CA2543324C - Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents - Google Patents
Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents Download PDFInfo
- Publication number
- CA2543324C CA2543324C CA2543324A CA2543324A CA2543324C CA 2543324 C CA2543324 C CA 2543324C CA 2543324 A CA2543324 A CA 2543324A CA 2543324 A CA2543324 A CA 2543324A CA 2543324 C CA2543324 C CA 2543324C
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- CA
- Canada
- Prior art keywords
- film
- water soluble
- active ingredient
- molecular weight
- daltons
- 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.)
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- 239000002537 cosmetic Substances 0.000 title claims abstract description 15
- 239000008177 pharmaceutical agent Substances 0.000 title claims description 8
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 239000004480 active ingredient Substances 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000945 filler Substances 0.000 claims abstract description 33
- 229920002472 Starch Polymers 0.000 claims abstract description 29
- 235000019698 starch Nutrition 0.000 claims abstract description 29
- 239000008107 starch Substances 0.000 claims abstract description 26
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 24
- 239000004014 plasticizer Substances 0.000 claims abstract description 24
- 239000008103 glucose Substances 0.000 claims abstract description 22
- 210000000214 mouth Anatomy 0.000 claims abstract description 12
- 239000003906 humectant Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002552 dosage form Substances 0.000 claims abstract description 10
- 239000002356 single layer Substances 0.000 claims abstract description 9
- 230000003232 mucoadhesive effect Effects 0.000 claims abstract description 7
- 229920003169 water-soluble polymer Polymers 0.000 claims description 24
- 229920000642 polymer Polymers 0.000 claims description 23
- 239000004094 surface-active agent Substances 0.000 claims description 23
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 19
- 239000000600 sorbitol Substances 0.000 claims description 19
- 229920002774 Maltodextrin Polymers 0.000 claims description 14
- 239000005913 Maltodextrin Substances 0.000 claims description 14
- 229940035034 maltodextrin Drugs 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 8
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims description 5
- 229960001985 dextromethorphan Drugs 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960000520 diphenhydramine Drugs 0.000 claims description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 4
- 210000004400 mucous membrane Anatomy 0.000 claims description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 210000002200 mouth mucosa Anatomy 0.000 abstract description 3
- 239000010408 film Substances 0.000 description 125
- 229920003091 Methocel™ Polymers 0.000 description 40
- 239000000796 flavoring agent Substances 0.000 description 23
- 235000019634 flavors Nutrition 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000004376 Sucralose Substances 0.000 description 18
- 235000019408 sucralose Nutrition 0.000 description 18
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- -1 polyethylene Polymers 0.000 description 13
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 12
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 12
- 239000006185 dispersion Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 235000003599 food sweetener Nutrition 0.000 description 7
- 239000003765 sweetening agent Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 6
- 229960001948 caffeine Drugs 0.000 description 6
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000005266 casting Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 235000012976 tarts Nutrition 0.000 description 5
- 239000010409 thin film Substances 0.000 description 5
- 229920002245 Dextrose equivalent Polymers 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 229920000945 Amylopectin Polymers 0.000 description 3
- 229920000856 Amylose Polymers 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 235000019800 disodium phosphate Nutrition 0.000 description 3
- 229920006158 high molecular weight polymer Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 2
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 2
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
Abstract
The invention provides disintegratable films containing a mixture of high molecular weight and low molecular weight water soluble components; and a pharmaceutically or cosmetically active ingredient. Optionally, the films contain a starch component, a glucose component, a filler, a plasticizer and/or humectant. The films are preferably in the form of a mucoadhesive monolayer having a thickness sufficient to rapidly disintegrate in the oral environment and release the active ingredient without undue discomfort to the oral mucosa. The monolayer can be cut to any desired size or shape to provide conveniently useable unit dosage forms for administration to oral or other mucosal surfaces for human pharmaceutical, cosmetic, or veterinary applications. The invention further provides methods of administering the film compositions by placing the composition into, for example, the oral cavity for a sufficient period of time to permit the film to disintegrate and release the active ingredient.
Description
RAPIDLY DISINTEGRATING FILMS FOR DELIVERY OF PHARMACEUTICAL
OR COSMETIC AGENTS
CROSS REFERENCE TO OTHER APPLICATION
[0001] This patent application claims the benefit of U.S. provisional patent application serial number 60/513,547, filed October 24, 2003, and titled RAPIDLY DISSOLVING FILMS FOR DELIVERY OF PHARMACEUTICAL
OR COSMETIC AGENTS. U.S. provisional patent application serial number 60/513,547 is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
OR COSMETIC AGENTS
CROSS REFERENCE TO OTHER APPLICATION
[0001] This patent application claims the benefit of U.S. provisional patent application serial number 60/513,547, filed October 24, 2003, and titled RAPIDLY DISSOLVING FILMS FOR DELIVERY OF PHARMACEUTICAL
OR COSMETIC AGENTS. U.S. provisional patent application serial number 60/513,547 is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to disintegratable films and methods for delivering pharmaceutically active or cosmetic agents. More particularly, the present invention provides in one embodiment a water soluble mucoadhesive film composition containing an active pharmaceutical or cosmetic ingredient for administration to the oral cavity in unit dosage form. Upon administration, the composition rapidly disintegrates to release the active ingredient.
BACKGROUND OF THE INVENTION
BACKGROUND OF THE INVENTION
[0003] Disintegratable films can provide a convenient and effective delivery vehicle for delivering active ingredients, such as pharmaceutical compounds and breath freshening or other cosmetic agents, to the mucosa of humans and animals. Upon placement onto the mucosa of, for example, the oral cavity, the film disintegrates and releases the active ingredient.
However, the film should have adequate strength for processing and use as a unit dosage form, and also ensure appropriate release of the active ingredient while eliminating or minimizing any undue discomfort to mucosal surfaces.
However, the film should have adequate strength for processing and use as a unit dosage form, and also ensure appropriate release of the active ingredient while eliminating or minimizing any undue discomfort to mucosal surfaces.
[0004] U.S. Patent Nos. 4,029,757; 4,029,758; and 4,031,200 refer to pharmaceutical dosage units formed from a multiplicity of edible webs that are sealed. One layer is fabricated by "fan folding" and compressing a continuous web structure, and subsequently sealing the composite into a geometric shape. The films rely on a complex process of fan folding and sealing to maintain the pharmaceutical compound internally within the multilayered dosage form.
[0005] U.S. Re 33,093 refers to controlled-release medicament-containing single or multi-layer thin films for infra-oral drug delivery. T'he thin film includes a polymeric matrix layer of 20-93% by weight of a hydroxypropyl cellulose having a molecular weight above 100,000; 5-60% of a homopolymer of ethylene oxide having a molecular weight from 3,000,000-5,000,000; 0-10%
of a water insoluble polymer selected from the group consisting of ethyl cellulose, propyl cellulose, polyethylene and polypropylene; 2-10% of a plasticizer; and a pharmaceutically effective amount of medicament. The controlled-release films of U.S. Re. 33,093 are relatively slow to dissolve/disintegrate in the mouth.
of a water insoluble polymer selected from the group consisting of ethyl cellulose, propyl cellulose, polyethylene and polypropylene; 2-10% of a plasticizer; and a pharmaceutically effective amount of medicament. The controlled-release films of U.S. Re. 33,093 are relatively slow to dissolve/disintegrate in the mouth.
[0006] U.S. Patent Nos. 5,984,430 (Reexamination Certificate issued March 4, 2003); 6,177,096; and 6,284,264 refer to oral films for the delivery of pharmaceutical and cosmetic compounds. The compositions referred to in these patents contain a water-soluble polymer, a polyalcohol, a surfactant, and a pharmaceutically or cosmetically active ingredient. According to these patents, inclusion of the surfactant component imparts "instant wettability"
followed by rapid disintegration of the film when placed into an aqueous environment such as the oral cavity.
followed by rapid disintegration of the film when placed into an aqueous environment such as the oral cavity.
[0007] U.S. Patent No. 4,136,145 refers to a pharmaceutical unit dosage composition in which the pharmaceutically active medicament is uniformly dissolved or suspended in a flexible, water-soluble film carrier. The compositions include various drug compounds, water-soluble polymers, surfactants, release agents, parting compounds, and fillers.
[0008] Each film delivery system can be characterized by its film strength and its disintegration profile (the speed at which the film will disintegrate in an aqueous.media such as saliva). Surfactants have been used to affect the disintegration speed and decrease the time required for complete film disintegration and thus release of the active ingredient. The present invention provides disintegratable film compositions that rapidly disintegrate upon application to mucosal surfaces and which, at the same time, have sufficient filin strength without requiring the use of any surfactant. While a surfactant is optional in certain embodiments of the present invention, as described below, other embodiments are surfactant-free or substantially free of surfactants.
BRIEF SUMMARY OF THE INVENTION
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides disintegratable film compositions prepared with a combination of ingredients that yield films of sufficient film strength and rapid disintegration profiles. Films prepared pursuant to this invention yield similar or improved disintegration speeds as compared to prior art films, including the prior art surfactant-containing films.
[0010] The filins according to the present invention contain a mixture of high molecular weight and low molecular weight water soluble components;
and a pharmaceutically or cosmetically active ingredient. Optionally, the films further contain a starch component, a glucose component, a plasticizer and/or a humectant. Also optionally, the films can include a filler, which is a dispersed phase or particle within the film and which, in certain embodiments, can cause faster disintegration of the films.
and a pharmaceutically or cosmetically active ingredient. Optionally, the films further contain a starch component, a glucose component, a plasticizer and/or a humectant. Also optionally, the films can include a filler, which is a dispersed phase or particle within the film and which, in certain embodiments, can cause faster disintegration of the films.
[0011] The films are preferably in the form of a monolayer having a ' thickness sufficient to rapidly disintegrate in the oral environment and release the active ingredient without undue discomfort to the oral mucosa. The monolayer can be cut to any desired size or shape to provide conveniently useable unit dosage forms for administration to oral or other mucosal surfaces for human pharmaceutical, cosmetic, or veterinary applications. The films are preferably mucoadhesive, in that upon contact with a mucosal surface the films adhere to the membrane until disintegration.
[0012] The invention further provides methods of administering the mucoadhesive film compositions by placing .the composition into, for example, the oral cavity for a sufficient period of time, typically a matter of seconds to less than about one minute, to permit the film to disintegrate and release the active ingredient.
[0013] These and other advantages and features of the invention will be more readily understood from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
[0014] Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes rnay be made without departing from the spirit and scope of the present invention.
[0015] The present invention provides compositions and methods for the use of film compositions which can be processed into single layer (monolayer) unit dosage forms or combined with other layers to prepare multilayer dosage forms comprising a thin film as described herein containing a pharmaceutically active or cosmetic ingredient. The thin disintegratable films according to the invention contain a mixture of high molecular weight and low molecular weight water soluble components; a pharmaceutically or cosmetically active ingredient; optionally a starch component, a glucose component, a plasticizer and/or humectant; and/or other excipients in suitable amounts as described below, or which may be determined by one of ordinary skill in the art pursuant to the guidance provided by the examples and teachings herein. The films will typically have a thickness in the range of about 10 to about 200 microns, although various other thicknesses are suitable as desired for particular applications as described in more detail below.
[0016] According to one embodiment, the disintegratable films according to the invention achieve their desirable characteristics of film strength and disintegration profile while requiring no and containing no or substantially no surfactants, release agents, or parting compounds, such as those found in U.S. Patent Nos. 4,136,145 and 5,984,430. The term "essentially free of surfactants" refers to trace amounts or higher levels of surfactants that are sufficiently low so as not to substantially increase the disintegration rate of the film composition following contact with a mucosal surface.
[0017] According to another embodiment, the disintegratable films according to the invention contain a filler. The filler is a dispersed phase or particle that in preferred embodiments causes the films to disintegrate faster upon contact with the targeted mucosal environment than without the filler.
The filler can be an optional component. Alternatively, in other embodiments, the active ingredient, when present in the film as a dispersed phase or particle, can serve the same purposes as a filler.
The filler can be an optional component. Alternatively, in other embodiments, the active ingredient, when present in the film as a dispersed phase or particle, can serve the same purposes as a filler.
[0018] In one exemplary embodiment, the water soluble components of the films according to the present invention include any pharmaceutically acceptable or food grade water-soluble polymers, including but not limited to, water-soluble hydroxypropylinethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, sodium carboxy methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacantha, guar gum, acacia gum, arabic gum, carrageenan, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, and various mixtures of the above and other known water-soluble polymers, cellulose derivatives, and/or gums.
[0019] We have found that particularly beneficial properties are obtained when the water soluble polymeric component includes a combination of low molecular weight polymers (e.g., those less than about 5,000 to about 60,000 daltons) and high molecular weight polymers (e:g., those of about 60,000 to about 150,00 daltons, and to about 500,000 daltons or higher). For example, a combination of hydroxypropyl cellulose (e.g., Klucel, grade JF, Hercules Inc., Aqualon Division) and hydroxypropyl methylcellulose (e.g., Methocel, grades E5, E50, E4M, and SG A16M by Dow Chemical) is suitable. 'These water soluble cellulose derivative polymers have molecular weights of about 140,000; 30,000; 90,000; 400,000; and greater than about 100,000 daltons, respectively.
[0020] Additional water soluble polymers include polyvinyl pyrrolidone (PVP), such as Plasdone K-29/32 by ISP Corp., which has a molecular weight of about 53,000 daltons; and a polyvinyl alcohol-polyethylene glycol copolymer, such as Kollicoat IR by BASF Pharma, which has about 75%
polyvinyl alcohol units and 25% polyethylene glycol units and has a molecular weight of about 49,000 daltons. Further, a water soluble polymer may serve the function of an additional optional component. For example, polyethylene oxide, specifically Polyox by Dow, having a molecular weight of about 200,000 daltons, can serve as a high molecular weight water soluble polymer and a plasticizer, as discussed below.
polyvinyl alcohol units and 25% polyethylene glycol units and has a molecular weight of about 49,000 daltons. Further, a water soluble polymer may serve the function of an additional optional component. For example, polyethylene oxide, specifically Polyox by Dow, having a molecular weight of about 200,000 daltons, can serve as a high molecular weight water soluble polymer and a plasticizer, as discussed below.
[0021] The molecular weights of the water soluble polymers can be determined as described in Keary, "Characterization of METHOCEL Cellulose Ethers by Aqueous SEC with Multiple Detectors," Carbohydrate Polymers Vol. 45, pp293-303 (2001), which is incorporated herein by reference.
[0022] Various other polymers can be selected by one of ordinary skill in the art given the teachings herein, so long as the polymer is water soluble, and preferably includes a sufficient amount of a high molecular weight component to impart adequate film strength, and a sufficient amount of a low molecular weight component to facilitate the desired film property of rapid disintegration profile. Various concentrations of each polymer may be utilized. Such concentrations will typically be in the range of about 2% to about 35% for each polymer based on the total weight of the dry film. In one embodiment, the concentration for the high molecular weight polymer is about 5% to 10% and the concentration of the low molecular weight polymer is about 5% to 10% of the dry film.
[0023] According to another exemplary embodiment of the invention, , the water soluble low molecular weight component need not be a water soluble polymer. Instead, the low molecular weight component may be a low molecular weight monomer or a combination of various low molecular weight monomers. The low molecular weight component can also serve the function of an additional optional component. For example, the low molecular weight component can also serve as the active ingredient, a glucose component, a plasticizer, starch, flavoring, colorant, and/or sweetener, and may include any of the specific compounds listed below or other suitable compounds, which are water soluble and have a molecular weight less than about 60,000 daltons.
The low molecular weight component serves to promote rapid disintegration, but is present in an amount such that film strength is adequate for processing and dispensing. Various concentrations of the low molecular weight component can be utilized. Such concentrations will typically be in the range of about 2% to about 80% or more based on the total weight of the dry film. In one embodiment, the concentration for the high molecular weight polymer is about 5% to 10% and the concentration of the low molecular weight component is about 30% to 80% of the dry film.
The low molecular weight component serves to promote rapid disintegration, but is present in an amount such that film strength is adequate for processing and dispensing. Various concentrations of the low molecular weight component can be utilized. Such concentrations will typically be in the range of about 2% to about 80% or more based on the total weight of the dry film. In one embodiment, the concentration for the high molecular weight polymer is about 5% to 10% and the concentration of the low molecular weight component is about 30% to 80% of the dry film.
[0024] Any pharmaceutically or cosmetically active ingredient may be used in accordance with the principles of this invention, whether dissolved or dispersed. Examples of pharmaceutically active compounds include hormones, e.g., cyproterone acetate, progesterone, estradiol, testosterone, insulin, triiodthyronin, cortisone, etc.; prostaglandins, e.g., prostaglandin E~, prostaglandin E2, prostaglandin A~ and prostaglandin F2a ;vitamins, e.g., vitamin A, vitamin Da, vitamin Ds, vitamin E, vitamin K~, vitamin K2 and derivatives of vitamin B~, e.g., thiamine tetrahydrofurfuryl disulfide or , thiamine propyldisulfide; antibiotics, e.g., erythromycin and tetracycline;
contraceptives, e.g., chlormadinone, chlormadinone acetate, megestrol acetate, d-norgestrel, medroxyprogesterone acetate, norethisterone, norethisterone acetate, etc.; spermicides, e.g., p-diisobutylphenoxypolyethoxyethanol, gestagens, estrogens and mixtures thereof; anxiolytics, sedatives, and hypnotics, such as bezodiazepines, e.g., diazepam and alprazolam, buspirone HCL, promethazine HCL, Phenobarbital; cerebral stimulants, such as methylphenidate HCL, pemoline, caffeine; anti-diabetics; sulfonamides;
proton pump inhibitors, such as omeprazole; trichomonal agents;
anesthetics/analgesics, such as benzocaine, lidocaine, procaine, dyclonine HCl, phenol, aspirin, phenacetin, acetaminophen, potassium nitrate, etc.; opiate agonists, such as fentanyl citrate, meperidine HCL, morphine sulphate;
anticaries agents, such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, etc.; anti-inflammatories, such as hydrocortisone acetate, triamcinolone acetonide, dipotassium, glycyrrhizinate, etc.; antihistamines, such as chlorpheniramine maleate, ephedrine HCI, diphenhydramine HCI, clemastine fumarate, loratadine, cetirizine, etc.; decongestants, such as pseudoephedrine; antibacterials, such as chlorhexidine, cetylpyridinium chloride, benzethonium chloride, dequalinium chloride, silver sulfadiazene, phenol, thymol, hexedine, hexetidine, alexidine, etc.; fungistats, such as nystatin, miconazole, ketoconazole, etc; antitussives, such as dextromethorphan, Iodine sulphate, menthol, etc.; anti-diarrheal agents, such as loperamide; anti-anginals, such as nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and other nitric oxide derivatives; anti-emetics, such as meclazine HCL; anti-flatulents, such as simethicone; miscellaneous autonomic and central nervous system agents, such as nicotine and sumatriptan, respectively; skeletal muscle relaxants, such as baclofen; antidepressants generally, such as olanzapine, risperidone, and specifically monoamine oxidase (MAO) inhibitors, e.g., phenelzine, selegiline, tricyclic antidepressants, e.g., amitriptyline HCL, clomipramine HCL, imipramine HCL; antipsychotics, such as phenothiazine derivatives, butyrophenone derivatives, e.g., haloperidol; smoking deterrents, such as bupropion; alcohol deterrents, such as disulfiram, naltrexone; enzymes, such as papain; cosmetic active ingredients, such as parsley seed oil; among others.
contraceptives, e.g., chlormadinone, chlormadinone acetate, megestrol acetate, d-norgestrel, medroxyprogesterone acetate, norethisterone, norethisterone acetate, etc.; spermicides, e.g., p-diisobutylphenoxypolyethoxyethanol, gestagens, estrogens and mixtures thereof; anxiolytics, sedatives, and hypnotics, such as bezodiazepines, e.g., diazepam and alprazolam, buspirone HCL, promethazine HCL, Phenobarbital; cerebral stimulants, such as methylphenidate HCL, pemoline, caffeine; anti-diabetics; sulfonamides;
proton pump inhibitors, such as omeprazole; trichomonal agents;
anesthetics/analgesics, such as benzocaine, lidocaine, procaine, dyclonine HCl, phenol, aspirin, phenacetin, acetaminophen, potassium nitrate, etc.; opiate agonists, such as fentanyl citrate, meperidine HCL, morphine sulphate;
anticaries agents, such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, etc.; anti-inflammatories, such as hydrocortisone acetate, triamcinolone acetonide, dipotassium, glycyrrhizinate, etc.; antihistamines, such as chlorpheniramine maleate, ephedrine HCI, diphenhydramine HCI, clemastine fumarate, loratadine, cetirizine, etc.; decongestants, such as pseudoephedrine; antibacterials, such as chlorhexidine, cetylpyridinium chloride, benzethonium chloride, dequalinium chloride, silver sulfadiazene, phenol, thymol, hexedine, hexetidine, alexidine, etc.; fungistats, such as nystatin, miconazole, ketoconazole, etc; antitussives, such as dextromethorphan, Iodine sulphate, menthol, etc.; anti-diarrheal agents, such as loperamide; anti-anginals, such as nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and other nitric oxide derivatives; anti-emetics, such as meclazine HCL; anti-flatulents, such as simethicone; miscellaneous autonomic and central nervous system agents, such as nicotine and sumatriptan, respectively; skeletal muscle relaxants, such as baclofen; antidepressants generally, such as olanzapine, risperidone, and specifically monoamine oxidase (MAO) inhibitors, e.g., phenelzine, selegiline, tricyclic antidepressants, e.g., amitriptyline HCL, clomipramine HCL, imipramine HCL; antipsychotics, such as phenothiazine derivatives, butyrophenone derivatives, e.g., haloperidol; smoking deterrents, such as bupropion; alcohol deterrents, such as disulfiram, naltrexone; enzymes, such as papain; cosmetic active ingredients, such as parsley seed oil; among others.
[0025] The optional glucose component of thin films according to the invention can be added as a sweetener and/or to promote rapid disintegration of the film. Preferably, the glucose component comprises a water soluble polymer or mixture of polymers having D-glucose units. The dextrose equivalent (DE) of the glucose component is preferably within the range of about 10 to about 25, or about 15 to about 20, although various other DE
ranges can also be used. The glucose component can be prepared, for example, by the partial hydrolysis of starch to yield D-glucose polymer mixtures. Suitable commercially available glucose components include, for example, maltodextrin, corn syrup solids, sucrose, and dextrose. Maltodextrin having a DE of about 16.5 to 19.5, such as that commercially available from Grain Processing Corp. (GPC) under the trade name "Maltrin M180," is particularly suitable, although various other glucose containing polymers and mixtures can be utilized, including, for example, other grades of "Maltrin,"
"Lycatab DH°' (Roquette Preres), and "Star-Dri" (A.E. Staley). Suitable concentrations as a weight percentage of the dry film composition will typically be in the range of about 2% to 20%, or about 3% to about 15%, although other concentrations also may be used depending on the selection of other components and the desired film properties.
ranges can also be used. The glucose component can be prepared, for example, by the partial hydrolysis of starch to yield D-glucose polymer mixtures. Suitable commercially available glucose components include, for example, maltodextrin, corn syrup solids, sucrose, and dextrose. Maltodextrin having a DE of about 16.5 to 19.5, such as that commercially available from Grain Processing Corp. (GPC) under the trade name "Maltrin M180," is particularly suitable, although various other glucose containing polymers and mixtures can be utilized, including, for example, other grades of "Maltrin,"
"Lycatab DH°' (Roquette Preres), and "Star-Dri" (A.E. Staley). Suitable concentrations as a weight percentage of the dry film composition will typically be in the range of about 2% to 20%, or about 3% to about 15%, although other concentrations also may be used depending on the selection of other components and the desired film properties.
[0026] The optional starch component of films according to the present invention can be added to promote rapid disintegration of the film and/or to aid in film formation. Preferably, the starch component is a water soluble polysaccharide composition containing amylose and/or amylopectin. Such compositions may be prepared by, for example, modifying natural starches, such as corn, wheat, rice, potato, or tapioca starch, to provide cold water soluble instant starches. Various water soluble compositions of amylose and/or amylopectin polysaccharides can be used. Typically, these can be made by heating a natural starch with steam to modify the natural starch product so that it is cold water soluble.
[0027] The instant starch commercially available from GPC, Muscatine IA, as "Instant Pure Cote B792," (IPC B792) is an exemplary starch component for purposes of the present invention. Other suitable commercially available instant starches include "Polartex Instant 12640," available from Cargill, Inc., and various others may also be utilized. The starch component will typically have an amylose to amylopectin ratio in the range, for example, of about 0 to about 2.5. The starch can be incorporated in the wet film composition in any suitable amount, including, but not limited to, about 2% to 50%, or about 3%
to about 35% by weight based on the dry film.
to about 35% by weight based on the dry film.
[0028] The disintegratable film compositions of the present invention may also optionally contain a plasticizer or humectant, for example, polyalcohols, sorbitan esters, and citric acid esters, to increase the flexibility of the films. The plasticizers can be added directly to the formulation during manufacture. Suitable compounds include polyethylene glycol (PEG), such as Lutrol E 400, by BASF Pharma; polyethylene oxide, such as Polyox by Dow;
polyoxamers, such as Lutrol F by BASF Pharma; polyvinyl alcohol; polyvinyl methyl ether, such as Lutanol by BASF; or mi,etures of those polymers;
triacetin; glycerin; mannitol; xylitol; and various other polyalcohols and other compounds having plasticizer and/or humectant properties can be satisfactorily employed. Sorbitol and PEG 400 are particularly suitable;
although compounds having a higher molecular weight (e.g., Polyox N80) than PEG 400 may be desirable for certain applications, since they are typically less volatile than sorbitol and PEG 400. The optional plasticizer and/or humectant may be present in any suitable range, including, for example about 3% to 30%,10% to 20%, or 15% to 18% by weight of the dry film.
polyoxamers, such as Lutrol F by BASF Pharma; polyvinyl alcohol; polyvinyl methyl ether, such as Lutanol by BASF; or mi,etures of those polymers;
triacetin; glycerin; mannitol; xylitol; and various other polyalcohols and other compounds having plasticizer and/or humectant properties can be satisfactorily employed. Sorbitol and PEG 400 are particularly suitable;
although compounds having a higher molecular weight (e.g., Polyox N80) than PEG 400 may be desirable for certain applications, since they are typically less volatile than sorbitol and PEG 400. The optional plasticizer and/or humectant may be present in any suitable range, including, for example about 3% to 30%,10% to 20%, or 15% to 18% by weight of the dry film.
[0029] Additional optional components can be added to films according to the invention. For example, flavors and sweeteners can be added to the film formulations of this invention to make the film more palatable to the patient or consumer for oral delivery. Flavors and sweeteners can be added directly to the formulation during manufacture. Flavors, sweeteners, artificial and natural, are known to those skilled in the art. The choice of flavor, sweetener, and/or other optional ingredients is not important for the practice of this invention.
[0030] Also, any color can be imparted to the film, depending upon the dye or pigment that is used. The dye or pigment is typically an FD&C
colorant that is approved for oral consumption. Further, buffers, stabilizers, additives and/or other components can be added to film formulations according to the invention to provide a film having desired properties.
colorant that is approved for oral consumption. Further, buffers, stabilizers, additives and/or other components can be added to film formulations according to the invention to provide a film having desired properties.
[0031] As noted above, according to one embodiment, the films according to the invention also contain a filler. The filler is a dispersed phase or particle that, in preferred embodiments, causes the films to disintegrate faster upon contact with the targeted mucosal surface. The active ingredient can itself act as a filler in certain embodiments. For example, a taste masked drug (e.g., encapsulated dextromethorphan or diphenhydramine) can act as a filler and promote rapid disintegration of the film. The encapsulated or taste masked drug is a dispersed particle. Methods of taste masking include encapsulation or complexation. For example, MicroMask° pseudoephedrine by Particle Dynamics is an encapsulated form of psuedoephedrine.
Additionally, when the active ingredient is present in the film at a concentration above its solubility saturation point, the excess active ingredient can act as a filler. For example, when caffeine is the active ingredient, the film can be supersaturated with the caffeine such that the excess caffeine acts as a disintegration-promoting filler.
Additionally, when the active ingredient is present in the film at a concentration above its solubility saturation point, the excess active ingredient can act as a filler. For example, when caffeine is the active ingredient, the film can be supersaturated with the caffeine such that the excess caffeine acts as a disintegration-promoting filler.
[0032] The filler can be an optional non-active component. Examples of such components include titanium oxide and microcrystalline cellulose, which is available under the name Avicel, among others. Air or other gasses can also be used as a filler according to the invention. When air is employed as the filler, a surfactant (e.g., sodium lauryl sulfate (SLS), available under the name Stepanol, Polysorbate 80, or Pluracare F87 Pril) may be included in the film formulation. The surfactant does not itself serve to significantly increase the rate of disintegration of the films upon contact with the targeted mucosal environment. Instead, the surfactant aids in the processing and formation of the film. Specifically, the surfactant stabilizes the gaseous bubbles as a dispersed phase within a solution to allow the solution to be processed, as described in more detail below, to form the film containing the gas or air as a dispersed phase filler.
[0033] The film compositions according to the invention may be prepared by several methods, including, but not limited to, adding the combination of high and low molecular weight water soluble components, the optional starch, and optional glucose polymer ingredients to a solvent that is capable of dissolving them, such as water or ethanol or a mixture of ethanol and water. Upon forming a homogeneous solution, the active ingredient and any of the other optional components, such as plasticizers, flavors, sweeteners, colorants, and/or other components may be blended into the active-containing polymer solution. Alternatively, all of the film components may be added and concurrently blended to form a solution or dispersion. Also, a dry blend can be compounded by a V-blender. The dry blend can be subsequently used to form a solution or dispersion. Additionally, the dry blend can be subsequently subjected to a melt extrusion to form a film upon cooling. It should be understood that no particular sequence of steps is required, except as needed to effectively prepare a desired film composition. For example, when a particular sequence yields an undesirable precipitate, an alternative sequence is necessary.
[0034] The active ingredient may be soluble in the solution or it may be suspended or dispersed in the solution.
[0035] The active ingredient-containing solution or dispersion may be further processed into a film by any one of many casting, drawing, or extruding techniques. For example, the solution or dispersion may be sprayed onto a support such as a release-treated belt. Alternatively, for example, the solution or dispersion may be roll coated onto a release treated paper or film substrate.
[0036] After coating of the solution or dispersion onto a support surface, the solvent may be removed by radiant energy (such as infra-red), heat, convection, vacuum, or any combination of these to yield a dry film containing an active ingredient. The resulting dry film can be wound up into a roll for storage prior to further processing into unit dose forms. Whether stored for future processing or immediately following removal of the solvent, the resulting film can be removed from the support surface and subsequently processed into unit dose form. Additional ingredients can be applied to the dried film by, for example, printing, spraying, dusting, or vapor adsorption processes, among others.
[0037] The dry film can be processed into unit dose form by any suitable ,techni.que, including, for example, by die-cutting or cutting across the width of a singular narrow roll to prepare unit dosage forms of any desired geometric size or shape. The unit dose forms may be subsequently packaged with various suitable materials known in the art to prevent degradation and protect the active ingredient from adulteration.
[0038] The preferred films according to the teachings of the present invention are mucoadhesive monolayers having a thickness in the range of about 20 microns (~) to about 1200w, more preferably, less than about 250,, or equal to or less than about 200.. In another thin film embodiment, the films have a thickness of less than about 175, or less than about 75~. When placed in the mouth, the films rapidly disintegrate to release the active ingredient without causing any undue discomfort to the oral cavity. By "rapid"
disintegration, we mean that the active ingredient, or the taste masked, encapsulated, or complexed form of the active ingredient, is released from the film matrix in a matter of a few seconds to less than a minute. Disintegration times can be determined using the test provided by (USP) 24, Disintegration <701>. See United States Pharmacopoeia, 24th ed., Ch. 701, p. 1941 (2000), which is incorporated herein by reference.
disintegration, we mean that the active ingredient, or the taste masked, encapsulated, or complexed form of the active ingredient, is released from the film matrix in a matter of a few seconds to less than a minute. Disintegration times can be determined using the test provided by (USP) 24, Disintegration <701>. See United States Pharmacopoeia, 24th ed., Ch. 701, p. 1941 (2000), which is incorporated herein by reference.
[0039] Preferably, the composition has already disintegrated in the oral cavity after less than about 20 to about 30 seconds from initially placing the composition in the mouth. At the same time, the films have adequate strength for processing, packaging, and administration without physical failure (e.g., breakage, fracture, or otherwise) during processing and normal handling prior to administration to the intended mucosal surface. T'he film strength, specifically, film resilience, springiness and burst strength, can be determined using the TA.XT2i Texture Analyzer by Texture Technologies Corp. and the ASTM D3763 "High-Speed Puncture Properties of Plastics Using Load and Displacement Sensors" test method. These properties of film strength and rapid disintegration are the result of the unique combination of the components described herein.
[0040] The film compositions may be administered to the oral mucosa or other mucous membranes where they are rapidly disintegrated by saliva and/or other aqueous materials on the mucosal surface. Upon disintegration, the films release one or more pharmaceutical or cosmetic compounds to the mucous membranes. The film compositions may be administered in such a manner so as to deliver an effective amount of the active ingredient, which may be present in pharmaceutically effective trace amounts up to about 60°l°
or more of the dry film.
or more of the dry film.
[0041] The following illustrative examples provide a number of specific formulations within the scope of the present invention. These examples are by way of illustration only and are not intended to be limiting in any way.
Various alternative components, concentrations, and optional excipients (plasticizers, humectants, fillers, preservatives, etc.) may be utilized given the teachings herein to yield thin monolayer films of suitable film strength and disintegration profile.
Various alternative components, concentrations, and optional excipients (plasticizers, humectants, fillers, preservatives, etc.) may be utilized given the teachings herein to yield thin monolayer films of suitable film strength and disintegration profile.
[0042] The specific embodiments of examples 1-29 below contain no surfactants. Surprisingly beneficial film quality can thus be achieved without any surfactants. The embodiments of examples 11-31 each contain a dispersed phase filler. In examples 11-24, the active ingredient also serves as a filler;
whereas, in examples 25-31 an additional component serves as a filler. The embodiments of examples 30 and 31 include air as the filler. Accordingly, examples 30 and 31 also include a surfactant for stabilizing the air bubbles during processing. The exemplary formulations below are described in the following manner: 1) the concentrations of the excipients are expressed in parts in the dry film and/or the wet solution or dispersion; 2) the weight percent of the excipients in the dry film and/or the wet solution or dispersion;
and/or 3) the amount of a stock solution (stock soln.) of the excipients expressed in grams, and the total weight of the wet solution or dispersion, and the total weight of the dry film expressed in grams.
EXAMPLES
Exam le 1 . Dry Film Concentration Parts Methocel E5 10.0 Methocel E50 FG 8.0 IPC B792 27.0 Sucralose 2 Sorbitol 5 Sucrose 10 FD&C Red #40 0.15 Cher Flavor 29.55 Chlor heniramine Maleate 8.3 Overall Sum 100 Solids 20%
Example 2 Dry Film ConcentrationWet Parts % wlw Methocel E5 6.32 2.59 Methocel E50 15.65 6.42 Klucel F 2.67 1.10 Maltodextrin M180 3.86 1.58 IPC 8792 3.71 1.52 Citric Acid 1.04 0.43 Sucralose ~ 9.22 3.79 Lemon-Gra efruit Flavor 12.72 5.22 Oran a Flavor 12.49 5.13 Pseudoe hedrine 16.48 6.76 Sorbitol 13.78 5.66 FD&C Red# 40 1.04 0.43 FD&C Blue# 1 1.04 0.43 Water --- 58.95 Overall Sum 100.02 100.01 Solids 41.05%
Exam le 3 4 Dry Film Dry Film Conc. Wet Conc. Wet tarts % w/w tarts % w/w Methocel E5 5.84 2.83 8.27 2.71 Methocel E50 14.67 7.10 20.63 6.75 Klucel 2.64 1.28 3.49 1.14 Maltodextrin M180 3.33 1.61 4.86 1.59 Instant Starch 8792 25.33 12.25 4.86 1.59 Sodium hos hate dibasic1.19 0.58 1.52 0.50 Sucralose 7.92 3.83 11.07 3.62 PEG 400 6.82 3.30 --- ---Mint Flavor 16.31 7.89 22.80 7.46 Lo eramide ;3.24 1.57 4.50 1.47 Sorbitol 12.62 6.10 17.90 5.86 FD&C Green Blend 551 0.06 0.05 0.11 0.04 Ethanol ___ ___ ___ ___ Water --- 51.63 --- 67.27 Overall Sum 99.97 100.02 100.01 100.00 Solids 48.37% 32.73%
Exam le 5 6 Dry Film Dry Film Conc. Wet Conc. Wet Parts % w/w Parts % w/w Methocel E5 7.73 2.53 7.37 2.50.
Methocel E50 17.74 5.82 16.81 5.71 Klucel F 3.27 1.07 3.27 1.11 Maltodextrin M180 4.66 1.53 4.32 1.47 IPC B792 4.66 1.53 4.68 1.59 FD&C Red #40 0.01 0.00 --- ---Mint Green Colorant--- --- 0.08 0.03 Prosweet G 1.87 0.61 1.62 0.55 Sucralose 6.71 2.20 6.43 2.18 PEG 400 3.73 1.22 3.73 1.26 Ome razole 39.81 13.05 37.74 12.81 Sorbitol 3.69 1.21 3.51 1.19 S earmint Flavor 6.12 2.01 5.54 1.88 Sodium H droxide --- --- 0.74 0.25 Sodium Phosphate Dibasic --- --- 4.16 1.41 Water --- 67.21 --- 66.06 Overall Sum 100.00 99.99 100.00 100.00 Solids 32.79% 33.94%
Exam le 7 Dry Film Concentration Parts Sorbitol ~ 11 Sucrose 11 Vanilla Extract Pure 17 Parsle Seed Oil 4 Verde Green 0.5 Mint #2684 10 Methocel E50 FG 15 IPC 8792 31.4 Sucralose 0.1 Overall Sum 100 Solids 31%
Exam le 8 Dry Film.
Concentration Parts Methocel E5 .9.96 Klucel F 7.12 Maltodextrin 14.31 Instant Starch 14.31 Sucralose 2.38 Flavor 27.00 Loratadine 10.00 Sorbitol 14.93 Overall Sum 100.01 Solids 40.89%
Exam le 9 Stock Soln.ams Base: 21.7 10.020 Methocel E5 6.9 0.691 Methocel E50 3.4 0.341 Klucel 3.0 0.301 Maltrin M180 4.2 0.421 IPC B792 4.2 0.421 Flavor 100 3.015 Saccharin 100 0.217 Dextromethor 100 0.502 han Wet Total (includin water) 13.754 D Total 5.908 Exam le 10 Dry Filin Concentration Wet Parts % W~W
Methocel E5 5.51 2.00 Methocel E50 13.33 4.84 Klucel F 2.38 0.87 Maltodextrin M180 3.06 1.11 IPC B792 3.66 1.33 Sodium phosphate dibasic 0.93 0.34 Sucralose 7.24 2.63 PEG 400 6.69 2.43 Cher Flavor 15.21 5.53 Pseudoe hedrine 29.47 10.71 Sorbitol 11.86 4.31 FD&C Red# 40 0.66 0.24 Ethanol --- 10.20 Water --- 53.46 Overall Sum 100.00 100.00 Solids 36.35%
Exam le 11 12 13 14 Stock Soln.ams ams rams ams Base: 21.7 9.826 9.852 9.967 81.676 Methocel E5 6.9 0.678 0.680 0.688 5.636 Methocel E50 3.4 0.334 0.335 0.339 2.777 Klucel F 3.0 0.295 0.296 0.299 2.450 Maltrin M180 4.2 0.413 0.414 0.419 3.430 IPC B792 4.2 0.413 0.414 0.419 3.430 Flavor 100 3.019 3.011 3.031 29.313 Saccharin 100 0.201 0.204 Taste Masked Dextromethor han 100 1.262 1.227 1.220 11.545 Methocel E50 10 11.661 Sucralose 25 7.858 Sorbitol 70 17.565 FD&C Red #40 10 1.121 Maltrin M180 100 1.909 Wet Total (including water) 16.217 17.114 14.218 160.739 D Total 8.523 6.580 6.414 74.120 Exam le 15 16 17 Stock Soln._ ams ams ams Base: 14.5 8.935 3.314 6.205 Methocel E50 9.3 0.831 0.308 0.577 Maltrin M180 2.6 0.232 0.086 0.161 IPC B792 2.6 0.232 0.086 0.161 Flavor 100 1.243 0.922 0.902 Taste Masked Dextromethor han 100 2.453 1.264 1.239 Sucralose 25 0.548 0.280 0.274 FD&C Red #40 1 0.507 0.242 0.238 PEG 400 100 0.608 PVP K29i32 55.19 0.908 2.376 1.664 Polyethyene oxide (about 100 200,000 daltons Wet Total 15.2028.398 10.522 D Total 6.243 4.050 4.030 Exam le 18 19 20 Stock Soln.ams ams ams Base: 20.3 81.930 Methocel E5 6.1 4.998 Methocel E50 4.3 3.523 Klucel 2.7 2.212 Maltrin M180 3.6 2.949 IPC B792 3.6 2.949 Flavor 100 25.765 0.995 1.102 Taste Masked Dextrornethor han 100 51.970 1.229 1.226 Methocel E50 10 101.579 Sucralose 25 10.397 0.289 0.283 Sorbitol 70 15.388 FD&C Red #40 2 0.269 0.261 FD&C Red #40 ~10 1.057 PEG 400 100 12.026 PVP 55.19 1.617 1.612 Polyethyene oxide (about 200,000 daltons 100 0.891 0.909 Water 170.08476 Wet Total (includin water) 300.112 9.233 8.836 D Total 130.027 4.082 4.200 Exam le 21 Dry film Concentration Parts Mefihocel E5 6.14164 Methocel E50 FG 4.34101 Klucel 2.71067 Maltrin M180 3.70464 IPC 8792 3.70193 Sorbitol 18.5 Sucralose 2 FD&C Red #40 0.15 Flavor 40.0001 Taste Masked Dextromethor han 18.75 Overall Sum 100 -p solids 53%
Exam le 22 Dry Film Casting Solution ConcentrationConcentration WIW % WIW
Methocel E5 3.96 1.62 Methocel E50 6.71 2.75 Klucel 2.07 0.848 Maltrin M180 5.01 2.05 IPC B792 4.73 1.94 Flavor 0.65 0.266 Taste Masked 60.05 24.60 Di henh dramine Sucralose 6.74 2.76 Sorbitol 4.40 1.80 FD&C Red #40 0.11 0.0434 PEG 400 5.58 2.29 Ethanol 9.84 Water 49.19 Overall Sum 100 100
whereas, in examples 25-31 an additional component serves as a filler. The embodiments of examples 30 and 31 include air as the filler. Accordingly, examples 30 and 31 also include a surfactant for stabilizing the air bubbles during processing. The exemplary formulations below are described in the following manner: 1) the concentrations of the excipients are expressed in parts in the dry film and/or the wet solution or dispersion; 2) the weight percent of the excipients in the dry film and/or the wet solution or dispersion;
and/or 3) the amount of a stock solution (stock soln.) of the excipients expressed in grams, and the total weight of the wet solution or dispersion, and the total weight of the dry film expressed in grams.
EXAMPLES
Exam le 1 . Dry Film Concentration Parts Methocel E5 10.0 Methocel E50 FG 8.0 IPC B792 27.0 Sucralose 2 Sorbitol 5 Sucrose 10 FD&C Red #40 0.15 Cher Flavor 29.55 Chlor heniramine Maleate 8.3 Overall Sum 100 Solids 20%
Example 2 Dry Film ConcentrationWet Parts % wlw Methocel E5 6.32 2.59 Methocel E50 15.65 6.42 Klucel F 2.67 1.10 Maltodextrin M180 3.86 1.58 IPC 8792 3.71 1.52 Citric Acid 1.04 0.43 Sucralose ~ 9.22 3.79 Lemon-Gra efruit Flavor 12.72 5.22 Oran a Flavor 12.49 5.13 Pseudoe hedrine 16.48 6.76 Sorbitol 13.78 5.66 FD&C Red# 40 1.04 0.43 FD&C Blue# 1 1.04 0.43 Water --- 58.95 Overall Sum 100.02 100.01 Solids 41.05%
Exam le 3 4 Dry Film Dry Film Conc. Wet Conc. Wet tarts % w/w tarts % w/w Methocel E5 5.84 2.83 8.27 2.71 Methocel E50 14.67 7.10 20.63 6.75 Klucel 2.64 1.28 3.49 1.14 Maltodextrin M180 3.33 1.61 4.86 1.59 Instant Starch 8792 25.33 12.25 4.86 1.59 Sodium hos hate dibasic1.19 0.58 1.52 0.50 Sucralose 7.92 3.83 11.07 3.62 PEG 400 6.82 3.30 --- ---Mint Flavor 16.31 7.89 22.80 7.46 Lo eramide ;3.24 1.57 4.50 1.47 Sorbitol 12.62 6.10 17.90 5.86 FD&C Green Blend 551 0.06 0.05 0.11 0.04 Ethanol ___ ___ ___ ___ Water --- 51.63 --- 67.27 Overall Sum 99.97 100.02 100.01 100.00 Solids 48.37% 32.73%
Exam le 5 6 Dry Film Dry Film Conc. Wet Conc. Wet Parts % w/w Parts % w/w Methocel E5 7.73 2.53 7.37 2.50.
Methocel E50 17.74 5.82 16.81 5.71 Klucel F 3.27 1.07 3.27 1.11 Maltodextrin M180 4.66 1.53 4.32 1.47 IPC B792 4.66 1.53 4.68 1.59 FD&C Red #40 0.01 0.00 --- ---Mint Green Colorant--- --- 0.08 0.03 Prosweet G 1.87 0.61 1.62 0.55 Sucralose 6.71 2.20 6.43 2.18 PEG 400 3.73 1.22 3.73 1.26 Ome razole 39.81 13.05 37.74 12.81 Sorbitol 3.69 1.21 3.51 1.19 S earmint Flavor 6.12 2.01 5.54 1.88 Sodium H droxide --- --- 0.74 0.25 Sodium Phosphate Dibasic --- --- 4.16 1.41 Water --- 67.21 --- 66.06 Overall Sum 100.00 99.99 100.00 100.00 Solids 32.79% 33.94%
Exam le 7 Dry Film Concentration Parts Sorbitol ~ 11 Sucrose 11 Vanilla Extract Pure 17 Parsle Seed Oil 4 Verde Green 0.5 Mint #2684 10 Methocel E50 FG 15 IPC 8792 31.4 Sucralose 0.1 Overall Sum 100 Solids 31%
Exam le 8 Dry Film.
Concentration Parts Methocel E5 .9.96 Klucel F 7.12 Maltodextrin 14.31 Instant Starch 14.31 Sucralose 2.38 Flavor 27.00 Loratadine 10.00 Sorbitol 14.93 Overall Sum 100.01 Solids 40.89%
Exam le 9 Stock Soln.ams Base: 21.7 10.020 Methocel E5 6.9 0.691 Methocel E50 3.4 0.341 Klucel 3.0 0.301 Maltrin M180 4.2 0.421 IPC B792 4.2 0.421 Flavor 100 3.015 Saccharin 100 0.217 Dextromethor 100 0.502 han Wet Total (includin water) 13.754 D Total 5.908 Exam le 10 Dry Filin Concentration Wet Parts % W~W
Methocel E5 5.51 2.00 Methocel E50 13.33 4.84 Klucel F 2.38 0.87 Maltodextrin M180 3.06 1.11 IPC B792 3.66 1.33 Sodium phosphate dibasic 0.93 0.34 Sucralose 7.24 2.63 PEG 400 6.69 2.43 Cher Flavor 15.21 5.53 Pseudoe hedrine 29.47 10.71 Sorbitol 11.86 4.31 FD&C Red# 40 0.66 0.24 Ethanol --- 10.20 Water --- 53.46 Overall Sum 100.00 100.00 Solids 36.35%
Exam le 11 12 13 14 Stock Soln.ams ams rams ams Base: 21.7 9.826 9.852 9.967 81.676 Methocel E5 6.9 0.678 0.680 0.688 5.636 Methocel E50 3.4 0.334 0.335 0.339 2.777 Klucel F 3.0 0.295 0.296 0.299 2.450 Maltrin M180 4.2 0.413 0.414 0.419 3.430 IPC B792 4.2 0.413 0.414 0.419 3.430 Flavor 100 3.019 3.011 3.031 29.313 Saccharin 100 0.201 0.204 Taste Masked Dextromethor han 100 1.262 1.227 1.220 11.545 Methocel E50 10 11.661 Sucralose 25 7.858 Sorbitol 70 17.565 FD&C Red #40 10 1.121 Maltrin M180 100 1.909 Wet Total (including water) 16.217 17.114 14.218 160.739 D Total 8.523 6.580 6.414 74.120 Exam le 15 16 17 Stock Soln._ ams ams ams Base: 14.5 8.935 3.314 6.205 Methocel E50 9.3 0.831 0.308 0.577 Maltrin M180 2.6 0.232 0.086 0.161 IPC B792 2.6 0.232 0.086 0.161 Flavor 100 1.243 0.922 0.902 Taste Masked Dextromethor han 100 2.453 1.264 1.239 Sucralose 25 0.548 0.280 0.274 FD&C Red #40 1 0.507 0.242 0.238 PEG 400 100 0.608 PVP K29i32 55.19 0.908 2.376 1.664 Polyethyene oxide (about 100 200,000 daltons Wet Total 15.2028.398 10.522 D Total 6.243 4.050 4.030 Exam le 18 19 20 Stock Soln.ams ams ams Base: 20.3 81.930 Methocel E5 6.1 4.998 Methocel E50 4.3 3.523 Klucel 2.7 2.212 Maltrin M180 3.6 2.949 IPC B792 3.6 2.949 Flavor 100 25.765 0.995 1.102 Taste Masked Dextrornethor han 100 51.970 1.229 1.226 Methocel E50 10 101.579 Sucralose 25 10.397 0.289 0.283 Sorbitol 70 15.388 FD&C Red #40 2 0.269 0.261 FD&C Red #40 ~10 1.057 PEG 400 100 12.026 PVP 55.19 1.617 1.612 Polyethyene oxide (about 200,000 daltons 100 0.891 0.909 Water 170.08476 Wet Total (includin water) 300.112 9.233 8.836 D Total 130.027 4.082 4.200 Exam le 21 Dry film Concentration Parts Mefihocel E5 6.14164 Methocel E50 FG 4.34101 Klucel 2.71067 Maltrin M180 3.70464 IPC 8792 3.70193 Sorbitol 18.5 Sucralose 2 FD&C Red #40 0.15 Flavor 40.0001 Taste Masked Dextromethor han 18.75 Overall Sum 100 -p solids 53%
Exam le 22 Dry Film Casting Solution ConcentrationConcentration WIW % WIW
Methocel E5 3.96 1.62 Methocel E50 6.71 2.75 Klucel 2.07 0.848 Maltrin M180 5.01 2.05 IPC B792 4.73 1.94 Flavor 0.65 0.266 Taste Masked 60.05 24.60 Di henh dramine Sucralose 6.74 2.76 Sorbitol 4.40 1.80 FD&C Red #40 0.11 0.0434 PEG 400 5.58 2.29 Ethanol 9.84 Water 49.19 Overall Sum 100 100
[0043) Examples 21 and 22 showed disintegration times of about 0 seconds to about 12 seconds for samples of about 35 grams to about 160 grams and for film thicknesses within the range of about 20 ~ to about 200 ~.
Disintegration times were determined using the test provided by (USP) 24, Disintegration <701>.
Exam le 23 Dry Film yet Concentration %w/w Parts Methocel E5 ' 28.50 6.49 Methocel E50 13.35 3.04 ProSweet G 4.83 1.1 As artarne 0.92 0.21 Sucralose 3.95 0.9 Flavor 11.77 2.68 Caffeine 36.67 8.35 Overall Sum 100 22.77 Solids 21.62%
Exam le 24 Dry Filin Concentration Parts Methocel E5 24.20 Methocel E50 11.33 ProSweet G 4.10 As artame 0.78 Sucralose 3.36 Flavor 9.99 Caffeine 31.13 PEG 400' 15.10 Overall Sum 100.0001 Solids 26.56%
The weight % of PEG
can range, for example, from between about 15% to about 52%.
Exam le 25 26 27 Dry Film Dry Film Dry Film Conc. Wet Conc. Wet Conc. Wet tarts % w/w tarts % w/w tarts % w/w Methocel 7.55 2.52 7.26 2.45 --- ---Methocel 20.71 6.92 20.02 6.75 28.89 6.73 Klucel F 3.36 1.12 3.22 1.08 3.43 0.80 Maltodextrin M180 4.67 1.56 4.56 1.54 8.58 2.00 IPC B792 4.58 1.53 4.43 1.49 8.54 1.99 Sucralose 8.92 2.98 12.48 4.21 13.80 3.22 PEG 400 22.50 7.52 15.15 5.11 6.40 1.49 Menthol 9.81 3.28 20.42 6.89 14.53 3.39 Sorbitol 17.92 5.99 12.33 4.16 15.83 3.69 Ti02 --- --- 0.15 0.05 --- ---Ethanol --- 3.28 --- 6.89 --- 3.39 Water --- 63.30 --- 59.39 --- 73.30 Overall Sum 100.02 100.00 100.02 100.01 100.00 100.00 Solids 33.42% 33.2% 23.31%
Exam le 28 Dry Film Casting Solution ConcentrationConcentration w/w % w/w Methocel E5 4.51 1.77 Methocel E50 8.66 3.41 Klucel F 1.84 0.72 Maltodextrin M180 2.85 1.12 IPC 8792 2.66 1.05 Sodium phosphate dibasic 1.62 0.638 Sucralose 9.59 3.78 PEG 400 6.83 2.69 Cherr Flavor 14.47 5.70 Pseudoe hedrine 24.39 9.60 Sorbitol 10.49 4.13 FD&C Red# 40 ~ 0.107 0.0419 FD&C Blue# 1 0.00128 0.000506 Avicel PH105 11.98 4.72 Ethanol 11.38 Water 49.25 Overall Sum 100 100 Solids 39.37 Exam le 29 Casting Dry Film Solution ConcentrationConcentration w/w / w/w Methocel E5 2._49 1.05 Methocel E50 6.93 2.92 Klucel JF 1.48 0.624 Maltodextrin M180 2.12 0.891 IPC 8792 2.24 0.944 Sucrose 4.26 1.79 Sucralose 10.06 4.23 PEG 400 1.55 0.652 Creme de Menthe Flavor 17.92 7.54 Pseudoe hedrine 19.43 8.17 Sorbitol 8.32 3.50 FD&C Red# 40 0.883 0.371 FD&C Blue# 1 ~ 0.00166 0.000699 Avicel CE15 22.31 9.38 Ethanol 21.12 Water - - 36.83 Overall Sum 100 100 Solids ~ 42.06%
Exam le 30 Dry Film Concentration w/w Methocel E5 8.09 Methocel E4M 3.66 Methocel SG A16M 4.45 Plasdone K29-32 2.79 Sucralose 1.70 Silica Gel 4.14 Pluracare F87 Prill 20.13 Avicel PH200 31.04 Gl cerin 11.49 PEG 400 11.28 Pa ain 0.408 Sodium Phos hate Monobasic 0.201 Sodium Phos hate Dibasic 0.215 FD&C Blue #1 0.00206 Ce 1 ridium Chloride 0.402 Overall Sum 100 Solids ~ 20.11%
Exam le 31 Dry Film Concentration w/w Methocel E5 12.06 Methocel E4M 5.41 Methocel SG A16M 6.58 Sorbitol 11.63 Calcium Stearate 10.03 Sodium Saccharin 2.01 Silica Gel 5.03 SLS 0.503 Avicel PH105 36.68 Triacetin 9.06 Pa ain 0.481 Sodium Phos hate Monobasic 0.251 Sodium Phos hate Dibasic ~ 0.257 FD&C Blue #1 0.00254 Overall Sum 100 Solids 20%
Disintegration times were determined using the test provided by (USP) 24, Disintegration <701>.
Exam le 23 Dry Film yet Concentration %w/w Parts Methocel E5 ' 28.50 6.49 Methocel E50 13.35 3.04 ProSweet G 4.83 1.1 As artarne 0.92 0.21 Sucralose 3.95 0.9 Flavor 11.77 2.68 Caffeine 36.67 8.35 Overall Sum 100 22.77 Solids 21.62%
Exam le 24 Dry Filin Concentration Parts Methocel E5 24.20 Methocel E50 11.33 ProSweet G 4.10 As artame 0.78 Sucralose 3.36 Flavor 9.99 Caffeine 31.13 PEG 400' 15.10 Overall Sum 100.0001 Solids 26.56%
The weight % of PEG
can range, for example, from between about 15% to about 52%.
Exam le 25 26 27 Dry Film Dry Film Dry Film Conc. Wet Conc. Wet Conc. Wet tarts % w/w tarts % w/w tarts % w/w Methocel 7.55 2.52 7.26 2.45 --- ---Methocel 20.71 6.92 20.02 6.75 28.89 6.73 Klucel F 3.36 1.12 3.22 1.08 3.43 0.80 Maltodextrin M180 4.67 1.56 4.56 1.54 8.58 2.00 IPC B792 4.58 1.53 4.43 1.49 8.54 1.99 Sucralose 8.92 2.98 12.48 4.21 13.80 3.22 PEG 400 22.50 7.52 15.15 5.11 6.40 1.49 Menthol 9.81 3.28 20.42 6.89 14.53 3.39 Sorbitol 17.92 5.99 12.33 4.16 15.83 3.69 Ti02 --- --- 0.15 0.05 --- ---Ethanol --- 3.28 --- 6.89 --- 3.39 Water --- 63.30 --- 59.39 --- 73.30 Overall Sum 100.02 100.00 100.02 100.01 100.00 100.00 Solids 33.42% 33.2% 23.31%
Exam le 28 Dry Film Casting Solution ConcentrationConcentration w/w % w/w Methocel E5 4.51 1.77 Methocel E50 8.66 3.41 Klucel F 1.84 0.72 Maltodextrin M180 2.85 1.12 IPC 8792 2.66 1.05 Sodium phosphate dibasic 1.62 0.638 Sucralose 9.59 3.78 PEG 400 6.83 2.69 Cherr Flavor 14.47 5.70 Pseudoe hedrine 24.39 9.60 Sorbitol 10.49 4.13 FD&C Red# 40 ~ 0.107 0.0419 FD&C Blue# 1 0.00128 0.000506 Avicel PH105 11.98 4.72 Ethanol 11.38 Water 49.25 Overall Sum 100 100 Solids 39.37 Exam le 29 Casting Dry Film Solution ConcentrationConcentration w/w / w/w Methocel E5 2._49 1.05 Methocel E50 6.93 2.92 Klucel JF 1.48 0.624 Maltodextrin M180 2.12 0.891 IPC 8792 2.24 0.944 Sucrose 4.26 1.79 Sucralose 10.06 4.23 PEG 400 1.55 0.652 Creme de Menthe Flavor 17.92 7.54 Pseudoe hedrine 19.43 8.17 Sorbitol 8.32 3.50 FD&C Red# 40 0.883 0.371 FD&C Blue# 1 ~ 0.00166 0.000699 Avicel CE15 22.31 9.38 Ethanol 21.12 Water - - 36.83 Overall Sum 100 100 Solids ~ 42.06%
Exam le 30 Dry Film Concentration w/w Methocel E5 8.09 Methocel E4M 3.66 Methocel SG A16M 4.45 Plasdone K29-32 2.79 Sucralose 1.70 Silica Gel 4.14 Pluracare F87 Prill 20.13 Avicel PH200 31.04 Gl cerin 11.49 PEG 400 11.28 Pa ain 0.408 Sodium Phos hate Monobasic 0.201 Sodium Phos hate Dibasic 0.215 FD&C Blue #1 0.00206 Ce 1 ridium Chloride 0.402 Overall Sum 100 Solids ~ 20.11%
Exam le 31 Dry Film Concentration w/w Methocel E5 12.06 Methocel E4M 5.41 Methocel SG A16M 6.58 Sorbitol 11.63 Calcium Stearate 10.03 Sodium Saccharin 2.01 Silica Gel 5.03 SLS 0.503 Avicel PH105 36.68 Triacetin 9.06 Pa ain 0.481 Sodium Phos hate Monobasic 0.251 Sodium Phos hate Dibasic ~ 0.257 FD&C Blue #1 0.00254 Overall Sum 100 Solids 20%
[0044] The formulation of example 31 was aerated prior to casting and drying. A liquid flavor was applied to the dry film such that the flavor concentration was approximately 15 % w/w of the total mass of the flavored film.
[0045] The above description is only illustrative of preferred embodiments which achieve the objects, features and advantages of the present invention. It is not intended that the present invention be limited to the illustrated embodiments. Any modification of the present invention which comes with the spirit and scope of the following claims is considered part of the present invention.
Claims (71)
1. A dissolvable film for delivering a pharmaceutical or cosmetic agent, comprising:
a first water soluble polymer having a molecular weight from about 5,000 daltons to about 60,000 daltons;
a second water soluble polymer having a molecular weight greater than about 60,000 daltons; and a pharmaceutically or cosmetically active ingredient;
wherein the film is in the form of a monolayer of a thickness sufficient to rapidly disintegrate in the oral environment to release the active ingredient.
a first water soluble polymer having a molecular weight from about 5,000 daltons to about 60,000 daltons;
a second water soluble polymer having a molecular weight greater than about 60,000 daltons; and a pharmaceutically or cosmetically active ingredient;
wherein the film is in the form of a monolayer of a thickness sufficient to rapidly disintegrate in the oral environment to release the active ingredient.
2. The film of claim 1 wherein at least one of the water soluble polymers comprises a cellulose derivative polymer.
3. The film of claim 1 wherein the concentration of the water soluble polymers present in the film is about 2% to 35% of the weight of the film.
4. The film of claim 1 wherein the second water soluble polymer has a molecular weight of about 60,000 to about 500,000 daltons.
5. The film of claim 1 wherein at least one of the water soluble polymers comprises hydroxypropyl cellulose.
6. The film of claim 1 wherein at least one of the water soluble polymers comprises hydroxypropyl methylcellulose.
7. The film of claim 1 further comprising a third water soluble polymer.
8. The film of claim 1 wherein at least one of the first and second water soluble polymers comprises a mixture of different polymers.
9. The film of claim 1 wherein the film is mucoadhesive.
10. The film of claim 1 wherein the film disintegrates within about 20 to about 60 seconds after contact with a mucous membrane.
11. The film of claim 1 wherein the film is in a unit dosage form.
12. The film of claim 1 wherein the film has a thickness of about 20 microns to about 1200 microns.
13. The film of claim 1 wherein the film is part of a multilayer device.
14. The film of claim 1 wherein the film is essentially free of surfactants.
15. The film of claim 1 further comprising a starch component.
16. The film of claim 15 wherein the concentration of the starch component is about 2% to 50% of the weight of the film.
17. The film of claim 15 wherein the starch component comprises instant starch.
18. The film of claim 1 further comprising a glucose component.
19. The film of claim 18 wherein the concentration of the glucose component is about 2% to 20% of the weight of the film.
20. The film of claim 18 wherein the glucose component comprises maltodextrin.
21. The film of claim 1 further comprising a plasticizer and/or humectant.
22. The film of claim 21 wherein the concentration of the plasticizer and/or humectant is about 3% to 30% of the weight of the film.
23. The film of claim 21 wherein the plasticizer is selected from the group consisting of sorbitol, polyethylene glycol and polyethylene oxide.
24. The film of claim 1 further comprising a filler.
25. The film of claim 1 wherein the active ingredient is present as a dispersed phase.
26. The film of claim 25 wherein the active ingredient is a taste masked drug.
27. The film of claim 24 wherein the filler comprises titanium oxide.
28. The film of claim 24 wherein the filler comprises excess active ingredient beyond the saturation point of the active ingredient in the film.
29. The film of claim 25 wherein the filler comprises gas.
30. A method of administering the composition of claim 1 wherein the composition is placed into the oral cavity for a sufficient period of time to disintegrate and release the active ingredient.
31. A disintegratable film for delivering a pharmaceutical or cosmetic agent, comprising:
a first water soluble component having a molecular weight below about 60,000 daltons;
a second water soluble component having a molecular weight greater than about 60,000 daltons; and a pharmaceutically or cosmetically active ingredient;
wherein the film is in the form of a monolayer and contains substantially no surfactant, and wherein the first and second water soluble components are present in relative amounts such that the film rapidly disintegrates in the oral environment to release the active ingredient.
a first water soluble component having a molecular weight below about 60,000 daltons;
a second water soluble component having a molecular weight greater than about 60,000 daltons; and a pharmaceutically or cosmetically active ingredient;
wherein the film is in the form of a monolayer and contains substantially no surfactant, and wherein the first and second water soluble components are present in relative amounts such that the film rapidly disintegrates in the oral environment to release the active ingredient.
32. The film of claim 31 wherein at least one of the first and second water soluble components comprises a cellulose derivative polymer.
33. The film of claim 31 wherein the second water soluble component has a molecular weight of about 60,000 to about 500,000 daltons.
34. The film of claim 31 wherein the second water soluble components comprises hydroxypropyl cellulose.
35. The film of claim 31 wherein at least one of the first and second water soluble components comprises hydroxypropyl methylcellulose.
36. The film of claim 31 wherein the first and second water soluble components are water soluble polymers.
37. The film of claim 36 wherein the second water soluble polymer comprises cellulose derivative polymers having a molecular weight in the range of about 60,000 to about 500,000 daltons, and wherein the first water soluble polymer comprises cellulose derivative polymers having a molecular weight of about 5,000 to about 60,000 daltons.
38. The film of claim 36 wherein the concentration of the first water soluble polymer is about 2% to 10% of the weight of the film and wherein the concentration of the second water soluble polymer is about 2% to 10% of the weight of the film.
39. The film of claim 31 wherein the film is mucoadhesive.
40. The film of claim 31 wherein the film disintegrates in less than about 60 seconds after contact with a mucous membrane.
41. The film of claim 31 wherein the film is in a unit dosage form.
42. The film of claim 31 wherein the film has a thickness of about 20 microns to about 1200 microns.
43. The film of claim 31 wherein the film is part of a multilayer device.
44. The film of claim 31 further comprising a starch component.
45. The film of claim 44 wherein the concentration of the starch component is about 2% to 50% of the weight of the film.
46. The film of claim 31 further comprising a glucose component.
47. The film of claim 46 wherein the concentration of the glucose component is about 2% to 20% of the weight of the film.
43. The film of claim 46 wherein the glucose component comprises maltodextrin.
49. The film of claim 31 further comprising a plasticizer and/or humectant.
50. The film of claim 49 wherein the concentration of the plasticizer and/or humectant is about 3% to 30% of the weight of the film.
51. The film of claim 49 wherein the plasticizer is selected from the group consisting of sorbitol, polyethylene glycol, polyethylene oxide.
52. The film of claim 31 further comprising a filler.
53. The film of claim 52 wherein the active ingredient is present as a dispersed phase.
54. The film of claim 53 wherein the active ingredient is a taste masked drug.
55. The film of claim 54, wherein the active ingredient is selected from the group consisting of diphenhydramine and dextromethorphan.
56. The film of claim 54 wherein the filler is a dispersed particle.
57. The film of claim 56 wherein the filler comprises titanium oxide.
58. The film of claim 54 wherein the filler comprises excess active ingredient beyond the saturation point of the active ingredient in the film.
59. The film of claim 52 wherein the filler comprises microcrystalline cellulose.
60. The film of claim 52 wherein the filler comprises gas.
61. The film of claim 60 wherein the gas comprises air.
62. A method of administering the composition of claim 31 wherein the composition is placed into the oral cavity for a sufficient period of time to disintegrate and release the active ingredient.
63. A dissolvable film for delivering a pharmaceutical or cosmetic agent, comprising:
a first hydroxypropyl methylcellulose polymer having a molecular weight of about 30,000 daltons;
a second hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose having a molecular weight of about 140,000 daltons;
taste masked dextromethorphan;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
a first hydroxypropyl methylcellulose polymer having a molecular weight of about 30,000 daltons;
a second hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose having a molecular weight of about 140,000 daltons;
taste masked dextromethorphan;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
64. The film of claim 63 further comprising polyvinyl pyrrolidone.
65. The film of claim 63 wherein the plasticizer is selected from the group consisting of polyethylene glycol and polyethylene oxide.
66. The film of claim 63 wherein the glucose component comprises maltodextrin.
67. A dissolvable film for delivering a pharmaceutical or cosmetic agent, comprising:
a hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose polymer having a molecular weight of about 140,000 daltons;
polyvinyl pyrrolidone;
taste masked dextromethorphan;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
a hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose polymer having a molecular weight of about 140,000 daltons;
polyvinyl pyrrolidone;
taste masked dextromethorphan;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
68. The film of claim 67 wherein the plasticizer is selected from the group consisting of polyethylene glycol and polyethylene oxide.
69. A dissolvable film for delivering a pharmaceutical or cosmetic agent, comprising:
a first hydroxypropyl methylcellulose polymer having a molecular weight of about 30,000 daltons;
a second hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose having a molecular weight of about 140,000 daltons;
taste masked diphenhydramine;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
a first hydroxypropyl methylcellulose polymer having a molecular weight of about 30,000 daltons;
a second hydroxypropyl methylcellulose polymer having a molecular weight of about 90,000 daltons;
a hydroxypropyl cellulose having a molecular weight of about 140,000 daltons;
taste masked diphenhydramine;
instant starch;
a glucose component; and a plasticizer;
the film being essentially free of surfactants.
70. The film of claim 69 wherein the plasticizer comprises polyethyene glycol.
71. The film of claim 69 wherein the glucose component comprises maltodextrin.
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PCT/US2004/035208 WO2005039499A2 (en) | 2003-10-24 | 2004-10-22 | Rapidly disintegrating film |
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CA2543324C true CA2543324C (en) | 2011-02-01 |
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CA2543324A Active CA2543324C (en) | 2003-10-24 | 2004-10-22 | Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents |
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CA2543350A Active CA2543350C (en) | 2003-10-24 | 2004-10-22 | Disintegratable films for diagnostic devices |
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WO2005039499A2 (en) | 2005-05-06 |
US20050118217A1 (en) | 2005-06-02 |
US7727466B2 (en) | 2010-06-01 |
EP1695094A2 (en) | 2006-08-30 |
EP1680079A2 (en) | 2006-07-19 |
EP1680079A4 (en) | 2008-01-02 |
JP2007514135A (en) | 2007-05-31 |
DK1695094T3 (en) | 2013-09-16 |
AU2004284080A1 (en) | 2005-05-06 |
WO2005040228A3 (en) | 2006-03-09 |
CA2543350A1 (en) | 2005-05-06 |
US20130095156A1 (en) | 2013-04-18 |
US20080299005A1 (en) | 2008-12-04 |
ES2426990T3 (en) | 2013-10-28 |
US9937123B2 (en) | 2018-04-10 |
US20090142850A1 (en) | 2009-06-04 |
US9585961B2 (en) | 2017-03-07 |
CA2543350C (en) | 2011-04-26 |
AU2004284080B2 (en) | 2008-10-02 |
US20170128358A1 (en) | 2017-05-11 |
WO2005039499A3 (en) | 2005-10-06 |
WO2005040228A2 (en) | 2005-05-06 |
JP4563393B2 (en) | 2010-10-13 |
US7470397B2 (en) | 2008-12-30 |
CA2543324A1 (en) | 2005-05-06 |
JP4838723B2 (en) | 2011-12-14 |
AU2004283721A1 (en) | 2005-05-06 |
AU2004283721B2 (en) | 2009-08-13 |
JP2007509172A (en) | 2007-04-12 |
EP1695094B1 (en) | 2013-06-19 |
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