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WO2008014610A1 - Compositions permettant de délivrer des médicaments et procédés pour les préparer et les utiliser - Google Patents

Compositions permettant de délivrer des médicaments et procédés pour les préparer et les utiliser Download PDF

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Publication number
WO2008014610A1
WO2008014610A1 PCT/CA2007/001354 CA2007001354W WO2008014610A1 WO 2008014610 A1 WO2008014610 A1 WO 2008014610A1 CA 2007001354 W CA2007001354 W CA 2007001354W WO 2008014610 A1 WO2008014610 A1 WO 2008014610A1
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WIPO (PCT)
Prior art keywords
drug
matrix
composition
solution
water
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Ceased
Application number
PCT/CA2007/001354
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English (en)
Inventor
Dean-Mo Liu
Dorna Hakimi-Mehr
Mao-Jung Maurice Lien
Doug Smith
Wladyslaw Budzynski
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MIV Therapeutics Inc
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MIV Therapeutics Inc
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Publication of WO2008014610A1 publication Critical patent/WO2008014610A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • This application relates to compositions formulated for delivery of drugs. This application also relates to methods of forming the compositions and using the compositions for drug delivery.
  • a mesoporous oxide film is used in order to act as a reservoir for the release of drug and also to improve adhesion between organic coatings and inorganic substrates.
  • silica or titania sol-gel are mixed with an organic (triblock copolymers) template and are deposited on a substrate, such as a cardiovascular stent.
  • the organic template and the solvents are further removed, resulting in a mesoporous structure having a pore size between 2 to 20 nm.
  • the mesoporous coating is impregnated with the therapeutic agent, namely paclitaxel or sirolimus, by dip coating in the drug solution or by spraying the drug solution onto the coating.
  • the therapeutic agent namely paclitaxel or sirolimus
  • W02005089825 describes the application of a ceramic porous coating on the surface of a medical device, namely a stent.
  • the porous coating acts as a reservoir for the drug and a polyelectrolyte multilayer, deposited on the surface of the porous coating, regulates the release of drug.
  • the therapeutic agent can also be encapsulated within the multilayer coating.
  • a poly(dimethylsiloxane)-silica, organic-inorganic, composite coating was prepared by Gao et al (Gao Z, Nahrup JS, Mark JE, Sakr A., Journal of Applied Polymer Science; 2005, 96: 494-501 ) for the controlled delivery of drugs.
  • the composite is mixed with channeling agents such as poly( ethylene glycol) in order to produce porosity for the drug release.
  • the final composition is further deposited on the surface of drug tablets to control the release of drugs.
  • EP1319416 discloses the use of a porous metallic stent with the porous surface coated with a ceramic material in order to improve the stability of the stent.
  • a pharmaceutical agent is further deposited in the porous surface and is covered by a polymer barrier layer to control the drug diffusion.
  • the polymer coating may also contain drugs which are released in a controlled manner.
  • W09952471 describes the use of thin film iridium oxide on a stent.
  • the oxide film is thin enough to be able to undergo significant stress during stent crimping and expansion.
  • a biodegradable coating may be applied on the oxide layer in order to deliver drugs.
  • a drug delivery composition comprising a non-polymeric, solidified matrix comprising matrix material selected from an organic metal salt and silica; and a drug dispersed in the matrix.
  • the matrix may also include titania.
  • the invention also relates to medical devices and pharmaceutical preparations comprising the composition and methods of formulating and using the composition to achieve gradual drug elution.
  • One embodiment provides a method of forming a drug delivery composition comprising: (a) providing a drug;
  • Another embodiment provides a drug delivery composition comprising:
  • Figure 1 is a schematic view showing a drug delivery composition coating an implantable medical device, in accordance with one embodiment of the invention
  • Figure 2 is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention
  • Figure 3 are photographs of (A) an aqueous matrix solution comprising a dispersing agent and a matrix material, and (B) a solution comprising paclitaxel drug dispersed in the matrix solution;
  • Figure 4 is a is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention.
  • Figure 5 is a is a flowchart illustrating a multi-step procedure for formulating a drug delivery composition in accordance with one embodiment of the invention
  • FIG. 6 is a scanning electron micrograph of paclitaxel drug nanoparticles embedded within a silica matrix; the drug particles have a spherical geometry and are each within a size range of approximately 100 nm - 200 run in diameter;
  • Figure 7 is a scanning electron micrograph of paclitaxel drug nanoparticles embedded within an organic salt matrix; the drug particles have an acicular geometry and are each within a size range of approximately 50 nm - 300 nm in length and approximately 100 nm - 200 nm in diameter; and
  • FIG. 8 is a graph of cumulative release of paclitaxel ( ⁇ g, y-axis) versus time (min., x-axis).
  • composition 10 includes a solid non- polymeric matrix 12.
  • matrix 12 is composed of a matrix material comprising an organic metal salt or silica, or a combination thereof.
  • Matrix 12 may also include a plurality of different organic metal salts in one embodiment.
  • matrix 12 may also include titania.
  • a therapeutic agent such as a drug 14 is dispersed in matrix 12 in particulate or molecular (i.e. fully dissolved) form.
  • the matrix material may encapsulate or physically entrap each particle of drug 14.
  • drug 14 may be dispersed relatively uniformly in matrix 12.
  • composition 10 may be applied as a coating on a substrate 18, such as an implantable medical device.
  • substrate 18 may include a biocompatible layer 20 on an outer surface thereof.
  • composition 10 may be deployed as a pharmaceutical preparation adapted for oral, injection, inhalation or topical administration.
  • composition 10 is shown schematically in Figure 2.
  • the drug to be delivered is water-insoluble.
  • many anti-thrombosis, anti-proliferative and anti-cancer drugs are water-insoluble.
  • a water- insoluble drug is paclitaxel.
  • the first step in the process is to dissolve the water-insoluble drug in a solvent to form a drug solution 22.
  • the solvent may be immiscible or only slightly miscible in water.
  • suitable solvents include methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, and xylenes.
  • the amount of drug dissolved in solution 22 may vary between about 5 - 20 weight percent.
  • a water-based solution 24 which includes a dispersing agent.
  • suitable dispersing agents include polysorbates, chitosan, didodecyldimethylammonium bromide (DMAB), dextranes, and mixtures thereof.
  • a typical amount of the dispersing agent that is effective for achieving a stable drug suspension can be in the range of 0.1 to 50 weight percent of the drug.
  • the amount of the dispersing agent may vary depending upon the size of drug particles required. A higher amount of the dispersing agent is typically required for drug particles less than 2 micrometers in diameter. In particular embodiments of the invention the drug particles are within the range of about 1 nm - 3000 nm in diameter.
  • Solutions 22 and 24 may be mixed in a high-speed homogenizer or other homogenization device for a time period long enough to completely remove the solvent by natural or forced evaporation. In the case of forced evaporation, a mild heating or vacuum can be applied. As shown in Figure 2, the homogenization process yields a drug colloidal suspension 26.
  • matrix solution 28 is prepared by dissolving organic metal salt(s) or silica precursor(s) or a combination thereof in an aqueous solvent. Additionally or alternatively titania precursors) may be dissolved in the aqueous solvent.
  • solution 28 may contain a mixture of water and alcohol. Typically the concentration of the alcohol is at or below 30 weight percent of matrix solution 28 and more particularly below 20 weight percent. The concentration of the organic metal salts, silica precursor(s), or titania precursor(s) in matrix solution 28 can vary within a range from 0% to 100%.
  • organic metal salts include calcium gluconate anhydrate, magnesium gluconate anhydrate, magnesium gluconate dihydrate, calcium lactate gluconate, calcium gluconate monohydrate, calcium saccharate tetrahydrate, calcium folinate, tricalcium citrate tetrahydrate, ferrous gluconate anhydrate, ferrous gluconate dehydrate, and monosodium citrate anhydrate.
  • organic metal salts may be selected that are weakly soluble in water at physiological temperatures. As used in this patent application, "weakly soluble" means that the organic metal salt has less than 10% solubility in water at physiological temperatures. In one embodiment the solubility of the salt in water is less than 5% and more preferably less than 3%.
  • salt ionic species should be selected that will not likely cause significant adverse effects when composition 10 is administered to humans.
  • aluminum ions should be avoided.
  • the salt ionic species may include both monovalent and divalent forms acceptable for administration to humans.
  • the organic metal salts may be in monomeric and oligomeric forms.
  • Suitable silica precursors for inclusion in matrix solution 28 include silicon alkoxides, such as tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), or silanols such as monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, and diethyl silane diol.
  • TEOS tetraethyl orthosilicate
  • TMOS tetramethyl orthosilicate
  • silanols such as monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, and diethyl silane diol.
  • silica precursors can also include other precursors or derivatives such as silicates, e.g. sodium silicate, colloidal silica, or a combination thereof.
  • the silica precursors can form more than 50 weight percent of matrix solution 28.
  • the next step in the formulation process in this example is to mix drug colloidal suspension 26 with matrix solution 28 to thereby form a liquid precursor solution 30 of composition 10 (see Figure 1 ).
  • Precursor solution 30 comprises drug 14 dispersed in matrix solution 28 as discussed above. This process is sometimes referred to herein as in situ encapsulation. For example, if drug 14 is nanoparticulate, nanoparticles of drug 14 may become physically entrapped or encapsulated in the matrix material during this mixing step.
  • Figure 3A illustrates a matrix solution 28 of dispersing agent (e.g., didodecyldimethylammonium bromide) and precursor (e.g., calcium gluconate anhydrate).
  • Figure 3B illustrates the matrix solution mixed with the drug colloidal suspension 26 to yield precursor solution 30.
  • the drug 14 namely 1 weight percent paclitaxel, remains stably suspended in precursor solution 30 in nanoparticulate form for greater than 24 hours.
  • Precursor solution 30 may be applied as a coating to a substrate 18 in a liquid form and allowed to dry to form a solidified composition 10.
  • the solidified matrix is porous.
  • the porous matrix is nanoporous, having pores ranging fromi nm to 1000 nm, e.g., from 1 nm to 500 nm.
  • substrate 18 may be an implantable medical device, such as a stent.
  • the coating may be applied to an outer biocompatible layer 20 of substrate 18 ( Figure 1 ).
  • liquid precursor 30 may be deployed in many other alternative means.
  • precursor solution 30 may optionally be combined with a pharmaceutically acceptable carrier to formulate a drug delivery product suitable for therapeutic or prophylactic administration.
  • composition 10 may include a lipid layer 16 applied to matrix 12 once it has solidified as shown in Figures 1 and 2.
  • Lipid layer 16 may serve to soften and lubricate the surface of matrix 12 to facilitate intravascular or other means of in vivo administration.
  • lipid layer 16 may serve to protect drug 14 from degradation by digestive acids.
  • the lipid forming lipid layer 16 may be a small molecule rather than a macromolecular lipid or polymeric lipid. Suitable lipids include oleic acid, vegetable oils, stearic acid, beeswax, 12-hydroxystearic acid, glycerol behenate, hydrogenated castor oil, hydrogenated soybean oils, phospholipids, soybean lecithin, and mixtures thereof.
  • Lipid layer 16 may be water-insoluble, biocompatible and enzymatically biodegradable in vivo to enable gradual exposure of matrix 12 and hence release of drug 14 as described further below.
  • the thickness of layer 16 may vary depending upon the degradation rate and the length of time the coating is required. For example, layer 16 may vary in thickness between about a few hundred nanometers and a few micrometers.
  • the physical characteristics of composition 10, such as the size, morphology and distribution of the nanoparticles of drug 14, may be varied or "tuned" depending the particular make-up of matrix 12.
  • Figure 6 and 7 show drug 14, namely paclitaxel nanoparticles, substantially uniformly distributed in a matrix 12 of silica, which was prepared in a manner similar to the method of Example 1 , below.
  • Figure 6 is an SEM picture of a resulting silica matrix containing paclitaxel.
  • Figure 7 is an SEM picture of matrix comprising organic metal salts, e.g., calcium gluconate anhydrate, with a dispersing agent (e.g., didodecyldimethylammonium bromide) and precursor (e.g., calcium gluconate anhydrate) and further containing paclitaxel.
  • organic metal salts e.g., calcium gluconate anhydrate
  • a dispersing agent e.g., didodecyldimethylammonium bromide
  • precursor e.g., calcium gluconate anhydrate
  • the size and morphology of the dispersed drug may be altered by adjusting the relative amounts of organic metal salts and silica forming the matrix composite.
  • the amount and distribution of drug 14 within matrix 12 of composition 10 may also be readily controlled by varying other process parameters including the concentration of the matrix material within matrix solution 28, the drying rate (natural or forced), and the particular coating process employed (e.g. dipping, spinning, or spraying).
  • the particle size of drug 14 may be manipulated to range between about 1 run to 3,000 run, or more particularly between about 10 run to 2,000 nm.
  • the concentration of drug 14 may vary depending upon the process parameters selected and the particular application. In one example the concentration of drug 14 may be increased up to about 80 weight percent of matrix 12 when in the solidified form.
  • Figure 4 illustrates an alternative process for manufacturing a composition 10 where drug 14 is incorporated in matrix 12 in a molecular (i.e. fully dissolved form) rather than a particulate form.
  • the process of Figure 4 is generally similar to the process of Figure 2 except that the drug 14 is water-insoluble and the formation of a drug colloidal suspension 28 in the presence of water is not required.
  • (precursor) matrix solution 28 forms a clear solution rather than a suspension (since drug 14 is in molecular form).
  • the water-insoluble drug can be dissolved in an alcohol and/or another organic solvent such as tetrahydrofuran or methylene chloride to form drug solution 22.
  • the dispersing agent may or may not be added to matrix solution 28.
  • suitable dispersing agents include polysorbates, chitosan, didodecyldimethylammonium bromide (DMAB), dextranes, and mixtures thereof.
  • Matrix solution 28 may be prepared from silica precursors such as, but not limited to, tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), monomethyl silane triol, dimethyl silane diol, trimethyl silanes, ethyl silane triol, and diethyl silane diol in acid water, and may be hydrolyzed before or after addition of drug solution 22.
  • the molar ratio of the silanols to water may vary, in one embodiment, between about 1 :4 to 1 :8 to minimize the amount of water and thereby inhibit precipitation of the drug.
  • Matrix solution 28 can be further diluted in alcohol or a solvent miscible with water such as ethyl alcohol or tetrahydrofuran. An organic metal salt may then be optionally added to the hydrolyzed silanol. The matrix solution 28 thus formed is permitted to age for about one day or more. The aging process can ensure that all hydrolysis and condensation reactions are fully completed (this process may occur either before or after drug 14 is added). [38] In this example, the drug solution 22 and matrix solution 28 are then mixed directly together to form coating 30 containing the drug in molecular rather than particulate form. The ratio of solvent/alcohol to water may be adjusted to ensure the solubility of drug 14 in precursor solution 30 (e.g. 20:1 ). Coating 30 may be a liquid or solid and may be further aged before application as a coating on a medical device or spray application of matrix particles for drug delivery.
  • water such as ethyl alcohol or tetrahydrofuran.
  • An organic metal salt may then be optionally added to the hydro
  • the physical microstructure of the silica matrix 12 and the entrapment of the drug inside the nanoporous structure of the matrix 12 will limit the crystallization of the drug.
  • the relative hydrophilicity and hydrophobicity of matrix 12 can be adjusted by changing the molar ratios of the components.
  • ethyl trimethoxysilane, methyl triethoxysilane, trimethylethoxy silane, triethylethoxy silane can be used in combination with TMOS and/or TEOS in the ratio range of 1-4:1 in order to produce the matrix 12.
  • Replacing TMOS or TEOS with the above-mentioned compounds can directly modify the chemistry of the pore-walls and can impart hydrophobic properties to the otherwise hydrophilic silica matrix 12.
  • a further alternative process for manufacturing a composition 10 incorporates drug 14 in matrix 12 in molecular rather than particulate form.
  • the drug is water soluble.
  • the water-soluble drug can be directly added into the matrix solution 28 for a subsequent shape-forming process (not shown), or, as shown in Figure 5, it may be dissolved in water first to form an aqueous drug solution 22A and then added to matrix solution 28. No non-aqueous solvent is used in this example.
  • the water-soluble drug can be physically encapsulated into the final salts or silica matrix 12 (see Figure 1) in molecular form or in form of small drug particles produced by recrystallization of drug within the microstructure of matrix 12 after water is removed.
  • a coating 30 is then formed
  • composition 10 may be deployed to a target location in vivo.
  • composition 10 may be coated on a stent substrate 18 and delivered to a target intravascular location.
  • Aqueous body fluids at the target location will penetrate the porous structure of matrix 12 and cause gradual release of drug 14.
  • the body fluids e.g. containing enzymes
  • the body fluids may first gradually degrade the lipid layer 16.
  • drug 14 since drug 14 is dispersed within matrix 14 in particulate or molecular form, there is a high surface area of drug 14 in contact with the body fluids, allowing the controlled release of the drug via inward-diffusion (of body fluid) and outward-diffusion (of dissolved drug molecules).
  • the mechanism of release of drug 14 from matrix 12 is governed by the diffusion of water or other aqueous media into the pores of the matrix 12 and subsequent dissolution and diffusion of drug 14 to the surface.
  • the relative hydrophilic and hydrophobic properties of matrix 12 will affect the diffusion rate of water into the porous structure and therefore influence the rate of release of drug 14.
  • the chemistry of the matrix material or precursors thereof will also influence the microstructure of the matrix 12, (e.g. pore size and volume) which will further affect the size, morphology, and crystallization of drug 14.
  • Example 1 The solution of Example 1 was spray coated on a stainless steel coronary stent to achieve a coating weight of about 100 ⁇ g.
  • Example 3 [44] The coated stents of Example 2 were placed in 9 ml_ PBS solution and were rotated at a speed of 20 rpm in a water bath at 37 0 C. Samples of the solution were taken at various time points and were analyzed using reverse phase high performance chromatography (HPLC).
  • HPLC reverse phase high performance chromatography
  • the system used is a Varian ProStar HPLC with dual pumps, uv detection and an autosampler.
  • the stationary phase is an L43 PFP 250x4.3mm Taxsil column (Varian), kept at a temperature of 30 0 C.
  • the mobile phase is acetonitrile:water (52:48), with an isocratic flow rate of 1 ml/min.
  • FIG. 8 shows the release profile of paclitaxel from the coated stents as a graph of cumulative paclitaxel ( ⁇ g, y-axis) versus time (min., x- axis). It can be seen that after an initial burst release, the drug is released steadily over time.

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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Inorganic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition permettant de délivrer un médicament, ladite composition comprenant une matrice non polymère solidifiée et un médicament dispersé dans la matrice. Le matériau constituant la matrice comprend un sel métallique organique ou de la silice ou du dioxyde de titane, ou l'une de leurs combinaisons. Selon l'un des modes de réalisation de l'invention, le médicament est dispersé de façon sensiblement uniforme sous forme particulaire dans la matrice. Le matériau de la matrice encapsule les particules de médicament et contrôle leur libération in vivo. Une couche lipidique biodégradable peut éventuellement être appliquée sur la matrice. Ladite composition permettant de délivrer un médicament peut être appliquée sur la surface d'un dispositif médical tel qu'une endoprothèse cardiovasculaire, ou elle peut être formulée en tant que préparation pharmaceutique administrable sous d'autres formes. L'invention concerne également des procédés de formation de ladite composition, ces procédés permettant d'encapsuler in situ des médicaments hydrosolubles et non hydrosolubles.
PCT/CA2007/001354 2006-08-04 2007-08-01 Compositions permettant de délivrer des médicaments et procédés pour les préparer et les utiliser Ceased WO2008014610A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same
CN114441699A (zh) * 2020-10-30 2022-05-06 江苏正大丰海制药有限公司 一种同时测定葡萄糖酸钙注射液中葡萄糖酸钙与葡萄糖二酸钙含量的方法

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