WO2012025730A2 - Soluble film - Google Patents

Soluble film Download PDF

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Publication number
WO2012025730A2
WO2012025730A2 PCT/GB2011/051439 GB2011051439W WO2012025730A2 WO 2012025730 A2 WO2012025730 A2 WO 2012025730A2 GB 2011051439 W GB2011051439 W GB 2011051439W WO 2012025730 A2 WO2012025730 A2 WO 2012025730A2
Authority
WO
WIPO (PCT)
Prior art keywords
water soluble
soluble film
simethicone
film according
weight
Prior art date
Application number
PCT/GB2011/051439
Other languages
French (fr)
Other versions
WO2012025730A3 (en
Inventor
Andrew Ingram
Alan Gibson
Original Assignee
Biofilm Limited
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 Biofilm Limited filed Critical Biofilm Limited
Publication of WO2012025730A2 publication Critical patent/WO2012025730A2/en
Publication of WO2012025730A3 publication Critical patent/WO2012025730A3/en

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the present invention relates to a soluble film. More particularly, the present invention relates to a soluble film comprising simethicone and a method of making such a film.
  • a further problem has related to stabilising a high dose of simethicone into a solid formulation such as film.
  • the problem of stabilising simethicone in concentration W/W of up to 50% is that leaching of the oil can be an issue, and thus a product with an oily finish is common, which can lead to problems in processing through machinery (oil build up, sticking to parts). An oily finish is also unacceptable in appearance and touch to consumers.
  • US 5,073,384 relates to preparation of free flowing granular simethicone prepared using maltodextrin, but the quantities of maltodextrin required to granulate a therapeutic dose of simethicone (50-90 w/w% maltodextrin) would make for a film with unacceptably high mass for satisfactory dissolution in the oral cavity.
  • US 5,073,384 is incorporated herein by reference.
  • WO 2005/039499 relates to rapidly dissolving films for delivery of pharmaceutical or cosmetic agents, where a combination of high molecular weight and low molecular weight film forming polymers in combination are used and the film may be essentially free of surfactants in certain embodiments.
  • This patent does not specifically refer to the issue of incorporating simethicone oil into a strip and thus cannot address any technical challenges that may be encountered.
  • US 7,341 ,742 relates to addition of magnesium carbonate to simethicone for manufacture of oil free simethicone tablets.
  • the process is not useful for film manufacture as the weight of the granulated simethicone, mixed with magnesium carbonate would make for an unacceptably thick film for rapid dissolution in the oral cavity.
  • US 7,341 ,742 is incorporated herein by reference.
  • Films for therapeutic applications comprising anti-tacking excipients are described in US 20070122455, and in some examples further comprise simethicone.
  • simethicone is only used as an anti-foaming excipient to prevent air entrapment in the casting medium from which films are made, and not as a therapeutically active component, thus it is present at levels no more than about 5%. At such low levels, none of the formulation problems addressed by the current disclosed invention would be encountered.
  • a water soluble film comprising:
  • the present invention therefore relates to a water soluble film that is devoid of organic solvent.
  • the water soluble film therefore is free of organic solvents e.g. methanol, ethanol etc which may have been used in the manufacturing process. This is in contrast to prior art films which contain significant amounts of organic solvent, due to the use of organic solvents in the manufacturing process.
  • Organic solvents provide several processing advantages, but also several disadvantages.
  • the inventors of the present application have found that through selection of specific emulsifiers and film formers it is possible to form a stabilised casting solution containing emulsified simethicone that is stable through a drying process (e.g. hot air) and which provides a product with an oil-free finish, with the desired physical and organoleptic properties. It has been surprisingly found that a mix of specific emulsifiers and film formers, mixed with an absorbent provides a product with an oil-free finish. The absorbent assists formation of a film with an oil-free finish by providing a matrix into which the simethicone can be absorbed during the drying process, thus preventing leaching of the simethicone from the solid matrix.
  • Typical emulsifiers used in the present invention may be any one of or combination of the following, with a hydrophilic lipophilic balance (HLB) value in the region of 15 to 17: Polysorbate 80; sucrose stearate; polyoxyl 40 stearate commonly in the region of between 0.1 % and 10% by weight of formulation.
  • a simethicone emulsion such as Dow-Corning 30% emulsion USP can be used as a source of simethicone, with one of the emulsifiers discussed above then added to obtain a suitable film as end product.
  • Typical film formers used in the present invention may be any one of or combination of the following: hydroxypropylmethylcellulose; pectin; carboxymethyl cellulose; pullulan; gelatin and hydroxypropylcellulose.
  • a preferred film composition may be that of any of the following: HPMC and blanose; pectin and CMC; pullulan and pectin and pullulan and CMC.
  • Typical absorbents used in the present invention may be any one of or combination of the following: colloidal silica; hydrophobically modified colloidal silica; magnesium carbonate; kaolin and microcrystalline cellulose.
  • emulsifiers with for example polyoxyl 40 stearate and sucrose stearate which have been found to be surprisingly effective in comparison to most others.
  • the presence of high amounts of emulsifier can however have a deleterious effect on film mechanical strength.
  • HPMC hydroxypropylmethylcellulose
  • CMC sodium carboxymethylcellulose
  • pullulan/CMC pullulan/CMC
  • pectin/CMC a film may be formed with good mechanical strength, simethicone oil retention and acceptable oral dissolution/dispersion rate.
  • Pectin:CMC blend may be found to have a beneficial effect on mechanical strength, without reducing solubility to an unacceptable level. If the ratio of pectin increases, solubility becomes too poor, if the ratio of CMC increases, mechanical strength worsens.
  • HPMC hydroxypropylmethylcellulose
  • CMC hydroxypropylmethylcellulose
  • a ratio of HPMC:CMC between about 2.6 and 2.75 to 1 has been found to be advantageous.
  • the soluble film is intended to disperse and/or dissolve in an oral cavity.
  • the oral cavity may usually be that of a human but can be other animals or mammals.
  • the soluble film may therefore be in the form of a thin strip suitable for oral consumption.
  • the soluble film preferably in the form of a strip, may be intended to quickly dissolve in the oral cavity.
  • the soluble film may dissolve in the oral cavity releasing the simethicone over a period of time.
  • the soluble film may dissolve in a period of less than about 120 seconds, less than about 60 seconds or less than about 30 seconds.
  • the soluble film may comprise a high level of simethicone such as about
  • the soluble film may comprise about 10 - 100 mg of simethicone, about 20 - 80 mg of simethicone or about 40 - 60 mg of simethicone.
  • the dry weight percentage is in the region of about 10 - 50%, about 20 - 40% or about 32% for some examples and about 30 - 60%, about 40 - 50% and about 47% simethicone for other examples.
  • Simethicone is an oral anti-foaming agent used to reduce bloating, discomfort and pain caused by excess gas in the stomach or intestinal tract. It is a mixture of polydimethylsiloxane and silica gel.
  • the simethicone may be impregnated throughout the content of the water soluble film.
  • the simethicone may be deposited as a layer onto the water soluble film.
  • the film of the present invention is therefore soluble in an aqueous water solution such as saliva in an oral cavity.
  • water soluble herein in reference to the water soluble polymeric film former may mean any polymeric material which forms a solution or colloidal solution, where the approximate volume of solvent in millilitres per gram of solute is in the range of about 0.01 to 10,000.
  • the film comprises a water soluble polymeric film former in an amount of about 1 - 90% by weight, about 20 - 80% by weight, about 30 - 70% by weight, about 40 - 80% by weight or about 50 - 60% by weight.
  • the film may comprise a water soluble polymeric film former in an amount of at least about 10% by weight, at least about 30% by weight, at least about 50% by weight, at least about 70% by weight or at least about 90% by weight.
  • the water soluble polymeric film former may be made from a polymer having an average molecular weight range of about 1 ,000 - 1 ,500,000, about 1 ,000 - 500,000, about 50,000 - 500,000, about 100,000 - 200,000, about 1 ,000 - 100,000, about 1 ,000 - 50,000, about 1 ,000 - 20,000 or about 10,000 - 20,000.
  • the average molecular weight may be about 50,000 - 250,000 or most preferably about 140,000.
  • the average molecular weight may be determined by size exclusion chromatography.
  • the film may also comprise other materials such as any one of or combination of the following: sweeteners; flavourings; antimicrobial agents; plasticising agents; colouring agents; saliva stimulating agents; cooling agents; surfactants; stabilising agents; emulsifying agents; thickening agents; preservatives; bulking agents; humectants; vitamins; minerals; fluorides; and fillers.
  • sweeteners such as any one of or combination of the following: sweeteners; flavourings; antimicrobial agents; plasticising agents; colouring agents; saliva stimulating agents; cooling agents; surfactants; stabilising agents; emulsifying agents; thickening agents; preservatives; bulking agents; humectants; vitamins; minerals; fluorides; and fillers.
  • the film may be in the form of a thin strip suitable for oral consumption.
  • the film may be a strip wherein the strip may be substantially rectangular in shape, but any shape of strip (e.g. substantially rounded rectangle, substantially oval, substantially square, substantially circular) may be used.
  • the strip may have a minimum thickness of about 10 ⁇ to allow ease of handling.
  • the strip may have a preferred maximum thickness of about 500 ⁇ , or more preferably about 200 ⁇ , so that the physical dimensions of the strip do not prevent the body from dissolving in a desired period of time in an oral cavity e.g. by the action of saliva.
  • the thickness of the strip may be in the range of about 20 to 200 ⁇ , and more usually about 40 to 140 ⁇ .
  • the width of the strip may be approximately about 0.05 - 5 cm or preferably about 1 - 2.5 cm, and the length may be about 0.05 - 10 cm or preferably about 2 - 8 cm.
  • the strip may be dry, by which is meant that the strip is dry to the touch.
  • the strip may contain approximately about 1 - 20% by weight, or about 1 - 15% by weight, of residual water, which remains after the manufacturing process.
  • the film may be generally formed of edible material.
  • edible material is meant a material that is acceptable for consumption by a user. Normally, this is a material approved for use by the appropriate regulatory authorities.
  • the strip may be formed from any suitable film-forming material or combination thereof.
  • any suitable hydrocolloid may be used.
  • the strip may be formed from any suitable edible water-soluble polymeric materials, such as any one of or combination of the following: carrageenan; cellulose derivatives or modified celluloses, such as methyl celluloses, (e.g. sodium carboxymethyl cellulose), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose; alginates (e.g. sodium alginate); gums (e.g.
  • xanthan gum tragacanth gum, guar gum, acacia gum, Arabic gum
  • starches and modified starches gelatin; copolymers of methyl vinyl ether and maleic anhydride, e.g. Gantrez (Trademark); carbopols (i.e.
  • carbomers polyvinyl acetate; polyvinyl alcohol; acrylic based polymers, such as methylmethacrylate polyacrylates and polymethacrylates and esters and salts and copolymers thereof; polycarbophils; proteins; pullulan; polyacrylic acid; carboxyvinyl polymer; amylase; high amylase starch; hydroxypropylated high amylase starch; dextrin; pectin; chitin; chitosan; levan; elsinan; collagen; gelatine; zein; gluten soy protein isolate; whey protein isolate and casein.
  • any suitable combination of the above compounds such as a mixture of two, three, four, or more, of the materials may be employed.
  • different layers in a multi-layer strip may comprise different combinations of materials.
  • Suitable flavourings may exhibit fragrant properties. Suitable flavourings may be added during the manufacturing process in the form of flavoured oils. The flavourings may form amounts of about 0 - 30 wt.% or about 0 - 10 wt.% of film. The flavourings may be chosen from natural oils, synthetic flavour oils, flavouring aromatics, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof.
  • Flavour oils which may be used include any one or combination of the following: spearmint oil; cinnamon oil; peppermint oil; clove oil; bay oil; thyme oil; cedar leaf oil; oil of nutmeg; oil of sage; and oil of bitter almonds.
  • flavours such as vanilla, chocolate, coffee, cocoa and 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.
  • sweetenings can be used individually or in a mixture.
  • Commonly used flavours include mints, such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavours, whether employed individually or in admixture.
  • Flavourings such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, and p-methylanisole, and so forth may also be used.
  • aldehyde flavourings include, but are not limited to any one or combination of the following: acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e. alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); helliotropine, i.e.
  • trans-2 berry fruits
  • tolyl aldehyde cherry, almond
  • veratraldehyde vanilla
  • 2,6-dimethyloctanal green fruit
  • 2-dodecenal citrus, mandarin
  • the film may comprise a sweetening agent or a combination of sweetening agents.
  • the sweetening agents may be present in an amount of less than about 30 wt.%, but more typically less than about 20 wt.%.
  • Typical sweeteners include monosaccharides, disaccharides and polysaccharides such as any one or combination of the following: xylose; ribose; glucose (dextrose); mannose; galactose; fructose (i.e. levulose); sucrose (i.e. sugar); and maltose; an invert sugar (i.e. a mixture of fructose and glucose derived from sucrose); partially hydrolysed starch; corn syrup solids; dihydrochalcones; monellin; steviosides; and glycyrrhizin.
  • water-soluble artificial sweeteners such as soluble saccharin salts may be used.
  • any one or combination of the following artificial sweeteners may be used: sodium or calcium saccharin salts; cyclamate salts; sodium, ammonium or calcium salts of 3,4-dihydro-6-methyl-1 ,2,3-oxathiazine-4- one-2,2-dioxide; potassium salts of 3,4-dihydro-6-methyl-1 ,2,3-oxathiazine-4- one-2,2-dioxide (acesulfame-K); sucralose; and the free acid form of saccharin.
  • dipeptide based sweeteners such as any one or combination of the following may be used: L-aspartic acid derived sweeteners, such as L- aspartyl-L-phenylalanine methyl ester (aspartame); L-alpha-aspartyl-/V-(2, 2,4,4- tetramethyl-3-thietanyl)-D-alaninamide hydrate; methyl esters of L-aspartyl-L- phenylglycerin and L-aspartyl-L-2,5-dihydrophenyl-glycine; L-aspartyl-2,5- dihydro-L-phenylalanine; and L-aspartyl-L-(1 -cyclohexyen)-alanine.
  • L-aspartic acid derived sweeteners such as L- aspartyl-L-phenylalanine methyl ester (aspartame); L-alpha-aspartyl-/V-(2, 2,4,
  • Water-soluble sweeteners derived from naturally occurring water-soluble sweeteners such as a chlorinated derivative of ordinary sugar (i.e. sucrose) may also be used.
  • protein based sweeteners such as thaumatoccous danielli (i.e. Thaumatin I and II) may be used.
  • Plasticising agents may also be included.
  • the plasticising agents may be present in an amount of about 0 - 25 wt.% or about 0 to 15 wt.% of the film.
  • plasticising agents such as triacetin, monoacetin, diacetin and polyols e.g. glycerol, sorbitol and mannitol may be used.
  • a drier which may be used to dry the aqueous formulation may comprise a tunnel of warm low humidity air or utilise other heat sources, such as Infra Red (IR) lamps, to evaporate the solvent and form a dry web.
  • IR Infra Red
  • the film may be cast into sheets and dried in an oven. The resulting film may then be cut and packed directly, or stored in reel or sheet format for future processing.
  • the soluble film may be formed by casting and/or depositing an aqueous formulation comprising the simethicone.
  • the aqueous formulation may be cast and/or spread using, for example, a knife blade over a roll-coater.
  • the cast and/or spread aqueous formulation may then be dried (e.g. air dried) for a period of time until the formed film is substantially dry. For example, a drying time of about 10 - 30 minutes or about 20 minutes may be used.
  • the film may be passed down a belt (e.g. a drying line) at, for example, about 0.5 metres per minute. As the film passes down the drying line a raised air temperature of about 50 - 60 Q C may be used for the drying process.
  • the drying temperature of 50 - 60 Q C is lower than other process such as described in US 2007/122455, which is incorporated herein by reference.
  • the formed film may then be cut and sachet packed.
  • the lower temperature leads to lower running costs and reduced risk of damage to sensitive active ingredients.
  • the aqueous formulation used to form the film may comprise emulsified simethicone.
  • the simethicone may be emulsified using an emulsifier such as, for example, sucrose stearate, polysorbate 80 or pre-emulsified simethicone may be used and a an additional emulsifier added such as, for example, polyoxyl 40 stearate.
  • aqueous-insoluble absorbent may be added to the formulation: the absorbent may be hydrophobically modified colloidal silica (Aerosil R972, Evonik) or cellulose (Avicel FD-100, FMC biopolymer).
  • An aqueous insoluble absorbent is a high surface area aqueous insoluble material that is known in the literature to be an efficacious absorbent for oils.
  • a mix of film formers may be added in each case, for example the formulation may comprise about 23.3% (w/w) hydroxypropylmethylcellulose (HPMC) and about 8.9% (w/w) CMC, or for example between about 8 and 14% (w/w) pectin or pullulan may be added and a matching quantity w/w % of CMC may be added.
  • HPMC hydroxypropylmethylcellulose
  • CMC hydroxypropylmethylcellulose
  • pectin or pullulan may be added and a matching quantity w/w % of CMC may be added.
  • the choice of film former is important, as different film formers can significantly affect the oil retention properties, mechanical strength and rate of dissolution of finished product.
  • films made from Genupectin (citrus) type USP-L may have greater mechanical strength than films where the pectin has been substituted with Methocel K3, but commonly will take longer to dissolve, and the Methocel K3 film would be more likely to produce a film containing simethicone that is oil free to the touch.
  • the film may be as described in the first aspect.
  • a film according to the first aspect in treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract.
  • a fourth aspect of the present invention there is provided a method of treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract using a film as defined in the first aspect.
  • the present invention resides in the provision of soluble film comprising simethicone in a high dosage.
  • the dry weight percent content is about 47% simethicone oil. It is necessary to keep this ratio of simethicone oil high to keep the strip weight sufficiently low, which in turns keeps rate of film dissolution/disintegration suitably quick.
  • the formulation described in the present application is free from organic solvent, which offers advantages in terms of health and safety, running costs, site insurance and labelling.
  • the drying temperature used in the present invention of about 50 - 60 Q C is also lower than previous drying temperatures such as described in US 2007/122455, which leads to lower running costs and reduced risk of damage to sensitive active ingredients. US 2007/122455 is incorporated herein by reference.
  • This application relates to the formation of soluble films, which will disperse in the oral cavity within about sixty seconds, and contain about 40 - 60 mg of simethicone.
  • Films are formed by casting an aqueous formulation using a knife blade over a roll-coater, and then air drying the mixture over approximately a 20 minute period as it travels down a drying line at 0.5 metres per minute. The air temperature is between about 50 - 60 Q C and is blown evenly over the mixture as it travels down the coating line, to yield a film which can then be cut and sachet packed as desired.
  • the aqueous formulation comprises emulsified simethicone, which can be emulsified using sucrose stearate in one embodiment or in another embodiment pre-emulsified simethicone is purchased from a commercial source and additional polyoxyl 40 stearate is added as well.
  • aqueous-insoluble absorbent is added to the formulation: the absorbent is hydrophobically modified colloidal silica (Aerosil R972, Evonik) for one example product and microcrystalline cellulose (Avicel FD-100, FMC biopolymer) for other examples.
  • a mix of film formers are added in each case.
  • the formulation comprises about 23.3% (w/w) hydroxypropylmethylcellulose (HPMC) and about 8.9% (w/w) CMC.
  • HPMC hydroxypropylmethylcellulose
  • CMC hydroxypropylmethylcellulose
  • pectin or pullulan is added and a matching quantity w/w % of CMC is added.
  • the ideal ratio is about 50:50 pectin or pullulan to CMC, although a range of about 40 - 60 pectin or pullulan to about 40 - 60 to CMC is also suitable.
  • HPMC:CMC the optimum ratio is between about 2.6:1 to 2.75:1 .
  • excipients include: Glycerol as plasticiser, artificial sweetener (select from acesulfame K, sodium saccharin and sucralose), flavouring (peppermint or cranberry), and preservative (potassium sorbate).
  • Peppermint flavour example B peppermint flavour example B
  • Titanium dioxide 1 .35% Acesulfame-K 0.20%
  • Titanium dioxide 1 .66%
  • the dry weight percent content is about 47% simethicone oil.
  • the disclosed invention is free from organic solvent, which offers advantages in terms of health and safety, running costs, site insurance, labelling.
  • the drying temperature of 50-60 Celsius for the products described herein is also lower than temperatures used in film manufacture as described in US 2007/122455, which leads to lower running costs and reduced risk of damage to sensitive active ingredients.
  • Polyethylene glycol 1500 5.00 g
  • Peppermint oil 4.50 g
  • This film was oil free to touch, but had an unacceptable dissolution and mouth feel with unacceptably poor tear strength and thus would not be capable of on processing through production machinery.
  • Poloxamer 407 is the emulsifier in this formulation, and HPC is the film former which combines to emulsify the oil effectively, but this combination leads to a film with poor dissolution and gummy mouthfeel, and the poloxamer significantly increases brittleness of the film in this formulation.
  • HPC the film former which combines to emulsify the oil effectively, but this combination leads to a film with poor dissolution and gummy mouthfeel, and the poloxamer significantly increases brittleness of the film in this formulation.
  • the examples below show the differences between a formulation with and without addition of CMC.
  • the product described in example 1 contains no CMC, has an oil-free finish but poor mechanical strength.
  • the film described in example 2 has CMC added and has improved mechanical strength, whilst still maintaining a film with no simethicone oil leached from the solid matrix.
  • Titanium dioxide 2.00 g
  • the below example relates to a 2.75:1 ratio of HPMC:CMC and provides robust film with an oil free finish.
  • Titanium dioxide 3.00 g
  • Peppermint oil 12.50 g
  • Spearmint flavour 6.25 g
  • Peppermint oil 12.50 g
  • the finished products contained significant amounts of leached simethicone oil, providing a finished product with an oily surface.
  • the increased amount of pectin in example 4 provided a more robust film, however with increased dissolution time compared to example 3.

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Abstract

There is herein described a soluble film. More particularly, there is described a soluble film comprising simethicone and a method of making such a film.

Description

SOLUBLE FILM
FIELD OF THE INVENTION
The present invention relates to a soluble film. More particularly, the present invention relates to a soluble film comprising simethicone and a method of making such a film.
BACKGROUND OF THE INVENTION
Although soluble films comprising simethicone exist in the prior art there are a number of problems associated with these previous films. For example, previous films have found it difficult to have high dosages of simethicone without compromising the structural integrity of the film. There have also been problems in maintaining good solubility with high concentrations of simethicone.
Previous soluble films comprising simethicone have also contained organic solvent which has led to health and safety problems, increased running costs, increased site insurance and labelling issues. Labelling issues may occur because if ethanol is used to process the films, it will need to be included in the label, and a warning will be present to warn the consumer the product contains ethanol. The use of organic solvent for film casting and drying is commonplace because it affords faster drying, more flexibility (less viscosity) and an ability to solubilise aqueous insoluble materials.
A further problem has related to stabilising a high dose of simethicone into a solid formulation such as film. The problem of stabilising simethicone in concentration W/W of up to 50% is that leaching of the oil can be an issue, and thus a product with an oily finish is common, which can lead to problems in processing through machinery (oil build up, sticking to parts). An oily finish is also unacceptable in appearance and touch to consumers.
US 5,073,384 relates to preparation of free flowing granular simethicone prepared using maltodextrin, but the quantities of maltodextrin required to granulate a therapeutic dose of simethicone (50-90 w/w% maltodextrin) would make for a film with unacceptably high mass for satisfactory dissolution in the oral cavity. US 5,073,384 is incorporated herein by reference.
WO 2005/039499 relates to rapidly dissolving films for delivery of pharmaceutical or cosmetic agents, where a combination of high molecular weight and low molecular weight film forming polymers in combination are used and the film may be essentially free of surfactants in certain embodiments. This patent does not specifically refer to the issue of incorporating simethicone oil into a strip and thus cannot address any technical challenges that may be encountered.
US 7,341 ,742 relates to addition of magnesium carbonate to simethicone for manufacture of oil free simethicone tablets. The process is not useful for film manufacture as the weight of the granulated simethicone, mixed with magnesium carbonate would make for an unacceptably thick film for rapid dissolution in the oral cavity. US 7,341 ,742 is incorporated herein by reference.
Films for therapeutic applications comprising anti-tacking excipients are described in US 20070122455, and in some examples further comprise simethicone. However the simethicone is only used as an anti-foaming excipient to prevent air entrapment in the casting medium from which films are made, and not as a therapeutically active component, thus it is present at levels no more than about 5%. At such low levels, none of the formulation problems addressed by the current disclosed invention would be encountered.
It is an object of at least one aspect of the present invention to obviate or mitigate at least one or more of the aforementioned problems.
It is a further object of at least one aspect of the present invention to provide an improved soluble film comprising simethicone in a high dosage.
It is a further object of at least one aspect of the present invention to provide a method of forming an improved soluble film comprising simethicone in a high dosage. SUMMARY OF THE INVENTION
According to a first aspect of the present invention there is provided a water soluble film comprising:
a water soluble polymeric film former;
at least one emulsifier;
simethicone; and
wherein the water soluble film is free from organic solvent.
The present invention therefore relates to a water soluble film that is devoid of organic solvent. The water soluble film therefore is free of organic solvents e.g. methanol, ethanol etc which may have been used in the manufacturing process. This is in contrast to prior art films which contain significant amounts of organic solvent, due to the use of organic solvents in the manufacturing process.
Organic solvents provide several processing advantages, but also several disadvantages. The inventors of the present application have found that through selection of specific emulsifiers and film formers it is possible to form a stabilised casting solution containing emulsified simethicone that is stable through a drying process (e.g. hot air) and which provides a product with an oil-free finish, with the desired physical and organoleptic properties. It has been surprisingly found that a mix of specific emulsifiers and film formers, mixed with an absorbent provides a product with an oil-free finish. The absorbent assists formation of a film with an oil-free finish by providing a matrix into which the simethicone can be absorbed during the drying process, thus preventing leaching of the simethicone from the solid matrix.
Typical emulsifiers used in the present invention may be any one of or combination of the following, with a hydrophilic lipophilic balance (HLB) value in the region of 15 to 17: Polysorbate 80; sucrose stearate; polyoxyl 40 stearate commonly in the region of between 0.1 % and 10% by weight of formulation. Alternatively, a simethicone emulsion such as Dow-Corning 30% emulsion USP can be used as a source of simethicone, with one of the emulsifiers discussed above then added to obtain a suitable film as end product. Typical film formers used in the present invention may be any one of or combination of the following: hydroxypropylmethylcellulose; pectin; carboxymethyl cellulose; pullulan; gelatin and hydroxypropylcellulose.
A preferred film composition may be that of any of the following: HPMC and blanose; pectin and CMC; pullulan and pectin and pullulan and CMC.
Typical absorbents used in the present invention may be any one of or combination of the following: colloidal silica; hydrophobically modified colloidal silica; magnesium carbonate; kaolin and microcrystalline cellulose.
The problem of incorporating high doses of simethicone into the film are overcome by selection of appropriate emulsifiers, with for example polyoxyl 40 stearate and sucrose stearate which have been found to be surprisingly effective in comparison to most others. The presence of high amounts of emulsifier can however have a deleterious effect on film mechanical strength. By using the combinations of hydroxypropylmethylcellulose (HPMC)/sodium carboxymethylcellulose (CMC), pullulan/CMC or pectin/CMC a film may be formed with good mechanical strength, simethicone oil retention and acceptable oral dissolution/dispersion rate.
About a 50:50 Pectin:CMC blend may be found to have a beneficial effect on mechanical strength, without reducing solubility to an unacceptable level. If the ratio of pectin increases, solubility becomes too poor, if the ratio of CMC increases, mechanical strength worsens.
About a 50:50 combination of pullulan:CMC has also been found to provide a good balance of mechanical strength, oil retention and oral solubility. An increase in CMC level results in poorer solubility, whereas a decrease leads to poorer oil retention within the finished product.
In another example a mixture of hydroxypropylmethylcellulose (HPMC) and CMC are used as film formers. If the HPMC ratio increases, mechanical strength is lost, if the CMC ratio increases, solubility is poorer. For example, a ratio of HPMC:CMC between about 2.6 and 2.75 to 1 has been found to be advantageous. The soluble film is intended to disperse and/or dissolve in an oral cavity. The oral cavity may usually be that of a human but can be other animals or mammals. The soluble film may therefore be in the form of a thin strip suitable for oral consumption.
The soluble film, preferably in the form of a strip, may be intended to quickly dissolve in the oral cavity. For example, the soluble film may dissolve in the oral cavity releasing the simethicone over a period of time. The soluble film may dissolve in a period of less than about 120 seconds, less than about 60 seconds or less than about 30 seconds.
The soluble film may comprise a high level of simethicone such as about
100 mg, about 80 mg, about 60 mg, about 40 mg or about 20 mg. Alternatively, the soluble film may comprise about 10 - 100 mg of simethicone, about 20 - 80 mg of simethicone or about 40 - 60 mg of simethicone. The dry weight percentage is in the region of about 10 - 50%, about 20 - 40% or about 32% for some examples and about 30 - 60%, about 40 - 50% and about 47% simethicone for other examples.
Simethicone is an oral anti-foaming agent used to reduce bloating, discomfort and pain caused by excess gas in the stomach or intestinal tract. It is a mixture of polydimethylsiloxane and silica gel.
Typically, the simethicone may be impregnated throughout the content of the water soluble film. Alternatively, the simethicone may be deposited as a layer onto the water soluble film.
The film of the present invention is therefore soluble in an aqueous water solution such as saliva in an oral cavity. By water soluble herein in reference to the water soluble polymeric film former may mean any polymeric material which forms a solution or colloidal solution, where the approximate volume of solvent in millilitres per gram of solute is in the range of about 0.01 to 10,000.
The film comprises a water soluble polymeric film former in an amount of about 1 - 90% by weight, about 20 - 80% by weight, about 30 - 70% by weight, about 40 - 80% by weight or about 50 - 60% by weight. Alternatively, the film may comprise a water soluble polymeric film former in an amount of at least about 10% by weight, at least about 30% by weight, at least about 50% by weight, at least about 70% by weight or at least about 90% by weight.
In particular embodiments, the water soluble polymeric film former may be made from a polymer having an average molecular weight range of about 1 ,000 - 1 ,500,000, about 1 ,000 - 500,000, about 50,000 - 500,000, about 100,000 - 200,000, about 1 ,000 - 100,000, about 1 ,000 - 50,000, about 1 ,000 - 20,000 or about 10,000 - 20,000. Preferably, the average molecular weight may be about 50,000 - 250,000 or most preferably about 140,000. The average molecular weight may be determined by size exclusion chromatography.
The film may also comprise other materials such as any one of or combination of the following: sweeteners; flavourings; antimicrobial agents; plasticising agents; colouring agents; saliva stimulating agents; cooling agents; surfactants; stabilising agents; emulsifying agents; thickening agents; preservatives; bulking agents; humectants; vitamins; minerals; fluorides; and fillers.
The film may be in the form of a thin strip suitable for oral consumption. Typically, the film may be a strip wherein the strip may be substantially rectangular in shape, but any shape of strip (e.g. substantially rounded rectangle, substantially oval, substantially square, substantially circular) may be used. The strip may have a minimum thickness of about 10 μππ to allow ease of handling. The strip may have a preferred maximum thickness of about 500 μππ, or more preferably about 200 μππ, so that the physical dimensions of the strip do not prevent the body from dissolving in a desired period of time in an oral cavity e.g. by the action of saliva. Generally, the thickness of the strip may be in the range of about 20 to 200 μππ, and more usually about 40 to 140 μππ.
The width of the strip may be approximately about 0.05 - 5 cm or preferably about 1 - 2.5 cm, and the length may be about 0.05 - 10 cm or preferably about 2 - 8 cm.
The strip may be dry, by which is meant that the strip is dry to the touch. However, the strip may contain approximately about 1 - 20% by weight, or about 1 - 15% by weight, of residual water, which remains after the manufacturing process.
The film may be generally formed of edible material. By "edible material" is meant a material that is acceptable for consumption by a user. Normally, this is a material approved for use by the appropriate regulatory authorities.
The strip may be formed from any suitable film-forming material or combination thereof. For example, any suitable hydrocolloid may be used. In particular, the strip may be formed from any suitable edible water-soluble polymeric materials, such as any one of or combination of the following: carrageenan; cellulose derivatives or modified celluloses, such as methyl celluloses, (e.g. sodium carboxymethyl cellulose), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose; alginates (e.g. sodium alginate); gums (e.g. xanthan gum, tragacanth gum, guar gum, acacia gum, Arabic gum); starches and modified starches; gelatin; copolymers of methyl vinyl ether and maleic anhydride, e.g. Gantrez (Trademark); carbopols (i.e. carbomers); polyvinyl acetate; polyvinyl alcohol; acrylic based polymers, such as methylmethacrylate polyacrylates and polymethacrylates and esters and salts and copolymers thereof; polycarbophils; proteins; pullulan; polyacrylic acid; carboxyvinyl polymer; amylase; high amylase starch; hydroxypropylated high amylase starch; dextrin; pectin; chitin; chitosan; levan; elsinan; collagen; gelatine; zein; gluten soy protein isolate; whey protein isolate and casein.
Any suitable combination of the above compounds such as a mixture of two, three, four, or more, of the materials may be employed. Additionally, different layers in a multi-layer strip may comprise different combinations of materials.
Flavourings may also be included. Suitable flavourings may exhibit fragrant properties. Suitable flavourings may be added during the manufacturing process in the form of flavoured oils. The flavourings may form amounts of about 0 - 30 wt.% or about 0 - 10 wt.% of film. The flavourings may be chosen from natural oils, synthetic flavour oils, flavouring aromatics, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof.
Flavour oils which may be used include any one or combination of the following: spearmint oil; cinnamon oil; peppermint oil; clove oil; bay oil; thyme oil; cedar leaf oil; oil of nutmeg; oil of sage; and oil of bitter almonds.
Also useful are artificial, natural or synthetic fruit flavours such as vanilla, chocolate, coffee, cocoa and 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. These flavourings can be used individually or in a mixture. Commonly used flavours include mints, such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavours, whether employed individually or in admixture. Flavourings such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, and p-methylanisole, and so forth may also be used.
Further examples of aldehyde flavourings include, but are not limited to any one or combination of the following: acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e. alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); helliotropine, i.e. piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruity flavours); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal; decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2,6-dimethyloctanal (green fruit); and 2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof; and the like.
As required, the film may comprise a sweetening agent or a combination of sweetening agents. The sweetening agents may be present in an amount of less than about 30 wt.%, but more typically less than about 20 wt.%. Typical sweeteners include monosaccharides, disaccharides and polysaccharides such as any one or combination of the following: xylose; ribose; glucose (dextrose); mannose; galactose; fructose (i.e. levulose); sucrose (i.e. sugar); and maltose; an invert sugar (i.e. a mixture of fructose and glucose derived from sucrose); partially hydrolysed starch; corn syrup solids; dihydrochalcones; monellin; steviosides; and glycyrrhizin.
Additionally, water-soluble artificial sweeteners such as soluble saccharin salts may be used. For example, any one or combination of the following artificial sweeteners may be used: sodium or calcium saccharin salts; cyclamate salts; sodium, ammonium or calcium salts of 3,4-dihydro-6-methyl-1 ,2,3-oxathiazine-4- one-2,2-dioxide; potassium salts of 3,4-dihydro-6-methyl-1 ,2,3-oxathiazine-4- one-2,2-dioxide (acesulfame-K); sucralose; and the free acid form of saccharin.
Moreover, dipeptide based sweeteners such as any one or combination of the following may be used: L-aspartic acid derived sweeteners, such as L- aspartyl-L-phenylalanine methyl ester (aspartame); L-alpha-aspartyl-/V-(2, 2,4,4- tetramethyl-3-thietanyl)-D-alaninamide hydrate; methyl esters of L-aspartyl-L- phenylglycerin and L-aspartyl-L-2,5-dihydrophenyl-glycine; L-aspartyl-2,5- dihydro-L-phenylalanine; and L-aspartyl-L-(1 -cyclohexyen)-alanine.
Water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivative of ordinary sugar (i.e. sucrose) may also be used.
Furthermore, protein based sweeteners such as thaumatoccous danielli (i.e. Thaumatin I and II) may be used.
Plasticising agents may also be included. The plasticising agents may be present in an amount of about 0 - 25 wt.% or about 0 to 15 wt.% of the film. For example, plasticising agents such as triacetin, monoacetin, diacetin and polyols e.g. glycerol, sorbitol and mannitol may be used.
To avoid adverse reactions, it may be preferred to minimise the time between formation of the aqueous solution/suspension and formation of the film.
A drier which may be used to dry the aqueous formulation may comprise a tunnel of warm low humidity air or utilise other heat sources, such as Infra Red (IR) lamps, to evaporate the solvent and form a dry web. Alternatively, the film may be cast into sheets and dried in an oven. The resulting film may then be cut and packed directly, or stored in reel or sheet format for future processing.
In particular embodiments, the soluble film may be formed by casting and/or depositing an aqueous formulation comprising the simethicone. The aqueous formulation may be cast and/or spread using, for example, a knife blade over a roll-coater. The cast and/or spread aqueous formulation may then be dried (e.g. air dried) for a period of time until the formed film is substantially dry. For example, a drying time of about 10 - 30 minutes or about 20 minutes may be used. During the drying period the film may be passed down a belt (e.g. a drying line) at, for example, about 0.5 metres per minute. As the film passes down the drying line a raised air temperature of about 50 - 60 QC may be used for the drying process. The drying temperature of 50 - 60 QC is lower than other process such as described in US 2007/122455, which is incorporated herein by reference. The formed film may then be cut and sachet packed. The lower temperature leads to lower running costs and reduced risk of damage to sensitive active ingredients.
The aqueous formulation used to form the film may comprise emulsified simethicone. The simethicone may be emulsified using an emulsifier such as, for example, sucrose stearate, polysorbate 80 or pre-emulsified simethicone may be used and a an additional emulsifier added such as, for example, polyoxyl 40 stearate. To stabilise the emulsion through the drying process and to aid simethicone absorption in the dried product, aqueous-insoluble absorbent may be added to the formulation: the absorbent may be hydrophobically modified colloidal silica (Aerosil R972, Evonik) or cellulose (Avicel FD-100, FMC biopolymer). An aqueous insoluble absorbent is a high surface area aqueous insoluble material that is known in the literature to be an efficacious absorbent for oils.
A mix of film formers may be added in each case, for example the formulation may comprise about 23.3% (w/w) hydroxypropylmethylcellulose (HPMC) and about 8.9% (w/w) CMC, or for example between about 8 and 14% (w/w) pectin or pullulan may be added and a matching quantity w/w % of CMC may be added. The choice of film former is important, as different film formers can significantly affect the oil retention properties, mechanical strength and rate of dissolution of finished product. For example films made from Genupectin (citrus) type USP-L may have greater mechanical strength than films where the pectin has been substituted with Methocel K3, but commonly will take longer to dissolve, and the Methocel K3 film would be more likely to produce a film containing simethicone that is oil free to the touch.
According to a second aspect of the present invention there is provided a method of forming a water soluble film said method comprising:
providing an aqueous solution of a water soluble polymeric film former containing an amount of simethicone and at least one emulsifier;
forming a water soluble film from the aqueous solution of a water soluble polymeric film former containing an amount of simethicone;
wherein the water soluble film is free from organic solvent.
The film may be as described in the first aspect.
According to a third aspect of the present invention there is provided use of a film according to the first aspect in treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract.
According to a fourth aspect of the present invention there is provided a method of treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract using a film as defined in the first aspect.
DESCRIPTION
Generally speaking, the present invention resides in the provision of soluble film comprising simethicone in a high dosage.
Stabilising a high dose of simethicone oil into a solid formulation presents a significant challenge. For example in one embodiment of the disclosed invention the dry weight percent content is about 47% simethicone oil. It is necessary to keep this ratio of simethicone oil high to keep the strip weight sufficiently low, which in turns keeps rate of film dissolution/disintegration suitably quick.
In comparison to other commercial products the formulation described in the present application is free from organic solvent, which offers advantages in terms of health and safety, running costs, site insurance and labelling.
The drying temperature used in the present invention of about 50 - 60QC is also lower than previous drying temperatures such as described in US 2007/122455, which leads to lower running costs and reduced risk of damage to sensitive active ingredients. US 2007/122455 is incorporated herein by reference.
This application relates to the formation of soluble films, which will disperse in the oral cavity within about sixty seconds, and contain about 40 - 60 mg of simethicone. Films are formed by casting an aqueous formulation using a knife blade over a roll-coater, and then air drying the mixture over approximately a 20 minute period as it travels down a drying line at 0.5 metres per minute. The air temperature is between about 50 - 60 QC and is blown evenly over the mixture as it travels down the coating line, to yield a film which can then be cut and sachet packed as desired.
The aqueous formulation comprises emulsified simethicone, which can be emulsified using sucrose stearate in one embodiment or in another embodiment pre-emulsified simethicone is purchased from a commercial source and additional polyoxyl 40 stearate is added as well. To stabilise the emulsion through the drying process and to aid simethicone absorption into the dried product, aqueous-insoluble absorbent is added to the formulation: the absorbent is hydrophobically modified colloidal silica (Aerosil R972, Evonik) for one example product and microcrystalline cellulose (Avicel FD-100, FMC biopolymer) for other examples.
A mix of film formers are added in each case. For one product the formulation comprises about 23.3% (w/w) hydroxypropylmethylcellulose (HPMC) and about 8.9% (w/w) CMC. For other products between about 8 - 14% (w/w) pectin or pullulan is added and a matching quantity w/w % of CMC is added.
The ideal ratio is about 50:50 pectin or pullulan to CMC, although a range of about 40 - 60 pectin or pullulan to about 40 - 60 to CMC is also suitable.
For HPMC:CMC the optimum ratio is between about 2.6:1 to 2.75:1 .
Other excipients include: Glycerol as plasticiser, artificial sweetener (select from acesulfame K, sodium saccharin and sucralose), flavouring (peppermint or cranberry), and preservative (potassium sorbate).
Below are key formulations for products described in the present application, with a general method described thereafter.
Peppermint flavour example A
Methocel K3 23.6%
Blanose 7LF 8.85%
Glycerol 7.72%
Si sterna SP70 C 1 .93%
Aerosil R972 5.08%
Peppermint Flavouring 5.08%
Simethicone 46.54%
Titanium Dioxide 0.81 %
Sucralose 0.25%
Potassium sorbate 0.15%
Peppermint flavour example B
Genupectin (citrus) type USP-L 1 1 .44%
Blanose 7LF 1 1 .44%
Glycerol 6.29%
Sisterna SP70 C 7.62%
Cellulose-Avicel FD100 7.62%
Peppermint Flavouring 6.10%
Simethicone 47.66% Titanium Dioxide 1 .43%
Sucralose 0.25%
Potassium sorbate 0.15% Peppermint flavour example C
Dow Corning Simethicone emulsion 49.95%
Cellulose-Avicel FD100 13.62%
Genupectin (citrus) type USP-L 8.73%
Blanose 7LF 8.73% Glycerol 4.81 %
Polyoxyl 40 stearate 3.58%
Flavour - peppermint 8.76%
Potassium sorbate 0.15%
Titanium dioxide 1 .35% Acesulfame-K 0.20%
Sodium saccharin 0.12%
Cranberry flavour example A
Dow Corning Simethicone emulsion 46.20% Cellulose-Avicel FD100 14.70%
Genupectin (citrus) type USP-L 9.39%
Blanose 7LF 9.39%
Glycerol 3.51 %
Polyoxyl 40 stearate 4.43% Flavour - Cranberry 10.06%
Potassium sorbate 0.15%
Titanium dioxide 1 .66%
Acesulfame-K 0.26%
Sodium saccharin 0.26% Cranberry flavour example B
Pullulan 1 1 .40%
Blanose 7LF 1 1.40%
Glycerol 4.96%
Sisterna SP70C 7.44%
Cellulose-Avicel FD100 9.91 %
Simethicone 44.61 %
Titanium Dioxide 1 .49%
Acesulfame K 0.36%
Sodium Saccharin 0.36%
Cranberry Flavour 7.93%
Potassium Sorbate 0.15%
Method: All ingredients are blended (except film forming polymers) in a high shear mixer in water. If polyoxyl 40 stearate is required it is first separately pre- dispersed in boiling water then added to remaining excipients in cold water and the film forming polymers are then added slowly with constant mixing.
Stabilising a high dose of simethicone oil into a solid formulation presents a significant challenge. For example in one embodiment of the disclosed invention the dry weight percent content is about 47% simethicone oil.
It is necessary to keep this ratio of simethicone oil high to keep the strip weight sufficiently low, which in turns keeps rate of film dissolution/disintegration suitably quick.
In comparison to prior art products the disclosed invention is free from organic solvent, which offers advantages in terms of health and safety, running costs, site insurance, labelling.
The drying temperature of 50-60 Celsius for the products described herein is also lower than temperatures used in film manufacture as described in US 2007/122455, which leads to lower running costs and reduced risk of damage to sensitive active ingredients. Examples
Comparative Example 1
Pullulan 146.3 g
Glycerol 1 1 .05 g
Simethicone oil 214.31 g
Tween 80 85.50 g
Span 80 85.50 g
Water 530 g The film product obtained from this formulation exhibited significant leaching of simethicone oil, providing a product with an oily surface, which is unsuitable for on processing. These emulsifiers were insufficient at emulsifying simethicone. Comparative Example 2
Klucel EF 40.00 g
Simethicone oil 60.00 g
Poloxamer 407 8.00 g
Polyethylene glycol 1500 5.00 g
Aerosil R972 8.00 g
Sucralose 0.08 g
Peppermint oil 4.50 g
This film was oil free to touch, but had an unacceptable dissolution and mouth feel with unacceptably poor tear strength and thus would not be capable of on processing through production machinery.
Poloxamer 407 is the emulsifier in this formulation, and HPC is the film former which combines to emulsify the oil effectively, but this combination leads to a film with poor dissolution and gummy mouthfeel, and the poloxamer significantly increases brittleness of the film in this formulation. Example 1
The examples below show the differences between a formulation with and without addition of CMC. The product described in example 1 contains no CMC, has an oil-free finish but poor mechanical strength. The film described in example 2 has CMC added and has improved mechanical strength, whilst still maintaining a film with no simethicone oil leached from the solid matrix.
Methocel K3 70.00 g
Glycerol 15.00 g
Simethicone oil 105.00 g
PEG 1500 15.00 g
Aerosil R972 15.00 g
Tween 80 6.00 g
Titanium dioxide 2.00 g
Sucralose 0.30 g
Peppermint oil 12.00 g
Water 300.00 g
Example 2
The below example relates to a 2.75:1 ratio of HPMC:CMC and provides robust film with an oil free finish.
Methocel K3 55.00 g
Blanose 7LF 20.00 g
Glycerol 18.50 g
Simethicone oil 105.00 g
PEG 1500 15.00 g
Aerosil R972 15.00 g
Tween 80 6.00 g
Titanium dioxide 3.00 g
Sucralose 0.30 g Peppermint oil 12.00 g
Water 350.00 g
The examples below show that an increase in pectin gives a more robust film, with an increased dissolution time.
Example 3
GenuPectin (citrus) type USP-L 62.50 g
Blanose 7LF 187.50 g
Glycerol 30.00 g
Simethicone emulsion 30% 730.00 g
(purchased from Dow Corning)
Acesulfame K 0.95 g
Polyoxyl 40 stearate 15.00 g
Cellulose-Avicel FD100 75.00 g
Sucralose 0.92 g
Spearmint flavour 6.25 g
Peppermint oil 12.50 g
Water 500.00 g
Example 4
GenuPectin (citrus) type USP-L 100.00 g
Blanose 7LF 100.00 g
Glycerol 30.00 g
Simethicone emulsion 30% 730.00 g
(purchased from Dow Corning)
Acesulfame K 0.95 g
Polyoxyl 40 stearate 22.00 g
Cellulose-Avicel FD100 75.00 g
Sucralose 0.92 g
Spearmint flavour 6.25 g Peppermint oil 12.50 g
Water 1000.00 g
In both examples 3 and 4 described above, the finished products contained significant amounts of leached simethicone oil, providing a finished product with an oily surface. The increased amount of pectin in example 4 provided a more robust film, however with increased dissolution time compared to example 3.

Claims

1. A water soluble film comprising:
a water soluble polymeric film former;
at least one emulsifiers;
simethicone; and
wherein the water soluble film is free from organic solvent.
2. A water soluble film according to claim 1 , wherein the water soluble film is capable of quickly dissolving in an oral cavity in a period of less than about 120 seconds, less than about 60 seconds or less than about 30 seconds.
3. A water soluble film according to any of claims 1 or 2, wherein the water soluble film former is selected from any one of or combination of the following: hydroxypropylmethylcellulose; sodium carboxymethylcellulose; pullulan hydroxpropylcellulose; polyvinylpyrollidinone; gelatin and pectin.
4. A water soluble film according to any preceding claim, wherein the at least one emulsifier with an HLB value between 15 and 17 is selected from any one of or combination of the following: Polyoxyl 40 stearate , sucrose stearate, poly(ethylene glycol)-£>/oc/(-poly(propylene glycol) copolymers, polyoxyethylenesorbitan monopalmitate, polyethylene glycol sorbitan monolaurate, polyoxyethylenesorbitan monolaurate or polyoxyethylene (20) sorbitan monooleate.
5. A water soluble film according to any preceding claim, wherein the at least one emulsifier is present in an amount in weight percent of the dry film of between about 0.1 % and 10%.
6. A water soluble film according to any preceding claim, wherein the water soluble film former is pectin, sodium carboxymethyl cellulose or hydroxypropylmethylcellulose and the emulsifiers are sucrose stearate and/or polyoxyl 40 stearate.
7. A water soluble film according to any preceding claim, where the simethicone is used as a commercially available pre-emulsified form, where an additional emulsifier as described in claim 6 is added, with the HLB for the system subsequently lowered to about between 10 and 15.
8. A water soluble film according to any preceding claim, wherein the water soluble film also comprises an absorbent selected from any one of or combination of the following: hydrophobically modified colloidal silica or microcrystalline cellulose.
9. A water soluble film according to any preceding claim, wherein the water soluble film also comprises an absorbent selected from any one of or combination of the following: magnesium carbonate; bentonite and kaolin.
10. A water soluble film according to any of claims 8 or 9, wherein the absorbent is present in an amount of about 0.1 % to 20%.
1 1 . A water soluble film according to any preceding claim, wherein the water soluble film comprises about 10 - 100 mg of simethicone, about 20 - 80 mg of simethicone or about 40 - 60 mg of simethicone.
12. A water soluble film according to any preceding claim, wherein the simethicone is impregnated throughout the content of the water soluble film.
13. A water soluble film according to any preceding claim, wherein the water soluble film comprises a water soluble polymeric film former in an amount of about 1 - 90% by weight, about 20 - 80% by weight, about 30 - 70% by weight, about 40 - 80% by weight or about 50 - 60% by weight.
14. A water soluble film according to any preceding claim, wherein the water soluble film comprises a water soluble polymeric film former in an amount of at least about 5% by weight, at least 10% by weight, at least about 30% by weight, at least about 50% by weight, at least about 70% by weight or at least about 90% by weight.
15. A water soluble film according to any preceding claim, wherein the water soluble polymeric film former is made from a polymer having an average molecular weight range of about 1 ,000 - 1 ,500,000, about 1 ,000 - 500,000, about 50,000 - 500,000, about 100,000 - 200,000, about 1 ,000 - 100,000, about 1 ,000 - 50,000, about 1 ,000 - 20,000 or about 10,000 - 20,000.
16. A water soluble film according to any preceding claim, wherein the water soluble film also comprises other materials such as any one of or combination of the following: sweeteners; flavourings; antimicrobial agents; plasticising agents; colouring agents; saliva stimulating agents; cooling agents; surfactants; stabilising agents; emulsifying agents; thickening agents; preservatives; bulking agents; humectants; vitamins; minerals; fluorides; and fillers.
17. A water soluble film according to any preceding claim, wherein the water soluble film is in the form of a thin strip suitable for oral consumption.
18. A water soluble film according to any preceding claim, wherein the water soluble film comprises any one of or combination of the following: carrageenan; cellulose derivatives or modified celluloses, such as methyl celluloses, (e.g. sodium carboxymethyl cellulose), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose; alginates (e.g. sodium alginate); gums (e.g. xanthan gum, tragacanth gum, guar gum, acacia gum, Arabic gum); starches and modified starches; gelatin; copolymers of methyl vinyl ether and maleic anhydride, e.g. Gantrez (Trademark); carbopols (i.e. carbomers); polyvinyl acetate; polyvinyl alcohol; acrylic based polymers, such as methylmethacrylate polyacrylates and polymethacrylates and esters and salts and copolymers thereof; polycarbophils; proteins; pullulan; polyacrylic acid; carboxyvinyl polymer; amylase; high amylase starch; hydroxypropylated high amylase starch; dextrin; pectin; chitin; chitosan; levan; elsinan; collagen; gelatine; zein; gluten soy protein isolate; whey protein isolate and casein.
19. A water soluble film according to any preceding claim, wherein an aqueous formulation used to form the film comprises emulsified simethicone.
20. A method of forming a water soluble film said method comprising:
providing an aqueous solution of a water soluble polymeric film former containing an amount of simethicone and emulsifiers
forming a water soluble film from the aqueous solution of a water soluble polymeric film former containing an amount of simethicone;
wherein the water soluble film is free from organic solvent.
21. A method of forming a water soluble film according to claim 20, wherein the soluble film is formed by casting and/or depositing an aqueous formulation comprising the simethicone.
22. A method of forming a water soluble film according to claim 21 , wherein the cast and/or spread aqueous formulation is dried (e.g. air dried) for a period of time until the formed film is substantially dry.
23. A method of forming a water soluble film according to claim 22, wherein as the film passes down a drying line a raised air temperature of about 50 - 60 QC is used for the drying process.
24. A method of forming a water soluble film according to claim 22, wherein to stabilise the emulsion through the drying process and to aid simethicone absorption in the dried product an aqueous-insoluble absorbent is added to the formulation.
25. A method of forming a water soluble film according to any of claims 20 to 24, wherein the formed film is as defined in any of claims 1 to 19.
26. Use of a film according to any of claims 1 to 19 in treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract.
27. A method of treating bloating, discomfort and/or pain caused by excess gas in the stomach and/or intestinal tract using a film according to any of claims 1 to 19.
PCT/GB2011/051439 2010-08-23 2011-07-29 Soluble film WO2012025730A2 (en)

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GB1014041.6 2010-08-23
GBGB1014041.6A GB201014041D0 (en) 2010-08-23 2010-08-23 Soluble film

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WO2012025730A2 true WO2012025730A2 (en) 2012-03-01
WO2012025730A3 WO2012025730A3 (en) 2012-07-26

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EP2612681A1 (en) * 2010-08-31 2013-07-10 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
US10829621B2 (en) 2013-01-11 2020-11-10 Monosol, Llc Edible water-soluble film
CN113347954A (en) * 2018-11-05 2021-09-03 因斯拜尔材料配方有限责任公司 Polydimethylsiloxane-based oral coating film

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EP2612681A1 (en) * 2010-08-31 2013-07-10 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
EP2612681A4 (en) * 2010-08-31 2014-04-30 Toray Industries Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
US9381248B2 (en) 2010-08-31 2016-07-05 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
US10829621B2 (en) 2013-01-11 2020-11-10 Monosol, Llc Edible water-soluble film
US11945936B2 (en) 2013-01-11 2024-04-02 Monosol, Llc Edible water-soluble film
CN113347954A (en) * 2018-11-05 2021-09-03 因斯拜尔材料配方有限责任公司 Polydimethylsiloxane-based oral coating film

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