Oral transmucosal drug delivery system
Inventors
Ahmed, Salah U. • Zu, Yanming • Neelam, Karunakar • MUNTAZIM, Saad • Chowdhury, Tahseen A. • TIAN, Shiying
Assignees
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Publication Number
US-9795616-B2
Publication Date
2017-10-24
Expiration Date
Abstract
This invention relates to dosage forms for the delivery of drugs across the oral mucosa having improved transmucosal permeability. More specifically, the invention relates to an oral transmucosal dosage form comprising a primary vehicle comprising a crystallization inhibition agent (CIA) system and a drug, and a secondary vehicle. It also relates to methods of designing and making this dosage form, methods of administering this dosage form and methods of packaging the dosage forms.
Core Innovation
The invention relates to an oral transmucosal dosage form comprising a primary vehicle and a secondary vehicle. The primary vehicle includes a crystallization inhibition agent selected from hydrophilic, lipophilic, amphiphilic, or combinations, and an estrogen combined with the crystallization inhibition agent to form the primary vehicle, wherein the crystallization inhibition agent reduces the crystallinity of the estrogen by at least 50% as measured by DSC relative to essentially pure estrogen not combined with the crystallization inhibition agent.
The secondary vehicle comprises a hydrophilic water soluble component and a texturizing agent. The oral transmucosal dosage form weighs about 250 mg to about 5000 mg, erodes in about 5 to about 60 minutes, but does not disintegrate, and is solid at 37° C.
The disclosed implementations include crystallization inhibition agent classes and examples such as PEGs, PVP, polyvinylpyrrolidone copolymers, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, oleic acid, hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, polyethylene glycol glycerides, vitamin E-TPGS, sucrose mono-, di-, and tri-esters with fatty acids, and lecithin. Characterization includes DSC thermograms using heat of fusion (ΔHf) and DSC-based decrystallization potential (QΔHf=0), together with XRPD diffractograms for loss of crystallinity.
Claims Coverage
The document provides three independent claim sets covering the dosage form and two methods of making the dosage form. Across the independent claims, the core inventive limitation is that the selected crystallization inhibition agent reduces estrogen crystallinity by at least 50% as measured by DSC, together with defined primary and secondary vehicle structures and oral transmucosal performance characteristics.
Oral transmucosal dosage form with estrogen-CIA primary vehicle and texturized secondary vehicle
An oral transmucosal dosage form comprising a primary vehicle comprising a crystallization inhibition agent selected from hydrophilic, lipophilic, amphiphilic, or any combination, and an estrogen combined with the crystallization inhibition agent to form the primary vehicle, wherein the crystallization inhibition agent reduces the crystallinity of the estrogen by at least 50% as measured by DSC relative to essentially pure estrogen not combined with the crystallization inhibition agent; and a secondary vehicle comprising a hydrophilic water soluble component and a texturizing agent, wherein the oral transmucosal dosage form weighs about 250 mg to about 5000 mg, erodes in about 5 to about 60 minutes, but does not disintegrate, and is solid at 37° C.
Method of making via molten CIA-estrogen, cooling, milling, secondary vehicle addition, and compression
A method of making an oral transmucosal dosage form comprising providing a crystallization inhibition agent selected from hydrophilic, lipophilic, amphiphilic, or any combination; applying heat to melt the crystallization inhibition agent and mixing to create a molten mixture; adding an estrogen to the molten mixture and mixing; cooling the molten mixture and milling to form a powder primary vehicle; adding a secondary vehicle comprising a hydrophilic water soluble component and a texturizing agent to the powder primary vehicle and mixing; and compressing into an oral transmucosal dosage form, wherein the transmucosal dosage form is about 250 mg to about 5000 mg, erodes in about 5 to about 60 minutes, but does not disintegrate, and is solid at 37° C, and wherein the crystallization inhibition agent reduces the crystallinity of the estrogen by at least 50% as measured by DSC relative to essentially pure estrogen not combined with the crystallization inhibition agent.
Method of making via solubilization, solvent evaporation to form primary blend, powder milling, additional secondary vehicle mixing, and compression
A method of making an oral transmucosal dosage form comprising mixing an estrogen with one or more crystallization inhibition agent(s) selected from hydrophilic, lipophilic, amphiphilic, or any combination; solubilizing the mixture in a solvent or mixture of solvents; mixing the solution with a secondary vehicle; evaporating the solvent(s) to form a combination of estrogen and crystallization inhibition agent(s) mixed uniformly with the secondary vehicle as a primary blend; milling the primary blend to form a powder; mixing the powder with additional secondary vehicle; and compressing the blend into an oral transmucosal dosage form, wherein the oral transmucosal dosage form weighs about 250 mg to about 5000 mg, erodes in about 5 to 60 minutes, but does not disintegrate and is solid at 37° C, wherein the secondary vehicle comprises a hydrophilic water soluble component and a texturizing agent, and wherein the crystallization inhibition agent reduces the crystallinity of the estrogen by at least 50% as measured by DSC relative to essentially pure estrogen not combined with the crystallization inhibition agent.
Across the independent claims, the coverage centers on an oral transmucosal dosage form where a crystallization inhibition agent selected from hydrophilic, lipophilic, amphiphilic, or combinations is combined with an estrogen in the primary vehicle such that DSC shows at least a 50% crystallinity reduction versus essentially pure estrogen, together with a secondary vehicle having a hydrophilic water soluble component and a texturizing agent and with specified erosion, non-disintegration, and solid-at-37° C characteristics. The independent method claims further define two manufacturing routes that end in an oral transmucosal dosage form meeting those same functional constraints and the DSC-based crystallinity reduction requirement.
Stated Advantages
Improves dissolution and transmucosal permeability/absorption while maintaining estrogen in a decrystallized/molecular dispersion state.
Avoids issues of first-pass metabolism and gastrointestinal conditions.
Increases drug release independence from saliva volume effects.
Improves diffusion/permeability across polysulfone and human buccal tissue models.
Provides synergistic effects from binary/ternary CIA systems.
Documented Applications
Oral transmucosal delivery/administration of an estrogen using a dosage form that erodes in about 5 to about 60 minutes, does not disintegrate, and is solid at 37° C.
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