WO2015117004A1 - Procédé de préparation de films - Google Patents

Procédé de préparation de films Download PDF

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Publication number
WO2015117004A1
WO2015117004A1 PCT/US2015/013916 US2015013916W WO2015117004A1 WO 2015117004 A1 WO2015117004 A1 WO 2015117004A1 US 2015013916 W US2015013916 W US 2015013916W WO 2015117004 A1 WO2015117004 A1 WO 2015117004A1
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WO
WIPO (PCT)
Prior art keywords
film
substrate
pharmaceutically acceptable
powder
layer
Prior art date
Application number
PCT/US2015/013916
Other languages
English (en)
Inventor
Justin M. Keen
James W. Mcginity
Justin R. Hughey
Robert O. Williams
Leena Kumari PRASAD
Original Assignee
Board Of Regents, The University Of Texas System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Board Of Regents, The University Of Texas System filed Critical Board Of Regents, The University Of Texas System
Publication of WO2015117004A1 publication Critical patent/WO2015117004A1/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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B12/00—Arrangements for controlling delivery; Arrangements for controlling the spray area
    • B05B12/16—Arrangements for controlling delivery; Arrangements for controlling the spray area for controlling the spray area
    • B05B12/20—Masking elements, i.e. elements defining uncoated areas on an object to be coated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
    • B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
    • B05B5/08—Plant for applying liquids or other fluent materials to objects
    • B05B5/081—Plant for applying liquids or other fluent materials to objects specially adapted for treating particulate materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
    • B05B5/08—Plant for applying liquids or other fluent materials to objects
    • B05B5/087—Arrangements of electrodes, e.g. of charging, shielding, collecting electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
    • B29C41/02—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor for making articles of definite length, i.e. discrete articles
    • B29C41/08—Coating a former, core or other substrate by spraying or fluidisation, e.g. spraying powder

Definitions

  • Polymeric films have been used commonly in pharmaceutical and medical products. For oral administration, polymeric films have been used as a tablet coating or as a free film for oral, buccal or sublingual drug delivery. Polymeric films are also used for topical and transdermal drug delivery, as well as functioning as bandaids or wound dressings with or without the incorporation of active ingredients.
  • Free films are typically prepared by solvent casting or hot melt extrusion methods.
  • Solvent casting techniques involve the casting of a solution or suspension to a suitable substrate and removing the solvent, whereby a film is formed on the substrate.
  • Solvent evaporation techniques also present challenges as some materials (actives and inactives) are insoluble or unstable in aqueous or organic solvents, and there is the additional problem of removing all the organic solvent from a preparation for human or animal use.
  • the materials are typically exposed to high temperature and high shear for from thirty seconds to two minutes or more in order to melt the polymeric material, thus limiting the technique to actives and inactives that can withstand such temperatures and shear.
  • Dry powder coating processes have been developed to produce film coatings without the need for water or organic solvents.
  • a charged mixture of finely ground particles and polymers is sprayed by an electrostatic gun onto a grounded substrate surface and then the particle layers are cured to form a film coating on the substrate.
  • powder coatings are applied to solid dosage forms such as tablets or pellets for cosmetic purposes, taste masking or in order to affect the release of the active from the dosage form, for delayed or controlled release, for example.
  • the entire tablet or pellet must be enclosed in the coating layer so that the active ingredient(s) are not exposed to the environment, or are exposed in a controlled manner.
  • the present disclosure relates to free film compositions and methods of producing free films that utilize electrostatic spray technology and that provide novel compositions of free films that are free of solvent and that are produced without exposing the ingredients to high heat, high heat for long durations of time, or shear.
  • a powder or processed powder is applied to a substrate using electrostatic charge, but the produced film does not strongly or permanently adhere to the substrate such that the film can be removed to produce an intact free film.
  • the substrate is selected, modified or treated such that the applied and cured film does not permanently or tightly adhere.
  • the substrate itself has a non-stick coating, or can take the form of a highly polished metal.
  • the powder is charged and applied to the grounded substrate using an electrostatic powder gun.
  • the substrate can be a non-conductive, thin material that is placed into direct contact with a grounded material such that the powder is sprayed on one side of the substrate and the other side of the substrate is contacting the grounded material.
  • This approach is a departure from the current uses of electrostatic powder guns, as those uses are intended to produce powder layers highly bound to their substrates such that a permanent or semi-permanent film coating is achieved.
  • energy is applied to the deposited powder layer effective to fuse the powder to form a film, which is then removed from the substrate.
  • Appropriate fusing techniques include, but are not limited to heat, infrared (IR) or UV irradiation.
  • a uniform film, deposited without solvents, containing active agent, nutrient, and/or flavorant is provided.
  • the materials can be pre-processed to prepare a uniform powder blend or milled to produce a particle size suitable for electrostatic powder layering prior to electrostatically depositing onto a non-stick conducting substrate.
  • Appropriate granulation processes include, but are not limited to, low or high shear granulation, dry granulation, fluid bed granulation, and thermal processing techniques. High shear granulation results in the agglomeration of powders using heat or small quantities of solvent.
  • the solvent is used to facilitate particle engineering and uniformity, and is substantially removed by drying prior to electrostatic layering.
  • Substantially removing the solvent is intended to convey its ordinary meaning in the art, and it is understood that in the described embodiments the solvent is removed to an appropriate or acceptable level, which can be but is not limited to, less than about 5%, less than 4%, less than 3%, less than 2% or less than about 1%.
  • the granules can also be formed by dry granulation—such as slugging or roller compaction— followed by milling.
  • the granules can be formed by thermal processing techniques such as hot melt extrusion, for example, to create an intimate mixture, promote interactions, or alter the solid state of the formulation components, including but not limited to the preparation of solid dispersions or amorphous solid dispersions.
  • thermal processing techniques such as hot melt extrusion, for example, to create an intimate mixture, promote interactions, or alter the solid state of the formulation components, including but not limited to the preparation of solid dispersions or amorphous solid dispersions.
  • the extruded product is then milled to the appropriate particle size.
  • the powder is prepared or processed as described above, or by alternate techniques known to those in the art such as spray drying, wet granulation or re-compression, and is subsequently applied to a substrate using an electrostatic powder layer technique, such as corona charging, or tribo charging.
  • the deposited powder layer is then cured into a uniform film by heating in an oven or by UV irradiation, for example, removed from the substrate and trimmed if necessary.
  • a film that contains a therapeutically active agent that is dispersed in the film as discrete particles that can themselves be processed or coated with a flavorant or sweetener (i.e., microencapsulated), such as would be desirable for bitter medicaments.
  • a blend of the processed therapeutic particles and a film former is prepared and electrostatically applied to a non-stick conducting substrate.
  • the film is formed by subjecting it to a radiant energy source such that the components of the therapeutic particle remain intact.
  • the resulting film can be administered orally for rapid disintegration and the remaining therapeutic particles swallowed.
  • the therapeutic particles can be deposited on a substrate followed by electrostatic deposition of the film forming composition, or prepared in the reverse order.
  • discrete film units are produced without the need for trimming or cutting.
  • a thin, non-conducting stencil is placed over a conductive substrate, where the voids in the stencil are in the shape of the desired film unit.
  • the conductive substrate is electrically grounded and the powder formulation is electrostatically deposited such that the powder adheres to the substrate only where there is an electric potential between the powder and the substrate and is held in place due to charge coupling of the powder with the substrate.
  • the powder is then cured into a film using radiant heat with an intensity selected such that the powder is softened and cured and the stencil material is substantially unaffected.
  • the curing step can be performed prior to or after removing the non-conductive stencil.
  • a segmented multilayered film is provided.
  • a thin, non-conducting stencil is placed over a conductive interchangeable substrate.
  • a first stencil is used to produce discrete shapes in contact with the substrate.
  • a powder formulation is then electrostatically deposited onto the substrate and cured, forming discrete domains on the substrate areas that are exposed and this layer is then cured.
  • the first stencil can be replaced with a stencil of a different design and a second powder electrostatically deposited on the substrate followed by a secondary curing step. This process can be repeated as desired to prepare a multitude of layered or segmented film structures. Films produced by this process can provide aesthetic or informative designs, for example, when colorants are added. Alternatively, films can be prepared containing multiple therapeutic agents, each embedded in a different location in the film.
  • a multilayered film is produced that contains an agent for controlled release. These films provide certain advantages for pharmaceutical delivery to the skin, or to a mucosal surface, wound or surgical cavity.
  • the films include a bioadhesive component, such as a mucoadhesive polymer.
  • exemplary mucoadhesives include polyethylene oxide, carbomer and polycarbophil.
  • a layered film can be prepared by depositing a layer of mucoadhesive powder followed by a layer of therapeutic agent and then followed by a non-adhesive impermeable polymer.
  • a further aspect of the disclosure is a method of forming a continuous film.
  • a substrate is continuously drawn across a conductive or grounded roll.
  • the composition and thickness of the substrate material are selected to allow electrostatic interaction of a charged powder and the substrate.
  • An electrostatic powder gun can be oriented in certain embodiments to apply a powder layer to the substrate immediately before the powder and web pass under a radiant heater to cure the film.
  • a large conducting or grounding roller can serve to continually index the substrate material across the path of an electrostatic gun and a radiant heater.
  • Fig. 1 is an example process for free film formation.
  • Step 1 shows the electrostatic layering of the powder on the substrate;
  • Step 2 depicts curing of the film with radiant heat; and
  • Step 3 shows the removal of the film from the substrate.
  • Fig. 2 is an example powder layering configuration for free film formation using a thin non-conducting stencil, where A is a non-conducting stencil, B is a conductive substrate, C is Ground, and D is an electrostatic gun.
  • Fig. 3 is an example of a powder layering configuration for preparing discrete film units on a thin non-conducting removable substrate, where A is a
  • B is a conductor configured to contact the substrate at discrete sites
  • C is Ground
  • D is an electrostatic gun.
  • Fig. 4 is an example of films prepared using interchangeable stencils.
  • A is an example of a film a discrete design.
  • B is a tri-layered film, in which the middle layer is discrete.
  • Fig. 5 is an example of continuous production using a continuous temporary substrate for the film formation process.
  • the present disclosure can be described as solvent free films that can be formed by solvent free electrospray deposition and in certain preferred embodiments are pharmaceutical, medicinal or even cosmetic films or strips for oral, buccal, sublingual or topical use by human or animal subjects.
  • Figs. 1 A-C a powder layering process for producing a free film as described herein is shown.
  • Fig. 1 A is the first step in which an electrospray gun 10 is connected to a negative voltage power supply 12 and to a supply of powder 14. The gun is used to spray charged powder particles onto a substrate 16 in whch the substrate is grounded 18 causing the powder to stick to the substrate through electrostatic attraction.
  • the deposited layer of powder is cured by exposure to radiant heat 24 in a ceramic heater 20 connected to a power source 25 to produce a cured film 22 on the substrate.
  • the substrate and powder are selected such that the free film 30 can be peeled from the substrate.
  • Fig. 2 is an alternate example of a powder layering powder process as shown in Fig. 1, layering configuration for free film formation using a thin non-conducting stencil, where a non-conducting stencil 32 is placed between the substrate 16 and the electrostatic spray gun 10 to create a patterned film.
  • FIGs. 3 A and B demonstrates an example of a powder layering
  • FIG. 3 A where an electrostatic gun 10 is used to spray powder onto a non-conducting and releasing substrate 42, that overlays a conductor 40 configured to contact the substrate at discrete sites to produce a patterned film.
  • An example of the conductor is shown in Fig. 3B from a side view (left) and substrate face view (right).
  • FIG. 4 demonstrates an example of films prepared using interchangeable stencils.
  • a discrete design can be added to a film in an alternate color or material, for example.
  • Fig. 4B shows an example of a tri-layered film, in which the middle layer can include a discrete design 56. The design is shown in broken lines because it is hidden from the top view as shown. A cross-sectional view is shown in Fig. 4C.
  • Fig. 5 is an example of continuous production using a continuous temporary substrate for the film formation process.
  • a film substrate 60 is transported across a grounded roller 62 for powder deposition.
  • the roller than moves the sprayed film substrate past a ceramic heater to produce a cured film 64.
  • This cured film is then contacted by a separating device 66 to free the film 64 from the substrate film 60 and produce a continuous free film.
  • electrostatic deposition or layering refers to the process of charging particles having a size range of less than about lmm, or from about 100 run to about 1mm, or between about 1 nm and 1 mm, between about lum and 200 ⁇ , or between 2 um and 250 ⁇ , or between 2 ⁇ and 60 ⁇ , and impacting them onto a substrate non-stick substrate such as Teflon, stainless steel and the like such that through an electrostatic interaction they are substantially immobilized until cured. While commercially available corona powder coating guns are designed for this purpose, suitable alternative methods known to one of ordinary skill in the art can be utilized to charge and deposit the particles on a suitable substrate.
  • Such electrostatic powder layering devices are designed for solvent-free coating applications.
  • An example of such a device is the Vantage spray coating gun, manufactured by Nordson Corporation (Westlake, Ohio).
  • adherence of the final film to the substrate is required and release of the film from the substrate is considered a defect.
  • electrostatic deposition techniques for the formation of free films that do not adhere to the substrate after curing provides a novel technical advance in the field.
  • Polymer webs that lightly adhere to surfaces and are easily removed such as polyvinylidine chloride and polyethylene (for instance, SaranTM plastic wrap), are well known.
  • the use of a polymer web the exact chemistry of which is unimportant provided that it is stable during the film formation process, can facilitate the electrostatic interaction of particles and a grounded support. Furthermore, once cured, this polymer web is easily removed from the film.
  • a polymer web material in the form of a continuous roll of material can be drawn across a conducting substrate in a continuous manner such that the electrostatic deposition produces a continuous web of powder layered web material that can subsequently pass through a radiant heater to continuously cure the film.
  • a conductive substrate that resists adherence during curing can be formed by highly polishing a metal surface, which effectively reduces the contact surface area between the film and the substrate and removes any surface defects that can serve as an anchor for the film. Polishing techniques are well known and can be applied to a variety of metals. In certain embodiments, chrome or titanium nitride rollers are employed in cast film extrusion processes to transport and cool molten polymer extrudate.
  • Metal conductive substrates having a non-stick coating are appropriate for certain embodiments.
  • polytetrafluoroethylene PTFE also known as Teflon®
  • Teflon® polytetrafluoroethylene
  • Any non-stick coating applied to a conductive substrate is potentially suitable; provided that it is stable during the film curing process and provided that the coating is sufficiently thin so that electrostatic interactions between the powder and the substrate allow demobilization of the particles for curing.
  • the "curing process” is intended to convey its normal meaning in the art and refers to the fusion, or melting together of particles for film formation.
  • a layer of lubricant or glidant can be applied to the substrate to disrupt direct molecular interactions between the substrate and the film formulation.
  • Suitable materials include, but are not limited to minerals, such as talc; magnesium stearate; sodium stearyl fumarate, silicon dioxide; waxes; micronized polyols and the like.
  • the films of the present disclosure can be thin and quick dissolving or can be relatively thick, composed in certain embodiments of multiple layers depending on the intended use.
  • the films can be of any appropriate thickness, for example, including but not limited to from 0.02 mm to 5 mm for oral or buccal dissolving films and from 0.25 mm to 10 mm for topical applications, for example.
  • the total thickness can be from 0.05 mm to 15 mm.
  • a film can be part of a multilayer composition and that the attachment of a film as described to a backing or adhesive layer, for example, is also encompassed by the present disclosure.
  • oral use or oral delivery of a strip is meant that the strip is manufactured to be placed in the mouth and held on the tongue, for example, and that in certain embodiments such a strip dissolves quickly when placed in the mouth of a human subject.
  • Dissolving quickly can mean dissolving in a time period from a few second to several minutes, including but not limited to from about 10 seconds to about 10 minutes, or about 10, 20, 30, 40, or 50 seconds or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes.
  • Buccal delivery refers to a product designed to be placed on the inside of the cheek. When placed under the tongue, the formulation is referred to as a sublingual delivery product. Topical delivery refers to delivery of a medicament or agent directly to the surface to be treated.
  • the free films of the present disclosure can include any of the inert ingredients known in the art for use in orally dissolving films, including but not limited to polymers, including water soluble, water insoluble, and water permeable polymers, plasticizers, sweetening agents, saliva stimulating agents, flavoring agents, coloring agents, stabilizers, buffers, thickeners and preservatives.
  • the films can also include any appropriate active agent known in the art and can be produced without active agents for non-therapeutic purposes such as for breath refreshment or flavor delivery as well.
  • active agents can be included in the films, including but not limited to agents for treatment of nausea, including chemotherapy and radiotherapy induced nausea, anticholinergics, antihistamines, surfactants, stomach buffering agents, hormones, addiction treatments including opioid addiction, anesthetics, analgesics, decongestants, cough suppressants, antipyretics, antitussives, antibiotics, breath fresheners, teeth whiteners. Actives can be absent or present in any appropriate concentration, including from 0.1% to 99%, from 1% to 90%, from 5% to 85%, from 10% to 70% from 20% to 50%,
  • water-soluble polymers are used in the disclosed formulations.
  • Such polymers can include, but are not limited to polyethylene oxide (PEO), ethylene oxide-propylene oxide co-polymers, polyethylene-polypropylene glycol (e.g.
  • polysaccharides such as carbomer, polycarbophil, chitosan, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, polyacrylates such as carbomer, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, polyhydroxyalkylcarboxylic acids, alginic acid and its derivatives such as carrageenate alginates, ammonium alginate and sodium alginate, starch and starch derivatives, polysaccharides,
  • carboxypolymethylene polyethylene glycol
  • natural gums such as gum guar, gum acacia, gum tragacanth, karaya gum and gum xanthan, povidone, gelatin or the like.
  • water insoluble polymers may also be used in the disclosed formulations.
  • Such polymers can include, but are not limited to ethylene vinyl acetate, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acylate, cellulose diactylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate and mono-, di- and tri-cellulose acrylates, acrylic polymers, acrylic copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl
  • methacrylate copolymers polyacrylic acid, polymethacrylic acid, methacrylic acid aklylamine copolymer, polymethyl methacrylate, polymethacrylic acid anhydride, polymethacrylate, polyacrylamide, polymethacrylic acid anhydride and glycidyl methacrylate copolymers.
  • Plasticizers suitable for use in the present disclosure include, but are not limited to low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, glycerol, and glycerin.
  • plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate.
  • compositions of the present disclosure can also include one or more functional excipients such as bioadhesive or mucoadhesive polymers, lubricants, thermal lubricants, antioxidants, buffering agents, alkalinizing agents, binders, diluents, sweeteners, chelating agents, colorants, flavorants, surfactants, solubilizers, wetting agents, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, retardants, pore formers, and fragrance.
  • functional excipients such as bioadhesive or mucoadhesive polymers, lubricants, thermal lubricants, antioxidants, buffering agents, alkalinizing agents, binders, diluents, sweeteners, chelating agents, colorants, flavorants, surfactants, solubilizers, wetting
  • Bioadhesive polymers include, but are not limited to polyethylene oxide, KLUCEL (hydroxypropylcellulose), CARBOPOL, polycarbophil, GANTREZ,
  • Poloxamer and combinations thereof, and others known to one of ordinary skill in the art.
  • Lubricants or thermal lubricants useful in the present disclosure include, but are not limited to fatty esters, glyceryl monooleate, glyceryl monostearate, wax, camauba wax, beeswax, vitamin E succinate, and a combination thereof.
  • antioxidant is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by oxidation due to the presence of oxygen free radicals or free metals in the composition.
  • Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
  • hypophophorous acid monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfite and others known to those of ordinary skill in the art.
  • suitable antioxidants include, for example, vitamin C, sodium bisulfite, vitamin E and its derivatives, propyl gallate or a sulfite derivative.
  • Binders suitable for use in the present disclosure include beeswax, camauba wax, cetyl palmitate, glycerol behenate, glyceryl monostearate, glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil, microcrystalline wax, paraffin wax, stearic acid, stearic alcohol, stearate 6000 WL1644, gelucire 50/13, poloxamer 188, and polyethylene glycol (PEG) 2000, 3000, 6000, 8000, 10000 or 20000.
  • a buffering agent is used to resist change in pH upon dilution or addition of acid or alkali.
  • Such compounds include, but are not limited to potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate, salts of inorganic or organic acids, salts of inorganic or organic bases, and others known to those of ordinary skill in the art.
  • alkalizing agent is intended to mean a compound used to provide alkaline medium for product stability.
  • Such compounds include, but are not limited to ammonia solution, ammonium carbonate, diethanolamine,
  • Exemplary binders include: polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene;
  • alkylcelluloses and cellulosic derivatives such as low substituted HPC
  • L-HPC methylcellulose
  • hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose
  • hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose
  • starches, pectins PLA and PLGA, polyesters (shellac), wax such as carnauba wax, beeswax
  • polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, and xanthan gum.
  • Exemplary chelating agents include EDTA and its salts, alphahydroxy acids such as citric acid, polycarboxylic acids, polyamines, derivatives thereof, and others known to those of ordinary skill in the art.
  • colorant is intended to mean a compound used to impart color to solid (e.g., tablets or film) pharmaceutical preparations.
  • Such compounds include, but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide, red, other F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and other materials known to one of ordinary skill in the art. The amount of coloring agent used will vary as desired.
  • flavorant is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation.
  • exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • Flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those of ordinary skill in the art.
  • Suitable surfactants include Polysorbate 80, sorbitan monooleate, polyoxymer, sodium lauryl sulfate or others known in the art. Soaps and synthetic detergents may be employed as surfactants. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts.
  • Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and
  • poly(oxyethylene)-block-poly(oxypropylene) copolymers for example, poly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphoteric detergents, for example, alkyl ⁇ -aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.
  • amphoteric detergents for example, alkyl ⁇ -aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.
  • a wetting agent is an agent that decreases the surface tension of a liquid.
  • Wetting agents would include alcohols, glycerin, proteins, peptides water miscible solvents such as glycols, hydrophilic polymers Polysorbate 80, sorbitan monooleate, sodium lauryl sulfate, fatty acid alkali metal, ammonium, and triethanolamine salts, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphoteric detergents,
  • Solubilizers include cyclodextrins, povidone, combinations thereof, and others known to those of ordinary skill in the art.
  • Exemplary waxes include carnauba wax, beeswax, microcrystalline wax and others known to one of ordinary skill in the art.
  • Exemplary absorption enhancers include dimethyl sulfoxide, Vitamin E PGS, sodium cholate and others known to one of ordinary skill in the art.
  • Preservatives include compounds used to prevent the growth of microorganisms. Suitable preservatives include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzyl alcohol,
  • cetylpyridinium chloride chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal and others known to those of ordinary skill in the art.
  • sweetener is intended to mean a compound used to impart sweetness to a preparation.
  • Such compounds include, by way of example and without limitation, aspartame, sucralose, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, malitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
  • compositions and active agents of this disclosure are administered in an "effective amount,” “effective dose,” or “therapeutically effective amount or dose.”
  • an “effective” amount or a “therapeutically effective amount” or dose of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect.
  • an “effective amount” is the amount of that composition or active agent that is effective to improve, ameliorate or prevent one or more symptoms of the condition being treated.
  • the amount that is "effective” will vary from subject to subject, depending on the age and general condition of the individual, or the particular active agent.
  • a therapeutic or effective dose or amount is determined by a physician and is often based on empirical data obtained by administering increasing doses until the best balance of benefit vs. side effects is reached.
  • the term "pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts as described (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm. ScL, 1997 (January), 86, 1, 1).
  • Other salts well known to those in the art may, however, be useful in the preparation of compositions of the disclosure including, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,
  • organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Example No. 1 The following examples are meant to illustrate the solution of preparing films by a solvent-free process that does not depend on viscoelastic flow properties.
  • Example No. 1 The following examples are meant to illustrate the solution of preparing films by a solvent-free process that does not depend on viscoelastic flow properties.
  • An orally administered pharmaceutical formulation for rapid disintegration containing the active ingredient chlorphenamine maleate was prepared from the components in Table 1.
  • Ingredient 2 was first passed through a 140-mesh sieve.
  • Ingredients 1-3 were then blended and the resulting blend was layered by electrostatic deposition onto a conductive copper substrate using a Nordson Vantage spray coating gun.
  • the substrate with layered powder was then cured in an infrared oven at 80°C until the film was fused.
  • the fused film was removed from heat and allowed to cool.
  • the film was peeled from the substrate, aided by initially separating the film from the substrate using a razor blade.
  • An orally administered pharmaceutical formulation containing the active ingredient dextromethorphan hydrobromide was prepared according the composition in Table 2. Ingredients 1-5 are blended. A stainless steel substrate was treated with magnesium stearate and the final powder blend was then layered by electrostatic deposition onto the treated substrate using a Nordson Vantage spray coating gun. The substrate was then placed in an infrared oven at 125 °C to fuse the powder into a film. The film was allowed to cool and subsequently peeled off the substrate, aided by separating the film from the substrate using a razor blade, to produce a free film.
  • Example No. 3 An orally administered pharmaceutical formulation containing the active ingredient albuterol sulfate was prepared according the composition in Table 3. Ingredients 1-8 are blended. A stainless steel substrate was treated with magnesium stearate and the final powder blend was then powder layered by electrostatic deposition onto the treated substrate using a Nordson Vantage spray coating gun. The substrate was then placed in an infrared oven at 125 °C to fuse the powder into a film. The film was allowed to cool and subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce a free film.
  • a pharmaceutical formulation for topical use in the oral cavity containing the active ingredient benzocaine was prepared from the components in Table 4.
  • Ingredients 1-2 were blended and layered by electrostatic deposition onto a conductive copper substrate using a Nordson Vantage spray coating gun. The substrate with layered powder was then cured in an infrared oven at 80°C until the film was fused. The layered substrate was removed from the oven and again grounded to allow the electrostatic deposition of the second layer.
  • Ingredients 3-4 were blended, passed through a sieve for deagglomeration and then layered by electrostatic deposition onto Layer 1. The bilayer film was again cured in an infrared oven at 110°C until fused. The film was allowed to cool and subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce a free film.
  • Verapamil has low oral bioavailability because of high hepatic first-pass metabolism.
  • a multilayer dosage form was prepared to directionally deliver the drug through a mucoadhesive layer into the oral mucosa, as it will adhere to the mucosa upon application to the mucosal surface and with an impermeable backing can provide directional release of the therapeutic agent.
  • the dosage form consists of three parts, an ethylcellulose backing layer, a mucoadhesive layer, and an internal compartment containing the verapamil, as shown in Table 5.
  • the multilayer dosage form was prepared by first electrostatically powder layering ingredient 1 onto a conductive substrate using aNordson Vantage spray coating gun and was then cured in an infrared oven at 80°C until the film was fused. The layered substrate was removed from the oven and again grounded to allow the electrostatic deposition of the second layer.
  • Ingredients 2-4 were blended and then layered by electrostatic deposition onto Layer 1.
  • the bilayer film was again cured in an infrared oven at 80°C until fused.
  • the bilayered substrate was removed from the oven and again grounded to allow the electrostatic deposition of the third layer.
  • Ingredient 5 was layered by electrostatic deposition on top of Layer 2.
  • the trilayer film was again cured in an infrared oven at 80°C until fused. The film was allowed to cool and subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce a free film.
  • a pharmaceutical formulation for transdermal administration containing the active ingredient lidocaine hydrochloride was prepared from the components in Table 6.
  • Ingredients 1-3 were blended and layered by electrostatic deposition onto a conducted stainless steel substrate using a Nordson Vantage spray-coating gun. The substrate with layered powder was then cured in an infrared oven at 80°C until the film was fused. The layered substrate was removed from the oven and again grounded for the electrostatic layering of the second layer.
  • Ingredient 4 was layered by electrostatic deposition onto Layer 1. The bilayer film was again cured in an infrared oven at 80°C until fused. The film was allowed to cool and was subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce a free film.
  • a pharmaceutical formulation for oral administration containing the active ingredient verapamil hydrochloride was prepared from the components in Table 7.
  • Ingredients 1-3 was blended and layered by electrostatic deposition onto a grounded stainless steel substrate using a Nordson Vantage spray-coating gun. The substrate with layered powder was then cured in an infrared oven at 80°C until the film was fused. The film was allowed to cool and was subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce a free film.
  • Itraconazole is known to be a poorly soluble compound and was prepared by being first molecularly dispersed in an enteric polymer. Itraconazole was prepared by hot melt extrusion in hydroxypropyl methylcellulose acetate succinate (HPMC AS), as well as Vitamin E TPGS and triethyl citrate (TEC). Alternatively, itraconazole can be dispersed in HPMC AS using the KinetiSol® process.
  • KinetiSol® is a fusion-based process that utilizes frictional and shear energies (no externally applied heat) to rapidly transition drug-polymer blends into a molten state with simultaneous high-intensity mixing.
  • Hot melt extruded and KinetiSol® based compositions require milling, such as with a ball mill.
  • the itraconazole composition was prepared according the composition in Table 8, using hot melt extrusion to produce an amorphous solid dispersion. The resulting extrudate was then milled, using a cryomill to produce a fine powder.
  • the processed dispersion powder was blended with ingredient 5 at varying dispersion loading as shown in Tablet 8.
  • Each final powder blend was then layered onto individual substrates, using a Nordson Vantage spray-coating gun.
  • the films were cured in an infrared oven at 80°C until fused.
  • the films were allowed to cool and subsequently peeled off the substrate, aided by initially separating the film from the substrate using a razor blade, to produce free films.
  • Free films were prepared using varying particle size distributions of polyethylene oxide, as shown in Table 9. Each particle size distribution was layered by electrostatic deposition onto a conductive substrate using aNordson Vantage spray-coating gun. Spraying was conducted for each particle size distribution for a duration of time in order to produce films with maximum thickness. The substrate with layered powder was then cured in an infrared oven at 80°C until the film was fused. The fused film was removed from heat and allowed to cool. The film was peeled from the substrate and characterized for weight, thickness, and disintegration time. Films of 2 cm x 2 cm were used for characterization. Average properties are reported below.
  • Example No. 1 Same as Example No. 1, except using a non-conductive, PET stencil with a void in the shape of a shaped, discrete film.
  • Example No. 2 Same as Example No. 2, except using a polyvinylidene chloride polymer web in contact with a stainless steel substrate. The substrate was then placed in an infrared oven at 80 °C to fuse the powder into a film. The film was allowed to cool and subsequently the web was removed from the substrate. The film was then peeled from the polymer web to produce a free film. Alternatively, the film can be removed from polymer web at point of use.

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Abstract

La présente invention concerne un procédé pour la préparation de films, sans l'utilisation de solutions ou de suspensions de solvant ou l'exposition à des températures élevées et à un cisaillement, à l'aide du dépôt ou de l'application en couches électrostatique. Une poudre ou une formulation de poudre traitée est appliquée en couches sur un substrat spécifiquement choisi ou traité de telle sorte que lors du durcissement de la poudre en un film, le film est retiré du substrat et peut être manipulé comme un film libre. Le film libre peut être utilisé pour l'administration par voie orale, buccale, transdermique ou topique d'un agent actif ou en l'absence d'un agent actif, comme bandage ou pansement.
PCT/US2015/013916 2014-01-31 2015-01-30 Procédé de préparation de films WO2015117004A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105054265A (zh) * 2015-09-08 2015-11-18 浙江大学 一种水产品静电裹粉装置及其方法
US11648197B2 (en) 2018-06-28 2023-05-16 Arx, Llc Dispensing method for producing dissolvable unit dose film constructs

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CA1086576A (fr) * 1975-04-22 1980-09-30 Addison B. Scholes Appareil a lubrifier des surfaces metalliques, et mode d'utilisation
US4748043A (en) * 1986-08-29 1988-05-31 Minnesota Mining And Manufacturing Company Electrospray coating process
WO2001043727A1 (fr) * 1999-12-17 2001-06-21 Phoqus Limited Application electrostatique d'un materiau en poudre sur des formes galeniques solides
US6375963B1 (en) * 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
US6670038B2 (en) * 1996-04-09 2003-12-30 Delsys Pharmaceutical Method of depositing particles with an electrostatic chuck
US6783768B1 (en) * 1996-11-13 2004-08-31 Phoqus Pharmaceuticals Limited Method and apparatus for the coating of substrates for pharmaceutical use
US20060099257A1 (en) * 2001-07-19 2006-05-11 Langridge John R Controlled drug delivery systems providing variable release rates
US20090181074A1 (en) * 2007-12-31 2009-07-16 Joshua Makower Mucosal Tissue Dressing And Method Of Use
US20090286435A1 (en) * 2005-04-14 2009-11-19 Badyal Jas Pal S Method for Producing, and a Substrate with, a Surface with Specific Characteristics
US7862848B2 (en) * 2005-08-03 2011-01-04 The University Of Western Ontario Direct coating solid dosage forms using powdered materials
US7897080B2 (en) * 2001-10-12 2011-03-01 Monosol Rx, Llc Polyethylene-oxide based films and drug delivery systems made therefrom
US20130011492A1 (en) * 2011-02-24 2013-01-10 The Research Foundation Of State University Of New York Electrochemical deposition of noble metal and chitosan coating
US20130017367A1 (en) * 2010-03-30 2013-01-17 Wise S.R.L. Method for the production of functionalized elastomeric manufactured articles and manufactured articles thus obtained
US8455057B2 (en) * 2006-08-24 2013-06-04 Stora Enso Oyj Method for controlling surface contact area of a paper or board substrate
US8531814B2 (en) * 2009-04-16 2013-09-10 Varian Semiconductor Equipment Associates, Inc. Removal of charge between a substrate and an electrostatic clamp

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Publication number Priority date Publication date Assignee Title
CA1086576A (fr) * 1975-04-22 1980-09-30 Addison B. Scholes Appareil a lubrifier des surfaces metalliques, et mode d'utilisation
US4748043A (en) * 1986-08-29 1988-05-31 Minnesota Mining And Manufacturing Company Electrospray coating process
US6670038B2 (en) * 1996-04-09 2003-12-30 Delsys Pharmaceutical Method of depositing particles with an electrostatic chuck
US6783768B1 (en) * 1996-11-13 2004-08-31 Phoqus Pharmaceuticals Limited Method and apparatus for the coating of substrates for pharmaceutical use
US6375963B1 (en) * 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
WO2001043727A1 (fr) * 1999-12-17 2001-06-21 Phoqus Limited Application electrostatique d'un materiau en poudre sur des formes galeniques solides
US20060099257A1 (en) * 2001-07-19 2006-05-11 Langridge John R Controlled drug delivery systems providing variable release rates
US7897080B2 (en) * 2001-10-12 2011-03-01 Monosol Rx, Llc Polyethylene-oxide based films and drug delivery systems made therefrom
US20090286435A1 (en) * 2005-04-14 2009-11-19 Badyal Jas Pal S Method for Producing, and a Substrate with, a Surface with Specific Characteristics
US7862848B2 (en) * 2005-08-03 2011-01-04 The University Of Western Ontario Direct coating solid dosage forms using powdered materials
US8455057B2 (en) * 2006-08-24 2013-06-04 Stora Enso Oyj Method for controlling surface contact area of a paper or board substrate
US20090181074A1 (en) * 2007-12-31 2009-07-16 Joshua Makower Mucosal Tissue Dressing And Method Of Use
US8531814B2 (en) * 2009-04-16 2013-09-10 Varian Semiconductor Equipment Associates, Inc. Removal of charge between a substrate and an electrostatic clamp
US20130017367A1 (en) * 2010-03-30 2013-01-17 Wise S.R.L. Method for the production of functionalized elastomeric manufactured articles and manufactured articles thus obtained
US20130011492A1 (en) * 2011-02-24 2013-01-10 The Research Foundation Of State University Of New York Electrochemical deposition of noble metal and chitosan coating

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105054265A (zh) * 2015-09-08 2015-11-18 浙江大学 一种水产品静电裹粉装置及其方法
US11648197B2 (en) 2018-06-28 2023-05-16 Arx, Llc Dispensing method for producing dissolvable unit dose film constructs

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