WO1994023752A1 - Systeme d'apport en medicament - Google Patents

Systeme d'apport en medicament Download PDF

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Publication number
WO1994023752A1
WO1994023752A1 PCT/GB1994/000806 GB9400806W WO9423752A1 WO 1994023752 A1 WO1994023752 A1 WO 1994023752A1 GB 9400806 W GB9400806 W GB 9400806W WO 9423752 A1 WO9423752 A1 WO 9423752A1
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WO
WIPO (PCT)
Prior art keywords
lectin
active agent
pharmacologically active
drug delivery
drug
Prior art date
Application number
PCT/GB1994/000806
Other languages
English (en)
Inventor
John David Smart
David John Rogers
Original Assignee
University Of Portsmouth Enterprise Limited
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
Priority claimed from GB939307904A external-priority patent/GB9307904D0/en
Priority claimed from GB939324682A external-priority patent/GB9324682D0/en
Application filed by University Of Portsmouth Enterprise Limited filed Critical University Of Portsmouth Enterprise Limited
Priority to AU65100/94A priority Critical patent/AU6510094A/en
Priority to GB9523475A priority patent/GB2292887B/en
Publication of WO1994023752A1 publication Critical patent/WO1994023752A1/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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers

Definitions

  • the present invention relates to a sustained release drug delivery system.
  • the present invention relates to a sustained release drug delivery system comprising a pharmacologically active agent and a lectin.
  • the invention specifically relates to the sustained delivery of ophthalmic drugs.
  • aqueous drug dosage forms such as eye drops suffer from the disadvantage that the applied drug is rapidly removed by drug dilution and drug elimination caused by the continuous turnover of the tear fluid.
  • the present invention overcomes the above discussed disadvantage, in that the system of the present invention is capable of binding to specific tissue sites. The binding of the drug delivery system, ensures that the drug to be delivered is releasably bound at the site of action. Thus it does not suffer from the disadvantage of aqueous drug dosage forms of being susceptible to being rapidly removed.
  • the present invention provides a drug delivery system comprising a lectin and a pharmacologically active agent wherein the active agent is reversibly bound to the lectin.
  • the pharmacologically active agent is a drug or pharmacologically active material.
  • the pharmacologically active agent is a microparticle or a nanoparticle comprising a pharmaceutical.
  • the size of the microparticle or nanoparticle should be such that it does not cause irritation to the eye.
  • the lectin is reversibly bound on an outer surface of the microparticle or nanoparticle.
  • the pharmacologically active agent is a liposome containing a pharmaceutical.
  • the lectin may be reversibly bound to an outer surface of the liposome.
  • the pharmacologically active agent is a gel having a pharmaceutical dispersed therein.
  • the pharmacologically active agent is bound to an ion- exchange resin or a macromolecular carrier such as albumin, polyacrylic acid or hyaluronic acid.
  • the pharmacologically active agent may comprise any system generally known to be suitable for sustained drug release and to which lectins may reversibly bind.
  • the drug delivery system of the present invention is to be brought into contact with, body surfaces including the eye and less aptly the mucous membranes of the mouth, the nose, the gastrointestinal tract, the anus and the vagina.
  • the pharmaceutically active agents which are particularly useful for contact with body surfaces including the eye include antibacterials as hereinafter described, antibiotics such as chloramphenicol, oxytetracycline, tetracycline, erythromycin; antifungal agents such as griseofulvin, amphotericin B, nystatin and the like and econazole and miconazole which are especially useful in the treatment of fungal infections of the mouth and vagina; antivirals such as idoxuridine, anaesthetics as hereafter described, anti-allergy compounds, and spermicides for vaginal use.
  • antibiotics such as chloramphenicol, oxytetracycline, tetracycline, erythromycin
  • antifungal agents such as griseofulvin, amphotericin B, nystatin and the like and econazole and miconazole which are especially useful in the treatment of fungal infections of the mouth and vagina
  • antivirals such as idoxuridine
  • the amount of pharmaceutical present in the pharmacologically active agent will depend on the type of body surface to be treated and the frequency of treatment. Generally the amount of pharmaceutical present will be between l ⁇ g and lOmg.
  • lectins There are numerous references in the literature to lectins . They may be classified as either glycoproteins or proteoglycans . It is well known that lectins are capable of binding to sugar residues. Lectins can be characterised according to the specific sugar residue to which they bind.
  • the pharmacologically active agent may be releasably bound to the lectin by covalent or non-covalent bonding.
  • the pharmacologically active agent is non-covalently bound to the lectin.
  • the non-covalent bonding may be by means of a non-labile bond such as by means of an ionic bond or by means of hydrogen bonding.
  • suitable forms of bonding will be known to those skilled in the art.
  • the lectins suitable for use in the present invention should have at least two binding sites ie. be bi-valent.
  • a first binding site is for binding to the specific sugar residue in the body tissue.
  • the sugar residue may be any residue normally found in animal or human tissue. Examples of such sugar residues include N- acetlyglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), -D mannose, ⁇ -D-glucose and -L-fucose.
  • the lectin releasably binds to the above sugar residues on coming into contact therewith.
  • the second binding site is for binding the pharmacologically active agent.
  • the pharmacologically active agent may be any agent capable of binding to the lectin.
  • the pharmacologically active agent comprises an ophthalmically active pharmaceutical.
  • the cornea is the outer facing surface of the eyeball and is a transparent avascular structure composed of five layers (Fig 1), it is the main functional barrier to the ocular penetration of drugs and has an extremely regular anatomical structure (Haskjold, E, Refsum, S B, Bjerknes, R (1980) APMIS 98,959-976.
  • the conjunctiva is attached to the sclera at the corneal margin and is reflected back to form the inner lining of the eyelid.
  • the surface of the cornea and conjunctiva are both mainly squamous stratified epithelia which are covered by a filamentous material called the glycocalyx that contains highly acidic glycoproteins. Overlying the glycocalyx is a mucin layer. (Wolff E (1961) In: “Anatomy of the Eye and Orbit” (Rev. by Last, R J London) 6th Ed.) which forms the inner part of the tear film. It is believed to be weakly bonded to the glycocalyx and there are chemical similarities in the glycoprotein constituents of the two.
  • Ocular tissues from rats have served as important animal models in experimental eye research.
  • lectin binding sites have been identified in the precorneal region using fixed tissues, however we have now demonstrated lectin binding of unfixed corneal and conjunctival tissues.
  • the drug delivery system of the present invention is suitable for the delivery of drugs to the precorneal region of the eye, thus allowing prolonged delivery of drugs to treat a range of conditions.
  • Suitable ophthalmic agents include anti-infective agents including antibacterials such a silver sulphadiazine, chloramphenicol, antibiotics such as econazole and miconazole, aminoglycosides including salts of neomycin or gentamicin, sodium sulphacetamide, and silver nitrate, mydriatics and cycloplegics such as atropine sulphate, cyclopentolatehydrochloride, phenylephrinehydrochloride and tropicamide; agents useful in the treatment of glaucoma and ocular hypertension, anti glaucoma agents, which include cholinergic agonists such as physostigmine salicylate, pilocarpine and salts thereof for example pilocarpine nitrate, sympathomimetics such as adrenaline and its salts, for example adrenaline tartrate, adrenaline with guanethidine, 6-blockers such as timolol and its salts, for
  • a method of treatment of a bacterial, fungal viral or allergic disorder which comprises the administration of a pharmacologically active agent to a patient suffering from such a disorder by the use of a drug delivery system as hereinbefore described.
  • a method of treatment of an ophthalmic disorder which comprises administration of a pharmacologically active agent to a patient suffering from such a disorder by the use of a drug delivery system as hereinbefore described.
  • the system may be prepared by allowing the lectin and a specific pharmacologically active agent to react together so as to form a bond therebetween.
  • the method of carrying out such a reaction may be according to any of the methods known to those skilled in the art.
  • the lectin is chosen from the group Con-A (Jack bean), Pisurn sativum (garden pea), Arachie hypogea (peanut), Helix pomatia (Roman edible snail), lycopersicon esculentum (tomato) and Ulex europaeus 1 (gorse).
  • Con-A Jack bean
  • Pisurn sativum garden pea
  • Arachie hypogea peanut
  • Helix pomatia Roman edible snail
  • lycopersicon esculentum tomato
  • Ulex europaeus 1 Ulex europaeus 1
  • Other suitable lectins include those isolated from potatoes, algae, and the horse-shoe carb as well as from Solanum tuberosum and Pisum sativum.
  • the lectin is either Helix pomatia (HPA) or Lycopersicon esculentum (LEA).
  • the drug delivery system of the present invention may comprise further pharmaceutically acceptable components in addition to the lectin and pharmacologically active agent.
  • an additional component may be a buffer, eg. TBS.
  • Such additional components may serve for example as a stabiliser or as a liquid vehicle, ie. a liquid phase for carrying the drug delivery system of the present invention.
  • the additional component should be storage stable and should not interact with either the lectin or the pharmacologically active agent.
  • the present invention further provides a pharmaceutical formulation comprising the drug delivery system of the present invention and a liquid vehicle.
  • the drug delivery system of the present invention may be stored and delivered in a pure undiluted state.
  • the tissues were blotted dry and placed in 2.5 - 3.0ml of 5mg L "1 streptavidin peroxidase in 0.125M TBS (made isotonic with NaCl) for 1 hr.
  • Tissues were then washed in 0.05M TBS blotted dry and incubated in a solution containing 0.05% w/v 3,3'-diaminobenzidine tetrahydrochloride (DAB) , 0.05M TBS and 0.015% v/v hydrogen peroxide for 10 min at room temperature.
  • DAB 3,3'-diaminobenzidine tetrahydrochloride
  • 0.05M TBS 0.015% v/v hydrogen peroxide for 10 min at room temperature.
  • fixation the tissues were place in 4% phosphate buffered formaldehyde for 24 hrs.
  • the procedure was completed 3 times for each lectin, and the binding was evaluated subjectively using the following scoring system: intensity of staining, absent to heavy (0/++++); no coverage to complete coverage (0- 5).
  • Example 1 Corneal and conjunctival epithelia from recently killed male Wistar rats were incubated with lO ⁇ g/ml of the appropriate biotinylated lectin in 0.05M tris buffered saline (TBS) pH 7.6, containing lmMCaCl 2 for 10s and 30s. Tissues were washed with TBS and placed in 5 ⁇ g/ml streptavidin peroxidase in isotonic 0.125M TBS for lh.
  • TBS tris buffered saline
  • the tissues were incubated in a solution containing 0.05% w/v 3,3'- diaminobenzidine tetrahydrochloride (DAB), 0.05M TBS and 0.15% v.v hydrogen peroxide for 10 min at room temperature.
  • DAB 3,3'- diaminobenzidine tetrahydrochloride
  • the tissues were incubated in the lectin solution for 10s then washed by aggitating in TBS and lmMCaCl 2f pH7.6 for 30min before proceeding. 5 ⁇ m sections were then cut and counterstained with 2% methylgreen. Each section was initially examined using light microscopy at x400 magnification. The presence of lectin on the surface epithelia was indicated by the brown precipitate of DAB.
  • the binding was evaluated subjectively using stain intensity (absent to heavy) and surface cover (no to complete coverage), as described by Nicholls et al (1993) J. Pharm, Pharmacol, 45:1122.
  • the stain width on the surface epithelia was measured at 100 representative positions on each section using video microscopy at x3432 magnification, as a measure of the extent of lectin binding. Staining was evident on both the corneal and conjunctival surfaces after 10 and 30s with both HPA and STA. These exposure times are more representative of the residence time of eye drops in the precorneal region than the 15 min used in previous work. Washing for 30 min had minimial effects on the staining observed with STA and HPA.
  • the lectin from C. fragile was isolated by affinity chromatography from aqueous extract of the plant using methods described in Rogers, D.J., Loveless, R.W. and Balding, P. (1986) Isolation and characterisation of the lectins from sub-species of Codium fragile. In: Lectins, Biology, Biochemistry, Clinical Biochemistry, Vol 5. Eds T.C. Bog-Hansen and E. Van Driessche. Walter de Gruyter, Berlin, pp 155-160. Approximately half of the purified lectin was labelled with biotin using the technique described in R.F. Masseyeff, W.H. Albert and N.A. Staines Eds. Methods of Immunological Analysis, Vol 2.
  • Unlabelled C. fragile lectin was applied to unfixed rat eye. Following washing, biotinylated Dolicho ⁇ biflorus lectin (GalNAc-specific) was applied to the eye. The presence of biotinylated D. biflorus lectin was then assessed using streptavidin-peroxidase and 3',3- diaminobenzidine tetrahydrochloride (DAB).
  • DAB 3',3- diaminobenzidine tetrahydrochloride
  • Biotinylated C. fragile lectin was applied to rat eyes. Binding was assessed with streptavidin-peroxidase DAB as above. Microscopical examination revealed the presence of a dense brown precipitate of DAB on the corneal and conjunctival surfaces. This investigation was repeated using various dilutions of the biotinylated C. fragile lectin. The intensity of the DAB brown precipitate on corneal and conjunctival surfaces was proportional to the concentration of the biotinylated C. fragile lectin used.
  • the GAlNAc-binding lectin from the green marine alga binds to the surfaces of rat cornea and conjunctiva and therefore has potential value in topical drug location in the eye. It is therefore believed that lectins derived from certain marine algae may be suitable agents for incorporation in topical drug delivery systems for the eye and mouth.
  • the aim of this study was to identify lectins that could be used to retain a dosage from within the oral cavity in order to prolong localised drug delivery or to enhance systemic drug absorption.
  • This initial study investigated the binding to viable human buccal epithelial cells of a variety of different lectins. The method used was adapted from that described by Nicholls T.J. et al (1993) J. Phar . Pharmac. 45 1122. Human buccal cells were gently scrapped from the buccal surface with a wooden spatula which was then immersed in 10 ml of 0.05M tris buffered saline (TBS) pH 7.6. The cell suspension was filtered through a Nucleopore membrane filter, pore size 3 ⁇ m.
  • the filter and retained cells was immersed in 5 ml of lOmgL "1 biotinylated lectin (BL) in TBS, containing lmMCaCl 2 , for 30 min and washed twice at 5 min intervals in 0.05M TBS, before treating with 5mgL _1 streptavidin peroxidase (SP) in 0.125M TBS for 1 h.
  • the filter was re-washed twice in 0.05M TBS and 0.015% (v/v) H z 0 2 for 7 min.
  • the filter was counterstained with methyl green after soaking in 95% ethanol. Appropriate controls were completed omitting the SP, DAB or the lectin.
  • the surface of the filter was examined using light microscopy at x400 magnification.
  • the intensity of the DAB staining, indicating bound lectin, was evaluated subjectively using the following scoring: Strong staining (+++) intermediate staining (++), weak staining (+) and no staining (0).
  • the lectins tested bind to unfixed buccal mucosal cells, and so may be used as a means of enhancing drug delivery to the oral cavity.
  • lectins identified in the preceding studies as ' ligands' to anchor an appropriate drug for delivery to the mucosal surfaces of the eye, mouth, vagina or the respiratory tract.
  • the delivery systems envisaged will be of the following types:
  • Lectin/ macromolecule/ drug complexes In this system an intervening polymer or macromolecule is included in the formulation as a spacer/carrier device. Any non-toxic water soluble polymer of a water soluble grade would be appropriate. Some possible formulations are described below.
  • the drug e.g. pilocarpine nitrate, chlorhexidine acetate.
  • Formulations should be made isotonic using sodium chloride, sterilised by autoclaving or filtration and a preservative (chlorocresol 0.05%, phenylmercuric nitrate 0.002%, benzalkonium chloride 0.01% or chlorhexidine acetate 0.01%) added.
  • microparticles on Concanavalin A can be produced using a standard procedure (e.g. water in oil emulsification followed by cross- linking, drying and filtering) by first blocking the sugar binding sites with methyl mannopyranoside, then cross-linking with glutaraldehyde (Pai, C. et al. J. Pharm. Sci. 81, 532-536, 1992). Continuous washing with cold acetate buffer will remove the bound sugar and Schiff base-linkages reduced with sodium cyanoborohydride. It may therefore be possible to introduce the drug directly into a lectin microparticle during the cross-linking process or afterwards by allowing the microparticles to swell in the presence of a concentrated solution of the drug. This system may be made isotonic with sodium chloride and an appropriate preservative added for ocular drug delivery. Similar formulations would be appropriate for the mouth and vagina.
  • liposomes The ophthalmic use of liposomes has been well reported in the literature e.g. to deliver triamcinolone acetonide (Singh K., Mezei, M. Int. J. Pharm. 16, 1993, 339-344) and pilocarpine HC1 (Benita S. et al., J. Microencapsulation 1, 1984, 203-216).
  • the formulation and therapeutic effects of liposomes for local and systemic delivery of drugs has been well documented.
  • proteoliposomes containing a derivative of Concanavalin A has been reported (Francis S.E. et al. Biochimica et Biophyscia Act, 1062, 1991, 117-122). It would therefore seem reasonable to combine the two technologies to produce liposomes that will bind to ocular, oral and vaginal surfaces, using the lectins identified in our studies.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On décrit un système d'apport en médicament comprenant une lectine ainsi qu'un agent pharmacologiquement actif dans lequel l'agent actif est lié de manière détachable à la lectine. On a découvert que la lectine se lie de manière sélective aux glycoprotéines, par exemple à l'intérieur de la cornée de l'÷il, ce qui permet ainsi d'y apporter de manière sélective un médicament.
PCT/GB1994/000806 1993-04-16 1994-04-15 Systeme d'apport en medicament WO1994023752A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU65100/94A AU6510094A (en) 1993-04-16 1994-04-15 Drug delivery system
GB9523475A GB2292887B (en) 1993-04-16 1994-04-15 Drug delivery system

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9307904.4 1993-04-16
GB939307904A GB9307904D0 (en) 1993-04-16 1993-04-16 Drug delivery system
GB939324682A GB9324682D0 (en) 1993-12-01 1993-12-01 Drug delivery system
GB9324682.5 1993-12-01

Publications (1)

Publication Number Publication Date
WO1994023752A1 true WO1994023752A1 (fr) 1994-10-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005267A2 (fr) * 1995-07-26 1997-02-13 Maxim Pharmaceuticals Apport de polynucleotides dans les muqueuses
EP0819008A1 (fr) * 1995-05-30 1998-01-21 Lectin Biopharma, Inc. Methode d'utilisation de lectines dans la prevention et le traitement de maladies et d'affections de la peau
WO2003103717A1 (fr) * 2002-06-11 2003-12-18 Cambridge Biotechnology Ltd Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000076A1 (fr) * 1991-06-24 1993-01-07 Minnesota Mining And Manufacturing Company Systemes d'excipients pour medicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000076A1 (fr) * 1991-06-24 1993-01-07 Minnesota Mining And Manufacturing Company Systemes d'excipients pour medicaments

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0819008A1 (fr) * 1995-05-30 1998-01-21 Lectin Biopharma, Inc. Methode d'utilisation de lectines dans la prevention et le traitement de maladies et d'affections de la peau
EP0819008A4 (fr) * 1995-05-30 2002-04-03 Lectin Biopharma Inc Methode d'utilisation de lectines dans la prevention et le traitement de maladies et d'affections de la peau
WO1997005267A2 (fr) * 1995-07-26 1997-02-13 Maxim Pharmaceuticals Apport de polynucleotides dans les muqueuses
WO1997005267A3 (fr) * 1995-07-26 1997-04-24 Maxim Pharmaceuticals Apport de polynucleotides dans les muqueuses
WO2003103717A1 (fr) * 2002-06-11 2003-12-18 Cambridge Biotechnology Ltd Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage

Also Published As

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GB9523475D0 (en) 1996-01-17
AU6510094A (en) 1994-11-08
GB2292887B (en) 1997-05-07
GB2292887A (en) 1996-03-13

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