WO2017145143A1 - Composition de film et procédés de production de celle-ci - Google Patents

Composition de film et procédés de production de celle-ci Download PDF

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Publication number
WO2017145143A1
WO2017145143A1 PCT/IL2016/050225 IL2016050225W WO2017145143A1 WO 2017145143 A1 WO2017145143 A1 WO 2017145143A1 IL 2016050225 W IL2016050225 W IL 2016050225W WO 2017145143 A1 WO2017145143 A1 WO 2017145143A1
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WIPO (PCT)
Prior art keywords
poly
acid
composition
block
copolymer
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PCT/IL2016/050225
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English (en)
Inventor
Adel Penhasi
Shiran ALON
Israel BALUASHVILI
Original Assignee
Degama Berrier Ltd.
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Publication date
Application filed by Degama Berrier Ltd. filed Critical Degama Berrier Ltd.
Priority to PCT/IL2016/050225 priority Critical patent/WO2017145143A1/fr
Priority to CN201680082816.0A priority patent/CN108697652A/zh
Priority to EP16891347.3A priority patent/EP3419608A4/fr
Publication of WO2017145143A1 publication Critical patent/WO2017145143A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K9/20—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
    • 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
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Definitions

  • the present invention relates to the fields of pharmaceutical, biomedical, packaging and food, and more particularly, to film compositions for coating
  • Another way to prevent or diminish the damage that may be caused by moisture and to reduce the need for special packaging is to coat the solid dosage forms with materials which have moisture barrier properties.
  • materials which have essentially a low water vapour permeation (WVP) or a low water vapor transition rate (WVTR).
  • WVP water vapour permeation
  • WVTR low water vapor transition rate
  • moisture sensitive drugs include atorvastatin, ranitidine, temazepam, most vitamins, numerous herbals, unsaturated fatty acids and probiotic bacteria.
  • the damage that may occur due to moisture may include, for example, degradation of active material by hydrolysis, destruction of probiotic bacteria or significant reduction in CFU (colony forming unites) value, changes in the appearance of the dosage form on storage, changes in the disintegration and/or dissolution times of the dosage form.
  • Moisture barrier coatings are thus applied to protect the dosage form from such damages.
  • a hydrophobic water insoluble polymer is used.
  • the polymers generally employed for this purpose are polyvinyl acetate, zein, shellac, cellulose acetate phthalate (CAP), EUDRAGIT® E 100 which is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2: 1 : 1 , ethylcellulose (EC) and the like.
  • CAP cellulose acetate phthalate
  • EUDRAGIT® E 100 which is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2: 1 : 1
  • EC ethylcellulose
  • Fig. 1 illustrates a structure of a micelle composed of a micelle- forming block copolymer having a lower critical solution temperature (LCST) and a critical micelle concentration (CMC) in which hydrophobic fatty component has been entrapped.
  • LCST critical solution temperature
  • CMC critical micelle concentration
  • Fig. 2 illustrates dry and wet cup methods for gravimetric Water Vapor
  • Fig. 3 illustrates a Water Vapor Transmission Rate (WVTR) technique using an IR detector.
  • WVTR Water Vapor Transmission Rate
  • Fig. 4 illustrates phase diagram graphs (a) and (b) depicting lower critical solution temperature (LCST) behavior and upper critical solution temperature (UCST) behavior, respectively, according to some demonstrative embodiments described herein.
  • LCST lower critical solution temperature
  • UST upper critical solution temperature
  • Fig. 5 is a schematic illustration of covalently linked networks, demonstrating the effect of temperature on the swelling of covalently linked networks.
  • Fig. 6 is a schematic illustration of a melt method for preparing a film
  • Fig. 7 is a schematic illustration of a specific micelle-forming triblock-copolymer and the structure of a micelle composed of micelle- forming block copolymer according to some demonstrative embodiments described herein.
  • Fig. 8 is a schematic illustration of a micelle structure according to some demonstrative embodiments described herein.
  • Figs. 9 and 10 demonstrate a block diagram illustrating a preparation process of a suspension for coating process based on a melt method according to some demonstrative embodiments described herein.
  • Figs. 11 and 12 demonstrate a block diagram illustrating the preparation process of a suspension for coating process based on an organic solution method according to some demonstrative embodiments described herein.
  • Fig. 13 is a schematic illustration of a film composition according to some demonstrative embodiments described herein.
  • Fig. 14 demonstrates a block diagram illustrating the preparation process of a suspension for coating process based on an oil solution method according to some demonstrative embodiments described herein.
  • Fig. 15A depicts a graph illustrating Stress-Strain curve representing the mechanical properties of different coating formulations, in accordance with some demonstrative embodiments.
  • Fig 15B depicts a Stress-Strain curve representing the mechanical properties of different film formulations consisting of a mixture of HPC and SA, in accordance with some demonstrative embodiments.
  • Fig. 16 demonstrates the appearance of the uncoated and coated tablets, in accordance with some demonstrative embodiments.
  • Figs. 17A and 17B demonstrate the weight gain (% w/w) in tablets coated by different coating formulations over time at room temperature and at 40°C, respectively, in accordance with some demonstrative embodiments.
  • Fig. 18 demonstrates photographs of SEM taken from HPC film, HPC:SA and two different film formulations according to some demonstrative embodiments of the present invention.
  • Fig. 19 is a thermogram demonstrating the thermal properties of HPC, in accordance with some demonstrative embodiments.
  • Fig 20 is a thermogram demonstrating the thermal properties of SA, in accordance with some demonstrative embodiments.
  • Fig 21 is a thermogram demonstrating the thermal properties of HPC:SA in a ratio of 80:20, respectively, in accordance with some demonstrative embodiments.
  • Fig 22 is a thermogram demonstrating the thermal properties of HPC:PSAA in a ratio of 80:20, respectively, in accordance with some demonstrative embodiments.
  • Fig 23 is a thermogram demonstrating the thermal properties of HPC:SA:PSAA in a ratio of 65:25: 10, respectively, in accordance with some demonstrative
  • Fig 24 is a thermogram demonstrating the thermal properties of HPC:SA:PSAA in a ratio of 65:30:5, respectively, in accordance with some demonstrative embodiments.
  • composition of film for coating a pharmaceutical, nutraceutical or nutritional composition.
  • the composition of film may contain at least one hydrophilic film forming polymer, at least one hydrophobic fatty component and at least one micelle-forming block copolymer.
  • At least one hydrophilic film forming polymer may have a thermo-sensitive sol gel forming properties having a lower critical solution temperature (LCST).
  • LCST critical solution temperature
  • the composition of film may have improved moisture barrier properties at ambient and elevated temperatures and thus low water vapour transition rate.
  • the composition of film may be used as a coating film for granules, microspheres, pellets, microcapsules, mini-tablets, tablets, caplets and capsules and the like.
  • the composition may also be used for microencapsulation for different food products (foodstuffs), nutritional, pharmaceutical and nutraceutical products, e.g., wherein the composition of the present invention may provide the active materials and probiotics of such products with high survival, viability and/or resistance.
  • the composition of the present invention may provide the active materials and probiotics with high survival, viability and/or resistance during different processes, e.g., processes which include elevated temepratures, and/or post production, e.g., during storage of the product.
  • the composition can also be used as degradable packaging material.
  • the present invention also provides for a formulation and method of production of a composition including hydrophilic polymer(s), hydrophobic fatty component(s) and micelle-forming block copolymer(s) for forming a sealing coat, wherein the components of the composition are in such a ratio which will not disrupt the basic and/or mechanical properties of the polymer, e.g., the film forming properties.
  • the composition may be based on a blend of the components at molecular level.
  • the present invention relates to a formulation for producing a film for coating solid dosage forms or moisture barrier membrane.
  • the formulation comprises at least 1) a hydrophilic film forming polymer having thermo- sensitive sol gel forming properties having a lower critical solution temperature (LCST), 2) at least a hydrophobic fatty component and 3) at least a micelle- forming block copolymer having a lower critical solution temperature (LCST) and a critical micelle concentration (CMC) and an HLB value of about 9 to 18 and whose LCST is higher than that of said hydrophilic film forming polymer, having improved moisture barrier at ambient and elevated temperature and thus low water vapour transition rate.
  • the formulation may include other additives such as glidant, plasticizer flavouring agents, colorant, such as a pigment, and the like.
  • the formulation will be useful for producing either a sprayable dispersion/emulsion or solution for coating on various substrates or film formation for producing membrane.
  • the present invention also relates to a process for producing the film formulation by either producing a dispersion/emulsion in an aqueous medium or solution in an organic solvent which will be ready for spraying on various substrates such as nutritional, nutraceutical or pharmaceutical active ingredient in a solid dosage form to produce a film coating on the nutritional, nutraceutical or pharmaceutical active ingredient in a solid dosage form or pouring to form a film membrane.
  • a film composition for coating a pharmaceutical, nutraceutical or nutritional composition which may comprise a molecular mixture of at least one hydrophilic film forming polymer having thermo- sensitive sol gel forming properties having a first lower critical solution temperature (LCST); at least one hydrophobic fatty component; and at least one micelle- forming block copolymer, e.g., a micelle-forming block copolymer having a second lower critical solution temperature (LCST) and an HLB value of about 9 to 20.
  • LCST first lower critical solution temperature
  • LCST low critical solution temperature
  • micelle-forming block copolymer e.g., a micelle-forming block copolymer having a second lower critical solution temperature (LCST) and an HLB value of about 9 to 20.
  • the second LCST is higher than said first LCST.
  • a film composition for coating a pharmaceutical, nutraceutical or nutritional composition which may comprise a molecular mixture of at least one hydrophilic film forming polymer having thermo- sensitive sol gel forming properties having a first lower critical solution temperature (LCST); at least one hydrophobic fatty component; and at least one micelle- forming block copolymer, e.g., a micelle-forming block copolymer having a second lower critical solution temperature (LCST) and an HLB value of about 9 to 20.
  • LCST first lower critical solution temperature
  • LCST low critical solution temperature
  • micelle-forming block copolymer e.g., a micelle-forming block copolymer having a second lower critical solution temperature (LCST) and an HLB value of about 9 to 20.
  • the second LCST is higher than said first LCST.
  • Fig. 1 is a schematic illustration of micelles-forming triblock-copolymer below its lower critical solution temperature (LCST) and the structure of a micelle composed of micelle- forming block copolymer having a lower critical solution temperature (LCST) and a critical micelle concentration (CMC) in which hydrophobic fatty component has been entrapped.
  • LCST lower critical solution temperature
  • CMC critical micelle concentration
  • triblockcopolymers to a micelle structure takes place at high temperature above LCST of the micelles-forming triblock-copolymer.
  • the micelle of the present invention may include a hydrophilic block 100, a hydrophobic block 102 and a hydrophobic fatty component 104.
  • the hydrophilic film forming polymer may include one or more of poly-N-substituted acrylamide derivative, polypropyleneoxide, polyvinylmethylether, partially-acetylated product of polyvinyl alcohol, Methylcellulose (MC), hydroxylpropylcellulose (HPC),
  • MHEC methylhydroxyethylcelluloce
  • HPMC hydroxylpropylmethylcellulose
  • HPEC hydroxypropylethylcellulose
  • HPEC hydroxymethylpropylcellulose
  • HMPC hydroxymethylpropylcellulose
  • EHEC ethylhydroxyethylcellulose
  • HEMC hydroxyethylmethylcellulose
  • HMEC hydroxymethylethylcellulose
  • PHEC propylhydroxyethylcellulose
  • NEXTON hydrophobically modified hydroxyethylcellulose
  • the poly-N-substituted acrylamide derivative may include one or more of poly(N-isopropylacrylamide) (PNIPAM), Poly-N- acryloylpiperidine, poly(N,N-diethylacrylamide) (PDEAAm), poly(N-vinlycaprolactam) (PVCL), poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) , poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), PEG methacrylate polymers (PEGMA), Poly-N-propylmethacrylamide, Poly-N-isopropylacrylamide Poly-N-diethylacrylamide, Poly-N-isopropylmethacrylamide, Poly-N-cyclopropylacrylamide, Poly-N- acryloylpyrrolidine, Poly-N,N-ethylmethylacrylamide, Poly-N- cyclopropylmethacrylamide, Poly-N-N- acrylo
  • methacrylamide derivatives copolymers comprising an N-substituted acrylamide derivative and an N-substituted methacrylamide derivative, and a copolymer of N- isopropylacrylamide and acrylic acid.
  • the hydrophilic monomer may include one or more of N-vinyl pyrrolidone, vinylpyridine, acrylamide, methacrylamide, N- methylacrylamide, hydroxyethylmethacrylate, hydroxymethylacrylate,
  • the hydrophobic monomer may include one or more of ethylacrylate, methylmethacrylate, and glycidylmethacrylate; N- substituted alkymethacrylamide derivatives such as N-n-butylmethacrylamide;
  • composition of the present invention may further include a polymer co-network comprising any combination of the above polymers.
  • the co-networks may include one or more of PNIPAAm and hydroxyethyl methacrylate (HEMA) copolymer, PNIPAAm-co- PHEMA, and NIPAAm with butyl methacrylate (BuMA), P(NIPAAm-co-BuMA), poly(dimethyl acrylamide) (PDMAAm) with Poly(methoxyethyl acrylate), PDMAAm- co-Poly(methoxyethyl acrylate), PNIPAAm hydrogels with polyamino acid crosslinked chains which are thermoresponsive degradable hydrogels, synthesized elastin like polymers with polypeptide repeat units, biodegradable hydrogel comprising
  • thermoresponsive PNIPAAm with cleavable lactic acid and dextran groups hydrogels of poly(ethylene glycol monomethyl ether methacylate (PEGMA), ABA triblock copolymers of PNIPAAm (block A) and poly(N,N-dimethylacrylamide) (PDMAAm, block B), Conetworks of PNIPAAm, PHEMA and a lactic acid monomer and thermoresponsive cellulose derivatives such as methylcellulose and hydroxypropyl cellulose based hydrogels.
  • PEGMA poly(ethylene glycol monomethyl ether methacylate
  • Conetworks of PNIPAAm, PHEMA and a lactic acid monomer and thermoresponsive cellulose derivatives such as methylcellulose and hydroxypropyl cellulose based hydrogels.
  • the micelle-forming block copolymer may be present at a concentration that is at least a critical micelle concentration (CMC) of said micelle-forming block copolymer.
  • CMC critical micelle concentration
  • the micelle-forming block copolymer may include one or more of amphiphilic di-block (hydrophilic— hydrophobic) or tri-block (hydrophilic— hydrophobic— hydrophilic) polymers, and/or graft (hydrophilic-g- hydrophobic) or ionic (hydrophilic-ionic) copolymers.
  • the micelle-forming block copolymer may include one or more of a PEO-PPO-PEO block copolymer, AP-A nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene
  • copolymers may include poloxamer blockcopolymer series (such as ; Poloxamer 124, Poloxamer 188 , Poloxamer 237, Poloxamer 338, and Poloxamer 407, wherein the molecular weight of the polyethylene oxide part may be 1200, 1800, 2250, 3250 and 4000 respectively and wherein the molecular weight of the blockcopolymers may be 4000, 6000, 8000, 10000 and 12000 respectively.
  • poloxamer blockcopolymer series such as ; Poloxamer 124, Poloxamer 188 , Poloxamer 237, Poloxamer 338, and Poloxamer 407
  • the molecular weight of the polyethylene oxide part may be 1200, 1800, 2250, 3250 and 4000 respectively
  • the molecular weight of the blockcopolymers may be 4000, 6000, 8000, 10000 and 12000 respectively.
  • the micelle-forming block copolymer may include one or more of a EO-PO-EO block copolymers , di-blocks of EO-PO and EO-B and tri-block versions, PO-EO-PO and BO-EO-BO (BO is butylene oxide) DG note - I need more explanation about these copolymers and also a list of examples AP :This is a block copolymer based on polybuthylene glycol or polybuthylene oxide (BO), poly (propylene oxide)-poly (ethylene oxide)- poly (propylene oxide) triblock copolymers (PPO-PEO-PPO), poly (butylene oxide)-poly (ethylene oxide)- (butylene oxide) triblock copolymers (PBO-EO-PBO), poly (ethylene oxide)-poly (butylene oxide)-poly (ethylene oxide) triblock copolymers (PEO-PBO-PEO), Poly(ethylene oxide)-poly (butylene oxide)-poly (
  • poly(ethyelene imine) block copolymers Poly(styrene)- poly(vinyleriphenylphosphine), block copolymers of polyamino acid- PEO copolymers with hydrophobic blocks of aspartic acid and aspartate derivatives, polylysine, polycaprolactone, and poly(lactide), polication-PEO copolymers containing, e.g., poly(ethyleneimine), ionic block copolymers such as polystyrene(PS)-b-polyacrylic acid (PAA), polystyrene(PS)-b- poly(methacrylic acid) (PMA), poly(styrene)- poly(ethylene-propylene) (PS-PEP) diblock and triblock copolymers, poly(styrene)-b- poly(ethylene-butylene) (PS-PEB) diblock and triblock copolymers, poly(styrene)-b- poly(t
  • the hydrophobic fatty component may include one or more of alkene chains, alkane chains, waxes, esters, fatty acids, alcohols, and glycols.
  • the alkene chains may include paraffin wax.
  • the waxes may include one or more of bee wax, carnauba wax, japan wax, bone wax, paraffin wax, Chinese wax, lanolin (wool wax), shellac wax, spermaceti, bayberry wax, candelilla wax, castor wax, esparto wax, jojoba oil, ouricury wax, rice bran wax, soy wax, ceresin waxes, montan wax, ozocerite, peat waxes, microcrystalline wax, petroleum jelly, polyethylene waxes, fischer-tropsch waxes, chemically modified waxes, substituted amide waxes; polymerized a-olefins; hydrogenated vegetable oil, hydrogenated castor oil; fatty acids, such as lauric acid, myristic acid, palmitic acid, palmitate, palmitoleate, hydroxypalmitate, stearic acid, arachidic acid, oleic acid
  • a method for preparing the composition as described herein including preparing a core containing a pharmaceutical, nutraceutical and/or nutritional composition; combining a hydrophobic fatty component and a micelle- forming block copolymer in a solution, suspension or dispersion; adding a hydrophilic film forming polymer to the solution, suspension or dispersion to form a coating; and coating the core with said coating.
  • combining the hydrophobic fatty component and the micelle- forming block copolymer may take place in a solution, suspension or dispersion and may include melting the hydrophobic fatty component and the micelle- forming block copolymer together.
  • the temperature of the melting may be above the first LCST.
  • combining the hydrophobic fatty component and the micelle- forming block copolymer in a solution, suspension or dispersion may include combining the hydrophobic fatty component and the micelle- forming block copolymer together with an organic solvent or with oil.
  • adding the hydrophilic film forming polymer to the solution, suspension or dispersion to form said coating may be performed at a temperature above said first LCST.
  • the pharmaceutical, nutraceutical or nutritional composition described herein may include a core and the film composition of the present invention coating the core.
  • the core may include granules, microspheres, pellets, microcapsules, mini-tablets, tablets, caplets, capsules and the like.
  • a film composition for coating a pharmaceutical, nutraceutical and nutritional for coating a pharmaceutical, nutraceutical and nutritional
  • composition comprising a molecular mixture of a Poloxamer, a fatty acid and HPC.
  • a film composition for coating a pharmaceutical, nutraceutical and nutritional composition wherein the film composition may include a molecular mixture of a polysorbate
  • a pharmaceutical nutraceutical or nutritional composition may include a core comprising an active ingredient, and a coating layered over the core.
  • the coating may include a molecular mixture of Poloxamer, a fatty acid and HPC.
  • a pharmaceutical, nutraceutical or nutritional composition may include core comprising an active ingredient, and a coating layered over said core, said coating comprising a molecular mixture of a polysorbate (Tween), a fatty acid and HPC.
  • core comprising an active ingredient
  • coating comprising a molecular mixture of a polysorbate (Tween), a fatty acid and HPC.
  • compositions based on a combination of at least two of the following: a hydrophilic film forming polymer having thermo- sensitive sol gel forming properties having a lower critical solution temperature (LCST) ; at least a hydrophobic fatty component and/or at least a micelle- forming block copolymer having a lower critical solution temperature (LCST) and a critical micelle concentration (CMC) and an HLB value of about 9 to 20 and whose LCST is higher than that of said hydrophilic film forming polymer, results in a remarkable decrease in the water vapour permeation through the film and significant increase in barrier properties of the resulting film coating.
  • LCST critical solution temperature
  • CMC critical micelle concentration
  • the composition according to the present invention may be based on a physically blended of components, e.g., in a molecular level, for achieving sealing properties.
  • these properties may be achieved by filling inter chains micro-voids existing in hydrophilic film forming polymer which are responsible for penetration of moisture specially at high temperatures by micelles in which the hydrophobic fatty component is entrapped ( Figure 1).
  • the micelles are also responsible for a more stable and tighter connection between hydrophilic film forming polymer and hydrophobic fatty component.
  • Permeation describes the transfer of gases and vapours in barrier materials such as polymeric plastics. The process involves:
  • permeation indicates a polymer's ability to transmit liquids, gases, and vapours.
  • Permeation is generally regarded as an important consideration in determining the performance of plastics or composites, and for good reason. All polymers are generally permeable, and structures such as dual laminates or sheet linings are essentially freestanding polymeric materials.
  • the transport rate for water vapour is much faster compared to the other components even though the polymer can be a hydrophobic material.
  • the permeability coefficient of a material is an intrinsic material property, since it gives a measure for the amount of gas permeating per second through a material with a surface area of 1 cm 2 and a thickness of 1 cm normalized for the driving force in cm.Hg.
  • the total amount of gas permeating is expressed as a flux of gas at standard temperature and pressure
  • D is the diffusion coefficient (cm2/s) and S the solubility coefficient (cm 3 (STP)/(cm 3 cmHg)).
  • D diffusion rate
  • solubility a thermodynamic parameter accounting for the amount sorbed by the membrane.
  • Permeation involves a combination of physical and chemical factors. In general increasing permeant concentration, temperature, pressure, permeant/polymer chem. Similarity, free volumes and voids in polymer may increase the rate of permeation and inversely increasing permeant size/shape, polymer thickness, polymer crystallinity, polymer chain stiffness and polymer inter-chain forces decreases the rate of permeation. Likewise in crystalline polymers, orientation will reduce permeability. Moisture sensitivity may also affect permeability for example some polymers are plasticized by water, causing their permeability to increase. Cross-linking can also affect permeation. The higher the cross linking degree is, the higher the moisture barrier of the membrane. Molecular weight and chemical nature (hydrophilic, hydrophobic) of the polymer are also key factors for permeability.
  • WVTR Water Vapor Transmission Rate
  • J flux which is the diffusion flow through unite area of film
  • D diffusion coefficient
  • c concentration of penetrante
  • x the distance of the point from the the film surface.
  • the permeability of the membrane is determined from the amount or rate of permeation and experimental parameters such as time, sample area, sample thickness, pressure difference, concentrations, etc. the permeability of the membrane can be calculated.
  • FIG. 2 Schematic illustration of dry and wet cup methods for gravimetric water vapor transmission rate (WVTR) measurement according to Standard Test Method (ASTM E398 Method), wherein said standard test method for water vapor transmission rate of sheet materials utilizes dynamic relative humidity (RH) measurement.
  • WVTR gravimetric water vapor transmission rate
  • ASTM E398 Method Standard Test Method
  • Fig. 3 illustrates a Water Vapor Transmission Rate (WVTR) technique using an IR detector.
  • WVTR Water Vapor Transmission Rate
  • a sample film is placed in a sealed cell containing a water/salt solution having a controlled RH.
  • a constant gas flow dry air
  • IR Infra-Red
  • Free volume is an intrinsic property of the polymer matrix and arises from the gaps left between entangled polymer chains. Since the gaps are at the molecular scale, it is not possible to directly observe free volume. Free volume can be thought of as extremely small-scale porosity but free volume pores are dynamic and transient in nature since the size (and existence) of any individual free volume 'pore' depends on the vibrations and transitions of the surrounding polymer chains. The transition of the polymer chains can open and close 'pores' and open/close channels between pores, providing 'pathways' for diffusion jumps.
  • the absorption and diffusion of molecules in polymer films will depend to a considerable extent on the available free volume within the polymer.
  • Free volume depends on the density and physical state of the polymer. Voids are on a larger size scale than free volume and are 'permanent' features, independent of polymer chain motion.
  • Voids tend to result from the generation of 'defects', e.g. included air, arising during processing but can also be generated in service (e.g. stress generated crazing or chemical swelling).
  • the volume fraction of voids in a sample will depend on the imposed stress state.
  • Voids like free volume, offer sites into which molecules can absorb and are far less of a barrier to transport than solid polymer. Voids may also provide sites into which liquids and vapors can condense and thereby dramatically increase their uptake.
  • a high level of void will increase permeability through increasing both the solubility and the effective diffusion coefficient. If voids are linked (open voids), then diffusion rates through these channels will be lead to very much greater permeation than if the voids are isolated (closed voids). The latter can specially happen under effect of temperature.
  • Thermosensitive sol gel forming polymers belong to a general group of polymers, smart polymers, which are materials that have the ability to respond to external stimuli.
  • Thermosensitive sol gel forming polymers are those polymers which respond to temperature and change their state under effect of temperature. Basically, There are two main types of thermoresponsive polymers; the first present a lower critical solution temperature (LCST) while the second present an upper critical solution temperature (UCST).
  • LCST lower critical solution temperature
  • UST upper critical solution temperature
  • LCST and UCST are the respective critical temperature points below and above which the polymer and solvent are completely miscible (for example, as shown in Figure 4.)
  • a polymer solution below the LCST is a clear, homogeneous solution while a polymer solution above the LCST appears cloudy (leading to LCST also being referred to as cloud point).
  • AG ⁇ - TAS (G: Gibbs free energy, H: enthalpy and S: entropy) the reason that phase separation is more favorable when increasing the temperature is mostly due to the entropy of the system.
  • the main driving force is the entropy of the water, that when the polymer is not in solution the water is less ordered and has a higher entropy. This is also called the "hydrophobic effect".
  • LCST is an entropically driven effect while UCST is an enthalpically driven effect.
  • chain-chain interactions hydrophobic effects
  • water- water interaction hydroogen bonding
  • Macroscopic response of the polymer will depend on the physical state of the chains.
  • the solution will change from mono-phasic to bi-phasic due to polymer precipitation when the transition occurs.
  • Polymer solution is a free-flowing liquid at ambient temperature and gels at high temperature. In some cases, if lowering the amount of thermo-gelling polymer is necessary, it may be blended with a pH-sensitive reversibly gelling polymer.
  • Fig. 4 illustrates phase diagram graphs (a) and (b) depicting lower critical solution temperature (LCST) behavior and upper critical solution temperature (UCST) behavior, respectively, according to some demonstrative embodiments described herein
  • phase diagrams (a) and (b) examine temperature in axis y vs. polymer volume fraction in axis x.
  • Phase diagram (a) demonstrates the lower critical solution temperature (LCST) behavior
  • Phase diagram (b) demonstrates the upper critical solution temperature (UCST) behavior.
  • LCST and UCST are the respective critical temperature points below and above which, respectively, the polymer and solvent are essentially completely miscible.
  • a polymer solution below the LCST would be a clear, homogeneous solution while a polymer solution above the LCST appears cloudy (LCST is also sometimes referred to as cloud point).
  • a polymer solution above the UCST would be a clear, homogeneous solution while a polymer solution below the UCST appears cloudy.
  • the LCST of a thermosensitive sol gel forming polymer may generally be dependent on molecular weight and architecture.
  • Thermosensitive sol gel forming polymers used as film forming polymer according to the present invention are preferably those that present an LCST.
  • thermo-sensitive polymers exhibiting thermally-driven phase transitions may include, but not limited to poly-N- substituted acrylamide derivatives such as for example poly(N-isopropylacrylamide) (PNIPAM), Poly-N-acryloylpiperidine, poly(N,N-diethylacrylamide) (PDEAAm) with an LCST over the range of 25 to 32°C, poly(N-vinlycaprolactam) (PVCL) with an LCST between 25 and 35°C, poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) with an LCST of around 50°C, poly(ethylene glycol) (PEG), also called poly(ethylene oxide) (PEO) whose LCST is around 85°C, PEG methacrylate polymers (PEGMA), having a side-PEG chain of 2-10 ethylene oxide units (EO) ⁇ 10 present a lower critical solution temperature (LCST) that varies depending on the length of
  • PIPAM poly(
  • the above mentioned poly-N- substituted acrylamide derivatives may be either a homopolymer or a copolymer comprising a monomer constituting the above polymer and "another monomer".
  • the "another monomer” may be a hydrophilic monomer, or a hydrophobic monomer.
  • the resultant cloud point temperature when copolymerization with a hydrophilic monomer is conducted, the resultant cloud point temperature may be increased. According to other embodiments, when copolymerization with a hydrophobic monomer is conducted, the resultant cloud point temperature may be decreased. Accordingly, a polymer having a desired cloud point (e.g., a cloud point of higher than 30° C), may be obtained by selecting monomers to be used for copolymerization. Examples of the above hydrophilic monomers may include: N-vinyl pyrrolidone, vinylpyridine, acrylamide,
  • hydrophilic monomer of the present invention is not restricted to these specific examples.
  • hydrophobic monomer may include acrylate derivatives and methacrylate derivatives such as ethylacrylate, methylmethacrylate, and glycidylmethacrylate; N-substituted alkymethacrylamide derivatives such as N-n- butylmethacrylamide; vinylchloride, acrylonitrile, styrene, vinyl acetate, etc.
  • acrylate derivatives and methacrylate derivatives such as ethylacrylate, methylmethacrylate, and glycidylmethacrylate
  • N-substituted alkymethacrylamide derivatives such as N-n- butylmethacrylamide
  • vinylchloride acrylonitrile, styrene, vinyl acetate, etc.
  • a thermo- sensitive polymers is an etherified cellulose represented by methylcellulose, hydroxypropylcellulose, etc., where the sol-gel transition temperature thereof is as high as about 45°C or higher.
  • HPC Hydroxypropylcellulose
  • DS degree of substitution
  • Thermosensitive sol gel forming polymers used as film forming polymer according to the present invention may also be a hydrogel.
  • Hydrogels are 3 -dimensional polymeric networks.
  • Physical gels may be formed by the physical entanglement of polymer chains and/or micelle ordering in solution and not from covalently linked polymer chains. Both of these gels, crosslinked or physical, have the ability to swell in a solvent depending on their compatibility with the solvent. However one of the differences between physical gels and crosslinked gels is that when a physical gel is in the appropriate solvent and it is given enough time and space it will dissolve in the solvent, whereas crosslinked gels will not.
  • Hydrogels are polymer networks dispersed in water which form semi solid states containing at least of 99% water w/w to polymer. These gels can be either covalently linked polymer networks or physical gels mentioned above. With reference to thermoresponsive polymers, covalently linked networks exhibit a change in their degree of swelling in response to temperature, whereas physical gels show a sol-gel transition.
  • FIG. 5 schematically illustrates covalently linked networks, demonstrating the effect of temperature on the swelling of covalently linked networks.
  • covalently linked networks e.g., hydrogel networks
  • dispersed in water may form semi solid states containing at least 99% water w/w to polymer weight.
  • These gels can be either covalently linked polymer networks or physical gels.
  • covalently linked networks exhibit a change in their degree of swelling in response to temperature whereas physical gels show a sol-gel transition, for example, when the solution temperature is below the LCST, the covalently linked networks will have a swollen network formation 504 and when the solution temperature is raised above the LCST, the covalently linked networks will have a collapsed network formation 502.
  • thermoresponsive polymers may be selected from the group consisting of conetworks such as for example PNIPAAm and hydroxyethyl methacrylate (HEMA) copolymer, PNIPAAm-co-PHEMA, and NIPAAm with butyl methacrylate (BuMA), P(NIPAAm-co-BuMA), poly(dimethyl acrylamide) (PDMAAm) with Poly(methoxyethyl acrylate), PDMAAm-co-Poly(methoxyethyl acrylate),
  • conetworks such as for example PNIPAAm and hydroxyethyl methacrylate (HEMA) copolymer, PNIPAAm-co-PHEMA, and NIPAAm with butyl methacrylate (BuMA), P(NIPAAm-co-BuMA), poly(dimethyl acrylamide) (PDMAAm) with Poly(methoxyethyl acrylate), PDMAAm-co-Poly(methoxyethyl acrylate),
  • HEMA
  • PNIPAAm hydrogels with polyamino acid crosslinked chains which are
  • thermoresponsive degradable hydrogels synthesized elastin like polymers with polypeptide repeat units, biodegradable hydrogel comprising thermoresponsive
  • PNIPAAm with cleavable lactic acid and dextran groups
  • PNIPAAm block A
  • PDMAAm poly(N,N-dimethylacrylamide)
  • Interpenetrating networks consist of two covalently linked polymer networks which may be bound together by physical entanglement as opposed to covalent bonds. Specifically, this requires the polymerization of both networks simultaneously and results in two intermixed networks that can only be separated by breaking bonds. These materials are of interest due to their ability to introduce new properties when the networks interact or two different properties when acting independently.
  • an interpenetrating network of polyacrylic acid (PAA) and polyacrylamide (PAAm) forms hydrogels that swell above their upper critical solution temperature (UCST), e.g., due to hydrogen bonding between the two different networks being disrupted at higher temperatures allowing the networks to swell.
  • UST critical solution temperature
  • SIPN Semi interpenetrating networks
  • IPNs are not entwined networks.
  • SIPNs consist of a crosslinked network with linear or branched polymer chains penetrating them.
  • SIPN may be synthesized from crosslinked gellan gum microspheres with interpenetrating PNIPAAm chains.
  • PNIPAAm-co-PAAc Another example of seminterpenetrating networks is PNIPAAm-co-PAAc with linear PAAc-co- peptide chains that shows degradation properties to be dependent on peptide crosslinks and PAAc-co-peptide concentrations.
  • the composition of the present invention may include at least one micelle-forming block copolymer.
  • the micelles- forming polymeric may include amphiphilic di-block (hydrophilic— hydrophobic) or tri-block (hydrophilic— hydrophobic— hydrophilic) polymers.
  • polymeric micelles are generally more stable, with a remarkably lowered CMC, and have a slower rate of dissociation.
  • Additional structures may include graft (hydrophilic-g-hydrophobic) or ionic (hydrophilic-ionic) copolymers.
  • the hydrophilic segment may be composed of poly(ethylene glycol) (PEG). While alternative hydrophilic polymers such as poly(ethylenimine) poly(aspartic acid), poly(acrylic acid), dextran and etc may also be used, hydrophobic or ionic segments are preferred.
  • the defining characteristic of micelle systems is the ability of polymer units to self-assemble into nano-scale aggregates.
  • Self-assembly is a thermodynamic process.
  • the potential for self-assembly is determined by the mass and composition of the copolymer backbone, the concentration of polymer chains, and the properties of fatty component which should be encapsulated into the micelles.
  • amphiphilic polymers may self-assemble in aqueous solutions with the hydrophobic chains aggregating together to form the core and the hydrophilic chains extended towards the aqueous environment.
  • the hydrophilic chains shield the hydrophobic chains from interaction with water, reducing the interfacial free energy of the polymer— water system.
  • any macromolecule assumes a conformation in solution that is directed by the balance between the strengths of interaction of the polymer segments between themselves and with the solvent molecules.
  • This balance is generically called solvent quality and has been assessed by a variety of parameters of which the most commonly used are the Hildebrand solubility parameter ⁇ and the Flory parameter X.
  • a good solvent would present a solubility parameter (which reflects its cohesive energy) closer to that of the macromolecule, whereas within Flory theory, the smaller (or more negative) the Flory parameter, the more favorable the monomer- solvent interaction.
  • the size of the macromolecule may play an important role in defining its solution conformation due to a configurational entropy contribution, which is most commonly assessed through lattice analysis, as proposed by Flory.
  • these copolymers may act as very effective surface active agents, being used in many applications for their interfacial activity.
  • the self-assembling may produce structures of the same kind as those verified in normal surfactant solutions, generically called micelles (possibly including a variety of shapes) and mesophases (possibly involving different geometry and arrangements), as depicted for example in Figs 1 and 7.
  • association processes involving these macromolecule s with respect to their similarity with normal surfactants.
  • the first one involves the initial state, where no association occurs, which for low-molecular- weight surfactants is associated with the term monomers. With block copolymers, this term would cause confusion with the macromolecule building units. Hence, the non-aggregated state is referred to as unimers. Sometimes, e.g., especially for copolymers with large insoluble blocks, liophobic sites are formed due to compact coiling of these units even at the non-aggregated state, generating what is known as "unimolecular micelles" .
  • the term "micelle” as used herein may refer to any form of aggregate of surfactant molecules dispersed in a liquid colloid.
  • the micelles of the present invention may be in a form a spheres, ellipsoids, cylinders, unilayers, bilayers and the like.
  • the micelles of the present invention may also be lack of any defined regular shape. According to some embodiments in normal surfactant solutions, micelles would be aggregates that are stable in a significant range of environmental conditions (e.g., concentration, temperature, and presence of additives) as to produce an aggregate with constant aggregation number, size, and shape..
  • the aggregation process may be significantly more complex.
  • the composition of present invention may include non-ionic and/or ionic copolymer aggregates formed in water, in non-aqueous solvents and/or in supercritical fluids.
  • a series of examples is described herein to represent the wide range of pssible applications involving the important aggregates of the present invention.
  • the critical micelle concentration is the minimum concentration of polymer required for micelles to form. At low polymer concentrations, there are insufficient numbers of chains to self-assemble and instead the chains are found distributed throughout the solution and act as surfactants, adsorbing at the air— water or aqueous— organic solvent interface. As the concentration of polymer increases, more chains are adsorbed at the interface. Eventually a concentration is reached at which both the bulk solution and interface are saturated with polymer chains— this is referred to as the CMC. Adding more polymer chains to the system beyond this point will result in micelle formation in the bulk solution to reduce the free energy of the system. At high polymer concentration, the micelles are stable unless they are diluted below the CMC. The micelles will then disassemble and free chains are again found in the bulk solution and adsorbed at the air— water interface or aqueous— organic solvent interface.
  • micelles are often pictured as spheres, according to some embodiments, the micelles are not always spherical and not solid particles.
  • the individual polymer chains that form a micelle may be in dynamic equilibrium with chains that remain in the bulk solution, at the solvent interface, and incorporated into adjacent micelles.
  • the structure, molecular weights and molar mass ratio between hydrophilic and hydrophobic segments of the polymer backbone have a direct impact on the size and shape of assembled micelles.
  • hydrophilic polymer segment corona
  • hydrophobic polymer segment core
  • micelle size may be determined by the molecular geometry of the individual chains which may be influenced by solution conditions such as ionic strength, pH, temperature, and polymer concentration.
  • micelles should preferably remain intact during formulation and administration to contain the fatty component of the film.
  • the stability of micelles can be thought of generally in terms of thermodynamic and kinetic stability. Thermodynamic stability describes how the system acts as micelles are formed and reach equilibrium. Kinetic stability describes the behavior of the system over time and details the rate of polymer exchange and micelle disassembly.
  • polymeric micelles exhibit lower CMC values than low molar mass surfactant micelles because the polymer chains have many more points of interaction than small molecules.
  • Polymer solutions exhibit different physical properties below and above the CMC.
  • polymeric micelle CMCs are at micro-molar concentrations.
  • the length of the hydrophobic segment correlates directly with stability.
  • the propensity for micelles to dissociate is related to the composition and cohesion of the hydrophobic core. According to some embodiments, increasing the hydrophobicity of the copolymer increases the cohesion of the hydrophobic core and results in a lower CMC.
  • an interaction between the fatty component of the micelle and the material encompassed within the core of the micelles may also affect and/or compromise stability.
  • an encapsulated, hydrophobic component may stabilize the micelle through additional hydrophobic interactions between the core and the fatty component.
  • Thermodynamic stability may be also influenced by the interactions between polymer chains in the corona with each other and with the aqueous environment.
  • Some micelles of the present invention may employ PEG as the hydrophilic segment.
  • individual PEG chains interact by intermolecular van der Waals forces; the PEG chains interact with water in the bulk solution by hydrophilic interactions, such as hydrogen bonding/dipole— dipole forces.
  • hydrophilic interactions such as hydrogen bonding/dipole— dipole forces.
  • increasing the PEG chain length and surface density may force the polymers to adopt more rigid and extended, e.g., brush-like conformations.
  • low MW PEG and low surface density of PEG may result in limited surface coverage of the micelle, leading to aqueous exposure to the hydrophobic core and micelle destabilization.
  • Sufficient hydrophilic polymer surface coverage is required to allow fluid movement of surface chains while also preventing exposure of the hydrophobic core.
  • the hydrophobic and hydrophilic chain lengths on the copolymer there is a balance between the hydrophobic and hydrophilic chain lengths on the copolymer, e.g., for achieving maximum stability. Beyond a certain point, increasing the hydrophobic chain length leads to micelles of less uniform shape, resulting in non-spherical aggregates.
  • the hydrophobicity of the core may also influence micelle stability.
  • the most hydrophobic copolymer has the lowest CMC. Increased hydrophobicity and stacking interactions in the core may decrease the CMC.
  • micelles formed from mixtures of two hydrophobic copolymer chains may have much higher CMCs. Therefore the hydrophobicity alone is insufficient to predict stability, and that intermolecular interactions in the micelle core, such as stacking interactions, resulted in a "glassy" state in the core can influence stability as well.
  • the composition including the hydrophobic chain may be paramount in micelle design.
  • increasing the hydrophobic chain length and/or degree of hydrophobicity may lead to more stable micelles. e g., as described in detail below.
  • Kinetic stability describes the behavior of the micelle system over time in aqueous solution, specifically dealing with the dynamics between individual micelles, their environment and each other. Any change in the environment of a micelle may impact stability.
  • As vehicles for entrapping fatty component in the hybrid film micelles are exposed to extreme and acute changes in their environment. After micellization, individual chains remain dynamic and exchange between micelles and the bulk solution. Finally, after being exposed to changes in the environment or by simple dilution, or spraying the emulsion formulation for coating granules or microspheres micelles may begin to fall apart. Therefore, kinetic stability is used to describe the dynamics of micelles over time and during the process of disassembly. It is essential to characterize the kinetic stability of micelles to ensure that the encapsulated fatty component cargo is not released prematurely.
  • KM is the micelle dissociation constant and has the units of concentration and n is the aggregation number of the micelle.
  • HLB Hydrophilic / Lipophilic Balance
  • HLB value is an indication of the solubility of the surfactant. The lower the HLB value the more lipophilic or oil soluble the surfactant is. On the contrary, the higher the HLB value the more water soluble or hydrophilic the surfactant is. This surfactant solubility property is an indicator of its likely end use.
  • HLB value is the molecular weight percent of the hydrophilic portion of the nonionic surfactant divided by five. This number is a relative or comparative number and not a mathematical calculation.
  • the micelles forming blockcopolymers according to the present invention have an HLB value of about 9 to 20.
  • Water is unique in terms of its properties as solvent, which arise from a singular cohesive energy due to the strongest hydrogen bridging network among polar solvents. Surface activity and tendency to self-assembly is displayed when a dissolved molecule presents an apolar moiety attached to polar (ionic or nonionic groups), due to its dual interaction with water.
  • the most common polar group found in aqueous block copolymer micelles is poly(ethylene oxide), attached to a variety of apolar moieties.
  • the simplest a polar group is a long hydrocarbon chain, as found in normal nonionic surfactants.
  • PEO Poly(ethylene oxide)
  • PEG poly(ethylene glycol)
  • UST upper critical solution temperature
  • PEO-PPO-PEO block copolymers [PPO standing for poly(propylene oxide)] which is a family of ABA-type tri-block copolymer consisting of more than 30 non-ionic amphiphilic copolymers.
  • PEO-PPO ratio controls the polymer solubility (or its HLB, hydrophilic-lipophilic balance, value), hence driving its most suitable application.
  • each poloxamer in terms of molecular weight, appearance (liquid, solid paste), hydrophilicity/hydrophobicity and solubility may be determined by the chain length of the polyoxyethylene (PEO) units and polyoxypropylene (PPO) units.
  • PEO polyoxyethylene
  • PPO polyoxypropylene
  • Copolymer aggregation may be directed by changes in either concentration or temperature or both.
  • a process for producing the composition as described herein the process may include a first aggregation step, from unimers to micelles, wherein the concentration at which micelles start to appear isdefined as the critical micelle concentration (cmc), likewise to normal surfactants,.
  • the temperature at which, for a given polymer concentration, micelles are formed is called critical micelle temperature (cmt).
  • the cmc and cmt values may be obtained by using a variety of techniques, similar to investigations with normal surfactants.
  • surface tension measurements which usually present more than one break point, solubilization of apolar dyes or spectroscopic probes, including absorption, fluorescence measurements, light- scattering Techniques, NMR spectroscopy, DSC (usually high sensitivity DSC) , and scanning densitometry; these last two techniques are appropriate only for cmt determination, whereas the other apply to both cmc and cmt measurements.
  • the sizes and radius of the copolymer micelles described herein may remain fairly constant as the copolymer concentration increases, but they generally increase as temperature is raised.
  • AmicG RT In cmc
  • NEO and NPO are the number of EO and PO segments in the polymer molecule.
  • cmt (NEO + NPO)(R lnX) "1 x [1000 Mw _1 (0.367 log C - 1.255) - 0.0045 log C - 0.0070]
  • the hydrophobic PO units there may be a dominant role for the hydrophobic PO units on the aggregation process.
  • the EO contribution may be quite small, if not negligible. This may occur due to a counterbalance of a contribution from increase in solubility as the EO chain increases, and an opposite one from configuration entropy, since the polymer chain becomes larger and more difficult to arrange in solution.
  • the enthalpy of micellization can be determined by the following relationship using a high- sensitivity DSC at 0.5% copolymer solutions.
  • NEO and NPO are the number of EO and PO units per polymer molecule. This behavior was interpreted in terms of the dehydration of the hydrophobic PO units (since data for phase separation of pure PPO conforms to the same relationship), which was then identified as the key step in the aggregation process. Although significant structural changes may be observed at higher temperatures due to formation of higher order aggregates or mesophases, and, ultimately, at phase separation, manifested by the so called cloud point, enthalpy changes at those events are much smaller.
  • One explanation for this finding is that the most energetic step, PO dehydration, was already accomplished at the first aggregation stage. After this, the other structural changes would only involve changes of copolymer packing and not an extensive EO dehydration.
  • copolymer aggregation is associated with an enthalpy increase (endothermic process), it must be driven by a larger entropy increase, attributed to the release of water molecules involved in polymer (mostly PO units) solvation, which is a general behavior for aggregation of low-molecular- weight surfacants in water.
  • phase transitions are also associated with enthalpy increase, although smaller, and should be also entropy driven.
  • block copolymers which are able to form micelles are di-blocks of EO-PO and EO-B and tri-block versions, PO-EO-PO
  • BO-EO-BO BO; butylenes oxide
  • the latter are, sometimes, called reverse block copolymers, since their end groups are hydrophobic, in contrast to those with EO as end groups. Because association in water is obtained via these end groups, this may cause an additional entropic barrier, due to constraints related to the curving the macromolecule chain and, hence, their micellization is less favorable (cmc values are about one order of magnitude higher) than that of diblock and EO-X-EO copolymers.
  • these mostly spherical block copolymer micelles are larger than the ones formed by low molecular weight surfactants.
  • these spherical micelles contain between 15 and 60 molecules per aggregate, with hydrodynamic radii in the range of 6 to 10 nm, and may be values of the same order of magnitude for EO-BO-EO block copolymers.
  • these aggregates are classed as block ionomers or block polyelectrolytes.
  • the former occurs in organic solvents, where the ionic moieties form the core of the aggregate, surrounded by the apolar blocks, in a way similar to the formation of reverse micelles by low molecular weight surfactants; in fact, this terminology also applies to macromolecular surfactants as these block copolymers.
  • the other arrangement, with the core composed by the noionic blocks and the micelle corona containing the ionic blocks is verified in water or mixtures of water and a polar organic solvent (like methanol).
  • star and crew-cut micelles Another division is based on the arrangement of these chains in solution, mostly affected by their relative sizes and stretching due to solvation, leading to two limit cases, known as star and crew-cut micelles.
  • the spherical star micelles may be composed of a small core and large corona region, associated with relatively smaller insoluble blocks. The latter regime is found when the copolymer presents a large nonionic block and a short ionic moiety.
  • Block polyelectrolytes may assemble in both regimes, whereas for block ionomers, crew-cut micelles have not been observed yet.
  • Example of micelle- forming block copolymers may be selected from the group consisting of di or triblock copolymers such as, for example, but not limited to Poloxamers which are a group of poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) triblock copolymers (PEO-PPO- PEO) (Pluronics®, Lutrol®, Kolliphor® or Synperonics®), poly (propylene oxide)-poly (ethylene oxide)- poly (propylene oxide) triblock copolymers (PPO-PEO-PPO), poly (butylene oxide)-poly (ethylene oxide)- (butylene oxide) triblock copolymers (PBO-EO- PBO), poly (ethylene oxide)-poly (butylene oxide)-poly (ethylene oxide) triblock copolymers (PEO-PBO-PEO), Poly(ethylene oxide)-Poly (butylene oxide)-poly (ethylene oxide) triblock copolymers (PEO-PBO
  • polyethylene glycol)-poly(aspartic acid) PEG-P[Asp(ADR)]
  • PEG-block-poly(N- hexyl stearate L-aspartamide) PEG-b-PHSA
  • poly(DL-lactide-co-2-methyl-2- carboxytrimethylene carbonate)-graft-PEG poly(LA-co-TMCC)-g-PEG
  • PEG- poly(benzyl aspartate) block-copolymer PEG-block poly(glutamic acid) PEG-b- poly(Glu)
  • polysorbates Tween
  • Polysorbate 20 Polyoxy ethylene and sorbitan monolaurate
  • Polysorbate 40 Polyoxyethylene and sorbitan monopalmitate
  • Polysorbate 60 Polyoxyethylene and sorbitan monostearate
  • Polysorbate 80 Polysorbate 80
  • hydrophobic fatty component The most suitable materials which can act as an appropriate hydrophobic fatty component according to the present invention are alkenes, waxes, esters, fatty acids, alcohols, and glycols, each with varying performance and properties independent of each other.
  • Example of materials that may be used as hydrophobic fatty component is selected from the group consisting of alkenes such as paraffin wax which is composed of a chain of alkenes, normal paraffins of type C n H 2 n+2 which are a family of saturated
  • hydrocarbons which are waxy solids having melting point in the range of 23-67°C (depending on the number of alkanes in the chain); both natural waxes (which are typically esters of fatty acids and long chain alcohols) and synthetic waxes (which are long-chain hydrocarbons lacking functional groups) such as bee wax, carnauba wax, japan wax, bone wax, paraffin wax, Chinese wax, lanolin (wool wax), shellac wax, spermaceti, bayberry wax, candeliUa wax, castor wax, esparto wax, jojoba oil, ouricury wax, rice bran wax, soy wax, ceresin waxes, montan wax, ozocerite, peat waxes, microcrystalline wax, petroleum jelly, polyethylene waxes, fischer-tropsch waxes, chemically modified waxes, substituted amide waxes; polymerized a-olefins;
  • fatty acids such as lauric acid, myristic acid, palmitic acid, palmitate, palmitoleate, hydroxypalmitate, stearic acid, arachidic acid, oleic acid, stearic acid, behenic acid, sodium stearat, calcium stearate, magnesiu stearate, hydroxyoctacosanyl hydroxystearate, , oleate esters of long-chain, esters of fatty acids, fatty alcohols, esterified fatty diols, hydroxylated fatty acid, hydrogenated fatty acid (saturated or partially saturated fatty acids), aliphatic alcohols, phospholipids, lecithin, phosphathydil cholin, triesters of fatty acids for example triglycerides received from fatty acids and glycerol (1,2,3-trihydroxypropane) including fats and oils such as coconut oil, hydrogenated coconut oil, cacao butter (also called
  • Blend polymer can also be used as an appropriate hydrophobic fatty component.
  • the blend can be either miscible or immiscible where the former generally results only in one melting point whereas the latter may show separated melting points attributed to the pure fatty component.
  • FFP HPC or a polymeric blend comprising HPC and PVA
  • FA OA, SA, MA, BA
  • Fig. 6 is a schematic illustration of a melt method for preparing a film composition according to some demonstrative embodiments described herein.
  • Fig. 6 illustrates a melt method for preparing a film composition containing hydrophilic film forming polymer, micelles forming blockcopolymer and a hydrophobic fatty component.
  • a base suspension where via elevating the temperature above a certain point, e.g., above the LCST, a resulting suspension is formed.
  • a base aqueous suspension 610 of hydrophilic film forming polymer comprising Hydroxypropyl cellulose (HPC) particle 608, Pluronic® particle 606, liquid Fatty Acid (FA) 604 and a few Pluronic® encapsulated fatty acid particles 602.
  • HPC Hydroxypropyl cellulose
  • Pluronic® particle 606 Pluronic® particle 606, liquid Fatty Acid (FA) 604 and a few Pluronic® encapsulated fatty acid particles 602.
  • the suspension is placed in a receptacle with a homogenizer 618, e.g., a high shear homogenizer.
  • the base suspension is exposed to a temperature higher than its LCST, e.g., 70C as shown in Fig. 6, and then a melt of both micelles forming blockcopolymer and a hydrophobic fatty component is added into the suspension while high agitation using a high shear homogenizer.
  • a temperature higher than its LCST e.g., 70C as shown in Fig. 6
  • a melt of both micelles forming blockcopolymer and a hydrophobic fatty component is added into the suspension while high agitation using a high shear homogenizer.
  • the resulting solution is comprised of HPC aqueous solution 612 which includes mainly Pluronic® encapsulated fatty acid particles 602, having a core of solid FA 616.
  • Fig. 7 is an example of specific micelle formation.
  • a micelle- forming blockcopolymer according to the present invention may have a PEO 700 and a PPO 702.
  • the micelle structure upon formation of the micelle, may include at least one micelle- forming blockcopolymer (poloxamer) 708 comprising POP group 704 and at least one POE group 706 .
  • FIG. 8 is a schematic illustration of a Pluronic® encapsulated fatty acid particles 800 in an HPC aqueous solution 802, and an enlarged view of a micelle structure 806 (Pluronic® micelle), having a solid FA core 804.
  • micelle structure 806 may contain the hydrophobic fatty component formed in melt method in the hydrophilic film forming polymer solution at a temperature below LCST of hydrophilic film forming polymer and above LCST of the micelles forming block-copolymer and at a concentration above its CMC.
  • Fig. 9 illustrates an exemplary preparation process of a suspension for coating process based on a melt method, according to the present invention, comprising hydroxypropyl cellulose (HPC) as hydrophilic film forming polymer, Poloxamer as a micelle forming block-copolymer and a fatty acid (FA) as a hydrophobic fatty component.
  • HPC hydroxypropyl cellulose
  • Poloxamer as a micelle forming block-copolymer
  • FA fatty acid
  • HPC is stirred with H 2 0 at 1 C of block 902.
  • FA and Poloxamer may undergo heating at 70°C to provide an FA and Poloxamer as shown in block 910.
  • Melt 910 undergoes homogenization and mixed with the solution of block 902 to provide an HPC suspension 906.
  • the suspension 906 is cooled to 40°C to provide an HPC Solution and Poloxamer /FA Micro-Solid Emulsion as shown in block 908, which may be used for coating at 4 fC.
  • Fig. 10 illustrates an exemplary preparation process of a suspension for coating based on a melt method, according to the present invention, comprising a polymeric blend comprising hydroxypropyl cellulose (HPC) and polyvinyl alcohol (PVA) as hydrophilic film forming polymer, Poloxamer as a micelle forming block-copolymer and a fatty acid (FA) as a hydrophobic fatty component.
  • HPC hydroxypropyl cellulose
  • PVA polyvinyl alcohol
  • Poloxamer as a micelle forming block-copolymer
  • FA fatty acid
  • a polymeric blend comprising PVA + HPC is stirred with H 2 0 at room temperature (RT), of block 1002.
  • FA and Poloxamer may undergo heating at 70°C to provide an FA and Poloxamer as shown in block 1010.
  • Melt 1010 undergoes homogenization and mixed with the solution of block 1002, which is preheated to 40°C, to provide an HPC suspension 1006.
  • the suspension 1006 is further heated at 40°C to provide an HPC Solution and Poloxamer /FA Micro-Solid Emulsion as shown in block 1008, which may be used for coating at 40 ° C.
  • Figs. 11 and 12 illustrate n exemplary preparation process of a suspension for coating process based on an organic solution method, according to some embodiments of the present invention.
  • the process comprising hydroxypropyl cellulose (HPC) as hydrophilic film forming polymer, Poloxamer as a micelle forming block-copolymer and a fatty acid (FA) as a hydrophobic fatty component.
  • HPC hydroxypropyl cellulose
  • Poloxamer as a micelle forming block-copolymer
  • FA fatty acid
  • FA and Poloxamer may undergo stirring at room temperature and mixed with EtOH, block 1114, at room temperature to yield FA and Poloxamer as shown in block 1112.
  • Melt 910 undergoes homogenization and mixed with the solution of block 1102 to provide an HPC solution 1106.
  • the solution 1 106 is mixed at 40 ° C to provide an HPC Solution and Poloxamer + FA Solid Suspension as shown in block 1110.
  • the suspension of block 1110 is then dried to yield a film 1108 which contains HPC + Poloxamer + FA Solid Dispersion.
  • film containing HPC + Poloxamer + FA Solid Dispersion undergoes milling to provide micro particles 1210 containing HPC + Poloxamer + FA Solid Dispersion.
  • HPC is stirred with H 2 0 at 1GC of block 1208.
  • Micro particles 1210 undergo homogenization and are mixed with the solution of block 1208 (which is cooled to a temperature of 40°C ) to provide an HPC solution 1204.
  • the HPC solution 1204 is further mixed at a temperature of 40 ° C to provide an HPC solution + Poloxamer /FA Micro-Solid Emulsion 1206.
  • Fig. 13 is a schematic illustration of a film composition 1302 according to some embodiments of the present invention, comprising hydrophilic film forming polymer in which hydrophobic fatty component is molecularly blended by a microstructure of micelles using a micelle forming block-copolymer.
  • film 1302 includes a Pluronic® Micelle 1302 having a Solid FA core 1308 and a Pluronic® Encapsulated FA 1306, dispersed in an HPC matrix film 1304.
  • Fig. 14 illustrates an exemplary preparation process of a suspension for coating process based on an oil solution method, according to the present invention, comprising hydroxypropyl cellulose (HPC) as hydrophilic film forming polymer, Poloxamer as a micelle forming block-copolymer and a fatty acid (FA) as a hydrophobic fatty component.
  • HPC hydroxypropyl cellulose
  • Poloxamer as a micelle forming block-copolymer
  • FA fatty acid
  • HPC is stirred with H 2 0 at 1 C, of block 1402.
  • FA and Poloxamer liquid as shown in block 1410.
  • FA and Poloxamer liquid of block 1410 undergoes homogenization and mixed with the solution of block 1402, which is cooled to 40°C, to provide an HPC solution 1406.
  • the solution 1406 is further mixed at 40°C to provide an Oil in Water (o/w)
  • Micro-Emulsion 14008 which contains HPC Solution and Poloxamer and FA and oil.
  • the O/W Micro-Emulsion 1408 may be used for coating.
  • Table 1 The materials list used for the preparation of different film formulations Name Brand Manufacturer Excipient Abbreviation
  • the stirring was kept for additional 45 min at about 35 °C.
  • the dispersion was then carefully poured into a polystyrene Petri dish and allowed to dry at room temperature under a laminar air flow using a regular chemical hood.
  • a Versaperm MkV Digital WVTR Meter with 10cm 2 measuring area, equipped with an electrolytic detection sensor was used to measure the WVTR of different films.
  • the method used was based on ISO 15106-3:2003 Plastics— Film and sheeting—
  • the results were expressed by the weight of water vapor (gram) transmitted through an area of 1 m 2 during 1 day (g/m 2 . day).
  • Table 3 presents comparatively the results of WVTR of the different films.
  • Example 7 Mechanical Properties Test Specimens Preparation Dog Bone shaped specimens were cut from the different films based on different formulations. The measuring are of the specimen was 30mm in length and 6mm in width. The thickness of the each specimen was measured and recorded. Measurement Method
  • the mechanical properties of different samples were measured using an INSTRON model 5982 with a load cell capacity of 100KN, which is a stress/strain apparatus of Instron (High Wycombe, UK). The test was carried out under the crosshead speed of 2mm/min in a relative humidity of 40-50% at room temperature. Three different specimens of the same type of film were analyzed in order to yield one mean mechanical measurement.
  • Fig. 15A depicts a graph illustrating Stress-Strain curve representing the mechanical properties of different coating formulations 1502, 1504 and
  • lo and Ao are respectively the initial length and cross section surface area of the sample.
  • Fig 15B depicts a Stress-Strain curve representing the mechanical properties of different film formulations consisting of a mixture of HPC and SA, in accordance with some demonstrative embodiments.
  • Fig. 15B shows stress vs. percentage of strain for different ratios of polymer to fatty acid showing reference line 1514 compared to film 32 (HPC:SA ratio of 80:20) represented by line 1512, compared to film 33 (HPC:SA ration of 90: 10) represented by line 1510 and film 31 (HPC:SA ration of 70:30) represented by line 1508.
  • Highly moisture sensitive tablets containing CaCl 2 as an active agent were prepared and coated with different film formulations. Unprotected (unpackaged) coated tablets were left at room temperature for different periods of time. At certain intervals of time the changes occurred in the tablets, in terms of the weight and appearance, were recorded and related to the specific coating film formulation.
  • Calcium chloride (CaCl 2 ), Avicel PH-101 (microcrystalline cellulose NF), lactose, spray-dried and magnesium stearate were used for preparing the highly moisture sensitive tablets.
  • Y-cone blender was used to prepare the mixture for tabletation.
  • a rotary tablet press -PTK was used to compress the tablet.
  • Calcium chloride (140g), Avicel (280g), lactose (973g) and magnesium stearate (7g) were properly mixed using a Y-cone blender for 15 minutes.
  • the resulting mixture powder were then compressed to an oval shaped caplets of 12/16 mm using a rotary tablet press of PTK Lab PR-LM.
  • the average weight of tablet was 270g.
  • the hardness of tablets was measured to be 12kp, tested using a hardness tester of Caleva THT - 15.
  • a Fluid Bed apparatus was used for coating the resulting caplets. This method consists of a continuous spraying of a coating solution into a fluidized bed onto the loaded solid particles. After an intermittently wetting and drying a continuous film is formed. A special attention is needed in this process to obtain a homogeneous film onto the surface of the tablets. Special care was taken of the following parameters: flow-rate of the spraying liquid, the atomizing air pressure, the flow rate and the temperature of the inlet fluidizing air.
  • Table 6 The results of the tablets stability test over the time at room temperature and 40 °C.
  • Figs. 17A and 17 B demonstrate the weight gain (% w/w) in tablets coated by different coating formulations over time at room temperature and at 40°C, respectively.
  • SEM Scanning Electron Microscope
  • HPC:SA:PSAA 70: 15: 15 (C) and HPC:SA:PSAA 65:30:5 (D) are depicted.
  • Example 10 Differential Scanning Calorimetry- (DSC)
  • the thermal properties of different samples based on different formulations were measured and compared to starting materials using a differential scanning calorimetry.
  • An empty aluminum pan was used as a reference and a heating rete of 10°C/minute was used to scan the thermal analysis from room temperature up to 100°C.
  • Fig. 19 is a thermogram demonstrating the thermal properties of HPC, in accordance with some demonstrative embodiments.
  • Fig 20 is a thermogram demonstrating the thermal properties of SA, in accordance with some demonstrative embodiments.
  • Fig 21 is a thermogram demonstrating the thermal properties of HPC:SA in a ratio of 80:20, respectively, in accordance with some demonstrative embodiments.
  • Fig 22 is a thermogram demonstrating the thermal properties of HPC:PSAA in a ratio of 80:20, respectively, in accordance with some demonstrative embodiments.
  • Fig 23 is a thermogram demonstrating the thermal properties of HPC:SA:PSAA in a ratio of 65:25: 10, respectively, in accordance with some demonstrative embodiments.
  • Fig 24 is a thermogram demonstrating the thermal properties of HPC:SA:PSAA in a ratio of 65:30:5, respectively, in accordance with some demonstrative embodiments.
  • the melting point and heat of fusion attributed to the SA of different samples are presented in Table 7.

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Abstract

La présente invention concerne une composition de film pour enrober une composition pharmaceutique, nutraceutique ou nutritionnelle comprenant un mélange moléculaire d'un polymère filmogène hydrophile ayant des propriétés de formation de sol-gel thermosensible et ayant une première température de solution critique inférieure (LCST), un composant gras hydrophobe et un copolymère séquencé de formation de micelles ayant une deuxième température de solution critique inférieure (LCST) et une valeur HLB d'environ 9 à 20, ladite deuxième LCST étant inférieure à ladite première LCST.
PCT/IL2016/050225 2016-02-28 2016-02-28 Composition de film et procédés de production de celle-ci WO2017145143A1 (fr)

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CN201680082816.0A CN108697652A (zh) 2016-02-28 2016-02-28 膜组合物及生产膜组合物的方法
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CN108610491A (zh) * 2018-05-09 2018-10-02 同济大学 温敏性接枝聚合物、可载细胞的水凝胶及制备方法与应用
WO2019202604A1 (fr) * 2018-04-20 2019-10-24 Polycaps Holdings Ltd. Granule probiotique résistant à l'humidité et ses procédés de production
CN111793236A (zh) * 2020-08-06 2020-10-20 香港中文大学（深圳） 复合凝胶及其制备方法和智能窗户
JPWO2021124393A1 (fr) * 2019-12-16 2021-06-24
CN114040755A (zh) * 2019-06-20 2022-02-11 溶致递送系统有限公司 嵌入有纳米域和/或生物活性物质的聚合物软膜及其生产方法
CN114539494A (zh) * 2022-03-15 2022-05-27 阜阳师范大学 一种基于温敏性聚合物的感温贴及其制备方法
WO2022212556A1 (fr) * 2021-03-30 2022-10-06 Apeel Technology, Inc. Composition de film barrière comestible
WO2024073633A3 (fr) * 2022-09-30 2024-05-10 Diaz Jairo A Contrôle précis de la taille et de la forme de colloïdes à l'aide de micelles de copolymère séquencé actif selon la température

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CN111072954B (zh) * 2019-12-27 2021-01-08 浙江大学 一种聚四氢呋喃-聚氨基酸嵌段共聚物及其合成方法
CN112022838B (zh) * 2020-09-17 2022-08-19 澳美制药厂有限公司 抗真菌药物组合物及其制备方法和成膜凝胶
CN112159537B (zh) * 2020-09-29 2023-03-21 扬州迈尔斯新材料科技有限公司 一种长度可控的液晶嵌段共聚物胶束及其制备方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019202604A1 (fr) * 2018-04-20 2019-10-24 Polycaps Holdings Ltd. Granule probiotique résistant à l'humidité et ses procédés de production
CN112292118A (zh) * 2018-04-20 2021-01-29 波利凯普斯控股有限公司 耐湿性益生菌颗粒剂及其产生方法
CN108610491A (zh) * 2018-05-09 2018-10-02 同济大学 温敏性接枝聚合物、可载细胞的水凝胶及制备方法与应用
CN114040755A (zh) * 2019-06-20 2022-02-11 溶致递送系统有限公司 嵌入有纳米域和/或生物活性物质的聚合物软膜及其生产方法
JPWO2021124393A1 (fr) * 2019-12-16 2021-06-24
CN111793236A (zh) * 2020-08-06 2020-10-20 香港中文大学（深圳） 复合凝胶及其制备方法和智能窗户
WO2022212556A1 (fr) * 2021-03-30 2022-10-06 Apeel Technology, Inc. Composition de film barrière comestible
CN114539494A (zh) * 2022-03-15 2022-05-27 阜阳师范大学 一种基于温敏性聚合物的感温贴及其制备方法
WO2024073633A3 (fr) * 2022-09-30 2024-05-10 Diaz Jairo A Contrôle précis de la taille et de la forme de colloïdes à l'aide de micelles de copolymère séquencé actif selon la température

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