WO2008015232A1 - Subcutaneous implants releasing an active principle over an extended period of time - Google Patents
Subcutaneous implants releasing an active principle over an extended period of time Download PDFInfo
- Publication number
- WO2008015232A1 WO2008015232A1 PCT/EP2007/057961 EP2007057961W WO2008015232A1 WO 2008015232 A1 WO2008015232 A1 WO 2008015232A1 EP 2007057961 W EP2007057961 W EP 2007057961W WO 2008015232 A1 WO2008015232 A1 WO 2008015232A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- subcutaneous implants
- plga
- implants according
- active ingredient
- subcutaneous
- Prior art date
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to subcutaneous implants obtained by extrusion containing an active ingredient, and a hydrophilic excipient dispersed in a PLGA matrix.
- controlled release implants are represented by subcutaneous implants.
- the subcutaneous implants described in WO00/33809 represent a net improvement with reference to previous subcutaneous implants containing as the active principle a polypeptide dispersed in a matrix of polylactic-glycolic acid in that they are able to release the aforesaid active principle in 6 months.
- the subcutaneous implants described in said previous patent differ also in that they present an essentially triphasic and not biphasic release profile as clarified in the following manner: release by pure diffusion, diffusion by release following to swelling and release by polymer degradation.
- the implant remains substantially unmodified for about 6 weeks and in this period releases approximately 30% of the peptide.
- the duration of this stage of pure diffusion is essentially determined by the level of heterogeneity of the peptide dimensions and the rate is essentially determined by the particle content in the PLGA matrix.
- a sufficient quantity of peptide remains after the first stage of dissolution and can be released in the successive stages mentioned, that is release by diffusion and swelling, or release by disintegration of the polymer.
- Subcutaneous implants including those above described suffer from a drawback essentially caused by the fact that the active ingredient release rate during the three successive phases is partially governed by the concentration of active ingredient within the polymeric matrix (the other factors being the intrinsic solubility and diffusion properties of the active ingredient and the characteristics of the PLGA).
- the amount of active ingredients (dose) to be incorporated into the implant depends on the activity of the product and on the expected dosing interval.
- big dimensions implants create problem insofar patients compliance is concerned on the other hand small dimensions subcutaneous implants create problems under industrial feasibility aspects since a very thin or very short implant may be difficult to handle and to package. It may therefore happen that implants containing a small amount of very potent active ingredient within a "normal" size (i.e.
- the Applicant has now unexpectedly found subcutaneous PLGA based implants formulations which overcome the above drawback.
- the present invention therefore relates to subcutaneous implants composed of a PLGA based polymeric matrix containing dispersed therein an active ingredient and a hydrophilic excipient so that the weight ratio:
- Figure 1 shows, in ordinates, the active ingredient release (% of the total amount released) versus, in abscissa, time expressed in days after immersion in the aqueous medium of the implants described of Example 1.
- Figure 2 shows, in ordinates, the active ingredient release (% of the dose) versus, in abscissa, time expressed in days after immersion of the implants described of
- Example 2 shows, in ordinates, the active ingredient release (mg of active ingredient) versus, in abscissa, time expressed in days after immersion of the formulations
- Figure 4 shows, in ordinates, the active ingredient release (% of the total amount released) versus, in abscissa, time expressed in days after immersion of the implants described of Example 3.
- the aforesaid weight ratio is preferably comprised between 0.3 and 0.9, more preferably between 0.4 and 0.8.
- the hydrophilic excipient is preferably selected from mannitol, sorbitol, trehalose, polyvinylpyrrolidone having an average molecular weight ranging from 6000 to
- the subcutaneous implants of the present invention preferably contain an active principle chosen from the class consisting of: a peptide, an analgesic-narcotic active principle. More preferably said peptide is chosen from: avorelin, triptorelin, goserelin and leuprorelin.
- morphine and morphinans i.e. compounds having a chemical structure and activity similar to that of morphine i.e. ⁇ receptor agonists, but also compounds with morphinic-type activity, in other words also ⁇ receptor agonists but with a different chemical structure such as those belonging to the phenylpiperidine class.
- phenylpiperidine ⁇ receptor agonists we cite as preferred at least one active principle chosen from the class consisting of meperidine, fentanyl and relative pharmaceutically acceptable salts, fentanyl congeners, for example sufentanyl, alfentanyl, lofentanyl, carfentanyl, remifentanyl and their pharmaceutically acceptable salts.
- the subcutaneous implants according to the present invention when they contain a peptide as the active ingredient, they show a heterogeneous particles size distribution more preferably ranging from 1 to 63 ⁇ m or from 1 to 100 ⁇ m.
- the subcutaneous implants of the invention when the subcutaneous implants of the invention contain the peptides having the aforesaid heterogeneous particles size dimensions, also the hydrophilic excipient has heterogeneous particles size distribution preferably ranging from 10 to 250 ⁇ m.
- hydrophilic excipient When the hydrophilic excipient is mannitol it is preferably present in the subcutaneous implants in weight ratio with respect to the active ingredient in amounts ranging from 2:1 to 5:1 and more preferably in weight ratio of 4:1.
- the hydrophilic excipient is trehalose or polyvinylpyrrolidone it is preferably present in weight ratio with respect to the active ingredient in amounts ranging from 1 :6 to 1 :1 , more preferably of from 1 : 5 to 1 :2.
- the PLGA contained in the subcutaneous implants according to the present invention has preferably a weight average molecular weight of from 50000. to 150000 Da and a lactic acid/ glycolic acid ranging from 50/50 to 95/5.
- the subcutaneous implants according to the present invention may contain a sole PLGA or that obtained by grinding an extruded product of a blend of: ⁇ at least two PLGA having different lactic acid/ glycolic acid molar ratios and different weight average molecular weights, ⁇ a PLGA and PLA having different weight average molecular weights subject matter of the co-pending application filed in the same day of the instant
- the present invention further relates to
- the process of preparation of the subcutaneous implants containing a sole PLGA which comprises the following steps: a) dry- mixing the active ingredient and the hydrophilic excipient, b) dry mixing or wet granulating the mixture obtained in step (a) with PLGA in a suitable solvent c) drying the wet granulated mixture coming from step (b) up to a maximum solvent content of from 0.5 to 3% d) extruding the dried granulated mixture coming from step (c) or the dry mixture coming from step (b).
- step (b) extruding the powder mixture coming from step (a) and then grinding the extruded PLGA mixture, thereby obtaining granules of the blended extruded PLGA,
- step (C) dry mixing or (D') wet granulating in a suitable solvent the mixture obtained in step (B) with PLGA coming from step (C)
- step (E) drying the wet granulated mixture coming from step (D') up to a maximum solvent content of from 0.5 to 3%
- Subcutaneous implants containing ingredients as described in the table below are prepared as described in WO00/33809
- Figure 1 shows, in ordinates, the active ingredient release (% of the total amount released) versus, in abscissa, time expressed in days after immersion of the implants described of Example 1.
- Subcutaneous implants containing ingredients as described in the table below are prepared as described in WO00/33809
- a 40 mg implant according to formulation 2#1 contains 1 1.6 mg of Active ingredient when, according to formulations 2#2 and 2#3, the same implant contains 8 mg of active ingredient.
- Figure 2 shows, in ordinates, the active ingredient release (% of the dose) versus, in abscissa, time expressed in days after immersion of the implants described of
- the dissolution profile from formulation 2#3 is also very informative. In this case,
- AI+E/PLGA ratio is close to 1/1. This means that half of the matrix is occupied by very hydrophilic molecules. Once dropped into the dissolution medium, such an implant presents a huge number of channels allowing the active ingredient to leave the matrix (through a percolation process).
- Figure 3 shows, in ordinates, the active ingredient release (mg of active ingredient) versus, in abscissa, time expressed in days after immersion of the formulations
- formulation 2#1 (containing 1 1.6 mg of active ingredient per depot) and formulation 2#2 (containing 8.0 mg of active ingredient per depot) release almost the same amount of active ingredient over the entire first month after immersion.
- excipient is clearly a powerful formulation tool. It is useful to allow for a specific implant to operate properly even with low active ingredient loading but it is also useful to modulate a suboptimal release profile up to exactly reach the target
- Subcutaneous implants containing ingredients as described in the table below are prepared as described in WO00/33809
- Figure 4 shows, in ordinates, the active ingredient release (% of the total amount released) versus, in abscissa, time expressed in days after immersion of the implants described of Example 3.
- Figure 4 demonstrates that, also with a small hydrophilic active molecule, adding an hydrophilic inactive substance results in increasing the initial release and delaying the PLGA degradation process.
- PVP polyvinyl pyrrolidone
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA200901148A EA017473B1 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
CA002658592A CA2658592A1 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
US12/309,790 US20090246245A1 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
ES07788130T ES2389981T3 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants for the release of an active substance over a prolonged period of time |
MX2009001231A MX2009001231A (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time. |
EP07788130A EP2054028B9 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
BRPI0714818-6A BRPI0714818A2 (en) | 2006-08-02 | 2007-08-01 | subcutaneous active principle release implants over a prolonged period of time |
CN2007800364294A CN101522169B (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
JP2009522272A JP2009545351A (en) | 2006-08-02 | 2007-08-01 | Release of active ingredient in subcutaneous graft beyond dilatation period |
AU2007280391A AU2007280391A1 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
PL07788130T PL2054028T3 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
HK09110171.1A HK1131546A1 (en) | 2006-08-02 | 2009-11-02 | Subcutaneous implants releasing an active principle over an extended period of time |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2006A001539 | 2006-08-02 | ||
IT001539A ITMI20061539A1 (en) | 2006-08-02 | 2006-08-02 | SUBCUTANEOUS PLANTS ABLE TO RELEASE THE ACTIVE PRINCIPLE FOR A PROLONGED PERIOD OF TIME |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008015232A1 true WO2008015232A1 (en) | 2008-02-07 |
WO2008015232A8 WO2008015232A8 (en) | 2008-05-22 |
Family
ID=37765841
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/057961 WO2008015232A1 (en) | 2006-08-02 | 2007-08-01 | Subcutaneous implants releasing an active principle over an extended period of time |
Country Status (16)
Country | Link |
---|---|
US (1) | US20090246245A1 (en) |
EP (1) | EP2054028B9 (en) |
JP (1) | JP2009545351A (en) |
KR (1) | KR20090046837A (en) |
CN (1) | CN101522169B (en) |
AU (1) | AU2007280391A1 (en) |
BR (1) | BRPI0714818A2 (en) |
CA (1) | CA2658592A1 (en) |
EA (1) | EA017473B1 (en) |
ES (1) | ES2389981T3 (en) |
HK (1) | HK1131546A1 (en) |
IT (1) | ITMI20061539A1 (en) |
MX (1) | MX2009001231A (en) |
PL (1) | PL2054028T3 (en) |
PT (1) | PT2054028E (en) |
WO (1) | WO2008015232A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014076703A1 (en) * | 2012-11-14 | 2014-05-22 | Silenseed Ltd. | Methods and compositions for treating cancer |
US8936740B2 (en) | 2010-08-13 | 2015-01-20 | Kimberly-Clark Worldwide, Inc. | Modified polylactic acid fibers |
US10753023B2 (en) | 2010-08-13 | 2020-08-25 | Kimberly-Clark Worldwide, Inc. | Toughened polylactic acid fibers |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012088304A2 (en) * | 2010-12-22 | 2012-06-28 | Psivida Us, Inc. | Two-piece injectable drug delivery device with heat-cured seal |
MX2017016217A (en) * | 2015-06-18 | 2018-04-24 | Acuitybio Corp | Implantable drug delivery compositions and methods of use thereof. |
JP2021529747A (en) * | 2018-06-25 | 2021-11-04 | タイタン ファーマシューティカルズ インコーポレイテッド | Implants for the release of lipophilic or amphipathic pharmaceutical substances |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005000278A1 (en) * | 2003-06-26 | 2005-01-06 | Mediolanum Pharmaceuticals Ltd. | Subcutaneous implants having limited initial release of the active principle and subsequent linearly varying extended release thereof |
WO2005000277A1 (en) * | 2003-06-26 | 2005-01-06 | Mediolanum Pharmaceuticals Ltd. | Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a plga matrix |
US20050244472A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intraocular drug delivery systems containing excipients with reduced toxicity and related methods |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1304152B1 (en) * | 1998-12-10 | 2001-03-08 | Mediolanum Farmaceutici Srl | COMPOSITIONS INCLUDING A PEPTIDE AND POLYLACTIC-GLYCOLIC ACID FOR THE PREPARATION OF SUBCUTANEOUS IMPLANTS HAVING A PROLONGED |
JP4758607B2 (en) * | 2001-06-22 | 2011-08-31 | ジョンズ ホプキンズ ユニヴァーシティー スクール オブ メディシン | Biodegradable polymer composition and method of use thereof |
-
2006
- 2006-08-02 IT IT001539A patent/ITMI20061539A1/en unknown
-
2007
- 2007-08-01 MX MX2009001231A patent/MX2009001231A/en active IP Right Grant
- 2007-08-01 WO PCT/EP2007/057961 patent/WO2008015232A1/en active Application Filing
- 2007-08-01 EA EA200901148A patent/EA017473B1/en not_active IP Right Cessation
- 2007-08-01 JP JP2009522272A patent/JP2009545351A/en active Pending
- 2007-08-01 CA CA002658592A patent/CA2658592A1/en not_active Abandoned
- 2007-08-01 ES ES07788130T patent/ES2389981T3/en active Active
- 2007-08-01 PL PL07788130T patent/PL2054028T3/en unknown
- 2007-08-01 US US12/309,790 patent/US20090246245A1/en not_active Abandoned
- 2007-08-01 BR BRPI0714818-6A patent/BRPI0714818A2/en not_active IP Right Cessation
- 2007-08-01 AU AU2007280391A patent/AU2007280391A1/en not_active Abandoned
- 2007-08-01 EP EP07788130A patent/EP2054028B9/en not_active Not-in-force
- 2007-08-01 PT PT07788130T patent/PT2054028E/en unknown
- 2007-08-01 KR KR1020097003184A patent/KR20090046837A/en not_active Application Discontinuation
- 2007-08-01 CN CN2007800364294A patent/CN101522169B/en not_active Expired - Fee Related
-
2009
- 2009-11-02 HK HK09110171.1A patent/HK1131546A1/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005000278A1 (en) * | 2003-06-26 | 2005-01-06 | Mediolanum Pharmaceuticals Ltd. | Subcutaneous implants having limited initial release of the active principle and subsequent linearly varying extended release thereof |
WO2005000277A1 (en) * | 2003-06-26 | 2005-01-06 | Mediolanum Pharmaceuticals Ltd. | Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a plga matrix |
US20050244472A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intraocular drug delivery systems containing excipients with reduced toxicity and related methods |
Non-Patent Citations (2)
Title |
---|
RENU BHARDWAJ ET AL.: "In vitro evaluation or poly(D,L-lactide-co-glycolide) polymer-based implants containing the alpha-melanocyte stimulating hormone Melatonan-I", JOURNAL OF CONTROLLED RELEASE, vol. 45, no. L, 1997, pages 49 - 55 |
RENU BHARDWAJ; ET AL.: "In vitro evaluation or Poly(D,L-lactide-co-glycolide) polymer-based implants containing the alpha-melanocyte stimulating hormone Melanotan-I", JOURNAL OF CONTROLLED RELEASE, vol. 45, no. 1, 1997, pages 49 - 55, XP004099354 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8936740B2 (en) | 2010-08-13 | 2015-01-20 | Kimberly-Clark Worldwide, Inc. | Modified polylactic acid fibers |
US10718069B2 (en) | 2010-08-13 | 2020-07-21 | Kimberly-Clark Worldwide, Inc. | Modified polylactic acid fibers |
US10753023B2 (en) | 2010-08-13 | 2020-08-25 | Kimberly-Clark Worldwide, Inc. | Toughened polylactic acid fibers |
WO2014076703A1 (en) * | 2012-11-14 | 2014-05-22 | Silenseed Ltd. | Methods and compositions for treating cancer |
US9687500B2 (en) | 2012-11-14 | 2017-06-27 | Silenseed Ltd. | Methods and compositions for treating cancer |
Also Published As
Publication number | Publication date |
---|---|
JP2009545351A (en) | 2009-12-24 |
WO2008015232A8 (en) | 2008-05-22 |
HK1131546A1 (en) | 2010-01-29 |
MX2009001231A (en) | 2009-04-28 |
EP2054028A1 (en) | 2009-05-06 |
ITMI20061539A1 (en) | 2008-02-03 |
PT2054028E (en) | 2012-10-10 |
US20090246245A1 (en) | 2009-10-01 |
CA2658592A1 (en) | 2008-02-07 |
AU2007280391A1 (en) | 2008-02-07 |
CN101522169B (en) | 2013-02-20 |
EP2054028B9 (en) | 2012-09-26 |
ES2389981T3 (en) | 2012-11-05 |
BRPI0714818A2 (en) | 2013-05-21 |
EA200901148A1 (en) | 2010-02-26 |
PL2054028T3 (en) | 2013-02-28 |
EA017473B1 (en) | 2012-12-28 |
CN101522169A (en) | 2009-09-02 |
EP2054028B1 (en) | 2012-06-27 |
KR20090046837A (en) | 2009-05-11 |
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