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WO1997010811A1 - Nanoparticules utilisees en therapie photodynamique - Google Patents

Nanoparticules utilisees en therapie photodynamique Download PDF

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Publication number
WO1997010811A1
WO1997010811A1 PCT/EP1996/003956 EP9603956W WO9710811A1 WO 1997010811 A1 WO1997010811 A1 WO 1997010811A1 EP 9603956 W EP9603956 W EP 9603956W WO 9710811 A1 WO9710811 A1 WO 9710811A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
composition according
nanoparticles
copolymer
Prior art date
Application number
PCT/EP1996/003956
Other languages
English (en)
Inventor
Robert Gurny
Eric Olivier ALLÉMANN
Jean-Christophe Leroux
Julijana Kristl
Eric Doelker
Original Assignee
Novartis 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 Novartis Ag filed Critical Novartis Ag
Priority to JP9512208A priority Critical patent/JPH11514986A/ja
Priority to AU71271/96A priority patent/AU7127196A/en
Priority to EP96932487A priority patent/EP0851754A1/fr
Publication of WO1997010811A1 publication Critical patent/WO1997010811A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine

Definitions

  • the present invention relates to a pharmaceutical composition comprising the zinc phthalo ⁇ cyanine complex and a polymer which is suitable for the formation of nanoparticles, to a process for the preparation of said pharmaceutical composition and to the therapeutic use thereof, e.g. in photodynamic therapy.
  • the zinc phthalocyanine complex is administered in vivo intraperitoneally to mice or rats in the form of an aqueous suspension, and the carcinoma induced in experimental animals is irradiated with high-energy light, preferably with concentrated visible light (LASER).
  • high-energy light preferably with concentrated visible light (LASER).
  • the intravenous dosage form allows the systemic distribution of the active ingredient, but requires solubility of the active agent in the aqueous injection fluid.
  • the zinc phthalocyanine complex is characterized by extremely low water solubility and insolubility in almost all organic solvents. As an exception to this observation, it has been found that the zinc phthalocyanine complex is soluble in some selected polar aprotic agents such as dimethyl sulfoxide, N-methyl-2-pyrrolidone or pyridine.
  • solubilize the zinc phthalo ⁇ cyanine complex in the aqueous phase by the addition of a vehicle.
  • a vehicle for example, phospholipids as solubilizers
  • the complex can be solubilized by encapsulation in uni- lamellar liposomes which are homogeneously dispersible in aqueous phase, q.v. Reddi et al., Br. J. Cancer , Vol. 56, pages 597-600 (1987).
  • This homogeneous liposome dispersion is nevertheless still unsuitable for the purposes of intravenous administration to humans because the dispersion is prepared in accordance with the so-called injection method using relatively large amounts of toxic pyridine, q.v. G. Valduga et ai, J. Inorg. Biochem. 59-65, Vol. 29 (1987).
  • Pyridine is one of the few solvents in which the zinc phthalocyanine complex is at all soluble. That solution is diluted with ethanol, and the pyridine-contai ⁇ ing ethanolic solution is injected at elevated temperature into water or a buffer solution.
  • a residue of the organic solvent will permanently remain in the aqueous phase as a result of the formation of an azeotropic mixture, even if the toxic solvent pyridine is replaced by less toxic organic solvents such as dimethyl sulfoxide or N-methyl-2-pyrrolidone.
  • the zinc phthalocyanine complex is encapsulated in pharmaceutically effective amounts in nanoparticles formed from selected pharmaceutically acceptable polymers.
  • the following invention relates to a pharmaceutical composition which is suitable for the solubilization of the zinc phthalocyanine complex.
  • the composition is characterized by the following components: a) the zinc phthalocyanine complex; b) a pharmaceutically acceptable polymer which is suitable for the formation of nanoparticles and, optionally; c) further pharmaceutically acceptable additives which are suitable for incorporation in a dosage form for the intended mode of administration.
  • the pharmaceutical composition according to the present invention has the benefit of providing enhanced solubilization of the zinc phthalocyanine complex and specific release in selected target regions of malignant tissues such as neoplasms. This renders the pharmaceutical composition particularly useful for use in photodynamic therapy.
  • composition means a mixture containing the zinc phthalocyanine complex that can be administered to a host in a therapeutic method of treating the disease or condition indicated.
  • the composition is especially suitable for parenteral administration, especially i.v., but also for topical administration.
  • solubilization defines the homogeneous dispersion of the zinc phthalocyanine complex of extremely low water solubility in an aqueous phase containing nanoparticles with the aid of a pharmaceutically acceptable solubilizer which is suitable for the preparation of nanoparticles.
  • Nanoparticles are solid spheroid particles ranging in size from about 10 to 1000 nm. When dispersed in an aqueous phase, they have colloidal properties.
  • the term nanoparticles is a generic term that comprises nanospheres and nanocapsules. Nanospheres have a polymeric matrix type structure, whereas nanocapsules have a shell formed of polymers surrounding a liquid core. Nanoparticles encapsulate the zinc phthalocyanine complex of extremely low water solubility.
  • encapsulation indicates the presence of the active agent zinc phthalocyanine in nanoparticles.
  • the active agent may be adsorbed at their surface or entrapped, e. g. as microcrystals, in the polymeric matrix, or may be dissolved therein.
  • the active agent may be dispersed in the liquid present in the core, but may also be adsorbed at the surface, entrapped or dissolved in the polymeric matrix.
  • Component a) - active agent the zinc phthalocyanine component is listed as "ciaftalan zinc" in List 74 of proposed INNs (International Nonproprietary Names) published in the Vol.9, No.4 (1995) issue of the WHO Drug Information.
  • Component b) - polymers a pharmaceutically acceptable polymer which is suitable for the formation of nanoparticles is, for example, a pharmaceutically acceptable homopolymer or copolymer from monomers selected from the group consisting of L-lactide N or S, D-lactide S, D,L-lactide S, glycolide S or trimethylene carbonate.
  • Those polymers are marketed under the trade-mark MEDISORB (Registered Trade-Mark of Medisorb Technologies Inc.), PURASORB (Registered Trade-Mark of PURAC Biochem.) or RESOMER (Registered Trademark of Boehringer Ingelheim, Germany).
  • Suitable products are MEDISORB polymers of the L or DL series, e.g. 100 L or DL, or 8515, 7525, 6535, or 5050 DL, or RESOMER homopolymers of the L series, formed from L- lactide, e.g. L 104, 206 - 210, or 214, R series formed from racemic D,L-lactide, e.g. R 104, 202, 203, or 206 - 208 or G series formed from glycolide, e.g. G 205, or copolymers of the LR series formed from L-lactide with D,L-lactide, e.g. LR 708, or 909 or DL-lactide with glycolide, e.g. RG 502 - 505, 752, 755, 756, or 858.
  • L- lactide e.g. L 104, 206 - 210, or 214
  • R series formed from racemic D,L-lactide
  • An alternative polymer is a pharmaceutically acceptable copolymer formed from monomers selected from the group consisting of methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters. These polymers are commercially available from Rohm Pharma GmbH, Rothstadt, Germany, and are marketed under the trademark EUDRAGIT (Registered Trademark of Rohm Pharma GmbH).
  • An especially preferred polymer of the EUDRAGIT series is the 1 :1- to 1 :2-copolymer which is formed from monomers selected from the group consisting of methacrylic acid and methacrylic acid lower alkyl esters, such as the 1 :1- to 1 :2-copolymer of methacrylic acid and methyl methacrylate.
  • the 1 :1 -copolymers are marketed in the EUDRAGIT L series, such as L 12.5, 100, or L 30 D.
  • the corresponding 1:2-copolymers are marketed in the EUDRAGIT S series, such as S 12.5 or S 100.
  • EUDRAGIT L 100-55 Another preferred polymer of the EUDRAGIT series is the 1 :1- copolymer of methacrylic acid and acrylic acid ethyl ester. This polymer is marketed under the product name EUDRAGIT L 100-55.
  • PVAP polyvinyl acetate phthalate
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • HPPMCP hydroxypropyl methyl cellulose phthalate
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • HPMCP is marketed by Eastman Kodak Corp..
  • HPMCP 50 USP/NF type 220824
  • HPMCP 55 USP/NF type 200731
  • CAP is marketed under the trademark AQUATERIC ( Registered Trademark of FMC Corp.) or is commercially available from Eastman (composition: phthalyl 35 %, acetyl 24 %, moisture 1 %, free acid 0.5 % (as phthalic acid)).
  • CAT is commercially available from Eastman (composition: trimellity! 29 %, acetyl 22 %, moisture 1 %, free acid 0.5 % (as phthalic acid)).
  • Component c) - additives Pharmaceutically acceptable additives are determined by the dosage form for the intended mode of administration.
  • a preferred mode of administration is parenteral, especially i.v., but also topical, e.g. ocular.
  • Parenteral dosage forms are particularly useful for intravenous, but also for intramuscular administration.
  • water is added that has been sterilized and freed from pyrogens, according to the prescriptions of national pharma ⁇ copoeias, such as The U.S. Pharmacopoeia (USP) or Deutsches Arzneibuch (DAB).
  • USP U.S. Pharmacopoeia
  • DAB Deutsches Arzneibuch
  • water-soluble additives which are suitable for the adjustment of isotonic conditions, is particularly preferred, typically sodium chloride, sorbitan, mannitol, glucose, lactose or fructose.
  • oily carrier liquids such as sesame oil or olive oil, but also lecithin, may be added.
  • Topical formulations are listed in standard textbooks, e.g. Remington's Pharmaceutical Sciences or Hagers Handbuch der Pharmazeutica für für nik.
  • Topical formulations are in particular creams, ointments, gels, pastes or topically administered aerosols and also suspensions of nanoparticles or ophthalmic compositions.
  • Suitable additives for topical and especially ophthalmic compositions are in particular inert carriers, solubilizers, tonicity-increasing agents, buffer substances, preservatives, thickeners, and other adjuncts.
  • Such additives are e.g. ethanol, vegetable oil, mineral oil containing hydroxyethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinyl- pyrrolidone, and other non-toxic water-soluble polymers intended for ophthalmic use, e.g.
  • cellulose ethers such as methyl cellulose, alkali metal salts of carboxymethyl cellulose or hydroxymethyl, hydroxyethyl, or hydroxypropyl cellulose, acrylates or methacrylates such assalts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenan, agar or acacia, starch derivatives such as starch acetate and hydroxypropyl starch, and also other synthetic additives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably crosslinked polyacrylic acid such as neutral Carbopo or mixtures of these polymers.
  • buffer substances are acetate, ascorbate, borate, bicarbonate/ carbonate, citrate, gluconate, lactate, phosphate, propionate, and so-called tris buffers.
  • the amount of buffer substance is added to maintain a physiologically acceptable pH-range.
  • Tonicity-enhancing agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, e.g. CaCI 2 , Kbr, KCI, LiCI, Nal, NaBr, or NaCI, or boric acid.
  • Non-ionic tonicity-enhancing agents are, for example, urea, glycerol, sorbitol , mannitol, propylene glycol, or dextrose.
  • Sufficient tonicity-enhancing agent is added that the ophthalmic composition has an osmolality in a preferred range of about 50 to 400 mOsmol.
  • preservatives examples include quaternary ammonium salts such as cetrimide, benzalkonium chloride, alkylmercury salts of thiosalicylic acid such as thiomersal, phenylmercury nitrate, acetate, or borate, parabens such as methylparaben or propylparaben, alcohol, e.g. chlorobutanol, benzyl alcohol, or phenylethanol, guanidine derivatives, e.g. chlorhexidine, or polyhexamethylenebiguanide, or sorbic acid. If desired, the amount of preservative which is necessary to ensure sterility is added to the ophthalmic composition.
  • quaternary ammonium salts such as cetrimide, benzalkonium chloride, alkylmercury salts of thiosalicylic acid such as thiomersal, phenylmercury nitrate, acetate, or borate
  • the present invention in particular relates to a pharmaceutical composition suitable for intravenous administration and containing a) the zinc phthalocyanine complex; b) a pharmaceutically acceptable homopolymer or copolymer from monomers selected from the group consisting of L-lactide N or S, D-lactide S, D,L-lactide S, or glycolide S; c) further pharmaceutically acceptable additives which are suitable for incorporation in a dosage form for intravenous administration.
  • the present invention also relates to a process for the preparation of said pharmaceutical composition which is characterized in that an aqueous dispersion of nanoparticles is formed containing a) the zinc phthalocyanine complex; b) a pharmaceutically acceptable polymer which is suitable for the formation of nanoparticles; and the dispersion is processed further with the optional addition of pharmaceutically acceptable additives c), which are suitable for incorporation into a dosage form for the intended mode of administration.
  • An especially preferred method comprises the preparation of an aqueous gel containing a hydrophilic polymer with the optional addition of a water-soluble salt.
  • This gel is mixed with a solution of an organic solvent containing the active agent and the polymer which is suitable for the formation of nanoparticles.
  • Phase separation is then observed, and, after addition of water, the nanoparticles formed are homogeneously dispersed in the aqueous phase.
  • the aqueous phase is then processed further to the pharmaceutical dosage form intended, e.g. by applying conventional purification and separation methods.
  • the preparation of the aqueous gel containing the hydrophilic polymer is disclosed in E. Allemann, loc. cit., and the additional references cited therein.
  • the gel is formed by adding water to the hydrophilic polymer.
  • Suitable hydrophilic polymers are polyvinyl alcohols such as the ones marketed under the trademark MOWIOL (Registered Trademark of Hoechst AG, Germany).
  • Preferred are polyvinyl alcohols having a degree of hydrolysis of more than 70 % (partially hydrolized grades), especially more than 87 %, e.g. MOWIOL of the 88 and 92 series, e.g. 4-88, 5-88, 8-88, 18-88, 23-88, 26-88, and 40-88.
  • a physiologically acceptable water-soluble salt e.g. magnesium chloride, or magnesium acetate.
  • the gel phase is added, with stirring, to a solution of the organic solvent, e.g. acetone or benzyl alcohol, which contains the active agent, e.g. the zinc phthalocyanine complex and the pharmaceutically acceptable polymer, which is suitable for the formation of nanoparticles defined above.
  • the organic solvent e.g. acetone or benzyl alcohol
  • the active agent e.g. the zinc phthalocyanine complex
  • the pharmaceutically acceptable polymer which is suitable for the formation of nanoparticles defined above.
  • the aqueous phase may be processed further by conventional purification and separation methods resulting in the preparation of the dosage form desired.
  • the dispersion so obtained may be defined as an aqueous suspension of nanoparticles containing zinc phthtalocyanine.
  • a homogeneous dispersion of nanospheres is obtained. Nanospheres are clearly distinguishable by physical methods, such as photon correlation spectroscopy (PCS), e. g.
  • a COULTER NANO-SIZER by LASER light scattering methods or electron microscopy, from other microparticles, such as liquid crystals, micells, reversed micells, liposomes, microspheres or microcapsules.
  • a mean average particle size between 60 and 300 nm has been determined. The size of the nanoparticles obtained depends on the established and known methods chosen for their preparation.
  • the homogeneous aqueous dispersion containing nanospheres is then processed further to a conventional pharmaceutical dosage form by applying standard purification methods, e.g. the ones known in the art for purifying nanoparticles, e.g. ultracentrifugation or cross-flow filtration.
  • the dispersion can also be lyophilized in conventional manner, and the lyophilisate is then reconstituted to the pharmaceutical dosage form desired. Even after reconstituting the lyophilisate, a homogeneous nanodispersion is formed again.
  • the addition of specific amounts of water-soluble additives is recommended.
  • the invention also relates to the use of the pharmaceutical composition in a method for treating the human or animal body by photodynamic therapy.
  • the composition is administered, preferably intravenously, in a range of 0.01 - 1 ,00 mg/kg, preferably 0.03 - 1.0 mg/kg active substance.
  • photodynamic therapy the patient is exposed 20 min.- 24 h after drug administration to a high energy light source of about 671 nm wavelength.
  • a parenteral dosage form is prepared by applying known methods such as the ones mentioned in Hagers Handbuch der Pharmazeutician für für für für für für für für für für für für für für assupra.
  • the additives customarily used for the preparation of parenteral dosage forms may be added if necessary. Their choice depends on the type of dosage form requested, e.g. intravenous or intramuscular dosage forms.
  • the homogeneous dispersion optionally after concentration to standardized volumes, or the lyophilisate is added to suitable containers for unitary dosage forms such as vials.
  • MOWIOL 4-88 polyvinyl alcohol
  • the nanoparticulate dispersion is then purified by cross-flow filtration using a SARTOCON Mini Device (Sartorius, Gottingen, Gemany) mounted with a polyolefin cartridge filter having a 100 nm pore size. The filtration procedure is stopped after collecting 10 I of filtrate. The aqueous dispersion is finally frozen for 10 minutes at -55° and f reeze-dried for 24 h at 0.05 mbar.
  • the lyophilisate is reconstituted in water with gentle agitation.
  • the average particle size measured with a COULTER NANO-SIZER before purification with cross-flow filtration is 264 nm (polydispersity index: 2) and after reconstitution of the lyophilisate is 268 nm (polydispersity index: 3).
  • the f reeze-dried nanoparticles contain 0,98 % of the active agent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne une composition pharmaceutique se présentant sous la forme d'une dispersion aqueuse de nanoparticules, lesquelles comprennent un complexe de phtalocyanine de zinc ainsi qu'un polymère approprié à la formation de nanoparticules; elle concerne également un procédé de préparation de cette composition pharmaceutique ainsi que l'utilisation de celle-ci en thérapie, par exemple en thérapie photodynamique.
PCT/EP1996/003956 1995-09-21 1996-09-10 Nanoparticules utilisees en therapie photodynamique WO1997010811A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9512208A JPH11514986A (ja) 1995-09-21 1996-09-10 光力学的療法におけるナノ粒子
AU71271/96A AU7127196A (en) 1995-09-21 1996-09-10 Nanoparticles in photodynamic therapy
EP96932487A EP0851754A1 (fr) 1995-09-21 1996-09-10 Nanoparticules utilisees en therapie photodynamique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95810594.2 1995-09-21
EP95810594 1995-09-21

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WO1997010811A1 true WO1997010811A1 (fr) 1997-03-27

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PCT/EP1996/003956 WO1997010811A1 (fr) 1995-09-21 1996-09-10 Nanoparticules utilisees en therapie photodynamique

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EP (1) EP0851754A1 (fr)
JP (1) JPH11514986A (fr)
AU (1) AU7127196A (fr)
CA (1) CA2229285A1 (fr)
WO (1) WO1997010811A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000052101A1 (fr) * 1999-03-05 2000-09-08 Case Western Reserve University Composition comprenant un agent photo-oxydant et utilisations de cet agent
WO2002000191A3 (fr) * 2000-06-29 2003-06-05 Bernina Biosystems Gmbh Bdellosomes
WO2003037297A3 (fr) * 2001-11-01 2003-08-28 Univ East Anglia Nanoparticules fonctionnalisees comportant un photosensibilisant
WO2003097096A1 (fr) * 2002-05-16 2003-11-27 Qlt Inc. Compositions et procedes permettant l'administration de medicaments photosensibles
US7951395B2 (en) 2000-07-17 2011-05-31 Photonamic Gmbh & Co. Kg Dermal application system for aminolaevulinic acid
WO2011071970A2 (fr) 2009-12-11 2011-06-16 Biolitec, Inc. Systèmes de véhicules nanoparticulaires à base de poly (acide dl-lactique - co - glycolique) (plga) pour thérapie photodynamique (pdt)
US7995787B2 (en) 2001-10-21 2011-08-09 Sonic Grip Limited Sound emitting device
US8257741B2 (en) 1997-08-11 2012-09-04 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US8309129B2 (en) 2007-05-03 2012-11-13 Bend Research, Inc. Nanoparticles comprising a drug, ethylcellulose, and a bile salt
CN102895955A (zh) * 2012-10-22 2013-01-30 复旦大学 基于5-膦酸异肽酸的微孔自组装材料的功能化材料及制备方法
US8465762B2 (en) * 2002-01-23 2013-06-18 Photonamic Gmbh & Co. Kg Dermal application system for aminolevulinic acid-derivatives
US8703204B2 (en) 2007-05-03 2014-04-22 Bend Research, Inc. Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer
US8974827B2 (en) 2007-06-04 2015-03-10 Bend Research, Inc. Nanoparticles comprising a non-ionizable cellulosic polymer and an amphiphilic non-ionizable block copolymer
US9233078B2 (en) 2007-12-06 2016-01-12 Bend Research, Inc. Nanoparticles comprising a non-ionizable polymer and an Amine-functionalized methacrylate copolymer
US9545384B2 (en) 2007-06-04 2017-01-17 Bend Research, Inc. Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glocol succinate
US9724362B2 (en) 2007-12-06 2017-08-08 Bend Research, Inc. Pharmaceutical compositions comprising nanoparticles and a resuspending material
US10548992B2 (en) 2014-04-11 2020-02-04 National Cancer Center Multipurpose medical image indicator and method for manufacturing the same
WO2023060147A1 (fr) * 2021-10-05 2023-04-13 The Trustees Of The University Of Pennsylvania Micelles chargées de phtalocyanine pour la visualisation directe de tumeurs

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WO2004067508A2 (fr) * 2003-01-24 2004-08-12 The Research Foundation Of State University Of Newyork Nanoparticules a base de ceramique permettant d'emprisonner des agents therapeutiques destinees a etre utilisees en therapie photodynamique et leur procede d'utilisation
WO2024181368A1 (fr) * 2023-02-27 2024-09-06 国立大学法人東北大学 Agent thérapeutique photodynamique

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E. ALLEMAN ET AL.: "PEG-COATED POLY (LACTIC) ACID NANOPARTICLES FOR THE DELIVERY OF HEXADECAFLUORO ZINC PHTHALOCYANINE TO EMT-6 MOUSE MAMMARY TUMORS.", J. PHARM. PHARMACOL., vol. 47, no. 5, 1995, pages 382 - 387 *
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US8431159B2 (en) 1997-08-11 2013-04-30 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US8367118B2 (en) 1997-08-11 2013-02-05 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US8337899B2 (en) 1997-08-11 2012-12-25 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US8263128B2 (en) 1997-08-11 2012-09-11 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
WO2000052101A1 (fr) * 1999-03-05 2000-09-08 Case Western Reserve University Composition comprenant un agent photo-oxydant et utilisations de cet agent
WO2002000191A3 (fr) * 2000-06-29 2003-06-05 Bernina Biosystems Gmbh Bdellosomes
US7951395B2 (en) 2000-07-17 2011-05-31 Photonamic Gmbh & Co. Kg Dermal application system for aminolaevulinic acid
US7995787B2 (en) 2001-10-21 2011-08-09 Sonic Grip Limited Sound emitting device
US7563818B2 (en) 2001-11-01 2009-07-21 Cancer Research Technology Limited Photosensitizer functionalised nanoparticles
WO2003037297A3 (fr) * 2001-11-01 2003-08-28 Univ East Anglia Nanoparticules fonctionnalisees comportant un photosensibilisant
US8465762B2 (en) * 2002-01-23 2013-06-18 Photonamic Gmbh & Co. Kg Dermal application system for aminolevulinic acid-derivatives
US7455858B2 (en) 2002-05-16 2008-11-25 Qlt Inc. Compositions and methods for delivery of photosensitive drugs
WO2003097096A1 (fr) * 2002-05-16 2003-11-27 Qlt Inc. Compositions et procedes permettant l'administration de medicaments photosensibles
US8309129B2 (en) 2007-05-03 2012-11-13 Bend Research, Inc. Nanoparticles comprising a drug, ethylcellulose, and a bile salt
US8703204B2 (en) 2007-05-03 2014-04-22 Bend Research, Inc. Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer
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JPH11514986A (ja) 1999-12-21
AU7127196A (en) 1997-04-09
CA2229285A1 (fr) 1997-03-27
EP0851754A1 (fr) 1998-07-08

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