WO2020002413A1 - Timbre multicouche pour administration de médicament post-opératoire - Google Patents

Timbre multicouche pour administration de médicament post-opératoire Download PDF

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Publication number
WO2020002413A1
WO2020002413A1 PCT/EP2019/066972 EP2019066972W WO2020002413A1 WO 2020002413 A1 WO2020002413 A1 WO 2020002413A1 EP 2019066972 W EP2019066972 W EP 2019066972W WO 2020002413 A1 WO2020002413 A1 WO 2020002413A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
multilayer patch
layer
patch according
multilayer
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2019/066972
Other languages
English (en)
Inventor
Massoud Mirshahi
Marc POCARD
Farzaneh Arefi-Khonsari
Jérôme PULPYTEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de la Santé et de la Recherche Médicale
Université Paris Diderot - Paris 7
Sorbonne Université
Original Assignee
Institut National de la Santé et de la Recherche Médicale
Université Paris Diderot - Paris 7
Sorbonne Université
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 Institut National de la Santé et de la Recherche Médicale, Université Paris Diderot - Paris 7, Sorbonne Université filed Critical Institut National de la Santé et de la Recherche Médicale
Publication of WO2020002413A1 publication Critical patent/WO2020002413A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0012—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Definitions

  • the present invention relates to the field of drug administration, in particular the field of in situ postoperative drug administration.
  • tumor ablation can be one of the most effective one, depending on the case and on the cancer type.
  • a given sponge can administrate only one drug, whereas the treatment of a tumor is more efficient when combining the effects of several drugs.
  • An object of the invention is therefore to provide a biocompatible patch which can be applied and fixed upon a zone to be treated after a surgery, typically an ablated zone, so as to release medications consisting in several drugs, preferably tailored to the tumor which is to be treated with the patch.
  • a multilayer patch for therapeutic use comprising:
  • a biocompatible carrier layer A first polymeric layer comprising a first drug, and
  • a second polymeric layer comprising a second drug, wherein the first drug is different from the second drug.
  • the multilayer patch according to the present invention can be manufactured on demand on a patient per patient basis so as to provide a tailored treatment, opening the way for personalized medicine.
  • the drugs contained on the multilayer patch can diffuse over a few millimeters in the tissues on which the patch is applied and treat the corresponding zone.
  • Using a local treatment allows for high concentration of drugs and corresponding greater efficiency of the treatment.
  • Such high concentrations cannot be used when the drugs are administrated through the general circulation. Indeed, in conventional practices, drug is systematically injected intravenously and then by binding to cytoskeleton, DNA strains, or other drug targets it results in the formation of various defects in DNA molecules, forcing the cell to undergo apoptotic death path.
  • the multilayer patch according to the present invention allows circumventing this issue.
  • the multilayer patch is particularly suited for all post-surgery residual tumor treatment consecutive to pelvis surgery and abdomen surgery, particularly in case of liver or pancreas cancer.
  • At least one layer of the multilayer patch according to the present invention may be tailored by undergoing processes selected from grafting and copolymerization.
  • the biocompatible carrier layer serves both as a mean for facilitating the acceptance of the patch in the body, as a mean for controlling the release rate of the drugs - the thicker the carrier layer, the slower the release - and as a mean for controlling the adherence of the patch.
  • the biocompatible carrier layer is preferably auto-adhesive. It can be provided together with a protection layer which is to be removed before used. If the biocompatible carrier layer is not auto-adhesive, it can be attached to the desired zone with any suitable means such as suture points.
  • the multilayer patch can be coupled with 3D impression processes with e.g. PLA or other nontoxic mono/polymers so as to better correspond to the shape of the zone to be treated.
  • the biocompatible carrier layer is designed so as to be easily distinguished over the other side of the patch.
  • Such distinction can take the form of a printing, of a different color, of a different texture, or any other suitable means.
  • the biocompatible carrier layer is preferably a medium which is permeable to the drugs and which allows their diffusions there through.
  • a preferred material for the biocompatible carrier layer is collagen, fibrin or any commercial biocompatible substrates such as Steralloy films (HAPCO), a bi- component commercial elastomer or even biocompatible PU.
  • HAPCO Steralloy films
  • collagen membranes are widely used in post-surgery treatments to provide isolation of operated zone, preventing adhesion of internal organs and scar tissue and intended to promote tissue regeneration. Such membranes thus represent an excellent base for drug delivery systems.
  • the bio compatible carrier layer preferably has a thickness comprised between 1 and 3 mm.
  • the thickness of the biocompatible carrier layer is chosen based on the drugs to be delivered and on the desired release rate of the drug. The aforementioned values are typical thicknesses which correspond to suitable release rates of typical
  • Each polymeric layer can be a single sort of polymer chosen e.g. from biocompatible polymers such as PEG or PCL. Alternatively, each polymeric layer can be in a mixture of polymers chosen from eg copolymers PCL-PEG. Each polymeric layer can also comprise non-polymeric material, as long as the layer contains a majority of polymers. The polymeric layer preferably consists only of biodegradable materials. Each layer can also comprise sublayers, each sublayer presenting its own composition. Typically, the drugs contained in the polymeric layers can be sandwiched between two sublayers.
  • Every polymeric layer can be identical to the others or, alternatively, some layer can be different than the other layers both in terms of thickness and in terms of composition.
  • the first polymeric layer preferably has a thickness comprised between 100 nm and 1000 nm.
  • the drugs contained in other polymeric layers, e.g. in the second polymeric layer will diffuse through the first polymeric layer toward the biocompatible carrier layer and the tissues to be treated. Therefore, the thickness of the polymeric layer is to be chosen depending on the drugs contained in the multilayer patch according to the present invention, depending on the desired release rates, the material of the layer and on the thickness of the bio compatible carrier layer.
  • the aforementioned values are preferred values between which the thickness of the layer can be chosen.
  • the second polymeric layer preferably has a thickness comprised between 70 and 500 nm.
  • the thickness of the polymeric layer is to be chosen depending on the drugs contained in the multilayer patch according to the present invention, depending on the desired release rates, the material of the layer and on the thickness of the biocompatible carrier layer and of the first polymeric layer.
  • the aforementioned values are preferred values between which the thickness of the layer can be chosen.
  • the first drug and/or the second drug preferably comprises an antibody.
  • the multilayer patch allows for personalized treatment, it is especially suited for immunotherapy.
  • the antibody can be chosen depending on the patient and the cancer type.
  • the combination of the multilayer patch according to the present invention with antibodies or with any kind of immunotherapy is a particularly advantageous embodiment of the present invention.
  • the first drug and/or the second drug is preferably an anti-cancer drug, more preferably an anti-cancer drug selected frompersonalized medication.
  • the first drug and/or the second drug can also comprise a platinum salt or carboplatin.
  • platinum salt is particularly suited for treating cancer, especially pancreas cancers.
  • the multilayer patch according to the present invention can further comprise at least one additional polymeric layer comprising at least one additional drug.
  • Said additional layers and drugs can be identical or different than the other polymeric layers and drugs.
  • Some polymeric layers can also comprise no drug e.g. so as to serve only as a retardant for the drugs comprised in a more external layer.
  • a patch with several layers comprising the same drug can have an interest so as to administrate a drug several times or over a longer period of time. Indeed, chemotherapies are efficient only when cells are in a proliferation phase. Therefore, it is important to repeat the treatment, which can be achieved by a patch comprising several layers with the same drugs. There is also an interest in a multilayer patch comprising different drugs, in order to administrate a complex treatment consisting of several drugs or medications.
  • At least one drug can be trapped between two polymeric layers.
  • a drug can be trapped between two polymeric layers.
  • suitable ways to imprison a drug into a polymeric layer such as impregnation, trapping a drug between two polymeric layers provides an easy to manufacture, efficient, patch.
  • the multilayer patch according to the present invention can further comprise a layer of PEG (Polyethylene glycol), preferably a layer of PEG which molecular weight is below 20,000 g/mol PEG can act as a good diffusion retardant if need be, as an external layer, or as a buffer layer.
  • the multilayer patch according to the present invention can further comprise a layer of PEG (Polyethylene glycol), preferably a less crosslinked layer and with retention of the EG moieties whose molecular weight is less than lOOOamu determined by MALDI-ToF.
  • Such layers present cell non-adhesive properties which avoid the adhesion of cells on the external layer of the DDS.
  • the polymeric layers are preferably made of Diethylene glycol dimethyl ether, PEG, e-caprolactone, poly (lactic acid) (PLA), poly (glycolic acid) (PGA), and poly(lactic-co-glycolic acid) (PLGA) and other nontoxic mono/polymers.
  • the patch according to the present invention is preferably for use in a medicament.
  • the patch according to the present invention is preferably for use in a method for a treatment of a patient suffering of cancer, preferably solid cancer, more preferably pancreas or liver cancer.
  • the present invention also relates to a manufacturing process of a multilayer patch according to the present invention comprising the step of depositing a polymeric layer under plasma.
  • the plasma used in the manufacturing method according to the present invention is preferably cold plasma.
  • cold plasma it is meant that the gas temperature is very low, e.g. ambient temperature whereas the electron temperature is very high. It is sometimes referred to as non-equilibrium plasma.
  • Another object of the present invention is a multilayer patch for therapeutic use according to the present invention comprising a treatment to treat a pathology of a patient, said multilayer patch being applied on a tumor or an ablated area resulting from an operation of the patient so as to ablate at least part of a tumor.
  • said pathology of a patient is a tumor which has been previously analyzed, and the treatment to treat said pathology has been selected so as to treat this specific tumor through
  • Another object of the present invention is a method of treatment comprising the steps of:
  • said multilayer patch comprises a treatment having previously been customized to treat a pathology of a patient
  • figure lb is a schematic representation of Polymers formation from Polycapro lactone PCL and Polyethylen glycol PEG via plasma radio pulses;
  • figure 2 is a SEM image of multilayer barrier film
  • figure 3 is a series of SEM images of multilayer patches according to the present invention.
  • An exemplary embodiment of a multilayer patch according to the present invention has been realized in the form of multilayer polymer layers with thicknesses ranging from a few nm to a few hundreds of nm..
  • These multi-layers were loaded with drug, in case of this exemplary embodiment, carboplatin, and ported on collagen biodegradable membranes.
  • the drug-loaded films were implanted in vivo in BALB/C mice model having already developed colon cancer. Scanning Electron Microscopy SEM-FEG, Energy-dispersive X-ray spectroscopy, histology and cell death detection were applied on produced tumors and implanted films to check their efficiency.
  • the multilayer patches according to the present invention were prepared as follows. Diethylene glycol dimethyl ether (diglyme, 134.17 g/Mol, C6H1403, Sigma- Aldrich) and e-caprolactone were used as the precursor materials and delivered into a low pressure inductively coupled plasma (ICP) reactor schematically illustrated in Figure la, through bubbling in argon gas. Operating pressure was set at 50 Pascals (375 mTorr) and controlled through adjusting argon gas flow rate and gate valve of turbomolecular pump. Power supply was controlled and programmed to deposit sequence of layers with varying density and thicknesses, so as to allow automating multi-step deposition procedures to deposit composite films with different deposition parameters and fabricate films with alternating or gradually changing density, chemical composition and mechanical properties.
  • ICP inductively coupled plasma
  • PCL Polycaprolactone
  • PEG Polyethylen glycol
  • Carboplatin, oxaloplatin drugs, Iron beats and M2yn were used to make films with mono- or multi-layers: 300pg of carbopaltin and, cis-Platin? oxaloplatin, X m ⁇ of Iron beats and 30m1 of M2yn were deposited for drug loaded film respectively.
  • Collagen films without drug which were considered as control films, and carboplatin loaded films were incubated in the culture medium for different amounts of time: 4h, 24h, 72h, l20h, l68h at 37°C, with 5% C0 2 and over 80% humidity.
  • the films and the media were then submitted to Energy-dispersive X-ray spectroscopy and ICP-MS (Inductively Coupled Plasma Mass Spectrometry, Elan DRCe, Perkin Elmer®) so as to measure carboplatin liberation.
  • ICP-MS Inductively Coupled Plasma Mass Spectrometry, Elan DRCe, Perkin Elmer®
  • the obtained DDS(Drug Delivery System) films have a thickness comprised between 10 and 2000 nanometer.
  • the obtained layers were deposited on 1 OOmhi of collagen as illustrated on Figure 31, 300 pg of carboplatin per square centimeter were deposited over a first plasma polymerized layer, i.e. a first polymeric layer, which allowed isolating the drug from reaching the collagen substrate and thus acted as a barrier film layer.
  • a first plasma polymerized layer i.e. a first polymeric layer
  • Another barrier film layer was deposited to encapsulate the drug inside the two layers.
  • Figure 3c is a scanning electronic microscopy(SEM-FEG) image of carboplatin deposited over the barrier film.
  • Fig 3d 3c is a scanning electronical microscopy image of the obtained sandwich structure.
  • Figures 3e and 3f show similar structures with, respectively, oxaloplatin and M2yn (a natural extract) instead of carboplatin.
  • Figures 3g and 3h represent multilayers structures. On Figure 3h, three layers can be identified. One of these layers contains oxaloplatin whilst another one contains carboplatin.
  • Figure 3i shows a multilayer structure according to the invention wherein a protection layer has been deposited on its most external part: a nano barrier film deposition of 290 nm has been highlighted.
  • mice After developing the tumor, mice were anesthetized with 2% isoflurane. Skin was opened around 2cm where the tumor is developed. The implants of collagen (1 x 0.5 cm) were deposited on the tumor and skin closed via stitching.
  • mice After 10 days of implantation, mice were anesthetized again for collecting the samples. The sizes of the tumors were measured so as to assess the efficiency of the treatment. Tumors and films were recuperated after marketing the contact side of the tumor with the film. Each tumor was divided into three parts, one for histological analysis, one for immunofluorescence study and one for checking the presence of carboplatin in the tumor after film implantation.
  • the tumors which had been applied a control patch showed a +3.78 increase in size whereas the tumors which had been applied a drug loaded multilayer patch only showed a +1.9 increase in size, thus effectively proving the technical advantage of the multilayer patch according to the present invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le domaine de l'administration de médicament, en particulier le domaine de l'administration de médicament post-opératoire in situ. Parmi les nombreuses options disponibles pour lutter contre le cancer, l'ablation de tumeur peut être la plus efficace, en fonction du cas et du type de cancer. Cependant, il existe certains cas dans lesquels les cellules tumorales résiduelles laissées après l'ablation peuvent ensemencer la propagation d'une nouvelle tumeur après. L'invention fournit une manière d'adresser ce problème et concerne un patch multicouche comprenant : - une couche de support biocompatible, - une première couche polymère comprenant un premier médicament, et - une seconde couche polymère comprenant un second médicament, le premier médicament étant différent du second médicament. En particulier, les inventeurs ont testé l'invention dans le cas de cancers du pancréas qui s'avèrent particulièrement utiles.
PCT/EP2019/066972 2018-06-27 2019-06-26 Timbre multicouche pour administration de médicament post-opératoire Ceased WO2020002413A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18305821 2018-06-27
EP18305821.3 2018-06-27

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WO2020002413A1 true WO2020002413A1 (fr) 2020-01-02

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070190102A1 (en) * 2000-06-30 2007-08-16 Ping Luo Method of preparing hydroxyapatite based drug delivery implant for infection and cancer treatment
US20080075718A1 (en) * 2006-05-31 2008-03-27 Yolonda Colson Films and Particles
US20120095418A1 (en) * 2010-10-19 2012-04-19 Joshua Stopek Self-Supporting Films For Delivery Of Therapeutic Agents
EP2644213A1 (fr) * 2012-03-30 2013-10-02 DuNing Incorporated Fibres bioabsorbables contenant un médicament et implants
EP2703016A1 (fr) * 2012-08-30 2014-03-05 Aristotle University Of Thessaloniki-Research Committee Méthode pour la production de revêtements de polymères multi-couches et nano-poreux et ses produits
EP2719717A1 (fr) * 2012-10-12 2014-04-16 Covidien LP Compositions et procédés de formation de films pour administration améliorée de médicaments
WO2016159240A1 (fr) * 2015-03-31 2016-10-06 Ｏｒｔｈｏｒｅｂｉｒｔｈ株式会社 Procédé de fabrication de matériau de fibre biodégradable contenant un médicament par filage électrostatique
US20170027864A1 (en) * 2015-07-28 2017-02-02 Board Of Regents, The University Of Texas System Implant compositions for the unidirectional delivery of therapeutic compounds to the brain
CN106902098A (zh) * 2017-02-18 2017-06-30 华中科技大学 一种抗肿瘤植入膜及其制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070190102A1 (en) * 2000-06-30 2007-08-16 Ping Luo Method of preparing hydroxyapatite based drug delivery implant for infection and cancer treatment
US20080075718A1 (en) * 2006-05-31 2008-03-27 Yolonda Colson Films and Particles
US20120095418A1 (en) * 2010-10-19 2012-04-19 Joshua Stopek Self-Supporting Films For Delivery Of Therapeutic Agents
EP2644213A1 (fr) * 2012-03-30 2013-10-02 DuNing Incorporated Fibres bioabsorbables contenant un médicament et implants
EP2703016A1 (fr) * 2012-08-30 2014-03-05 Aristotle University Of Thessaloniki-Research Committee Méthode pour la production de revêtements de polymères multi-couches et nano-poreux et ses produits
EP2719717A1 (fr) * 2012-10-12 2014-04-16 Covidien LP Compositions et procédés de formation de films pour administration améliorée de médicaments
WO2016159240A1 (fr) * 2015-03-31 2016-10-06 Ｏｒｔｈｏｒｅｂｉｒｔｈ株式会社 Procédé de fabrication de matériau de fibre biodégradable contenant un médicament par filage électrostatique
US20170027864A1 (en) * 2015-07-28 2017-02-02 Board Of Regents, The University Of Texas System Implant compositions for the unidirectional delivery of therapeutic compounds to the brain
CN106902098A (zh) * 2017-02-18 2017-06-30 华中科技大学 一种抗肿瘤植入膜及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHRISTIAN BILLARD: "The BH3-only protein Noxa is stimulated during apoptosis of chronic lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract", INTERNATIONAL JOURNAL OF ONCOLOGY, 12 July 2011 (2011-07-12), GR, XP055530552, ISSN: 1019-6439, DOI: 10.3892/ijo.2011.1121 *

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