WO2000033816A1 - Formulations d'administration d'un materiau donne a des membranes de muqueuses - Google Patents

Formulations d'administration d'un materiau donne a des membranes de muqueuses Download PDF

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Publication number
WO2000033816A1
WO2000033816A1 PCT/GB1999/004096 GB9904096W WO0033816A1 WO 2000033816 A1 WO2000033816 A1 WO 2000033816A1 GB 9904096 W GB9904096 W GB 9904096W WO 0033816 A1 WO0033816 A1 WO 0033816A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
particulate material
membrane
matrix
dose form
Prior art date
Application number
PCT/GB1999/004096
Other languages
English (en)
Inventor
John Herman Collett
David Attwood
Original Assignee
The Victoria University Of Manchester
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 The Victoria University Of Manchester filed Critical The Victoria University Of Manchester
Priority to AU18667/00A priority Critical patent/AU1866700A/en
Publication of WO2000033816A1 publication Critical patent/WO2000033816A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1279—Plasters, bandages, dressings, patches or adhesives
    • 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
    • A61K9/0031—Rectum, anus
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • the present invention relates to a formulation and method for the delivery of agents, e.g. diagnostic o therapeutic agents, across a mucosal membrane.
  • amphiphilic substances i.e. compounds having both "hydrophilic” and “hydrophobic” character.
  • amphiphilic molecules include mono, di-, or tri-acyl esters of glycerol with a long chain (e.g. C ⁇ 2 -C 20 ) carboxylic acid (usually but not necessarily one having a degree of unsaturation).
  • a particular example of an amphiphilic substance is glycerol monooleate (monoolein).
  • GB-A-2 212 723 proposes a transdermal delivery formulation comprised of a matrix of glycerol monooleate incorporating, as a therapeutic agent to be delivered, a steroid, a nitrate or bisperiden.
  • the formulation is stated to be particularly useful for the delivery of the therapeutic agents across skin although it is also a stated object of the invention of GB-A-2 212 723 to increase the permeability of body surfaces including the mucous and other membranes.
  • WO-A-9534287 discloses a biologically active composition comprised of (a) a diacyl glycerol, (b) a phospholipid and, optionally, (c) a polar liquid in such proportions that they together form an L2- phase or a cubic crystalline phase, the composition incorporating a biologically active material dissolved or dispersed therein.
  • the biologically active material may for example be an antibiotic, antimycotic, protein, peptide, steroid, local anaesthetic, chemotherapeutic agent or an antiviral substance.
  • compositions as disclosed in WO- A-9534287 are proposed for a number of uses, e.g. parenteral administration of drugs, administration of drugs for treating paradontosis, preparation of depot formulations, enhancing absorption of proteins and peptides, and for treating infections in or adjacent mucous membranes.
  • WO-A-9526715 discloses bioadhesive/mucoadhesive drug delivery formulations which contain a therapeutic agent and which are intended for application to or through undamaged or damaged skin or mucosa of an animal so as to remain in contact with the skin or mucosa for an extended period of time to prolong delivery of the drug.
  • Such formulations have the benefit that the drug delivery system can be localised on a specific site for the purpose of local therapy, e.g. for the purpose of targeting specific diseased tissue.
  • the formulation of WO-A-9726715 comprises the therapeutic agent in admixture with a fatty acid ester having a molecular weight below about 1000 daltons.
  • the bioadhesive nature of the formulation is achieved by "contact" of the ester with a hydrophilic medium, e.g. water.
  • a hydrophilic medium e.g. water.
  • the formulation of WO-A-9526715 may be bioadhesive/mucoadhesive in the form in which it is to be administered (by virtue of the formulation having been prepared with water or glycerol) or may become bioadhesive/mucoadhesive only on contact with body fluids associated with the tissue to which the formulation is administered.
  • the bioreductive/mucoadhesive formulations of WO-A-9526715 incorporate a liquid crystalline phase formed by the fatty acid ester and the hydrophilic liquid.
  • WO-A-9526715 A wide range of therapeutic agents is listed in WO-A-9526715, many of which are relatively small molecules. It is however also contemplated in WO-A- 9526715 that the therapeutic agent may be a sulfated polysaccharide, e.g. heparin, which is of high molecular weight. Other high molecular weight therapeutic agents which the skilled person would contemplate for incorporation in the delivery formulations of WO-A-9526715 would include such agents having a molecular weight in excess of 5000 or 10000 daltons and would include proteins and nucleic acids although there would be the disadvantage of a significant degradation of such "naked" molecules.
  • WO-A-9323025 also gives a summary of the liquid crystalline phases formed when amphiphilic molecules are admixed with polar liquids such as water.
  • polar liquids such as water.
  • the prior art has addressed the delivery of various drugs across skin and mucosal membranes using the permeation enhancing effects of amphiphilic molecules.
  • the prior art has not addressed the delivery of particulate material across mucosal membranes.
  • delivery of such particles to or across membranes would be useful.
  • the delivery of diagnostic colloids, colloidal therapeutic agents and macromolecular therapeutic agents to target tissues. There is thus a need to effect such delivery and the present invention seeks to address this need
  • a delivery formulation for administration to a mucous membrane which is either, mucoadhesive per se or becomes mucoadhesive on contact with a mucous membrane, said formulation comprising a particulate material to be delivered to or across the membrane in a matrix or dose form containing an amphiphilic substance.
  • a method of delivering a particulate material to or across a membrane comprising providing a formulation comprised of the particulate material to be delivered in a matrix or dose form containing an amphiphilic substance in contact with the membrane for a period of time for the particulate material to pass in or across the membrane.
  • the present invention has been based on our finding that mucoadhesive formulations (or formulations which become mucoadhesive in contact with a mucous membrane) containing an amphiphilic substance provide for effective delivery of particulate materials to or across the membrane.
  • amphiphilic substances are known to provide an increase in the permeability of skin and mucosal membranes sufficient to deliver molecules across the membrane, it is surprising that such substances may be used to provide delivery of particulate materials to a membrane.
  • delivery formulations according to the first aspect of the invention are able to provide prolonged delivery of the particulate material.
  • the formulation adheres to the membrane and acts as a reservoir from which the particulate material may be released to or across the membrane.
  • the combination of the amphiphilic substance with the particulate material appears to act to improve the adhesion and in particular to promote the transfer of the particulate material across the membrane.
  • the formulation also allows the release of the particulate material (and any active agent associated therewith) over a substantial period of time.
  • the formulation may be used for delivering a particulate material across a vaginal, intestinal, buccal, nasal or rectal membrane.
  • Particulate material which may be used in formulations according to the invention will generally have the size of lOnm to lOO ⁇ m. More preferably, the particulate material will have a size in the range of lOOnm to lO ⁇ m.
  • the particulate material may for example comprise radioactive particles to be delivered across the mucosal membrane for the purpose of diagnosis or therapy.
  • the particulate material may be a technetium colloid, irridium or tin.
  • the particulate material may be one which is associated, and acts a carrier for, a therapeutic agent to be delivered across the membrane.
  • the therapeutic agent may be absorbed on the surface of a particulate carrier or contained within the carrier.
  • the carrier may be polymeric or non-polymeric; biodegradable or non-biodegradable; polar, non-polar or non-ionic.
  • Therapeutic agents which may be delivered in this way include proteins, peptides, nucleic acids, biologically engineered molecules and other therapeutic agents prescribed in particulate form.
  • high molecular weight therapeutic agents may be associated with a particulate carrier and delivered across a mucosal membrane.
  • high molecular weight we mean at least 5000 daltons although the invention may be used for the delivery of therapeutic agents having a molecular weight in excess of 10000 daltons.
  • high molecular weight therapeutic agents examples include proteins and nucleic acids.
  • An advantage of delivering high molecular weight therapeutic agents in association with the carrier is that the agents may be protected by the carrier from degradation as they pass through the mucosal membrane.
  • the delivery of diagnostic or therapeutic agents using the techniques of the invention may be for the purpose of topical, local, site-specific or systemic delivery to a subject to be treated.
  • Formulations in accordance with the invention will preferably comprise 0.01% to 5% by weight of the particulate material to be delivered across the membrane but we do not preclude amounts outside this range.
  • the formulation of the invention may be one which is mucoadhesive per se or one which becomes mucoadhesive on contact with a mucosal membrane. It is particularly preferred that the formulation to be administered is mucoadhesive per se. most preferably the formulation of the invention is (for ease of administration) a solid or semi-solid and consists essentially of the particulate material to be delivered, the amphiphilic substance and (optionally) an agent (e.g. water) which generate mucoadhesive properties with the amphiphilic substance and/or particulate material.
  • the formulation of the invention includes conventional excipients such that the formulation is a gel, ointment, suppository, pessary etc.
  • amphiphilic substances may be used for producing formulations in accordance with the invention. It is however particularly preferred that the amphiphilic substance is a mono- or higher ester of a C 2 -C 4 polyhydric alcohol with a carboxylic acid having a chain of 12-22 carbon atoms, said chain possibly containing at least one (preferably cis) olefinic unsaturated bond. Depending on the number of carbon atoms in the polyhydric alcohol, the ester may be a mono-, di-, tri- or tetra-ester. Examples of carboxylic acids with which the polyhydric may be esterified include oleic acid, linoleic acid and other unsaturated fatty acids. It is particularly preferred in accordance with the invention that the amphiphilic substance is a mono-, di-, or tri-glyceride but not exclusively.
  • the matrix or dose form incorporating the particulate material may take a number of forms.
  • certain of the amphiphilic substances contemplated for use in accordance with the invention are capable of forming liquid crystal phases when admixed with water or other polar liquid (for a discussion of the liquid crystal phases which may be formed with amphiphilic substances see for example WO-A-8402076 and WO-A-9534287).
  • Liquid crystal phases may be formed by both saturated and unsaturated glycerides.
  • saturated monoglycerides of between 12 and 20 carbon atoms form various liquid crystal phases.
  • 12 carbon glycerides e.g. monolaurin
  • the phases are similar to the saturated monoglycerides, although the unsaturated hydrocarbon chain affects the relative position of the phase boundaries.
  • the trans- unsaturated compound, monelaidin (C18) forms a lamellar phase at temperatures approximately 30 °C lower than the equivalent saturated monoglyceride monostearin.
  • Preferred formulations in accordance with the invention comprise a matrix or does form of the amphiphilic substance in a liquid crystal phase, the matrix or dose form incorporating the particulate material to be delivered.
  • the use of such liquid crystal phases for formulations of the invention has been found to be particularly advantageous since they have mucoadhesive properties which make the formulation particularly easy to apply and retain in position.
  • Such formulations may be semi-solid or solid and easy to handle.
  • the matrix or dose form may be a lamellar phase, a cubic phase, a reversed hexagonal phase, or a reversed micellar phase.
  • Amphiphilic substances capable of forming liquid crystal phases are generally mono- or higher esters of glycerol with a carboxylic acid having a Cj 2 - 22 carbon chain possibly containing at least one olefinically unsaturated bond.
  • Formulation in accordance with the invention in which the amphiphilic substance is present as a liquid crystalline phase may be produced by simply mixing the amphiphilic substance, water and particulate material.
  • Particularly preferred formulations in accordance with the invention comprise, 60 to 80% by weight of glycerol monooleate present as a liquid crystal phase and correspondingly 20% to 40% by weight of water (these percentage being based on the total weight of the glycerol monoleate and water).
  • glycerol monooleate is particularly advantageous in that it is regarded as non-toxic, and biocompatible, and is subject to lipolysis by enzymes present in the various tissues of the body.
  • Formulations in accordance with the invention comprising a triglyceride as matrix may be produced by melting the triglyceride, mixing the melt with the particulate material and allowing the mixture to solidify.
  • Formulations in accordance with the invention may be used for delivering particulate, material across any mucosal membrane in the human or animal body.
  • a technetium 99m labelled tin-colloid having a particle size of 400nm was incorporated in a composition comprising 70%> monolein (myeroids -99) and 30% > water.
  • the resulting formulation was administered intra-vaginally to a rabbit and the delivery of particulate material across the membrane assessed.
  • the movement, or the degree of spreading of the technetium 99m labelled tin- colloid, in the 70/30 wt ratio monolein/water gel was estimated by counting the number of elements within each region of interest on the gamma camera images, which represented the area containing the radioactive formulation.
  • Technetium 99m labelled tin-colloid was chosen as an insoluble, non- absorbable marker with an average colloid particle size of 400nm.
  • the gamma scintigraphs in Figure 1 were taken after the vaginal administration of technetium 9 m labelled tin-colloid to a rabbit in the form of a monolein/water gel (0, 6 and 24 hours after administration).
  • the gamma scintigraph shows a vaginal site and a second site of activity appearing with time in the liver/spleen area of the rabbit. The appearance of this unexpected second site of activity may be accounted for by the absorption of the technetium 99m labelled tin-colloid through the vaginal membrane and illustrating the effectiveness of the invention in providing for delivery of particles across the membrane.
  • formulations according to the first aspect of the invention are able to provide delivery of particulate material (and active agents associated therewith) over a longer period of time than known formulations (e.g. Witespol W35 pessaries). Therefore an advantage of the formulations according to the invention is that they provide sustained release of the particulate material (and its payload) over a mucous membrane.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dispersion Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formulations d'administration, permettant d'administrer un agent thérapeutique à une muqueuse, lesdites formulations étant mucoadhésives per se ou devenant mucoadhésives par contact avec une muqueuse. Ces formulations comprennent un matériau particulaire, à administrer à la membrane ou sur celle-ci, dans une matrice ou une dose posologique contenant une substance amphiphile. Selon l'invention, des formulations préférées comprennent une matrice ou une dose posologique de la substance amphiphile en phase de cristaux liquides, la matrice ou la dose posologique incorporant le matériau particulaire à administrer.
PCT/GB1999/004096 1998-12-10 1999-12-10 Formulations d'administration d'un materiau donne a des membranes de muqueuses WO2000033816A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18667/00A AU1866700A (en) 1998-12-10 1999-12-10 Formulation for delivery of particulate material to mucosal membranes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9827034A GB9827034D0 (en) 1998-12-10 1998-12-10 Delivery formulation
GB9827034.1 1998-12-10

Publications (1)

Publication Number Publication Date
WO2000033816A1 true WO2000033816A1 (fr) 2000-06-15

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Family Applications (1)

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PCT/GB1999/004096 WO2000033816A1 (fr) 1998-12-10 1999-12-10 Formulations d'administration d'un materiau donne a des membranes de muqueuses

Country Status (3)

Country Link
AU (1) AU1866700A (fr)
GB (1) GB9827034D0 (fr)
WO (1) WO2000033816A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009122A1 (fr) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Composition mucoadhesive et formulation pour une solubilisation de medicaments insolubles et preparation associee
US6894071B2 (en) 2001-11-01 2005-05-17 Spectrum Pharmaceuticals, Inc. Medical compositions for intravesical treatment of bladder cancer
WO2008153966A1 (fr) * 2007-06-11 2008-12-18 Biocure, Inc. Vésicules mucoadhésives pour l'administration de médicament
WO2012119838A1 (fr) * 2011-03-04 2012-09-13 Unilever Nv Composition auto-adhésive de nettoyage de surface dure
CN102805734A (zh) * 2002-12-10 2012-12-05 Cps奥罗瑟尔有限责任公司 制备生物活性制剂的方法
US8563592B2 (en) 2001-11-01 2013-10-22 Spectrum Pharmaceuticals, Inc. Bladder cancer treatment and methods

Citations (5)

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Publication number Priority date Publication date Assignee Title
EP0122799A2 (fr) * 1983-04-13 1984-10-24 AMERSHAM INTERNATIONAL plc Réactif pour la préparation d'un colloide d'étain marqué au technetium-99m pour l'exploration scintigraphique du corps
WO1992009272A1 (fr) * 1990-11-21 1992-06-11 A/S Dumex (Dumex Ltd.) Procede et composition assurant une liberation regulee d'agents biologiquement actifs
WO1995034287A1 (fr) * 1994-06-15 1995-12-21 Gs Development Ab Composition lipidique a base de diacylglycerol, de phospholipide, de liquide polaire et de principe actif d'origine biologique
JPH0967273A (ja) * 1995-08-31 1997-03-11 Saga Univ コーティングされた薬剤内包架橋キトサン組成物、その製造方法および薬剤徐放制御システムとしての用途
WO1997013528A1 (fr) * 1995-10-12 1997-04-17 Gs Development Ab Composition pharmaceutique pour l'administration d'un principe actif sur ou au travers d'une surface cutanee ou muqueuse

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0122799A2 (fr) * 1983-04-13 1984-10-24 AMERSHAM INTERNATIONAL plc Réactif pour la préparation d'un colloide d'étain marqué au technetium-99m pour l'exploration scintigraphique du corps
WO1992009272A1 (fr) * 1990-11-21 1992-06-11 A/S Dumex (Dumex Ltd.) Procede et composition assurant une liberation regulee d'agents biologiquement actifs
WO1995034287A1 (fr) * 1994-06-15 1995-12-21 Gs Development Ab Composition lipidique a base de diacylglycerol, de phospholipide, de liquide polaire et de principe actif d'origine biologique
JPH0967273A (ja) * 1995-08-31 1997-03-11 Saga Univ コーティングされた薬剤内包架橋キトサン組成物、その製造方法および薬剤徐放制御システムとしての用途
WO1997013528A1 (fr) * 1995-10-12 1997-04-17 Gs Development Ab Composition pharmaceutique pour l'administration d'un principe actif sur ou au travers d'une surface cutanee ou muqueuse

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Title
DATABASE WPI Section Ch Week 199720, Derwent World Patents Index; Class A96, AN 1997-221705, XP002134273 *
GERAGHTY PB, ET AL.: "An investigation of the parameters influencing the bioadhesive properties of Myverol 18-99/water gels", BIOMATERIALS, vol. 18, no. 1, 1997, ISSN 0142-9612, pages 63 - 67, XP004070846 *
PATENT ABSTRACTS OF JAPAN vol. 1997, no. 7 31 July 1997 (1997-07-31) *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6894071B2 (en) 2001-11-01 2005-05-17 Spectrum Pharmaceuticals, Inc. Medical compositions for intravesical treatment of bladder cancer
US7977369B2 (en) 2001-11-01 2011-07-12 Spectrum Pharmaceuticals, Inc. Medical compositions for intravesical treatment of bladder cancer
US8563592B2 (en) 2001-11-01 2013-10-22 Spectrum Pharmaceuticals, Inc. Bladder cancer treatment and methods
US8648108B2 (en) 2001-11-01 2014-02-11 Spectrum Pharmaceuticals, Inc. Medical compositions for intravesical treatment of bladder cancer
US9295666B2 (en) 2001-11-01 2016-03-29 Spectrum Pharmaceuticals, Inc. Bladder cancer treatment and methods
WO2004009122A1 (fr) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Composition mucoadhesive et formulation pour une solubilisation de medicaments insolubles et preparation associee
CN102805734A (zh) * 2002-12-10 2012-12-05 Cps奥罗瑟尔有限责任公司 制备生物活性制剂的方法
WO2008153966A1 (fr) * 2007-06-11 2008-12-18 Biocure, Inc. Vésicules mucoadhésives pour l'administration de médicament
WO2012119838A1 (fr) * 2011-03-04 2012-09-13 Unilever Nv Composition auto-adhésive de nettoyage de surface dure

Also Published As

Publication number Publication date
AU1866700A (en) 2000-06-26
GB9827034D0 (en) 1999-02-03

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