WO2010146601A4

WO2010146601A4 - Rapid dissolvable oral film for delivering herbal extract/s with or without other pharmaceutically active agents

Info

Publication number: WO2010146601A4
Application number: PCT/IN2010/000404
Authority: WO
Inventors: Vinita Vijay Kale; Amarnath Bhaskarrao Wattamwar; Anwar Siraj Daud
Original assignee: Unijules Life Sciences Ltd
Priority date: 2009-06-15
Filing date: 2010-06-15
Publication date: 2011-03-10
Also published as: WO2010146601A1

Abstract

The invention comprises an oral film, single layer or multilayer, for delivering an active ingredients, herbal or non-herbal, to oral cavity, wherein the said oral film requires at least a delay of about 5 seconds after coming in contact with oral mucosa to stick to the mucosa surface in contact and rapidly dissolves thereafter. The said oral film takes about 1 to 1.15 minutes for dissolution in an oral cavity after hydration. The said film is having low hygroscopicity and high mucoadhesivity, absorbs less than 5% moisture, and preferably less than 2%, of its weight and is stable at 75 % RH (relative humidity). Mucodhesivity and higher dissolving rate is imparted by hydroxy alkyl derivative of cellulose, preferably by Hydroxypropyl Methyl Cellulose, and low- hygroscopicity is imparted by polyvinyl alcohol polyethylene glycol graft polymer, preferably by Kollicoat^® IR. Disclosed are single and multilayer films carrying herbal extracts from all botanical parts of plants, by several methods of extraction as well as some non-herbal actives that are useful as treatments for disease indication and processes for making them and bearing optional identification marks.

Claims

AMENDED CLAIMS

received by the International Bureau on 11 January 2011 (11.01.2011 )

1. An oral film for delivering one or more of an active ingredient to oral cavity, wherein the said oral film requires at least a delay of about 5 seconds after coming in contact with oral mucosa to stick to the mucosa surface in contact and rapidly dissolves thereafter.

2. An oral film of claim 1 further comprising the said active ingredient as a herbal or a non-herbal.

3. Ah oral film of claim 2 comprising a single layer film or a multilayer film.

4. An oral film of claim 3 comprising a polyvinyl alcohol polyethylene glycol graft polymer having low viscosity and a cellulose derivative as film forming polymers and additives.

5. An oral film of claim 4 wherein the said additives comprise an additional one more water soluble polymer, a surfactant, a stabilizing agent, an emulsifier, a plasticizer, a water soluble sugar, a binder, a sweetener, a flavors, a plasticizer, an antioxidant, a volatile oil and combinations thereof.

6. An oral film of claim 4 or 5 wherein: a. polyvinyl alcohol polyethylene glycol graft polymer, is present in the film composition to the extent of between 5% and 50%, more preferably 5% - 40% by weight of the film composition, and/or b. the said other water soluble polymer present in the film formulation in combination with graft polymer may include one or more of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, guar gum, carboxy methyl guar gum, carboxy methyl locust bean gum, acacia gum, arabic gum, pectin,

57 chitosan, mixtures thereof to the extent of between 10% and 50% by weight of the film composition, and/or c. the said polyvinyl alcohol polyethylene glycol graft polymer has a viscosity in the range of 130 to 190 millipascal seconds, when viscosity of a 20 % solution is found at 23 °C , more preferably 150 to 170 millipascal seconds when viscosity of a 20 % solution is found at 23°C, and/or d. the said water soluble sugar including one or more of glucose, dextrose, fructose, lactose, maltose, xylose, sucrose, trehalose G and combinations thereof to the extent of between 1% and 10%; more preferably the high water soluble sugar used is trehalose G to the extent 1% - 10% or more preferably to the extent of 2% - 8% by weight of the film composition, and/or e. the said sweetener is selected from the group consisting of synthetic sweeteners and natural sweeteners including one or more of sorbitol, hexitol, Maltitol, xylitol, mannitol, aspartame, saccharine sodium, sucralfate, alitame, cyclamate, acesulfame; in an amount ranging from about 0.2% to about 20% by weight and preferably about 2% to about 15% by weight, and further used singly or in a combination of sweeteners preferably selected from the group consisting of synthetic sweeteners and sugar-related compound in an amount ranging from about 0.2% to about 20% by weight and preferably about 2% to about 15% by weight of the film composition, and/or f. the said antioxidant is selected from two categories, which include water soluble and oil soluble antioxidants, further including one or more of sodium sulphite, sodium metabisulfite, sodium bisulphite, sodium

58 thiosulphate, sodium formaldehyde sulfoxylate, sulphur dioxide, ascorbic acid, gallic acid, propyl gallate, isoascorbic acid, thioglycerol, thioglycolic acid, cysteine hydrochloride, acetylcysteine, butylated hydroxy toluene, butylated hydroxy anisole, alpha tocopherols, lecithin, ascorbyl palmitate, propyl gallate, nordihydroguaiaretic acid in an amount ranging from about 0.1% to about 10% by weight and preferably about 0.2% to about 5% by weight of the film composition, and/or g. the said surfactant is selected from polyethylene glycol, propylene glycol, glycerin, polysorbates, used singly or in combination in a range of about 0.5% to about 15% by weight and preferably about 1% to about 8.5% by weight of the film composition, and/or h. the said volatile oil comprises a fractionated isolated volatile oil fraction including one or more of lemon oil, orange oil, lemon grass oil, cinnamon oil, clove oil, ginger oil, spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, mentha piperita (menthol), to the extent between 0.1% and 5%; or an isolated volatile oil fractions including one or more of eugenol, fenchone, anethol, gingerol, shagoal, piperine, methyl salicylate to the extent between 0.1% and 5% by weight of the film composition, and/or i. the said surfactant is selected from the group polysorbate 80, atoms 300, pluronic acid, sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid ester or a polyoxyethylene castor oil derivatives to the extent between 1 to 5%, more preferably to 2 to 4 % by weight of the film composition, and/or, j. the said stabilizing agent is selected from the group xanthan gum, locust bean gum, carrageenan, guar gum and mixtures thereof to the extent

59 between 1 to 5%, more preferably to 1 to 3 % by weight of the film composition, and/or, k. the said emulsifier is selected from the group lecithin, stearates, non ionic surfactants, synthetic waxes, polyoxyethylene alkyl ethers, or polyoxyethylene castor oil to the extent between 1 to 5 %, more preferably between 2 to 3 % by weight of the film composition, and/or,

1. the said plasticizer is selected from the group polyethylene glycol, propylene glycol, glycerin, polysorbates to the extent between 0.5 to 15 %, more preferably between 1 to 8.5 % by weight of the film composition, and/or, m. the said binder is polyoxyethylene to the extent between 0.5 to 3 % more preferably between 0.5 to 2% by weight of the film composition, and/or, n. the said flavor is selected from the group lemon oil, orange oil, lemon grass oil, cinnamon oil, clove oil, ginger oil, spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, Mentha piperita (menthol), methyl salicylate , peppermint, vanilla to the extent between 0.1 to 10, more preferably between 0.4 to 5 % by weight of the film composition.

7. An oral film of claim 6 comprising at least one herbal or non-herbal active ingredient and (a) in a single film additional ingredients comprising Hydroxypropyl methyl cellulose, Polyvinyl alcohol polyethylene glycol graft polymer (available in market under Tradename Kollicoat^®IR), Trehalose, Tween

80, Menthol, Clove oil, Aspartame, Bronopol and Sunset yellow (colour), and (b) in a multilayer film, further additional ingredients comprising polyoxyethylene and Butylated hydroxyl toluene.

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8. An oral film of claim 6 wherein the herbal extract ingredient is prepared from a botanical part of the plant.

9. An oral film of claim 8 wherein the said botanical part of a plant comprises at least whole or part of a root, a stem, a bark, a leaf, a flower, a fruit, a seed or whole plant.

10. An oral film of claim 8 wherein the extraction process of said herbal extract ingredient comprises at least one from group of processes comprising cold extraction technique, soxhlet extraction, making a decoction, supercritical extraction, microwave extraction using a variety of different extraction solvents.

11. An oral film of claim 10 wherein the said solvents include a solvent selected from the group ethanol, methanol, acetone, acetonitrile, chloroform, water, hydroalcoholic mixture and isopropyl alcohol.

12. An oral film of claim 1 1, wherein the said herbal ingredient extracts with medicinal or nutraceutical value is selected from a group of plants including one o more of Zingiber officinale Roxb., Piper longum Linn., Boswellian serrata Roxb., Vitex negunda Linn., Tinospora codifolia, Curcuma longa Linn., Centella asiatica Linn., Bacopa monnieri Linn., Momordica charantia Linn., Azadirachta indica, Ocimum sanctum, Picrorhiza kurroa Royle ex benth, Withania som ifera, Tribulus terristris Linn., Nardostachys jatamansi, Boerhavia diffusa Linn., Phyllanthus niruri Linn., Cassia angustifolia Vahl., Holarrhena antidysentrica (Roth), Asparagus racemosus Willd., Allivum sativum Linn., Euphorbia hirta Linn., Peuraria tuberosa., Leptadia reticulata, Trigonella foenum-graceum Linn., Mucuna prureins Baker., Terminalia arjuna, Achyranthes bidentatae Wall, Achyranthes aspera Linn, Achyranthes prophyristachya Wall, Aconitum napellus Linn, Acorus americanus, Actinidia arguta, Actinidia arguta, Actinidia arisanensis, actinidia callosa, Adenophora tetraphylla Radix, Albizia julibrissin, Alisma caniculatum, Alisma orientale, Alpinia magnifera Rose, Alpenia galangal Willd, panax quinquefolium Linn, Asparagusracemosus Willd, Astragalus membranaceus, Atractylodesmacrocephalae, Biota orientalis Semen, Bupleurum Chinese Radix, Chrysanthemum morifolium Flos, chrysanthemum indicum Flos, Cibotium barometz, cnidium monnieri, codonopsis pilosula Radix, Coix lachrymal, Cornus officinalis, Crataegus pinnatifida, Cuscuta chinensis Semen, Cynomorium songaricum, Dioscorea bulbifera, Dioscorea opposite Radix, Dioscorea hypoglauca, Drynaria fortune, Eucommia ulmoides, Evodia rutaecarpa, Foeniculum vulgare, Gingko bilobae, Panax ginseng, Gynostemma pentaphyllum Radix, Ligusticum sinesis Radix, Ligusticum wqallichii Radix, Liigustrum lucidum, lilium brownie, Lycium barbarum, Morinda officinalis Radix, Ophiopogonis japonicum, Polygonatum sibiricum, Polygonum multifori Radix, polyporum umbellatum, Psoralea cordifolia, Pueraria lobata Radix, Rehmania glutinosa Radix, Rhodiola rosea, Rubus chingii, Wrighta tinctoria, Cadaba indica, Salvia miltiorrhiza Radix, Schisandra chinensis, Uncaria Rhynchophylla, Zizyphus jejuba, and Zizyphus spinose .

13. A single layer film of Claim 12 wherein herbal active comprises an extract or extracts of: a. Zingiber officinale Roxb. and Piper longum Linn. , or b. Bacopa monnieri Linn and Centella asiatica Linn; „ or c. Momordica charantia Linn., or d. Azadirachta indica A Juss., or e. Withania somnifera Dunal., Bacopa monnieri Linn., Nardostachys jatamansi DCor f. Boerhavia diffusa Linn., Tribulus terrestris Linn., or g- Picrorhiza kurroa Royle ex Benth., Phyllanthus niruri Linn. , or h. Holarrhena antidysentrica (Roth) A. DC, Euprhorbia hirta Linn. , or i. Asparagus racemosus Willd., Euphorbia hitra Linn., Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal, or j. Tribulus terrestris Linn., Terminalia arjuna, Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal.

A film of claim 13 comprising the active ingredient/s incorporated, as % of weight of the film, between a range of 10% to 65%, more preferably between a range of 10% to 45%.

A film of claim 14 that is: a. anti-emetic, comprising extracts of Zingiber officinale Roxb. and Piper longum Linn., b. memory supporting, comprising extracts of Bacopa monnieri Linn and Centella asiatica Linn, c. antidiabetic, comprising extracts of Momordica charantia Linn., d. antidiabetic, comprising extract of Azadirachta indica A Juss. , e. antistress, comprising extracts of Withania somnifera Dunal., Bacopa monnieri Linn., Nardostachys jatamansi DCor f. diuretic, comprising extracts of Boerhavia diffusa Linn., Tribulus terrestris Linn. ,

63 g. hepatoprotective, comprising extracts of Picrorhiza kurroa Royle ex Benth. , Phyllanthus niruri Linn. , h. antidiarrhoeal, comprising extracts of Holarrhena antidysentrica (Roth) A. DC, Euprhorbia hirta Linn., i. galactogogue, comprising extracts of Asparagus racemosus Willd., Euphorbia hitra Linn., Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal, j. cardiotonic, comprising extracts of T ibulus terrestris Linn., Terminalia arjuna, Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal.

16. A film of claim 15, wherein: a. anti-emetic film comprises incorporation of extracts of Zingiber officinale Roxb. and Piper longum Linn at about 10 % each by weight of the film composition, b. memory support film comprises incorporation of extracts of Bacopa monnieri Linn and Centella asiatica Linn at about 10 % each by weight of the film composition, c. antidiabetic film comprises incorporation of extract of Momordica charantia Linn, at about 15 % each by weight of the film composition, d. antidiabetic film comprises incorporation of extract of Azadirachta indica A Juss. at about 15 % each by weight of the film composition, e. antistress film comprises incorporation of extract of comprising extracts of Withania ^' somnifera Dunal., Bacopa monnieri Linn., Nardostachys

64 jatamansi DCor at about 6, 9 and 5 % each respectively by weight of the film composition, f. diuretic film comprises incorporation of extract of comprising extracts of Boerhavia diffusa Linn., Tribulus terrestris Linn, at about 10 % each by weight of the film composition, g. hepatoprotective film comprises incorporation of extract of comprising extracts of Picrorhiza kurroa Royle ex Benth. , Phyllanthus niruri Linn, at about 7 % and 13 % each respectively, by weight of the film composition, h. antidiarrho'eal film comprises incorporation of extract of comprising extracts of comprising extracts of Holarrhena antidysentrica (Roth) A. DC, Euprhorbia hirta Linn, at about 15 % and 5 % each respectively by weight of the film composition, i. galactogogue film comprises incorporation of extract of comprising extracts of comprising extracts of Asparagus racemosus Willd., Euphorbia hitra Linn,, Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal. at about 7%, 2.5%, 4%, 4%, 3% and 2% each respectively by weight of the film composition, j. cardiotonic film comprises incorporation of extract of comprising extracts of comprising extracts of Tribulus terrestris Linn., Terminalia arjuna, Pueraria tuberose DC, Trigonella foenum- graceum Linn., Leptadenia raticulata, Withania somnifera Dunal at about 7%, 13%, 4%, 4%, 3% and 2% each respectively by weight of the film composition.

17. A multilayer film of claim 12 comprising extracts of Zingiber officinale Roxb. and Piper longum Linn.; preferably containing the active ingredient in a range of about 20% and 2% respectively by weight of the film composition.

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18. A multilayer film of claim 7 comprising non-herbal pharmaceutical active.

19. A multilayer film of claim 18 comprising extract of chlorpheniramine maleate and Phenylephrine preferably containing the active ingredient in a range of about 20% and 2% respectively by weight of the film composition.

20. A process of making an oral dissolving film that requires at least a delay of about 5 seconds after coming in contact with oral mucosa to stick to the mucosa surface in contact and rapidly dissolves thereafter,.comprising forming the film by using a polyvinyl alcohol polyethylene glycol graft polymer having low viscosity and a cellulose derivative as film forming polymers and additives for forming the film.

21. A process of claim 20 of making single layer or multilayer film comprises selecting at least one step as per requirement of product from the following: a. formation of slurry of an extract/pharmaceutical ly active ingredient added to a film forming composition in aqueous or any suitable solvent, b. debubbling of formed slurry, Casting of slurry done by one of any methods selected from blade over belt method, spray cast method, slot die coating, comma blade process, pouring on substrate method, c. drying of casted wet film at an elevated temperature, preferably at a temperature of about 40 - 70 °C, d. cooling of casting line along with dry film at the end of casting line, so as to reduce recoiling of film, e. for making a multilayer film, adding one or more of an inert or / and active containing layer on primary film by gluing or casting, optionally compacting by passing through a roller, f. drying of multiple layer film,

66 g. cooling of casting line along with dry film at the end of casting line, so as to reduce recoiling of film, h. cutting and slitting of film strips in different size and shape to form a readily, unobtrusively consumable thin film formulation.

22. A process of claim 21 wherein the said film forming composition comprises one or more of an additional one more water soluble polymer, a surfactant, a stabilizing agent, an emulsifier, a plasticizer, a water soluble sugar, a binder, a sweetener, a flavors, a plasticizer, an antioxidant, a volatile oil and combinations thereof.

23. A process of claim 22 wherein binder used for gluing the films or incorporating in the secondary film for making multi layer films is Polyoxyethylene.

24. A film of claim 1 having unique identification markings on the surface of the films, both artistic and informational markings comprising company name or symbol, product code, product name, potency of the product, calendar wise or day wise prescription schedule printed or embossed on the film surface, printed line printed or embossed on the film or film portions separated by perforations are provided for taking exactly ½, 1/3 , ¼ portion of film for taking exact dose as prescribed.

25. An oral rapid dissolving film for oral delivery of an active ingredient wherein wherein the said oral film requires at least a delay of about 5 seconds after coming in contact with oral mucosa to stick to the mucosa surface in contact and rapidly dissolves thereafter, the said film is having low hygroscopicity and high mucoadhesivity.

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26. An oral film of claim 25 wherein the said film absorbs less than 5% moisture, and preferably less than 2%, of its weight and are stable at 75% RH (relative humidity).

27. An oral film of claim 26 wherein the mucodhesivity and higher dissolving rate is imparted by hydroxy alkyl derivative of cellulose, preferably by Hydroxypropyl Methyl Cellulose, and low- hygroscopicity is imparted by polyvinyl alcohol polyethylene glycol graft polymer, preferably by polyvinyl alcohol polyethylene glycol graft polymer available by Tradename Kollicoat^® IR.

28. An oral film of claim 1 which takes about 1 to 1 .15 minutes for dissolution in an oral cavity after hydration.

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