LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME

1 - 24 . (canceled)

25 . A pharmaceutical composition comprising from about 0.5 to about 9 mg of doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and from about 20% to about 99.9% w/w silicified microcrystalline cellulose.

26 . The composition of claim 25 , wherein the silicified microcrystalline cellulose (SMCC) is provided in an amount of about 92% to about 99.8% W/W.

27 . The composition of claim 25 , further comprising from about 0.1 to about 1.5% w/w colloidal silicon dioxide.

28 . The composition of claim 25 , further comprising from about 0.25 to about 1.5% w/w magnesium stearate.

29 . The composition of claim 25 , wherein the doxepin is provided in an amount of about 0.8 to about 2 mg.

30 . The composition of claim 29 , wherein the doxepin is provided in an amount of about 1 mg.

31 . The composition of claim 29 , wherein the SMCC is provided in an amount of about 98.5% w/w.

32 . The composition of claim 25 , wherein the doxepin is provided in an amount of about 2.5 to about 4 mg.

33 . The composition of claim 32 , wherein the doxepin is provided in an amount of about 3 mg.

34 . The composition of claim 32 , wherein the SMCC is provided in an amount of about 96.7% w/w.

35 . The composition of claim 25 , wherein the doxepin is provided in an amount of about 5.5 to about 7 mg.

36 . The composition of claim 35 , wherein the doxepin is provided in an amount of about 6 mg.

37 . The composition of claim 35 , wherein the SMCC is provided in an amount of about 94% w/w.

38 . The composition of claim 25 , wherein the composition is in the form of a tablet, a film coated tablet, a capsule, a gel cap, a caplet, a pellet, or a bead.

39 . The composition of claim 38 , wherein the composition is in the form of a film coated tablet.

40 . The composition of claim 25 , wherein the composition has a total weight of about 50 mg to about 500 mg.

41 . (canceled)

42 . The composition of claim 40 , wherein the composition has a total weight of about 150 mg.

43 . (canceled)

44 . The pharmaceutical composition of claim 82 , wherein the composition comprises at least 80% release of doxepin within 15 minutes using compendial method for measuring dissolution of doxepin.

45 - 49 . (canceled)

50 . The pharmaceutical composition of claim 82 , wherein the composition is in the form of a tablet comprising from about 0.5 to about 9 mg doxepin or a pharmaceutically acceptable salt or prodrug of doxepin, the tablet having a hardness value of at least 2 Kp.

51 - 54 . (canceled)

55 . The tablet of claim 50 , having a hardness value of about 12 Kp.

56 . (canceled)

57 . The pharmaceutical composition of claim 82 , wherein the composition is in the form of a tablet comprising from about 0.5 to about 9 mg doxepin or a pharmaceutically acceptable salt or prodrug of doxepin, the tablet having a friability value of 1% or less.

58 - 59 . (canceled)

60 . The tablet of claim 56 , having a friability value of about 0.25%.

61 . The pharmaceutical composition of claim 82 , wherein the pharmaceutical composition comprises from about 0.5 to about 9 mg doxepin or a pharmaceutically acceptable salt or prodrug of doxepin, the composition has a disintegration time of about 1 minute per USP protocols.

62 - 66 . (canceled)

67 . The pharmaceutical composition of claim 82 , wherein the composition has at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in 0.1 N HCl or Simulated Gastric Fluid USP without enzymes.

68 - 72 . (canceled)

73 . The composition of claim 82 , having at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 4.5 buffer.

74 . The composition of claim 82 , having at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopoeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.

75 - 78 . (canceled)

79 . The composition of claim 73 , having at least a 90 percent release rate at 30 minutes.

80 - 81 . (canceled)

82 . A pharmaceutical composition comprising 0.5 to 9 mg doxepin or a pharmaceutically acceptable salt or prodrug of doxepin, the composition having one or more of the characteristics selected from the group consisting of: a hardness value of at least 2 Kp, a friability value of 1% or less, a disintegration time of about 1 minute as per USP protocols, at least an 80% release of doxepin within 15 minutes using compendial method for measuring dissolution of doxepin, at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in 0.1 N HCl or Simulated Gastric Fluid USP without enzymes, at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia C(SP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 4.5 buffer, and at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.

83 . A batch of at least 50 unit dosage forms, each comprising from about 0.5 to about 9 mg doxepin, a doxepin salt or a doxepin prodrug, and said batch having content uniformity values between about 85% to 115% of label claim.

84 . The batch of unit dosage forms of claim 83 having content uniformity values of between about 90% to 110% of label claim.

85 . The batch of unit dosage forms of claim 83 having a content uniformity values of between about 95% to 105% of label claim.

86 - 89 . (canceled)

90 . A batch of unit dosage forms, each comprising from about 0.5 to about 9 mg doxepin, a doxepin salt or a doxepin prodrug, having a content uniformity percent relative standard deviation of less than 5%.

91 . (canceled)

92 . The batch of unit dosage forms of claim 90 , having a content uniformity percent relative standard deviation of less than 3%.

93 - 94 . (canceled)

95 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of claim 25 to said individual.

96 - 97 . (canceled)

98 . A method of making a doxepin dosage form comprising combining from about 0.5 to about 9 mg doxepin, doxepin salt or doxepin prodrug, and about 20% to about 99.9% silicified microcrystalline cellulose.

99 . The method of claim 98 , wherein the silicified microcrystalline cellulose is provided in amount of about 92% to about 99.8% w/w.

100 - 138 . (canceled)

139 . A method of preparing a uniform low-dose doxepin pre-blend comprising serially diluting and mixing a low concentration of doxepin with higher concentration formulation excipients.

140 - 155 . (canceled)

156 . A pharmaceutical unit dosage form, comprising:

doxepin, a pharmaceutically-acceptable salt thereof or a prodrug thereof in an amount equivalent to about 1, 3 or 6 mg doxepin hydrochloride;

one or more pharmaceutically-acceptable excipients; and optionally,

a capsule or coating;

wherein the excipients and any capsule or coating are selected to provide a swallowable unit dosage that is at least externally solid and that has dissolution and bioavailablity characteristics such that after administration to a 70 kg human, the dosage form provides a plasma concentration of at least 0.05 ng/mL doxepin within a time frame of not more than about 90 minutes.

157 . A pharmaceutical unit dosage form, comprising:

doxepin, a pharmaceutically-acceptable salt thereof or a prodrug thereof in an amount equivalent to about 3 or 6 mg doxepin hydrochloride;

one or more pharmaceutically-acceptable excipients; and optionally,

a capsule or coating;

wherein the excipients and any capsule or coating are selected to provide a swallowable unit dosage that is at least externally solid and that has dissolution and bioavailablity characteristics such that after administration to a 70 kg human, the dosage form provides a plasma concentration of at least 0.1 ng/mL doxepin within a time frame of not more than about 60 minutes.

158 . The unit dosage form of Claim 157 , wherein the dosage form is selected from a tablet, a film coated tablet, a capsule, a pill, a caplet, a gel cap, a pellet, a bead, and a dragee.

159 . The unit dosage form of claim 158 , wherein the dosage form is a film coated tablet.

160 - 161 . (canceled)

162 . The unit dosage form of claim 156 , wherein the doxepin, the pharmaceutically-acceptable salt thereof or the prodrug thereof is in an amount equivalent to about 1 mg doxepin hydrochloride.

163 . The unit dosage form of claim 156 , wherein the doxepin, the pharmaceutically-acceptable salt thereof or the prodrug thereof is in an amount equivalent to about 3 mg doxepin hydrochloride.

164 . The unit dosage form of claim 156 , wherein the doxepin, the pharmaceutically-acceptable salt thereof or the prodrug thereof is in an amount equivalent to about 6 mg doxepin hydrochloride.

165 - 167 . (canceled)

168 . A method of minimizing agglomeration of doxepin in a low dose doxepin production process, comprising using a cone mill or a co mill to blend the doxepin and one or more fillers.

169 . A pharmaceutical dosage form, comprising

from about 0.5 mg to about 7 mg doxepin, a pharmaceutically-acceptable salt thereof or a prodrug thereof;

one or more pharmaceutically-acceptable excipients; and optionally,

a capsule or coating;

wherein the excipients and any capsule or coating provide a swallowable unit dosage form that after administration results in an AUC from about 1.4 to about 22.8 ng*h/mL.

170 - 172 . (canceled)

173 . A pharmaceutical dosage form, comprising

from about 0.5 mg to about 7 mg doxepin, a pharmaceutically-acceptable salt thereof or a prodrug thereof,

one or more pharmaceutically-acceptable excipients; and optionally,

a capsule or coating;

wherein the excipients and any capsule or coating provide a swallowable unit dosage form that after administration results in a C max about 0.15 ng/mL to about 1.24 ng/mL.

174 - 176 . (canceled)

177 . A pharmaceutical composition comprising from about 0.5 to about 9 mg of doxepin, or a pharmaceutically acceptable salt or a prodrug thereof, and at least one filler, wherein the at least one filler is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, lactose, a compressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic, calcium carbonate DC, and a calcium silicate.

178 . The composition of claim 177 , further comprising at least a second filler selected from the group consisting of microcrystalline cellulose, lactose, compressible sugars, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic, and calcium carbonate DC.

179 . The composition of claim 177 , further comprising a lubricant selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, and polyethylene glycd.

180 . The composition of claim 177 , further comprising a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, pregelatinized starch, corn starch, alginic acid, and ion exchange resin.

181 . The composition of claim 177 , further comprising a supplemental binder selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, and sodium carboxy methylcellulose.