U.S. patent application number 12/965703 was filed with the patent office on 2012-06-14 for testosterone undecanoate compositions.
Invention is credited to Basawaraj Chickmath, Chandrashekar Giliyar, Chidambaram Nachiappan, Mahesh V. Patel, Srinivansan Venkateshwaran.
Application Number | 20120148675 12/965703 |
Document ID | / |
Family ID | 46199623 |
Filed Date | 2012-06-14 |
United States Patent
Application |
20120148675 |
Kind Code |
A1 |
Chickmath; Basawaraj ; et
al. |
June 14, 2012 |
TESTOSTERONE UNDECANOATE COMPOSITIONS
Abstract
The present disclosure is drawn to pharmaceutical compositions
and oral dosage forms containing testosterone undecanoate, as well
as related methods of treatment. In one embodiment, the oral dosage
form can include a therapeutically effective amount of testosterone
undecanoate and a pharmaceutically acceptable carrier. The dosage
form can be formulated such that, when measured using a USP Type II
apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37.degree.
C. and 100 rpm, the oral dosage form releases at least 20% more
testosterone undecanoate after the first 120 minutes than an
equivalent dose testosterone undecanoate containing oral dosage
form without the pharmaceutically acceptable carrier.
Inventors: |
Chickmath; Basawaraj; (Salt
Lake City, UT) ; Giliyar; Chandrashekar; (Salt Lake
City, UT) ; Nachiappan; Chidambaram; (Sandy, UT)
; Patel; Mahesh V.; (Salt Lake City, UT) ;
Venkateshwaran; Srinivansan; (Salt Lake City, UT) |
Family ID: |
46199623 |
Appl. No.: |
12/965703 |
Filed: |
December 10, 2010 |
Current U.S.
Class: |
424/489 ;
514/179 |
Current CPC
Class: |
A61K 9/146 20130101;
A61K 9/2866 20130101; A61K 47/40 20130101; A61K 9/286 20130101;
A61K 9/14 20130101; A61K 31/568 20130101; A61K 47/36 20130101; A61P
19/00 20180101; A61K 9/4875 20130101; A61K 9/4866 20130101; A61K
9/148 20130101; A61K 9/2031 20130101; A61K 9/282 20130101; A61K
9/1676 20130101; A61K 9/2018 20130101; A61K 47/10 20130101; A61K
9/1652 20130101; A61P 5/26 20180101; A61K 9/2054 20130101; A61K
9/2853 20130101; A61K 9/2013 20130101; A61K 9/205 20130101; A61P
15/10 20180101; A61K 47/38 20130101; A61K 9/1694 20130101 |
Class at
Publication: |
424/489 ;
514/179 |
International
Class: |
A61K 31/568 20060101
A61K031/568; A61P 19/00 20060101 A61P019/00; A61P 15/10 20060101
A61P015/10; A61K 9/14 20060101 A61K009/14; A61P 5/26 20060101
A61P005/26 |
Claims
1. A solid oral dosage form, comprising: a therapeutically
effective amount of testosterone undecanoate, and a
pharmaceutically acceptable carrier, wherein when tested using a
USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in water at
37.degree. C. and 100 rpm, the oral dosage form releases at least
20% more testosterone undecanoate after the first 120 minutes than
an equivalent dose testosterone undecanoate containing oral dosage
form without the pharmaceutically acceptable carrier.
2. The solid oral dosage form of claim 1, wherein the testosterone
undecanoate is present as a solid particulate.
3. The solid oral dosage form of claim 1, wherein the oral dosage
form does not form an oil-in-water emulsion upon contact with
water.
4. The solid oral dosage form of claim 1, wherein the
pharmaceutically acceptable carrier includes a compound selected
from the group consisting of hydrophilic additives, lipophilic
additives, or combinations thereof.
5. The dosage form of claim 1, wherein the pharmaceutical carrier
is not a lipid substance with chain length greater than
C.sub.12.
6. The solid oral dosage form of claim 1, wherein the
pharmaceutically acceptable carrier includes a compound selected
from the group consisting of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; cyclodextrins; maltodextrin;
hydroxypropyl methyl cellulose; carbomers; gelatin; poloxamers;
ethyl alcohol; benzyl alcohol; benzyl benzoate, and combinations
thereof.
7. A The solid oral dosage form of claim 1, wherein the
pharmaceutically acceptable carrier includes a compound selected
from the group consisting of ethyl cellulose, cellulose acetate
phthalates, glyceryl distearate, acrylic acid and methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid) (anhydride), methyl methacrylate,
polymethacrylate, stearic acid, poly(methyl methacrylate)
copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,
poly(methacrylic acid anhydride), and glycidyl methacrylate
copolymers.
8. The solid oral dosage form of claim 4, wherein the composition
includes a hydrophilic additive that is not a hydrophilic
surfactant.
9. The solid oral dosage form of claim 4, wherein the composition
includes a lipophilic additive that is not a lipophilic
surfactant.
10. The solid oral dosage form of claim 4, wherein the composition
is free of triglycerides, animal and vegetable oils.
11. The solid oral dosage form of claim 1, wherein the testosterone
undecanoate is present in an amount of about 0.5 mg to about 750
mg.
12. The solid oral dosage form of claim 1, wherein the oral dosage
form is formulated for administration to a human female and the
testosterone undecanoate is present in an amount of about 0.5 mg to
about 200 mg.
13. The solid oral dosage form of claim 1, wherein the oral dosage
form is formulated for administration to a human male and the
testosterone undecanoate is present in an amount of about 50 mg to
about 750 mg.
14. The solid oral dosage form of claim 1, wherein the oral dosage
form releases about 85 wt % or less of the testosterone undecanoate
in the first 30 minutes.
15. The solid oral dosage form of claim 1, wherein the oral dosage
form releases about 70% or less of the testosterone undecanoate in
the first 30 minutes.
16. The solid oral dosage form of claim 1, wherein the oral dosage
form releases at least 35 wt % of the testosterone undecanoate in
the first 120 minutes.
17. The solid oral dosage form of claim 1, wherein the oral dosage
form releases at least 45 wt % of the testosterone undecanoate in
the first 120 minutes.
18. The solid oral dosage form of claim 1, wherein, when
administered to a human male, the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 4.5.times.10.sup.4 dL
to 4.times.10.sup.6 dL.
19. The solid oral dosage form of claim 1, wherein, when
administered to a human female, the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 5.times.10.sup.3 dL to
2.times.10.sup.7 dL.
20. The oral dosage capsule of claim 1 wherein the oral dosage form
upon single administration to a human subject, provides a ratio of
serum testosterone undecanoate C.sub.avg to serum total
testosterone C.sub.avg of about 3:1 to about 100:1.
21. The solid oral dosage form of claim 1, wherein the oral dosage
form has a testosterone undecanoate to pharmaceutically acceptable
carrier ratio of about 8:1 (w/w) to about 1:8 (w/w).
22. The solid oral dosage form of claim 1, wherein the oral dosage
form has a testosterone undecanoate to pharmaceutically acceptable
carrier ratio of about 4:1 (w/w) to about 1:4 (w/w).
23. The solid oral dosage form of claim 1, wherein the oral dosage
form is a tablet or a capsule.
24. The solid oral dosage form of claim 1, wherein the oral dosage
form is a multiparticulate oral dosage form.
25. The solid oral dosage form of claim 1, wherein the testosterone
undecanoate is present in an amorphous and/or crystalline form
having a mean particle diameter of about 30 .mu.m or less.
26. The solid oral dosage form of claim 1, wherein, when after
administration to a human male, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 300 ng/dL to about
1100 ng/dL.
27. The solid oral dosage form of claim 1, wherein, when after
administration to a human male, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 350 ng/dL to about 800
ng/dL.
28. The solid oral dosage form of claim 1, wherein, when after
administration to a human male, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 400 ng/dL to about 600
ng/dL
29. The solid oral dosage form of claim 1, wherein, when after
administrations to a human male, the oral dosage form provides a
testosterone undecanoate C.sub.avg of about 1.5 ng/mL to about 1
.mu.g/mL.
30. The solid oral dosage form of claim 1, wherein, when after
administrations to a human male, the oral dosage form provides a
testosterone undecanoate C.sub.avg of about 10 ng/mL to about 850
ng/mL.
31. The solid oral dosage form of claim 1, wherein when
administered to a human female, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 1 ng/dL to about 100
ng/dL.
32. The solid oral dosage form of claim 1, wherein, when
administered to a human female, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 20 ng/dL to about 80
ng/dL.
33. The solid oral dosage form of claim 1, wherein, when
administered to a human female, the oral dosage form provides a
plasma total testosterone C.sub.avg of about 30 ng/dL to about 70
ng/dL.
34. A method of treating a subject in need of testosterone therapy,
comprising: administering a solid oral dosage form of claim 1 to
the subject.
35. The method of claim 34 wherein the administration is done once
every 24 hours.
36. The method of claim 34 wherein the administration is done once
every 12 hours.
37. The method of claim 34 wherein the subject is a male and the
need for testosterone therapy is associated with a condition
selected from the group consisting of hypogonadism; erectile
dysfunction; Klienfelter Syndrome; reduced libido; low muscle mass
and low bone density; metabolic syndrome, and combinations
thereof.
38. The method of claim 34 wherein the subject is a human male and
the solid oral dosage form provides a daily dose of testosterone
undecanoate of about 50 mg to about 1500 mg per day.
39. The method of claim 34 wherein the subject is a female and the
need for testosterone therapy is associated with a condition
selected from the group consisting of hypoactive sexual desire
disorder, arousal disorder, dyspareunia, anorgasmia, and
combinations thereof.
40. The method of claim 34 wherein the subject is a human female
and the solid oral dosage form provides a daily dose of
testosterone undecanoate of about 0.5 mg to about 200 mg per day.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to solid testosterone
undecanoate containing pharmaceutical compositions and oral dosage
forms as well as associated methods of treatment. Accordingly, this
invention involves the fields of chemistry, pharmaceutical
sciences, medicine and other health sciences.
BACKGROUND OF THE INVENTION
[0002] The need for testosterone supplementation, often caused by
testosterone deficiency, is a condition that can affect both men
and women. Testosterone deficiency can be accompanied by a variety
of symptoms including sexual dysfunction, reduced muscle mass and
muscle strength, depressed mood, and osteoporosis. Male
hypogonadism and female sexual dysfunction is characterized by a
deficiency of endogenous testosterone production resulting in
abnormally low levels of circulating testosterone. Currently,
common testosterone therapy treatment can include administration of
invasive intramuscular products, topical gels, topical solution and
patches, or multiple units of liquid oral dosage capsules. There
are challenges and drawbacks associated with each of these
therapies. For example, use of topical gels or topical solutions
can result in accidental transfer of the active agent to others,
such as children or partners.
[0003] Current standard therapies for males aim at restoring
physiologically relevant levels of testosterone in serum. It is
generally recognized that in a normal adult man of age 17 to 54
yrs, the average serum testosterone (T) a major androgenic hormone
in males, is between about 300 ng/dL to about 1100 ng/dL, known as
the eugonadal range. Testosterone replacement in males should in
theory approximate the natural, endogenous production of the
hormone. The average male produces 4-7 mg of testosterone per day
in a circadian pattern, with maximal plasma levels attained in
early morning and minimal levels in the evening.
[0004] Low or reduced sexual desire is a condition that impacts
millions of women, particularly those over the age of 50.
Testosterone (T) levels can steeply decline in women as they age or
after surgical menopause. Endogenous testosterone levels in women
at age 40 are one half of those of women at age 21 and endogenous
testosterone levels in women after oophorectomy are 50% less than
before oophorectomy. There is strong indication that supplemental
testosterone therapy may be beneficial for the treatment of women
with reduced sexual desire. Currently in the United States, there
is no approved testosterone product available for the treatment of
female sexual dysfunction and reduced sexual desire. The human
female has substantially lower normal blood levels of total
testosterone (10-100 ng/dL compared to males .about.300-1100 ng/dL)
so it can be logically surmised that efficacious doses for women
can be substantially lower (about 10-50 times) than that for
men.
[0005] While oral is typically the most preferred and patient
friendly route for administration, the oral delivery of
testosterone as testosterone remains a huge challenge. This is due
to extremely poor bioavailability requiring very high dose as well
as the short serum half-life requiring frequent dosing. These
problems with orally administered testosterone are primarily due to
first pass metabolism. Moreover, direct, oral delivery of
testosterone is also known to cause enzyme induction resulting in
potential drug-drug interactions. Currently, modified
testosterones, in form of methyl analogue of testosterone, and as
an undecanoate ester, testosterone undecanoate (TU) are available
for oral administration for patients in need of testosterone
therapy. However, liver damage including cholestasis, peliosis
hepatitis, nodular regenerative hyperplasia, and primary hepatic
tumors has been reported with use of methyl testosterone.
Testosterone undecanoate, a prodrug of testosterone, containing
oral dosage forms are marketed in various countries under various
trade names, e.g. Andriol.RTM., Restandol.RTM., Andriol
Testocap.RTM. etc., each of which are liquid filled soft-gelatin
capsule formulations containing about 40 mg of TU in a liquid
carrier. Testosterone undecanoate is converted in vivo to
pharmacologically active testosterone.
[0006] However, a huge drawback of the current state of the art
oral liquid testosterone undecanoate formulations is that it has to
be encapsulated in a capsule dosage form presenting it with
limitations with respect to acceptable capsule sizes and related
drug loading limitations due to testosterone undecanoate's poor
solubility. Such limitations present challenges with respect to
patient compliance, because patients typically have to take
multiple capsule units in order to get a sufficient dose to provide
the desired efficacy. Additionally, liquid capsule formulations
tend to require more complicated and costly manufacturing processes
and often require special storage and handling. Moreover, liquid
lipidic compositions can present oxidative instability challenges
with respect to testosterone and its derivatives. Due to
testosterone undecanoate's poor solubility, the production of a
solid oral dosage forms such as tablets, caplets, and particulates
remains an area of continuous research and development.
SUMMARY OF THE INVENTION
[0007] The present disclosure is drawn to pharmaceutical
compositions and oral dosage forms containing testosterone
undecanoate, as well as related methods of treatment. In one
embodiment, a solid composition is provided. The dosage form can
include a therapeutically effective amount of testosterone
undecanoate and a pharmaceutically acceptable carrier. The oral
dosage form can be formulated to release at least 35 wt % of the
dosage form's testosterone undecanoate in the first 120 minutes
when measured using a USP Type II apparatus in 1000 mL of 8 wt %
Triton X-100 in water at 37.degree. C. and 100 rpm. In one
embodiment, the testosterone undecanoate can be present in the
composition as a solid particulate. In yet a further embodiment,
the carrier can be free of lipid substance, or lipophilic
surfactant or hydrophilic surfactants.
[0008] In another embodiment, a solid oral dosage form is provided.
The oral dosage form can include a therapeutically effective amount
of testosterone undecanoate and a pharmaceutically acceptable
carrier. The dosage form can be formulated such that, when measured
using a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in
water at 37.degree. C. and 100 rpm, the oral dosage form releases
at least 20% more testosterone undecanoate after the first 120
minutes than a equivalent dose testosterone undecanoate containing
oral dosage form without the pharmaceutically acceptable carrier.
In one embodiment, testosterone undecanoate is not present in the
solid composition in a solubilized form. In another embodiment the
oral dosage form can be formulated to include the testosterone
undecanoate dose in the form of solid particulates. In another
embodiment the oral dosage form of this invention can include a
composition comprising solid particulates that can be solid
testosterone undecanoate and/or a solid pharmaceutically acceptable
carrier.
[0009] In yet another embodiment, a method for treating a subject
in need of testosterone therapy is provided. The method includes
administering a solid oral dosage form of the present invention. In
one embodiment, the administration can be once daily. In another
embodiment, the administration can be once every twelve hours.
DETAILED DESCRIPTION
[0010] Before the present testosterone undecanoate compositions,
oral dosage forms and related methods of use are disclosed and
described, it is to be understood that this invention is not
limited to the particular process steps and materials disclosed
herein, but is extended to equivalents thereof, as would be
recognized by those ordinarily skilled in the relevant arts. It
should also be understood that terminology employed herein is used
for the purpose of describing particular embodiments only and is
not intended to be limiting.
[0011] It should be noted that, the singular forms "a," "an," and,
"the" include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to "an excipient" includes
reference to one or more of such excipients, and reference to "the
carrier" includes reference to one or more of such carriers.
DEFINITIONS
[0012] As used herein, the term "treatment," when used in
conjunction with the administration of pharmaceutical compositions
and oral dosage form containing testosterone undecanoate, refers to
the administration of the oral dosage form and pharmaceutically
acceptable composition to subjects who are either asymptomatic or
symptomatic. In other words, "treatment" can both be to reduce or
eliminate symptoms associated with a condition or it can be
prophylactic treatment, i.e. to prevent the occurrence of the
symptoms. Such prophylactic treatment can also be referred to as
prevention of the condition.
[0013] As used herein, the terms "formulation" and "composition"
are used interchangeably and refer to a mixture of two or more
compounds, elements, or molecules. In some aspects the terms
"formulation" and "composition" may be used to refer to a mixture
of one or more active agents with a carrier or other excipients.
Furthermore, the term "dosage form" can include one or more
formulation(s) or composition(s) provided in a format for
administration to a subject. When any of the above terms is
modified by the term "oral" such terms refer to compositions,
formulations, or dosage forms formulated and intended for oral
administration to subjects.
[0014] As used herein, the term "lipophilic" when used in
combination with both solid and liquid lipophilic additives, refers
to additives that have poor or no solubility in water. "Lipophilic
surfactants" refer to lipophilic additives that have HLB values of
10 or less, preferably between 2 to 10. Conversely, the term
"hydrophilic," when used in combination with both solid and liquid
hydrophilic additives, refers to additives that have average or
good solubility in water. "Hydrophilic surfactants" are hydrophilic
additives that have significant surface active property and that
have HLB values of more than 10.
[0015] As used herein, the term "lipid" or lipid substance" as used
in connection, with various compounds, refers to fatty acid (unless
otherwise specified, having chain length greater than C.sub.6) or
fatty acid esters or glycerides of fatty acid esters, mixtures
thereof and derivatives thereof, although not including salts
thereof.
[0016] As used herein, "subject" refers to a mammal that may
benefit from the administration of a drug composition or method of
this invention. Examples of subjects include humans, and may also
include other animals such as horses, pigs, cattle, dogs, cats,
rabbits, and aquatic mammals. In one embodiment, the subject is a
human subject. In one embodiment, the human subject is a male. In
another embodiment, the human subject is a female.
[0017] As used herein, the term "solid particulate" means relating
to, or formed of minute separate particles, as of a granular
substance or powder and that is a solid at room temperature. The
term "multiparticulate" represents coated or uncoated drug delivery
system, in which the dosage of the drug is divided among several
discrete delivery entities, in contrast to a single-unit delivery
entity. Multiparticulate systems can be powder, granule,
mini-tablets, beads, prills, pellets, or combinations thereof. The
term "matrix" represents coated or uncoated drug delivery system,
in which the dosage of the drug is a single-unit monolithic
delivery entity, such as tablet.
[0018] The term "oral administration" represents any method of
administration in which an active agent can be administered by
swallowing, chewing, or sucking of the dosage form; or admixing the
dosage form or its contents with food and/or beverage immediately
prior to consuming.
[0019] As used herein, the terms "release", "release rate", are
used interchangeably to refer to the discharge or liberation of a
substance, including without limitation a drug, from the dosage
form into a surrounding environment such as an aqueous medium
either in vitro or in vivo.
[0020] As used herein, an "effective amount" or a "therapeutically
effective amount" of a drug refers to a non-toxic, but sufficient
amount of the drug, to achieve therapeutic results in treating a
condition for which the drug is known to be effective. It is
understood that various biological factors may affect the ability
of a substance to perform its intended task. Therefore, an
"effective amount" or a "therapeutically effective amount" may be
dependent in some instances on such biological factors. Further,
while the achievement of therapeutic effects may be measured by a
physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and
response to treatments may make the achievement of therapeutic
effects a somewhat subjective decision. The determination of an
effective amount is well within the ordinary skill in the art of
pharmaceutical sciences and medicine. See, for example, Meiner and
Tonascia, "Clinical Trials: Design, Conduct, and Analysis,"
Monographs in Epidemiology and Biostatistics, Vol. 8 (1986),
incorporated herein by reference.
[0021] As used herein, the term "C.sub.avg or "C-average" is used
interchangeably, and is determined as the AUC.sub.0-t or the mean
AUC divided by the time period (t). For example, C.sub.avg-8h is
the average plasma concentration over a period of 8 hours
post-dosing determined by dividing the AUC.sub.0-8 value by 8.
Similarly, C.sub.avg-12h is the average plasma concentration over a
period of 12 hours post-dosing determined by dividing the
AUC.sub.0-12 value by 12; C.sub.avg-24h is the average plasma
concentration over a period of 24 hours post-dosing determined by
dividing the AUC.sub.0-24h value by 24, and so on.
[0022] For the purpose of this invention, the average baseline
plasma testosterone concentration (T-C.sub.avg-B) of the human
subject refers to the arithmetic mean of the total plasma
testosterone concentrations determined on at least two consecutive
times prior to any androgen treatment. In one aspect, the plasma
testosterone concentration of the human male can be determined by
automated or manual immunoassay methods, liquid chromatography or
liquid chromatography-tandem mass spectrometry (LC-MSMS) methods or
equivalent methods or combination of methods thereof.
[0023] As used herein, the terms "plasma testosterone
concentration", "serum testosterone concentration" or "testosterone
concentration in blood" are used interchangeably and refers to the
total testosterone including both free and bound testosterone,
present in the plasma, serum or blood of a subject.
[0024] The terms "carrier" or "pharmaceutically acceptable carrier"
are used interchangeably and refer to a pharmaceutically acceptable
substances that enable a solid dosage form and that alter the
release rate and/or extent of the active agent, for example
testosterone undecanoate, from the composition and/or the dosage
form. In one aspect of the invention, a pharmaceutically acceptable
carrier is a compound or a mixture of compounds that enables the
release of testosterone undecanoate from an oral dosage
composition, when tested using a USP Type II apparatus in 1000 mL
of 8 wt % Triton X-100 in water at 37.degree. C. and 100 rpm, such
that the oral dosage form releases at least 20% more testosterone
undecanoate after the first 120 minutes compared to an equivalent
dose testosterone undecanoate oral dosage form without the
pharmaceutically acceptable carrier.
[0025] As used herein, the term "delayed release" is defined as
release of testosterone undecanoate from the composition or oral
dosage form which, upon contact with an aqueous medium, occurs in a
time delayed manner attributed either to the characteristics of the
dosage form via for example, coating, encapsulating shell, etc., or
due to the inherent nature of the composition. When the oral dosage
form or composition includes a conventional capsule shell, the
delay in release is calculated after the capsule shell is dissolved
or compromised.
[0026] As used herein, the term "about" is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint. As
used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0027] As used herein, a pharmaceutical "formulation" or
"composition" is defined as including a pharmaceutically active
agent and a pharmaceutically acceptable carrier that may or may not
be processed or incorporated into a dosage form.
[0028] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0029] Concentrations, amounts, levels and other numerical data may
be expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges or decimal units encompassed within that range as if
each numerical value and sub-range is explicitly recited. As an
illustration, a numerical range of "about 1 to about 5" should be
interpreted to include not only the explicitly recited values of
about 1 to about 5, but also include individual values and
sub-ranges within the indicated range. Thus, included in this
numerical range are individual values such as 2, 3, and 4 and
sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well
as 1, 2, 3, 4, and 5, individually. This same principle applies to
ranges reciting only one numerical value as a minimum or a maximum.
Furthermore, such an interpretation should apply regardless of the
breadth of the range or the characteristics being described.
[0030] Invention
[0031] Reference will now be made in detail to preferred
embodiments of the invention. While the invention will be described
in conjunction with the preferred embodiments, it will be
understood that it is not intended to limit the invention to those
preferred embodiments. To the contrary, it is intended to cover
alternatives, variants, modifications, and equivalents as may be
included within the spirit and scope of the invention as defined by
the appended claims.
[0032] The present disclosure is drawn to pharmaceutical
compositions and oral dosage forms containing testosterone
undecanoate, as well as related methods of treatment. In
particular, it has been discovered that testosterone undecanoate
can be formulated into solid compositions containing solid
testosterone undecanoate that are capable of providing the
necessary release, in vitro or in vivo, and bioavailability to
provide therapeutic effectiveness. For example, in one embodiment,
a solid oral dosage form is provided. The solid oral dosage form
can include a therapeutically effective amount of testosterone
undecanoate and a pharmaceutically acceptable carrier. The solid
oral dosage form can include a solid composition comprising a
therapeutically effective amount of testosterone undecanoate and a
pharmaceutically acceptable carrier. The solid composition of the
present invention can be formulated to release at least 35 wt % of
its testosterone undecanoate in the first 120 minutes, when
measured using a USP Type II apparatus in 1000 mL of 8 wt % Triton
X-100 in water at 37.degree. C. and 100 rpm. Similarly, the oral
dosage form can be formulated to release at least 35 wt % of the
dosage form's testosterone undecanoate in the first 120 minutes
when measured using a USP Type II apparatus in 1000 mL of 8 wt %
Triton X-100 in water at 37.degree. C. and 100 rpm.
[0033] In another embodiment, a solid oral dosage form is provided.
The oral dosage form can include a therapeutically effective amount
of testosterone undecanoate and a pharmaceutically acceptable
carrier. The dosage form can be formulated such that, when measured
using a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in
water at 37.degree. C. and 100 rpm, the oral dosage form releases
at least 20% more testosterone undecanoate after the first 120
minutes than a equivalent dose testosterone undecanoate containing
oral dosage form without the pharmaceutically acceptable carrier.
The oral dosage forms and related solid compositions disclosed
herein do not form oil-in-water emulsions when contacted with water
with adequate mixing within 15 minutes as observed by appearance of
uniform opaque or translucent liquid or by other appropriate means.
The term "oil in water (0/W) emulsion," as used herein, refers to a
multi-phase system wherein oil or oil-like small globules are
dispersed in water. Such globules can have the average diameters of
greater than about 200 nm or exhibit absorbance of about 0.5 or
more when spectrophotometrically measured at about 400 nm. The oil
or oil-like globules can have the tendency to coalesce and are
distinctly different from thermodynamically stable micelles or
microemulsions.
[0034] The oral dosage forms and related solid compositions
disclosed herein do not include lipid substance. The oral dosage
forms and related solid compositions disclosed herein do not
include lipid substance having a fatty acid chain length greater
than C.sub.12.
[0035] In one embodiment, the oral dosage form of this invention
can include a solid particulate which can be solid testosterone
undecanoate and/or a solid pharmaceutically acceptable carrier. The
solid oral dosage form of the present invention can be administered
as any oral dosage form known in the art. Specific examples of oral
dosage forms include tablets, capsules, sachets, lozenges,
granules, powders, fast melt, lyophilized, sprinkle, suspension or
combinations thereof. In another embodiment, the dosage form is
coated. In one embodiment, the solid composition can be a matrix.
In one embodiment, the solid oral dosage form is a tablet or a
capsule. In another embodiment oral dosage form is a
multiparticulate oral dosage form. In another embodiment, the
composition can be multiparticulate. Regardless of the type, the
oral dosage forms or compositions can be formulated to provide
modified, delayed, sustained, extended, and/or controlled release
of the testosterone undecanoate. The modified, delayed, extended,
pulsatile, and/or controlled release can be achieved by any method
known in the art so long as it does not interfere with the function
of the solid oral dosage forms. Non-limiting examples of such
methods includes coatings, polymers, and the like. In one
embodiment, the oral dosage form can be uncoated. In one embodiment
the solid composition of the invention is a solid dispersion, solid
solution, molecular dispersion, co-precipitate, amorphate,
solidified suspension, admixture, eutectic mixture, melt extrude,
drug-carrier complex, thermosetting system, or combinations
thereof.
[0036] The compositions of this invention can include compounds or
systems that increase mean residence time of the composition/dosage
form in the gastrointestinal tract to enable prolonged drug release
resulting in longer duration of action. This can be accomplished by
using approaches that delays stomach emptying, mucoadhesion,
floatation, sedimentation, expansion, and/or modified shape
systems.
[0037] The solid oral dosage forms the present invention can be
manufactured as tablet or capsule dosage forms either by dry
granulation methods, or by wet granulation methods. For example,
testosterone undecanoate can be combined with one or more
pharmaceutically acceptable carrier and blended to get a homogenous
mixture which can be compressed into a tablet or disposed into a
capsule. In another embodiment, the homogenous mixture can be
kneaded with a binder solution to get a wet granulate mass which
can be dried and sized, for example by passing through ASTM mesh
#30. The resulting granules can be optionally blended with
pharmaceutical aids such as diluents, lubricants, disintegrants
etc, and disposed into capsules or compressed into tablets. In
another particular case, the tablets can be coated. In one
embodiment the tablet is a matrix tablet. In another embodiment,
the tablet can be multi-layered tablet dosage form which can
achieve release characteristics that can accommodate dose
splitting.
[0038] The solid oral dosage forms can also be formulated using
melt-extrusion processes alone or in combination with other known
processes. For example, in one embodiment, an amount of
testosterone undecanoate can be homogeneously combined with a
sufficient amount of one or more carrier substances prior to
undergoing extrusion. The carrier suitable for the compositions of
this invention, specifically melt extrusion process, can be
lipophilic or hydrophilic carrier. Combinations of lipophilic and
hydrophilic carriers may also be used.
[0039] For the purpose of current invention, the terms "melt" and
"melting" should be interpreted broadly, and include not only the
alteration from a solid state to a liquid state, but can also refer
to a transition to a glassy state or a rubbery state in which it is
possible for one component of the mixture to get embedded more or
less homogeneously into the other. In particular cases, one
component can melt and the other component(s) can dissolve in the
melt, thus forming a solution which, upon cooling, may form a solid
composition having advantageous properties. In another particular
case, one component can melt and the other component(s) can suspend
thus forming a suspension which upon cooling may form a solid
suspension having advantageous properties.
[0040] The melt-extruded solid compositions used to make the solid
oral dosage forms of the present disclosure can be granular,
multiparticulates, pellets, beads, mini-tablets or tablets. The
melt-extruded solids can be used alone as the solid oral dosage
form or can be disposed into capsules or formed into tablets.
[0041] The carrier for a melt-extruded composition and/or dosage
form can include, but is not limited to, carriers such as ethyl
cellulose, cellulose acetate phthalates, glyceryl distearate,
acrylic acid and methacrylic acid copolymers, methyl methacrylate
copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,
aminoalkyl methacrylate copolymer, poly(acrylic acid),
poly(methacrylic acid), methacrylic acid alkylamide copolymer,
poly(methyl methacrylate), poly(methacrylic acid) (anhydride),
methyl methacrylate, polymethacrylate, stearic acid, poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
[0042] In one embodiment, the carrier for a melt-extruded solid
oral dosage form can be one or more pharmaceutically acceptable
polymers including, but not limited to polyvinyl alcohol, polyvinyl
pyrrolidone, polyethylene glycols having molecular weight of about
1000 to about 20,000, gelatin, carbomer, poloxamer, hydroxypropyl
methyl cellulose; hydroxypropyl ethyl cellulose hydroxypropyl
cellulose, carboxymethyl cellulose. It is noteworthy that some
pharmaceutical carriers can be used in more than one manufacturing
process, such as a wet milling or dry milling process as well as a
melt extrusion process.
[0043] In a further aspect, the compositions of the current
invention can be formulated to provide a gastro-retentive dosage
form. In one embodiment, the gastro-retentive dosage form can be a
capsule or a tablet. In another embodiment, the gastro-retentive
dosage form can be retained in the upper gastro intestinal tract
for at least one hour post-dosing. In another embodiment, the
gastro-retentive dosage form can be retained in the upper gastro
intestinal tract for at least two hours post-dosing. In another
embodiment, the gastro-retentive dosage form can be retained in the
upper gastro intestinal tract for at least 4 hours post-dosing. In
another embodiment, the gastro-retentive dosage form can be
formulated to float in the upper gastro intestinal tract after
dosing. In another embodiment, the gastro-retentive dosage form is
formulated to increase in the dosage form volume by at least 10%
when it comes in contact with an aqueous use environment compared
to its volume when it is not in contact with the aqueous use
environment. In another embodiment, the gastro-retentive dosage
form is formulated to adhere to the lining of the upper gastro
intestinal tract wall after dosing.
[0044] The compositions and the oral dosage forms of the current
invention can also include one or more of the pharmaceutical
process aids selected from the group known in the art, consisting
of binders, bufferants, diluents, disintegrants, flavors,
colorants, taste-masking agents, resins, pH modifiers, lubricants,
glidants, thickening agent, opacifying agent, humectants,
desiccants, effervescing agents, plasticizing agents and the
like.
[0045] In a further aspect, the dosage form can comprise two or
more of populations of testosterone undecanoate compositions of the
present invention. In one embodiment, at least one of the
populations can be formulated to start releasing testosterone
undecanoate immediately into a surrounding aqueous medium. In
another embodiment, at least one of the populations can be
formulated to start releasing testosterone undecanoate after at
least 2 hours. In another embodiment, at least one the populations
can be formulated to release testosterone undecanoate after about 4
hours, or after about 6 hours, or after about 8 hours, or after
about 10 hours, into a surrounding aqueous medium.
[0046] In yet a further embodiment, at least one of the populations
can be formulated to start releasing testosterone undecanoate
immediately after oral administration to a human. In one particular
case, at least one of the populations can be formulated to start
releasing testosterone undecanoate in the duodenal region after
oral administration to a human. In another particular case, at
least one of the populations can be formulated to start releasing
testosterone undecanoate in the small intestine after oral
administration to a human.
[0047] In yet a further embodiment, at least one of the populations
includes a pH sensitive substance. In a particular case, at least
one of the populations can be formulated to start releasing
testosterone undecanoate at a pH of from about 1.0 to about 3.4. In
another particular case, at least one of the populations can be
formulated to start releasing testosterone undecanoate at a pH of
from about 3.5 to about 5.5. In another particular case, at least
one of the populations can be formulated to start releasing
testosterone undecanoate at a pH of from about 5.6 to about 6.8. In
another particular case, at least one of the populations can be
formulated to start releasing testosterone undecanoate at a pH
about 7.0 or more.
[0048] In yet another aspect, the dosage form comprising two or
more of populations of testosterone undecanoate compositions of the
present invention is a capsule or a tablet or a granular admixture.
In a particular case, the dosage form is a capsule-in-capsule
dosage form. In another particular case the dosage form is a
tablet-in-capsule dosage form. In another particular case the
dosage form is a tablet-in-tablet dosage form. In another
particular case, the dosage form is a granules and/or pellets in
capsule dosage form. In another particular case, the dosage form is
a granule, pellet and/or tablet in a capsule dosage form.
[0049] Non-limiting examples of the processes that can be used to
prepare the compositions and dosage forms of this invention include
mixing melting, prilling, size reduction, melt-spray congealing,
co-precipitation, co-crystallization, encapsulation, co-milling,
spray or freeze drying, complexing, granulating, extruding,
slugging, or combinations thereof.
[0050] The amount of testosterone undecanoate present in the oral
dosage forms of the present invention can vary depending on the
desired therapeutic effect. For example, a solid oral dosage form
intended to provide treatment of hypogonadism in males would likely
have a greater amount of testosterone undecanoate present in the
oral dosage form than a similar dosage form intended to treat
sexual dysfunction in females. With this in mind, in one
embodiment, the oral dosage forms of the present invention can
include testosterone undecanoate in an amount of about 0.5 mg to
about 750 mg. In another embodiment, the solid oral dosage form,
wherein the testosterone undecanoate is present in an amount of
about 1 mg to about 500 mg. In another embodiment, the solid oral
dosage form, wherein the testosterone undecanoate is present in an
amount of about 5 mg to about 400 mg. In another embodiment, the
testosterone undecanoate can be present in the oral dosage form in
an amount of about 10 mg to about 250 mg.
[0051] In one aspect the solid oral dosage form can be formulated
for administration to a human male and the testosterone undecanoate
is present in an amount of about 50 mg to about 750 mg. In one
embodiment, the solid oral dosage form is formulated for
administration to a human male and the testosterone undecanoate is
present in an amount of about 75 mg to about 600 mg. In another
embodiment, the solid oral dosage form is formulated for
administration to a human male and the testosterone undecanoate is
present in an amount of about 100 mg to about 400 mg. In yet
another aspect, the solid oral dosage form is formulated for
administration to a human female and the testosterone undecanoate
is present in an amount of about 0.5 mg to about 200 mg. In one
embodiment, the solid oral dosage form is formulated for
administration to a human female and the testosterone undecanoate
is present in an amount of about 1 mg to about 100 mg. In another
embodiment, the solid oral dosage form is formulated for
administration to a human female and the testosterone undecanoate
is present in an amount of about 2 mg to about 50 mg.
[0052] The testosterone undecanoate can be present in the solid
composition, or oral dosage form, in the crystalline or amorphous
form or combinations thereof. In another embodiment, the
testosterone undecanoate can be controlled precipitated, milled,
micronized or nanosized, or combination thereof. In another
embodiment, the testosterone undecanoate can have a mean particle
diameter of about 50 .mu.m or less. In another embodiment, the
testosterone undecanoate can have a mean particle diameter of about
40 .mu.m or less. In another embodiment, the testosterone
undecanoate can have a mean particle diameter of about 30 .mu.m or
less. In another embodiment, the testosterone undecanoate can have
a mean particle diameter of about 20 .mu.m or less. In another
embodiment, the testosterone undecanoate can have a mean particle
diameter of about 10 .mu.m or less. In another embodiment, the
testosterone undecanoate can have a mean particle diameter of about
5 .mu.m or less. In another embodiment, the testosterone
undecanoate can have a mean particle diameter of about 2 .mu.m or
less. In another embodiment, the testosterone undecanoate can have
a mean particle diameter of about 200 nm or less.
[0053] The testosterone undecanoate can be present in the solid
oral dosage form as solid particulates. In one embodiment, the
solid particulates are not solubilized in the carrier present in
oral dosage form. In one embodiment, the solid particulates of
testosterone undecanoate can comprise 5% (w/w) or more of the
testosterone undecanoate present in the oral dosage form. In one
embodiment, the solid particulates of testosterone undecanoate can
comprise 15% (w/w) or more of the testosterone undecanoate present
in the oral dosage form. In another embodiment, the solid
particulates of testosterone undecanoate can comprise 30% (w/w) or
more of the testosterone undecanoate present in the oral dosage
form. In another embodiment, the solid particulates of testosterone
undecanoate can comprise 50% (w/w) or more of the testosterone
undecanoate present in the oral dosage form. In another embodiment,
the solid particulates of testosterone undecanoate can comprise 70%
(w/w) or more of the testosterone undecanoate present in the oral
dosage form. In another embodiment, the solid particulates of
testosterone undecanoate can comprise 90% (w/w) or more of the
testosterone undecanoate present in the oral dosage form.
[0054] In one embodiment, the testosterone undecanoate can be
present in or on particles having effective average particle sizes
of less than 2000 nm or less in diameter. The particles can have at
least one surface stabilizer that can be adsorbed on or associated
with the surface of the particles having the testosterone
undecanoate, or polymorph thereof. Preferably, the surface
stabilizer adheres onto, or associates with, the surface of the
particles, but does not react chemically with the particles or with
other surface stabilizer molecules. Individually adsorbed molecules
of the surface stabilizer are essentially free of intermolecular
cross-linkages. The relative amounts of the testosterone
undecanoate, or polymorph thereof, and surface stabilizer present
in the composition of the present invention can vary widely. The
amount of the individual components can depend upon, among other
things, the particular polymorph selected, the
hydrophilic-lipophilic balance (HLB), the melting point, and the
surface tension of water solutions of the stabilizer. The
concentration of the testosterone undecanoate, or polymorph
thereof, can vary from about 99.5% to about 0.001%, from about 95%
to about 0.1%, or from about 90% to about 0.5%, by weight, based on
the total combined weight of the testosterone undecanoate, or
polymorph thereof, and the surface stabilizer(s), not including
other excipients. Likewise, the concentration of the surface
stabilizer(s) can vary from about 0.5% to about 99.999%, from about
5.0% to about 99.9%, or from about 10% to about 99.5%, by weight,
based on the total combined dry weight of the testosterone
undecanoate, or polymorph thereof, and surface stabilizer(s), not
including other excipients.
[0055] It has been discovered that solid oral dosage forms can be
formulated to provide the required drug release and bioavailability
when appropriate carrier is selected. The amount of the
pharmaceutically acceptable carrier used in the oral dosage form
can vary depending on factors such as the amount of testosterone
undecanoate present in the oral dosage form. In one embodiment, the
solid oral dosage form can have an amount of testosterone
undecanoate to amount of pharmaceutically acceptable carrier ratio
of about 8:1 (w/w) to about 1:8 (w/w). In another embodiment, the
solid oral dosage form can have an amount of testosterone
undecanoate to amount of pharmaceutically acceptable carrier ratio
of about 4:1 (w/w) to about 1:4 (w/w). In another embodiment, the
solid oral dosage form can have an amount of testosterone
undecanoate to amount of pharmaceutically acceptable carrier ratio
of about 2:1 (w/w) to about 1:2 (w/w).
[0056] The pharmaceutically acceptable carriers that are included
in the oral dosage forms of the present invention can act to
facilitate the bioavailability of the testosterone undecanoate. In
one embodiment, the pharmaceutically acceptable carrier can include
hydrophilic additives, lipophilic additives, or combinations
thereof. In one embodiment, the hydrophilic additive is not a
hydrophilic surfactant. In another embodiment, the lipophilic
additive is not a lipophilic surfactant. In another embodiment, the
composition is free of triglyceride, animal and vegetable oils.
[0057] In another embodiment, the carrier can be free of
hydrophilic surfactants. In another embodiment, the formulation can
include a hydrophilic surfactant that does not or does not
substantially contribute to the solubility of the testosterone
undecanoate within the composition. It is noteworthy, that the
phrase "substantially contribute" as it refers to the hydrophilic
surfactant's effect on the testosterone undecanoate's solubility
refers to the hydrophilic surfactant solubilizing less than 10 wt %
of the testosterone undecanoate. In one embodiment, substantially
contributes refers to the hydrophilic surfactant solubilizing less
than 5 wt % of the testosterone undecanoate. In one embodiment,
substantially contributes refers to the hydrophilic surfactant
solubilizing less than 1 wt % of the testosterone undecanoate. In
other embodiment the hydrophilic surfactant does not solubilize
testosterone undecanoate. In another embodiment the carrier is not
a hydrophilic surfactant.
[0058] The oral dosage forms may also be free of oils. As used
herein, the term "oils" refers to pharmaceutically acceptable
glycerides that have a triglyceride content of at least 40 wt %.
Similarly, another embodiment of the invention provides for the
oral dosage form to be free of triglycerides. In one embodiment,
the pharmaceutically acceptable carrier in the dosage form is not a
lipid substance.
[0059] Non-limiting examples of pharmaceutically acceptable
carriers can include methyl cellulose; ethyl cellulose;
noncrystalline cellulose; microcrystalline cellulose; hypromellose
(hydroxypropyl methylcellulose, for example, Methocel, having a
viscosity range from 2 to about 140000 cPs); hydroxyethyl
cellulose; hydroxypropyl cellulose; carboxymethylcellulose or its
salts or combinations thereof; dextrose; cellulose acetate;
cellulose acetate pthalate; cellulose acetate butyrate; cellulose
acetate trimellitate; cellulose nitrate; carbomers; croscarmellose;
cyclodextrins; .beta.-cyclodextrins; .alpha.-cyclodextrin;
dextrates; sorbitol; lactose; sucrose; maltose; galactose;
polyvinylpyrrolidone (povidone K 12 to K120); crospovidone;
polyvinyl alcohol; glycerol; glucose; polyols; such as mannitol;
xylitol or sorbitol or their combinations; polyethylene glycol
esters; alginates; sodium alginate; poly(lactide coglycolide);
gelatin; crosslinked gelatin; agar-agar; sodium dodecyl sulfate;
polyethylene glycols of mol wt range from about 100 to about 20,000
or their mixtures; guar gum; xanthan gum; starches; gum arabic;
dextrins; dibasic calcium phosphate; sodium starch glyco late;
croscarmellose sodium; galactomannan; tricalcium phosphate;
maltodextrin or its derivatives and their combinations;
polyoxyethylene stearate; carnuaba wax; poloxamers; deoxycholic
acid; polyoxyl sorbitan derivatives; polysorbate; lauroyl
macrogolglycerides; polyoxylglycerides; fatty alcohols; sugar
esters; sugar ethers; shellacs; tocopherol; tocopherol
polyethyleneglycol succinate; tocopherol succinate; tocopherol
acetate; pentaerythritol; urea; stearic acid; stearic acid salts;
hydroxystearic acid urethane; hydroxyalkyl xanthines; carrageenan;
chitosan; benzyl alcohol; ethyl alcohol; cetyl alcohol; cetosterayl
alcohol; polycaprolactone; polylactic acid; polyglycolic acid;
polylactide-co-glycolides; talc; magnesium stearate; fumed silica;
micronized silica; hydrogenated vegetable oils; capric acid;
caprylic acid; undecanoic acid; oleic acid; linoleic acid;
eicosapentaenoic acid; docosahexanoic acid; caprylic/capric mono
and/or diglycerides; caprylic/capric triglyceride;
caprylic/capric/lauric triglyceride; caprylocaproyl
macrogolglycerides; oleoyl macrogolglycerides; corn glycerides;
corn oil monoglycerides; mono-diglycerides of corn oil, coconut
oil, safflower oil, sunflower oil, maize oil; or mixtures thereof;
glyceryl mono linoleate; glyceryl stearate; glyceryl
palmitostearate; glyceryl oleate; hydrogenated castor oils; medium
and/or long chain mono-, di- or triglycerides; sodium benzoate;
sodium acetate; acetylated monoglycerides; long-chain alcohols and
silicone derivatives; gallic acid; propyl gallate; ascorbic acid;
ascorbyl palmitate; bentonite; vinyl pyrrolidone copolymers;
hydrochloric acid; phosphoric acid; sulfuric acid; nitric acid;
acetic acid; citric acid; tartaric acid; succinic acid; boric acid;
phosphoric acid; acrylic acid; adipic acid; alginic acid,
alkanesulfonic acid, amino acids, benzoic acid, butyric acid,
carbonic acid, fatty acids, formic acid, fumaric acid, gluconic
acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic
acid, oxalic acid, propionic acid, salicylic acid, tannic acid,
thioglycolic acid, toluenesulfonic acid; uric acid; amino acid
ester; ammonium hydroxide, potassium hydroxide, sodium hydroxide,
sodium hydrogen carbonate, aluminum hydroxide, magnesium hydroxide;
magnesium aluminum hydroxide; magnesium aluminum silicate,
synthetic aluminum silicate, synthetic hydrotalcite,
diisopropylethylamine, ethanolamine, ethylenediamine,
triethanolamine, triethylamine, triisopropanolamine, or a salt of a
ethylenediaminetetraacetic acid and its salts; titanium dioxide,
food dyes, lakes, natural vegetable colorants, iron oxides,
silicates, sulfates, aluminum hydroxidecitric acid, sodium
chloride, potassium chloride, calcium sulfate, magnesium oxide,
essential oils and ethyl vanillin; styrene/divinyl benzene
copolymers, quaternary ammonium compounds, triethyl citrate, acetyl
triethyl citrate, acetyltributyl citrate, propylene glycol,
phthalate esters (e.g., diethyl phthalate, dibutyl phthalate),
castor oil, sorbitol and dibutyl seccateascorbic acid, sorbic acid,
parabens, phenols, butylated hydroxyanisole, butylated
hydroxytoluene, proteins (e.g., collagen, Zein, gluten, mussel
protein, lipoprotein), glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lower alcohol fatty acids esters;
polyethylene glycol fatty acids esters; polypropylene glycol fatty
acid esters; polyoxyethylene glycerides lactic acid esters of
mono/diglycerides; propylene glycol diglycerides; polyoxyethylene
alkylethers; polyoxyethylene-polyoxypropylene block copolymers such
as poloxamer--108, 188, 217, 238, 288, 338, 407, 124, 182, 183,
212, 331, or 335, or combinations thereof; trans-esterified
vegetable oils; sterols; cholesterol; sterol derivatives;
sucroglycerides; polyoxyethylene vegetable oils; and
polyoxyethylene hydrogenated vegetable oils, lecithins,
phospholipids, sodium docusate; dioctyl sulfosuccinate; acyl
lactylates; mono- and diacetylated tartaric acid esters of mono-
and diglycerides; succinylated monoglycerides, paraffin oil,
paraffin wax, silicone oil, dimethicone, simethicone, silicon
dioxide, macrogol 15 hydroxystearate (Solutol), sucrose acetate
isobutyrate, polyethoxylated cholesterol; stearoyl
polyoxyglycerides; acrylic acid polymers such as methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid) (anhydride), methyl methacrylate,
polymethacrylate, polyacrylamide, glycidyl methacrylate copolymers,
and combinations thereof.
[0060] In one embodiment, the pharmaceutically acceptable carrier
can include at least one of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; propylene glycol; starches; sodium
starch glycolate; croscarmellose; sucrose; lactose; cyclodextrins;
carboxymethyl cellulose; microcrystalline cellulose, hydroxyl
propyl methyl cellulose; ethyl cellulose; carbomers; gelatin;
poloxamers; sodium dodecyl sulfate; sodium docusate; sorbitan
esters, polyoxyethylene sorbitan esters; glycerin; paraffin oil;
silicone oils; magnesium aluminosilicates; silicon dioxide; ethyl
alcohol; benzyl alcohol; benzyl benzoate; ascorbic acid; oleic
acid; linoleic acid; stearic acid; capric acid; caprylic acid;
caprylic/capric fatty acid mono and/or diglycerides; hydrogenated
castor oil; corn oil macrogolglycerides; linoleic/oleic fatty acid
mono- and/or diglycerides; caprylocaproyl macrogolglycerides; mono-
and/or diglycerides of coconut oil or maize oil or safflower oil or
sunflower oil or mixtures thereof; glycerol esters of saturated
C.sub.12-C.sub.18 fatty acid; glyceryl monostearate; glyceryl
distearate; glyceryl palmitostearate; glyceryl behenate; glyceryl
monolinoleate; triglycerides; oils; fatty acids; triethyl citrate;
linoleoyl macrogolglycerides, lauroyl macrogolglycerides; sugar
esters; acetylated mono- and/or diglycerides; stearoyl
polyoxyglycerides; trans-esterified vegetable oils; lecithin;
phospholipids; polyethoxylated cholesterol; glyceryl oleate,
cholesterol; tocopherol; tocopherol succinate; medium and/or long
chain mono-, diglycerides; polyoxyl castor oils or mixtures
thereof.
[0061] In another embodiment, the pharmaceutically acceptable
carrier can include at least one of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; cyclodextrins; maltodextrin;
hydroxylpropyl methyl cellulose; carbomers; gelatin; poloxamers;
sodium dodecyl sulfate; sodium docusate; sorbitan esters,
polyoxyethylene sorbitan esters; ethyl alcohol; benzyl alcohol;
benzyl benzoate; oleic acid; linoleic acid; stearic acid; capric
acid; caprylic acid; caprylocaproyl macrogolglycerides; corn oil
macrogolglycerides; glyceryl monostearate; glyceryl distearate;
glyceryl palmitostearate; glyceryl monolinoleate; cholesterol;
tocopherol; polyoxyl vegetable oils; triethyl citrate; linoleoyl
macrogolglycerides, lauroyl macrogolglycerides; sugar esters;
stearoyl polyoxyglycerides; lecithin; phospholipids;
polyethoxylated cholesterol; or mixtures thereof.
[0062] In another embodiment, the pharmaceutically acceptable
carrier can include at least one of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; cyclodextrins; maltodextrin;
hydroxylpropyl methyl cellulose; carbomers; gelatin; poloxamers;
sodium dodecyl sulfate; sodium docusate; polyoxyethylene sorbitan
esters; ethyl alcohol; benzyl alcohol; benzyl benzoate;
caprylocaproyl macrogolglycerides; corn oil macrogolglycerides;
polyoxyl castor oils; polyoxyl vegetable oils; triethyl citrate;
linoleoyl macrogolglycerides, lauroyl macrogolglycerides; sugar
esters; stearoyl polyoxyglycerides; or mixtures thereof.
[0063] In another embodiment, the pharmaceutically acceptable
carrier can include at least one of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; propylene glycol; starches; sodium
starch glycolate; croscarmellose; sucrose; lactose; cyclodextrins;
carboxymethyl cellulose; microcrystalline cellulose; hydroxyl
propyl methyl cellulose; ethyl cellulose; carbomers; gelatin;
sorbitan esters; glycerin; paraffin oil; silicone oils; magnesium
aluminosilicates; silicon dioxide; ethyl alcohol; benzyl alcohol;
benzyl benzoate; ascorbic acid; oleic acid; linoleic acid; stearic
acid; capric acid; caprylic acid; caprylic/capric mono and/or
diglycerides; hydrogenated castor oil; mono- and/or diglycerides of
coconut oil or, maize oil, safflower oil, sunflower oil, or
mixtures thereof; glyceryl monostearate; glyceryl distearate;
glyceryl palmitostearate; glyceryl behenate; glyceryl mono
linoleate; glyceryl oleate, cholesterol; tocopherol; tocopherol
succinate; medium and/or long chain mono-, diglycerides; fatty
acids; triethyl citrate; linoleoyl macrogolglycerides, lauroyl
macrogolglycerides; sugar esters; acetylated mono- and/or
diglycerides; steroyl polyoxyglycerides; trans-esterified vegetable
oils; lecithin; phospholipids; or mixtures thereof.
[0064] In another embodiment, the pharmaceutically acceptable
carrier can include at least one of polyvinyl alcohol, polyvinyl
pyrrolidones, polyethylene glycols having molecular weight from
about 100 to about 20,000; propylene glycol; starches; sodium
starch glycolate; croscarmellose; sucrose; lactose; cyclodextrins;
carboxymethyl cellulose; microcrystalline cellulose, hydroxyl
propyl methyl cellulose; ethyl cellulose; carbomers; gelatin;
poloxamers; sodium dodecyl sulfate; sodium docusate;
polyoxyethylene sorbitan esters; glycerin; paraffin oil; silicone
oils; magnesium aluminosilicates; silicon dioxide; ethyl alcohol;
benzyl alcohol; benzyl benzoate; ascorbic acid; oleic acid;
linoleic acid; stearic acid; capric acid; caprylic acid;
hydrogenated castor oil; caprylocaproyl macrogolglycerides;
cholesterol; tocopherol; tocopherol succinate; polyoxyl castor
oils; polyethoxylated cholesterol or mixtures thereof.
[0065] In another embodiment, the preferred pharmaceutically
acceptable carrier is free of lipophilic additives and can include
at least one of polyvinyl alcohol, polyvinyl pyrrolidones,
polyethylene glycols having molecular weight from about 100 to
about 20,000; cyclodextrins; maltodextrin; hydroxylpropyl methyl
cellulose; carbomers; gelatin; poloxamers; sodium dodecyl sulfate;
sodium docusate; polyoxyethylene sorbitan esters; ethyl alcohol;
benzyl alcohol; benzyl benzoate; caprylocaproyl macrogolglycerides;
polyoxyl castor oils; polyoxyl vegetable oils; triethyl citrate;
lauroyl macrogolglycerides; sugar esters; stearoyl
polyoxyglycerides or mixtures thereof.
[0066] In yet another embodiment, the pharmaceutically acceptable
carrier is free of hydrophilic surfactants and includes at least
one of polyvinyl alcohol, polyvinyl pyrrolidones, polyethylene
glycols having molecular weight from about 100 to about 20,000;
propylene glycol; starches; sodium starch glycolate;
croscarmellose; sucrose; lactose; cyclodextrins; carboxymethyl
cellulose; microcrystalline cellulose, hydroxylpropyl methyl
cellulose; ethyl cellulose; carbomers; gelatin; sorbitan esters,
glycerin; paraffin oil; silicone oils; magnesium aluminosilicates;
silicon dioxide; ethyl alcohol; benzyl alcohol; benzyl benzoate;
ascorbic acid; oleic acid; linoleic acid; stearic acid; capric
acid; caprylic acid; caprylic/capric mono and/or diglycerides;
hydrogenated castor oil; mono- and/or diglycerides of coconut oil
or, maize oil, safflower oil, sunflower oil, or mixtures thereof;
glyceryl monostearate; glyceryl distearate; glyceryl
palmitostearate; glyceryl behenate; glyceryl monolinoleate;
glyceryl oleate, cholesterol; tocopherol; tocopherol succinate;
medium and/or long chain mono-, diglycerides; fatty acids; triethyl
citrate; linoleoyl macrogolglyceride; lauroyl macrogolglycerides;
sugar esters; acetylated mono- and/or diglycerides; steroyl
polyoxyglycerides; trans-esterfied vegetable oils; lecithin;
phospholipids; or mixtures thereof.
[0067] In another embodiment, the pharmaceutically acceptable
carrier is free of lipophilic surfactants and includes at least one
of polyvinyl alcohol, polyvinyl pyrrolidones, polyethylene glycols
having molecular weight from about 100 to about 20,000; propylene
glycol; starches; sodium starch glycolate; croscarmellose; sucrose;
lactose; cyclodextrins; carboxymethyl cellulose; microcrystalline
cellulose, hydroxylpropyl methyl cellulose; ethyl cellulose;
carbomers; gelatin; poloxamers; sodium dodecyl sulfate; sodium
docusate; polyoxyethylene sorbitan esters; glycerin; paraffin oil;
silicone oils; magnesium aluminosilicates; silicon dioxide; ethyl
alcohol; benzyl alcohol; benzyl benzoate; ascorbic acid; oleic
acid; linoleic acid; stearic acid; capric acid; caprylic acid;
hydrogenated castor oil; caprylocaproyl macrogolglycerides;
cholesterol; tocopherol; tocopherol succinate; polyoxyl castor
oils; polyethoxylated cholesterol or mixtures thereof.
[0068] In another embodiment, the pharmaceutically acceptable
carrier is free of lipid substance and includes at least one of
polyvinyl alcohol, polyvinyl pyrrolidones, polyethylene glycols
having molecular weight from about 100 to about 20,000;
cyclodextrins; maltodextrin; hydroxylpropyl methyl cellulose;
carbomers; gelatin; poloxamers; ethyl alcohol; benzyl alcohol;
benzyl benzoate or combinations thereof.
[0069] In yet another embodiment, the pharmaceutically acceptable
carrier can include polyvinyl alcohol, polyvinyl pyrrolidones,
polyethylene glycols having molecular weight from about 1000 to
about 20,000, or combination thereof. In a further embodiment, the
solid composition of the current invention includes less than 30 wt
% of polyethylene glycol. In a particular embodiment, the solid
composition of the current invention includes from about 0.1 wt %
to about 27 wt % of polyethylene glycol. In another embodiment, the
solid composition of the current invention includes from about 3 wt
% to about 20 wt % of polyethylene glycol. In another particular
embodiment, the solid composition of the current invention can
include from about 6 wt % to about 15 wt % of polyethylene
glycol.
[0070] In a further embodiment, the solid composition or dosage
form of the current invention includes about 45% or less of a lipid
substance. In a further embodiment, the solid composition or dosage
form includes about 30% or less of a lipid substance. In a further
embodiment, the solid composition or dosage form includes about 15%
or less of a lipid substance. In a further embodiment, the solid
composition or dosage form includes about 5% or less of a lipid
substance. In another particular embodiment, the solid composition
or dosage form is free of lipid substance. In another embodiment,
the pharmaceutical carrier in the dosage form does not include a
lipid substance with chain length greater than C.sub.12.
[0071] The solid oral dosage forms are capable of providing
adequate in vivo bioavailability to provide therapeutic effect for
testosterone therapy of both female and male subjects. In one
aspect of the invention, the oral dosage form can be formulated to
have a delayed release such that the testosterone undecanoate does
not have any release, or any significant (not more than 10 wt %)
release, in the first 15 minutes following administration. It has
been discovered that by delaying the initial release of the
testosterone undecanoate for this time period, the oral dosage form
provides a pharmacokinetic profile that may be more acceptable than
when the testosterone undecanoate is allowed to release
immediately.
[0072] With this in mind, the solid oral dosage forms of the
present invention can be formulated to release about 85 wt % or
less of the testosterone undecanoate in the first 30 minutes
following administration to a subject. In one embodiment, the solid
oral dosage form can release less than 70 wt % of the testosterone
undecanoate in the first 30 minutes following administration. In
another embodiment, the solid oral dosage form can be formulated to
release at least 35 wt % of the testosterone undecanoate in the
first 120 minutes following administration to a human subject. In
another embodiment, the solid oral dosage form can be formulated to
release at least 45 wt % of the testosterone undecanoate in the
first 120 minutes following administration to a human subject. In
yet a further embodiment, the solid oral dosage form can be
formulated to release at least about 50 wt % in the first 120
minutes following administration to a human subject.
[0073] As discussed above, the solid oral dosage forms of the
present invention provide adequate bioavailability of the
testosterone undecanoate so as to generate therapeutically
effective pharmacokinetic levels of testosterone undecanoate and
testosterone, without the need to administer excessive amounts of
the active agent. In one embodiment, the dosage form when
administered to a human male the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 4.5.times.10.sup.4 dL
to 4.times.10.sup.6 dL. In another embodiment, the dosage form when
administered to a human male the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 6.times.10.sup.4 dL to
3.times.10.sup.6 dL. In another embodiment, the dosage form when
administered to a human male, the oral dosage provides a dose to
plasma testosterone C.sub.avg ratio of 9.times.10.sup.4 dL to
2.times.10.sup.6 dL.
[0074] In one embodiment, the dosage form when administered to a
human female, the oral dosage provides a dose to plasma total
testosterone C.sub.avg ratio of 5.times.10.sup.3 dL to
2.times.10.sup.7. In another embodiment, the dosage form when
administered to a human female, the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 1.times.10.sup.4 dL to
1.times.10.sup.7 dL. In another embodiment, the dosage form when
administered to a human female, the oral dosage provides a dose to
plasma total testosterone C.sub.avg ratio of 2.times.10.sup.4 dL to
5.times.10.sup.6 dL.
[0075] In one embodiment, the oral dosage form, when after
administration to a human male, can provide a plasma total
testosterone C.sub.avg of about 300 ng/dL to about 1100 ng/dL. In
another embodiment, the oral dosage form, when after
administrations to a human male, can provide a plasma total
testosterone C.sub.avg of about 350 ng/dL to about 800 ng/dL. In
another embodiment, the oral dosage form, when after
administrations to a human male, can provide a plasma total
testosterone C.sub.avg of about 400 ng/dL to about 600 ng/dL. In
yet another embodiment, the oral dosage form, when after
administrations to a human male, the oral dosage form provides a
plasma total testosterone undecanoate C.sub.avg of about 1.5 ng/mL
to about 1 .mu.g/mL. In another embodiment, the oral dosage form,
when after administrations to a human male, can provide a plasma
total testosterone undecanoate C.sub.avg of about 10 ng/mL to about
850 ng/mL.
[0076] When administered to a human female, the oral dosage forms
of the present invention can be formulated to provide a plasma
total testosterone C.sub.avg of about 1 ng/dL to about 100 ng/dL.
In another embodiment, when administered to a human female, the
oral dosage form can provide a plasma total testosterone C.sub.avg
of about 20 ng/dL to about 80 ng/dL. In yet a further embodiment,
when administered to a human female, the oral dosage form can
provide a plasma total testosterone C.sub.avg of about 30 ng/dL to
about 70 ng/dL.
[0077] In a further embodiment, the dosage forms can be formulated
such that when administered to a human subject, provides a ratio of
serum testosterone undecanoate C.sub.avg to serum total
testosterone C.sub.avg of about 3:1 to about 100:1. In a further
embodiment, the dosage forms can be formulated such that when
administered to a human subject, provides a ratio of serum
testosterone undecanoate C.sub.avg to serum total testosterone
C.sub.avg of about 4:1 to about 50:1.
[0078] In one embodiment, a single dose of the testosterone
undecanoate composition or oral dosage form can provide a C.sub.avg
for testosterone of about 300 ng/dL or more from about 0.5 hours to
about 24 hours after oral administration with a meal. In a further
embodiment, a single dose of a testosterone undecanoate composition
or oral dosage form can provide a C.sub.avg for plasma total
testosterone of about 300 ng/dL or more at about 20 hours after
oral administration with a meal. In yet a further embodiment, a
single dose of the testosterone undecanoate composition can provide
a C.sub.avg for plasma total testosterone of about 300 ng/dL or
more at about 18 hours after oral administration with a meal. In
still a further embodiment, a single dose of the testosterone
undecanoate oral dosage form can provide a C.sub.avg for plasma
total testosterone of about 300 ng/dL or more at about 16 hours
after oral administration with a meal. In still a further
embodiment, a single dose of the testosterone undecanoate oral
dosage form can provide a C.sub.avg for plasma total testosterone
of about 300 ng/dL or more at about 12 hours after administration
after oral administration with a meal. In still a further
embodiment, a single dose of the testosterone undecanoate oral
dosage form can provide a C.sub.avg for plasma total testosterone
of about 300 ng/dL or more at about 8 hours after oral
administration with a meal. The meal that is administered with the
composition or oral dosage form can be a standard meal (comprising
about 30 g to about 35 g fat).
[0079] In another embodiment, a pharmaceutical oral dosage form,
when administered once daily, provides a plasma total testosterone
C.sub.avg of about 300 ng/dL to 700 ng/dL. In another embodiment, a
pharmaceutical oral dosage form, when administered once daily,
provides a plasma total testosterone C.sub.avg of about 300 ng/dL
to 600 ng/dL.
[0080] In one embodiment, the pharmaceutical oral dosage form can,
when administered twice daily (e.g. once every 12 hours), provide a
plasma total testosterone C.sub.avg of about 300 ng/dL to 1000
ng/dL. In another embodiment, the pharmaceutical oral dosage form
can, when administered twice daily, provide a plasma total
testosterone C.sub.avg of about 350 ng/dL to 800 ng/dL. In another
embodiment, the pharmaceutical oral dosage form can, when
administered twice daily, provide a plasma total testosterone
C.sub.avg of about 400 ng/dL to 600 ng/dL. In another embodiment,
the pharmaceutical oral dosage form can, when administered twice
daily, provide a plasma total testosterone C.sub.avg of about 300
ng/dL to 1000 ng/dL. In another embodiment, the pharmaceutical oral
form, when administered twice daily such that more than 100 mg
testosterone undecanoate is administered during the day and less
than 100 mg administered during the night, can provide a plasma
total testosterone C.sub.avg of about 300 ng/dL to 1000 ng/dL. In
another embodiment, the pharmaceutical oral form, when administered
twice daily such that more than 100 mg testosterone undecanoate is
administered during the day and less than 100 mg administered
during the night, can provide a plasma total testosterone C.sub.avg
of about 300 ng/dL to 800 ng/dL. In another embodiment, the
pharmaceutical oral form, when administered twice daily such that
more than 100 mg testosterone undecanoate is administered during
the day and less than 100 mg administered during the night, can
provide a plasma total testosterone C.sub.avg of about 400 ng/dL to
700 ng/dL. In another embodiment, the pharmaceutical oral form,
when administered twice daily such that more than 100 mg
testosterone undecanoate is administered during the day and less
than 100 mg administered during the night, can provide a plasma
total testosterone C.sub.avg of 400 ng/dL to 600 ng/dL.
[0081] The oral dosage forms of the present invention can be used
to treat testosterone deficiency in post menopausal women. In one
embodiment, a pharmaceutical oral dosage form is provided that,
when administered once daily to post menopausal women, provides a
plasma total testosterone C.sub.avg of about 10 ng/dL to 100 ng/dL.
In another embodiment, a pharmaceutical oral dosage form is
provided that, when administered once daily to post menopausal
women, provides a plasma total testosterone C.sub.avg of about 20
ng/dL to 60 ng/dL. In another embodiment, a pharmaceutical oral
dosage form is provided that, when administered once daily to post
menopausal women, provides a plasma total testosterone C.sub.avg of
about 20 ng/dL to 40 ng/dL
[0082] The oral dosage forms disclosed herein can also be used to
treat testosterone deficiency in pre-menopausal women. In another
embodiment, a pharmaceutical oral dosage form is provided that,
when administered once daily to pre menopausal women in order to
provides, plasma total testosterone C.sub.avg of about 10 ng/dL to
100 ng/dL. In another embodiment, a pharmaceutical oral dosage form
is provided that, when administered once daily to pre menopausal
women in order to provides, plasma total testosterone C.sub.avg of
about 20 ng/dL to 60 ng/dL. In another embodiment, a pharmaceutical
oral dosage form is provided that, when administered once daily to
pre menopausal women in order to provides, plasma total
testosterone C.sub.avg of about 20 ng/dL to 40 ng/dL.
[0083] The oral dosage forms may also be used to treat testosterone
deficiency in perimenopausal women as well as in oopherectomized
women. In one embodiment, a pharmaceutical oral dosage form is
provided that, when administered once daily to perimenopausal
women, provides a plasma total testosterone C.sub.avg of about 10
ng/dL to 100 ng/dL. In one embodiment, a pharmaceutical oral dosage
form is provided that, when administered once daily to
peri-menopausal women, provides a plasma total testosterone
C.sub.avg of about 20 ng/dL to 60 ng/dL. In one embodiment, a
pharmaceutical oral dosage form is provided that, when administered
once daily to peri-menopausal women, provides a plasma total
testosterone C.sub.avg of about 20 ng/dL to 40 ng/dL. In one
embodiment, a pharmaceutical oral dosage form is provided that,
when administered once daily to oopherectomized women, provides a
plasma total testosterone C.sub.avg of about 10 ng/dL to 100 ng/dL.
In one embodiment, a pharmaceutical oral dosage form is provided
that, when administered once daily to oopherectomized women,
provides a plasma total testosterone C.sub.avg of about 20 ng/dL to
60 ng/dL. In one embodiment, a pharmaceutical oral dosage form is
provided that, when administered once daily to oopherectomized
women, provides a plasma total testosterone C.sub.avg of about 20
ng/dL to 40 ng/dL.
[0084] The oral dosage forms of the present invention can be used
to treat subjects in need of testosterone therapy, both males and
females. In another embodiment, a method of treating a subject in
need of testosterone therapy is provided that includes
administering to the subject any of the solid oral dosage forms of
the present invention. Depending on the particular oral dosage form
and the needed therapy, the administration can be done once every
24 hours, once every 12 hours, or once every eight hours. In one
embodiment, the administration can include more than one unit of
the solid oral dosage form. In one embodiment, the subject can be a
human male and the solid oral dosage form provides a daily dose of
testosterone undecanoate of about 50 mg to about 1500 mg per day.
In another embodiment, the subject can be a human female and the
solid oral dosage form can provide a daily dose of testosterone
undecanoate of 0.5 to 200 mg per day.
[0085] The testosterone undecanoate dosage compositions and oral
dosage forms disclosed herein can be orally administered in a 24
hours' dosing regimen (also referred to as or a daily dosing
regimen) that is suitable to the needs of the subject. The 24
hours' dosing regimen can include administering the dosage forms
after meals in the morning, at about noon, in the evening, at about
night time or combinations thereof. The 24 hours' dosing regimen
can include dosing one or more dosage units at one or more
administration times.
[0086] The compositions and oral dosage forms disclosed herein can
be orally administered with food without regards to the food or
food content. In one embodiment, the oral dosage form can be orally
administered without food. In another embodiment, the composition
or oral dosage form can be administered with a meal, such as a meal
that provides about 200 calories to about 1000 calories of energy.
In another embodiment, the composition or oral dosage form can be
administered with a meal that provides about 50% of the calories
from the fat. In another embodiment, the composition or oral dosage
form can be administered with a high-fat, high calorie meal. In
another embodiment, the composition or oral dosage form can be
administered with a standard meal that provides about 500 calories
to about 1000 calories of energy. The compositional make-up of the
meals that are administered can vary depending on the tastes and
dietary needs of a subject. However, in some situations it may be
beneficial to administer the compositions and oral dosage forms
with meals that provide no fat to about 50 g of fat. In one
embodiment, the meal can provide about 10 g to about 50 g of fat.
In yet a further embodiment, the meal can provide 15 g to about 35
g of fat. In one embodiment, when the oral dosage form is
administered to a human female, it can be done without regard to
the presence of or nutritional make-up of a meal.
[0087] In another embodiment, when administering the oral dosage
form, the total daily dose of the testosterone undecanotate
administered to human subject with standard meal is between about
20% to about 70% of the total daily dose administered without
meals, for a similar therapeutic benefit.
[0088] It has been surprisingly discovered that the testosterone
undecanoate oral dosage forms of the present invention can provide
in vitro release of less than about 85% of the testosterone
undecanoate in the oral dosage form in the first 30 minutes, and
that such release provides, upon a single oral administration with
meals to a human subject, about 10% or more testosterone
undecanoate AUC as compared to an equivalent dose of testosterone
undecanoate in an immediate release dosage capsule administered
under same conditions. The in vitro release profile is determined
in about 1000 mL of 8% w/v Triton X-100 solution at about
37.degree. C. in an USP Type-2 Apparatus at about 100 rpm.
Immediate release dosage forms are dosage forms that release more
than 85% of the testosterone undecanoate in the dosage form within
the first 30 minutes in the above in vitro release conditions.
[0089] In one embodiment, the testosterone undecanoate oral dosage
forms of the current invention, when compared to an equivalent dose
testosterone undecanoate containing immediate release dosage form,
can provide upon a single oral administration with meal to a human
subject about 15% or more testosterone undecanoate AUC. In another
embodiment, the testosterone undecanoate oral dosage form can
provide 10% or more testosterone undecanoate bioavailability as
compared to an equivalently dosed immediate release oral dosage
form. In another embodiment, the testosterone undecanoate oral
dosage form can provide 10% or more reduction in the inter-subject
variability of the testosterone undecanoate C.sub.max, testosterone
undecanoate AUC, or both as compared to an equivalently dosed
immediate release oral dosage form. In another embodiment, the
testosterone undecanoate oral dosage form can provide 10% or more
testosterone exposure or bioavailability in subjects as compared to
equivalent dosed immediate release oral dosage forms. In another
embodiment, the testosterone undecanoate oral dosage form can
provide 10% or more reduction in the variability of plasma total
testosterone C.sub.max, testosterone AUC, or both.
[0090] The need for testosterone therapy can be associated with a
variety of conditions, and thus the oral dosage forms of the
present invention can be used to treat a variety of conditions.
Generally, the compositions and oral dosage forms of the present
invention can be used to treat any condition associated with
testosterone deficiency, including complete absence, of endogenous
testosterone. In one embodiment, the subject can be a male and the
need for testosterone therapy can be associated with a condition
selected from the group consisting of hygonadism; erectile
dysfunction; Klienfelter Syndrome; reduced libido; low muscle mass,
and low bone density; metabolic syndrome, and combinations
thereof.
[0091] In another embodiment, the subject can be a human female and
the need for testosterone therapy can be associated with a
condition selected from the group consisting of hypoactive sexual
desire disorder, arousal disorder, dyspareunia, anorgasmia, and
combinations thereof. In further embodiments, the oral dosage form
of the present disclosure can be administered to menopausal women
to can achieve one or more of the following: increase their sexual
desire, increase their sexual activity, increase their libido,
increase their sexual fantasy, increase satisfaction in their
sexual activity, increase their subjective quality of sexual acts,
increase their frequency of sexual thoughts, increase their self
reported mood, increase their self reported energy, increase their
bone mineral density, increase their cognitive function, treat
their hormone-related depression, treat their arousal disorder, or
treat their hypoactive sexual disorder.
[0092] Other examples of conditions associated with testosterone
deficiency that can also be treated using the oral dosage capsules
and/or compositions of the present invention are also provided
below. It is understood that some of the conditions are gender
specific while others may be treated in both genders. Knowledge of
such conditions is well within the knowledge of own of ordinary
skill in the art. With this in mind, additional conditions that can
be treated with the compositions and oral dosage forms of the
present invention include, but are not limited to congenital or
acquired primary hypogonadism, hypogonadotropic hypogonadism,
cryptorchidism, bilateral torsion, orchitis, vanishing testis
syndrome, orchidectomy, Klinefelter's syndrome, post castration,
eunuchoidism, hypopituitarism, endocrine impotence, infertility due
to spermatogenic disorders, impotence, male sexual dysfunction
(MSD) including conditions such as premature ejaculation; erectile
dysfunction, decreased libido, and the like, micropenis and
constitutional delay, penile enlargement, appetite stimulation,
testosterone deficiency associated with chemotherapy, testosterone
deficiency associated with toxic damage from alcohol, testosterone
deficiency associated with toxic damage from heavy metal,
osteoporosis associated with androgen deficiency, hot flashes, dry
and thin skin, weight gain, and combinations thereof.
[0093] Other conditions that can be treated by the compositions and
oral dosage forms disclosed herein include idiopathic gonadotropin,
LHRH deficiency, or pituitary hypothalamic injury from tumors,
trauma, or radiation. Typically, these subjects have low serum
testosterone levels but have gonadotropins in the normal or low
range. In one embodiment, the compositions or oral dosage forms may
be used to stimulate puberty in carefully selected males with
clearly delayed puberty not secondary to pathological disorder. In
another embodiment, the compositions and oral dosage forms may be
used in female-to-male transsexuals in order to maintain or restore
male physical and sexual characteristics including body muscle
mass, muscle tone, bone density, body mass index (BMI), enhanced
energy, motivation and endurance, restoring psychosexual activity
etc. In some embodiments, the testosterone undecanoate compositions
and oral dosage capsules may be useful in providing hormonal male
contraception. Additionally, testosterone therapy can also be used
to improve the quality of life of subjects suffering for conditions
such as decreased libido, anemia due to marrow failure, renal
failure, chronic respiratory or cardiac failure, steroid-dependent
autoimmune disease, muscle wasting associated with various diseases
such as AIDS, preventing attacks of hereditary angioedema or
urticaria; andropause, and palliating terminal breast cancer. In
some situations, certain biomarkers such as for example, increased
SHBG levels, can be used to diagnose a subject who may be in need
of testosterone therapy. These biomarkers can be associated with
conditions/disease states such as anorexia nervosa,
hyperthyroidism, hypogonadism, androgen insensitivity/deficiency,
alcoholic hepatic cirrhosis, primary biliary cirrhosis, and the
like.
[0094] Subjects that can be treated by the testosterone undecanoate
compositions and oral dosage capsule of the present disclosure can
be any male or female in need thereof. In particular, in one
embodiment, the human male may be at least 14 years of age. In
another embodiment, the human male is an adult of at least age 30.
In a further embodiment, the subject can be an adult male of at
least age 50. In yet a further embodiment, the subject can be an
adult male of at least age 60.
[0095] As discussed above, the compositions and oral dosage forms
disclosed herein can be used to treat testosterone deficiency in
human males. In one embodiment, the human male being treated can
have an average baseline plasma testosterone concentration
(T-C.sub.avg-B) of about 400 ng/dL or less. In another embodiment,
the human male being treated can have an average baseline plasma
testosterone concentration of about 350 ng/dL or less. In another
embodiment, the human male being treated can have an average
baseline plasma testosterone concentration of about 300 ng/dL or
less. In another embodiment, the human male being treated can have
an average baseline plasma testosterone concentration of about 250
ng/dL or less. In still another embodiment, the human male being
treated can have an average baseline plasma testosterone
concentration of about of about 190 ng/dL or less. In still a
further embodiment, the human male has an average baseline plasma
testosterone concentration (T-C.sub.avg-B) of about 400 ng/dL or
less, along with a co-morbid condition of insulin resistance.
[0096] Further, there are several biomarkers that can be used to
identify patients who need testosterone therapy. Accordingly, in
one embodiment, the human male being treated can have a low density
lipoproteins (LDL) level in greater than about 130 mg/dL of blood.
In another embodiment, the human male being treated can have a high
density lipoproteins (HDL) level less than about 40 mg/dL of blood.
In still another embodiment, the human male being treated can have
a total cholesterol level greater than about 220 mg/dL of blood. In
yet a further embodiment, the human male being treated can have an
average TG (triglycerides) levels greater than 250 mg/dL of blood.
In one embodiment, the testosterone undecanoate dosage forms of the
current invention can be administered to human male whose
bioavailable or free or un-bound plasma estradiol levels are about
20 pg/mL or less. In another embodiment, dosage forms of the
current invention can be administered to human male who has a ratio
of the bioavailable or free or unbound plasma testosterone level to
the bioavailable or free or un-bound plasma estradiol level at
about 100 or less.
[0097] The testosterone undecanoate compositions and oral dosage
forms of the current invention can be administered orally to a
human male who has an average body mass index (BMI) of about 30
kg/m.sup.2 or more. In another embodiment, the human male has an
average BMI of about 37 kg/m.sup.2 or more. In a further
embodiment, the subject male being treated can have a serum sex
hormone binding globulin (SHBG) levels of about 40 nmol/L or more.
In yet still another embodiment, the human male being treated can
have a serum SHBG levels of about 60 nmol/L or more.
[0098] The compositions and associated oral dosage forms of the
present invention can be used in conjunction with or as a component
of a diagnostic or treatment kit that enables diagnosis and
treatment of patients in need of testosterone therapy. The
diagnostic or treatment kit may comprise one or more testosterone
undecanoate compositions or oral dosage forms with one or more
other components, including, but not limited to 1) instructions to
enable those ordinarily skilled in the art to prepare a dosage form
for immediate dispensing to the subject in need of; 2) one or more
containers filled with one or more of the ingredients of the oral
pharmaceutical dosage forms of the invention. Suitable containers
include, for example, a bottle, a box, a blister card, a foil
packet, or a combination thereof; 3) a tamper proof container or
packaging; 4) other pharmaceutical dosage forms including other
active agents including estrogens, progesterones, PDE-5 inhibitors
and glucocorticosteroids; 5) Notice or printed instructions: in a
form prescribed by a governmental agency regulating the
manufacture, use, or sale of pharmaceuticals or biological
products, which notice reflects approval by the agency of the
manufacture, use, or sale for human administration to treat a
condition that could be treated by oral testosterone therapy; 6) A
"planner" for monitoring and tracking administration of the oral
dosage forms; 7) Containers for storing and transporting the
components of the kit. 8) total testosterone or free testosterone
testing kits 9) Sex Hormone binding globulin, SHBG, testing kits
10) Body mass index testing materials to identify high risk
patients; 11) tests for identifying patients with hypogonadism 12)
tests to assess testicular function or impotency 13) test for bone
mineral density/osteoporosis 14) test for hair density 15) test for
muscle mass and strength 16) test for determining erectile
dysfunction 17) test for decreased libido 18) test for fatigue,
depression, mood disorders or irritability 19) test for infertility
20) test for prostate condition 21) test for determining hypoactive
sexual desire disorder 22) test for determining mood disorder. 23)
test for determining cardiovascular effects 24) test for
determining cancers such as breast, uterine, etc.
[0099] The oral dosage compositions and oral dosage capsules
disclosed herein can be co-administered with other active agents in
order to treat a target condition. For example, phosphodiesterase
type 5 (PDE-5) inhibitors, such as sildenafil citrate, tadalafil,
vardenafil avanafil, lodenafil, mirodenafil, udenafil, and the
like, are used to block the degradative action of phosphodiesterase
type 5 enzyme on cyclic GMP in the smooth muscle cells lining the
blood vessels supplying the corpus cavernosum of the penis and are
frequently used to treat erectile dysfunction. Such compounds could
be co-administered with the compositions and oral dosage forms of
the present invention in order to provide improved clinical
outcomes through synergistic pharmacological action as measured by
improved (sooner, better and longer lasting) erection, potency,
libido, mood, body mass, etc. in males relative to administration
of the testosterone or the co-administered PDE-5 alone. The
testosterone undecanoate compositions and oral dosage capsules can
also be co-administered with one or more other active agents such
as aromatase inhibitors (for example letrozole, anastrozole,
exemestane, fadrozole, vorozole, formestane etc.), dopamine
agonists (for example apomorphine, bromocriptine, cabergoline,
pergolide, ropinirole, rotigotine, pramipexole, fenoldopam etc.),
prostaglandins (for example alprostadil), alpha blockers (for
example yohimbine, phentolamine), vasodilators (for example
minoxidil) and the like, for improved clinical outcomes through
synergistic pharmacological action as measured by improvements in
one or more of the secondary sexual characteristics in males such
as sexual activity, potency, libido, erection etc., mood, body mass
and the like, relative to administration of either the testosterone
or the co-administered active agent alone.
EXAMPLES
[0100] The following examples are provided to promote a more clear
understanding of certain embodiments of the present invention, and
are in no way meant as a limitation thereon. Unless otherwise
specified/mentioned, all the compositions provided in the examples
are with respect to % w/w of the final composition. Note that,
except in the formulations of Examples 1, 6, 9, 16 and 21 the
testosterone undecanoate of all other example formulations can be
in either treated (milled, micronized, or nanosized) or untreated
form. The testosterone undecanoate in formulations 1, 6, 9, 16 and
21 are untreated for size reduction (unmilled, non-micronized, or
non-nanosized), and had average particle size greater than 50
micrometer.
Examples 1-5
Testosterone Undecanoate Compositions
[0101] Testosterone undecanoate formulations of Examples 1 through
5 were prepared by using the respective components shown in Table
I. Example 1 is just crystalline untreated (for example, unmilled
or non-micronized, having mean particle size more than 50
micrometer). Testosterone undecanoate filled into a hard gelatin
capsule, and Examples 2-5 are prepared as follows: The required
quantities of each of the components of the respective formulation,
except testosterone undecanoate, are taken in a clean stainless
steel container and mixed at about 50.degree. C. to 70.degree. C.
using a stirrer. A molten clear-to-hazy mixture is obtained. The
required amount of the testosterone undecanoate is added to the
clear-to-hazy mixture and stirred to form a homogenous liquid
mixture. A predetermined weight of the resulting liquid mixture is
disposed into appropriate size capsules according to the
testosterone undecanoate dose required. The capsules were allowed
to solidify at room temperature and then banded, and packaged in
HDPE bottles and sealed with a tightly closing lid.
[0102] Each of the formulations was tested for release of the
testosterone undecanoate using a USP Type II apparatus in 1000 mL
of 8 wt % Triton X-100 in water at 37.degree. C. and 100 rpm. The
percent of the testosterone undecanoate released from each
formulation was analyzed using HPLC. The results of the drug
release testing are also shown in Table I. It should be noted that
the Example 1 (having TU without a carrier) and Example-2
(lipid-based liquid formulation wherein entire TU amount in the
dosage unit is solubilized) can be used for comparison purposes to
help illustrate the advantages of the solid compositions and dosage
forms of the current invention.
TABLE-US-00001 TABLE I Composition in % w/w. Ingredients Example 1
Example 2 Example 3 Example 4 Example 5 Testosterone Undecanoate
100 12 15 11 18 Triglyceride: -- 53 -- 48 -- Ex: Castor Oil NF
Lipophilic additive: -- 35 -- 32 -- Ex: Lauroglycol FCC Lipophilic
additive: -- -- 63 -- 75 Glyceryl Monolinoleate, NF Hydrophilic
additive: -- -- 16 -- -- Polyoxyl 40 Hydrogenated Castor Oil, NF
Hydrophilic additive: -- -- 6 9 7 PEG 8000 USP % release in 30 mins
12 100 85 67 62 % release in 120 mins 30 100 101 100 100
[0103] Testosterone undecanoate formulations of Examples 6 through
9 can be prepared by using the components shown in Table II. Each
of the formulations was tested for release of the testosterone
undecanoate using a USP Type II apparatus in 1000 mL of 8 wt %
Triton X-100 in water at 37.degree. C. and 100 rpm.
TABLE-US-00002 TABLE II Composition in % w/w. Example Example
Example Example Ingredients 6 7 8 9 Testosterone Undecanoate 90-99
70 (particle >50 micrometer) Testosterone Undecanoate -- 90 -99
-- -- micronized or nanosized Testosterone Undecanoate -- -- 90-99
-- (milled) Lactose 1-10 1-10 1-10 30 Organic granulating solvent
-- -- -- q.s (example, alcohol)* % release in 30 mins <30 <85
<85 <85 % release in 120 mins <35 >45 >35 <35
*removed during drying process.
[0104] It should be noted that the compositions of Examples 6 to 9
can be formulated to enable tablet dosage form with the inclusion
of appropriate tabletting aids such as binder, disintegrant,
lubricants etc.
[0105] Unlike Example 1 and 6, the calculated drug release profile
of Examples 7, 8 and 9 shown in Table II, illustrate the advantages
of the carrier for testosterone undecanoate of varied particle size
or through organic solvent granulation.
Example 10
Testosterone Undecanoate Coated Tablets
[0106] Testosterone undecanoate tablets of Example 6 through 9 can
be further coated with a coating solution having typical
composition set forth in Table III, using the conventional tablet
coating procedures known in the art to a weight gain of about
3.0%.
TABLE-US-00003 TABLE III Ingredients Composition in % w/w
Hypromellose (Methocel E 5) 8.0 Polyethylene glycol, NF 8000 0.6
Isopropyl alcohol, USP 54.8 Water 36.6
Examples 11-15
Testosterone Undecanoate Composition
[0107] Testosterone undecanoate formulations of Examples 11-15 were
prepared by using the components set forth in Table IV and the
method similar to that described for Examples 2-5. Each of the
formulations was tested for release of the testosterone undecanoate
using a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in
water at 37.degree. C. and 100 rpm. The percent of the testosterone
undecanoate released from each formulation was analyzed using HPLC.
The release profiles are also shown in Table IV.
TABLE-US-00004 TABLE IV Composition % w/w Example Example Example
Example Example Ingredients 11 12 13 14 15 Testosterone Undecanoate
14 14 15 22 25 Oleic acid 75 -- -- -- -- Lipophilic additive: -- 68
63 -- -- Glyceryl Monolinoleate, NF Hydrophilic additive: -- 7 11
-- -- Polyoxyl 40 Hydrogenated Castor Oil, NF Polyoxyl 35 Castor
Oil, NF -- -- -- -- 21 (Cremophor .RTM. EL) Glyceryl
Palmitostearate -- -- 5 -- -- (Glyceryl distearate GDS, Precirol
ATO 5) Tocopherol Polyethylene Glycol -- -- -- 22 -- Succinate, NF
Vitamin E, USP (d,l-.alpha.-tocopherol) -- -- -- 34 48 Hydrophilic
additive: Polyethylene 11 11 6 4 6 Glycol 8000, USP Hypromellose
(100,000 cPs) -- -- -- 18 -- % release in 30 mins 69 61 34 11 32 %
release in 120 mins 100 100 88 48 99
Example 16
Testosterone Undecanoate Tablets
[0108] Testosterone undecanoate containing granules for tableting
having the components set forth in Table V can be prepared by wet
granulation methods. Accordingly, testosterone undecanoate,
microcrystalline cellulose and croscarmellose sodium are passed
through an ASTM mesh #40 mesh sieve and mixed in a low shear
granulator to form a uniform blend. A binder solution of Starch
1500 in deionized water can be used to granulate the dry powder
blend to a typical granulation end-point. The wet granulate dried
using a tray dryer or fluid air dryer can be passed through a
sized/screened, lubricated with Aerosil 200 and magnesium stearate,
and compressed into tablets.
TABLE-US-00005 TABLE V Ingredients Composition in % w/w
Testosterone Undecanoate 28 Microcrystalline Cellulose 52.5 (Avicel
PH 102) Croscarmellose sodium 10 Pregelatineized starch 8
(Starch1500) Colloidal silicon dioxide 0.5 (Aerosil 200) Magnesium
stearate 1
The tablets of Example 16 exhibit about 30% testosterone
undecanoate release in the first 120 minutes when tested using a
USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in water at
37.degree. C. and 100 rpm.
Examples 17-22
Testosterone Undecanoate Compositions
[0109] Testosterone undecanoate formulations of Table VI are free
of lipid substances. Examples 17, 18 and 19 were prepared by using
the components set forth in Table VI and according to the following
method: The Testosterone Undecanoate was dissolved in ethanol along
with the correspondingly indicated hydrophilic additives. The clear
solution so obtained was then slowly poured on microcrystalline
cellulose under low-shear mixing. The granules were dried under a
gentle current of air at room temperature. The dried granules were
passed through ASTM #40 mesh. A predetermined weight of the
resulting granules was filled into appropriate size capsules
according to the testosterone undecanoate dose required.
[0110] Testosterone undecanoate formulations of Examples 20, 21 and
22 can be prepared by using the components set forth in Table VI
and according to the following method: The required quantities of
the respective inactive component and the testosterone undecanoate,
were taken in a clean stainless steel container and mixed gently at
about 50.degree. C. to 70.degree. C. using a stirrer, to get a
clear-to-hazy liquid mixture. A predetermined weight of the
resulting liquid mixture is disposed into hard gelatin capsule and
allowed to solidify at room temperature.
[0111] The dosage forms of each Example 17-22 were tested for
release of the testosterone undecanoate using a USP Type II
apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37.degree.
C. and 100 rpm. The percent of the testosterone undecanoate
released from each formulation was analyzed using HPLC. The results
of the release testing are also shown in Table VI. It should be
noted that the compositions of Examples 17-22 can be formulated to
enable tablet dosage form with the inclusion of appropriate
tabletting aids such as diluents, binder, disintegrant, lubricants
etc.
TABLE-US-00006 TABLE VI Composition in % w/w Example Example
Example Example Example Example Ingredients 17 18 19 20 21 22
Testosterone Undecanoate 45 40 40 91 34 60 Hydrophilic additive: --
-- -- 7 30 40 (ex. PEG 8000 USP) Hydrophilic additive: 10 9 9 -- --
-- Sodium Lauryl sulfate Microcrystalline 45 40 39 -- -- --
Cellulose*, Hydrophilic additive: 0 11 11 -- -- -- (ex. Pluronic F
68) Hydrophilic additive: 0 0 1 2 36 -- (ex. Polyvinylpyrrolidone
(Povidone K 30)) % release in 30 mins 19 23 24 19 17 18 % release
in 120 mins 52 56 59 48 60 59 *Magnesium alumnometasilicate
(Neuslin .RTM.), lactose and other similar substances can be
used
[0112] The in vitro testosterone undecanoate release profiles of
Examples 17 to 22 could be seen to be superior over the release
profile of the Example 16.
Examples 23-27
Testosterone Undecanoate Compositions
[0113] Testosterone undecanoate formulations of Examples 23-27 were
prepared by using the components set forth in Table VII. Each of
the formulations was prepared by melting the testosterone
undecanoate together with the corresponding inactive component in a
stainless steel container at about 50.degree. C. to 70.degree. C.
with gentle stirring to get a clear-to hazy liquid mixture. A
predetermined weight of the resulting liquid mixture is disposed
into hard gelatin capsule and allowed to solidify at room
temperature. It should be noted that the liquid mixture can also be
allowed to solidify to room temperature to get solid aggregates
which may be sized through a ASTM mesh #30 to get granular
particulates, which can be further filled in hard gelatin
capsules.
[0114] Each of the formulations was tested for release of the
testosterone undecanoate using a USP Type II apparatus in 1000 mL
of 8 wt % Triton X-100 in water at 37.degree. C. and 100 rpm. The
percent of the testosterone undecanoate released from each
formulation was analyzed using HPLC. The results of the release
testing are also shown in Table VII.
TABLE-US-00007 TABLE VII Composition in % w/w Example Example
Example Example Example Ingredients 23 24 25 26 27 Testosterone 91
50 25 20 85 Undecanoate Hydrophilic additive: 9 50 75 -- -- (e.g.
Povidone K 17) Lipophilic additive: -- -- -- 80 15 (e.g. Glycerol
esters of C.sub.12-C.sub.18 fatty acids) % release in 30 mins 12 20
15 35 16 % release in 120 mins 32 50 65 48 43
Example 28
Testosterone Undecanoate Spray Dried Multiparticulates
[0115] Testosterone undecanoate multiparticulates can be prepared
as follows: 15 g of a milled testosterone undecanoate and lactose,
mixture (95:5 w/w), are passed through ASTM mesh #60 sieve and
added under mixing to about 250 mL solution of, 8% w/v povidone K17
in water The resulting suspension can be spray dried using a
conventional spray drying equipment with settings, for example, at
heat inlet temperature of about 60-75.degree. C. and an outlet
temperature of about 30-38.degree. C., aspirator set at 90-100%,
the pump set at about 8-12 mL/min, and the flow rate set at about
500-600 L/hr. The final solid multiparticulate testosterone
undecanoate composition can have a compositional makeup of about 53
wt % testosterone undecanoate, about 2.8 wt % lactose and about
44.2 wt % povidone K17.
Example 29
Testosterone Undecanoate Cyclodextrin Complexes
[0116] Testosterone undecanoate cyclodextrin complexes can be
prepared by co-precipitation methods using various molar ratios of
1:1, 2:1, 3:1, and 1:2 of the testosterone undecanoate to
beta-cyclodextrin, respectively. A significantly increased release
rate of testosterone undecanoate can be achieved with the
cyclodextrins complexes in an in vitro release testing in about
1000 mL of a 8% w/w Triton X-100 solution at 37.degree. C. in a
USP-2 apparatus set at 100 rpm, when compared to the free form of
the drug. Granulates of the cyclodextrin/testosterone undecanoate
complex can be made using the standard granulation or pelleting
techniques using additional conventional pharmaceutical processing
aids known in the art.
Example 30-34
Testosterone Undecanoate Compositions
[0117] A mixture of testosterone undecanoate and the corresponding
formulation components can be melted together to get thermosetting
fill to be disposed into capsule. Alternatively, the mixture can be
fed into a melt-extruder apparatus for example, a single-screw
extruder (Killion, Model KLB 100) equipped with about 1 inch
diameter screw and about 6 inch flex lip die, and the die opening
adjusted to about 0.005 inches and the screw speed was set at about
50 rpm. The residence time of the materials within the extruder can
be set for about 2 to 8 minutes. The extruded strands can be cooled
to room temperature by passing over a chilled roll. The strands can
then be sized through an ASTM mesh #40 and the powder disposed into
capsules. The exemplary formulations for melt-extrusion are
indicated in Table VIII. These dosage forms can release 35% or more
testosterone undecanoate in about first 120 minutes and about 85%
or less in the first 30 minutes.
[0118] It should be noted that the testosterone undecanoate
compositions of Table VIII can be further formulated to include one
or more of other substances such as lactose, starches,
hydroxypropyl methyl cellulose, methacrylate etc., at varying
concentrations from about 12% to about 88% by weight of the total
composition either prior to melt-extrusion or after sizing the
melt-extruded composition, in order to prepare solid
multi-particulates for tablets.
TABLE-US-00008 TABLE VIII Composition in % w/w Example Example
Example Example Example Ingredients 30 31 32 33 34 Testosterone 70
40 50 80 60 Undecanoate Polyethylene glycol 10 -- 20 15 20 8000 USP
(Glyceryl distearate 10 40 20 -- -- GDS, Precirol ATO 5) Stearic
acid 10 20 10 -- Cholesterol -- -- -- 5 20
Example 35
Testosterone Undecanoate Compositions Produced by Co-Milling
[0119] A testosterone undecanoate containing composition can be
prepared by co-milling (co-grinding) 80 g solid testosterone
undecanoate along with 15 g PVP K 17 and 5 g of sodium lauryl
sulphate for a period from about 12 hours to about 24 hours using a
ceramic ball-mill maintained at about 20.+-.5.degree. C. The
co-milled composition can provide a superior in vitro drug release
profile which could be at least 20% more when compared to the in
vitro release profile of Example 1 when tested using a USP Type II
apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37.degree.
C. and 100 rpm.
Example 36
Testosterone Undecanoate Loaded Pellets
[0120] Testosterone undecanoate coated pellets were prepared using
the ingredients set forth in Table IX. A spraying solution of the
coating materials can be prepared by dissolving 25 g of
testosterone undecanoate, 6 g of Pluronic F 68 and 5 g of PVP K 30
in about 250 mL of dehydrated alcohol. The spray solution can be
intermittently sprayed on to a rolling bed of 64 g commercially
available microcrystalline cellulose spheres (for example, having a
mean particle size in the range of about 250 .mu.m to about 600
.mu.m) taken in a convention coating pan. After all the spray
solution is loaded on the spheres, it can be dried under gentle
current of air for at least 1 hour to remove the solvent. Thus, by
adjusting the pan speed, spray rate and the inlet air flow and
temperature, the testosterone undecanoate loaded pellets or beads
can be obtained which can be disposed into a capsule. Auxiliary
pharmaceutical process aids such as talc, starch etc. may be dusted
during the spraying process to avoid agglomeration of the
pellets.
[0121] It should be noted that appropriate similar or equivalent
equipment known in the art may be used for the purpose. Also, by
varying the quantity of spray solution sprayed on the spheres or by
varying the concentration of testosterone undecanoate in the spray
solution, pellets of different drug loading can be achieved.
TABLE-US-00009 TABLE IX Ingredients Composition in % w/w
Testosterone Undecanoate 25 Pluronic F 68 6 Polyvinylpyrrolidone K
30 5 Dehydrated Alcohol 250 mL microcrystalline cellulose spheres
(Celsphere) 64
Example 37
Testosterone Undecanoate Composition with Hydrophilic Additive
[0122] Enhancement of the release rate of testosterone undecanoate
can be achieved by eutectic or non-eutectic mixtures with a
hydrophilic additive such as polyethylene glycol (PEG),
particularly PEG having molecular weights of about 1000 or more.
For example, about 1 g of testosterone undecanoate can be combined
with 0.3 g of PEG (molecular weight 8000) and 0.5 g of Poloxamer
(Pluronic F68). The mixture can be melted at about 60.degree.
C.-70.degree. C. under stirring and then subsequently solidified to
room temperature. The resulting solid can be sized through an ASTM
mesh #30 and filled into capsule or pressed into a tablet. It
should be noted that pharmaceutical aids such as diluents,
disintegrates and/or lubricants can be optionally used to get the
tablets or capsules.
Example 38
Testosterone Undecanoate Compositions with Lipophilic Additive
[0123] Enhancement of the release rate of testosterone undecanoate
can be achieved by eutectic or non-eutectic mixtures with a
lipophilic additive such as hydrogenated castor oil, glyceryl
palmitostearate, glyceryl distearate, stearic acid etc. For
example, about 10 g of testosterone undecanoate can be combined
with 0.5 g of glyceryl palmitostearate (Precirol.RTM. ATO 5) and 1
g of stearic acid. The mixture can be melted at about 60.degree.
C.-70.degree. C. under stirring and allowed to solidify at room
temperature. The resulting solid can be sized through an ASTM mesh
#30 and filled into capsule or pressed into a tablet. It should be
noted that pharmaceutical aids such as diluents, disintegrates
and/or lubricants can be optionally used to get the tablets or
capsules.
[0124] Numerous modifications and alternative arrangements may be
devised by those skilled in the art without departing from the
spirit and scope of the present invention and the appended claims
are intended to cover such modifications and arrangements. Thus,
while the present invention has been described above with
particularity and detail in connection with what is presently
deemed to be the most practical and preferred embodiments of the
invention, it will be apparent to those of ordinary skill in the
art that variations including, but not limited to, variations in
size, materials, shape, form, function and manner of operation,
assembly and use may be made without departing from the principles
and concepts set forth herein.
* * * * *