U.S. patent application number 17/408945 was filed with the patent office on 2022-04-14 for low-dose doxepin formulations and methods of making and using the same.
This patent application is currently assigned to Currax Pharmaceuticals LLC. The applicant listed for this patent is Currax Pharmaceuticals LLC. Invention is credited to John Carter, Cara Baron Casseday, Brian Talmadge Dorsey, Philip Jochelson, Bryan Knox, Robert Mansbach, Meredith Perry, Roberta L. Rogowski, Luigi Schioppi, Michael Skinner.
Application Number | 20220110908 17/408945 |
Document ID | / |
Family ID | 1000006052000 |
Filed Date | 2022-04-14 |
![](/patent/app/20220110908/US20220110908A1-20220414-D00001.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00002.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00003.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00004.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00005.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00006.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00007.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00008.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00009.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00010.png)
![](/patent/app/20220110908/US20220110908A1-20220414-D00011.png)
View All Diagrams
United States Patent
Application |
20220110908 |
Kind Code |
A1 |
Schioppi; Luigi ; et
al. |
April 14, 2022 |
Low-Dose Doxepin Formulations And Methods Of Making And Using The
Same
Abstract
The invention disclosed herein generally relates to low-dose
oral doxepin pharmaceutical formulations and the use of these
formulations to promote sleep.
Inventors: |
Schioppi; Luigi; (Escondido,
CA) ; Dorsey; Brian Talmadge; (Encinitas, CA)
; Skinner; Michael; (San Diego, CA) ; Carter;
John; (Keswick, CA) ; Mansbach; Robert; (San
Diego, CA) ; Jochelson; Philip; (San Diego, CA)
; Rogowski; Roberta L.; (Rancho Santa Fe, CA) ;
Casseday; Cara Baron; (San Diego, CA) ; Perry;
Meredith; (El Cajon, CA) ; Knox; Bryan; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Currax Pharmaceuticals LLC |
Brentwood |
TN |
US |
|
|
Assignee: |
Currax Pharmaceuticals LLC
Brentwood
TN
|
Family ID: |
1000006052000 |
Appl. No.: |
17/408945 |
Filed: |
August 23, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16779901 |
Feb 3, 2020 |
11096920 |
|
|
17408945 |
|
|
|
|
15911496 |
Mar 5, 2018 |
10548871 |
|
|
16779901 |
|
|
|
|
15394912 |
Dec 30, 2016 |
9907780 |
|
|
15911496 |
|
|
|
|
13898364 |
May 20, 2013 |
9532971 |
|
|
15394912 |
|
|
|
|
12101917 |
Apr 11, 2008 |
|
|
|
13898364 |
|
|
|
|
60911806 |
Apr 13, 2007 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/335 20130101;
A61K 9/2054 20130101; A61K 9/2009 20130101; A61K 47/02 20130101;
A61K 47/38 20130101; A61K 9/2806 20130101 |
International
Class: |
A61K 31/335 20060101
A61K031/335; A61K 9/28 20060101 A61K009/28; A61K 9/20 20060101
A61K009/20; A61K 47/38 20060101 A61K047/38; A61K 47/02 20060101
A61K047/02 |
Claims
1. A pharmaceutical composition comprising from about 0.5 to about
7 mg of doxepin, or a pharmaceutically acceptable salt or prodrug
thereof, and from about 20% to about 99.9% w/w silicified
microcrystalline cellulose, 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 (USP)
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.
2. The composition of claim 1, wherein the silicified
microcrystalline cellulose (SMCC) is provided in an amount of about
92% to about 99.8% w/w.
3. The composition of claim 1, further comprising from about 0.1 to
about 1.5% w/w colloidal silicon dioxide.
4. The composition of claim 1, further comprising from about 0.25
to about 1.5% w/w magnesium stearate.
5. The composition of claim 1, wherein the doxepin is provided in
an amount of about 2.5 to about 4 mg.
6. The composition of claim 5, wherein the doxepin is provided in
an amount of about 3 mg.
7. The composition of claim 1, wherein the doxepin is provided in
an amount of about 6 mg.
8. A method of manufacturing a doxepin dosage, doxepin salt or
doxepin prodrug form comprising, forming a drug substance pre-blend
by mixing a first filler and doxepin, doxepin salt or doxepin
prodrug; forming a final blend by mixing a second filler and the
drug substance pre-blend; forming a doxepin, doxepin salt or
doxepin prodrug dosage form from the final blend.
9. The method of claim 8, wherein the first filler and the second
filler are selected from the group consisting of silicified
microcrystalline cellulose, microcrystalline cellulose, lactose,
compressible sugars, xylitol, sorbitol, mannitol, pregelatinized
starch, maltodextrin, calcium phosphate dibasic, calcium phosphate
tribasic, and calcium carbonate DC.
10. The method of claim 9, wherein the first and second fillers are
not the same.
11. The method of claim 10, wherein the first or the second filler
is silicified microcrystalline cellulose.
12. The method of claim 9, wherein the first and second fillers are
the same.
13. The method of claim 12, wherein the first and the second filler
is silicified microcrystalline cellulose.
14. The method of claim 8, wherein the drug substance pre-blend or
the final blend comprises an additional filler.
15. The method of claim 14, wherein the additional filler is
selected from the group consisting of silicified microcrystalline
cellulose, microcrystalline cellulose, lactose, compressible
sugars, xylitol, sorbitol, mannitol, pregelatinized starch,
maltodextrin, calcium phosphate dibasic, calcium phosphate
tribasic, and calcium carbonate DC.
16. 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
bioavailability 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.
17. The unit dosage form of claim 16, wherein the time frame to
provide a plasma concentration of at least 0.1 ng/mL is not more
than about 50 minutes.
18. The unit dosage form of claim 16, wherein the doxepin, the
pharmaceutically-acceptable salt thereof or the prodrug thereof is
in an amount equivalent to about 3 mg doxepin hydrochloride.
19. The unit dosage form of claim 16, wherein the doxepin, the
pharmaceutically-acceptable salt thereof or the prodrug thereof is
in an amount equivalent to about 6 mg doxepin hydrochloride.
20. The method of claim 16, wherein the excipients comprises
silicified microcrystalline cellulose.
Description
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
[0001] Any and all priority claims identified in the Application
Data Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57.
FIELD
[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
[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 onset), waking frequently
during the night (fragmented sleep), waking too early (premature
final awakening), and/or waking up feeling un-refreshed. In the
National Sleep Foundation's (NSF) Sleep in America Poll 2005, 42%
of survey respondents reported that they awoke frequently during
the night, 22% of adults reported waking too early and not being
able to return to sleep and 38% reported waking and feeling
un-refreshed.
[0004] Doxepin is a tricyclic compound currently approved for
treatment of depression or anxiety at a daily dose of 75 mg to 300
mg. Non-liquid forms of doxepin are currently available in 10, 25,
50, 75, 100 and 150 mg capsules. Liquid concentrate doxepin is
available in a dosage of 10 mg/mL. It should be noted that some
embodiments can specifically exclude formulations of doxepin in
capsule form, in particular capsules with a powder therein.
Capsules with 10 or more mg of doxepin can be excluded from some
embodiments. Also, gelatin coated capsules with or without a powder
therein can be excluded from some embodiments. Methods of treating
sleep using 10 mg capsules or drug taken (e.g., taking a fraction
of the powder from the capsule) or derived (e.g., diluting material
from a capsule prior to taking) from 10 mg capsules can be
specifically excluded from some embodiments.
[0005] Making low dose formulations can present technical and
economic challenges that are not present for higher dose
formulations. Furthermore, existing doxepin formulations do not
take into account the unique aspects of sleep disorders.
[0006] Embodiments of the invention provide low dose formulations
of doxepin and doxepin compounds, and also address and overcome the
challenges and problems associated with formulating and
manufacturing low-dose doxepin dosage forms.
SUMMARY
[0007] Embodiments of the invention disclosed herein relate to low
dose doxepin formulations. Also, some embodiments relate to
manufacturing processes for the formulations, as well as methods of
using the formulations. In some aspects the formulations have one
or more desirable physical properties, have preferable functional
characteristics, and/or permit efficient and economical
manufacturing of low dose doxepin dosage forms.
[0008] In the development of pharmaceutical dosage forms, it can be
desirable to achieve any of several different objectives. For
example, preferably the dosage form can be uniform with respect to
drug substance content, fast dissolving, stable, easy to swallow,
palatable, and otherwise acceptable to patients in order to
maximize patient compliance. In certain contexts, early and/or
accelerated onset of drug action also can be advantageous. For
example, in the context of sleep, early onset of drug action can be
important due to the discreet window of time in which a patient
needs to sleep. Also in the context of sleep, the dosage form
preferably maintains sleep for a full 7 or 8 hour sleep cycle
without significant next-day sedation.
[0009] Additionally, it may be desirable to have a manufacturing
process that is economical, efficient, robust, and preferably,
simple-requiring a minimal number of steps and/or excipients.
Furthermore, the active ingredient and excipients preferably have
suitable flow properties to ensure efficient mixing and acceptable
content uniformity, weight uniformity, hardness, and friability of
the final dosage form. Good flow properties also may be beneficial
for precise volumetric feeding of the material to a die cavity.
However, efficient mixing and acceptable content uniformity are
difficult to achieve for low dose dosage forms.
[0010] 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.
Active substances with a small particle size mixed with excipients
having a larger particle size will typically segregate or de-mix
during the formulation process. The problem of small particle size
and poor flowability can be addressed by enlarging the particle
size of the active substance, usually by granulation of the active
ingredient either alone or in combination with a filler and/or
other conventional excipients. Granulation processes may be energy
intensive unit operations requiring complicated and expensive
equipment as well as technical skill.
[0011] Extensive laboratory and full-scale research have resulted
in a new and inventive process for directly compressing low-dose
doxepin dosage forms. Accordingly, embodiments of the invention
disclosed herein address and achieve one or more of the
above-mentioned considerations. Some embodiments surprisingly
achieve several or many of the considerations.
[0012] In particular, embodiments disclosed herein relate to
pharmaceutical dosage forms comprising low doses of doxepin
hydrochloride, methods of manufacturing low-dose doxepin dosage
forms, and methods of using the formulations and dosage forms.
Preferably, the low doses of doxepin hydrochloride can be provided
as rapidly dissolving dosage forms, as described herein, which can
be advantageously used for treatment of insomnia. In some aspects,
the formulations have one or more of: improved friability,
compression, dissolution, uniformity, dissolvability, palatability,
and the like. Also, in some aspects, the formulations can permit at
least one or more of: rapid onset, greater and/or more rapid plasma
levels, and the like.
[0013] Additional embodiments disclosed herein relate to new and
economic methods of manufacture for low-dose dosage forms of
doxepin, including, for example, on a large scale. In a preferred
embodiment, the methods of manufacture can achieve uniformity of
drug substance content and overcome segregation issues that can
plague low dose formulations, and can do so in an economical and
efficient manner. Some embodiments of the invention relate to low
dose doxepin formulations that are amenable to direct compression
and that produce a high yield of low dose doxepin dosage forms
having acceptable content uniformity, hardness, and friability.
[0014] Thus, embodiments of the invention disclosed herein relate
to pharmaceutical compositions 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. In one embodiment, silicified
microcrystalline cellulose (SMCC) can be provided in an amount of
about 92% to about 99.8% w/w. The compositions can further comprise
from about 0.1 to about 1.5% w/w colloidal silicon dioxide. In
another embodiment, the compositions further comprise from about
0.25 to about 1.5% w/w magnesium stearate. In another embodiment,
doxepin can be provided in an amount of about 0.8 mg to about 2 mg
or about 1 to about 2 mg. In yet another embodiment, doxepin is
provided in an amount of about 1 mg. SMCC can be provided in an
amount of about 98.5% w/w. In one aspect, doxepin is provided in an
amount of about 2.5 mg to about 4 mg or about 3 to about 4 mg. In
another aspect, doxepin is provided in an amount of about 3 mg. In
one embodiment, SMCC is provided in an amount of about 96.7% w/w.
In another embodiment, doxepin is provided in an amount of about
5.5 to about 7 mg or about 6 to about 7 mg. In one aspect of this
embodiment, doxepin is provided in an amount of about 6 mg. In
another embodiment, SMCC is provided in an amount of about 94% w/w.
The compositions disclosed herein can be in the form of a tablet, a
film coated tablet, a capsule, a gel cap, a caplet, a pellet, a
bead, or the like. In one embodiment, the compositions are in the
form of tablets. In another embodiment, the compositions preferably
are in the form of film coated tablets. In another embodiment, the
compositions each have a total weight of about 50 mg to about 500
mg. In one aspect of this embodiment, the compositions each have a
total weight of 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300
mg, 350 mg, 400 mg, 450 mg, 500 mg, or the like. In one embodiment,
the compositions each have a total weight of about 150 mg.
[0015] Embodiments of the invention also can include pharmaceutical
compositions comprising from about 0.5 to about 9 mg of doxepin, or
a pharmaceutically acceptable salt or prodrug thereof, and at least
one filler. In one embodiment, the filler can be, for example,
silicified microcrystalline cellulose, microcrystalline cellulose,
lactose, a compressible sugar, xylitol, sorbitol, mannitol,
pregelatinized starch, maltodextrin, calcium phosphate dibasic,
calcium phosphate tribasic, calcium carbonate DC, a calcium
silicate, a combinations of one or more of the same, or the like.
In one aspect of this embodiment, the at least one filler can be
silicified microcrystalline cellulose. The silicified
microcrystalline cellulose can be provided in an amount of about
20% to about 99.9% w/w; of about 80% to about 99.8% w/w; or of
about 94% to about 98.5% w/w, for example. The compositions can
further comprise at least one of the following second fillers,
microcrystalline cellulose, lactose, compressible sugars, xylitol,
sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium
phosphate dibasic, calcium phosphate tribasic, calcium carbonate
DC, a combinations of one or more of the same, or the like.
[0016] In one embodiment, the compositions further can comprise at
least one glidant. In one aspect of this embodiment, the glidant
can be, for example, colloidal silicon dioxide. In one embodiment,
the colloidal silicon dioxide can be provided in an amount of about
0.1 to about 1.5% w/w, for example.
[0017] In one embodiment, the compositions further can comprise at
least one lubricant. In one embodiment, the lubricant can be, for
example, magnesium stearate, calcium stearate, sodium stearyl
fumarate, stearic acid, hydrogenated vegetable oil, glyceryl
behenate, polyethylene glycol, a combinations of one or more of the
same, and the like. In one aspect of this embodiment, the lubricant
can be magnesium stearate. In one embodiment, magnesium stearate
can be provided, for example, in an amount of about 0.25 to about
1.5% w/w.
[0018] In one embodiment, the compositions further can comprise at
least one disintegrant or at least one supplemental binder. In one
aspect of this embodiment, the disintegrant can be, for example,
croscarmellose sodium, sodium starch glycolate, crospovidone,
microcrystalline cellulose, pregelatinized starch, corn starch,
alginic acid, ion exchange resin, combinations of one or more of
the same, and the like. In another embodiment, the supplemental
binder can be, for example, hydroxypropyl cellulose,
polyvinylpyrrolidone, methylcellulose, hydroxypropyl
methylcellulose, ethylcellulose, or sodium carboxy methylcellulose,
combinations of one or more of the same, and the like.
[0019] The compositions disclosed herein can be in the form of
tablets, film coated tablets, capsules, gel caps, caplets, pellets,
beads, or the like. The doxepin can be provided, for example, in an
amount of about 0.5 mg to about 9 mg. Also, doxepin can be provided
in an amount of about 1 to about 2 mg. In one embodiment, doxepin
can be provided in an amount of about 1 mg. In another embodiment,
doxepin can be provided in an amount of about 3 to about 4 mg. In
another aspect, doxepin can be provided in an amount of about 3 mg.
In another embodiment, doxepin can be provided in an amount of
about 6 to about 7 mg. In one aspect of this embodiment, doxepin
can be provided in an amount of about 6 mg.
[0020] Embodiments of the invention also provide compositions
comprising from about 0.5 to about 9 mg doxepin having hardness
values of at least 2 Kp, for example. In other embodiments, the
compositions have hardness values of at least 4 Kp, at least 6 Kp,
at least 8 Kp, at least 10 Kp or about 12 Kp, for example.
[0021] There is also provided a tablet, including a film coated
tablet, comprising from about 0.5 to about 9 mg doxepin having a
friability value of 1% or less, for example. In other embodiments,
the tablet can have a friability value of about 0.75%, of about
0.5% or of about 0.25%, for example.
[0022] Embodiments of the invention also provide pharmaceutical
compositions comprising from about 0.5 to about 9 mg doxepin having
disintegration times of less than 1 minute per U.S. Pharmacopeia
(USP) protocols (accessible on the world wide web and usp.org; the
Pharmacopeia is incorporated herein by reference in its entirety),
for example. In other embodiments, the compositions can have
disintegration times of less than 30 seconds, of less than 20
seconds, of less than 10 seconds or of less than 6 seconds, for
example.
[0023] Another embodiment provides pharmaceutical compositions
comprising from about 0.5 to about 9 mg doxepin 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 0.1 N HCl or Simulated Gastric Fluid USP without enzymes.
In other embodiments, the composition can have, for example, at
least an 85 percent release rate at 15 minutes, at least an 85
percent release rate at 10 minutes, at least an 85 percent release
rate at 5 minutes, at least a 90 percent release rate at 30
minutes, at least a 95 percent release rate at 30 minutes. In some
aspects of this embodiment, the compositions also can have 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 and/or 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 of
Simulated Intestinal Fluid USP without enzymes.
[0024] Some embodiments of the invention provide pharmaceutical
compositions comprising from about 0.5 to about 9 mg doxepin 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. In other embodiments, the compositions
can have, for example, at least an 85 percent release rate at 15
minutes, at least an 85 percent release rate at 10 minutes, at
least an 85 percent release rate at 5 minutes, at least a 90
percent release rate at 30 minutes or at least a 95 percent release
rate at 30 minutes.
[0025] Another embodiment provides pharmaceutical compositions
comprising from about 0.5 to about 9 mg doxepin 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 6.8 buffer or Simulated Intestinal Fluid USP without
enzymes.
[0026] Embodiments of the invention also provide pharmaceutical
compositions comprising about 0.5 to about 9 mg doxepin having two
or more of the following characteristics: a hardness value of at
least 2 Kp, a friability value of 1% or less, a disintegration time
of less than 1 minute as per USP protocols, 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 (USP)
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.
[0027] Another embodiment provides a batch of unit dosage forms,
each comprising from about 0.5 to about 9 mg doxepin, and the batch
having content uniformity values between about 85% to 115% of a
label claim. In other embodiments, the batch of unit dosage forms
can have, for example, content uniformity values of between about
90% to 110% of label claim or of between about 95% to 105% of label
claim. For example, the batch can comprise at least 50 unit dosage
forms, e.g., tablets or film coated tablets.
[0028] In some embodiments the batch of unit dosage forms can
comprise from about 100,000 to about 10,000,000 units, from about
500,000 to about 5,000,000 units, from about 1,000,000 to about
4,000,000 units, or from about 3,000,000 to about 4,000,000 units,
for example. The units can be in the form of tablets, film coated
tablets, capsules, caplets, pills, gel caps, pellets, beads, and
the likes
[0029] Embodiments of the invention also provide a batch of unit
dosage forms, each comprising from about 0.5 to about 9 mg doxepin,
having a content uniformity percent relative standard deviation of
less than 5%. In other embodiments, the batch of unit dosage forms
can have, for example, a content uniformity percent relative
standard deviation of less than 4%, less than 3%, less than 2% or
less than 1%.
[0030] Another embodiment provides a method of treating insomnia,
comprising identifying an individual in need of such treatment, and
administering any of the compositions disclosed herein to the
individual.
[0031] Another embodiment relates to a method of treating insomnia,
comprising identifying an individual in need of such treatment,
providing the individual with instructions to take a doxepin dosage
form according to any of the embodiments disclosed herein and
providing any of the dosage forms disclosed herein to the
individual.
[0032] Yet another embodiment provides a method of enhancing sleep
maintenance, comprising identifying an individual in need of such
enhancement, and administering any of the compositions disclosed
herein to the individual.
[0033] Some embodiments provide methods of making a doxepin dosage
form comprising combining from about 0.5 to about 9 mg doxepin and
about 20% to about 99.9% silicified microcrystalline cellulose. In
one embodiment, the silicified microcrystalline cellulose can be
provided, for example, in amount of about 92% to about 99.8% w/w.
The methods can further comprise adding from about 0.1 to about
1.5% w/w colloidal silicon dioxide and/or about 0.25 to about 1.5%
w/w magnesium stearate. In other embodiments, doxepin can be
provided in an amount of about 1 to about 2 mg, or about 3 to about
4 mg, or about 7 mg, for example. The silicified microcrystalline
cellulose can be provided in amount of about 92% to about 99.8%
w/w, of about 92% to about 99.8% w/w or of about 92% to about 99.8%
w/w, for example. In another embodiment, doxepin and silicified
microcrystalline cellulose can be combined with at least one filler
selected from microcrystalline cellulose, lactose, compressible
sugars, xylitol, sorbitol, mannitol, pregelatinized starch,
maltodextrin, calcium phosphate dibasic, calcium phosphate
tribasic, calcium carbonate DC, combinations of one or more of the
same, and the like.
[0034] Embodiments of the invention also provide methods of making
doxepin dosage forms comprising serially diluting and mixing a low
concentration of doxepin with a higher concentration formulation
excipient.
[0035] There is also provided a method of manufacturing a doxepin
dosage form, wherein the method includes forming a drug substance
pre-blend by mixing silicified microcrystalline cellulose and
doxepin; forming a final blend by mixing silicified
microcrystalline cellulose and the drug substance pre-blend; and
forming a doxepin dosage form from the final blend. In one
embodiment, the final blend can be compressed to form a doxepin
tablet. The doxepin tablet also can be a film coated tablet. In
some embodiments, the method can further comprise screening the
drug substance pre-blend prior to forming the main blend. In
another embodiment, the method further can comprise mixing the
final blend for a time period sufficient to obtain a uniform
distribution of doxepin prior to forming the tablet. In yet another
embodiment, the method further can comprise mixing the final blend
with magnesium stearate prior to forming the tablet. In some
aspects the methods can include applying a coating to form a film
coated tablet.
[0036] Another embodiment is a method of manufacturing a doxepin
dosage form, wherein the method includes forming a drug substance
pre-blend by mixing a first filler and doxepin; forming a final
blend by mixing a second filler and the drug substance pre-blend;
and forming a doxepin dosage form from the final blend. In one
aspect of this embodiment, the first filler and the second filler
can be, for example, silicified microcrystalline cellulose,
microcrystalline cellulose, lactose, compressible sugars, xylitol,
sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium
phosphate dibasic, calcium phosphate tribasic, calcium carbonate
DC, combinations of one or more of the same, and the like. In one
embodiment, the first and second fillers are not the same. In one
embodiment, the first and/or the second filler can be silicified
microcrystalline cellulose. In another embodiment, the first and
second fillers can be the same. In yet another embodiment, the
first and the second filler can be silicified microcrystalline
cellulose. In another embodiment, the drug substance pre-blend or
the final blend can comprise an additional filler. The additional
filler can be, for example, silicified microcrystalline cellulose,
microcrystalline cellulose, lactose, compressible sugars, xylitol,
sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium
phosphate dibasic, calcium phosphate tribasic, calcium carbonate
DC, combinations of one or more of the same, and the like.
[0037] Embodiments of the invention also provide methods of
manufacturing a doxepin dosage form by direct compression. The
methods can include, for example, forming a color blend by mixing
one or more pharmaceutically acceptable colorants and silicified
microcrystalline cellulose; forming an initial drug substance
pre-blend by mixing silicified microcrystalline cellulose and
doxepin; forming a final drug substance pre-blend by mixing the
color blend and initial drug substance pre-blend; screening the
final drug-substance pre-blend; forming a main blend by mixing
silicified microcrystalline cellulose and the final drug-substance
pre-blend; mixing the main blend for a time period sufficient to
obtain a uniform distribution of doxepin; forming a final blend by
mixing a lubricant and the main blend; and forming the final blend
into a doxepin dosage form.
[0038] In one aspect of this embodiment, forming the initial drug
substance pre-blend can comprise sequentially screening a first
portion of the silicified microcrystalline cellulose, screening the
doxepin, and screening a second portion of the silicified
microcrystalline cellulose. In some aspects, the methods preferably
can include methods to prevent re-agglomeration of the materials.
For example, the screened powders can be placed into a blender and
mixed, and the initial drug substance pre-blend can be screened
using a vibrating sieve, a cone mill or a co mill, which operate in
manner that prevents re-agglomeration of cohesive powders. In
another embodiment, forming the final drug substance pre-blend can
comprise sequentially adding a first portion of the color pre-blend
or filler, adding the initial drug substance pre-blend, and adding
a second portion of the color pre-blend or filler. In another
embodiment, the final drug substance pre-blend can comprise
combining two, equivalent initial drug substance pre-blends.
[0039] In another embodiment, color can be imparted with a tablet
coating process which obviates the need for a color pre-blend. For
the low dose embodiments, in some aspects the absence of a color
pre-blend can result in the preparation of only one drug substance
pre-blend rather than an initial and final drug substance
pre-blend. In some embodiments, screening the final drug-substance
pre-blend step can be repeated prior to forming the main blend. In
another embodiment, screening the final drug-substance pre-blend
can comprise using a vibrating sieve. In aspects of this
embodiment, the final drug-substance pre-blend can be screened
using a vibrating sieve, for example, equipped with a 10 to 200
mesh screen, a 20 to 80 mesh screen, or a 30 mesh screen, or the
like. In some embodiments, forming the main blend can comprise
sequentially adding a first portion of the silicified
microcrystalline cellulose, adding the drug-substance pre-blend,
and adding a second portion of the silicified microcrystalline
cellulose. In other embodiments, the main blend can be mixed, for
example, for about 5 to about 60 minutes, for about 10 to about 40
minutes or for about 20 minutes. In one embodiment, the main blend
can be mixed, for example, in an in-bin blender. The lubricant can
be, for example, magnesium stearate, calcium stearate, sodium
stearyl fumarate, stearic acid, hydrogenated vegetable oil,
glyceryl behenate, polyethylene glycol, combinations of one or more
of the same, and the like. In one embodiment, the lubricant can
comprise magnesium stearate. In some embodiments, the final blend
can be compressed to form the tablet, for example.
[0040] Another embodiment provides 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.
[0041] Embodiments of the invention also provide methods of making
a plurality of doxepin dosage forms. The methods can include, for
example, providing an amount of doxepin to obtain a plurality of
doxepin tablets, including film coated tablets, wherein each tablet
comprises between about 0.1 mg to 9 mg of doxepin; providing one or
more excipients; mixing said doxepin and excipients such that the
plurality of doxepin dosage forms comprises at least one of content
uniformity values between about 85% and 115% of label claim or a
content uniformity percent relative standard deviation of less than
5%. In other embodiments, the plurality of dosage forms can
comprise content uniformity values between about 90% to 110% of
label claim, or between about 95% to 105% of a label claim, for
example. In other embodiments, the plurality of dosage forms can
comprise a content uniformity percent relative standard deviation
of less than 5%, of less than 4 of less than 3%, of less than 2%,
or of less than 1%, for example.
[0042] In one aspect of this embodiment, the one or more excipients
can comprise SMCC. The one or more excipients can further comprise
an excipient, such as, for example, microcrystalline cellulose,
lactose, a compressible sugar, xylitol, sorbitol, mannitol,
pregelatinized starch, maltodextrin, calcium phosphate dibasic,
calcium phosphate tribasic, calcium carbonate DC, a calcium
silicate, and the like. In another embodiment, the one or more
excipients can comprise, for example, between about 20% and 100%
SMCC. In other embodiments, the plurality of dosage forms can
comprise, for example, from about 100,000 to about 10,000,000
units, from about 500,000 to about 5,000,000 units, from about
1,000,000 to about 4,000,000 units or from about 3,000,000 to about
4,000,000 units.
[0043] Some embodiments relate to pharmaceutical unit dosage form,
comprising doxepin, a pharmaceutically-acceptable salt or prodrug
thereof in an amount equivalent to about 1 mg doxepin
hydrochloride; one or more pharmaceutically-acceptable excipients;
and optionally, a capsule or coating. In some embodiments, the
excipients and any capsule or coating can be selected to provide a
swallowable unit dosage that is at least externally solid and that
has dissolution and bioavailability 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, for example. The dosage form can be
a tablet, a film coated tablet, a capsule, a pill, a caplet, a gel
cap, a pellet, a bead, or a dragee. In one embodiment, the dosage
form can be a tablet. In some embodiments, the dosage form
preferably can be a film coated tablet. In another embodiment, the
dosage form can be a capsule. In yet another embodiment, the time
frame to provide a plasma concentration of at least 0.05 ng/mL is
not more than about 80 minutes, for example.
[0044] Another embodiment of the invention is directed to a
pharmaceutical unit dosage form, comprising doxepin, a
pharmaceutically-acceptable salt or prodrug thereof in an amount
equivalent to about 1 mg, 3 mg, or 6 mg doxepin hydrochloride; one
or more pharmaceutically-acceptable excipients; and optionally, a
capsule or coating. In some embodiments, the excipients and any
capsule or coating can be selected to provide a swallowable unit
dosage that is at least externally solid and that has dissolution
and bioavailability 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. In yet another embodiment, the time frame to
provide a plasma concentration of at least 0.1 ng/mL is not more
than about 50 minutes. In some aspects, the dosage form can provide
a plasma concentration of at least 0.05 ng/mL doxepin within a time
frame of not more than about 90 minutes, for example. The dosage
form can be a tablet, a film coated tablet, a capsule, a pill, a
caplet, a gel cap, a pellet, a bead, or a dragee. In one
embodiment, the dosage form can be a tablet. In some embodiments,
the dosage form preferably can be a film coated tablet. In another
embodiment, the dosage form can be a capsule.
[0045] Some embodiments relate to pharmaceutical compositions
comprising 0.5 to 9 mg doxepin or a pharmaceutically acceptable
salt or prodrug of doxepin where the composition comprises at least
two or more of the characteristics of: a hardness value of at least
2 Kp, a friability value of 1% or less, a disintegration time of
less than 1 minute as per U.S. Pharmacopeia (USP) protocols, at
least an 80% release of doxepin within 15 minutes using compendial
method for measuring dissolution of doxepin. Preferably, the
compositions comprise at least 80% release of doxepin within 15
minutes. Also, some embodiments relate to compositions or
formulations that release at least from about 60% to about 99.5%
doxepin after about 5 to about 40 minutes. The release or
dissolution can be determined using the USP-based methods.
Preferably, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99.5% doxepin
is released after 3, 5, 10, 15 or 30 minutes, for example. Thus,
some embodiments relate to low dose doxepin formulations that have
the unexpected dissolution properties listed above and elsewhere
herein.
[0046] Some embodiments relate to methods for processing or
producing low dose doxepin dosage forms, for example, from about
0.5 mg to about 9 mg doxepin, while obtaining high content
uniformity. The methods can include minimizing segregation of low
dose doxepin, which segregation can cause a lack of uniformity of
dosage forms, by minimizing fluidization of low dose doxepin
blended with a filler, including any of the fillers listed herein.
In some embodiments, the minimizing of fluidization can be
accomplished by minimizing airflow through a blend of low dose
doxepin and one more fillers. Examples of minimizing airflow can
include providing vents, valves or other devices that permit the
release of air from containment devices that transport or hold the
low dose doxepin blend. Also, fluidization can be minimized by
reducing the amount of airspace in a dosage form press, such that
there is less opportunity for contact of the blend with air. Also,
the low dose formulations can be produced using a wet granulation
method in order to avoid fluidization. Furthermore, carriers or
fillers that bind with greater strength to the doxepin can be
utilized. Such carriers/fillers can be easily incorporated by one
of skill in the art.
[0047] Also, content uniformity can be maintained or enhanced by
minimizing agglomeration or re-agglomeration of doxepin in the low
dose doxepin formulations. Examples of minimizing agglomeration are
described herein. Such methods can include, for example, diluting
or layering the low dose doxepin with one or more fillers
(including those listed or described herein). The methods can also
include the use of a cone mill, a co mill or the like, including
devices that minimize the separation of the doxepin from filler
blends and dilution blends/mixes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 is a graph showing the blend uniformity with and
without drug substance pre-blend.
[0049] FIG. 2 is a graph showing a batch content uniformity
comparison.
[0050] FIGS. 3A-3C are flow charts showing an exemplary
manufacturing process.
[0051] FIGS. 4-6 are flow charts showing preparation of a color
pre-blend.
[0052] FIGS. 7-8 are flow charts showing preparation of a drug
substance pre-blend.
[0053] FIG. 9 is a flow chart showing preparation of a final
blend.
[0054] FIG. 10 is a graph showing percentage of tablet dissolved
vs. time (min).
[0055] FIGS. 11A-B are flow charts showing a fluid bed granulation
process for use in the invention disclosed herein.
[0056] FIGS. 12A-B are flow charts showing a wet granulation
process for use in the invention disclosed herein.
[0057] FIGS. 13A-B are flow charts showing a dry granulation
process for use in the invention disclosed herein.
[0058] FIG. 14 is a manufacturing process flow chart depicting an
example of a process for film-coated tablets.
[0059] FIG. 15 is a graph of the dissolution data for
commercially-available, high-dose doxepin formulations as well as
lactose and SM CC-based formulations of low-dose doxepin.
DETAILED DESCRIPTION
[0060] Embodiments of the invention generally relate to new and
surprisingly effective doxepin formulations and methods of using
low-dose forms of doxepin, including, for example, use in the
treatment of insomnia. Also, some embodiments of this invention
relate to novel and economical methods of manufacturing low-dose
dosage forms of doxepin, pharmaceutically acceptable salts thereof,
or prodrugs thereof.
[0061] Doxepin is a tricyclic compound currently approved for
treatment of depression or anxiety at a daily dose of 75 mg to 300
mg. Doxepin is marketed under the commercial name SINEQUAN.RTM. and
in generic form, and can be obtained in the United States generally
from pharmacies in capsule form in amounts of 10, 25, 50, 75, 100
and 150 mg dosage, and in liquid concentrate form at 10 mg/mL. The
capsule formulations contain Doxepin HCl with cornstarch and
magnesium stearate/sodium lauryl sulfate. Capsule shells can also
contain gelatin, sodium lauryl sulfate, sodium metabisulfate and
colorants. Such capsule formulations or formulations using one or
more of the features of the capsule formulations can be
specifically excluded from some embodiments herein. For example,
doxepin formulations comprising starch and/or a gelatin shell can
be exclude from some embodiments.
[0062] The use of low dose doxepin for the treatment of insomnia is
described in U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire
contents of which are incorporated herein by reference. As
mentioned above, many individuals currently suffer from sleep
disorders, such as insomnia. There is a need for improved
compositions and methods for treating such individuals.
Compounds
Doxepin
[0063] Doxepin HCl is a tricyclic compound currently approved and
available for treatment of depression and anxiety.
[0064] Doxepin belongs to a class of psychotherapeutic agents known
as dibenzoxepin tricyclic compounds, and is currently approved and
prescribed for use as an antidepressant to treat depression and
anxiety. Doxepin has a well-established safety profile, having been
prescribed for over 35 years.
[0065] It is contemplated that doxepin for use in the compositions
and methods described herein can be obtained from any suitable
source or made by any suitable method. For example, doxepin HCl can
be obtained from Plantex Ltd. (DMF No. 3230). In the
Biopharmaceutic Classification System, doxepin HCl, USP is
designated as a Class One compound, with high solubility and high
permeability. The Plantex-supplied doxepin HCl, USP has a particle
size specification of not less than 80% smaller than 38 microns and
not less than 90% smaller than 125 microns as measured by an Air
Jet Sieve method.
[0066] Also, doxepin can be prepared according to the method
described in U.S. Pat. No. 3,438,981, which is incorporated herein
by reference in its entirety. As another illustration, doxepin can
be prepared from
11-[3-(Dimethylamino)propyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol
as taught in U.S. Pat. No. 3,420,851, which is incorporated herein
by reference in its entirety. It should be noted and understood
that although many of the embodiments described herein specifically
refer to "doxepin," other doxepin-related compounds can also be
used, including, for example, pharmaceutically acceptable salts,
prodrugs, in-situ salts of doxepin formed after administration, and
solid state forms, including polymorphs and hydrates.
Pharmaceutically Acceptable Salts:
[0067] As mentioned above, the methods and other embodiments
described herein can utilize any suitable pharmaceutically
acceptable salt or prodrug of doxepin. Therefore, the substitution
or use in combination of salts and prodrugs is specifically
contemplated in the embodiments described herein. The
pharmaceutically acceptable salts and prodrugs can be made by any
suitable method.
[0068] The term "pharmaceutically acceptable salt" refers to an
ionic form of a compound that does not cause significant irritation
to an organism to which it is administered and does not abrogate
the biological activity and properties of the compound.
Pharmaceutical salts can be obtained by reacting a compound, for
example, doxepin, with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like. Pharmaceutical salts can also be
obtained by reacting a compound of the invention with a base to
form a salt such as an ammonium salt, an alkali metal salt, such as
a sodium or a potassium salt, an alkaline earth metal salt, such as
a calcium or a magnesium salt, a salt of organic bases such as
dicyclohexylamine, N-methyl-D-glutamine,
tris(hydroxymethyl)methylamine, and salts with amino acids such as
arginine, lysine, and the like. Pharmaceutically acceptable salts
are more fully described in the following paragraph.
[0069] The acids that can be used to prepare pharmaceutically
acceptable acid addition salts include, for example, those that
form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, such as the acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
clavulanate, citrate, dihydrochloride, edetate, dislyate, estolate,
esylate, ethylsuccinate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, iodide, isothionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate
(embonate), palmitate, pantothenate, phosphate/diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate,
tannate, tartrate, teoclate, tosylate, triethiodide, and valerate
salts.
[0070] The bases that can be used to prepare pharmaceutically
acceptable base addition salts include, for example, those that
form non-toxic base addition salts, i.e., base salts formed with
metals or amines, such as alkali and alkaline earth metals or
organic amines. Non-limiting examples of metals used as cations
include sodium, potassium, magnesium, calcium, and the like. Also
included are heavy metal salts such as for example silver, zinc,
cobalt, and cerium. Non-limiting examples of suitable amines
include N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamene, N-methylglucamine, and
procaine.
Prodrugs:
[0071] The term "prodrug" refers to an agent that is converted into
the active drug in vivo. Prodrugs are often useful because, in some
situations, they can be easier to administer than the active drug.
They can, for instance, be bioavailable by oral administration
whereas the active drug is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the active drug. An
example, without limitation, of a prodrug would be a compound of
the present invention which is administered as an ester (the
"prodrug") to facilitate transmittal across a cell membrane where
water solubility is detrimental to mobility but which then is
metabolically hydrolyzed to the carboxylic acid, the active entity,
once inside the cell where water-solubility is beneficial. A
further example of a prodrug might be a short peptide
(polyaminoacid) bonded to an acid group where the peptide is
metabolized to reveal the active moiety. Examples of prodrug groups
can be found in, for example, T. Higuchi and V. Stella, in
"Pro-drugs as Novel Delivery Systems," Vol. 14, A.C.S. Symposium
Series, American Chemical Society (1975); H. Bundgaard, "Design of
Prodrugs," Elsevier Science, 1985; and "Bioreversible Carriers in
Drug Design: Theory and Application," edited by E. B. Roche,
Pergamon Press: New York, 14-21 (1987), each of which is hereby
incorporated by reference in its entirety.
Compositions
[0072] Dosage form development requires the selection of excipients
based on the properties of the drug substance being formulated.
Several preferred embodiments of this invention are provided. These
should not be construed as limiting the scope of this
invention.
[0073] Some embodiments of the invention are based upon the new
discovery of previously unknown physical characteristics and
challenges associated with low-dose doxepin compositions, and also
upon a new understanding of pharmacokinetics of doxepin when it is
used to treat sleep disorders.
[0074] For example, it has been found that formulation of
compositions at the lower dose range can present a considerable
challenge in maintaining consistent potency and uniformity in the
drug product manufacturing process, while also maintaining a high
yield. For example, assuring the homogeneity of the powder blend
for production of low-dose dosage forms can represent a major
quality assurance consideration. The selection of the particular
excipient or excipients used, and how to properly blend and prevent
non-uniformity and segregation were based upon previously
unrecognized characteristics and needs for doxepin formulation,
particularly low-dose formulations.
[0075] Also, in some embodiments, the compositions are based upon
previously unknown pharmacokinetics of low-dose doxepin for sleep.
Although doxepin dissolves quickly in the stomach, it can take some
time for the sleep promoting action of the drug to take place. No
one previously recognized the sleep pharmacokinetics of doxepin,
such as, sleep onset characteristics of doxepin; and for sleep,
even decreasing induction time by a few minutes can provide an
enormous benefit. In the context of sleep, early onset of drug
action can be important due to the discreet window of time (e.g., 8
hours) in which a patient needs to sleep. As a consequence, some
embodiments relate to compositions that can contribute to
accelerated action of the drug. That need was not recognized
previously, in particular for depression and anxiety where there
was no need for fast onset due to the ongoing and chronic nature of
those conditions. The unique needs of doxepin for treating sleep
were not appreciated in the prior art.
[0076] Accordingly, some embodiments relate to compositions for the
treatment of such disorders where careful selection of excipients
was used to address the previously unrecognized characteristics of
low-dose doxepin and doxepin for use in treating sleep disorders.
Described below and elsewhere herein are new and unexpectedly
effective doxepin formulations.
[0077] Doxepin HCl, USP, is a white crystalline powder with a
slight amine-like odor supplied by Plantex Ltd. In the
Biopharmaceutic Classification System, doxepin HCl, USP is
designated as a Class One compound, with high solubility and high
permeability (Wu-Benet, 2005). The Plantex-supplied doxepin HCl,
USP has a particle size specification of not less than 80% smaller
than 38 microns and not less than 90% smaller than 125 microns as
measured by an Air Jet Sieve method.
[0078] In a preferred embodiment, the compositions disclosed herein
can include from about 0.01 mg to about 9 mg of doxepin, or from
about 0.5 mg to about 7 mg doxepin, or from about 1 mg to about 6
mg doxepin. In some embodiments, the compositions include from
about 0.5 mg to about 2 mg doxepin, or from about 2.5 mg to about 4
mg, or from about 5.9 mg to about 7 mg doxepin.
[0079] As discussed above, in some embodiments, doxepin prodrugs or
pharmaceutically acceptable salts of doxepin can be used in place
of, or in addition to, low-dose doxepin in the formulations
described herein.
[0080] Some embodiments provide low-dose doxepin tablets, film
coated tablets, capsules, caplets, pills, gel caps, pellets, beads,
or dragee dosage forms. Some embodiments specifically exclude one
or more such dosage forms.
[0081] Preferably, the formulations disclosed herein can provide
favorable drug processing qualities, including, for example, but
not limited to, rapid tablet press speeds, reduced compression
force, reduced ejection forces, blend uniformity, content
uniformity, uniform dispersal of color, accelerated disintegration
time, rapid dissolution, low friability (preferable for downstream
processing such as packaging, shipping, pick-and-pack, etc.) and
dosage form physical characteristics (e.g., weight, hardness,
thickness, friability) with little variation. Many of these
qualities, notably, content uniformity and blend uniformity, are
difficult to obtain in low dose formulations.
[0082] Making the drug available for absorption with minimal delay
can be important in the treatment of medical conditions such as
insomnia. In a preferred embodiment, the formulations can yield
extremely rapid disintegration times of 1 minute or less as per USP
protocols. Preferably, the formulation yields disintegration times
of 50, 40, 30, 25, 10 seconds or less. More preferably, the
formulation yields dosage form disintegration times of 8 seconds or
less, and even more preferably 6 seconds or less. In a preferred
embodiment, silicified microcrystalline cellulose (SMCC), e.g.,
Prosolv SMCC.RTM. (JRS Pharma Inc., Patterson, N.Y.) is used as a
diluent or filler to impart favorable disintegration times.
[0083] In other embodiments, the formulation yields a rapidly
dissolving dosage form, for which at least 85% of the labeled
amount of the drug substance dissolves within 30 minutes, using
U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at
50 rpm) in a volume of 900 ml or less in each of the following
media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated
Intestinal Fluid USP without enzymes.
[0084] In some embodiments, the formulations require minimal tablet
compression forces to achieve a hardness of about 2 to about 25 kp.
In some aspects, the formulation can require compression forces to
achieve a hardness of, for example, at least 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 15, 18, 20 or 21 kp. Such minimal compression forces
can enables the tablets to remain relatively porous and
disintegrate fast with minimal wear on compression tooling and the
tablet press. In one embodiment of the invention disclosed herein,
the use of SMCC as a diluent imparts favorable compressibility and
disintegration of the dosage form.
[0085] In other embodiments, the formulations can yield tablets,
including film coated tablets, having a friability value of 1% or
less. Thus, in some embodiments, the friability value is about
0.9%, 0.8%, 0/75%, 0.6%, 0.5%, 0.4%, 0.3%, 0.25% or less.
[0086] Preferably, the formulations disclosed herein provide a
batch of low-dose doxepin dosage forms having content uniformity
values between about 75% to about 125% of label claim, or from
about 85% to about 115% of label claim, more preferably between
about 90% to about 110% of label claim, and more preferably between
about 95% to about 105% of label claim. In some embodiments, the
formulations yield a batch of low-dose doxepin dosage forms having
a content uniformity percent relative standard deviation of 7.8% or
less. In some embodiments, the relative standard deviation is equal
to or less than 6%, 5%, 4%, 3%, 2%, or 1%. Preferably, the
formulations disclosed herein provide a high yield of low-dose
doxepin dosage forms having acceptable content uniformity. The
batch can include, for example, about from about 50 to about
5,000,000 unit dosage forms or any amount in between, or even more
if desired.
[0087] In other preferred embodiments, tablet ejection forces are
very low enabling lubrication levels to be kept low and preventing
adverse effects due to over lubrication, including, for example,
soft tablets, retarded dissolution, etc. This further reduces wear
on compression tooling. In a preferred embodiment, the use of SMCC
permits the use of low ejection forces.
[0088] In some embodiments, the product does not exhibit a
sensitivity of product performance (tablet hardness and
dissolution) to the lubricant blend time. For example, in one
embodiment the SMCC based formulation unexpectedly and surprisingly
is resistant to the impact of over-lubrication normally associated
with magnesium stearate. In many cases, lubricant blend time can
affect product performance. Very surprisingly, here lubrication
with magnesium stearate can result in low dose doxepin formulations
that are resistant to the normal over-lubrication effects.
[0089] In a preferred embodiment, the low-dose dosage forms
described herein are formulated to yield two or more favorable drug
characteristics.
[0090] The compounds can be formulated readily, for example, by
combining the drug substance with any suitable pharmaceutically
acceptable excipient for example, but not limited to, binders,
diluents, disintegrants, lubricants, fillers, carriers, and the
like, as set forth below. Such compositions can be prepared for
storage and for subsequent processing.
[0091] Acceptable excipients for therapeutic use are well known in
the pharmaceutical art, and are described, for example, in Handbook
of Pharmaceutical Excipients, 5th edition (Raymond C Rowe, Paul J
Sheskey and Sian C Owen, eds. 2005), and Remington: The Science and
Practice of Pharmacy, 21st edition (Lippincott Williams &
Wilkins, 2005), each of which is hereby incorporated in its
entirety. The term "carrier" material or "excipient" herein can
mean any substance, not itself a therapeutic agent, used as a
carrier and/or diluent and/or adjuvant, or vehicle for delivery of
a therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule, tablet, film coated
tablet, caplet, gel cap, pill, pellet, bead, and the like suitable
for oral administration. Excipients can include, by way of
illustration and not limitation, diluents, disintegrants, binding
agents, wetting agents, polymers, lubricants, glidants, substances
added to mask or counteract a disagreeable taste or odor, flavors,
colorants, fragrances, and substances added to improve appearance
of the composition.
[0092] Acceptable excipients include, for example, but are not
limited to, SMCC, microcrystalline cellulose, lactose, sucrose,
starch powder, maize starch or derivatives thereof, cellulose
esters of alkanoic acids, cellulose alkyl esters, talc, stearic
acid, magnesium stearate, magnesium oxide, sodium and calcium salts
of phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline,
dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate,
cysteine hydrochloride, and the like. Examples of suitable
excipients for soft gelatin capsules include vegetable oils, waxes,
fats, semisolid and liquid polyols. Suitable excipients for the
preparation of solutions and syrups include, without limitation,
water, polyols, sucrose, invert sugar and glucose. The compound can
also be made in microencapsulated form. If desired, absorption
enhancing preparations (for example, liposomes), can be
utilized.
[0093] The compositions and formulations can include any other
agents that provide improved transfer, delivery, tolerance, and the
like. These compositions and formulations can include, for example,
powders, pastes, jellies, waxes, oils, lipids, lipid (cationic or
anionic) containing vesicles (such as Lipofectin.TM.), DNA
conjugates, anhydrous absorption pastes, oil-in-water and
water-in-oil emulsions, emulsions carbowax (polyethylene glycols of
various molecular weights), semi-solid gels, and semi-solid
mixtures containing carbowax.
[0094] Any of the foregoing mixtures can be appropriate in
treatments and therapies in accordance with the invention disclosed
herein, provided that the active ingredient in the formulation is
not inactivated by the formulation and the formulation is
physiologically compatible and tolerable with the route of
administration. See also Baldrick P. "Pharmaceutical excipient
development: the need for preclinical guidance." Regul. Toxicol.
Pharmacol. 32(2):210-8 (2000), Charman W N "Lipids, lipophilic
drugs, and oral drug delivery-some emerging concepts." J Pharm Sci.
89(8):967-78 (2000), and the citations therein for additional
information related to formulations, excipients and carriers well
known to pharmaceutical chemists.
[0095] In some embodiments, one or more, or any combination of the
listed excipients can be specifically included or excluded from the
formulations and/or methods disclosed herein. For example, in some
embodiments, microcrystalline cellulose can be specifically
excluded.
[0096] The formulation can be in form suitable for bolus
administration, for example. Oral administration can be
accomplished using orally administered formulations, for example,
tablets, film coated tablets, capsules, gel caps, caplets, pellets,
beads, pills, and the like. In addition, stabilizers can be added.
All formulations for oral administration should be in dosages
suitable for such administration.
[0097] As will be appreciated by those of skill in the art, the
amounts of excipients will be determined by drug dosage and dosage
form size. In some embodiments disclosed herein, the dosage form
size is 150 mg. This dosage form weight is arbitrary and one
skilled in the art will realize that a range of weights can be made
and are encompassed by this invention. The preferred dosage form
range is 50 mg to 500 mg, more preferably 75 mg to 300 mg, more
preferably 100 to 200 mg, with the preferred dosage form weight
being 150 mg.
[0098] In some embodiments, a high functionality excipient can be
used in the formulations. The term "high functionality excipient"
is defined as an inactive ingredient that meets the following four
criteria: (1) multifunctional in that one excipient contributes two
or more functions to a formulation, (2) high inherent functional
performance even at low use levels, allowing for increased batch
sizes and higher drug loading (3) does not require complex
processing steps, making it ideal for cost effective direct
compression processes and (4) imparts high inherent functional
performance to the overall formulation. High functionality
excipients provide the means for simplifying formulation
development, and improving overall operational costs while
preserving the quality that is essential for pharmaceutical
products.
[0099] In a preferred embodiment, low doses of doxepin are combined
with silicified microcrystalline cellulose (SMCC), e.g., Prosolv
SMCC.RTM. (JRS Pharma Inc., Patterson, N.Y.). For example, based on
a 150 mg dosage form weight, the range of drug substance is from
about 0.75% to about 4.5% w/w and the range of SMCC is from about
90 to 99.8% w/w, or from about 92% to about 99% w/w, or from about
94% to about 98.5% w/w.
[0100] "Silicified microcrystalline cellulose," also referred to by
the acronym "SMCC", is composed of 98% microcrystalline cellulose
USP/NF and 2% colloidal silicon dioxide USP/NF. The silicification
of the microcrystalline cellulose forms an intimate association
between the colloidal silicon dioxide and the microcrystalline
cellulose. SMCC provides the role of a high functionality excipient
and imparts the functions of diluent, binder and/or disintegrant.
The use of SMCC is disclosed in U.S. Pat. Nos. 5,585,115,
5,725,884, 5,866,166, 6,217,909, 6,358,533, 6,471,994, 6,521,261,
6,476,693, 6,936,277, each of which is hereby incorporated by
reference in its entirety. Several grades of SMCC are currently
available, with particle size and bulk density being a principle
differentiating properties among the grades. Preferably, the
particle size of the diluent can be selected based on consideration
of the particle size of the drug substance. In one embodiment of
the invention disclosed herein, the particular grade has a median
particle size (by sieve analysis) of approximately 90 .mu.m.
[0101] The silicified microcrystalline cellulose used in the
preparations disclosed herein can be any combination of
microcrystalline cellulose co-processed with colloidal silicon
dioxide, including, for example, that which can be obtained
commercially from JRS Pharma Inc. under the name ProSolv SMCC.RTM..
There are different grades of SMCC available, with particle size
and bulk density being exemplary differentiating properties among
the grades. It should be noted that as described below, other
excipients can be used in combination with or substituted for SMCC
in order to formulate suitable doxepin dosage forms.
[0102] The use of SMCC as a diluent or filler imparts favorable
drug processing qualities, including, for example, but not limited
to, rapid tablet press speeds, reduced compression force, reduced
ejection force, blend uniformity, content uniformity, uniform
dispersal of color, accelerated disintegration time, rapid
dissolution, low friability (preferable for downstream processing
such as packaging, shipping, pick-and-pack, etc.) and dosage form
physical characteristics (e.g., weight, hardness, thickness,
friability) with little variation.
[0103] In addition, SMCC is easily compacted (an efficient binder)
and possesses effective disintegration properties. These two
characteristics create hard tablets that rapidly dissolve. In some
embodiments, SMCC is also used to serially dilute the drug
substance and colorants to promote their uniform distribution in
the formulation as well as to dry-rinse the equipment surfaces to
minimize any potential loss of drug substance during the
manufacturing process.
[0104] In one embodiment, a dry pharmaceutical blend of silicified
microcrystalline cellulose and low-dose doxepin, or a low-dose
doxepin-related compound, is used to produce the final dosage form
by direct compression. Typically, the dry blend contains from about
0.1% to about 10% w/w, or from about 0.5% to about 5% w/w, or from
about 0.7% to about 4.5% w/w of low-dose doxepin or a low-dose
doxepin-related compound. In one embodiment, the doxepin or
doxepin-related compound, in the dry blend is non-granulated. In
addition to doxepin, the blend can contain from about 20% to about
99.9% w/w SMCC, or from about 50% to about 99.5% w/w SMCC, or from
about 75% to about 99% w/w SMCC, or from about 80% to about 98.7%
SMCC, or from about 92% to about 98.5% w/w SMCC, or from about 94%
to about 98% w/w SMCC.
[0105] In some embodiments, SMCC can be combined or replaced with
one or more of the following excipients: microcrystalline
cellulose, lactose monohydrate (spray dried), a compressible sugar,
xylitol (Xylitab), sorbitol, mannitol, pregelatinized starch,
maltodextrin, calcium phosphate dibasic, calcium phosphate
tribasic, calcium carbonate DC, and the like. Accordingly, in one
embodiment, one or more of the above excipients can be combined
with SMCC in various ratios. For example, assuming the total filler
to be 100%, about 80% SMCC can be combined with about 20% of one or
more alternate filler(s). Alternatively, about 70% SMCC can be
combined with about 30% of one or more alternate filler(s), or
about 60% SMCC can be combined with about 40% of one or more
alternate filler(s), or about 50% SMCC can be combined with about
50% of one or more alternate filler(s), or about 40% SMCC can be
combined with about 60% of one or more alternate filler(s), or
about 30% SMCC can be combined with about 70% of one or more
alternate filler(s), or about 20% SMCC can be combined with about
80% of one or more alternate filler(s).
[0106] In alternate embodiments, SMCC can be replaced with one or
more alternate excipients. Preferably, alternate excipients are
selected to provide favorable drug processing qualities. For
example, in one embodiment a 50:50 ratio of microcrystalline
cellulose to lactose can be used in place of SMCC. In this example,
the overall compressibility of the lactose would be improved
allowing for less compression force resulting in a more porous
tablet, film coated tablet, caplet, pellet, bead, or pill that can
show improved dissolution over the microcrystalline cellulose or
lactose alone. Other favorable excipient combinations will be
apparent to one of skill in the art.
[0107] The dry blend can also include at least one additional
suitable pharmaceutically acceptable excipient. Additional
excipients can include processing aids that improve the direct
compression tablet-forming properties of the dry blend, and/or
powder flowability. In the dry blend, excipients suitable for use
in direct compression include, but are not limited to, binders,
diluents, disintegrants, lubricants, fillers, carriers, and the
like as set forth above.
[0108] In one embodiment, the formulation comprises a mixture of
the drug substance with SMCC, and additional processing aides, such
as, for example, magnesium stearate and colloidal silicon dioxide,
and optionally, colorant(s). For example, in some embodiments,
colloidal silicon dioxide, which is a component of SMCC, is also
added separately to the formulation as a glidant to facilitate mass
flow of the powder mixture during blending and tablet compression
operations. Colloidal silicon dioxide can be added at
concentrations ranging from about 0.1% to about 5.0% w/w, or from
about 0.25% to about 2% w/w, or from about 0.5% to about 1%
w/w.
[0109] In some embodiments, magnesium stearate can be added as a
lubricant, for example, to improve powder flow, prevent the blend
from adhering to tableting equipment and punch surfaces and provide
lubrication to allow tablets to be cleanly ejected from tablet
dies. Magnesium stearate can typically be added to pharmaceutical
formulations at concentrations ranging from about 0.1% to about
5.0% w/w, or from about 0.25% to about 2% w/w, or from about 0.5%
to about 1% w/w.
[0110] In some embodiments, color additives also can be included.
The colorants can be used in amounts sufficient to distinguish
dosage form strengths. Preferably, color additives approved for use
in drugs (21 CFR 74, which is incorporated herein by reference in
its entirety) are added to the commercial formulations to
differentiate tablet strengths. The use of other pharmaceutically
acceptable colorants and combinations thereof are encompassed by
the current invention.
[0111] Binders can be used, for example, to impart cohesive
qualities to a formulation, and thus ensure that the resulting
dosage form remains intact after compaction. Suitable binder
materials include, but are not limited to, microcrystalline
cellulose, gelatin, sugars (including, for example, sucrose,
glucose, dextrose and maltodextrin), polyethylene glycol, waxes,
natural and synthetic gums, polyvinylpyrrolidone, cellulosic
polymers (including, for example, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl
cellulose, and the like).
[0112] Accordingly, in some embodiments, the formulations disclosed
herein can include at least one binder to enhance the
compressibility of the major excipient(s). For example, the
formulation can include at least one of the following binders in
the following preferred ranges: from about 2 to about 6% w/w
hydroxypropyl cellulose (Klucel), from about 2 to about 5% w/w
polyvinylpyrrolidone (PVP), from about 1 to about 5% w/w
methylcellulose, from about 2 to about 5% hydroxypropyl
methylcellulose, from about 1 to about 5% w/w ethylcellulose, from
about 1 to about 5% w/w sodium carboxy methylcellulose, and the
like. The above ranges are exemplary preferred ranges. One of
ordinary skill in the art would recognize additional binders and/or
amounts that can be used in the formulations described herein. As
would be recognized by one of ordinary skill in the art, when
incorporated into the formulations disclosed herein, the amounts of
the major filler(s) and/or other excipients can be reduced
accordingly to accommodate the amount of binder added in order to
keep the overall unit weight of the tablet unchanged. In one
embodiment, the binder(s) is(are) sprayed on from solution, e.g.
wet granulation, to increase binding activity.
[0113] Lubricants can be employed herein in the manufacture of
certain dosage forms. For example, a lubricant will often be
employed when producing tablets. In an embodiment of the invention
disclosed, a lubricant can be added just before the tableting step,
and can be mixed with the formulation for a minimum period of time
to obtain good dispersal. In some embodiments, one or more
lubricants can be used. Examples of suitable lubricants include,
but are not limited to, magnesium stearate, calcium stearate, zinc
stearate, stearic acid, talc, glyceryl behenate, polyethylene
glycol, polyethylene oxide polymers (for example, available under
the registered trademarks of Carbowax.RTM. for polyethylene glycol
and Polyox.RTM. for polyethylene oxide from Dow Chemical Company,
Midland, Mich.), sodium lauryl sulfate, magnesium lauryl sulfate,
sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal
silica, and others as known in the art. Preferred lubricants are
magnesium stearate, calcium stearate, zinc stearate and mixtures of
magnesium stearate with sodium lauryl sulfate. Lubricants can
comprise from about 0.25% to about 10% of the tablet weight, more
preferably from about 0.5% to about 3%.
[0114] Thus, in some embodiments, the formulations disclosed herein
can include at least one lubricant in the following preferred
ranges: from about 0.25 to about 2% w/w magnesium stearate, from
about 0.25 to about 2% w/w calcium stearate, from about 0.25 to
about 2% w/w sodium stearyl fumarate, from about 0.25 to about 2%
w/w stearic acid, from about 0.25 to about 2% w/w hydrogenated
vegetable oil, from about 0.25 to about 2% w/w glyceryl behenate,
from about 0.25 to about 2% w/w polyethylene glycol 4000-6000, and
the like. The above ranges are examples of preferred ranges. One of
ordinary skill in the art would recognize additional lubricants
and/or amounts that can be used in the formulations described
herein. As would be recognized by one of ordinary skill in the art,
when incorporated into the formulations disclosed herein, the
amounts of the major filler(s) and/or other excipients can be
reduced accordingly to accommodate the amount of lubricant(s) added
in order to keep the overall unit weight of the tablet
unchanged.
[0115] Disintegrants can be used, for example, to facilitate tablet
disintegration after administration, and are generally starches,
clays, celluloses, algins, gums or crosslinked polymers. Suitable
disintegrants include, but are not limited to, crosslinked
polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, and
croscarmellose sodium. If desired, the pharmaceutical formulation
can also contain minor amounts of nontoxic auxiliary substances
such as wetting or emulsifying agents, pH buffering agents and the
like, for example, sodium acetate, sorbitan monolaurate,
triethanolamine sodium acetate, triethanolamine oleate, sodium
lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene
sorbitan fatty acid esters, etc. and the like.
[0116] In some embodiments, at least one additional disintegrant
can be included in the following preferred ranges: from about 1 to
about 3% w/w croscarmellose sodium, from about 4 to about 6% w/w
sodium starch glycolate, from about 2 to about 4% w/w crospovidone,
from about 10 to about 20% w/w microcrystalline cellulose, from
about 5 to about 10% w/w pregelatinized starch, from about 5 to
about 10% w/w corn starch, from about 5 to about 10% w/w alginic
acid, from about 1 to about 5% w/w ion exchange resin (Amberlite
88), and the like. The above ranges are examples of preferred
ranges. One of ordinary skill in the art would recognize additional
disintegrants and/or amounts of disintegrants that can be used in
the formulations described herein. As would be recognized by one of
ordinary skill in the art, when incorporated into the formulations
disclosed herein, the amounts of the major filler(s) and/or other
excipients can be reduced accordingly to accommodate the amount of
disintegrant added in order to keep the overall unit weight of the
tablet unchanged.
[0117] In some embodiments, the formulations can include a coating,
for example, a film coating. Where film coatings are involved,
coating preparations can include, for example, a film-forming
polymer, a plasticizer, or the like. Also, the coatings can include
pigments and/or opacifiers. Non-limiting examples of film-forming
polymers include hydroxypropyl methylcellulose, hydroxypropyl
cellulose, methylcellulose, polyvinyl pyrrolidine, and starches.
Non-limiting examples of plasticizers include polyethylene glycol,
tributyl citrate, dibutyl sebecate, castor oil, and acetylated
monoglyceride. Furthermore, non-limiting examples of pigments and
opacifiers include iron oxides of various colors, lake dyes of many
colors, titanium dioxide, and the like.
Dosage
[0118] The selected dosage level can depend upon, for example, the
route of administration, the severity of the condition being
treated, and the condition and prior medical history of the patient
being treated. However, it is within the skill of the art to start
doses of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved with an acceptable safety
profile. It will be understood, however, that the specific dose
level for any particular patient can depend upon a variety of
factors including, for example, the genetic makeup, body weight,
general health, diet, time and route of administration, combination
with other drugs and the particular condition being treated, and
its severity. For the treatment of insomnia, preferably one dose is
administered prior to bedtime.
[0119] As used herein, the term "unit dosage form," refers to
physically discrete units suitable as unitary dosages for human and
animal subjects, each unit containing a predetermined quantity of
doxepin calculated in an amount sufficient to produce the desired
effect in association with a pharmaceutically acceptable excipient,
carrier or vehicle. In some embodiments, the unit dosage form can
be, for example, a pill, a tablet, a film coated tablet, capsule, a
caplet, a gel cap, a pellet, a bead, or the like. In some
embodiments, the unit dosage form can be a tablet. In some
embodiments, the unit dosage form can be a film coated tablet. In
some embodiments, the amount of doxepin in a unit dosage form can
be about 0.5 mg to about 9 mg, or about 1 mg to about 9 mg, or
about 1 mg to about 6 mg.
[0120] In some embodiments, daily dosages of low dose doxepin can
be about 1, 2, 3, 4, 5, 6, 7, 8, or 9 milligrams. In one
embodiment, an initial daily dosage of about 1 milligram can be
given. If the desired improvement in sleep is not achieved, then
the dosage can be incrementally increased until the desired effect
is achieved or until a maximum desired dosage is reached which can
be, for example, 2 milligrams, 3 milligrams, 4 milligrams, 5
milligrams or 6 milligrams. It should be noted that other dosages
of doxepin can be used in the embodiments described herein. For
example, the dosage can be about 0.1 to about 10 milligrams.
[0121] The term "low dose" can refer to a daily dose range of
between about 0.01 and 9 milligrams, or to even lower doses. In
some embodiments the preferable dosage of doxepin can be between
about 0.1 milligram and 9 milligrams. Preferably, the dosage can be
about 0.1 milligrams, about 0.2 milligrams, about 0.3 milligrams,
about 0.5 milligrams, about 1 milligram, about 2 milligrams, about
3 milligrams, about 4 milligrams, about 5 milligrams, 6 milligrams,
about 7 milligrams, about 8 milligrams, or about 9 milligrams.
[0122] It should be noted that in some embodiments the formulations
and methods described herein can be applied to any dosage of
doxepin, including higher doses used to treat depression and
anxiety. As one example, the formulations and methods can be
applied to dosages between about 10 milligrams and 20 milligrams or
higher.
Methods of Making Compositions
[0123] The compositions described herein can be made by any
suitable process, including any process that results in the a
composition having one or more of the properties described herein.
Several examples of processes and methods that can be used to make
compositions are described herein.
[0124] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipients with a pharmaceutical
composition as described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. In one embodiment, the compositions can be prepared using a
dry granulation process. Alternatively, a wet granulation process
can be used. In other embodiments, fluid bed granulation processing
techniques are used.
[0125] One such granulation method is the "wet" granulation
process, wherein dry solids (drug substance, filler, binder etc.)
are blended and moistened with water or another wetting agent (e.g.
an alcohol) and agglomerates or granules are built up of the
moistened solids. Wet massing is continued until a desired
homogenous particle size has been achieved whereupon the granulated
product is dried. Some embodiments can include the use of wet
granulation processes as part of the methods of making
compositions.
[0126] In a preferred embodiment, the compositions disclosed herein
can be prepared using direct compression. In another preferred
embodiment, compressed tablets can be film coated. In some
embodiments of the invention disclosed herein, the use of wet
granulation techniques can be specifically excluded.
[0127] As used herein, "direct compression" means that the solid
unit dosage form is prepared by compression of a simple mixture of
the active pharmaceutical ingredient and excipients, without the
active ingredient having been subjected to an intermediate
granulation process in order to embed it in a larger particle and
improve its fluidity properties.
[0128] In direct compression, the formulation ingredients,
including the active pharmaceutical ingredient and processing aids,
are incorporated into a free flowing blend. In one embodiment, the
active ingredient, excipients, and other substances are blended and
then compressed into tablets. Tablets are typically formed by
pressure being applied to a material in a tablet press. Compressed
tablets can be film coated.
[0129] Advantages of direct compression over wet and dry
granulation processes, can include, for example, shorter processing
times and cost advantages.
[0130] In one embodiment, a dry blend is used in forming low-dose
doxepin or doxepin-related compound tablets, including film coated
tablets, through gravity-fed, direct compression tableting. By
"gravity fed tableting press" it is meant that a pharmaceutical
formulation is not force fed into a die, and that the flow of the
pharmaceutical formulation is induced by gravity. An example of a
gravity fed tableting press is the Manesty F-press.
[0131] Preferably, the doxepin hydrochloride tablet products
(including film coated and non-film coated tablets) disclosed
herein are manufactured with common and simple processes including
direct blending, compression and film-coating using commercially
available pharmaceutical equipment. These operations utilize
readily available equipment, do not expose the API to excessive
moisture and heat, and are scalable. Preferably, the commercial
manufacturing process produces and maintains blends and tablets
with uniform potency that meet all quality characteristics. In a
preferred embodiment, the manufacturing processes for all dosage
strength formulations can be the same.
[0132] The manufacturing process can include the steps of: (1)
preparing a color pre-blend; (2) preparing a drug substance
pre-blend (also known as an active blend); (3) creating a main
blend with all ingredients except magnesium stearate (lubricant);
(4) adding lubricant and performing the final blend mixing step;
(5) compressing the blend to produce tablets and (6) film-coating
tablets. In some aspects, one or more of the above-listed steps can
be excluded and the steps can be performed in any suitable order,
not just the listed order.
[0133] The process can optionally include several techniques to
facilitate formation of blends and batches of finished drug product
with homogeneous distribution of drug substance and colorants
including, for example: (1) de-agglomerating ingredients prior to
blending; and/or (2) layering the drug substance and colorant
components between additions of SMCC prior to mixing to create
uniform pre-blends; and/or (3) serially diluting the drug substance
and colorant pre-blends with SMCC and other formulation excipients
to create uniform final blends. In addition, the process can
optionally include, for example, (1) performing blend mixing time
studies and assessing drug substance uniformity; and/or (2)
optimizing the blend batch size with respect to the effective
working capacity of the blenders.
[0134] Efficient mixing and acceptable blend and content uniformity
are difficult to obtain for low dose dosage forms. Preferably, the
choice of blenders and the configuration of the storage container
to tablet press powder transfer chute are selected based on
optimization and maintenance of content uniformity. In addition,
excipients and process parameters can be selected to optimize main
compression force and tablet press speed on the physical
characteristics (hardness, friability, thickness and weight) of the
finished dosage form.
[0135] In addition, the process can be optimized to compensate for
the tendency for fluidization segregation of drug substance. For
example, fluidization segregation can be reduced by eliminating
process steps during which streams of air come in contact with the
powder, for example, the step in the process when the blend is
discharged from a V-blender into storage containers, and/or the
step in the process when powder is fed from storage containers to
the tablet press feed hopper.
[0136] In a preferred embodiment, the formulation is simple and
contains few functional components. Thus, in one embodiment, SMCC
can be the major excipient and no additional diluents, binders or
disintegrants are used to achieve a readily compressible tablet
formulation. In another embodiment, only one or two additional
excipients are used.
[0137] Preferably, the formulation can have excellent compression
and flow properties and the tablet press can be operated at very
high press speeds and this allows relatively manageable tablet
press run times for even large batch sizes.
[0138] In some embodiments, the direct compression manufacturing
processes disclosed herein achieve a uniform drug product of a
small unit dose of drug substance without the need for complex wet
or dry granulation manufacturing techniques. In a preferred
embodiment, the manufacturing process avoids costly techniques,
such as those requiring large capital equipment investments, long
manufacturing cycle times and associated low throughput.
[0139] In one embodiment, the manufacturing process is designed to
achieve a uniform blend by using multiple blending steps, a
specific order of addition in the blenders and screening steps to
facilitate effective dispersion of the drug substance and
excipients. For example, a screening step can be introduced to
prevent agglomerates of drug substance from being carried over to
subsequent manufacturing steps.
[0140] In another embodiment, the manufacturing process is designed
to maintain the uniform blend through to tableting via minimizing
the transfer steps, for example, by using an in-bin blender to form
the final blend and for example via use of a vented and valved
transfer chute to the tablet press.
Methods of Using Low Dose Doxepin
[0141] Some embodiments relate to methods for improving sleep in a
patient in need thereof, for example by providing or administering
low-dose doxepin, or a low-dose doxepin-related compound, in a
tablet formulation (including coated tablet formulations) as
described herein. The term "administer" and its variants
contemplate both self-administration (by the patient) and
administration by a third party. In a preferred embodiment, the
oral pharmaceutical SMCC-containing doxepin formulations described
herein are administered orally.
[0142] As mentioned above and elsewhere, the methods described
herein can be used to treat individuals suffering from a sleep
disorder, such as insomnia. The individual can suffer from a
chronic insomnia or a non-chronic insomnia. For chronic (e.g.,
greater than 3-4 weeks) or non-chronic insomnias, a patient may
suffer from difficulties in sleep onset, sleep maintenance
(interruption of sleep during the night by periods of wakefulness),
sleep duration, sleep efficiency, premature early-morning
awakening, or a combination thereof. Also, the insomnia may be
attributable to the concurrent use of other medication, for
example. The non-chronic insomnia can be, for example, a short term
insomnia or a transient insomnia. The chronic or non-chronic
insomnia can be a primary insomnia or an insomnia that is secondary
or attributable to another condition, for example a disease such as
depression or chronic fatigue syndrome. In some aspects, the
patient can be one that is not suffering from an insomnia that is a
component of a disease, or a patient can be treated that is
otherwise healthy. As previously mentioned, the chronic or
non-chronic insomnia can be a primary insomnia, that is, one that
is not attributable to another mental disorder, a general medical
condition, or a substance. In many cases, such conditions may be
associated with a chronic insomnia and can include, but are not
limited to, insomnia attributable to a diagnosable DSM-IV disorder,
a disorder such as anxiety or depression, or a disturbance of the
physiological sleep-wake system. In some aspects the insomnia can
be non-chronic, or of short duration (e.g., less than 3-4 weeks).
Examples of causes of such insomnia may be extrinsic or intrinsic
and include, but are not limited to environmental sleep disorders
as defined by the International Classification of Sleep Disorders
(ICSD) such as inadequate sleep hygiene, altitude insomnia or
adjustment sleep disorder (e.g., bereavement). Also, short-term
insomnia may also be caused by disturbances such as shift-work
sleep disorder.
[0143] It should be noted that in some aspects, the methods can
specifically exclude one or more of any of the sleep disorders
described in the previous paragraph or elsewhere herein. For
example, without being limited thereto, in some aspects the methods
can specifically exclude treating a chronic insomnia. As another
example, without being limited thereto, in some aspects the methods
can specifically exclude treating an insomnia that is attributable
to a condition such as depression, anxiety or chronic fatigue.
[0144] In a preferred embodiment, the methods can include treating
onset, duration, and maintenance aspects of insomnia in a
patient.
[0145] The pharmaceutical tablet formulations (including coated
tablets) disclosed herein have surprising efficacy, even in low
doses, and also can allow a full 7 or 8 hours of sleep, or more,
without significant next-day sedation. It is believed that these
formulations are safe, provide rapid sleep onset, maintains sleep
throughout the night for a full 7 or 8 hour sleep cycle, and allow
normal activity the next day without hangover or unsafe levels of
sedation.
EXAMPLES
[0146] Several of the examples below describe multiple strengths (1
mg, 3 mg and 6 mg) of a stable, immediate-release, solid, oral
dosage. Tablet formulations were developed after extensive testing
and development, and after overcoming several previously unmet and
unexpected challenges.
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-US-00001 TABLE 1 Non-film coated tablets 1 mg 3 mg 6 mg Item
Material % Mg/tab % Mg/tab % Mg/tab 1 Doxepin HCl 0.753 1.13 2.26
3.39 4.52 6.78 2 Silicified 98.53 147.80 96.71 145.07 94.00 141.00
Microcrystalline Cellulose 3 Colloidal Silicon 0.16 0.24 0.47 0.71
0.88 1.32 Dioxide 4 FD&C Blue 1 Al -- -- 0.05 0.08 0.02 0.03
Lake 10-13% 5 DC Yellow 10 Al 0.04 0.06 -- -- 0.08 0.12 Lake 36-42%
6 FD&C Yellow #6 Al 0.01 0.015 -- -- -- -- Lake 15-18% 7
Magnesium Stearate 0.50 0.75 0.50 0.75 0.50 0.75 Totals 100.00
150.00 100.00 150.00 100.00 150.00 Film coated tablets 1 mg 3 mg 6
mg Item Material % Mg/tab % Mg/tab % Mg/tab 1 Doxepin HCl 0.724
1.13 2.17 3.39 4.35 6.78 2 Silicified 94.79 147.88 93.04 145.15
90.48 141.15 Microcrystalline Cellulose 3 Colloidal Silicon 0.15
0.24 0.46 0.71 0.85 1.32 Dioxide 4 Magnesium Stearate 0.48 0.75
0.48 0.75 0.48 0.75 5 Film coat 3.8 6 3.8 6 3.8 6 Totals 100.00
156.00 100.00 156.00 100.00 156.00
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.degree. C..+-.0.5.degree. 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-US-00002 TABLE 3 Simulated Gastric 0.05M Acetate Simulated
Intestinal Fluid (pH 1.2) Buffer (pH 4.5) Fluid (pH 6.8) Time point
1 mg 6 mg 1 mg 6 mg 1 mg 6 mg 3 minutes *83% 70% *84% 71% 55% 57% 5
minutes *91% *85% *93% *80% 69% 72% 10 minutes *94% *90% *99% *91%
79% *81% 15 minutes *96% *94% *101% *95% *81% *84% 30 minutes *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 falling below
Q--15%.
Example 3: Comparative Dissolution
[0150] Table 4 contains comparative dissolution data generated for
commercially-available, high-dose doxepin (i.e. 50 mg and 75 mg
Sinequan) as well as lactose and SMCC-based, low-dose doxepin
formulations. The reported data are an average of a least 6
dissolution values for the various formulations at the indicated
time points and were generated using the USP-based method, which
methods are incorporated herein by reference in their entireties,
for measurement of doxepin dissolution. These data clearly show
that the low-dose doxepin formulations exhibit significantly faster
dissolution characteristics.
TABLE-US-00003 TABLE 4 Dissolution Percent (%) Released Low Dose
Low Dose Low Dose Doxepin Doxepin Elapsed Doxepin Tablet - Tablet -
Time Sinequan Sinequan Capsule Uncoated Coated (minutes) (50 mg)
(75 mg) (lactose) (SMCC) (SMCC) 0 0 0 0 0 0 3 NT.sup.a NT NT 75.3
63.1 5 6 16 92.1 94.3 81.8 8 NT NT 91.8 NT NT 10 40 38 ND 96.9 91.6
12 NT NT 92.9 NT NT 15 70 62 93.6 97.9 94.1 30 101 96 89.9 99.1 97
.sup.aNT = "Not tested" at that time point for that formulation
[0151] Thus, some embodiments relate to low dose doxepin
formulations that have the unexpected dissolution properties listed
above. For example, some embodiments relate to formulations that
release at least from about 60% to about 99.5% doxepin after about
5 to about 40 minutes. The release or dissolution can be determined
using the USP-based methods. Preferably, 60%, 65%, 70%, 75%, 80%,
85%, 90%, 95% or 99.5% doxepin is released after 3, 5, 10, 15 or 30
minutes, for example.
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 SMCC. 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.
Example 5: Content Uniformity--Fluidized Segregation
[0154] Following the production of 10 kg batches for clinical
evaluation, the drug product manufacturing process was scaled up to
120 kg and the final formulation (colored tablets) was
manufactured. Evaluation of content uniformity data associated with
tablets compressed from these 120 kg batches demonstrated lower
than expected assay values for tablets produced at the beginning of
the tablet compression operation and higher than expected assay
values for tablets produced at the end of the compression
operation. Fluidization segregation was determined to be
responsible for this content uniformity variability.
[0155] In order to avoid fluidization segregation, process steps
that allow streams of air to come in contact with free falling
powder were eliminated. Thus, in some embodiments, the process
steps can include reducing the contact of streams of air with the
free falling powder and/or any other fluidization segregation
reduction method.
[0156] In scaling up the process to 560 kg, the following process
and equipment changes were implemented to optimize tablet content
uniformity. The changes are not meant to limit the manner in which
the formulations can be produced or to be construed as teaching
away from the uses of certain apparatus or to exclude the use of
certain of the changed apparatus. In fact, the changed apparatus
and/or methods can be utilized in some aspects alone or in any
combination. The changes are provided to show several preferred
aspects of the embodiments.
[0157] Change 1: Use a 5 ft.sup.3 V-blender rather than a 3
ft.sup.3 cross-flow blender for the preparation of the active
pre-blend and a 60 ft.sup.3 in-bin blender rather than a 10
ft.sup.3 V-blender for final blend to assure that the volume of
powder in the blenders does not exceed the effective working volume
of tumble blenders.
[0158] Change 2: Store final blend in the 60 ft.sup.3 in-bin
blender rather than discharge from V-blender into storage
containers in order to eliminate a process step that can cause
fluidization segregation.
[0159] Change 3: Addition of valves and vents to the powder
transfer chute through which blend is delivered to the tablet press
from the blend storage container. A multi-segment transfer chute
equipped with a series of valves that are sequentially opened
allows the gradual introduction of blend into the tablet press feed
frame rather than blend free-falling from the blend storage vessel
through the current single-piece chute. The presence of
filter-equipped vents on the multi-segment powder transfer chute
allows air, displaced when a segment of the powder transfer chute
fills with powder, to escape through a vent rather than the
displaced air being forced through the blend in the bin. This
eliminates another potential source of drug substance fluidization
segregation.
[0160] To confirm that the foregoing process changes resulted in
better content uniformity, two feasibility batches were produced at
approximately commercial scale. Both batches were formulated at a
theoretical potency of 1 mg since that dosage strength exhibited
content uniformity values greater than 10% from target at both the
beginning and end of the compression operation. To facilitate
uniform dispersal of drug substance in the formulation, the
strategies of layering doxepin HCl, USP between additions of SMCC
to create a drug substance pre-blend and taking opportunities to
serially dilute the drug substance pre-blend with additional SMCC
were incorporated into the scaled-up manufacturing process. FIG. 2
presents a graphical comparison of content uniformity associated
with tablets systematically sampled throughout the 120 kg
registration stability batch (3047751R) and the feasibility batches
at commercial scale (PTR 1556 and 1605).
[0161] Briefly, low-dose doxepin tablets were manufactured at a
scale of 560 kg by standard processes which included dry blending,
direct compression and primary packaging into high density
polyethylene bottles with polypropylene child-resistant closures
and pharmaceutical cotton for void fill (HDPE bottles) as well as
polyvinyl chloride/polyvinylidene chloride (PVC/PVDC), heat-sealed
foil-laminate blister strips (blisters) using commonly available
pharmaceutical equipment.
[0162] Thus, some embodiments relate to methods of improving
uniformity by minimizing segregation, including fluidized
segregation. The methods can include one or more of utilizing
devices with vents, valves or other mechanisms that permit the
escape of air or that minimize the contact of air with the low dose
doxepin blends, for example.
Example 6: Content Uniformity--API Agglomeration
[0163] Low dose doxepin tablets can exhibit potencies outside the
USP range that constitutes uniformity of dosage units. This can be
caused by non-uniform distribution of drug substance in the
formulation. This can be due, for example, to small agglomerates of
drug substance present in the final blend following the series of
operational steps associated with the blend manufacturing process.
A technical investigation unexpectedly confirmed that drug
substance was re-agglomerating following operational steps that
allowed screened particles of cohesive powders to re-associate. For
instance, when particles of insufficiently-diluted drug substance
pass through the screen on a SWECO-type vibratory sieve, they fall
onto a shelf below the screen. The circular, vibrating motion of
the sieve can cause re-agglomeration of drug substance as the
screened particles physically interact during their
mechanically-induced migration to the discharge orifice of the
vibratory sieve. To avoid drug substance re-agglomeration, portions
of drug substance were layered between larger portions of SMCC and
mixed to adequately dilute the drug substance. The diluted and
mixed drug substance pre-blend was then screened using a cone-mill
that eliminates situations in which inadequately diluted portions
of drug substance were screened in a manner that allowed
re-agglomeration.
[0164] Thus, some embodiments relate to methods of preventing,
avoiding or minimizing re-agglomeration low dose doxepin mixtures
or formulations. Such methods can include diluting the drug
substance, for example, as described above by layering the drug
substance between larger portions of SMCC. Any other suitable
method can also be used which dilutes the drug substance and/or
which minimizes re-agglomeration. Also, the methods can include the
use of a cone mill, a co mill or any other like device.
Example 9: Large Scale Manufacturing Process for Non-Film Coated
Tablets
[0165] The following manufacturing process description is for the 3
mg formulation at a 560 kg batch size and is relevant for the other
low-dose tablet formulations. FIGS. 3A-3C provide a summary of the
process described below. The batch size is representative of
potential commercial batch sizes and is not intended to limit the
invention. One skilled in the art would appreciate that the batch
size is arbitrary and a range of batch sizes are encompassed by
this invention.
[0166] Color Pre-Blend (FIGS. 4-6)
[0167] A color pre-blend was prepared by a three step
blend-mill-blend process. Approximately 5% (25.7 kg) of SMCC, the
entire quantity of colorant and another approximately 5% of SMCC
were sequentially added to a 5 cubic foot V-blender and mixed for
20 minutes. Then, this blend was processed in a hammer mill
equipped with an 80 mesh screen at high speed with the hammers
forward. Prior to hammer milling the color pre-blend, a 2 kg
portion of SMCC was processed. This allowed layering of the milled
color pre-blend between layers of SMCC following the dry rinsing of
the hammer mill with another 2 kg portion of SMCC. Lastly, the
hammer-milled color pre-blend was added to a 10 cubic V-blender
containing 21 kg of SMCC. 2.63 kg colloidal silicon dioxide was
added to the V-blender followed by another 21 kg of SMCC to again
layer and serially-dilute the color component. The powder mixture
was mixed for 30 minutes and discharged directly through a
vibrating sieve equipped with a 30 mesh screen into two separate
drums.
[0168] The approximately equal quantities of color pre-blend in the
two drums were used to layer the drug substance in the next phase
of the manufacturing process.
[0169] Drug Substance Pre-Blend (FIGS. 7 and 8)
[0170] Next, the drug substance was de-agglomerated. Briefly, the
entire quantity, 12.65 Kg, of doxepin hydrochloride was screened
through the vibrating sieve equipped with a 30 mesh screen into an
appropriate polyethylene-lined vessel containing 2 kg of SMCC. A
small portion of SMCC was used to dry rinse the bag into which the
drug substance was initially dispensed. This portion of SMCC was
then passed through the vibrating sieve followed by a 20 kg portion
of SMCC to dry rinse the 30-mesh screen.
[0171] The de-agglomerated drug substance and SMCC were added to
the 10 cubic V-blender and mixed for 10 minutes. The initial drug
substance was discharged and screened using a vibrating sieve
equipped with a 30 mesh screen. The screened initial drug substance
pre-blend was added to a 10 cubic foot V-blender containing one
drum of screened color pre-blend. The second drum of screened color
pre-blend was then added to the 10 cubic V-blender to layer the
drug substance. A portion of the powder from the second drum was
used to dry rinse the polyethylene bag, into which the drug
substance was screened, and added to the V-blender. The material
was mixed for 10 minutes and then discharged directly through the
vibrating sieve equipped with a 30 mesh screen into polyethylene
lined containers. The screened drug substance pre-blend was
returned to the 10 cubic foot V-blender and mixed for an additional
10 minutes. The drug substance pre-blend was discharged directly
through a vibrating sieve equipped with a 30-mesh screen into
poly-lined containers.
[0172] In another embodiment, the doxepin hydrochloride drug
substance can be milled using a pharmaceutically acceptable mill
such as a fluid energy, impact, cutting, compression, screening or
tumbling mill as defined in the Guidance for Industry SUPAC-IR/MR:
Immediate Release and Modified Release Solid Oral Dosage
Forms--Manufacturing Equipment Addendum, January 1999. This
blending process step can use milled or de-agglomerated drug
substance, for example.
[0173] Preparation of the Final Blend (FIG. 9)
[0174] The final blend was prepared by adding the screened drug
substance pre-blend to a 60 cubic foot in-bin tumble blender
containing 212 kg of SMCC. Another 212 kg of SMCC was then added to
the 60 cubic foot in-bin tumble blender to layer and serially
dilute the drug substance pre-blend. The material was mixed for 20
minutes.
[0175] Optionally, magnesium stearate, 2.8 kg, was then added to
the 60 cubic foot in-bin tumble blender and mixed for 8 minutes.
The blend was stored in the in-bin tumble blender until compressed
into tablets.
[0176] Tablet Compression (FIG. 9)
[0177] Tablets were manufactured by positioning the final blend
contained in the in-bin blender tote above the tablet press feed
hopper. A segmented powder transfer chute was used to introduce
doxepin powder mixtures into the press hopper with each segment of
the powder transfer chute being equipped with a valve and a vent.
The valves on the in-bin blender tote and each segment of the
powder transfer chute were opened sequentially to reduce the volume
of air that comes into contact with free-falling powder and to
prevent fluidization segregation. Tablets were compressed on a
single-sided, 38-station rotary HATA tablet press at a target speed
of 35 to 70 rpm and main compression force of approximately 0.30
metric tons.
Example 8: Large Scale Manufacturing Process for Film-Coated
Tablets
[0178] The following manufacturing process description is for a 3
mg formulation and can be used for other low-dose tablet
formulations. The batch size is representative of potential
commercial batch sizes and is not intended to limit the invention.
One skilled in the art will appreciate that the batch size is
arbitrary and a range of batch sizes are encompassed by this
invention.
[0179] Drug Substance Pre-Blend (FIGS. 14 and 15)
[0180] Briefly, 12.66 Kg, of doxepin hydrochloride and 2.65 Kg of
silicon dioxide are added to a ten cubic foot V-blender containing
55.93 Kg of SMCC. Another 55.93 Kg of SMCC are added to the blender
and mixed for approximately 10 minutes. The discharged drug
substance pre-blend is deagglomerated through a cone mill equipped
with a 0.8 mm screen. The screened drug substance pre-blend is
returned to the ten cubic foot V-blender and mixed for another 10
minutes. The drug substance pre-blend is discharged directly
through a vibratory sieve equipped with a 30-mesh screen. The drug
substance pre-blend is again returned to the V-blender, mixed for
another 10 minutes and screened using a vibratory sieve equipped
with a 30-mesh screen.
[0181] In another embodiment, the doxepin hydrochloride drug
substance can be milled using a pharmaceutically acceptable mill
such as a fluid energy, impact, cutting, compression, screening or
tumbling mill as defined in the Guidance for Industry SUPAC-IR/MR:
Immediate Release and Modified Release Solid Oral Dosage
Forms--Manufacturing Equipment Addendum, January 1999, which is
incorporated herein by reference in its entirety. This blending
process step can use milled or de-agglomerated drug substance, for
example.
[0182] Preparation of the Final Blend (FIG. 9)
[0183] The final blend was prepared by adding the screened drug
substance pre-blend to a 60 cubic foot in-bin tumble blender
containing 215 kg of SMCC. Another 215 kg of SMCC was then added to
the 60 cubic foot in-bin tumble blender to layer and serially
dilute the drug substance pre-blend. The material was mixed for 20
minutes.
[0184] Optionally, magnesium stearate, 2.8 kg, was then added to
the 60 cubic foot in-bin tumble blender and mixed for 5 minutes.
The blend was stored in the in-bin tumble blender until compressed
into tablets.
[0185] Tablet Compression (FIG. 9)
[0186] Tablets were manufactured by positioning the final blend
contained in the in-bin blender tote above the tablet press feed
hopper. A segmented powder transfer chute was used to introduce
doxepin powder mixtures into the press hopper with each segment of
the powder transfer chute being equipped with a valve and a vent.
The valves on the in-bin blender tote and each segment of the
powder transfer chute were opened sequentially to reduce the volume
of air that comes into contact with free-falling powder and to
prevent fluidization segregation. Tablets were compressed on a
single-sided, 38-station rotary HATA tablet press at a target speed
of 35 to 70 rpm and main compression force of approximately 0.30
metric tons.
[0187] Film-Coating:
[0188] The approximately 560 Kg of tablets is divided into five,
approximately 110 Kg portions of tablets. One portion of compressed
tablets was added to a 48 inch coating pan. The doxepin recipe is
accessed in the process control computer and the following settings
are input onto the screen.
TABLE-US-00004 Atomization Air 125 SLPM Pattern Air 55 SLPM Nozzle
Air 72 psi Gun Position A = 8; B = 2 and C = 6
[0189] At the conclusion of the computer controlled application
process, an average percent weight gain for the tablet cores is
calculated. The above process is repeated
Example 9: Comparison of SMCC with Other Direct Compression (DC)
Excipients
[0190] 12 kg SMCC and other common excipient formulations with
colorants (Yellow #6 and Yellow #10) and doxepin at a theoretical
concentration of 1 mg were generally prepared using the process set
forth above.
[0191] Briefly, experiments were performed to confirm the role
silicified microcrystalline cellulose (ProSolv) plays in imparting
some preferred quality characteristics to low-dose doxepin tablets.
Common, best-in-class, direct-compression-type excipients were
directly substituted for SMCC, a high-functionality excipient, in
the formulation set forth above. These substitute excipients
included the following.
[0192] Vivapur (microcrystalline cellulose)
[0193] Dipac (a directly compressible sugar)
[0194] Emcompress (Dicalcium phosphate)
[0195] Mannogem (mannitol, a directly compressible alcohol)
[0196] Pharmatose (spray-dried lactose)
[0197] Starch 1500 (pre-gelatinized starch)
[0198] The compaction and ejection forces necessary to manufacture
tablets from these formulations on an automated, rotary tablet
press, at a target hardness value of 10 kp, were recorded.
Unexpectedly, the SMCC formulation exhibited an average hardness of
9.1 kp with a standard deviation of 1.16 using a compaction force
of 136 pounds. The Dipac, Pharmatose and Vivapur formulations
achieved satisfactory levels of hardness but required average
compaction forces of 1,204 pounds, 807 pounds, and 189 pounds,
respectively.
[0199] For the SMCC and other four substitute formulations, tablets
samples were systematically taken throughout the compression
operation and tested for weight, hardness, thickness and
friability. The SMCC formulation achieved a friability value of
0.11%. The Vivapur, Pharmatose, and the Dipac formulations achieved
friability values of 0.07%, 0.09%, 0.17%, respectively.
[0200] These data associated with the non-SMCC formulations were
compared to the corresponding SMCC data to detect statistically
significant differences in mean values (t-test) and degree of data
variability (F-test). Disintegration, dissolution profile and
content uniformity testing were also conducted on representative
tablets samples from these compressed formulations. Dissolution
profiles in simulated gastric fluid without enzyme pH 1.2 are
provided in FIG. 10. Dissolution data calculations were performed
to determine the f.sub.2 similarity factor for each formulation
relative to the SMCC formulation.
[0201] Unexpectedly, no substitute formulation achieved the
threshold dissolution f.sub.2 similarity factor value of 50
compared to an SMCC based formulation. The f.sub.2 values ranged
from 4.2 to 30.8. Disintegration is another drug product
performance characteristic for which the SMCC formulation can be a
preferred formulation. SMCC formulation disintegration rate was
less than 6 seconds based on USP protocols. The Vivapur formulation
disintegration rate was approximately 1 to 2 minutes.
[0202] The SMCC formulation statistically differentiated (i.e. p
values<<0.05) itself with respect to the variability of the
in-process weight data from the Vivapur formulation and in-process
thickness data for substitute formulations. In addition, the SMCC
formulation required lower compaction and ejection forces compared
to substitute formulations. The degree of difference has
significant ramifications related to tablet machine and tooling
wear.
[0203] Although, SMCC demonstrates some preferred characteristics
and is a preferred material in some aspects of the embodiments, it
should be understood that other materials, including those tested
above, can also be used alone or in combination with each other
and/or SMCC in various aspects of the embodiments. Some examples of
combinations are described further in the examples and elsewhere
herein.
Example 10. Fluid Bed Granulation Process
[0204] A flow chart depicting an exemplary fluid bed granulation
manufacturing process for use with the formulations described
herein is provided in FIGS. 11A and 11B.
Example 11: Wet Granulation Process
[0205] A flow chart depicting an exemplary wet granulation
manufacturing process for use with the formulations described
herein is provided in FIGS. 12A and 12B.
[0206] In some aspects a wet granulation process can be utilized to
minimize segregation of the low dose doxepin during the production
of dosage forms.
Example 12: Dry Granulation Process
[0207] A flow chart depicting an exemplary dry granulation
manufacturing process for use with the formulations described
herein is provided in FIGS. 13A and 13B.
Example 13: Formulations Demonstrating Unique pK Profile
[0208] The pharmacokinetic performance of oral, low dose doxepin
formulations is well suited to the treatment of insomnia. The
pharmacokinetic performance of capsules containing 1, 3 or 6 mg
doxepin, as well as tablets containing 6 mg doxepin, was evaluated
in healthy adult volunteers under a crossover design.
[0209] Table 5 presents the results.
TABLE-US-00005 TABLE 5 Descriptive Statistics for Doxepin
Pharmacokinetic Parameters Parameter (6 mg (6 mg (3 mg (1 mg
(Unit).sup.[a] capsules) tablets) capsules) capsules) AUC.sub.0-t
13.76 (82.9) 13.03 (70.8) 5.689 (68.9) 1.561 (76.7) (ng*h/mL) [n =
16] [n = 16] [n =13] [n = 13] AUC.sub.0-.infin. 16.26 (81.6) 15.19
(69.1) 7.518 (64.6) [b] (ng*h/mL) [n = 16] [n = 16] [n = 12] [n =
2] C.sub.max 0.9458 (64.5) 0.8864 (59.4) 0.4445 (54.0) 0.1587
(55.5) (ng/mL) [n = 16] [n = 16] [n = 13] [n = 15] T.sub.max 4.0
(1.0-6.0) 3.5 (2.0-6.0) 4.0 (1.0-6.0) 4.0 (1.5-8.0) (h) [n = 16] [n
= 16] [n = 13] [n = 14] t.sub.1/2 15.13 (41.9) 15.32 (31.3) 14.28
(46.8) [b] (h) [n = 16] [n = 16] [n = 12] [n = 5] .sup.[a]Estimates
presented are the arithmetic mean and (CV %) for AUC, C.sub.max and
t.sub.1/2 and the median and (range) for T.sub.max. [b] Parameter
could not be calculated accurately.
[0210] Of special note was the time taken to reach the maximum
plasma concentration (Tmax), which, on average, was 3.5-4 hours for
all doses, and the half-life, which, on average, fell between 14.28
and 15.32 hours. Of further interest to the pharmacokinetic
performance of these doxepin formulations was the time necessary to
reach certain plasma concentrations. Reaching particular
concentrations in plasma can play a role in establishing
therapeutic benefit. In particular, doxepin concentrations in
plasma reach 0.05 ng/mL in the majority of subjects for all doses
within 90 minutes after dosing. For the 3 and 6 mg doses, a plasma
concentration of 0.1 ng/mL was reached in the majority of subjects
within 60 minutes of dosing. Such pharmacokinetic performance is
beneficial in the treatment of insomnia, as reaching measurable
plasma concentrations in a timely manner can be preferred for
facilitating the onset of sleep.
[0211] Thus, the therapeutic properties of doxepin in insomnia are
reflected in a correspondence between plasma concentrations and the
state of wakefulness, as well as the particular profile of such
concentrations over the course of the night. Taking the 3 mg dose
as an example, doxepin plasma concentrations, on average, reached
0.1 mg/mL approximately 1 hour after dosing. Because of doxepin's
high affinity for histamine H1 receptors, this concentration is
sufficient to initiate and maintain sleep. Accordingly, taking the
customary pretreatment period of 30 minutes before bed into
account, sleep onset can occur approximately at the time the
concentration reached 0.1 ng/mL. This preferable concentration may
vary due to individual differences in drug sensitivity or disease
severity. In examining polysomnographic endpoints in adult insomnia
patients treated with 3 mg doxepin, sleep onset was reached, on
average, 27 minutes after bedtime, a time point roughly 1 hour
after dosing. Further, the same patients experienced improvements
in the maintenance of sleep. In accordance with the pharmacokinetic
profile afforded by doxepin formulations, the improvements in sleep
maintenance persisted throughout the entire night (8 hours) but not
followed by residual sedation. The combination of high solubility
and high permeability with rapid dissolution, absorption and a
metabolic clearance rate which afforded therapeutic concentrations
throughout the night all contributed to the beneficial
pharmacokinetic profile. Having a formulation with a rapid
absorption phase corresponding with Cmax at 3-4 hours post-dose,
and a half-life of approximately 14-15 hours can be preferable for
the safety and efficacy profile of low dose doxepin in
insomnia.
[0212] Thus, some embodiments relate to formulations comprising low
dose doxepin, preferably between about 0.5 and 7 mg doxepin, which
formulations after administration (e.g., to a 70 kg human), provide
a plasma concentration of at least 0.05 ng/mL doxepin within a time
frame of not more than about 80 or 90 minutes or a plasma
concentration of at least 0.1 ng/mL within a time frame of not more
than about 50 or 60 minutes.
[0213] The formulations of some of the present embodiments can
provide rapid rise in plasma concentrations following
administration, e.g., achieving a plasma concentration of about 0.1
ng/mL following a 3 mg or a 6 mg dose in 60 minutes or less, for
example, within 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30
minutes, or less. Also, some can achieve plasma concentrations of
about 0.05 ng/mL following a 1 mg, 3 mg or a 6 mg dose in 90
minutes or less, for example, 85 minutes or less, 80 minutes or
less, 75 minutes or less, 70 minutes or less, 65 minutes or less,
60 minutes or less, for example, within 50 minutes, 45 minutes, 40
minutes, 35 minutes, 30 minutes, or less. Accordingly, some
embodiments relate to formulations and dosage forms that result in
more rapid achievement of effective plasma concentrations of
doxepin leading to more rapid drug onset (e.g., sleep onset) at the
dosages described herein, including, for example, dosages of 1 mg,
3 mg or 6 mg.
[0214] Furthermore some embodiments relate to formulations
comprising low dose doxepin, which formulations after
administration result in any one or more of the pK results shown in
Table 5. For example, the formulations can result in an AUC from
about 1.4 to about 14 ng*h/mL. Preferably, a 1 mg formulation upon
administration can result in an AUC of about 1.5 ng*h/mL.
Preferably, a 3 mg formulation upon administration can result in an
AUC of about 5-6 ng*h/mL. Preferably, a 6 mg formulation upon
administration can result in an AUC of about 12.5-14 ng*h/mL.
[0215] Some embodiments relate to formulations that upon
administration can result in a C.sub.max of about 0.15 ng/mL to
about 1.0 ng/mL. Preferably, a 1 mg formulation upon administration
can result in a C.sub.max of about 0.14-0.16 ng/mL. Preferably, a 3
mg formulation upon administration can result in a C.sub.max of
about 0.4-0.5 ng/mL. Also, preferably, a 6 mg formulation upon
administration can result in a C.sub.max of about 0.8-1.0
ng/mL.
Example 14: Alternate Formulations
[0216] In some embodiments, SMCC is combined or replaced with one
or more of the following excipients: microcrystalline cellulose,
lactose monohydrate (spray dried), a compressible sugar, xylitol
(Xylitab), sorbitol, mannitol, pregelatinized starch, maltodextrin,
calcium phosphate dibasic, calcium phosphate tribasic, calcium
carbonate DC, and the like. Accordingly, in one embodiment,
assuming the total filler to be 100%, about 50% SMCC is combined
with about 50% microcrystalline cellulose, lactose monohydrate
(spray dried), a compressible sugar, xylitol (Xylitab), sorbitol,
mannitol, pregelatinized starch, maltodextrin, calcium phosphate
dibasic, calcium phosphate tribasic, calcium carbonate DC, or a
combination of any of the same.
[0217] In alternate embodiments, SMCC is entirely replaced with one
or more alternate excipients. For example, in one embodiment a
50:50 ratio of microcrystalline cellulose to lactose is used in
place of SMCC. In this example, the overall compressibility of the
lactose is improved allowing for less compression force resulting
in a more porous tablet or caplet that shows improved dissolution
over the microcrystalline cellulose or lactose alone.
[0218] In some embodiments, the formulation includes at least one
additional pharmaceutically acceptable excipient, such as a binder,
a diluent, a disintegrant, a lubricant, a filler, a carrier, and
the like, to improve, for example, the direct compression
tablet-forming properties of the dry blend, and/or powder
flowability. When incorporated into the formulations disclosed
herein, the amounts of the major filler(s) can be reduced
accordingly to accommodate the amount of additional excipient(s)
added in order to keep the overall unit weight of the tablet
unchanged.
[0219] For example, in some embodiments, colloidal silicon dioxide,
is added to the formulation as a glidant to facilitate mass flow of
the powder mixture during blending and tablet compression
operations. Colloidal silicon dioxide is added at concentrations
ranging from about 0.1% to about 5.0% w/w, or from about 0.25% to
about 2% w/w, or from about 0.5% to about 1% w/w.
[0220] In some embodiments, magnesium stearate is added as a
lubricant to improve powder flow, prevent the blend from adhering
to tableting equipment and punch surfaces and provide lubrication
to allow tablets to be cleanly ejected from tablet dies. Magnesium
stearate is added to pharmaceutical formulations at concentrations
ranging from about 0.1% to about 5.0% w/w, or from about 0.25% to
about 2% w/w, or from about 0.5% to about 1% w/w.
[0221] In some embodiments, at least one binder is added to enhance
the compressibility of the major excipient(s). In some embodiments,
the formulation includes at least one of the following binders in
the following preferred ranges: from about 2 to about 6% w/w
hydroxypropyl cellulose (Klucel), from about 2 to about 5% w/w
polyvinylpyrrolidone (PVP), from about 1 to about 5% w/w
methylcellulose, from about 2 to about 5% hydroxypropyl
methylcellulose, from about 1 to about 5% w/w ethylcellulose, from
about 1 to about 5% w/w sodium carboxy methylcellulose, and the
like.
[0222] In some embodiments, the formulations include at least one
lubricant in the following preferred ranges: from about 0.25 to
about 2% w/w magnesium stearate, from about 0.25 to about 2% w/w
calcium stearate, from about 0.25 to about 2% w/w sodium stearyl
fumarate, from about 0.25 to about 2% w/w stearic acid, from about
0.25 to about 2% w/w hydrogenated vegetable oil, from about 0.25 to
about 2% w/w glyceryl behenate, from about 0.25 to about 2% w/w
polyethylene glycol 4000-6000, and the like.
[0223] In some embodiments, at least one additional disintegrant is
included to facilitate tablet disintegration after administration.
For example, at least one of the following preferred disintegrants
is added in the following preferred ranges: from about 1 to about
3% w/w croscarmellose sodium, from about 4 to about 6% w/w sodium
starch glycolate, from about 2 to about 4% w/w crospovidone, from
about 10 to about 20% w/w microcrystalline cellulose, from about 5
to about 10% w/w pregelatinized starch, from about 5 to about 10%
w/w corn starch, from about 5 to about 10% w/w alginic acid, from
about 1 to about 5% w/w ion exchange resin (Amberlite 88), and the
like.
[0224] The alternate formulations described above provide favorable
drug processing qualities, including, for example, rapid tablet
press speeds, reduced compression force, reduced ejection force,
blend uniformity, content uniformity, uniform dispersal of color,
accelerated disintegration time, rapid dissolution, low friability,
and the like. For example, the formulations achieve average
hardness values of at least 2 Kp using minimal compaction force,
average friability values of 1% or less, and disintegration rates
of 1 minute or less based on USP protocols. In addition, the
alternate formulations each result in a batch of dosage forms
having content uniformity values between 85% to 115% of label claim
with a relative standard deviation of 6% or less.
[0225] It should be noted that some embodiments can specifically
exclude the formulations that include one or more of the following
ingredients used with doxepin. In some aspects, the methods and
formulation can specifically exclude formulations that include the
following hard gelatin capsules (which may contain Blue 1, Red 3,
Red 40, Yellow 10, and other inert ingredients); magnesium
stearate; sodium lauryl sulfate; starch; glycerin; methylparaben;
peppermint oil; propylparaben; water and 10 mg of doxepin or
more.
[0226] Many modifications and variations of the embodiments
described herein may be made without departing from the scope, as
is apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only.
* * * * *