U.S. patent application number 11/699456 was filed with the patent office on 2007-05-31 for storage stable thyroxine active drug formulations and methods for their production.
This patent application is currently assigned to Mylan Pharmaceuticals Inc.. Invention is credited to Dwight D. JR. Hanshew, David John Wargo.
Application Number | 20070122476 11/699456 |
Document ID | / |
Family ID | 25533060 |
Filed Date | 2007-05-31 |
United States Patent
Application |
20070122476 |
Kind Code |
A1 |
Hanshew; Dwight D. JR. ; et
al. |
May 31, 2007 |
Storage stable thyroxine active drug formulations and methods for
their production
Abstract
This invention provides a storage-stable dosage form of a
thyroxine active drug composition which exhibits an improved
stability. The formulation contains a thyroxine active drug
substance, an alditol, and a saccharide, and, optionally,
additional pharmaceutically accepted excipients. Levothyroxine
sodium is the preferred active drug substance, mannitol is the
preferred alditol, and sucrose is the9 preferred saccharide.
Additional preferred excipients include, for example,
microcrystalline cellulose, crospovidone, magnesium stearate,
colloidal silicon dioxide, and sodium lauryl sulfate.
Inventors: |
Hanshew; Dwight D. JR.;
(North Wales, WV) ; Wargo; David John;
(Pittsburgh, PA) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
Mylan Pharmaceuticals Inc.
Morgantown
WV
|
Family ID: |
25533060 |
Appl. No.: |
11/699456 |
Filed: |
January 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11143645 |
Jun 3, 2005 |
7195779 |
|
|
11699456 |
Jan 30, 2007 |
|
|
|
10443135 |
May 22, 2003 |
6936274 |
|
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11143645 |
Jun 3, 2005 |
|
|
|
09987130 |
Nov 13, 2001 |
6645526 |
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10443135 |
May 22, 2003 |
|
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Current U.S.
Class: |
424/464 ;
424/488; 514/567 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 9/2077 20130101; A61K 31/198 20130101; A61K 9/2054 20130101;
A61K 9/205 20130101; A61K 9/2018 20130101 |
Class at
Publication: |
424/464 ;
424/488; 514/567 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/20 20060101 A61K009/20; A61K 9/14 20060101
A61K009/14 |
Claims
1. A storage stable pharmaceutical composition which comprises a
therapeutically effective amount of a thyroxine active drug, a
stabilizing amount of an alditol, a stabilizing amount of a
saccharide, and optionally further comprises other pharmaceutically
acceptable excipients.
2. The composition of claim 1, wherein said thyroxine active drug
is levothyroxine sodium.
3. The composition of claim 1, wherein said alditol is selected
from the group consisting of mannitol, sorbitol, maltitol and
xylitol.
4. The composition of claim 1, wherein said alditol is
mannitol.
5. The composition of claim 1, wherein said saccharide is selected
from a reducing sugar, an aldose, a hemiacetal, a cyclic hemiacetal
and a cyclized aldose.
6. The composition of claim 1, wherein said saccharide is selected
from the group consisting of a monosaccharide, a disaccharide, and
an oligosaccharide.
7. The composition of claim 1, wherein said saccharide is selected
from the group consisting of sucrose, maltose, cellobiose, lactose,
trehalose, glucose, fructose, galactose, ribose and
deoxyribose.
8. The composition of claim 1, wherein said saccharide is a
disaccharide.
9. The composition of claim 8, wherein said disaccharide is
sucrose.
10. A storage stable pharmaceutical composition which comprises a
therapeutically effective amount of a thyroxine active drug, an
alditol in the amount of about 5% to about 90% of the total weight
of said composition, and a saccharide in an amount of about 5% to
about 70% of the total weight of said composition.
11. The composition of claim 1, which comprises at least one
further pharmaceutical excipient.
12. A storage stable oral pharmaceutical composition which
comprises a therapeutically effective amount of levothyroxine
sodium, a stabilizing amount of mannitol, a stabilizing amount of
sucrose, and optionally further comprises other pharmaceutically
acceptable excipients.
13. The composition of claim 12, wherein said stabilizing amount of
mannitol is from about 5% to about 90% of the total weight of said
composition and wherein said stabilizing amount of sucrose is from
about 5% to about 70% of the total weight of said composition.
14. The composition of claim 12, wherein said stabilizing amount of
mannitol is from about 15% to about 80% of the total weight of said
composition and wherein said stabilizing amount of sucrose is from
about 10% to about 60% of the total weight of said composition.
15. A storage stable oral pharmaceutical composition which
comprises a therapeutically effective amount of levothyroxine
sodium, mannitol in an amount of about 5% to about 90% of the total
weight of said composition, sucrose in an amount of about 5% to
about 70% of the total weight of said composition, and optionally
further comprises microcrystalline cellulose, polyvinylpyrrolidone,
crospovidone, magnesium stearate, sodium lauryl sulfate, and
colloidal silicon dioxide.
16. The composition of claim 1, which is a solid oral dosage
form.
17. The composition of claim 1, which is selected from the group
consisting of a tablet, a capsule, a rectal suppository, a vaginal
suppository, a pill, a dragee, a lozenge, granules, beads,
microspheres, pellets, a powder or any combination thereof.
18. The composition of claim 1, which is a powder.
19. The composition of claim 1, which is a granulate.
20. The composition of claim 1, which is a tablet.
21. The composition of claim 1, which is formulated for oral,
rectal, vaginal, transmucosal, transdermal, parental, subcutaneous
or intramuscular administration.
22. A method for the treatment of thyroid disorders comprising
orally administering the composition of claim 1, to a human.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 11/143,645 filed Jun. 3, 2005, which is a continuation of U.S.
application Ser. No. 10/443,135 filed May 22, 2003, now U.S. Pat.
No. 6,936,274, which is a continuation of U.S. application Ser. No.
09/987,130 filed Nov. 13, 2001, now U.S. Pat. No. 6,645,526.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates generally to the field of medicinal
formulations, and more particularly to methods of preparing storage
stable pharmaceutical compositions in unit dosage form of
levothyroxine sodium with increased shelf life and compositions
made by these methods.
[0004] 2. Description of the Background Art
[0005] Thyroxine active drugs are known for both therapeutic and
prophylactic treatment of thyroid disorders. For example,
levothyroxine sodium is prescribed for thyroid hormone replacement
therapy in cases of reduced or absent thyroid function in e.g.,
ailments such as myxedema, cretinism and obesity. See, for example,
Post and Warren in Analytical Profiles of Drug Substances, Vol. 5,
Florey (ed.); Academic Press, New York (1976), pp. 226-281.
Levothyroxine sodium is quite unstable, hygroscopic and degrades
rapidly when subjected to high humidity, light or high temperature.
See, for example, Won, Pharm. Res. 9(1):131-137, 1992. Because of
the chemicophysical properties of the drug, formulations of
levothyroxine sodium have extremely short stability duration,
worsened under conditions of high humidity and temperature. Tablets
may decompose approximately 1 percent per month. Gupta et. al., J.
Clin. Pharm. Ther. 15:331-335, 1990. The stability problem has been
so widespread that some drug companies marketing levothyroxine
sodium tablets have been forced to recall various batches due to
lack of stability.
[0006] Formulations containing levothyroxine sodium have been known
in the art since the late 1950s. There have been recent attempts to
develop more stable dosage formulations of levothyroxine sodium.
For example, U.S. Pat. No. 5,635,209 discloses levothyroxine sodium
in combination with potassium iodide as part of a stabilizing
excipient. In the manufacture of this formulation, levothyroxine
sodium was first mixed with microcrystalline cellulose, and then
added to a dried granulation of potassium iodide and
microcrystalline cellulose. The formulation purportedly provided
increased active drug potency over a three month period in
comparison to then commercially available formulations.
[0007] U.S. Pat. No. 5,225,204 discloses a complex of levothyroxine
sodium and a cellulose, polyvinylpyrrolidone or Poloxamer. The
formulation may be prepared by dissolving the drug complex in a
polar organic solvent, adding a cellulose carrier to the liquid,
and drying the resulting mixture to obtain a complex of
levothyroxine sodium and polyvinylpyrrolidone or Poloxamer adsorbed
on the cellulose carrier.
[0008] Although purportedly increasing the stability of the
formulation, the deposition onto cellulose may have resulted in
some increased stability due to improved content uniformity. Tests
of such combinations yielded stability results at best equal to
commercially available preparations such as those described in U.S.
Pat. No. 5,955,105, and in some cases substantially worse.
[0009] The inventors of this stabilized composition teach one of
skill in the art away from the use of carbohydrates in
levothyroxine sodium formulations, stating that instability of the
dosage form was the result of an interaction between the active
drug substance and carbohydrate excipients.
[0010] The inventors of U.S. Pat. No. 5,955,105 also teach that the
instability of thyroxine drugs is due to an interaction between the
drug and the excipient. These inventors incorporated into the
formulation a soluble glucose polymer designed to eliminate the
interaction between the drug and other excipients contained in the
final blend.
[0011] Because of degradation of the active ingredient in currently
available formulations of levothyroxine sodium, new methods of
formulating solid dosage forms of this drug would be highly
desirable. Although different methods for producing a formulation
stable enough to meet requirements for shelf-life have been
attempted, no method has been entirely successful. There is, then,
a great need for new formulations of thyroxine active drugs with
increased stability and shelf life.
SUMMARY OF THE INVENTION
[0012] The present invention relates to methods and compositions
which increase the stability of levothyroxine sodium and other
thyroxine active drugs. This invention prevents the decreases in
effective dosage which plague prior art thyroxine active drug
formulations and substantially increases shelf life. The
compositions include an active thyroxine drug with an alditol and a
saccharide. Other optional ingredients in the composition include
but are not limited to pharmaceutically acceptable excipients such
as cellulose polymers or carbohydrates, disintegrants, lubricants
and glidants.
[0013] Accordingly, the present invention provides a storage stable
oral pharmaceutical composition which comprises a therapeutically
effective amount of a thyroxine active drug and stabilizing amounts
of an alditol and a saccharide. In a preferred embodiment, the
thyroxine active drug is levothyroxine sodium, the alditol is
mannitol, and the saccharide is sucrose. In yet another embodiment,
compositions of the invention comprise at least one further
pharmaceutical excipient, such as a carbohydrate, a starch or a
modified starch, for example microcrystalline cellulose. In yet a
further embodiment, this invention provides storage stable oral
pharmaceutical compositions in unit dosage form comprising the
compositions discussed above, and particularly a storage stable
oral dosage form composition which comprises levothyroxine sodium,
mannitol, sucrose, and optionally further comprises
microcrystalline cellulose, polyvinylpyrrolidone, crospovidone,
magnesium stearate, sodium lauryl sulfate, and colloidal silicon
dioxide. The invention preferably provides such storage stable oral
dosage forms in the form of tablets.
[0014] A preferred embodiment of the invention encompasses a
storage stable oral pharmaceutical composition which comprises a
therapeutically effective amount of levothyroxine sodium; about 58%
by weight mannitol; about 14% by weight sucrose; about 25% by
weight microcrystalline cellulose; about 1.5% by weight
polyvinylpyrrolidone; about 1.4% by weight magnesium stearate;
about 0.3% by weight colloidal silicon dioxide; and about 0.1% by
weight sodium lauryl sulfate.
[0015] Another preferred embodiment of the invention encompasses a
storage stable oral pharmaceutical composition which comprises a
therapeutically effective amount of levothyroxine sodium; about 39%
by weight mannitol; about 23% by weight sucrose; about 28% by
weight microcrystalline cellulose; about 1.5% by weight
polyvinylpyrrolidone; about 6% by weight crospovidone; about 2% by
weight magnesium stearate; about 0.3% by weight colloidal silicon
dioxide; and about 0.1% by weight sodium lauryl sulfate.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention relates to storage stable granulation
intermediates and oral pharmaceutical compositions in unit dosage
form of a thyroxine active drug and methods by which they are
produced. The methods involve a granulation intermediate containing
the thyroxine active drug substance, an alditol, and a
monosaccharide or disaccharide to provide a formulation with an
increase of stability of both the granulation intermediates and the
final oral dosage forms prepared from these granulation
intermediates. Thus, the present invention provides a stable dosage
form in which the dosage of thyroxine active drug is maintained at
a predictable level for a longer period of time.
[0017] Formulations of levothyroxine with greatly increased
resistance to degradation can be produced by providing excipients
which reduce or eliminate degradation of the active substance.
Although the prior art indicates that reaction between
levothyroxine sodium and certain carbohydrate, monosaccharide or
disaccharide excipients is responsible for the poor stability of
the drug, the present inventive formulation achieves surprisingly
stable levothyroxine dosage forms using these previously disfavored
excipients. Additionally, preferred formulations are maintained at
a pH of less than about 10.
[0018] The methods and formulations of this invention take
advantage of the discovery that including an alditol and a
saccharide results in a surprisingly stable levothyroxine sodium
composition. This invention can be used to produce stable
formulations of any natural or synthetic thyroid hormone
replacement drug. Therefore, although the following description and
example refer to ##STR1## compositions and methods using
levothyroxine sodium, the hormone medications of the general
formula hormone ations of invention is understood to encompass
other thyroid hormone medications of the general formula wherein
R.sub.1 and R.sub.3 may be the same or different and are selected
from hydrogen; halogen; alkyl; aryl; cycloalkyl; heterocycloalkyl;
amide; alcohol; acid; ester; ether; acyl; alkenyl; and alkynyl;
wherein R.sub.2 is ##STR2## wherein R.sub.4 and R.sub.5 may be the
same or different and are selected from hydrogen; halogen; alkyl;
aryl; cycloalkyl; heterocycloalkyl; amide; alcohol; acid; ester;
ether; acyl; alkenyl; and alkynyl. The medication can be in the
form of a free acid, a free base, an organic salt, an inorganic
salt, or a hydrate. Liothyronine is an example of a drug
encompassed by the above-mentioned general formula.
[0019] According to this invention, stabilized pharmaceutical
compositions are produced by blending the active ingredient with an
alditol and a saccharide such as a monosaccharide or disaccharide
to form a granulation intermediate. Addition of any additional
pharmaceutical excipients, diluents or granulation aids is
optional. Generally, further pharmaceutical excipients are added to
produce final oral dosage forms such as tablets or capsules.
[0020] Formulations according to this invention are made according
to the following general steps. Those of skill in the art are aware
of equivalent methods and variations which produce the same general
result. Therefore, the general instructions and the example which
follows should not be considered to be strictly limiting. The
active thyroxine ingredient, for example, levothyroxine sodium, is
blended with an alditol and/or a saccharide to form a pre-blend for
ease of handling. Preferred granulation intermediates are produced
by making a wet granulation of the active ingredient with an
alditol such as mannitol, a saccharide such as sucrose and a
granulation aid such as microcrystalline cellulose. Preferably, the
active ingredient is blended first with the alditol, sucrose is
then added and the material is blended again. According to the
invention, further excipients such as microcrystalline cellulose
(also polyvinylpyrrolidone as binder) may also be incorporated into
the granulation, but need not be added until the active ingredient
is intimately mixed with the alditol and/or the sucrose. Therefore,
the microcrystalline cellulose or other diluent functions as a
granulation aid and compression enhancer (for tablet or capsule
formulations) and not as a specific carrier for the thyroxine
active drug.
[0021] In preferred embodiments, the wet granulation is dried,
milled and optionally further blended. The granulation intermediate
then may be stored or directly mixed with further ingredients to
form a composition suitable for compression into tablets, filling
into capsules or dissolved or suspended to form a liquid dosage
form.
[0022] Without wishing to be bound by theory, it is believed that
the stabilizing effect achieved with the inventive formulations is
due to the presence of the alditol and the saccharide in the final
dosage form, and specifically the mixing of the alditol and
saccharide with the active ingredient at an early stage of
manufacture. Preferably, processing of the active ingredient should
be conducted at temperatures below about 45.degree. C.
[0023] Alditols which are suitable for use in this invention are
those whose presence stabilizes the thyroxine drug. Alditols are
widely known in the art. Preferred alditols include, but are not
limited to, one or more of the following: mannitol, sorbitol,
maltitol and xylitol. Most preferably, the alditol is mannitol.
Saccharides for use with this invention are those that stabilize
the thyroxine drug. Such saccharides include one or more
monosaccharides, disaccharides and oligosaccharides composed of
2-10 monosaccharides. Monosaccharides, also known as reducing
sugars, which may be used in the present invention generally
include aldoses, hemiacetals and cyclic hemiacetals. Disaccharides
are generally defined as two monosaccharide units joined together
by a glycoside linkage. Oligosaccharides are generally defined as
carbohydrates that hydrolyze to yield 2 to 10 molecules of a
monosaccharide. Preferred monosaccharides, disaccharides, and
oligosaccharides include, but are not limited to: sucrose, maltose,
cellobiose, lactose, trehalose, glucose, fructose, galactose,
ribose or deoxyribose. Preferably, the saccharide is a
monosaccharide or a disaccharide, and more preferably is a
disaccharide. The most preferred saccharide is sucrose.
[0024] Pharmaceutical compositions of this invention may be
prepared for administration orally, rectally, vaginally,
transmucosally, transdermally, parenterally, subcutaneously, and
intramuscularly. Pharmaceutically acceptable excipients which are
suitable for use in formulations for these methods of
administration are known to those of skill in the art and may be
included in formulations according to this invention. Generally,
excipients contemplated for use in the inventive formulations may
include, but are not limited to adjuvants; preservatives; buffers;
fillers, extenders, carriers, binders and diluents; glidants and
lubricants; surfactants, wetting agents and surface active agents;
suspending agents and solvents. Compounds such as dyes and
colorants, sweeteners, flavorings, perfuming agents and
taste-masking ingredients also may be included in formulations
according to this invention. Any pharmaceutically acceptable
excipient, such as ingredients to aid in processing or to improve
taste or appearance are contemplated for use with these
formulations. Further excipients may be included according to the
judgment of the pharmaceutical scientist formulating the
medicament. In addition, other active ingredients may be included
to produce a dual or multiple ingredient medication.
[0025] Exemplary surfactants and surface active agents may be
selected from known pharmaceutical excipients such as, for example,
gelatin, casein, lecithin, gum acacia, stearic acid or other fatty
acids, benzalkonium chloride, calcium stearate, glyceryl
monostearate or other fatty acid salts, polyethylene glycols,
silicon dioxide, methylcelluloses or carboxymethylcelluloses,
sodium stearyl fumarate, magnesium stearate, alginate, or any other
surface modifying compounds known in the art. Compounds which
function as wetting agents, such as, for example, pharmaceutically
acceptable detergents and cetyl alcohols also are contemplated for
use with the inventive formulations.
[0026] Lubricants such as talc, calcium stearate, sodium stearyl
fumarate, stearic acid, magnesium stearate, solid polyethylene
glycols and cocoa butter are useful with the inventive
formulations, as are one or more binders, fillers or extenders such
as starches, lactose or other sugars, polyvinylpyrrolidone, sodium
citrate, dicalcium phosphate and other alkaline inorganic salts,
carboxylmethylcellulose and other cellulose polymers, alginates,
gelatins, microcrystalline cellulose, sorbitol, sodium chloride,
chitosan, hydrogenated vegetable oil, kaolin, glycerol
palmitostearate, magnesium carbonate, and calcium carbonate.
[0027] Solid dosage forms which may be prepared according to this
invention can include tablets, capsules, rectal or vaginal
suppositories, pills, dragees, lozenges, granules, beads,
microspheres, pellets and powders, or any combination thereof.
Formulations also may be prepared in the form of solutions,
suspensions, emulsions, syrups and elixirs. These liquid dosage
forms may include liquid diluents in addition to the solid
ingredients discussed above. Such diluents may include, but are not
limited to solvents, solubilizing agents, suspending agents and
emulsifiers such as water or saline solutions, ethanol and other
pharmaceutically acceptable alcohols; ethyl carbonate; ethyl
acetate; propylene glycol; dimethyl formamide; pharmaceutically
acceptable oils such as cottonseed, corn, olive, castor and sesame;
fatty acid esters of sorbitan; polyoxyethylene sorbitol; and
agar-agar. Formulations can be either immediate or modified
release.
[0028] The formulations of this invention may be used for any
convenient dosage amount of the active ingredient. Generally, the
level of the active ingredient may be increased or decreased
according to the judgment of the physician, pharmacist,
pharmaceutical scientist or other person of skill in the art. The
amount of the remaining non-active ingredients can be adjusted as
needed. Preferably, the amount of alditol is adjusted to compensate
for changes in the amount of active ingredient.
[0029] The preferred active ingredient in the formulations of this
invention is levothyroxine sodium. Therapeutically effective dosage
amounts for this drug generally range from about 0.1 .mu.g to about
5000 .mu.g and are most preferably from about 25 .mu.g to about 300
.mu.g. Exemplary dosages therefore include, but are not limited to
20 .mu.g, 25 .mu.g, 50 .mu.g, 75 .mu.g, 88 .mu.g, 100 .mu.g 112
.mu.g, 125 .mu.g, 150 .mu.g, 175 .mu.g, 200 .mu.g and 300 .mu.g.
Preferred solid dosage forms prepared according to this invention
contain the following compounds: levothyroxine sodium (active drug
substance); mannitol; microcrystalline cellulose (diluent);
polyvinylpyrrolidone (binder); sucrose; crospovidone
(disintegrant); magnesium stearate (lubricant); sodium lauryl
sulfate (surfactant); and colloidal silicon dioxide (glidant).
[0030] Formulations of thyroxine active drugs prepared according to
this invention contain about 0.1 .mu.g to about 5000 .mu.g
thyroxine active drug substance, preferably about 1 .mu.g to about
1000 .mu.g and most preferably about 25 .mu.g to about 300 .mu.g.
Alditols should be present at from about 5% to about 90% (by
weight) of the final formulation, preferably from about 15% to
about 80% and most preferably from about 25% to about 70%. Filler,
such as carbohydrates (starch or cellulose polymer), for example
microcrystalline cellulose, generally should comprise from about 5%
to about 90% by weight of the final formulations, preferably from
about 15% to about 80% and most preferably from about 25% to about
70%. Final dosage forms generally contain from about 5% to about
70% saccharide, by weight, preferably from about 10% to about 60%,
and most preferably from about 20% to about 40%. Further optional
ingredients in the final dosage form may include a disintegrant,
which if present, generally forms from about 2% to about 30% of the
final formulation by weight, preferably from about 2% to about 15%
and most preferably from about 3% to about 10%. Lubricants may be
present in the final formulation at from about 0.1% to about 5% by
weight, preferably from about 0.2% to about 3% and most preferably
from about 0.5% to about 2.5%. Glidants may be present in final
formulations according to this invention at from about 0.05% to
about 2% by weight, preferably from about 0.075% to about 1% and
most preferably from about 0.1% to about 0.5%. Surfactants may be
present in final formulation according to this invention at from
about 0.005% to about 1% by weight, preferably from about 0.01% to
about 0.5% by weight, and most preferably from about 0.01% to about
0.2%. Binders may be present in final formulation according to this
invention at from about 0.1% to about 10% by weight, preferably
from about 0.5% to about 5% by weight, and most preferably from
about 1% to about 3% by weight.
[0031] After the solid ingredients of the formulation are blended,
the stabilized drug preparation preferably is compressed into
tablets. Alternatively, the preparation may be used to fill
capsules such as hard gelatin capsules or used to prepare any other
convenient solid dosage form. Compositions according to the
invention may be stored in the form of powders, granulates,
intermediates, suspensions, or solutions prior to addition of
additional desired pharmaceutical excipients for the production of
final dosage forms such as tablets or solid-filled capsules, or
final liquid dosage forms such as solutions, syrups, suspensions,
emulsions and the like.
[0032] The following example further illustrates the invention and
is not to be construed to limit the claims in any manner.
EXAMPLE 1
[0033] TABLE-US-00001 TABLE 1 Levothyroxine 25 mcg tablets were
prepared using the following ingredients: 0.0334% Levothyroxine
Sodium Granulation Intermediate Levothyroxine Sodium 567.2 mg
Mannitol 723.4 g Sucrose 425.0 g Microcrystalline Cellulose 517.0 g
Polyvinylpyrrolidone K30 34.0 g Purified Water 165.0 g Ethanol 200
proof 29.0 g Levothyroxine Sodium 25 mcg Tablets 0.0334%
Levothyroxine Sodium Granulation 1125.0 g Intermediate Colloidal
Silicon Dioxide 5.3 g Magnesium Stearate/Sodium Lauryl Sulfate 94/6
30.0 g FD&C Yellow Aluminum Lake No. 6 4.5 g Microcrystalline
Cellulose 136.5 g Mannitol 648.8 g
[0034] The mannitol and the levothyroxine sodium were blended for
10 minutes using conventional mixing equipment. The blended
material, microcrystalline cellulose, and the sucrose were then
passed through a hammer mill and the milled materials were blended
for 15 minutes. With continuous mixing, the powders were granulated
with a 15% w/w hydroalcoholic solution of polyvinylpyrrolidone.
Additional water was added as needed for consistency of the
granulation. The wet granulation mixture was dried in a fluidized
bed dryer at 40.degree. C. until the moisture content was less then
4%. The dried granulation was sized by passing it through a hammer
mill then blended for 5 minutes using conventional mixing
equipment.
[0035] The colloidal silicon dioxide, the magnesium stearate/sodium
lauryl sulfate (94/6), and the FD&C Yellow Aluminum Lake No. 6
lake were blended for 3 minutes and the mixture was passed through
a #30 mesh screen. The microcrystalline cellulose and the mannitol
were sized by screening and milling, respectively. The screened
ingredients were then blended with the levothyroxine sodium
granulation intermediate for 15 minutes until uniform. The mixture
was compressed into tablets, each weighing approximately 130 mg, on
a rotary tableting machine.
[0036] Table 2 represents the stability data generated for storage
of tablets made according to Example 1. These tablets were stored
at 25, 40, and 50.degree. C. for 5 days at ambient humidity in 75
cc standard HDPE pharmaceutical containers. Samples of these
tablets were analyzed for drug potency using an HPLC standard
assay. Evaluation of the potency for these tablets demonstrates
that the stabilized formulation of Example 1 yields a product which
demonstrates good stability at all temperatures at or below
40.degree. C. TABLE-US-00002 TABLE 2 Stability Data Temperature
Potency 25.degree. C. 100.9% 40.degree. C. 99.3% 50.degree. C.
93.3%
* * * * *