EXTRUDED DEPOT FORM FOR CONTINUING ACTIVE SUBSTANCE RELEASE

Abstract

The invention relates to an extruded depot form for a continuing active substance release, comprising at least one active substance and at least two compounds of the class of substances which can be broken down by lipases. The at least two compounds comprise a low-melting compound and a high-melting compound, and the ratio of the low-melting compound to the high-melting compound ranges from 1:9 to 9:1. The depot form also optionally comprises at least one auxiliary agent for modulating the active substance release, wherein b), or optionally b) and c), constitute at least 60 wt. % of the dry weight of the depot form.

Claims

1. An extruded depot form, for continuing active substance release, comprising (a) at least one active substance, (b) at least two compounds of the class of substances which can be broken down by lipases, wherein the at least two compounds comprise a low-melting compound and a high-melting compound, and wherein the ratio of the low-melting compound to the high-melting compound ranges from 1:9 to 9:1, preferably ranges from 1:3 to 5:1, and (c) optionally at least one auxiliary agent for modulating the active substance release, wherein b), or b) and c), constitute at least 60 wt. % of the dry weight of the depot form.

2. The extruded depot form according to claim 1, wherein the melting point of a first compound which can be broken down by lipase is at most 45 C. and/or the melting point of a second compound which can be broken down by lipases is above 45 C.

3. The extruded depot form according to claim 1, wherein both the low-melting compound and the high-melting compound are selected from a fat, a hard fat, a mono-, di- and/or triglyceride and salts thereof.

4. The extruded depot form according to claim 1, wherein the at least two compounds of the class of substances which can be broken down by lipases are selected from esterifications of glycerin with saturated and unsaturated fatty acids of a length of from 5 to 20 carbon atoms.

5. The extruded depot form according to claim 1, wherein the at least one auxiliary agent for modulating the active substance release is selected from starch, cellulose, trehalose, dextrin, poly-(D,L-lactide-co-glycolide), polyethylene glycol, hydroxyethyl starch, trehalose, polyethylene glycol and/or poly-(D,L-lactide-co-glycolide).

6. The extruded depot form according to claim 1, wherein the at least one active substance is selected from the group consisting of VEGF inhibitors, growth factor inhibitors, kinase inhibitors, cytostatics, vaccines, monoclonal antibodies, peptide hormones, fusion proteins, anticoagulants, growth hormones, gonadotropin-releasing hormone analogues, breast cancer therapeutic agents, multiple sclerosis therapeutic agents, programmed cell death receptor 1 antagonists, neuroleptics, protein drugs against paroxysmal nocturnal haemoglobinuria, anti-diabetics, antidepressants, Bevacizumab, Ranibizumab, Citalopram, Risperidon, Octreotide, Insulin, Glucagon-like peptide 1 (GLP-1) analogues, Liraglutide, Albiglutide, Dulaglutide, Lixisenatide and Exenatide.

7. The extruded depot form according to claim 1, wherein the extruded depot form is a homogeneous mixture.

8. The extruded depot form according to claim 1 comprising a homogeneous core coating which comprises the components a), b) and/or c).

9. The extruded depot form according to claim 1, wherein the extruded depot form has a length ranging from 0.1 cm to 5 cm.

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

11. A method for producing the extruded depot form according to claim 1, comprising the steps of (i) providing at least one homogeneous mixture comprising (a), (b) and optionally (c), (ii) extruding the mixture, to obtain the extrudate at a temperature below the melting point of the high-melting compound, (iii) cutting the extrudate into pieces of suitable size, (iv) optionally rounding the pieces, (v) optionally applying the coating mixture to the extrudate obtained above, (vi) optionally carrying out a sterilisation process and/or packaging the depot form.

12. The method for producing an extruded depot form according to claim 11, wherein the method, after step (ii), comprises the following steps: (iii) optionally cutting the extrudate from step (ii) into pieces of suitable size, (viii) extruding the mixture, at a temperature below the melting point of the high-melting compound, (ix) cutting the extrudate into pieces of suitable size, (x) optionally rounding the pieces, (xi) optionally applying the coating mixture to the extrudate obtained above, (ix) optionally carrying out a sterilisation process and/or packaging the depot form.

13. (canceled)

14. The extruded depot form according to claim 1, wherein, following one-time addition of an incretin mimetic, a prolonged plasma concentration of the active substance of at least 50 pg/ml over a period of time from at least a week to at most 12 months, is retained.

15. (canceled)

16. A method of treatment of a condition by providing a pharmaceutically effective amount of the extended depot form according to claim 1, wherein the condition includes cancer diseases, retroviral infections, dementia, Alzheimer's disease, arteriosclerosis, bronchial asthma, hypertonia, COPD, hepatitis, osteoporosis, coronary heart disease, macular degeneration, hyposomatotropism, anaemia, fertility disorders, Pubertas praecox, endometriosis, paroxysmal nocturnal haemoglobinuria, as sedatives, for gender reassignment measures, mastodynia, Tourette's syndrome, depression, personality disorders, compulsive disorders, ADHS in children, irritability in foetal alcohol syndrome and autism, delusions, hallucinations, rheumatoid arthritis, Crohn's disease, ulcerative colitis, spondylitis ankylosans (morbus bechterew), psoriasis arthritis, psoriasis, multiple sclerosis, diabetic macular oedema, type 1 diabetes mellitus, and type 2 diabetes mellitus.

Description

[0130] Further features of the invention will become clear from the following description of exemplary embodiments in conjunction with the claims and the drawings. It should be noted that the invention is not limited to the embodiments of the described examples, but is specified by the scope of the accompanying claims. In particular, the individual features in embodiments according to the invention can be implemented in combinations other than those presented in the examples described below. The following explanation of some exemplary embodiments of the invention is provided with reference to the accompanying drawings. In the drawings:

[0131] FIG. 1 shows release profiles of depot forms according to the invention with different exenatide-containing formulations and with a diameter of approximately 1.5 mm. Solid line: 10 wt. % Exenatide; Witepsol E85/Dynasan 118=35:65. Dashed line: 5 wt. % Exenatide; 5 wt. % PEG8000; Witepsol E85/Dynasan 118=35:65.

[0132] FIG. 2 shows release profiles of depot forms according to the invention containing Bevacizumab and having a diameter of approximately 1.9 mm. Solid line: 10 wt. % Bevacizumab; 10 wt. % PEG 6000; Witepsol H12/Dynasan 118=30:70. Dashed line: 10 wt. % Bevacizumab; 10 wt. % PEG 6000; Dynasan 112/Dynasan 118=30:70.

[0133] FIG. 3 shows release profiles of depot forms according to the invention containing IgG1 antibodies and having a diameter of approximately 1.9 mm. Solid line: 5 wt. % IgG1; 10 wt. % PEG 6000; Witepsol H12/Dynasan 118=30:70. Dashed line: 5 wt. % IgG1; 10 wt. % PEG 6000; Dynasan 112/Dynasan 118=30:70.

[0134] FIG. 4 shows a release profile of a depot form according to the invention containing IgG1 antibodies and having a diameter of approximately 1.5 mm and a length of 2 cm. Solid line: 10 wt. % IgG1 lyophilisate; Witepsol E85/Dynasan 118=50:50.

[0135] FIG. 5 shows a release profile of a depot form according to the invention containing Exenatide. The depot form was produced with the aid of a double extrusion, has a diameter of 1.2 mm, and a length of 1.5 cm. The depot form contains 10 wt. % Exenatide lyophilisate and E85/Dynasan 118=60/40.

EXAMPLES

Example 1

[0136] For the production of the depot forms according to the invention, lipid pellets formed from a low-melting hard fat (Witepsol E85, 101 Oleo GmbH, Hamburg, Germany) and a high-melting triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) were cryo-ground separately (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Mnchen, Germany) and then 45 wt. % of the high-melting triglyceride and 45 wt. % of the low-melting hard fat were mixed with 10 wt. % Exenatide lyophilisate (Bachem, Bubendorf, Switzerland) to form a homogeneous mixture (Speedmixer, Hauschild, Hamm, Germany).

[0137] The following extrusion was carried out by way of co-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 35 to 42 C. and a screw speed of 40 rpm. The diameter for the extrudate was set using a nozzle to 1.5 mm. Optionally, a temperature-controlled step can be performed here, the temperature of which is coordinated with the melting point of the low-melting lipid and is approximately 35 to 45 C. The extrudate strand was cut to form extrudates of suitable length. Alternatively, the extrudate could be shaped by spheronisation to form microparticles.

Example 2

[0138] The production was performed in accordance with Example 1, however the composition of the depot forms according to the invention was supplemented with trehalose (Sigma Aldrich, Vienna, Austria). The powder mixture consisted of 40 wt. % of a high-melting triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany), 40 wt. % of a low-melting hard fat (Witepsol E85, 101 Oleo GmbH, Hamburg, Germany), 10 wt. % trehalose, and 10 wt. % Exenatide lyophilisate (Bachem, Bubendorf, Switzerland).

Example 3

[0139] The production was performed again in accordance with Example 1, wherein, in addition, PLGA was incorporated into the matrix. The powder mixture consisted of 35 wt. % of a high-melting triglyceride (Dynasan 118, IOI Oleo GmbH, Hamburg, Germany), 35 wt. % of a low-melting hard fat (Witepsol E85, IOI Oleo GmbH, Hamburg, Germany), 20 wt. % PLGA (Evonik Industries AG, Essen, Germany), and 10 wt. % Exenatide lyophilisate (Bachem, Bubendorf, Switzerland).

[0140] In order to examine the active substance release, exemplary depot forms according to the invention in the suitable size and shape (for example cut into cylinders of from 1.5 to 2 cm length) were firstly weighed individually.

[0141] The depot forms according to the invention were introduced into release cells and were mixed with 25 mL release medium (50 mM phosphate buffer). At the time at which the sample was taken, the release medium was replaced in full. The release rates were determined by UV-metric analysis.

Example 4

[0142] Lipid pellets formed from Witepsol H12 and Dynasan 118 in a ratio 1:1 were cryo-ground for the production of depot forms according to the invention. 90 wt. % of the resultant powder mixture was then provided with 10% Bevacizumab lyophilisate (for example lyophilised Avastin, Roche, Basel, Switzerland) and processed to form a homogeneous mixture.

[0143] In order to examine the active substance release, exemplary depot forms according to the invention in the suitable size and shape (for example cut into cylinders of from 1.5 to 2 cm length) were firstly weighed individually.

[0144] The depot forms according to the invention were introduced into 2 mL Eppendorf tubes, and the release was analysed using a horizontal shaker (40 rpm) at 37 C. in PBS buffer (pH 7.4). Samples were taken at the measurement times. The active substance content was then determined at 280 nm using a UV vis spectrometer (Agilent, Boblingen, Germany).

Example 5

[0145] For the production of the depot forms according to the invention, lipid pellets formed from a low-melting hard fat (Witepsol E85, 101 Oleo GmbH, Hamburg, Germany) and a high-melting triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) were cryo-ground separately (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Mnchen, Germany) and then 36 wt. % of the high-melting triglyceride and 54 wt. % of the low-melting hard fat were mixed with 10 wt. % Exenatide lyophilisate (Bachem, Bubendorf, Switzerland) to form a homogeneous mixture (Speedmixer, Hauschild, Hamm, Germany).

[0146] The following extrusion was carried out by way of counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 38 to 40 C. and a screw speed of 20 rpm. In a next step exclusion was performed a second time under the same conditions. The diameter for the extrudate was set using a nozzle to 1.5 mm. Optionally, a temperature-controlled step can be performed here, the temperature of which is coordinated with the melting point of the low-melting lipid and is approximately 40 to 45 C. The extrudate strand was cut to form extrudates of suitable length. Alternatively, the extrudate could be shaped by spheronisation to form microparticles.

Example 6

[0147] For the production of the depot forms according to the invention, lipid pellets formed from a low-melting hard fat (Witepsol E85, 101 Oleo GmbH, Hamburg, Germany) and a high-melting triglyceride (Dynasan 118, 101 Oleo GmbH, Hamburg, Germany) were cryo-ground separately (Freezer/Mill, C3 Prozess- and Analysentechnik GmbH, Haar bei Mnchen, Germany) and then 42.5 wt. % of the high-melting triglyceride and 42.5 wt. % of the low-melting hard fat were mixed with 15 wt. % Octreotide lyophilisate (Chemi S.P.A., Mailand, Italy) to form a homogeneous mixture (Speedmixer, Hauschild, Hamm, Germany).

[0148] The following extrusion was carried out by way of counter-rotating screw melt extrusion (Mini CTW, Thermo Fisher Scientific GmbH, Karlsruhe, Germany) at 40 to 42 C. and a screw speed of 20 rpm. In a next step exclusion was performed a second time under the same conditions. The diameter for the extrudate was set using a nozzle to 1.5 mm. Optionally, a temperature-controlled step can be performed here, the temperature of which is coordinated with the melting point of the low-melting lipid and is approximately 40 to 45 C. The extrudate strand was cut to form extrudates of suitable length. Alternatively, the extrudate could be shaped by spheronisation to form microparticles.