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WO1994003269A1 - Microbilles en matieres polyhydroxyliques - Google Patents

Microbilles en matieres polyhydroxyliques Download PDF

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Publication number
WO1994003269A1
WO1994003269A1 PCT/GB1993/001692 GB9301692W WO9403269A1 WO 1994003269 A1 WO1994003269 A1 WO 1994003269A1 GB 9301692 W GB9301692 W GB 9301692W WO 9403269 A1 WO9403269 A1 WO 9403269A1
Authority
WO
WIPO (PCT)
Prior art keywords
microspheres
polyhydroxylic
polysaccharide
microsphere
cross
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/GB1993/001692
Other languages
English (en)
Inventor
Paul Finch
Chui Sheung Leung
Ann Denise Wheeler
Helmut Weigel
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.)
Royal Holloway and Bedford New College
Bedford New College
Original Assignee
Royal Holloway and Bedford New College
Bedford New College
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 Royal Holloway and Bedford New College, Bedford New College filed Critical Royal Holloway and Bedford New College
Publication of WO1994003269A1 publication Critical patent/WO1994003269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A61K49/0414—Particles, beads, capsules or spheres
    • A61K49/0419—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking

Definitions

  • the present invention relates generally to microspheres of polymeric material, particularly of a polyhydroxylic material, especially but not exclusively of polysaccharide, and to methods for their synthesis and derivatisat on.
  • Biodegradable polymeric microspheres have been developed in recent years for use in medicine. They are particularly useful as jLri vivo carriers for drugs or diagnostic agents which may be covalently bound thereto and/or encapsulated therein or may even be an integral part of the polymer itself.
  • One way in which these microspheres can be made is by an emulsion preparative technique. An aqueous solution of the polymer is dispersed as micelles in an organic phase and the polymer then cross-linked to form water-insoluble microspheres.
  • the polysaccharide is reacted via its hydroxyl groups with an aliphatic chloroepoxide to yield microspheres of the polysaccharide having ether-bonded cross-linking bridges of a hydroxyl-substituted straight or branched chain aliphatic saturated hydrocarbon.
  • these cross linking bridges include -OCH 2 -CH(OH)CH2 ⁇ -,
  • microsphere synthesis involves first reaction of a polysaccharide with a glycidyl ester or acyl chloride of acrylic acid followed by a free radical polymerisation to form the cross-linking bridges. If necessary, the microspheres can then be activated, in order to form covalent links with appropriate drugs/diagnostic agents.
  • this reagent can be employed in an emulsion preparation to cross-link and simultaneously activate the hydroxyl groups of polyhydroxylic materials, e.g. polysaccharides , in aqueous micelles to form activated microspheres in one reaction step.
  • polyhydroxylic materials e.g. polysaccharides
  • the polyhydroxylic material is cross- linked as well as activated for further reaction in one single step, instead of the previous two.
  • Phosgene and ethylchloroformate can also be similarly utilised and the invention includes the use of such materials.
  • a method of making reactive polyhydroxylic microspheres which comprises the steps of preparing an emulsion of an aqueous solution of the polyhydroxylic material in an organic solvent, and treating the emulsion with 1 , 1' -carbonyldiimidaxole , phosgene or ethylchoroformate to form cross-linked water-insoluble microspheres.
  • the invention also includes reactive polyhydroxylic microspheres cross-linked by using 1 , 1 '-carbonyl ⁇ diimidazole, phosgene or ethylchloroformate.
  • the cross-linking agent e.g. 1,1'- carbonyldiimidazole activates the hydroxyl groups of the polyhydroxylic material in the aqueous micelles to form P-O-CO-N2C3H3 (where P is the polyhydroxylic backbone). Subsequent displacement of the imidazole group by the oxygen atom of another hydroxyl group of the polyhydroxylic material can lead to the formation of carbonate as the cross-linker.
  • the provision of the diester of carbonic acid as a cross-linking group i.e.
  • one single carbon atom as the cross-linking bridge has the advantage over prior art bridges of being more susceptible to chemical or enzymic hydrolysis to form carbon dioxide and glucose. Consequently, it is to be expected that upon degradation of these microspheres iji vivo no aliphatic hydrocarbon chains will remain as residue. In contrast, the breakdown of polysaccharide microspheres made by prior art methods can result in fragments containing glucose units attached to hydrocarbon chains of varying length which are only degraded slowly ij vivo.
  • the preferred polyhydroxylic material for the microspheres of the invention is polysaccharide material, and the preferred cross-linking/activating agent is 1,1'- ⁇ carbonyldiimidazole (hereinafter "CDI").
  • CDI 1,1'- ⁇ carbonyldiimidazole
  • the cross-linking agent is brought into contact with an emulsion of an aqueous solution of the polysaccharide in an organic solvent.
  • the emulsion is prepared by firstly mixing the surfactant and organic solvent, and then adding the aqueous solution of polysaccharide and homogenising the mixture.
  • the polysaccharide is thus held within aqueous micelles encased by surfactant molecules, and the surfactant molecules form a stable emulsion of the aqueous micelles in the organic solvent.
  • the subsequent addition of cross- linker provides cross-linking bridges between the polysaccharide molecules within each aqueous micelle to form a cross-linked microsphere in each micelle.
  • the spherical shape and limited size range (e.g. 0.5 microns to 2 microns dry) of the microspheres are dictated by the forms of the aqueous micelles which are, in turn, determined by the molar ratio of surfactant to water in the reaction chamber. Both ionic and neutral surfactants can be used, and the solvent will generally be chosen in dependence on the surfactant.
  • the polysaccharide microspheres so formed may be derivatised by direct reaction with nucleophiles such as primary or other amines e.g. alkyl amines, aryl amines, arylalkyl amines, or other nucleophiles such as alkyl alcohols, aryl alcohols or alkyl thiols.
  • nucleophiles such as primary or other amines e.g. alkyl amines, aryl amines, arylalkyl amines, or other nucleophiles such as alkyl alcohols, aryl alcohols or alkyl thiols.
  • the derivatisation process may be carried out with or without first isolating the microspheres from the other emulsion constituents.
  • the nucleophilic substituent bound to the microsphere in the derivatisation process may comprise, for example, a drug, protein, or a diagnostic agent such as an X-ray opaque substance. Release of the substance carried by the microsphere may be effected by enzymic hydrolysis of the polysaccharide comprising- the microsphere. Instead of covalently binding the drug or diagnostic agent to the microsphere, the microsphere could be formed encapsulating the drug or diagnostic agent. In this case, release could be effected simply by diffusion. Furthermore, the drug/diagnostic agent could even form an integral part of the polysaccharide itself.
  • the reaction mixture can be advantageous to include in the reaction mixture one or more bi- or polyfunctional reactive compounds in addition to the CDI and the polysaccharide.
  • These compounds can, for example, act to extend the length of the cross-linking bridges which can improve biodegradability provided the compound itself is appropriately chosen.
  • Polyols are generally useful, of which glycerol is one example.
  • the compounds it is also possible for the compounds to react to increase the number of hydroxyl groups in the polysaccharide and thus the number of CDI units linked thereto, so making the cross-linked microspheres more active for bonding to other substances.
  • the polysaccharide microspheres of the invention as freshly prepared contain reactive groups, evg. carbonyl imidazole groups. Furthermore, even after derivatisation, there may be a few such groups still remaining. These reactive groups can be selectively removed if desired by raising the pH, eg. to about pH 10.
  • polysaccharide chosen for the formation of the microspheres should suit the intended application.
  • microspheres of cellulose derivatives might be adequate if diffusion release were intended.
  • Starch is generally the most preferred polysaccharide but other potentially suitable polysaccharides include, for example, starch derivatives, dextran, heparin and hyaluronic acid.
  • an iron-containing polysaccharide would be useful.
  • the reactive microspheres of the invention can be stored in an organic solvent and then brought into contact with a nucleophile as desired. Alternatively, and more preferably, the reactive microspheres are stored lyophilised.
  • the derivatised microspheres can likewise be stored in suspension or lyophilised. If desired, the microspheres can be successfully sterilized by, for example, autoclaving or ⁇ -irradiation.
  • Example 1 describes starch microsphere synthesis and isolation
  • Example 2 describes derivatisation of the isolated starch microspheres
  • Example 3 describes starch microsphere synthesis and derivatisation without isolation of the activated microspheres
  • Example 4 describes selective removal of carbonylimidazole groups from activated microspheres
  • Examp.le-5 illustrates sterilisation.
  • Figure 1 is an electron micrograph of the starch microspheres of Example 1
  • Figure 2 is an electron micrograph of the X-ray opaque iodine-containing starch microspheres of Example 3.
  • aqueous solution of starch (10%, 10ml), having a molecular weight of 10,000, is homogenised for 3 min. with ethylene dichloride (100 ml) and Gafac PE510 (trade mark; 2.5 g), acting as surfactant, using as agitator the Ultra- Turrax T25 at a speed of 13,500 rp .
  • a solution of 1,1'- carbonyldiimidazole (1 g) in ethylene dichloride (25 ml) is added in portions to the emulsion at room temperature with stirring. The reaction mixture is stirred for a further 30 min. Acetone (400 ml) is added to precipitate the starch.
  • Activated starch microspheres (100 mg) are suspended in dioxan (4 ml). The suspension i> sonicated for 30 min. A solution of methyl 3-amino-2,4,6-triiodpbenzoate (250 mg) in dioxan (4 ml) is added and the mixture stirred at room temperature for -16 h. The mixture is centrifuged-at 2750g and the sediment washed with dioxan (3 x 50 ml) and water (3 x 50 ml). Freeze-drying affords pale mauve coloured spheres (100 mg). Alkaline hydrolysis, followed by spectroscopic analysis shows the spheres to contain 12% iodine. The material has no obvious toxic effect in rats.
  • a portion (1.5 g) of freeze-dried reactive starch microspheres of- the invention is dried in vacuo at 50°C. Its -CO.N2C3H3 content, is determined by complete hydrolysis, followed by colorimetric determination of the imidazole liberated.
  • Reactive starch microspheres from Example 1 or derivatised starch microspheres from Example 2 (100 mg) are suspended in water (50 ml) and autoclaved at 115°C for 15 min and at 121°C for 30 min. No significant change in the integrity of the spheres was observed by scanning electron microscopy.
  • Dried reactive starch microspheres (from Example 1) or derivatised starch micro-spheres (from Example 2) were subjected to ⁇ -irradiation with a dose rate of 2.5 megarads, No change in physical appearance was observed by scanning electron microscopy.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des microbilles polymères biodégradables à usage médical et autres qui se composent d'un polymère polyhydroxylique réticulé à l'aide de 1,1'-carbonyldiimidazole, de phosgène ou d'éthylchloroformate, lesdites microbilles étant directement réactives avec les nucléophiles. Les microbilles selon l'invention sont fabriquées par réticulation d'une émulsion aqueuse de ladite matière polymère à l'aide d'un des agents de réticulation mentionnés ci-dessus. Le polymère est généralement un polysaccharide, et les microbilles peuvent être directement liées à des produits tels que des médicaments, des protéines et d'autres réactifs diagnostiques.
PCT/GB1993/001692 1992-08-10 1993-08-10 Microbilles en matieres polyhydroxyliques Ceased WO1994003269A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929216925A GB9216925D0 (en) 1992-08-10 1992-08-10 Microspheres of polyhydroxylic materials
GB9216925.9 1992-08-10

Publications (1)

Publication Number Publication Date
WO1994003269A1 true WO1994003269A1 (fr) 1994-02-17

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PCT/GB1993/001692 Ceased WO1994003269A1 (fr) 1992-08-10 1993-08-10 Microbilles en matieres polyhydroxyliques

Country Status (2)

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GB (1) GB9216925D0 (fr)
WO (1) WO1994003269A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078358A3 (fr) * 1999-06-18 2001-06-14 Collaborative Group Ltd Microspheres d'acide hyaluronique pour le transfert continu de genes
WO2005061603A1 (fr) * 2003-12-17 2005-07-07 The Procter & Gamble Company Structures polymeres comprenant un systeme hydrophile/lipophile
US7426775B2 (en) 2003-12-17 2008-09-23 The Procter + Gamble Company Polymeric structures comprising a hydrophile/lipophile system
US11642415B2 (en) 2017-03-22 2023-05-09 Ascendis Pharma A/S Hydrogel cross-linked hyaluronic acid prodrug compositions and methods

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2220304A1 (fr) * 1973-03-09 1974-10-04 Bayer Ag
US3899602A (en) * 1972-09-11 1975-08-12 Nat Starch Chem Corp Inhibited starch products containing labile and non-labile cross-links
JPS6130502A (ja) * 1984-07-23 1986-02-12 Nippon Kayaku Co Ltd 土壌害虫防除剤
JPS6354385A (ja) * 1986-08-26 1988-03-08 Tosoh Corp 混合酸型重合性リン脂質誘導体及びその製造法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899602A (en) * 1972-09-11 1975-08-12 Nat Starch Chem Corp Inhibited starch products containing labile and non-labile cross-links
FR2220304A1 (fr) * 1973-03-09 1974-10-04 Bayer Ag
JPS6130502A (ja) * 1984-07-23 1986-02-12 Nippon Kayaku Co Ltd 土壌害虫防除剤
JPS6354385A (ja) * 1986-08-26 1988-03-08 Tosoh Corp 混合酸型重合性リン脂質誘導体及びその製造法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 15, 13 April 1987, Columbus, Ohio, US; abstract no. 116042b, MCCONWAY, M. G. ET AL: "Application of solid-phase antibodies to radioimmunoassay. Evaluation of two polymeric microparticles, Dynospheres and nylon activated by carbonyldiimidazole or tresyl chloride" *
DATABASE WPI Section Ch Week 8613, Derwent World Patents Index; Class A97, AN 86-084399 *
DATABASE WPI Section Ch Week 8815, Derwent World Patents Index; Class A11, AN 88-103090 *
J. IMMUNOL. METHODS, 95(2), 259-66, 1986 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078358A3 (fr) * 1999-06-18 2001-06-14 Collaborative Group Ltd Microspheres d'acide hyaluronique pour le transfert continu de genes
WO2005061603A1 (fr) * 2003-12-17 2005-07-07 The Procter & Gamble Company Structures polymeres comprenant un systeme hydrophile/lipophile
US7426775B2 (en) 2003-12-17 2008-09-23 The Procter + Gamble Company Polymeric structures comprising a hydrophile/lipophile system
US7714065B2 (en) 2003-12-17 2010-05-11 The Procter & Gamble Company Polymeric structures comprising a hydrophile/lipophile system
US8071203B2 (en) 2003-12-17 2011-12-06 The Procter & Gamble Company Polymeric structures comprising a hydrophile/lipophile system
US8137797B2 (en) 2003-12-17 2012-03-20 The Procter & Gamble Company Polymeric structures comprising a hydrophile
US8241738B2 (en) 2003-12-17 2012-08-14 The Procter & Gamble Company Polymeric structures comprising a sulfosuccinate
US8445100B2 (en) 2003-12-17 2013-05-21 The Procter & Gamble Company Polymeric structures comprising a sulfosuccinate
US8709585B2 (en) 2003-12-17 2014-04-29 The Procter & Gamble Company Polymeric structures comprising a siloxane
US9103051B2 (en) 2003-12-17 2015-08-11 The Procter & Gamble Company Polymeric structures comprising a sulfosuccinate
US11642415B2 (en) 2017-03-22 2023-05-09 Ascendis Pharma A/S Hydrogel cross-linked hyaluronic acid prodrug compositions and methods
US12246070B2 (en) 2017-03-22 2025-03-11 Ascendis Pharma A/S Hydrogel cross-linked hyaluronic acid prodrug compositions and methods

Also Published As

Publication number Publication date
GB9216925D0 (en) 1992-09-23

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