Solid oral film dosage forms and methods for making same

Abstract

Improved pharmaceutical solid oral film dosage forms for the buccal and/or sublingual delivery of pharmaceutical, nutraceutical or cosmetic ingredients are endowed with instant hydration potential and complete dissolution potentially enabling the active ingredient to become immediately available for enhanced buccal and/or sublingual absorption and/or reduced absorption through the gastrointestinal route. The improved delivery systems for solubilizing and stabilizing pharmaceutically active ingredients exhibit enhanced stability by the use of a combination of crystallization inhibitors, which together can maintain the active ingredient in a desired plurality of particles in an effective size range within a polymeric film matrix.

1 . A oral film dosage form that maintains a plurality of active ingredient particles in an effective particle size range to maintain reduced structural order, and/or improve solubility and bioavailability of the active, comprising:
 at least one pharmaceutically active ingredient in the form of particles and capable of existing in amorphous and crystalline forms;   at least one primary crystallization inhibitor present in an amount that inhibits growth and/or agglomeration of the particles of the pharmaceutically active ingredient;   at least one liquid crystallization inhibitor present in an amount that enhances inhibition of crystallization and/or agglomeration of the particles of the pharmaceutically active ingredient; and   at least one plasticizer present in an amount that is effective to increase flexibility and elasticity of the film dosage form.   
     
     
         2 . The dosage form of  claim 1 , wherein said primary crystallization inhibitor is selected from polyvinyl pyrrolidone, polyethylene oxide, or poloxamer. 
     
     
         3 . The dosage form of  claim 1 , wherein said primary crystallization inhibitor is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, or hydroxypropylmethyl cellulose, carboxymethyl cellulose. carbomers, pregelatinized modified starch, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthane gum, tragacantha, guar gum, acacia gum, arabic gum or carboxyvinyl copolymers, polyethylene glycols, polyoxyl glycerides, propylene glycol esters, diethylene glycol esters, glyceryl esters, polyoxyethylene sorbitan fatty acid esters; ethylene alkyl ethers; polyoxyethylene alkyl phenols; polyethylene glycol glycerol fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. 
     
     
         4 . The dosage form of  claim 1 , wherein said plasticizer is selected from triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, dibutyl sebacate, triacetine, or derivatives thereof . 
     
     
         5 . The dosage form of  claim 1 , wherein said composition further comprises at least one surfactant. 
     
     
         6 . The dosage form of  claim 1 , wherein said composition further comprises at least one penetration enhancer selected from benzalkonium chloride, cetylpyridinium chloride, cyclodextrins, dextran sulfate, lauric acid/propylene glycol, menthol, oleic acid, oleic acid derivatives, polyoxyethylene, polysorbates, sodium EDTA, sodium lauryl sulfate or sodium salicylate. 
     
     
         7 . The dosage form of  claim 1 , wherein said composition further comprises at least one sweetener. 
     
     
         8 . The dosage form of  claim 1 , wherein said composition further comprises at least one colorant. 
     
     
         9 . The dosage form of  claim 1 , wherein said composition further comprises at least one taste masker. 
     
     
         10 . The dosage form of  claim 1 , wherein said composition further comprises at least one antioxidant. 
     
     
         11 . The dosage form of  claim 1 , wherein said composition further comprises at least one flavoring agent. 
     
     
         12 . The dosage form of  claim 1 , wherein said composition further comprises at least one mucoadhesive polymer. 
     
     
         13 . The dosage form of  claim 1 , wherein said composition further comprises at least one pharmaceutically acceptable excipient. 
     
     
         14 . The dosage form of  claim 1 , wherein said pharmaceutically active ingredient is selected from: hypnotics, sedatives, antiepileptics, awakening agents, psychoneurotropic agents, neuromuscular blocking agents, antispasmodic agents, antihistaminics, antiallergics, antidiarrhetics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussive expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumor agents, antibiotics and chemotherapeutics, and narcotics. 
     
     
         15 . A method of administering a therapeutically effective amount of at least one active ingredient present as an effectively stabilized plurality of particles in an oral film dosage form, comprising:
 disposing a pharmaceutically active ingredient in the form of particles that is capable of existing in both amorphous and crystalline forms into a suitable liquid medium containing at least one primary crystallization inhibitor present in an amount that inhibits growth and/or agglomeration of the particles of the pharmaceutically active ingredient, at least liquid crystallization inhibitor present in an amount that enhances inhibition of crystallization and/or agglomeration of the particles of the pharmaceutically active ingredient, and at least one plasticizer present in an amount that is effective to increase flexibility and elasticity of the film dosage form;   casting and drying the composition to make a solid oral dosage form;   applying the dosage form in a subject's mouth and having the subject maintain the dosage form in the subject's mouth until an effective quantity of the dosage form has dissolved, whereby a therapeutic effect is achieved.   
     
     
         16 . The method of  claim 15 , wherein said primary crystallization inhibitor is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, or hydroxypropylmethyl cellulose, carboxymethyl cellulose. carbomers, pregelatinized modified starch, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthane gum, tragacantha, guar gum, acacia gum, arabic gum or carboxyvinyl copolymers, polyethylene glycols, polyoxyl glycerides, propylene glycol esters, diethylene glycol esters, glyceryl esters, polyoxyethylene sorbitan fatty acid esters; ethylene alkyl ethers; polyoxyethylene alkyl phenols; polyethylene glycol glycerol fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. 
     
     
         17 . The method of  claim 15 , wherein the primary crystallization inhibitor is selected from polyethylene glycols, polyoxyl glycerides, propylene glycol esters, diethylene glycol esters, glyceryl esters, polyoxyethylene sorbitan fatty acid esters; ethylene alkyl ethers; polyoxyethylene alkyl phenols; polyethylene glycol glycerol fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. 
     
     
         18 . The method of  claim 15 , wherein said plasticizer is selected from triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, dibutyl sebacate, triacetine, or derivatives thereof . 
     
     
         19 . The method of  claim 15 , wherein the liquid medium is non-polar. 
     
     
         20 . The method of  claim 15 , wherein the liquid medium is polar. 
     
     
         21 . An oral film dosage form demonstrating a solubilization profile of at least one active ingredient resulting from the combination of two or more distinct, effectively stabilized, particle size ranges, comprising:
 at least one primary crystallization inhibitor present in an amount that inhibits growth and/or agglomeration of the particles of the pharmaceutically active ingredient;   at least one liquid crystallization inhibitor present in an amount that enhances inhibition of crystallization and/or agglomeration of the particles of the pharmaceutically active ingredient; and   at least one plasticizer present in an amount that is effective to increase flexibility and elasticity of the film dosage form.   
     
     
         22 . The dosage form of  claim 21 , wherein said primary crystallization inhibitor is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, or hydroxypropylmethyl cellulose, carboxymethyl cellulose. carbomers, pregelatinized modified starch, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthane gum, tragacantha, guar gum, acacia gum, arabic gum or carboxyvinyl copolymers, polyethylene glycols, polyoxyl glycerides, propylene glycol esters, diethylene glycol esters, glyceryl esters, polyoxyethylene sorbitan fatty acid esters; ethylene alkyl ethers; polyoxyethylene alkyl phenols; polyethylene glycol glycerol fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. 
     
     
         23 . The dosage form of  claim 21 , wherein said liquid crystallization inhibitor is selected from polyethylene glycols, polyoxyl glycerides, propylene glycol esters, diethylen glycol esters, glyceryl esters, polyoxyethylene sorbitan fatty acid esters; ethylene alkyl ethers; polyoxyethylene alkyl phenols; polyethylene glycol glycerol fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. 
     
     
         24 . The dosage form of  claim 21 , wherein said plasticizer is selected from triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, dibutyl sebacate, triacetine, or derivatives thereof . 
     
     
         25 . The dosage form of  claim 21 , wherein said composition further comprises at least one surfactant. 
     
     
         26 . The dosage form of  claim 21 , wherein said composition further comprises at least one penetration enhancer selected from benzalkonium chloride, cetylpyridinium chloride, cyclodextrins, dextran sulfate, lauric acid/propylene glycol, menthol, oleic acid, oleic acid derivatives, polyoxyethylene, polysorbates, sodium EDTA, sodium lauryl sulfate or sodium salicylate 
     
     
         27 . The dosage form of  claim 21 , wherein said composition further comprises at least one sweetener. 
     
     
         28 . The dosage form of  claim 21 , wherein said composition further comprises at least one colorant. 
     
     
         29 . The dosage form of  claim 21 , wherein said composition further comprises at least one taste masker. 
     
     
         30 . The dosage form of  claim 21 , wherein said composition further comprises at least one antioxidant. 
     
     
         31 . The dosage form of  claim 21 , wherein said composition further comprises at least one flavoring agent. 
     
     
         32 . The dosage form of  claim 21 , wherein said composition further comprises at least one mucoadhesive polymer. 
     
     
         33 . The dosage form of  claim 21 , wherein said composition further comprises at least one pharmaceutically acceptable excipient 
     
     
         34 . The dosage form of  claim 21 , wherein said pharmaceutically active ingredient is selected from: hypnotics, sedatives, antiepileptics, awakening agents, psychoneurotropic agents, neuromuscular blocking agents, antispasmodic agents, antihistaminics, antiallergics, antidiarrhetics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussive expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumor agents, antibiotics and chemotherapeutics, and narcotics. 
     
     
         35 . The dosage form of  claim 1 , in which the amount of the primary crystallization inhibitor is from 25% to 85% of the mass of the film dosage form. 
     
     
         36 . The dosage form of  claim 35 , in which the amount of the liquid crystallization inhibitor is from 1% to 19% of the mass of the film dosage form. 
     
     
         37 . The dosage form of  claim 36 , in which the amount of the plasticizer is from 2% to 25% of the mass of the film dosage form.