture was produced which consisted of 33.5% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 33.5% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany) and 33% by weight of octreotide lyophilisate (Bachem, Bubendorf, Switzerland). This powdered mixture was homogeneously mixed by cryogenic milling (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Munchen, Germany).

[0146] The subsequent extrusion was carried out by means of counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 85° C. to 92° C. and at a screw rotation speed of 5-15 rpm (revolutions per minute). The diameter of the extrudate was set at 2.0 mm with a nozzle. The extruded rod was cut into extrudates of a suitable length (in the present example to a length of 2.0 cm).

[0147] Determination of the in vitro release of the active substance from the depot forms (Examples 1 to 6 as well as comparative example):

[0148] In order to investigate the in vitro release of the active substance from the depot forms, the depot forms (in accordance with Examples 1-6) were added to release cells and supplemented with 50 mL of release medium (disodium hydrogen phosphate, pH 7.4). The depot forms were then placed in an incubating shaker (IKA®-Werke GmbH & Co. KG, Germany) at 37° C. for the desired application period.

[0149] At the respective sampling times, approximately 1 mL of sample solution was removed with a disposable pipette and placed directly into a HPLC column. After each sampling time, the release medium was replaced in its entirety.

[0150] Example 7, in accordance with the invention:

[0151] In order to produce depot forms in accordance with the invention, a powdered mixture was weighed out which consisted of 42% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 42 by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 5.5 by weight of a triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 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). The subsequent extrusion was carried out by means of co-rotating screw melt extrusion (Mini Extruder ZE-5, Three-Tec GmbH, Birnen, Switzerland) at 85° C. to 90° C. and at a screw rotation speed of 10 rpm (revolutions per minute). The diameter for the extrudate was set to 0.5 mm with a nozzle. The extruded rod was cut into extrudates of a suitable length (in the present example to a length of 0.5 cm).

[0152] The expression (assay of GFP activity) was monitored with the aid of the GFP Assay System (Arbor Assays LLC, USA). Here, the following protocol was used: the depot form in accordance with the invention was added to a human cell culture. The release from the depot form and the activity of the coded protein were detected by the fluorescence assay. Upon excitation with light at a wavelength of 395 nm, the cells which had taken up the mRNA and expressed the GFP gene emitted measurable light at a wavelength of 509 nm. In cell cultures which had received a negative control (without mRNA), no substantial fluorescence could be measured.

[0153] Example 8, in accordance with the invention:

[0154] Production was as described in Example 1, but the composition of the depot form in accordance with the invention was supplemented with glycerol dibehenate. The powdered mixture consisted of 40% by weight of polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 40% by weight of polylactic acid (Resomer® R202H, Evonik Industries, Germany), 5% by weight of triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 4.5% by weight of glycerol dibehenate (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). The expression was assayed in the same manner as in Example 7.

[0155] Example 9, in accordance with the invention:

[0156] In order to produce depot forms in accordance with the invention, a powdered mixture was weighed out which consisted of 74.5% by weight of the polylactic acid-co-glycolic acid polymer (Resomer® RG752H, Evonik Industries, Germany), 15% by weight of a triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 10% by weight of mRNA (CleanCap® FLuc mRNA, TriLink Biotechnologies, Inc. USA) and 0.5% by weight of lipase (triacylglycerol lipase from Pseudomonas sp., Merck KGaA, Darmstadt). This powdered mixture was homogeneously mixed by cryogenic milling (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei München, Germany). The subsequent extrusion was carried out by means of co-rotating screw melt extrusion (Mini Extruder ZE-5, Three-Tec GmbH, Birnen, Switzerland) at 83° C. to 92° C. and at a screw rotation speed of 10 rpm.

[0157] The expression (assay of luciferase activity) was monitored with the aid of the Luciferase Assay System E1500 (Promega Corporation, USA). Here, the following protocol was used: the depot form in accordance with the invention was added to a human cell culture. The release from the depot form and the activity of the coded protein were detected by the luciferase assay. Upon adding the substrate (luciferin), the cells which had taken up the mRNA and expressed the luciferase enzyme emitted measurable light. In cell cultures which had received a negative control (without mRNA), no substantial fluorescence could be measured.