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EP2705088A1 - Talc-free polyvinyl alcohol composition - Google Patents

Talc-free polyvinyl alcohol composition

Info

Publication number
EP2705088A1
EP2705088A1 EP12721984.8A EP12721984A EP2705088A1 EP 2705088 A1 EP2705088 A1 EP 2705088A1 EP 12721984 A EP12721984 A EP 12721984A EP 2705088 A1 EP2705088 A1 EP 2705088A1
Authority
EP
European Patent Office
Prior art keywords
talc
free composition
film
tacky
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12721984.8A
Other languages
German (de)
French (fr)
Inventor
Paul J. Sheskey
Michal E. Matteucci
Paula C. GARCIA TODD
Karen M. Balwinski
Debora L. Holbrook
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dow Global Technologies LLC
Original Assignee
Dow Global Technologies LLC
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 Dow Global Technologies LLC filed Critical Dow Global Technologies LLC
Publication of EP2705088A1 publication Critical patent/EP2705088A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D129/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Coating compositions based on hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Coating compositions based on derivatives of such polymers
    • C09D129/02—Homopolymers or copolymers of unsaturated alcohols
    • C09D129/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids

Definitions

  • the invention generally relates to a non-tacky talc-free composition, the non-tacky film, manufactured article comprising the composition, and a method of coating a dosage form with the composition.
  • Talc-containing coatings of pharmaceutical and nutraceutical dosage forms are currently in commercial use.
  • the talc desirably imparts a low tack or tack-free property to the coatings, enabling faster packaging and providing cleaner process (no tablet dust generation) during manufacturing, and making dosage forms easier for patients to handle and swallow.
  • talc is used to reduce tackiness in a commercial PVOH-based coating, OPADRY II (Colorcon, Inc., Harleysville, Pennsylvania; BPSI Holdings LLC, Wilmington Delaware, both of USA).
  • Some coatings of pharmaceutical or nutraceutical dosage forms are known that supposedly do not require talc, although they may desirably employ talc in preferred embodiments. Some, but not all, of these coatings employ polyvinyl alcohol (PVOH) or carboxymethylcellulose (CMC), but not both, as a film-forming agent.
  • PVH polyvinyl alcohol
  • CMC carboxymethylcellulose
  • WO 2009/031039 A2 mentions using particular molecular weight-modified CMC coating materials either alone or in combination with other types of hydrocolloids, biogums, cellulose ethers, and the like.
  • the coating materials may also comprise other additional film-forming agents other than the hydrocolloids, cellulose ethers, and/or biogums.
  • US 2010/0062062 Al mentions, among other things, compressing a mixture of selected excipients and PVOH-coated drug powders or particulates into tablets. The compressing of the coated drug powders or particulates into tablets therefore requires the coatings thereof to adhere or stick to each other, the excipients, or both in such a way so as to form the tablet.
  • the PVOH coating undesirably is tacky.
  • a problem addressed by the present invention includes providing a talc-free composition that is characterizable as non-tacky and having low water vapor permeability.
  • the present inventors recognized that talc opaques and whitens coatings, which is undesirable for some dosage form applications that require coatings that are colored, clear, or both.
  • coatings comprising PVOH alone or CMC alone independently have one or more drawbacks comprising being tacky, opaque, colored, permeable to water vapor, or a combination thereof. They found the coatings of PVOH alone to be at least tacky and the coatings of CMC alone to be at least hazy and unacceptably permeable to water vapor.
  • the inventors unexpectedly discovered a talc-free composition that is characterizable as non-tacky and having low water vapor permeability.
  • the talc-free composition is also substantially clear, hazeless, or a combination thereof. In some embodiments the talc-free composition is also colorless unless a separate color additive (e.g., pigment or dye) has been added thereto.
  • a separate color additive e.g., pigment or dye
  • the present invention provides a talc-free composition characterizable as non-tacky and having an average water vapor permeability of at most 5.0 times 10 " ⁇ (0.0000005) grams per Pascal-hour-meter (g/Pa.h.m) and having a capability of forming a non-tacky film having
  • the non-tacky film prepared from the talc-free composition further has at least one of properties (a) and (b): (a) a normalized film clarity of at least 500 percent per millimeter of film thickness (%/mm); and (b) a film haze of at most 13 percent.
  • property (b) is a normalized film haze of at most 250 percent per millimeter of film thickness (%/mm), preferably at most 180 %/mm, more preferably at most 120 %/mm, still more preferably at most 80 %/mm, even more preferably at most 25 %/mm, and yet more preferably at most 13 %/mm of film thickness (%/mm).
  • the invention non- tacky film would have a haze of at most 13%.
  • the talc-free composition at least comprises property (a), in other embodiments at least property (b), and still other embodiments both properties (a) and (b).
  • the present invention provides a method of preparing a coated solid dosage form, the method comprising contacting a coating-effective amount of the talc-free composition with a solid health formulation comprising an active ingredient, the contacting being performed in such a way so as to coat the solid health formulation to give a coated solid dosage form comprising a non-tacky film comprising the talc-free composition, the non-tacky film being in coating operative contact with the solid health formulation and having an average water
  • the coating operative contact means the non-tacky film completely covers the surface of the solid dosage form.
  • the present invention provides a manufactured article comprising the talc-free composition.
  • the manufactured article comprises the coated solid dosage form.
  • the present invention provides the non-tacky film comprising the talc-free composition.
  • the invention compositions are useful, for example, as binders for wet granulation of solid health formulations; a coating or film for preparing coated solid dosage forms, especially of pharmaceutical, veterinary, and nutraceutical dosage forms (collectively referred to herein as dosage forms).
  • the invention compositions can be used to coat nutraceutical tablets to give coated tablets, where consumers prefer their nutraceutical tablets to look natural; to produce a gloss on pharmaceutical or veterinary tablets; and to prepare clear or colored coatings.
  • the colored coatings would desirably impart aesthetic and tailorable light-blocking functionalities to the dosage forms and could be used to distinguish between different dosage strengths.
  • the invention composition is also useful in other applications such as adhesive, sizing (e.g., textile and paper sizing), and solution emulsifying, suspending, and thickening applications.
  • the invention provides a talc-free composition capable of forming a non- tacky film or coating having an average water vapor permeability of at most 5.0 times 10 " ⁇ g/Pa.h.m.
  • the talc-free composition has at least one of the aforementioned properties (a) and (b), and more preferably both properties (a) and (b). Additional advantages can include the film reduces tackiness during tablet coating methods such that the coated tablets do not agglomerate, improves visual film appearance (e.g., reduction in film defects (e.g., cracking) compared to talc-containing non-invention coatings, and shortens time required for coating tablets.
  • the term “active ingredient” means any compound or substance that is intended to provide a health benefit in a nutraceutical, pharmaceutical or veterinary context.
  • coated means having a surface covering or film.
  • coating-effective amount means a quantity sufficient to cover as by forming a film.
  • coating operative contact means a surface covering that indirectly (via an intermediate material) or, preferably, directly physically touches, preferably substantially the entire surface.
  • composition means the qualitative and quantitative make-up of a chemical substance and includes homogeneous and heterogeneous substances.
  • the term "contacting” (as in contacting with) and the like means causing a coming together or touching.
  • the term “dosage form” means a physical shape or structure suitable for administration of the active ingredient therein to a human or animal.
  • coated solid dosage form means a film-covered variant of a health formulation having a definite shape and volume (as opposed to being “fluid”).
  • the term “health formulation” means a preparation of at least an active ingredient and at least one other ingredient or component that is suitable for use in a nutraceutical, pharmaceutical or veterinary context.
  • the term “film” means a thin covering, typically having a thickness of at most 1.0 millimeter (mm).
  • the term "manufactured article” means a member of a class of things, wherein the member is not found in nature.
  • non-tacky means a result of "not adhering” as determined using the Tackiness Test Method described later.
  • film clarity and “normalized film clarity” respectively mean a result or a transformed result of the Film Clarity Test Method described later that is useful for comparison.
  • film haze and “normalized film haze” respectively mean a result or a transformed result of the Film
  • operative contact means an indirect (via an intermediate material) or, preferably, direct physical touching.
  • talc- free means lacking the mineral composed of hydrated magnesium silicate having the chemical formula
  • water vapor permeability and WVT permeability are synonymous and mean a result of the Water Vapor Transmission Rate Test Method described later.
  • Numerical ranges any lower limit of a range of numbers, or any preferred lower limit of the range, may be combined with any upper limit of the range, or any preferred upper limit of the range, to define a preferred aspect or embodiment of the range.
  • each range of numbers includes all numbers, both rational and irrational numbers, subsumed in that range (e.g., "from 1 to 5" includes, for example, 1, 1.5, 2, 2.75, 3, 3.81, 4, and 5).
  • the talc-free composition can include additional ingredients provided they do not cancel the basic and novel characteristics of the present invention.
  • Such basic and novel characteristics of the present invention are the aforementioned non-tackiness and average water vapor permeability.
  • the basic and novel characteristics also include at least one, preferably both, of the properties (a) and (b).
  • the talc-free composition comprises a low viscosity polyvinyl alcohol (LV- PVOH) and a tack-reducing organic adjuvant, wherein the weight/weight ratio of the LV-PVOH to tack-reducing organic (TRO) adjuvant in the composition is from >60:40 to ⁇ 95:5.
  • the LV-PVOH/TRO adjuvant wt/wt ratio is at least: 61 :39, in other embodiments at least 65:35, in other embodiments at least 7:3, and in other embodiments at least 8:2.
  • the LV-PVOH/TRO adjuvant is at most 94:6, in other embodiments at most 91 :9, in other embodiments at most 90: 10, and in other embodiments at most 8:2.
  • the LV-PVOH/TRO adjuvant wt/wt ratio is 6:4, in other embodiments 7:3, in other embodiments 8:2, in other embodiments 9:1, and in other embodiments 19:1.
  • low viscosity polyvinyl alcohol and "LV-PVOH” are synonymous and mean an oligomeric or polymeric material having repeat units derived from vinyl alcohol, a dynamic viscosity of from 2 milliPascal-seconds (mPa.s) to 10 mPa.s measured with a 4 weight/volume percent (wt/vol%, weight in grams (g) of LV-PVOH per volume in milliliters (mL) of deionized water) aqueous solution thereof at 20 °C; and a saponification degree of from 80 mole percent (mol%) to 95 mol%.
  • the dynamic viscosity is from 3 mPa.s to 9 mPa.s, and more preferably from 3.5 mPa.s to 8 mPa.s (e.g., from 4 mPa.s to 7 mPa.s), all measured with a 4 wt/vol% aqueous solution thereof at 20 °C.
  • the saponification degree is from 84 mol% to 92 mol%, and more preferably from 85 mol% to 90 mol% (e.g., from 86.5 mol% to 89.0 mol%).
  • the saponification degree is relevant to LV-PVOH prepared by saponifying (e.g., hydrolyzing with NaOH) the aforementioned mol% of acetate functionalities in a penultimate poly( vinyl acetate) to give the LV-PVOH and acetic acid (upon neutralization of pH), and removing the acetic acid (e.g., by evaporation).
  • tack-reducing organic adjuvant or "TRO adjuvant” means a material other than PVOH, wherein the material comprises carbon, hydrogen, and oxygen atoms, and optionally, nitrogen atoms, wherein the material functions to reduce tackiness of the LV-PVOH and, preferably, also improve at least one property of the LV-PVOH that is a light transmission property (e.g., clarity, haze, or preferably both) or water vapor permeability property so as to enable a functionality of the invention composition that is not enabled by PVOH alone.
  • the TRO adjuvant is a clear, non-tacky film forming organic polymer.
  • the TRO adjuvant is a carboxymethylcellulose (CMC), poly(ethylene glycol), hydroxypropyl methyl cellulose (HPMC), maltodextrin, methylcellulose, or polyvinylpyrrolidone (PVP), or a combination thereof. More preferably, the TRO adjuvant is a CMC.
  • the talc-free composition further comprises or consists essentially of a non-canceling amount of at least one additional ingredient that is a secondary organic adjuvant.
  • non-canceling amount means a quantity that does not negate the aforementioned non- tackiness and average water vapor permeability.
  • the quantity also does not negative at least one of, preferably both, the properties (a) and (b).
  • the at least one additional ingredient (secondary organic adjuvant) is a plasticizer, removable dispersant, surface-active agent (surfactant), or a combination of at least two thereof.
  • the plasticizer and TRO adjuvant are the same ingredient, and in other embodiments different ingredients.
  • the plasticizer and removable dispersant are the same ingredient, and in other embodiments different ingredients. In some embodiments the plasticizer and surfactant are the same ingredient, and in other embodiments different ingredients.
  • the term "removable dispersant” means a volatile substance effective for producing a suspension, solution, or combination thereof containing a wide distribution of the LV-PVOH and TRO adjuvant in the volatile substance, the volatile substance having a boiling point (b.p.) below about 130 degrees Celsius (°C) at 101 kilopascals (kPa) pressure.
  • b.p. boiling point below about 130 degrees Celsius (°C) at 101 kilopascals (kPa) pressure.
  • the removable dispersant is a liquid at 20 °C and 101 kPa.
  • the removable dispersant is from 50 wt% to 99 wt%, and typically from 50 wt% to 98 wt% of total weight of the talc-free composition, including weight of the removable dispersant.
  • the removable dispersant is a solvent effective for dissolving the talc-free composition to give a solution thereof, wherein the solution is at a temperature useful for applying same to the solid health formulation.
  • preferred removable dispersants are acetic acid, acetone, ethanol, ethyl acetate, methanol, and, more preferably, water.
  • the term "plasticizer" means a solid or liquid substance effective for increasing fluidity of the talc-free composition.
  • the plasticizer is from 0.01 wt% to 20 wt% of total weight of the talc-free composition, not including weight of any removable dispersant.
  • the plasticizer is non-volatile (i.e., has a b.p. greater than about 150 degrees Celsius (°C) at 101 kPa pressure), and substantially remains in the talc-free composition after removal of any removable dispersant therefrom.
  • the plasticizer forms a blend with the talc-free composition without covalently bonding thereto, and in other embodiments at least some of the plasticizer reacts to form a covalent bond (e.g., via carboxylic acid esterification reaction) with at least some of the LV-PVOH or TRO adjuvant.
  • preferred plasticizers are glycerol, a poly(ethylene glycol) (PEG), and lecithin.
  • PEGs examples include PEG-400, PEG-3350 and others that are commercially available from Sigma-Aldrich Company, St. Louis, Missouri, USA, or The Dow Chemical Company, Midland, Michigan, USA.
  • Dow provides CARBOWAXTM brand PEGs in number average molecular weight range of from 200 g/mol to 8000 g/mol.
  • PEGs average M n range in g/mol
  • PEG-6 average M n range in g/mol
  • PEG-8 (380-420), PEG-6/PEG-32 blend, PEG-12 (570-630), PEG-20 (950-1050), PEG- 32 (1305-1595), PEG-75 (3015-3685), PEG-90 (3600-4400), PEG-100 (4400-4800), and PEG-180 (7000-9000), wherein these PEGs are named according to the established PEG nomenclature of the Personal Care Products Council (formerly Cosmetics, Toiletries and Fragrances Association),
  • the talc-free composition further comprises the plasticizer, the TRO adjuvant is a different ingredient than the plasticizer, and the plasticizer is a poly(ethylene glycol), preferably PEG-400.
  • the terms "surface-active agent” and surfactant” are synonymous and mean a substance that can reduce surface tension of water.
  • the surfactant is from 0.001 wt% to 1 wt% of total weight of the talc-free composition, not including weight of any removable dispersant.
  • Examples of functional classifications of surfactants are emulsifiers, wetting agents, foaming agents, dispersing agents and anti-foaming agents.
  • Examples of structural classifications of surfactants are ionic surfactants and nonionic surfactants.
  • Examples of ionic surfactants are anionic surfactants (e.g., sodium tartrate), sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium
  • laurylsulfate examples include cationic surfactants (e.g., cetyl trimethylammonium bromide), and zwitterionic surfactants (e.g., amino acids).
  • nonionic surfactants are fatty alcohols,
  • polyoxypropylene glycol and polysorbates (e.g., polyoxymethylene (20) sorbitan monooleate (i.e., polysorbate 80, which is commercially known as Tween 80)).
  • polysorbates e.g., polyoxymethylene (20) sorbitan monooleate (i.e., polysorbate 80, which is commercially known as Tween 80)).
  • the talc-free composition further comprises glycerol or a PEG as the non-volatile plasticizer. In some embodiments the talc -free composition further comprises glycerol or a PEG as the non-volatile plasticizer and a polysorbate surfactant. In some embodiments the talc- free composition further comprises water as the removable dispersant, and in other embodiments the talc-free composition substantially lacks removable dispersant. In some embodiments the talc-free composition comprises the LV-PVOH, CMC as the TRO adjuvant, and a PEG as the non-volatile plasticizer.
  • the talc-free composition comprises the LV-PVOH, CMC as the TRO adjuvant, the PEG as the non-volatile plasticizer, and a polysorbate surfactant.
  • the talc-free composition comprises an aqueous solution of the LV-PVOH, CMC, and PEG, and in other embodiments an aqueous solution of the LV-PVOH, CMC, PEG, and polysorbates.
  • the talc-free composition lacks lecithin, and in other embodiments further comprises at most a low concentration (e.g., ⁇ 1 weight percent (wt%)) of lecithin.
  • the talc-free composition is as described in any one of the foregoing embodiments in this paragraph except CMC is the only TRO adjuvant, i.e., the talc-free composition lacks HPMC, methylcellulose, maltodextrin, and PVP.
  • the talc-free composition is as described in any one of the foregoing embodiments, but the immediately preceding one, in this paragraph except the CMC is entirely replaced by HPMC, methylcellulose (e.g., a METHOCELTM), maltodextrin, PVP, or a combination thereof.
  • the health formulation is a nutraceutical, pharmaceutical, or veterinary dosage form.
  • the dosage form is a unit dosage form.
  • the health formulation can be in any physical form. Examples of suitable physical forms are solid and liquid-containing physical forms. Examples of suitable solid health formulations are a bead (e.g., nonpareil bead), powder, granule, tablet (e.g., prepared by compressing powder), capsule (e.g., gelatin capsule or components thereof), gelcap tablet, lozenge, patch, and troche. At least some of the ingredients of the solid health formulation are solid ingredients.
  • the invention contemplates solid health formulations that in some embodiments further contain a relatively small amount of at least one liquid ingredient, and in other embodiments contain only solid ingredients.
  • Each of the solid ingredient(s) of the solid health formulation can be characterized as being amorphous, partially crystalline, or crystalline.
  • the invention composition can be used as an ingredient in, or preferably to coat or form a film on, the solid health formulations.
  • suitable liquid-containing health formulations are a cream, elixir, emulsion, gel, lotion, ointment, solution (e.g., in water), and syrup.
  • the invention composition can be used as an ingredient in the liquid-containing health formulations.
  • the active ingredient is a nutraceutically, pharmaceutically, or veterinary active ingredient.
  • the nutraceutically active ingredient provides a dietary, nutritional, or preventative health benefit.
  • the active ingredient can be a solid or liquid.
  • the solid health formulation comprises the liquid active ingredient widely distributed on or in a solid excipient (e.g., solid carrier), in other embodiments a solid active ingredient widely distributed in a liquid excipient (e.g., liquid carrier), and in still other embodiments a solid active ingredient widely distributed in a solid excipient so as to form a blend therewith.
  • nutraceutically active ingredients are a dietary supplement (e.g., an antioxidant (e.g., resveratrol), flavinoid (e.g., from citrus fruit, tea, wine, or cocoa bean), herb, mineral, naturally-occurring amino acid, and vitamin) and an enriched food (e.g., a soya protein enriched granola bar).
  • the pharmaceutically or veterinary active ingredient provides a disease treating health benefit (e.g., increases time to onset of at least one symptom in prophylactic treatment, diminishes severity of at least one symptom in palliative treatment, or inhibits progression of a pathological effect in a disease modifying treatment of a disease or disorder in a human or animal patient in need of such treatment.
  • an analgesic e.g., carprofen
  • angiotensin converting enzyme (ACE) inhibitor e.g., quinapril, e.g., quinapril hydrochloride
  • antibiotic e.g., azithromycin
  • anti-convulsant e.g., gabapentin
  • anti-depressant e.g., sertraline, e.g., sertraline hydrochloride
  • anti-fibromyalgic e.g., pregabalin
  • anti-hypertensive e.g., amlodipine, e.g., amlodipine besylate
  • a cholesterol lowering drug e.g., atorvastatin, e.g., atorvastatin calcium
  • the health formulation further comprises at least one acceptable excipient in admixture with the active ingredient.
  • admixture means a product of being blended together.
  • accepted excipient means any compound or substance other than the active ingredient(s) that is suitable for use in the health formulation.
  • the acceptable excipient is a nutraceutically, pharmaceutically, or veterinary acceptable excipient. Examples of nutraceutically, pharmaceutically, or veterinary acceptable excipients are carriers; diluents;
  • capsule shells e.g., gelatin capsule shells
  • the talc-free composition further comprises and the method of preparing the coated solid dosage form further employs the removable dispersant.
  • the coating of the solid health formulation to give the coated solid dosage form is preferably carried out by applying a surface-coating effective amount of a suspension or, preferably, solution of the talc-free composition in the removable dispersant (e.g., a solvent such as ethanol or water) to an exposed surface of the (solid) health formulation in such a way so as to evenly cover the exposed surface of the (solid) health formulation with the talc-free composition; and removing the removable dispersant from the covered (solid) health formulation to give the coated solid dosage form.
  • a surface-coating effective amount means a quantity sufficient to cover the exposed surface.
  • the suspension or solution of the talc-free composition preferably is prepared by contacting the talc- free composition to the suitable amount of the removable dispersant (e.g., a solvent such as ethanol or water) so as to give the suspension or solution thereof.
  • the suitable amount of the removable dispersant e.g., a solvent such as ethanol or water
  • Examples of contacting are agitating, shaking, spraying, stirring, and tumbling.
  • the manufactured article comprises a health formulation comprising an active ingredient and the talc-free composition in operative contact therewith.
  • LV-PVOH designated Gohsenol EG-05P from Nippon Gohsei, Osaka, Japan.
  • Gohsenol EG-05P has a saponification degree of 86.5 mol% to 89.0 mol% and a dynamic viscosity of 4.8 mPa.s to 5.8 mPa.s measured as a 4 wt/vol% aqueous solution at 20 °C.
  • PEG-400 and PEG-3350 respectively designated CARBOWAX SENTRY Polyethylene glycol 400NF, WL0101 AAKC and CARBOWAX SENTRY Polyethylene glycol 3350, from The Dow Chemical Company.
  • Polysorbate 80 (Tween 80) designated enzyme grade, 943317 from Fisher Scientific.
  • Placebo tablets designated Placebo tablets (100 g red caplet cores, 493 g white oval tablets, 6.5 g white disks) from The Dow Chemical Company.
  • Film preparation Complete all film preparations and storage in a constant temperature (22°C) and relative humidity (50% RH) environment. Hand draw wet films (1 mm) on glass plates by slowly pouring a 20 wt% solution near an edge of a 1 mm gapped casting (drawn down) bar, and then steadily draw the solution to minimize bubbles and defects. Dry the films on the plates for two days, remove them from the plates, and anneal the films for an additional 1 day. Measure film properties on the annealed film. Preferably conclude all film testing within 4 days of film removal to minimize any sample-to-sample variance. When not testing films, store films between sheets of paper and at the constant temperature and relative humidity.
  • Film Clarity Test Method Measure film clarity of films using a Pacific Scientific PG-5500 from Gardner Laboratory Inc., Bethesda, Maryland, USA and a Zebedee CL-100 from Zebedee Corporation, Moore, South Carolina, USA, calibrated with an open port, a black standard and a Mylar film standard at 100, 0, and 87 (+/- 1) percent clarity, respectively. Read clarity
  • Film Haze Test Method Measure haze of prepared films with a Haze-gard Plus from BYK Gardner, Columbia, Maryland, USA, Catalog Number 4725. Report both haze and transmission readings as a percentage. Record an average value of four readings.
  • the tackiness of the coated tablets can be a qualitative visual observation of coated tablets agglomerating and sticking to each other or not agglomerating or sticking to each other.
  • the tackiness is a quantitative weight percent equal to weight of agglomerated portion, if any, of the coated tablets as a percentage of total weight of coated tablets prepared (i.e., weight of individual coated tablets plus any agglomerated portion). If the agglomerated portion is ⁇ 10 wt%, preferably ⁇ 5 wt%, and more preferably ⁇ 1 wt%, and still more preferably 0 wt% (i.e., there is no
  • the talc-free composition and coating of the coated tablets are deemed to be "non- tacky" for purposes of this invention. Photograph samples to compare experimental runs.
  • Water Vapor Transmission Rate Test Method Measure water vapor transmission rates using a "dry cup” method. Weigh calcium chloride (2.0 g) into a 4 ounce (120 mL) jar, and allow it to sit at 50% relative humidity (73 °C) with a closed ring cap (2.5 cm diameter hole therein) for 1 hour. Next, place a small amount of vacuum grease around the edge of the jar's mouth. Cut films into approximately 1.3 inch (3.3 centimeter (cm)) diameter circles using a metal punch. Place film sample circle on top of the jar, and place a lid having a 1-inch (2.5 cm) diameter hole on top of the film circle. Tighten the lid to form a seal while making sure not to crack the film circle. Place jars into a temperature -humidity chamber equipped with an Environ-Cab controller (Lab-Line
  • m t is the change in mass with time (grams per hour (g/hr)) and A is the exposed film area in square centimeters (cm z ).
  • S is the saturated vapor pressure of water at 25 °C
  • RH2 is 0.75 (75% relative humidity)
  • RHj is 0.
  • the S(RH 2 -RHj) term is the driving force for mass transfer of water through the film.
  • Films of the invention talc-free compositions can be favorably compared to the following films of non-invention talc-free compositions (a) to (d):
  • Examples 1 to 6 talc-free compositions of LV-PVOH and CMC. Dissolve a total of 8g to 25 g (e.g., 10 g) of Gohsenol EG-05P (LV-PVOH) and CMC and, optionally, plasticizer according to Table 1 below in deionized (DI) water (e.g., 100 g) with mixing to give talc-free composition as a solution (4 wt% to 15 wt% solids) of each of Examples 1 to 6.
  • DI deionized
  • LV-PVOH wt% based on total weight of LV-PVOH, CMC, and any plasticizer.
  • Examples A to F Coated tablets.
  • LDCS Vector Hi-Coater model LDCS, having a temperature exhaust set point of 40 °C, with tablets.
  • the talc-free composition is capable of forming a non-tacky film or coating on a solid dosage form, the film or coating unexpectedly having an advantageous combination or characteristics comprising an average water vapor permeability of at most 5.0 times n
  • the coated tablets have coatings comprising embodiments of the invention non-tack film and are of a film thickness suitable for use in pharmaceutical, nutraceutical, and veterinarian coated tablet applications.

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Abstract

The present invention provides a talc-free composition characterizable as non-tacky and having an average water vapor permeability of at most 5.0 times 10-7 grams per Pascal-hour-meter and having a capability of forming a non-tacky film having an average water vapor permeability of at most 5.0 times 10-7 grams per Pascal-hour-meter. Also provided are the non-tacky film, a method of coating a dosage form with the composition, and a manufactured article comprising the composition.

Description

TALC-FREE POLYVINYL ALCOHOL COMPOSITION
FIELD
The invention generally relates to a non-tacky talc-free composition, the non-tacky film, manufactured article comprising the composition, and a method of coating a dosage form with the composition.
BACKGROUND
Talc-containing coatings of pharmaceutical and nutraceutical dosage forms are currently in commercial use. The talc desirably imparts a low tack or tack-free property to the coatings, enabling faster packaging and providing cleaner process (no tablet dust generation) during manufacturing, and making dosage forms easier for patients to handle and swallow. For example, talc is used to reduce tackiness in a commercial PVOH-based coating, OPADRY II (Colorcon, Inc., Harleysville, Pennsylvania; BPSI Holdings LLC, Wilmington Delaware, both of USA).
Some coatings of pharmaceutical or nutraceutical dosage forms are known that supposedly do not require talc, although they may desirably employ talc in preferred embodiments. Some, but not all, of these coatings employ polyvinyl alcohol (PVOH) or carboxymethylcellulose (CMC), but not both, as a film-forming agent. For example, see WO 2009/031039 A2 and US 2010/0062062 Al. WO 2009/031039 A2 mentions using particular molecular weight-modified CMC coating materials either alone or in combination with other types of hydrocolloids, biogums, cellulose ethers, and the like. In addition to the above essential modified CMC coating agents, the coating materials may also comprise other additional film-forming agents other than the hydrocolloids, cellulose ethers, and/or biogums. US 2010/0062062 Al mentions, among other things, compressing a mixture of selected excipients and PVOH-coated drug powders or particulates into tablets. The compressing of the coated drug powders or particulates into tablets therefore requires the coatings thereof to adhere or stick to each other, the excipients, or both in such a way so as to form the tablet. Thus in US 2010/0062062 Al, the PVOH coating undesirably is tacky.
A problem addressed by the present invention includes providing a talc-free composition that is characterizable as non-tacky and having low water vapor permeability.
BRIEF SUMMARY OF THE INVENTION
The present inventors recognized that talc opaques and whitens coatings, which is undesirable for some dosage form applications that require coatings that are colored, clear, or both. The inventors also recognized that coatings comprising PVOH alone or CMC alone independently have one or more drawbacks comprising being tacky, opaque, colored, permeable to water vapor, or a combination thereof. They found the coatings of PVOH alone to be at least tacky and the coatings of CMC alone to be at least hazy and unacceptably permeable to water vapor. The inventors unexpectedly discovered a talc-free composition that is characterizable as non-tacky and having low water vapor permeability. In preferred embodiments the talc-free composition is also substantially clear, hazeless, or a combination thereof. In some embodiments the talc-free composition is also colorless unless a separate color additive (e.g., pigment or dye) has been added thereto.
In a first embodiment the present invention provides a talc-free composition characterizable as non-tacky and having an average water vapor permeability of at most 5.0 times 10"^ (0.0000005) grams per Pascal-hour-meter (g/Pa.h.m) and having a capability of forming a non-tacky film having
n
an average water vapor permeability of at most 5.0 times 10" g/Pa.h.m.
Preferably, the non-tacky film prepared from the talc-free composition further has at least one of properties (a) and (b): (a) a normalized film clarity of at least 500 percent per millimeter of film thickness (%/mm); and (b) a film haze of at most 13 percent. In other embodiments property (b) is a normalized film haze of at most 250 percent per millimeter of film thickness (%/mm), preferably at most 180 %/mm, more preferably at most 120 %/mm, still more preferably at most 80 %/mm, even more preferably at most 25 %/mm, and yet more preferably at most 13 %/mm of film thickness (%/mm). At film thicknesses typically employed in commercial solid dosage coating applications (e.g., pharmaceutical, nutraceutical, and veterinarian applications), the invention non- tacky film would have a haze of at most 13%. In some embodiments the talc-free composition at least comprises property (a), in other embodiments at least property (b), and still other embodiments both properties (a) and (b).
In a second embodiment the present invention provides a method of preparing a coated solid dosage form, the method comprising contacting a coating-effective amount of the talc-free composition with a solid health formulation comprising an active ingredient, the contacting being performed in such a way so as to coat the solid health formulation to give a coated solid dosage form comprising a non-tacky film comprising the talc-free composition, the non-tacky film being in coating operative contact with the solid health formulation and having an average water
n
permeability of at most 5.0 times 10 grams per Pascal-hour -meter. Preferably, the coating operative contact means the non-tacky film completely covers the surface of the solid dosage form.
In a third embodiment the present invention provides a manufactured article comprising the talc-free composition. Preferably, the manufactured article comprises the coated solid dosage form.
In another embodiment the present invention provides the non-tacky film comprising the talc-free composition.
The invention compositions are useful, for example, as binders for wet granulation of solid health formulations; a coating or film for preparing coated solid dosage forms, especially of pharmaceutical, veterinary, and nutraceutical dosage forms (collectively referred to herein as dosage forms). For example, the invention compositions can be used to coat nutraceutical tablets to give coated tablets, where consumers prefer their nutraceutical tablets to look natural; to produce a gloss on pharmaceutical or veterinary tablets; and to prepare clear or colored coatings. The colored coatings would desirably impart aesthetic and tailorable light-blocking functionalities to the dosage forms and could be used to distinguish between different dosage strengths. The invention composition is also useful in other applications such as adhesive, sizing (e.g., textile and paper sizing), and solution emulsifying, suspending, and thickening applications.
Advantageously, the invention provides a talc-free composition capable of forming a non- tacky film or coating having an average water vapor permeability of at most 5.0 times 10"^ g/Pa.h.m. In preferred embodiments the talc-free composition has at least one of the aforementioned properties (a) and (b), and more preferably both properties (a) and (b). Additional advantages can include the film reduces tackiness during tablet coating methods such that the coated tablets do not agglomerate, improves visual film appearance (e.g., reduction in film defects (e.g., cracking) compared to talc-containing non-invention coatings, and shortens time required for coating tablets.
Additional invention embodiments are described in the remainder of the specification, including the claims.
DETAILED DESCRIPTION OF THE INVENTION
The embodiments of the present invention summarized previously and the Abstract are incorporated here by reference. As used herein, the term "active ingredient" means any compound or substance that is intended to provide a health benefit in a nutraceutical, pharmaceutical or veterinary context. The term "coated" means having a surface covering or film. The term "coating-effective amount" means a quantity sufficient to cover as by forming a film. The term "coating operative contact" means a surface covering that indirectly (via an intermediate material) or, preferably, directly physically touches, preferably substantially the entire surface. The term "composition" means the qualitative and quantitative make-up of a chemical substance and includes homogeneous and heterogeneous substances. The term "contacting" (as in contacting with) and the like means causing a coming together or touching. The term "dosage form" means a physical shape or structure suitable for administration of the active ingredient therein to a human or animal. The term "coated solid dosage form" means a film-covered variant of a health formulation having a definite shape and volume (as opposed to being "fluid"). The term "health formulation" means a preparation of at least an active ingredient and at least one other ingredient or component that is suitable for use in a nutraceutical, pharmaceutical or veterinary context. The term "film" means a thin covering, typically having a thickness of at most 1.0 millimeter (mm). The term "manufactured article" means a member of a class of things, wherein the member is not found in nature. The term "non-tacky" means a result of "not adhering" as determined using the Tackiness Test Method described later. The terms "film clarity" and "normalized film clarity" respectively mean a result or a transformed result of the Film Clarity Test Method described later that is useful for comparison. The terms "film haze" and "normalized film haze" respectively mean a result or a transformed result of the Film
Haze Test Method described later that is useful for comparison. The term "operative contact" means an indirect (via an intermediate material) or, preferably, direct physical touching. The term "talc- free" means lacking the mineral composed of hydrated magnesium silicate having the chemical formula The terms "water vapor permeability" and "WVT permeability" are synonymous and mean a result of the Water Vapor Transmission Rate Test Method described later.
Conflict Resolution: what is written in the present specification controls any conflict with what is written in a patent, patent application, or patent application publication, or a portion thereof that is incorporated by reference. The structure controls any conflict with a compound name. The unit value recited without parentheses controls any conflict with an intended corresponding unit value that is parenthetically recited.
Numerical ranges: any lower limit of a range of numbers, or any preferred lower limit of the range, may be combined with any upper limit of the range, or any preferred upper limit of the range, to define a preferred aspect or embodiment of the range. Unless otherwise indicated, each range of numbers includes all numbers, both rational and irrational numbers, subsumed in that range (e.g., "from 1 to 5" includes, for example, 1, 1.5, 2, 2.75, 3, 3.81, 4, and 5).
In some embodiments the partially closed phrase, "consisting essentially of replaces the open term "comprising." In such embodiments the talc-free composition can include additional ingredients provided they do not cancel the basic and novel characteristics of the present invention. Such basic and novel characteristics of the present invention are the aforementioned non-tackiness and average water vapor permeability. In some embodiments the basic and novel characteristics also include at least one, preferably both, of the properties (a) and (b).
Preferably, the talc-free composition comprises a low viscosity polyvinyl alcohol (LV- PVOH) and a tack-reducing organic adjuvant, wherein the weight/weight ratio of the LV-PVOH to tack-reducing organic (TRO) adjuvant in the composition is from >60:40 to < 95:5. In some embodiments the LV-PVOH/TRO adjuvant wt/wt ratio is at least: 61 :39, in other embodiments at least 65:35, in other embodiments at least 7:3, and in other embodiments at least 8:2. In some embodiments the LV-PVOH/TRO adjuvant is at most 94:6, in other embodiments at most 91 :9, in other embodiments at most 90: 10, and in other embodiments at most 8:2. In some embodiments the LV-PVOH/TRO adjuvant wt/wt ratio is 6:4, in other embodiments 7:3, in other embodiments 8:2, in other embodiments 9:1, and in other embodiments 19:1. The terms "low viscosity polyvinyl alcohol" and "LV-PVOH" are synonymous and mean an oligomeric or polymeric material having repeat units derived from vinyl alcohol, a dynamic viscosity of from 2 milliPascal-seconds (mPa.s) to 10 mPa.s measured with a 4 weight/volume percent (wt/vol%, weight in grams (g) of LV-PVOH per volume in milliliters (mL) of deionized water) aqueous solution thereof at 20 °C; and a saponification degree of from 80 mole percent (mol%) to 95 mol%. Preferably, the dynamic viscosity is from 3 mPa.s to 9 mPa.s, and more preferably from 3.5 mPa.s to 8 mPa.s (e.g., from 4 mPa.s to 7 mPa.s), all measured with a 4 wt/vol% aqueous solution thereof at 20 °C. Preferably, the saponification degree is from 84 mol% to 92 mol%, and more preferably from 85 mol% to 90 mol% (e.g., from 86.5 mol% to 89.0 mol%). The saponification degree is relevant to LV-PVOH prepared by saponifying (e.g., hydrolyzing with NaOH) the aforementioned mol% of acetate functionalities in a penultimate poly( vinyl acetate) to give the LV-PVOH and acetic acid (upon neutralization of pH), and removing the acetic acid (e.g., by evaporation).
As used herein, the term "tack-reducing organic adjuvant" or "TRO adjuvant" means a material other than PVOH, wherein the material comprises carbon, hydrogen, and oxygen atoms, and optionally, nitrogen atoms, wherein the material functions to reduce tackiness of the LV-PVOH and, preferably, also improve at least one property of the LV-PVOH that is a light transmission property (e.g., clarity, haze, or preferably both) or water vapor permeability property so as to enable a functionality of the invention composition that is not enabled by PVOH alone. Preferably, the TRO adjuvant is a clear, non-tacky film forming organic polymer. In some embodiments the TRO adjuvant is a carboxymethylcellulose (CMC), poly(ethylene glycol), hydroxypropyl methyl cellulose (HPMC), maltodextrin, methylcellulose, or polyvinylpyrrolidone (PVP), or a combination thereof. More preferably, the TRO adjuvant is a CMC.
In some embodiments the talc-free composition further comprises or consists essentially of a non-canceling amount of at least one additional ingredient that is a secondary organic adjuvant. The term "non-canceling amount" means a quantity that does not negate the aforementioned non- tackiness and average water vapor permeability. Preferably, the quantity also does not negative at least one of, preferably both, the properties (a) and (b). Preferably, the at least one additional ingredient (secondary organic adjuvant) is a plasticizer, removable dispersant, surface-active agent (surfactant), or a combination of at least two thereof. In some embodiments the plasticizer and TRO adjuvant are the same ingredient, and in other embodiments different ingredients. In some embodiments the plasticizer and removable dispersant are the same ingredient, and in other embodiments different ingredients. In some embodiments the plasticizer and surfactant are the same ingredient, and in other embodiments different ingredients. The term "removable dispersant" means a volatile substance effective for producing a suspension, solution, or combination thereof containing a wide distribution of the LV-PVOH and TRO adjuvant in the volatile substance, the volatile substance having a boiling point (b.p.) below about 130 degrees Celsius (°C) at 101 kilopascals (kPa) pressure. Preferably, the b.p. of the volatile substance is from about 0 °C to about 115 °C, more preferably from about 30 °C to 110 °C, and still more preferably from about 34 °C to about 105 °C, all at 101 kPa. Preferably, the removable dispersant is a liquid at 20 °C and 101 kPa. When the talc-free composition further comprises the removable dispersant, preferably the removable dispersant is from 50 wt% to 99 wt%, and typically from 50 wt% to 98 wt% of total weight of the talc-free composition, including weight of the removable dispersant. Preferably, the removable dispersant is a solvent effective for dissolving the talc-free composition to give a solution thereof, wherein the solution is at a temperature useful for applying same to the solid health formulation. Examples of preferred removable dispersants are acetic acid, acetone, ethanol, ethyl acetate, methanol, and, more preferably, water. The term "plasticizer" means a solid or liquid substance effective for increasing fluidity of the talc-free composition. When the talc-free composition further comprises the plasticizer, preferably the plasticizer is from 0.01 wt% to 20 wt% of total weight of the talc-free composition, not including weight of any removable dispersant.
Preferably, the plasticizer is non-volatile (i.e., has a b.p. greater than about 150 degrees Celsius (°C) at 101 kPa pressure), and substantially remains in the talc-free composition after removal of any removable dispersant therefrom. When employed, in some embodiments the plasticizer forms a blend with the talc-free composition without covalently bonding thereto, and in other embodiments at least some of the plasticizer reacts to form a covalent bond (e.g., via carboxylic acid esterification reaction) with at least some of the LV-PVOH or TRO adjuvant. Examples of preferred plasticizers are glycerol, a poly(ethylene glycol) (PEG), and lecithin. Examples of suitable PEGs are PEG-400, PEG-3350 and others that are commercially available from Sigma-Aldrich Company, St. Louis, Missouri, USA, or The Dow Chemical Company, Midland, Michigan, USA. For example, Dow provides CARBOWAX™ brand PEGs in number average molecular weight range of from 200 g/mol to 8000 g/mol. These PEGs (average Mn range in g/mol) include PEG-4 (190-210), PEG-6
(285-315), PEG-8 (380-420), PEG-6/PEG-32 blend, PEG-12 (570-630), PEG-20 (950-1050), PEG- 32 (1305-1595), PEG-75 (3015-3685), PEG-90 (3600-4400), PEG-100 (4400-4800), and PEG-180 (7000-9000), wherein these PEGs are named according to the established PEG nomenclature of the Personal Care Products Council (formerly Cosmetics, Toiletries and Fragrances Association),
Washington, D.C., USA, using International Nomenclature Cosmetic Ingredient naming convention. In some embodiments the talc-free composition further comprises the plasticizer, the TRO adjuvant is a different ingredient than the plasticizer, and the plasticizer is a poly(ethylene glycol), preferably PEG-400. The terms "surface-active agent" and surfactant" are synonymous and mean a substance that can reduce surface tension of water. When the talc-free composition further comprises the surfactant, preferably the surfactant is from 0.001 wt% to 1 wt% of total weight of the talc-free composition, not including weight of any removable dispersant. Examples of functional classifications of surfactants are emulsifiers, wetting agents, foaming agents, dispersing agents and anti-foaming agents. Examples of structural classifications of surfactants are ionic surfactants and nonionic surfactants. Examples of ionic surfactants are anionic surfactants (e.g., sodium
laurylsulfate), cationic surfactants (e.g., cetyl trimethylammonium bromide), and zwitterionic surfactants (e.g., amino acids). Examples of nonionic surfactants are fatty alcohols,
polyoxypropylene glycol, and polysorbates (e.g., polyoxymethylene (20) sorbitan monooleate (i.e., polysorbate 80, which is commercially known as Tween 80)).
In some embodiments the talc-free composition further comprises glycerol or a PEG as the non-volatile plasticizer. In some embodiments the talc -free composition further comprises glycerol or a PEG as the non-volatile plasticizer and a polysorbate surfactant. In some embodiments the talc- free composition further comprises water as the removable dispersant, and in other embodiments the talc-free composition substantially lacks removable dispersant. In some embodiments the talc-free composition comprises the LV-PVOH, CMC as the TRO adjuvant, and a PEG as the non-volatile plasticizer. In some embodiments the talc-free composition comprises the LV-PVOH, CMC as the TRO adjuvant, the PEG as the non-volatile plasticizer, and a polysorbate surfactant. In some embodiments the talc-free composition comprises an aqueous solution of the LV-PVOH, CMC, and PEG, and in other embodiments an aqueous solution of the LV-PVOH, CMC, PEG, and polysorbates. In some embodiments the talc-free composition lacks lecithin, and in other embodiments further comprises at most a low concentration (e.g., < 1 weight percent (wt%)) of lecithin. In some embodiments the talc-free composition is as described in any one of the foregoing embodiments in this paragraph except CMC is the only TRO adjuvant, i.e., the talc-free composition lacks HPMC, methylcellulose, maltodextrin, and PVP. In some embodiments the talc-free composition is as described in any one of the foregoing embodiments, but the immediately preceding one, in this paragraph except the CMC is entirely replaced by HPMC, methylcellulose (e.g., a METHOCEL™), maltodextrin, PVP, or a combination thereof.
Preferably, the health formulation is a nutraceutical, pharmaceutical, or veterinary dosage form. Preferably, the dosage form is a unit dosage form. The health formulation can be in any physical form. Examples of suitable physical forms are solid and liquid-containing physical forms. Examples of suitable solid health formulations are a bead (e.g., nonpareil bead), powder, granule, tablet (e.g., prepared by compressing powder), capsule (e.g., gelatin capsule or components thereof), gelcap tablet, lozenge, patch, and troche. At least some of the ingredients of the solid health formulation are solid ingredients. The invention contemplates solid health formulations that in some embodiments further contain a relatively small amount of at least one liquid ingredient, and in other embodiments contain only solid ingredients. Each of the solid ingredient(s) of the solid health formulation can be characterized as being amorphous, partially crystalline, or crystalline. The invention composition can be used as an ingredient in, or preferably to coat or form a film on, the solid health formulations. Examples of suitable liquid-containing health formulations are a cream, elixir, emulsion, gel, lotion, ointment, solution (e.g., in water), and syrup. The invention composition can be used as an ingredient in the liquid-containing health formulations.
Preferably, the active ingredient is a nutraceutically, pharmaceutically, or veterinary active ingredient. The nutraceutically active ingredient provides a dietary, nutritional, or preventative health benefit. The active ingredient can be a solid or liquid. In some embodiments the solid health formulation comprises the liquid active ingredient widely distributed on or in a solid excipient (e.g., solid carrier), in other embodiments a solid active ingredient widely distributed in a liquid excipient (e.g., liquid carrier), and in still other embodiments a solid active ingredient widely distributed in a solid excipient so as to form a blend therewith. Examples of nutraceutically active ingredients are a dietary supplement (e.g., an antioxidant (e.g., resveratrol), flavinoid (e.g., from citrus fruit, tea, wine, or cocoa bean), herb, mineral, naturally-occurring amino acid, and vitamin) and an enriched food (e.g., a soya protein enriched granola bar). The pharmaceutically or veterinary active ingredient provides a disease treating health benefit (e.g., increases time to onset of at least one symptom in prophylactic treatment, diminishes severity of at least one symptom in palliative treatment, or inhibits progression of a pathological effect in a disease modifying treatment of a disease or disorder in a human or animal patient in need of such treatment. Examples of pharmaceutically or veterinary active ingredients are an analgesic (e.g., carprofen), angiotensin converting enzyme (ACE) inhibitor (e.g., quinapril, e.g., quinapril hydrochloride), antibiotic (e.g., azithromycin), anti-convulsant (e.g., gabapentin), anti-depressant (e.g., sertraline, e.g., sertraline hydrochloride), anti-fibromyalgic (e.g., pregabalin), anti-hypertensive (e.g., amlodipine, e.g., amlodipine besylate), and a cholesterol lowering drug (e.g., atorvastatin, e.g., atorvastatin calcium).
In some embodiments the health formulation further comprises at least one acceptable excipient in admixture with the active ingredient. The term "admixture" means a product of being blended together. The term "acceptable excipient" means any compound or substance other than the active ingredient(s) that is suitable for use in the health formulation. Preferably, the acceptable excipient is a nutraceutically, pharmaceutically, or veterinary acceptable excipient. Examples of nutraceutically, pharmaceutically, or veterinary acceptable excipients are carriers; diluents;
stabilizers; nutraceutical, pharmaceutical, and veterinary adjuvants; and characteristic components of the dosage form such as capsule shells (e.g., gelatin capsule shells) for capsules and
semipermeable membranes and backings for transdermal patches.
In some embodiments the talc-free composition further comprises and the method of preparing the coated solid dosage form further employs the removable dispersant. The coating of the solid health formulation to give the coated solid dosage form is preferably carried out by applying a surface-coating effective amount of a suspension or, preferably, solution of the talc-free composition in the removable dispersant (e.g., a solvent such as ethanol or water) to an exposed surface of the (solid) health formulation in such a way so as to evenly cover the exposed surface of the (solid) health formulation with the talc-free composition; and removing the removable dispersant from the covered (solid) health formulation to give the coated solid dosage form. The term "surface-coating effective amount" means a quantity sufficient to cover the exposed surface. Examples of applying are spraying, dipping, and tumbling. Examples of removing are evaporating, blotting, and wiping. The suspension or solution of the talc-free composition preferably is prepared by contacting the talc- free composition to the suitable amount of the removable dispersant (e.g., a solvent such as ethanol or water) so as to give the suspension or solution thereof. Examples of contacting are agitating, shaking, spraying, stirring, and tumbling.
Preferably, the manufactured article comprises a health formulation comprising an active ingredient and the talc-free composition in operative contact therewith.
Illustrative examples of the present invention are provided later where the examples employ certain methods and materials, which include certain preparations. The methods and materials and preparations are described in the following section.
LV-PVOH: designated Gohsenol EG-05P from Nippon Gohsei, Osaka, Japan. Gohsenol EG-05P has a saponification degree of 86.5 mol% to 89.0 mol% and a dynamic viscosity of 4.8 mPa.s to 5.8 mPa.s measured as a 4 wt/vol% aqueous solution at 20 °C.
CMC: designated Sodium Carboxy Methyl Cellulose CRT-30 PA, DS=0.9, lot 7M650 from The Dow Chemical Company, Midland, Michigan, USA.
PEG-400 and PEG-3350: respectively designated CARBOWAX SENTRY Polyethylene glycol 400NF, WL0101 AAKC and CARBOWAX SENTRY Polyethylene glycol 3350, from The Dow Chemical Company.
Polysorbate 80: (Tween 80) designated enzyme grade, 943317 from Fisher Scientific.
Tablets: designated Placebo tablets (100 g red caplet cores, 493 g white oval tablets, 6.5 g white disks) from The Dow Chemical Company.
Dynamic Viscosity Test Method: Measure solution viscosities using a Brookfield- II,
D06719, using an appropriate spindle number 2,3,5, or 7 and relevant 10, 20, 50 and 100 revolutions per minute (rpm).
Film preparation: Complete all film preparations and storage in a constant temperature (22°C) and relative humidity (50% RH) environment. Hand draw wet films (1 mm) on glass plates by slowly pouring a 20 wt% solution near an edge of a 1 mm gapped casting (drawn down) bar, and then steadily draw the solution to minimize bubbles and defects. Dry the films on the plates for two days, remove them from the plates, and anneal the films for an additional 1 day. Measure film properties on the annealed film. Preferably conclude all film testing within 4 days of film removal to minimize any sample-to-sample variance. When not testing films, store films between sheets of paper and at the constant temperature and relative humidity.
Film Clarity Test Method: Measure film clarity of films using a Pacific Scientific PG-5500 from Gardner Laboratory Inc., Bethesda, Maryland, USA and a Zebedee CL-100 from Zebedee Corporation, Moore, South Carolina, USA, calibrated with an open port, a black standard and a Mylar film standard at 100, 0, and 87 (+/- 1) percent clarity, respectively. Read clarity
measurements on four different locations on each film. Record the average of the four
measurements.
Film Haze Test Method: Measure haze of prepared films with a Haze-gard Plus from BYK Gardner, Columbia, Maryland, USA, Catalog Number 4725. Report both haze and transmission readings as a percentage. Record an average value of four readings.
Divide percent film haze and clarity values by film thickness in millimeters to give the percent normalized film haze and percent normalized film clarity.
Tackiness Test Method: Tablets are coated according to the ad rem Examples described later. The tackiness of the coated tablets can be a qualitative visual observation of coated tablets agglomerating and sticking to each other or not agglomerating or sticking to each other. Preferably the tackiness is a quantitative weight percent equal to weight of agglomerated portion, if any, of the coated tablets as a percentage of total weight of coated tablets prepared (i.e., weight of individual coated tablets plus any agglomerated portion). If the agglomerated portion is < 10 wt%, preferably < 5 wt%, and more preferably < 1 wt%, and still more preferably 0 wt% (i.e., there is no
agglomeration), the talc-free composition and coating of the coated tablets are deemed to be "non- tacky" for purposes of this invention. Photograph samples to compare experimental runs.
Water Vapor Transmission Rate Test Method: Measure water vapor transmission rates using a "dry cup" method. Weigh calcium chloride (2.0 g) into a 4 ounce (120 mL) jar, and allow it to sit at 50% relative humidity (73 °C) with a closed ring cap (2.5 cm diameter hole therein) for 1 hour. Next, place a small amount of vacuum grease around the edge of the jar's mouth. Cut films into approximately 1.3 inch (3.3 centimeter (cm)) diameter circles using a metal punch. Place film sample circle on top of the jar, and place a lid having a 1-inch (2.5 cm) diameter hole on top of the film circle. Tighten the lid to form a seal while making sure not to crack the film circle. Place jars into a temperature -humidity chamber equipped with an Environ-Cab controller (Lab-Line
Instrument, Inc.) set to 75% relative humidity and 25 °C. Record total weight of the jar, lid, films, and calcium chloride and re-measure total weight every 24 hours for 5 days. Use a linear regression of total weight gain (m) versus time (t) to obtain a mass transfer rate. Divide the mass transfer rate by the area of the exposed film to provide a water vapor transmission (WVT) rate in grams per square centimeters. hour (g/cm hr),
m,
WVT = ^ ,
A
where mt is the change in mass with time (grams per hour (g/hr)) and A is the exposed film area in square centimeters (cmz). Calculate the film permeability according to the following equation:
WVT * l
Permeability = ,
S(RH2 - RH^
where / is the film thickness, S is the saturated vapor pressure of water at 25 °C, RH2 is 0.75 (75% relative humidity) and RHj is 0. The S(RH2-RHj) term is the driving force for mass transfer of water through the film.
Films of the invention talc-free compositions can be favorably compared to the following films of non-invention talc-free compositions (a) to (d):
(a) a film of 100% CMC, which film has a normalized film haze of 14 %/mm, a normalized
n
film clarity of 472 %/mm, and an average WVT permeability of 12 times 10 g/Pa.h.m;
(b) a film of 100% Gohsenol EG-05P, which film is tacky (13 wt% agglomerated portion when tablets are coated therewith according to the tablet coating procedure described later);
(c) a film of 100% Gohsenol EG-40P (a high viscosity PVOH that has a saponification degree of 86.5 mol% to 89.0 mol% and a dynamic viscosity of 40 mPa.s to 46 mPa.s measured as a 4 wt/vol% aqueous solution at 20 °C), which film is tacky and has substantially increased normalized film haze and decreased normalized film clarity compared to those of film (b); and
(d) a film of 50:50 Gohsenol EG-05P/CMC, which film has an average water permeability of 7 times 10"^ g/Pa.h.m.
Some invention embodiments are described in more detail in the following Examples.
Examples 1 to 6: talc-free compositions of LV-PVOH and CMC. Dissolve a total of 8g to 25 g (e.g., 10 g) of Gohsenol EG-05P (LV-PVOH) and CMC and, optionally, plasticizer according to Table 1 below in deionized (DI) water (e.g., 100 g) with mixing to give talc-free composition as a solution (4 wt% to 15 wt% solids) of each of Examples 1 to 6. Evaporate water from a portion of the solution to give a dried talc-free composition of each of Examples 1 to 6 having Gohsenol EG-05P LV-PVOH, CMC, and, optionally, plasticizer as shown in Table 1. Table 1 : Examples 1 to 6
:wt% based on total weight of LV-PVOH, CMC, and any plasticizer.
Examples A to F: Coated tablets. In separate experiments, charge a Vector Hi-Coater model LDCS, having a temperature exhaust set point of 40 °C, with tablets. Spray the solution of any one of Examples 1 to 6 at a spray rate of 2.0 to 2.7 grams per minute (g/min) onto the tablets for a time period calculated to achieve a theoretical film weight gain of 1 to 3% to give coated tablets of each of Examples A to F, respectively. Evaluate films and coated tablets for tackiness, average water permeability in grams per Pascal-hour-meter x 10~7; film thickness normalized film clarity in percent clarity per millimeter film thickness; film haze in percent; and film thickness normalized film haze in percent haze per millimeter film thickness.
Table 2: Examples A to F
As shown by the Examples, the talc-free composition is capable of forming a non-tacky film or coating on a solid dosage form, the film or coating unexpectedly having an advantageous combination or characteristics comprising an average water vapor permeability of at most 5.0 times n
W g/Pa.h .m; a normalized film clarity of > 500 %/mm; a film haze of <13%; and in some embodiments also a normalized film haze of < 13 %/mm. The coated tablets have coatings comprising embodiments of the invention non-tack film and are of a film thickness suitable for use in pharmaceutical, nutraceutical, and veterinarian coated tablet applications.

Claims

WHAT IS CLAIMED IS:
1. A talc-free composition characterizable as non-tacky and having an average water permeability of at most 5.0 times 10"^ grams per Pascal-hour -meter and having a capability of forming a non- tacky film having an average water vapor permeability of at most 5.0 times 10"^ grams per Pascal- hour -meter.
2. The talc-free composition of claim 1 further characterizable as having at least a normalized film clarity of at least 500 percent per millimeter of film thickness.
3. The talc-free composition of claim 1 or claim 2 further characterizable as having a film haze of at most 13 percent.
4. The talc-free composition of any one of claims 1 to 3 consisting essentially of a low viscosity polyvinyl alcohol and a tack-reducing organic adjuvant, wherein the weight/weight ratio of the low viscosity polyvinyl alcohol to tack-reducing organic adjuvant in the composition is from > 60:40 to < 95:5.
5. The talc-free composition of claim 4, wherein the tack-reducing organic adjuvant is a carboxymethylcellulose, poly(ethylene glycol), hydroxypropyl methyl cellulose, maltodextrin, methylcellulose, or polyvinylpyrrolidone, or a combination thereof.
6. The talc-free composition of claim 5, wherein the tack-reducing organic adjuvant is a carboxymethylcellulose.
7. The talc-free composition of any one of the preceding claims further consisting essentially of a non-canceling amount of at least one secondary organic adjuvant that is a plasticizer, surfactant, or removable dispersant.
8. The talc-free composition of claim 7, wherein the secondary organic adjuvant is poly(ethylene glycol), polysorbate, water; or a combination of poly(ethylene glycol), polysorbate, and, optionally, water.
9. A method of preparing a coated solid dosage form, the method comprising contacting a coating- effective amount of the talc-free composition of one of the preceding claims with a solid health formulation comprising an active ingredient, the contacting being performed in such a way so as to coat the solid health formulation to give a coated solid dosage form comprising a non-tacky film comprising the talc-free composition in coating operative contact with the solid health formulation.
10. A manufactured article comprising the talc-free composition of any one of claims 1-8.
11. The manufactured article of claim 10 comprising a coated solid dosage form comprising a non- tacky film comprising the talc-free composition, the non-tacky film being in coating operative contact with the solid health formulation and having an average water permeability of at most 5.0 times 10"^ grams per Pascal-hour -meter.
12. A non-tacky film comprising the talc-free composition of any one of claims 1-8.
EP12721984.8A 2011-05-04 2012-04-25 Talc-free polyvinyl alcohol composition Withdrawn EP2705088A1 (en)

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