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WO2011124359A1 - Procédé de libération pour implants - Google Patents

Procédé de libération pour implants Download PDF

Info

Publication number
WO2011124359A1
WO2011124359A1 PCT/EP2011/001684 EP2011001684W WO2011124359A1 WO 2011124359 A1 WO2011124359 A1 WO 2011124359A1 EP 2011001684 W EP2011001684 W EP 2011001684W WO 2011124359 A1 WO2011124359 A1 WO 2011124359A1
Authority
WO
WIPO (PCT)
Prior art keywords
release
implant
container
carried out
rpm
Prior art date
Application number
PCT/EP2011/001684
Other languages
German (de)
English (en)
Inventor
Martina Sprengholz
Original Assignee
Acino Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Acino Ag filed Critical Acino Ag
Publication of WO2011124359A1 publication Critical patent/WO2011124359A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/38—Diluting, dispersing or mixing samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4055—Concentrating samples by solubility techniques

Definitions

  • the present invention relates to a method for the in vitro release of an active substance from an implant, which is characterized in that the implant is placed in a container with release medium and the container is subsequently subjected to a shaking motion.
  • in vitro release profiles of implants with goserelin as the active ingredient are not identical to corresponding in vivo release profiles. As a rule, only about 75% is released after 28 days instead of 100% of the active ingredient, while in vivo after 28 days almost all of the drug is released.
  • the present invention relates to a method for the in vitro release of an active agent from an implant, thereby characterized in that the implant is placed in a container with release medium and the container is then subjected to a shaking movement.
  • the shaking motion is a uniform and controlled shaking motion.
  • the shaking motion is a circular motion.
  • the circular shaking is carried out with a number of revolutions of at least 300 rpm, preferably at least 500 rpm (in particular at least 600 rpm).
  • the preferred maximum number of revolutions is 1500 rpm, in particular 1000 rpm (revolutions per minute).
  • the shaking is carried out in a thermal mixer.
  • the container is a plastic or a
  • Glass jar e.g. a sample tube (microtube).
  • sample tube microtube
  • the preferred capacity of the container is 500 to 3000 ⁇ , in particular 1000 to 2000 ⁇ .
  • the most preferred size is 1.5 to 2.0 ml (especially 2.0 ml)
  • a liquid medium is preferably used (for example, a liquid / a solvent or mixtures thereof).
  • the release medium is an aqueous phosphate buffer solution or an acetate buffer solution; in particular a phosphate buffer solution.
  • sodium azide e.g., about 0.01% by weight
  • the release medium may be added to the release medium.
  • a preferred phosphate buffer solution of pH 7.4 is used e.g. prepared as follows: 12.0 g of disodium hydrogen phosphate dodecahydrate, 3.0 g of sodium chloride, 0.30 g of potassium chloride and 0.23 g of sodium dihydrogen phosphate monohydrate are dissolved in 1.5 1 of highly purified water. The pH is adjusted to 7.4 with 85% phosphoric acid. Suitable additives are, for example: 0.30 g of sodium azide, 80 ml of ethanol (96%, denatured).
  • the release medium has a pH of 7 to 8, preferably from 7.3 to 7.5, in particular from about 7.4. In principle, however, any other pH value can also be used. If, for example, a pH of 4.0 is used, the release is accelerated, similar to an increase in temperature.
  • the optimum pH (or pH range) can easily be determined by a person skilled in the art. In particular, the method is suitable for the quantitative release of an active substance or of several active substances from an implant.
  • the process is carried out at a constant temperature. More preferably, the constant temperature is in a range of 30 to 55 ° C, more preferably in the range of 34 to 50 ° C (for example, 34 to 40 ° C). More preferably, the process is carried out at a temperature of about 37 ° C or about 50 ° C. According to another embodiment, it is preferred that the temperature above the
  • Preferred active ingredients are goserelin, leuprorelin, triptorelin, buserelin and nafarelin. Particularly preferred is the active ingredient goserelin.
  • the implant material is a polymer or copolymer, in particular a lactic acid-glycolic acid copolymer.
  • the implant material may also include mixtures of polymers and / or copolymers.
  • the implant is a goserelin implant with goserelin acetate as the active ingredient and a matrix of a lactic acid-glycolic acid copolymer (PLGA).
  • PLGA lactic acid-glycolic acid copolymer
  • the implant is preferably a leuprorelin implant with leuprorelin acetate as active ingredient and a matrix of a lactic acid-glycolic acid copolymer (PLGA).
  • PLGA lactic acid-glycolic acid copolymer
  • the present invention relates to a method for measuring the release of an active substance (or active ingredients) from an implant, which is characterized in that the implant is placed in a container with release medium and the container is then subjected to a shaking motion, wherein in the course of Samples of the release solution are taken and analyzed for their active ingredient content.
  • the samples are taken at intervals of three to four days, more preferably starting on the first day.
  • the analysis can be analyzed in any manner appropriate to the particular drug or mixture of drugs.
  • the analysis is preferably carried out by means of HPLC, in particular in conjunction with a photometric analysis.
  • the method of the present invention is useful for investigating drug release from implants. These are for this purpose e.g. in Eppendorf "" caps with release medium and in the Thermomixer, for example at 37 ° C (or 50 ° C with accelerated release) and e.g. shaken at 600 rpm.
  • one or more samples may be withdrawn each time and media may be added e.g. be exchanged after the half-change method.
  • media e.g. be exchanged after the half-change method.
  • half of the release medium is taken along with the sample and fresh
  • the implant residues can be worked up so that the residual content can be determined. This is e.g. a control of how much total drug was released.
  • An alternative solvent e.g. Acetonitrile be used, for example, to completely dissolve the remaining implant.
  • the conditions under which the process according to the invention is carried out largely correspond to the conditions present in the in vivo release of an active substance (or several active substances). These can be adapted by a specialist.
  • the inventive method has the advantage that within a certain time (eg 28 days), which is shorter than when using a flow cell, approximately 100% of the active ingredient (or the active ingredients) can be released from an implant.
  • a certain time eg 28 days
  • an in vivo release can be simulated realistically.
  • similar release profiles can be achieved as in in vivo release.
  • the method can also be adapted, for example, by adapting one or more of the above-mentioned parameters to an in vivo release profile and thereby realistically reconstructing the in vivo release.
  • the calibration of the results on the basis of existing in vivo data is possible.
  • the process of the present invention is also inexpensive to purchase and to carry out. Less release medium is needed than in flow cells with less space and easier and faster handling.
  • the implants were introduced together with 1000 ⁇ release medium in 1.5 ml microtubes and shaken at a temperature of 37 ° C and 50 ° C and at a speed of 600 rpm.
  • sample draw days a sample was drawn analogously to the release in the flow cell and the medium was replaced by the half-change method.
  • the implant residues were processed so that the residual content could be determined. It was found that almost complete release of the active substance from 3.6 mg goserelin implants was achieved in the thermomixer within 28 days. embodiment
  • each drug implant was determined.
  • the implants were then placed in 1.5 ml microtubes (Eppendorf caps) and overlayed with 1000 ⁇ release medium (e.g., phosphate buffer solution pH 7.4).
  • 1000 ⁇ release medium e.g., phosphate buffer solution pH 7.4
  • the drug release assay was finally performed with a thermomixer (HLC BioTechdeThermoMixer MKR 13, Bovenden, Germany) at a temperature of either 37 ° C or 50 ° C and at a speed of 600 rpm (revolutions per minute).
  • the microtubes were completely released from the release medium and 250 ⁇ acetonitrile was added. To the remaining implants To completely dissolve the microtubes were shaken manually for 20 to 30 seconds. Thereafter, 1000 ⁇ of ultrapure water was added and shaken for about 10 s. Subsequently, as described above, samples were taken (dilution 1:10 with release medium). This determined the residual content.
  • each drug implant was determined.
  • the implants were placed in suitable cylindrical cuvettes which were sealed on both sides with permeable frits. After attachment to a holding device connected to tubing, these cuvettes were flooded by means of a syringe with 3 ml of release medium (degassed with helium) (start of release study). Subsequently, a constant flow rate of 0.3 ml / h was set by means of a Döring Combimat 2000 syringe pump (Munich, Germany). The drug release study was performed during the first 24 hours at room temperature. During this time, the samples were collected in plastic containers of known weight, each containing 2.00 ml of ethanol (96%, denatured).
  • the cuvettes were immersed in a temperature controlled at either 37 ° C or 50 ° C water bath (Julabo bath thermostat ED, Seelbach, Germany).
  • samples were further collected in the same containers containing 1.38 ml of ethanol (96%, denatured).
  • sampling took place on day one (24 hours after onset) and then at predetermined intervals up to a maximum of day 28 (at 37 ° C) and day 14 (at 50 ° C).
  • the Plastic containers were weighed for this and about 1 ml of each drug-containing solution was pipetted into an ampoule which was sealed and then stored in a freezer at -20 ° C. Thereafter, the vessels were completely emptied and reused.
  • sample vials of the in vitro release assays were brought to room temperature and shaken manually for about ten seconds. 10 ⁇ of each sample were then in a Shimadzu high performance liquid chromatography (HPLC) system (LC 10 / SPD / CTO ADVP 10, Duisburg, Germany) was injected, which (with a C8 guard column Phenomenex ® 4x3.0 mm ID, Torrance, USA was) and a C18 column (Phenomenex Jupiter ® ® 300 a, 50x2.0 mm, 5 pm) equipped.
  • HPLC Shimadzu high performance liquid chromatography
  • the isocratic eluent of 77.5% ultrapure water, 22.5% acetonitrile, and 0.05% trifluoroacetic acid (v / v) was at a flow rate of 0.35 ml / h and a temperature of 40 ° C (oven temperature) passed.
  • the photometric detection of goserelin was performed at 220 nm. Each sample required a total run time of seven minutes and was measured in duplicate.
  • the release medium and a standard goserelin solution 38 g / mL in highly purified water / acetonitrile, 80/20 (v / v)) were additionally analyzed for calibration and control.
  • the data obtained using the Chromeleon ® software (Dionex, Sunnyvale, USA) were evaluated, which allows the calculation of goserelin content.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé de libération in vitro d'une substance active à partir d'un implant, qui est caractérisé en ce que l'implant est transféré dans un contenant avec un agent de libération, puis le contenant est soumis à un mouvement d'agitation.
PCT/EP2011/001684 2010-04-07 2011-04-05 Procédé de libération pour implants WO2011124359A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010014113.5 2010-04-07
DE201010014113 DE102010014113A1 (de) 2010-04-07 2010-04-07 Freisetzungsverfahren für Implantate

Publications (1)

Publication Number Publication Date
WO2011124359A1 true WO2011124359A1 (fr) 2011-10-13

Family

ID=44168795

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/001684 WO2011124359A1 (fr) 2010-04-07 2011-04-05 Procédé de libération pour implants

Country Status (2)

Country Link
DE (1) DE102010014113A1 (fr)
WO (1) WO2011124359A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110954491A (zh) * 2019-12-09 2020-04-03 北京博恩特药业有限公司 用于测量醋酸戈舍瑞林缓释植入剂体外溶出度的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013595A1 (fr) * 1990-03-15 1991-09-19 The United States Of America, As Represented By The Secretary Of The Army Traitement chimiotherapeutique d'infections bacteriennes a l'aide d'un antibiotique encapsule dans une matrice polymere biodegradable
US20030105067A1 (en) * 1997-09-02 2003-06-05 The Johns Hopkins University Vitamin D3 analog loaded polymer formulations for cancer and neurodegenerative disorders
US20050048099A1 (en) * 2003-01-09 2005-03-03 Allergan, Inc. Ocular implant made by a double extrusion process
EP1797871A1 (fr) * 2004-09-21 2007-06-20 Shandong Luye Pharmaceutical Co., Ltd. Formulation à libération lente et prolongée contenant un agoniste du récepteur de la dopamine et son procédé de préparation
US20070239253A1 (en) * 2006-04-06 2007-10-11 Jagger Karl A Oscillation assisted drug elution apparatus and method

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DE20321445U1 (de) * 1980-01-12 2007-08-09 Schering Oy Otorhinologische Abgabevorrichtung
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5733565A (en) * 1996-02-23 1998-03-31 The Population Council, Center For Biomedical Research Male contraceptive implant
US8119154B2 (en) * 2004-04-30 2012-02-21 Allergan, Inc. Sustained release intraocular implants and related methods

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013595A1 (fr) * 1990-03-15 1991-09-19 The United States Of America, As Represented By The Secretary Of The Army Traitement chimiotherapeutique d'infections bacteriennes a l'aide d'un antibiotique encapsule dans une matrice polymere biodegradable
US20030105067A1 (en) * 1997-09-02 2003-06-05 The Johns Hopkins University Vitamin D3 analog loaded polymer formulations for cancer and neurodegenerative disorders
US20050048099A1 (en) * 2003-01-09 2005-03-03 Allergan, Inc. Ocular implant made by a double extrusion process
EP1797871A1 (fr) * 2004-09-21 2007-06-20 Shandong Luye Pharmaceutical Co., Ltd. Formulation à libération lente et prolongée contenant un agoniste du récepteur de la dopamine et son procédé de préparation
US20070239253A1 (en) * 2006-04-06 2007-10-11 Jagger Karl A Oscillation assisted drug elution apparatus and method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FAN H ET AL: "Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 213, no. 1-2, 1 February 2001 (2001-02-01), pages 103 - 116, XP027384580, ISSN: 0378-5173, [retrieved on 20010201] *
KASHAPPA GOUD H DESAI ET AL: "Formulation and In Vitro-In Vivo Evaluation of Black Raspberry Extract-Loaded PLGA/PLA Injectable Millicylindrical Implants for Sustained Delivery of Chemopreventive Anthocyanins", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 27, no. 4, 11 February 2010 (2010-02-11), pages 628 - 643, XP019793928, ISSN: 1573-904X, DOI: DOI:10.1007/S11095-009-0038-5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110954491A (zh) * 2019-12-09 2020-04-03 北京博恩特药业有限公司 用于测量醋酸戈舍瑞林缓释植入剂体外溶出度的方法

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