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Low-dose doxepin formulations and methods of making and using the same

a technology of doxepin and low dose, which is applied in the direction of biocide, drug composition, organic non-active ingredients, etc., can solve the problems of complex and expensive equipment, complex granulation process, and difficulty in achieving acceptable content uniformity, and achieves the effect of minimizing fluidization, minimizing fluidization, and high content uniformity

Inactive Publication Date: 2009-03-19
SOMAXON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention relates to low dose doxepin formulations and methods of manufacturing them. The formulations have improved physical properties, such as uniform drug content, fast dissolution, and good flow properties. The methods of manufacturing the formulations are economical and efficient. The formulations can be in the form of tablets, film coated tablets, capsules, or other suitable dosage forms. The technical effects of the invention include improved patient compliance, faster onset of drug action, and better stability and palatability of the dosage forms."

Problems solved by technology

However, efficient mixing and acceptable content uniformity are difficult to achieve for low dose dosage forms.
Mixed particle sized powders can segregate due to operational vibrations, resulting in final dosage forms with poor drug or active pharmaceutical ingredient (API) content uniformity.
Granulation processes may be energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.

Method used

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  • Low-dose doxepin formulations and methods of making and using the same
  • Low-dose doxepin formulations and methods of making and using the same
  • Low-dose doxepin formulations and methods of making and using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

1 mg, 3 mg, and 6 mg Formulations

[0147]Examples of 1 mg, 3 mg, and 6 mg formulations are provided in Table 1 and Table 2.

TABLE 1Non-film coated tablets1 mg3 mg6 mgItemMaterial%Mg / tab%Mg / tab%Mg / tab1Doxepin HCl0.7531.132.263.394.526.782Silicified98.53147.8096.71145.0794.00141.00MicrocrystallineCellulose3Colloidal Silicon0.160.240.470.710.881.32Dioxide4FD&C Blue 1 Al Lake——0.050.080.020.0310-13%5DC Yellow 10 Al0.040.06——0.080.12Lake 36-42%6FD&C Yellow #6 Al0.010.015————Lake 15-18%7Magnesium Stearate0.500.750.500.750.500.75Totals:100.00150.00100.00150.00100.00150.00

TABLE 2Film-coated tablets1 mg3 mg6 mgItemMaterial%Mg / tab%Mg / tab%Mg / tab1Doxepin HCl0.7241.132.173.394.356.782Silicified94.79147.8893.04145.1590.48141.15MicrocrystallineCellulose3Colloidal Silicon0.150.240.460.710.851.32Dioxide4Magnesium Stearate0.480.750.480.750.480.755Film coat3.863.863.86Totals:100.00156.00100.00156.00100.00156.00

example 2

Doxepin Multimedia Dissolution Study

[0148]The dissolution of 1 mg (Lot Number 3047751R) and 6 mg (Lot Number 3047758R) SMCC-formulated, doxepin tablets in Simulated Gastric Fluid without enzymes (pH 1.2), 0.05 M acetate buffer (pH 4.5) and Simulated Intestinal Fluid USP without enzymes (pH 6.8) was measured with USP Apparatus 2 at 50 rpm using 900 mL of 37° C. i 0.5° C. dissolution media at 3, 5, 10, 15 and 30 minute time points. The average (n=12 tablets) percent doxepin released for each dosage strength in the two media at each time point is reported in Table 3.

TABLE 3Simulated Gastric0.05 M AcetateSimulated IntestinalFluid (pH 1.2)Buffer (pH 4.5)Fluid (pH 6.8)Time point1 mg6 mg1 mg6 mg1 mg6 mg3minutes*83% 70%*84% 71%55% 57%5minutes*91%*85%*93%*80%69% 72%10minutes*94%*90%*99%*91%79%*81%15minutes*96%*94%*101% *95%*81% *84%30minutes*97%*97%*102% *98%*86% *87%

[0149]The conditions with an asterisk in Table 2 achieve a Q value of 80% with none of the individual dissolution values falli...

example 4

Blend Uniformity

[0152]Due to the very low concentrations of drug substance in these tablet formulations, the blending process included preparation of a drug substance pre-blend created by layering doxepin HCl between additions of SMCC, followed by mixing. The uniformity of unit dose potency was further promoted by serially diluting and mixing the drug substance pre-blend with the remaining SMCC and colloidal silicon dioxide. FIG. 1 graphically illustrates the preparation of a drug substance pre-blend, which can result in the uniform distribution of drug substance in the drug product.

[0153]Thus, some embodiments relate to methods of improving blend uniformity, for example, by layering low dose doxepin with a filler, such as SMC C. It should be noted that other fillers can be used rather than SMCC or in addition to SMCC. Furthermore, uniformity can be improved by serially diluting the mixtures as described above with SMCC or any other filler or combination of fillers.

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Abstract

The invention disclosed herein generally relates to low-dose oral doxepin pharmaceutical formulations and the use of these formulations to promote sleep.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 911,806 filed on Apr. 13, 2007, both entitled LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME; the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]Embodiments of the invention disclosed herein relate to low-dose oral doxepin pharmaceutical formulations, methods of making the formulations, and the use of these formulations to promote sleep.BACKGROUND OF THE INVENTION[0003]Low doses of doxepin can be used to treat sleep disorders, such as insomnia. Sleep is essential for health and quality of life. Insomnia is a growing health problem in the United States. It is believed that more than 10-15 million people suffer from chronic insomnia and up to an additional 70 million people suffer from some form of insomnia each year. Insomnia is a condition characterized by difficulty falling asleep (sleep ons...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/20A61K9/28A61K31/352A61P25/20
CPCA61K9/2009A61K31/335A61K9/2806A61K9/2054A61P25/20A61K47/02A61K47/38
Inventor SCHIOPPI, LUIGIDORSEY, BRIAN TALMADGESKINNER, MICHAELCARTER, JOHNMANSBACH, ROBERTJOCHELSON, PHILIPROGOWSKI, ROBERTA L.CASSEDAY, CARAPERRY, MEREDITHKNOX, BRYAN
Owner SOMAXON PHARMA
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