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WO2013009253A1 - Films de cellulose microfibrillée pour la libération contrôlée d'agents actifs - Google Patents

Films de cellulose microfibrillée pour la libération contrôlée d'agents actifs Download PDF

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Publication number
WO2013009253A1
WO2013009253A1 PCT/SE2012/050813 SE2012050813W WO2013009253A1 WO 2013009253 A1 WO2013009253 A1 WO 2013009253A1 SE 2012050813 W SE2012050813 W SE 2012050813W WO 2013009253 A1 WO2013009253 A1 WO 2013009253A1
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Prior art keywords
water
film
films
hpmc
mfc
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Ceased
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PCT/SE2012/050813
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English (en)
Inventor
Anette Larsson
Mikael Larsson
Johan HJÄRTSTAM
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Chalmers Tekniska Hogskola AB
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Chalmers Tekniska Hogskola AB
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Publication of WO2013009253A1 publication Critical patent/WO2013009253A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D101/00—Coating compositions based on cellulose, modified cellulose, or cellulose derivatives
    • C09D101/08—Cellulose derivatives
    • C09D101/26—Cellulose ethers
    • C09D101/28—Alkyl ethers
    • C09D101/284—Alkyl ethers with hydroxylated hydrocarbon radicals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/02—Cellulose; Modified cellulose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/26—Cellulose ethers
    • C08L1/28—Alkyl ethers
    • C08L1/284—Alkyl ethers with hydroxylated hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/06—Pectin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D189/00—Coating compositions based on proteins; Coating compositions based on derivatives thereof

Definitions

  • Drug delivery is a very important field when it comes to pharmacy.
  • Some substances may have disadvantages that may limit their clinical use, e.g. short in vivo half-lives and low oral bioavailability, which may result in the need for frequent administration of the active substance using different administration methods. Frequent administrations are inconvenient, and result in poor patient compliance and an oscillating drug concentration in the blood. These problems can be circumvented through the use of some sort of controlled release technology. Controlled release products provide prolonged delivery of a drug while maintaining its blood concentration within therapeutic limits.
  • Barriers around reservoirs are often used to control release of drugs, pesticides and herbicides. These barriers can have different physicochemical characteristics and chemical compositions, but it is essential that one can vary the transport and the permeation of the penetrant through the membranes and thus be able to control the release of the penetrant.
  • the barriers are made of water-insoluble materials.
  • One way to regulate the release rate is to add water-soluble agents to the barrier-forming solution. During exposure to water the water-soluble agent dissolves and leaves pores in the membrane. Thus generally, by regulating the number of pores in the barrier, the permeability of the barrier and the drug release can be controlled.
  • Micro fibrillated cellulose consists of long microfibrils produced by delamination of cellulosic fibres in high-pressure homogenizers. MFC is an extensively studied material since it is renewable and has desirable properties originating from its nano- and microstructures. Despite this, very few studies focus on the "wet applications" of MFC, and to the inventors' knowledge no studies are related to the permeability of, or diffusion in, MFC containing films in the wet state (dried films exposed to aqueous solutions).
  • MFC films have promising properties as an oxygen and air barrier, or even as an oil barrier (1)
  • MFC solutions form strong hydrogels even at low concentrations (2), and MFC has been shown to strongly augment composite hydrogel properties (3).
  • the present invention relates to films of water-insoluble microfibrillated cellulose (MFC; also known as cellulose nanofibrilles, nanofibril cellulose (NFC)) and/or whiskers (also known as nanocrystalline cellulose (NCC) or nanocellulose). These films would have a great potential in the controlled release area. Such controlled release mainly depends on the diffusion properties of the films, which in turn depends on the porosity and structure of the films. Films for controlled release are often made of one insoluble film-forming polymer and a pore-forming agent. We believe that it for first time has been shown that MFC might be used as the water-insoluble component in films for controlled release of e.g. drugs.
  • a well known class of pore-forming agents is water-soluble cellulose derivatives, such as hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC), which are commonly used in controlled release preparations, see for example U.S. 2009/0214642, US Patent No. 4,680,323 or S. Kamel et al. (4).
  • HPMC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPMC as the water-soluble (expected pore-forming) agent
  • the permeability of the film is on the contrary reduced upon contact with the aqueous solution. This is partly due to that HPMC interacts so strongly with the MFC film that it does not leave the film completely upon aqueous contact, but instead forms a gel inside the film that blocks the intrinsic pores of the MFC film so that the permeability decreases.
  • HPMC partially forms a gel inside the films and swells the films leading to longer pathway and lower permeability.
  • the formed multi-layered structure of the MFC-film also decreases the permeability of the film, the unique structure probably forming due to HPMC induced modification of the aggregation of MFC.
  • HPMC may be replaced by other hydrophilic polymers, such as HPC or chitosan, which would function in a similar way.
  • This low permeability of the films is very interesting from a controlled release perspective, rendering many possible applications. . It would therefore be interesting to use MFC-containing films, with a content of water-soluble agent from 1-80%, for controlled release of e.g. drugs. Even though including a water-soluble agent is preferred, it is believed that pure MFC films may also have potential in the controlled release area.
  • One traditional way of producing films for controlled release is to dissolve both the water-insoluble component (such as a water-insoluble polymer) and the water-soluble agent, like a hydrophilic polymer, in an organic solvent. During the film formation the solvent evaporates and the two polymers often phase separate into different regions, which gives rise to a film structure with insoluble and soluble regions. The structure of the water-soluble polymer in dry film will determine the pore structure of the film after exposure to water. Thus, the phase separation is critical for the final pore structure and thus also for controlling the release rates.
  • the polymers used for controlling films are synthetic or semi synthetic. If one could replace these with unmodified cellulose, which is a green biomaterial, it would be a benefit for society. In addition, the film formation process using MFC will not include pore formation, which will lead to more robust structures and ways to control the release rates.
  • Another traditional way to produce films for controlling the release rates is by using aqueous latex dispersions of insoluble polymer and sometimes dissolved hydrophilic agents.
  • the latex dispersions are stabilized by surfactants.
  • surfactants During the film formation the latex particles should coaleasce to form a film.
  • the film formation process includes some problems like migration of dispersion stabilizers.
  • a further difficulty with this process is that films formed using different process parameters and annealing temperatures and times will lead to differing results, different film annealing, and thus different release rates.
  • MFC, NFC or NCC would be advantageous from an environmental point of view.
  • the lack of surfactants in the water suspension during the film forming process would also avoid the problem of surfactant migration in the films. It is also likely that the film formation process when using eg. MFC, NFC or NCC would be more robust. Further, surfactant migration can cause problems if the material is used on a person's skin as surfactants often cause skin rash or dermatitis
  • barriers or films containing MFC would be beneficial from several aspects, such as environmental (MFC is renewable and there is no need for organic solvents), stability (more stable structure and permeability over time compared to latex particle films, whose permeability is affected by the time of storage) and better permeability control since the permeability is mainly due to the one-dimensional swelling compared to a pore structure through the film, and thus less sensitive to structural changes.
  • environmental MFC is renewable and there is no need for organic solvents
  • stability more stable structure and permeability over time compared to latex particle films, whose permeability is affected by the time of storage
  • better permeability control since the permeability is mainly due to the one-dimensional swelling compared to a pore structure through the film, and thus less sensitive to structural changes.
  • Patent application WO 10069046 relates to a method of controlling the dispersibility and barrier properties of dried forms of NCC in aqueous media by controlling the ionic strength and/or the pH of the aqueous media.
  • the application concerns barrier properties of NCC films in aqueous solutions, but does not relate to the area of pharmaceuticals or controlled release. Further, the usage of other additives to control the structure and permeability is not discussed. The application thus does not disclose the scope of the invention.
  • U.S. Patent No. 6,821,531 discloses the development of a powdered/microfibrillated cellulose excipient suitable for use as a filler-binder-disintegrant in the design and development of solid compacts and capsules, and as a drug carrier or bodying agent in the manufacture of dermatological products.
  • MFC is intended to be inside and fill the capsules, instead of being around the capsules as a controlled release film.
  • the cellulose disintegrates the tablet and thus speeds up the release but does not control or extend the drug release rate.
  • NCC drug delivery excipient.
  • the very large area and negative charge of NCC suggests that large amounts of drugs might be bound to the surface of this material with the potential for high payloads and optimal control of dosing.
  • NCC is thus used as a drug carrier. Rather than being used as a barrier/film around the drug, the drug is bound to the surface of the NCC.
  • the interaction between drugs and the surface of NCC will depend on ionic strength, the solvent and temperature used, which may lead to less robust drug release rates compared to barrier system where the effect of these parameters will have minor influence on the drug release rate.
  • the controlled release is due to surface interactions between NCC and the drug.
  • the paper describes prolonged release from a suspension in contrast to the present invention, which relates to controlled release from a well defined depot. Additionally, the paper discusses pure NCC, and thus relates to an ionic interaction between an active agent and NCC surface.
  • U.S. Patent No. 6,627,749 describes powdered oxidized cellulose as a drug carrier. It relates to the manufacture of powdered/microfibrillated oxidized cellulose suitable for use as an immobilizing matrix or a carrier for drugs.
  • the patent relates to the release from microparticles or pellets of the material, but does not use the cellulose as a barrier for controlled release, nor does it focus on the use of other exipients for modification of the material structure or release.
  • the cellulose that is used in this patent was oxidized, so that it contains pH sensitive acid groups, and thus showed a pH dependent behavior. In contrast, a pH dependence is not desired or expected for the present invention, where a constant behavior (permeability) is desired.
  • MFC might be used as the water-insoluble component in films for controlled release of e.g. drugs.
  • these films have excellent properties when it comes to permeability and permeability control, since the permeability may be controlled by the amount of the hydrophilic polymer or water- soluble agent.
  • the general purpose of the invention is to provide films comprising MFC, NFC and/or NCC (herein after referred to as MFC/NFC/NCC) providing controlled permeability of molecules or compounds.
  • MFC/NFC/NCC MFC/NFC/NCC
  • the ratio between MFC/NFC/NCC and other components in the film mixture can be used to control the permeability thereof.
  • a primary object of the invention is to provide mixtures of MFC and/or NFC and/or NCC and optionally a hydrophilic polymer, such as HPMC, to form films or barriers that control the permeability of molecules or active agents, such as drugs, water, pesticides, herbicides, taste-masking agents, flavourings, food additives, nutrients and vitamins.
  • a hydrophilic polymer such as HPMC
  • the ratio between MFC and HPMC may be used to control the permeability of the films.
  • HPMC may be replaced by other polymers with the ability to hydrate and swell, or with other agents that dissolve in water, such as lactose, but without the possibilities to swell.
  • Another object of the present invention is to use films or barriers comprising MFC and/or NFC and/or NCC for the controlled release of active agents, drugs, pesticides, herbicides, taste-masking agents, flavorings, food additives, nutrients and vitamins.
  • the invention is based on the surprising finding that, when using MFC and/or NFC and/or NCC as the insoluble component when preparing a film, the water-soluble (expected pore-forming) agent does not form pores in the barrier. Instead it is partially released upon contact with an aqueous solution, the part not released from the films remains due to interactions with the MFC/NFC/NCC.
  • Figure 1 shows a typical plot of the volume of radioactive labelled water that have diffused across the film at given time points, here for a sample with 50 % w/w HPMC and a thickness of 38 ⁇ .
  • Figure 4 shows percentage of HPMC released at different times for MFC-HPMC films with 20 % (x), 35 % (o) and 65 % (A) w/w HPMC.
  • Figure 5 (a-f) illustrates micrographs of MFC-HP MC films after preparation. Top are SEM images of films with: (a) 0 %, (b) 20 % and (c) 50 % w/w HPMC. Bottom are AFM images of films with: (d) 0 %, (e) 20 % and (f) 50 % w/w.
  • Figure 6 shows SEM images of swollen and freeze dried MFC HPMC films. Top row images are at a magnification of lOOOOX for samples with initial HPMC contents of (a) 0 %, (b) 20 % and (c) 50 % w/w. Bottom row is images are at a magnification of 100000X for samples with initial HPMC contents of (d) 0 %, (e) 20 % and (f) 50 % w/w.
  • Figure 7 shows a SEM image of the cross-section of a swollen and freeze dried MFC HPMC film having initial HPMC content of 50 % w/w.
  • Figure 8 illustrates a schematic drawing of the close to unidirectional swelling of a layered-structured film composed of non-swelling lamellas and swelling inter layer regions.
  • a schematic example is given of the tortuous path experienced by penetrants (illustrated as an orange spheres) crossing the film in the swollen state.
  • the present invention relates to barriers in the form of films of water-insoluble microfibrillated cellulose, MFC, also known as cellulose nanofibrilles or nanofibril cellulose (NFC), or whiskers, also known as nanocrystalline cellulose (NCC) or nanocellulose.
  • MFC water-insoluble microfibrillated cellulose
  • NFC nanofibrilles or nanofibril cellulose
  • NCC nanocrystalline cellulose
  • the general purpose of the invention is to provide films of MFC/NFC/NCC that decrease the permeability of molecules such as active agents, drugs, water, pesticides, herbicides, hygiene products, taste-masking agents, flavorings, food additives, food agents, food products, nutrients or vitamins, i.e. that functions as a barrier.
  • the ratio between MFC/NFC/NCC and water soluble agent can be used to control the permeability.
  • MFC may be replaced by nanocrystalline cellulose (NCC) or nanofibrillar cellulose (NFC). This means that MFC and/or NFC and/or NCC, i.e. mixtures of these in any combination, may be used as the water-insoluble component of the film.
  • MFC/NFC/NCC might be used without a water-soluble (hydrophilic) agent.
  • a well-known class of water-soluble pore-forming agents are cellulose derivates, such as hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC).
  • HPMC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl methyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • MFC/NFC/NCC as the water-insoluble component of a film
  • HPMC water-soluble (expected pore-forming) agent
  • the permeability of the film is on the contrary reduced upon contact with the aqueous solution. This is due to the fact that HPMC interacts so strong to the MFC/NFC/NCC film that it does not leave the film completely upon aqueous contact, but instead forms a gel inside the film that blocks the intrinsic pores of the
  • the film of MFC/NFC/NCC and HPMC can exhibit a layered structure.
  • the layered structure causes the film to swell unidirectionally, i.e. mostly increasing the film thickness, and causes a longer diffusive path for a penetrant when crossing the film. This further decreases the permeability of the film.
  • HPMC may be replaced by other hydrophilic polymers, such as HPC or, methyl cellulose, sodium carboxymethylcellolose, hydroxyethylcellulose, ethyl hydroxyethylcellulose or other modified hydrophilic cellulose derivatives, or modified starch, or chitosan, alginate or other water-soluble polysaccharides or chemically modified versions thereof, or polyacrylic acid, or polyethylene oxide, or polymethacrylates or povidone or polyethylene oxide or other water- soluble synthetic polymers, or salts of the above mentioned polymers, which would function in the same way.
  • the hydrophilic polymers listed above can also be crosslinked.
  • the inventors have the following three different hypotheses for the observed close to unidirectional swelling (increasing film thickness) and the observed decrease in permeability.
  • the film structure formed during the film creation is influenced by the addition of hydrophilic or water soluble agent in such a way that the MFC/NFC/NCC in the film forms a multi-layer structure.
  • the MFC/NFC/NCC is initially swollen by the swelling pressure from the water soluble component pushing the MFC/NFC/NCC layers apart, when the water soluble agent is released from the film the film maintains its swollen structure.
  • the film structure formed during the film creation is influenced by the addition of hydrophilic or water soluble agent in such a way that the MFC NFC/NCC in the films forms a multi-layer structure.
  • hydrophilic agent for example a crosslinked polymer
  • water soluble agent that interacts strongly with the MFC/NFC/NCC
  • the agent will not leave the film.
  • the agent will remain in the film and swell, leading to swelling of the film as a whole.
  • the difference from hypothesis 1 is that the swollen agent remains in the film.
  • the effect on permeability is derived from the swelling of the film, the structure of the film and any effects from the remaining hydrophilic or water soluble agent on diffusion inside the film.
  • the film structure formed during the film creation is influenced by the addition of hydrophilic or water soluble agent in such a way that the MFC/NFC/NCC in the film forms a multi-layer structure.
  • the water soluble agent for example non polymer salts
  • the water soluble agent would not swell.
  • agent do induce the formation of a multi-layered MFC/NFC/NCC structure the MFC/NFC/NCC film could swell by that water occupies the inter layer spaces and pushes the layers apart. Similar to hypothesis 1, the effect on permeability is for this hypothesis 3 derived from the swelling of the
  • hypothesis 3 motivates the use of water-soluble agents that are non swelling for achieving the desired effects of the innovation.
  • the phenomena according to these hypotheses could also occur simultaneously.
  • one part of a water soluble polymer could act according to hypothesis 1 , whilst another part could interact with the MFC/NFC/NCC, acting according to hypothesis 2.
  • the low permeability of the films according to the invention is very interesting from a controlled release perspective, rendering many possible applications in pharmaceutics, food products, pesticides, herbicides, hygiene products, medical devices, implants etc, and may be used in many forms such as; tablet coatings, pellet coatings, capsule coatings, on
  • microspheres controlled release layers etc.
  • films comprising MFC, with a content of water-soluble (hydrophilic) agent from 1-80% (w/w), such as 1% water-soluble agent, or 5%, or 10% or 15% or 20% or 25% or 30% or 35% or 40% or 45% or 50% or 55% or 60% or 65% or 70% or 75% or 80% (w/w) water-soluble agent, for controlled release of active agents, e.g. drugs.
  • the content water-soluble agent may vary in the interval from 1-80% (w/w), or 5-80% or 5-65% or 15-65% or 20-65% or 20-55% (w/w) water-soluble agent.
  • films comprising NFC, with a content of water- soluble (hydrophilic) agent from 1-50% (w/w), such as 1% water-soluble agent, or 5%, or 10% or 15% or 20% or 25% or 30% or 35% or 40% or 45% or 50% water-soluble agent, for controlled release of active agents, e.g. drugs.
  • the content water-soluble agent may vary in the interval from 1 -50% (w/w), or 5-50% or 5-40% or 15-40% or 20-35% or 20-35% (w/w) water-soluble agent.
  • films comprising NCC or whiskers, with a content of water-soluble (hydrophilic) agent from 1-50% (w/w), such as 1% water-soluble agent, or 5%, or 10% or 15% or 20% or 25% or 30% or 35% or 40% or 45% or 50% water- soluble agent, for controlled release of active agents, e.g. drugs.
  • the content water-soluble agent may vary in the interval from 1-50% (w/w), or 5-50% or 5-40% or 15-40% or 20-35% or 20-35%) (w/w) water-soluble agent.
  • films comprising MFC, NFC, whiskers or NCC, without any water-soluble (hydrophilic) agent for controlled release of active agents, e.g. drugs.
  • film means an object having a larger ratio between surface area and thickness, i.e. essentially two-dimensional. It can provided as a coating on an object or it can be free-standing, i.e. it can be handled as a separate object.
  • water soluble agent means an agent where a minimum of 1 g of the agent can be dissolved in 10000 g solvent.
  • hydrophilic polymer means a polymer that either is soluble in water according to the above definition or swells (absorbs water solutions) at least 10 % per dry weight of polymer.
  • the invention provides an absorbent composite comprising a superabsorbent polymer and cellulosic fibrils.
  • Superabsorbent materials are commonly understood as being crosslinked polymers with the capacity to absorb liquid many times their own weight upon swelling.
  • the cellulosic fibrils are nano fibrils.
  • nanofibrils means individual fibrils having a diameter equal to or less than 100 nm at all points along the nanofibril. The diameter may vary along its length.
  • the nanofibrils may exist as individual fibres and/or as clusters of nanofibrils.
  • nanofibrillated cellulose NFC
  • nanofibrils From nanofibrils one can produce “Whiskers”. These are a particular form of nanofibrils having an aspect ratio (length/width) of at least 2. Nanofibrils having a smaller aspect ratio do not qualify as whiskers.
  • microfibres means individual fibres having a diameter equal or greater than 100 nm but less than or equal to 100 ⁇ at all points along the microfibre. More specifically, the microfibres may have a diameter greater than 100 nm but less than or equal to 10 ⁇ or a diameter greater than 100 nm but less than or equal to 1 ⁇ .
  • the diameter may vary along the length of the microfibre.
  • the microfibres may exist as individual microfibres and/or as clusters of microfibres in the composite.
  • MFC microfibrillated cellulose
  • Microfibrillated cellulose may comprise a fraction of nanofibrils.
  • the composite does not contain cellulosic fibres having an average diameter greater than 100 ⁇ .
  • the absorbent composite may further comprise cellulosic microfibres having a diameter greater than 100 nm but less than or equal to 100 ⁇ . Additionally, the absorbent composite may comprise cellulosic microfibres having a diameter greater than 100 nm but less than or equal to 10 ⁇ .
  • Nanocrystalline cellulose (NCC) or cellulose whiskers are cellulosic material having dimensions less than 100 nm in any direction. The aspect ratio of whiskers should be least 2.
  • cellulosic refers to fibrils or fibres from natural sources such as woody and non-woody plants, regenerated cellulose and the derivatives from these fibres by means of chemical, mechanical, thermal treatment or any combination of these. Further, “cellulosic” also refers to cellulosic or cellulose-containing fibres produced by microorganisms.
  • polymer includes, but is not limited to, homopolymers, copolymers, such as for example, block, graft, random and alternating copolymers, terpolymers, etc. and blends and modifications thereof. Furthermore, unless otherwise specifically limited, the term
  • polymer shall include all possible configurational isomers of the material.
  • configurations include, but are not limited to isotactic, syndiotactic and atactic symmetries.
  • crosslinked is used herein to describe a material composed of linear polymer chains which have been submitted to crosslinking by means of a cross-linking agent so that the linear polymer chain has been transformed into a 3-dimensional network structure.
  • swelling (or any alternative forms thereof) is used to describe when a material (for example polymers, crosslinked or not) is diluted by absorbing water, but retains a structural integrity separating it (making it distinguishable by analysis) from the surrounding liquid on timescales relevant for the application.
  • controlled release means release of an agent at a controlled rate for an extended time, at least 1 h.
  • film or “barrier” or “membrane” is meant a thin coating or layer that acts as a bar for passage of an agent.
  • a primary object of the invention is to provide mixtures of MFC and/or NFC and/or NCC, and HPMC, or other suitable hydrophilic polymer, to form films or barriers that decrease the permeability of e.g. water.
  • the ratio between MFC/NFC/NCC and e.g. HPMC may be used to control e.g. the water permeability and diffusion properties of the films.
  • An increased amount of e.g. HPMC decreases the film permeability.
  • HPMC may also be replaced in the mixture by other polymers with the ability to hydrate and swell, such as HPC or, methyl cellulose, sodium carboxymethylcellolose, hydroxyethylcellulose, ethyl hydroxyethylcellulose or other modified hydrophilic cellulose derivatives, or modified starch, or chitosan, alginate, pectin or other water-soluble polysaccharides or chemically modified versions thereof, or other polysaccharides, or polyacrylic acid, or polyethylene oxide, or polymethacrylates or povidone or polyethylene oxide or polyvinylalcohol (PVOH) or polyvinylaccetate (PVA) other water-soluble synthetic polymers, or sodium alginate, lignin, keratin, fibroin, proteins, or salts of the above mentioned polymers or the crosslinked versions of the above mentioned polymers.
  • other polymers with the ability to hydrate and swell such as HPC or, methyl cellulose, sodium carboxymethylcellolose, hydroxy
  • HPMC may be replaced by other agents that dissolve in water, such as sugars and sugar alcohols, such as lactose, mannitol, glucose or taste improving agents such as water-soluble salts or sodium chloride, but without the possibilities to swell.
  • sugars and sugar alcohols such as lactose, mannitol, glucose or taste improving agents such as water-soluble salts or sodium chloride, but without the possibilities to swell.
  • Another object of the present invention is to use MFC-containing films as barriers, for the controlled release of active agents, drugs, chemical compounds, pesticides, herbicides, taste-masking agents, flavorings, food additives, food products, nutrients, vitamins or other active agents.
  • the barriers in the form of films may surround reservoirs like tablets, dry capsules, microspheres and solutions (to form a capsule with liquid in the inner part), or be used as controlled release layers in medical devices or other devices requiring controlled release, or implants.
  • the barrier material can be applied on tablets and capsules with ordinary coating technologies, such as film coating in fluidized beds or pan coating, or electrospinning, wet spinning, dry spinning, dry-jet wet spinning, melt spinning- gel spinning, electrospraying, casting, spray drying, aerosolizing, atomizing, molding, pressing or extruding.
  • ordinary coating technologies such as film coating in fluidized beds or pan coating, or electrospinning, wet spinning, dry spinning, dry-jet wet spinning, melt spinning- gel spinning, electrospraying, casting, spray drying, aerosolizing, atomizing, molding, pressing or extruding.
  • One embodiment of the invention is to provide a film containing microfibrillated cellulose (MFC), nanofibril cellulose, nanocellulose, nanocrystalline cellulose or whiskers, and prefereably a water-soluble agent.
  • MFC microfibrillated cellulose
  • nanofibril cellulose nanocellulose
  • nanocrystalline cellulose or whiskers and prefereably a water-soluble agent.
  • a water-soluble agent is also a possibility.
  • Another embodiment is providing a film, wherein the water-soluble agent is a hydrophilic polymer, such as a water-soluble cellulose derivative.
  • the hydrophilic polymer is chosen from HPMC, HPC, chitosan, polyacrylic acid, sodium alginate, pectin cellulose, starch, lignin keratin, fibroin, polysaccharides, proteins, polyvinylalcohol (PVOH), polyvinylaccetate (PVA), methyl cellulose, sodium carboxymethylcellolose, hydroxyethylcellulose, ethyl
  • the hydrophilic polymer is HPMC.
  • the water-soluble agent is chosen from sugars or sugar alcohols, such as lactose, mannitol or glucose, or taste improving agents such as water-soluble salts or sodium chloride.
  • concentration of the water-soluble agent is 1 -80%, preferably 1- 60% in the film. In another embodiment the concentration of the water-soluble agent is 5- 80%. In another embodiment the concentration of the water-soluble agent is 5-65%. In another embodiment the concentration of the water-soluble agent is 15-65%. In another embodiment the concentration of the water-soluble agent is 5-50%. In another embodiment the concentration of the water-soluble agent is 10-50%. In another embodiment the concentration of the water-soluble agent is 20-65%. In another embodiment the concentration of the water-soluble agent is 20-55%.
  • Another embodiment of the invention is use of the film mentioned above, for the controlled release of a compound.
  • the compound is a drugs, water, pesticides, herbicides, taste-masking agents, flavourings, food additives, food agents, food products, nutrients or vitamins.
  • the compound is a drug.
  • Another embodiment of the invention is the use of said film, for the coating of an object, such as a microsphere, a tablet, a capsule, a nanocapsule, a pellet, an implant, a solution or a medical device.
  • an object such as a microsphere, a tablet, a capsule, a nanocapsule, a pellet, an implant, a solution or a medical device.
  • Another embodiment is the use of said coated objects for the controlled release of a compound.
  • the compound may be an active agent, drug, water, pesticides, herbicides, taste-masking agents, flavourings, food additives, food agents, food products, nutrients or vitamins.
  • Another embodiment of the invention is a method for modifying the permeability of a film comprising MFC/NFC/NCC by altering the concentration of a water-soluble agent.
  • the water-soluble agent is chosen from HPMC, HPC, chitosan, polyacrylic acid, sodium alginate, pectin cellulose, starch, lignin keratin, fibroin, polysaccharides, proteins, polyvinylalcohol (PVOH), polyvinylaccetate (PVA), methyl cellulose, sodium carboxymethylcellolose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, polyethylene oxide, or polymethacrylates or povidone or polyethylene oxide, modified starch, sugars or sugar alcohols, such as lactose, mannitol or glucose, or taste improving agents such as water- soluble salts or sodium chloride.
  • a higher concentration of the water-soluble agent corresponds to a decreased permeability of the film.
  • step b) Coating an object with the coating composition from step a), using, any of film coating in fluidized beds or pan coating, or electrospinning, wet spinning, dry spinning, dry-jet wet spinning, melt spinning- gel spinning, electrospraying, casting, spray drying, aerosolizing, atomizing, molding, pressing or extruding, or other suitable methods.
  • the inventors have made films acting as barriers of water-insoluble microfibrillated cellulose, with surprising properties. In particular it can be used as a barrier that can control the release of compounds. It has been previously assumed that addition of the water-soluble agent, HPMC, would create pores in the films and thus increase the permeability. However, it was surprisingly found that the water permeability decreased by adding the water-soluble and pharmaceutically approved polymer HPMC. SEM pictures did not show any increased pore formation, rather the opposite. One could see macroscopic one-dimensional swelling increasing the thickness of the barriers and it was found that the water-soluble agent was partially released. Freeze drying of barriers after exposure to water showed that a layered structure had been formed.
  • HPMC water-soluble agent
  • the layers are mainly composed of MFC, and were probably formed through alteration of the inherent aggregation tendency of MFC in the presence of HPMC.
  • the HPMC has swelling capability and the inventors assume that this is one reason for the observed macroscopic swelling that is mainly one-dimensional, i.e. dramatically increasing the film thickness without significantly altering the film in the length dimension.
  • the HPMC is partially dissolved during the experiment, but not completely released.
  • the decrease in permeability can be explained by that the transport distance for the penetrant increases due to that it must pass around the MFC planes with low permeability and that the thickness of the barrier has increased due to the swelling.
  • the permeability of a film is determined by the rate of diffusion of molecules through the film. Fick's first law of diffusion for ideal solutions is:
  • permeability coefficient is depending on the effective diffusion coefficient in the film (D e ) and the film thickness (h) as:
  • HPMC hydrophilic agent
  • MFC metal-oxide-semiconductor
  • HPMC hydrophilic agent
  • the similarity of the materials may make it possible for non-substituted regions of the HPMC to form hydrogen bonds with the MFC surfaces. If HPMC binds strongly to the MFC, it will not leave the film, but will gel inside the film. This will lead to gel blocking of the inherent pores of the MFC films, thus decreasing the permeability of the films. This leads to gel blocking of the inherent pores of the MFC films, which leads to decreasing D e and reduced permeability of the films.
  • the structured multi layers formed in the MFC film further decrease D e and thereby the permeability.
  • the layered structure causes unidirectional swelling of the film thickness (h), decreasing the permeability even further.
  • HPMC and MFC/NFC/NCC were prepared as stock solutions and mixed to achieve HPMC concentrations of 0, 20, 35, 50 65 and 80% w/w in the formed films.
  • the structure of the MFC/NFC/NCC -HPMC film was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM).
  • SEM scanning electron microscopy
  • AMF atomic force microscopy
  • the water permeability of the films was determined using an Ussing chamber utilizing tritiated water as the diffusing probe. Films with ⁇ 50% HPMC were durable and kept their integrity throughout the 3 h analysis. The diffusive flow through the films was close to constant. Films with >50% HPMC were increasingly fragile, but showed a constant diffusive flow up to the point of rupture.
  • the MFC/NFC/NCC containing barriers of the invention may be used in several applications, such as coatings, films and controlled release layers. These barriers, coatings, layers and films may be used to surround reservoirs like tablets, dry capsules, nanocapsules, microspheres and solutions (to form a capsule with liquid in the inner part) and may further be used as controlled release layers in medical devices, implants or other devices requiring controlled release. These reservoirs may be used in different controlled release applications, such as slow release from tablets, pellets, microspheres, microcapsules, patches, transdermal delivery systems etc, and may be administered by several routes, such as via oral, rectal, vaginal, nasal, subcutaneous, transdermal, pulmonary, intravenous or intramuscular administration, or via injections.
  • the controlled release layers may be used for active agents, drugs, chemical agents, pesticides, herbicides, hygiene products, taste-masking agents, flavorings, food additives, food agents, food products, nutrients or vitamins, or to deliver other molecules to the body.
  • the inventors for the first time shows that the permeability of films composed of MFC/NFC/NCC and HPMC surprisingly decreased with increasing HPMC content.
  • the observed permeability values were in the same range as for film systems used in controlled drug delivery, indicating these films as possible new alternatives for controlled release.
  • the films with high MFC contents were also shown to have great swelling capacity per weight network in the films, in fact being in the superabsorbent range. It is believed that the observed swelling and permeability is due to HPMC affecting the nano and micro structure of the formed films by influencing the aggregation of MFC, with the MFC self assembling into fine layered structures.
  • Micro fibrillated cellulose was bought from the Paper and Fibre Research Institute PFI, Trondheim, Norway.
  • the MFC had been prepared from commercial bleached kraft pulp using a mechanical pre-treatment followed by homogenization according to Eriksson et al (6), and has previously been characterized as highly heterogeneous (3).
  • HPMC Hydroxypropyl methyl cellulose
  • Electron Microscopy Group, Germany in secondary electron detection mode.
  • the previously submerged films were prepared for analysis both by drying at 70 °C and by freezing at -32 °C followed by freeze drying using a Jouan LP3 freeze dryer (Jouan, France).
  • Jouan LP3 freeze dryer Jouan, France.
  • All samples were sputter coated with gold in Argon atmosphere for about 1 min using a S150B Sputter Coater (Edwards, England).
  • AFM analysis of films after preparation was performed using a Digital Instrument Nanoscope Ilia with a type G scanner (Digital Instrument Inc.).
  • the used cantilever was a Mikro Masch silicon cantilever NSC 15.
  • the AFM was operated at a resonance frequency of about 330 kHz in tapping mode, scan rate was 1 Hz and the measurements were performed in air.
  • Water permeability was analyzed using a modified Ussing chamber with the setup previously described (12). Briefly, a film sample was placed between a donor and acceptor compartment. Initial film thickness was measured at five different positions using an IP 54 micrometer (Mitutoyo, Japan) and was averaged. Initially 15 ml of dissolution H 2 0 was simultaneously added to the donor and the acceptor compartments, and two paddles were used to stir the contents of the two chambers at a speed of about 200 rpm. After 5 minutes a small amount of tritiated labelled water (10 ⁇ , 400 kBq) was added to the donor compartment. At determined times 500 ⁇ sample was extracted from the acceptor compartment and was replaced by the same amount of H 2 0. The temperature was maintained at 37 °C during the analyses.
  • the extracted samples were weighed and analyzed using a scintillator counter (1414 LSC, Win Spectral, Wallac).
  • the tritium activity in the acceptor compartment at the different times was used to calculate the amount of water that had diffused through the film at each time.
  • the film permeability was then calculated from Eq. 5.
  • the permeability normalized for initial film thickness (PN) was about the same for 0 and 20 % w/w HPMC content.
  • PN decreased more than twofold, opposite of what would normally be expected with increasing content of water- soluble polymer (13, 14).
  • HPMC contents of 35 - 80 % w/w the permeability was also reduced, with a small minimum for 50 % w/w HPMC (see Fig. 2).
  • PN initial film thickness
  • HPMC release from the films was determined as follows. Film pieces were cut out and their dry weights recorded. The film pieces were then subjected to USP release studies; 500 ml phosphate buffer, pH 6.8, 75 rpm, 37 °C. Samples were taken out at specified time point and were analyzed with regard to HPMC concentration using a SEC-MALS-RI system.
  • the column used was a TSKgel GMPWxl 7.8mmx300mm 13um (TOSOHAAS, Germany).
  • the MALS used was a DAWN EOS (Wyatt Technology, Santa Barbara, USA) and the RI detector was an OPTILAB rEX (Wyatt Technology, Santa Barbara, USA).
  • Nano fibrillated cellulose (NFC, generation 1) was kindly provided by INNVENTIA
  • nanocrystalline cellulose (NCC) was prepared as follows:
  • Microcrystalline cellulose (MCC) powder (Avicel PH 101, FMC) was mixed with Milli-q water and hydrolysed by adding sulphuric acid drop wise to a final acid concentration of 64% w/w for 3 h at 45 °C with continuous stirring. The hydrolysis was quenched by adding a 10- fold amount of water to the reaction mixture. The resulting mixture was centrifuged (5100 rpm, Sigma 4K15 centrifuge, UK) for 10 minutes at room temperature. The supernatant was decanted to concentrate the cellulose and remove excess water and acid. The precipitate was rinsed, re-centrifuged and dialyzed against water for 5 days.
  • the suspension was sonicated (Vibracell Sonicator, Sonics and Materials Inc., Danbury, CT) at 60% output while cooling in an ice bath.
  • the cellulose were then converted to sodium salt by conductometric titration with 0.020 M NaOH.
  • the sulphonate groups of the nanocrystals were removed according to Kloser and Gray (Kloser, E.; Gray, D G. Langmuir. 2010, 26 (16), 13450-13456.).
  • HPMC Hydroxypropyl methyl cellulose
  • Stock solutions of HPMC and NFC were prepared having a total concentration of 0.47 % w/v, with a HPMC concentration of 0 or 35% (w/w) in the film.
  • Stock solution from NCC was prepared having a total concentration of 0.97% (w/v), with HPMC concentration of 35% (w/w) in the film.
  • the films was sprayed using an airbrush compressor (Dynamic TC318 - Airbrush Kompressor) through a nozzle.
  • the extracted samples were weighed and analysed using a scintillator counter (Tri-Carb Liquid Scintillation Analyzer B2810TR, PerkinElmer, USA).
  • the tritium activity in the acceptor compartment at the different times was used to calculate the amount of water that had diffused through the film at each time.
  • the film permeability was then calculated.

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Abstract

L'invention concerne de nouvelles barrières destinées à être utilisées dans le domaine de la libération contrôlée. Les barrières peuvent contenir de la cellulose microfibrillée (CMF) ou de la cellulose nanocristalline comme composant insoluble. Ces barrières peuvent également contenir un agent hydrophile, un polymère hydrosoluble comme l'hydroxypropylméthylcellulose (HPMC), à des concentrations différentes pour réguler la perméabilité à l'eau et les propriétés de diffusion des barrières. Les barrières peuvent former des films et entourer, par exemple, des comprimés ou des capsules, et peuvent être utilisées pour la libération contrôlée d'agents actifs, de médicaments, de pesticides, d'herbicides et d'autres molécules.
PCT/SE2012/050813 2011-07-08 2012-07-09 Films de cellulose microfibrillée pour la libération contrôlée d'agents actifs Ceased WO2013009253A1 (fr)

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