U.S. patent application number 15/190109 was filed with the patent office on 2017-02-09 for 17-hydroxyprogesterone ester-containing oral compositions and related methods.
This patent application is currently assigned to Lipocine Inc.. The applicant listed for this patent is Lipocine Inc.. Invention is credited to Basawaraj Chickmath, Nachiappan Chidambaram, Chandrashekar Giliyar, Satish Nachaegari, Mahesh Patel, Srinivasan Venkateshwaran.
Application Number | 20170035781 15/190109 |
Document ID | / |
Family ID | 57586205 |
Filed Date | 2017-02-09 |
United States Patent
Application |
20170035781 |
Kind Code |
A1 |
Giliyar; Chandrashekar ; et
al. |
February 9, 2017 |
17-HYDROXYPROGESTERONE ESTER-CONTAINING ORAL COMPOSITIONS AND
RELATED METHODS
Abstract
The present invention provides for bioavailable oral dosage
forms containing esters of 17-hydroxyprogesterone as well as
related methods. The oral dosage forms can be formulated for
pregnancy support and can include a therapeutically effective
amount of an ester of 17-hydroxyprogesterone and a pharmaceutically
acceptable carrier. In another embodiment, a pharmaceutically
acceptable oral dosage form for pregnancy support is provided. The
pharmaceutically acceptable oral dosage can include a
therapeutically effective amount of an ester of
17-hydroxyprogesterone and a pharmaceutically acceptable carrier.
The oral dosage form can, when measured using a USP Type-II
dissolution apparatus in 900 mL of deionized water with 0.5 (w/v)
of sodium lauryl sulfate at 50 RPM at 37.degree. C., release at
least 20 wt % of the dose of the ester of 17-hydroxyprogesterone
after 60 minutes, or in the alternative release at least 20 wt %
more after 60 minutes than an equivalently dosed oral dosage form
without the carrier.
Inventors: |
Giliyar; Chandrashekar;
(North Maple Grove, MN) ; Venkateshwaran; Srinivasan;
(Salt Lake City, UT) ; Chickmath; Basawaraj;
(Plymouth, MN) ; Nachaegari; Satish; (Holladay,
UT) ; Chidambaram; Nachiappan; (Salt Lake City,
UT) ; Patel; Mahesh; (Salt Lake City, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lipocine Inc. |
Salt Lake City |
UT |
US |
|
|
Assignee: |
Lipocine Inc.
Salt Lake City
UT
|
Family ID: |
57586205 |
Appl. No.: |
15/190109 |
Filed: |
June 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62183031 |
Jun 22, 2015 |
|
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62295951 |
Feb 16, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/57 20130101;
A61P 15/06 20180101; A61K 9/20 20130101; A61P 3/12 20180101; A61K
9/0053 20130101; A61K 9/14 20130101; A61K 9/2086 20130101; A61P
3/14 20180101; A61P 3/02 20180101 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61K 9/14 20060101 A61K009/14; A61K 9/20 20060101
A61K009/20; A61K 9/00 20060101 A61K009/00 |
Claims
1. An oral pharmaceutical composition comprising: a therapeutically
effective amount of 17-hydroxyprogesterone caproate, and a
pharmaceutically acceptable carrier said therapeutically effective
amount ranging from 150 mg to 750 mg 17-hydroxyprogesterone
caproate.
2. The oral pharmaceutical pharmaceutical composition of claim 1,
wherein the composition releases greater than 10% after 1 hour when
tested using a USP Type II apparatus at 50 rpm in an aqueous media
having 1.5.times. or greater sink condition at 37.0.degree. C.
(.+-.0.5).
3. The oral pharmaceutical pharmaceutical composition of claim 1,
wherein the composition releases greater than 10% after 1 hour when
tested using a USP Type II apparatus at 50 rpm in an aqueous media
having 3.times. or greater sink condition at 37.0.degree. C.
(.+-.0.5).
4. The oral pharmaceutical composition of claim 1, wherein the
composition has from about 225 mg to 800 mg of
17-hydroxyprogesterone caproate.
5. The oral pharmaceutical composition of claim 1, said
pharmaceutically acceptable carrier having one or more of a
diluent, binder, disintegrant, lubricant or surfactant.
6. The oral pharmaceutical composition of claim 1, said
pharmaceutically acceptable carrier having a lipophilic or
hydrophilic additive.
7. The oral pharmaceutical composition of claim 1, said
pharmaceutically acceptable carrier having a lipophilic or
hydrophilic surfactant.
8. The oral pharmaceutical composition of claim 1, said
pharmaceutically acceptable carrier having a lipophilic or
hydrophilic surfactant.
9. The oral pharmaceutical composition of claim 1, said
pharmaceutically acceptable carrier having a non-ionic or ionic
surfactant.
10. The oral pharmaceutical composition of claim 1, said 17 HPC
being fully solubilized, partially solubilized, crystalline
particulate, amorphous particulate, or a combination thereof.
11. The oral pharmaceutical composition of claim 1, said 17 HPC
being particulate and having a mean particle diameter of less than
200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50
.mu.m, from 50 to 250 .mu.m, from 250 to 500 .mu.m, from 500 to
1000 .mu.m, or greater than 1000 .mu.m.
12. The oral pharmaceutical composition of claim 1, said 17 HPC
being particulate and having a mean particle diameter of from 50-40
.mu.m, 40-30 .mu.m, 30-20 .mu.m, 20-10 .mu.m, or 10-1 .mu.m.
13. The oral pharmaceutical composition of claim 1, wherein the
composition has a crystallization inhibitor or a particle
agglomeration inhibitor.
14. The oral pharmaceutical composition of claim 1, wherein the
composition is a powder, granulate, particulate, bead, pellet,
sprinkle, suspension, solution, tablet, caplet, capsule, or a
combination thereof.
15. The oral pharmaceutical composition of claim 1, wherein the
composition is controlled release or immediate release.
16. The oral pharmaceutical composition of claim 1, wherein the
compmosition is a coated or uncoated tablet or caplet.
17. The oral pharmaceutical composition of claim 1, wherein the
composition is a monolithic or multilayered tablet.
18. The oral pharmaceutical composition of claim 1, which when
administered once, twice or three times a day as one to twelve unit
dosage forms total per day to human subject, provides a
17-hydroxyprogesterone caproate C.sub.avg-24h of greater than about
0.1, 0.5 or 1.0 ng/mL.
19. A method of treatment said method comprising administering to a
subject an oral pharmaceutical composition comprising: a
therapeutically effective amount of 17-hydroxyprogesterone
caproate, and a pharmaceutically acceptable carrier and one or more
additional agents chosen from pharmaceutical agents, vitamins,
minerals, supplements.
20. The method of claim 19, wherein said method comprises
administering said pharmaceutical composition once, twice or three
times a day as one to twelve unit dosage forms total per day to
human subject, to provide a 17-hydroxyprogesterone caproate
C.sub.avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL.
21. The method of claim 19, wherein said administering is for 7
days or more.
22. The method of claim 19, wherein said administering is for 14
days or more.
23. The method of claim 19, wherein said administering is for 28
days or more.
24. The method of claim 19, wherein said administering is for 2
months or more.
25. The method of claim 19, wherein said administering is to a
pregnant female for 7 days or more.
26. The method of claim 19, wherein said administering is to a
pregnant female from at least 1 day after conception through birth
of an infant.
27. The method of claim 19, wherein said administering is to a
pregnant that has had preterm labor arrested.
28. The method of claim 19, wherein said administering is to a
pregnant that has had preterm labor arrested with a tocolytic.
29. The method of claim 19, wherein said administering is twice a
day.
30. The method of claim 19, wherein said pharmaceutical composition
has from 200 mg to 900 mg of 17-hydroxyprogesterone caproate.
31. The method of claim 19, wherein said pharmaceutical composition
is a tablet, capsule or caplet.
32. The method of claim 19, wherein the pharmaceutical composition
comprises a pharmaceutically acceptable carrier having one or more
of a diluent, binder, disintegrant, lubricant or surfactant.
33. The method of claim 19, wherein the pharmaceutical composition
comprises a lipohilic, hydrophilic additive or both.
34. The method of claim 19, wherein the one or more additional
agents are chosen from a progestogen, a corticosteroid, a
tocolytic, an antibiotic, a vitamin D compound or a combination
thereof.
35. The method of claim 19, wherein the one or more additional
agents are chosen from vitamin A, B3, B6, C, D, folic acid,
calcium, iron, magnesium, manganese, phosphorus, potassium, sodium,
zinc, omega-3, eicosapentaenoic acid (EPA), docosahexaenoic (DHA)
or a combination thereof.
36. The method of claim 19, said pharmaceutical composition
releasing greater than 10% after 1 hour when tested using a USP
Type II apparatus at 50 rpm in an aqueous media having 3x or
greater sink condition at 37.0.degree. C. (.+-.0.5).
37. A method of treatment said method comprising administering to a
subject an oral pharmaceutical composition comprising: a
therapeutically effective amount of 17-hydroxyprogesterone
caproate, and a pharmaceutically acceptable carrier said method
further comprising a dose evaluation, change or titration based on
a target biomarker, gestational age or a combination thereof.
38. The method of claim 37, wherein said method comprises
administering said pharmaceutical composition once, twice or three
times a day as one to twelve unit dosage forms total per day to
human subject, to provide a 17-hydroxyprogesterone caproate
C.sub.avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL.
39. The method of claim 37, wherein said administering is for 7
days or more.
40. The method of claim 37, wherein said administering is for 14
days or more.
41. The method of claim 37, wherein said administering is for 28
days or more.
42. The method of claim 37, wherein said administering is for 2
months or more.
43. The method of claim 37, wherein said administering is to a
pregnant female for 7 days or more.
44. The method of claim 37, wherein said administering is to a
pregnant female from at least 1 day after conception through birth
of an infant.
45. The method of claim 37, wherein said administering is to a
pregnant that has had preterm labor arrested.
46. The method of claim 37, wherein said administering is to a
pregnant that has had preterm labor arrested with a tocolytic.
47. The method of claim 37, wherein said administering is twice a
day.
48. The method of claim 37, wherein said pharmaceutical composition
has from 200 mg to 900 mg of 17-hydroxyprogesterone caproate.
49. The method of claim 37, wherein said pharmaceutical composition
is a tablet, capsule or caplet.
50. The method of claim 37, wherein the pharmaceutical composition
comprises a pharmaceutically acceptable carrier having one or more
of a diluent, binder, disintegrant, lubricant or surfactant.
51. The method of claim 37, wherein the pharmaceutical composition
comprises a lipophilic or hydrophilic additive.
52. The method of claim 37, wherein the pharmaceutical composition
comprises a lipophilic or hydrophilic surfactant.
53. The method of claim 37, wherein the pharmaceutical composition
releases greater than 10% after 1 hour when tested using a USP Type
II apparatus at 50 rpm in an aqueous media having 1.5.times. or
greater sink condition at 37.0.degree. C. (.+-.0.5).
54. The method of claim 37, wherein the pharmaceutical composition
releases greater than 10% after 1 hour when tested using a USP Type
II apparatus at 50 rpm in an aqueous media having 3.times. or
greater sink condition at 37.0.degree. C. (.+-.0.5).
55. The method of claim 37, wherein the target biomarker is a serum
17-hydroxyprogesterone caproate level with a C.sub.avg-24h greater
than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0,
15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0, 75.0 or 100
ng/mL; less than any of these values; or within a range defined by
any two of these values.
56. The method of claim 37, wherein the dose evaluation or
titration comprises determining serum or plasma 17 HPC levels after
single dose administration at steady state.
57. The method of claim 37, wherein the dose evaluation or
titration comprises determining serum or plasma 17 HPC levels after
single dose administration at steady state at a single time point
within 12 hours of administering the single dose.
58. The method of claim 37, wherein the dose evaluation or
titration comprises determining serum or plasma 17 HPC levels after
single dose administration at steady state at a single time point
at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after
administering the single dose.
59. The method of claim 37, wherein the dose evaluation or
titration comprises determining serum or plasma 17 HPC levels after
single dose administration at steady state at a single time point
at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after
administering the single dose or between any two consecutive
values.
60. The method of claim 37, wherein when the serum or plasma 17 HPC
levels of the dose evaluation or titration after single dose
administration at steady state at a single time point at about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administering the
single dose are too low, the daily dose of 17 HPC is increased or
too high the daily dose of 17 HPC is decreased.
61. The pharmaceutical composition of claim 1, having a
pharmaceutically acceptable carrier including at least a
hydrophilic surfactant chosen from a poloxamer, a polyethylene
glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a
polyethylene glycol glycerol fatty acid ester, sodium lauryl
sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or
a combination thereof and said pharmaceutically acceptable carrier
further comprising polyvinylpyrrolidone, croscarmellose,
microcrystalline cellulose, magnesium stearate, silicon dioxide,
stearic acid, mannitol, a polyvinyl alcohol copolymer, a
polyvinylpyrrolidone copolymer, a polyethylene glycol copolymer, a
methacrylic acid copolymer or a combination thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/183,031 filed Jun. 22, 2015 and U.S. Provisional
Application No. 62/295,951 filed Feb. 16, 2016 both of which are
incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to 17-hydroxyprogesterone
ester containing compositions, oral dosage forms thereof, and
associated methods. Accordingly, this invention involves the fields
of chemistry, pharmaceutical sciences, medicine and other health
sciences.
BACKGROUND OF THE INVENTION
[0003] 17-alpha hydroxyprogesterone (alternatively hereinafter
referred to as 17-hydroxyprogesterone or "17HP") is a C-21
endogenous steroid hormone produced during the syntheses of
glucocorticoids and sex steroids. Like progesterone, 17HP is a
natural progestagen. It has been isolated from both adrenal glands
and corpora lutea. Esters of 17HP are reported to have
progestogenic effects and hence, can be used for indications
related to pregnancy support as well as non-pregnancy support in
both pre- and post-menopausal women. It is reported that 17HP,
without esterification, has no progestational activity. However,
the synthetic esters of 17HP such 17-hydroxyprogesterone acetate or
17-alpha-hydroxyprogesterone caproate (also referred hereafter as
17 hydroxyprogesterone caproate or 17 HPC) have been shown to
exhibit marked progestational activity when administered
intramuscularly in animal experiments. 17-Hydroxyprogesterone
caproate is a commonly used progestin available for intramuscular
injection to prevent Preterm Birth (alternatively hereinafter
referred to as "PTB"). This synthetic caproate ester is reportedly
inactive when given by mouth but works as a long-acting progestin
when administered intramuscularly. The metabolism of 17HP and the
metabolism of 17-hydroxyprogesterone caproate in the human female
are not yet fully established. Data from humans and animals
indicate that intramuscularly administered 17-hydroxyprogesterone
caproate has more potent progestational effect on endometrium and
is longer lasting than progesterone (alternatively hereinafter
referred to as "P"). This may be due to more avid binding of
17-hydroxyprogesterone caproate to the progesterone receptors
(alternatively referred to hereinafter as "PR") and placental
glucocorticoid receptors (alternatively referred to hereinafter as
"GR") that could prevent an increase of placental corticotropin
releasing hormone which is associated with onset of labor.
17-hydroxyprogesterone caproate is reportedly effective in
providing luteal support in patients undergoing IVF-Embryo Transfer
Cycles.
[0004] PTB is medically defined as delivery from 20 to 36 weeks of
gestation. According to the 2009 Center for Disease Control Report,
PTB occurs in about 12.3% of births in the US alone translating to
about half a million PTBs annually. Spontaneous PTB accounts for
approximately 70-80% of PTB. Of all the pregnancies in the US, one
out of every eight live-born infants is born preterm representing
an increase of>18% since 1990. Late pre-term birth between 35-36
weeks of gestation contributes to more than half of all PTBs. PTB
is the primary cause of neonatal morbidity and mortality. Mortality
risk is three fold higher at 35-36 weeks and morbidities such as
respiratory distress requiring oxygen, temperature instability,
hypoglycemia, jaundice, attention deficit disorders, cerebral
palsy, developmental delay, etc. are quite common. PTB related time
and costs in intensive care are a major health, social and economic
issue with an average cost of PTB delivery amounting to up to
10.times. that of normal delivery.
[0005] Major risk factors implicated in PTB are as follows: History
of previous spontaneous PTB (past obstetrics history), cervical
length (<2.5 cm at mid pregnancy), presence of fetal fibronectin
in vaginal secretions; multiple gestation, low maternal Body Mass
Index (BMI), maternal race; maternal age (<17 and>35 years),
and smoking. The prior history of at least one PTB is a good
indicator of future occurrence potential with 17-50% recurrence
potential and 28-70% recurrence potential with two previous PTBs.
Benefits of prolonging pregnancy to full term with therapeutic
intervention include improved child survival as a function of
gestational age, and reduced neonatal hospital stay.
[0006] Intramuscular injection of 17-hydroxyprogesterone caproate
is available for reducing the risk of PTB in women with singleton
pregnancy and history of single spontaneous PTB. The injection
marketed as .sup.Makena.RTM. (250 mg 17-hydroxyprogesterone
caproate in 1 mL) mandates regular visits to the doctor's office,
as the typical treatment cycle consists of 16-20 weeks of injection
repeated every week. This therapy regimen could result increasing
the patient's distress and/or anxiety in addition to increasing the
repeated travel risks for the patient and fetus. The injection
therapy's interferences with the personal and family activities and
disruption in professional life are also a major disadvantage.
[0007] In addition, adverse events associated with injection of
17-hydroxyprogesterone caproate (e.g. Makena.RTM.) at once weekly
intervals (every 7 days) the injection site reactions (.about.45%)
such as urticaria, pruritis, swelling, nodule formation and pain at
the site of injection have been reported as significant.
[0008] Esters of hydroxy progesterone such as acetate, caproate,
undecanoate are more lipophilic than hydroxy progesterone. The
active substance (17-hydroxyprogesterone caproate) in Makena.RTM.
is known to be extremely insoluble in water (<20 ng/mL), and
very lipophilic with ClogP of about 5.7. Moreover,
17-hydroxyprogesterone caproate has the potential to be metabolized
in the presence of fetal and adult hepatocytes and is a substrate
for cytochrome inactivation such as CYP3A4 which is overly
expressed in pregnant women (.about.40% upregulation). Due to its
extremely low water solubility and a potential to be susceptible
for first pass hepatic inactivation oral delivery of long chain
esters of 17HP has remained a challenge. It is reported that there
is no oral activity with 17 hydroxyprogesterone caproate, an ester
of 17 HP, (Saxton D J et.al. Reproductive Biology and Endocrinology
2004, 2:80; Greene M F, NJEM1 348:2453-2455). This could be likely
due to very poor or no oral bioavailability of 17 HPC. Although
much desired, to date the development of an orally active
composition of long chain ester of hydroxyl progesterone remains a
significant unmet need. In addition, development of dosage forms
that enable administration of lesser number of dosage units per
dose and/or at reduced frequency per day is most often
desirable.
SUMMARY OF THE INVENTION
[0009] It has now been surprisingly found that esters of 17HP can
be effectively delivered orally to mammals. The pharmaceutical oral
compositions and dosage forms of the present inventions can provide
effective bioavailability of an ester of 17HP. Further, the
compositions and/or dosage forms disclosed herein provide effective
release enhancement for 17 HP esters. We have also surprisingly
found that an ester of 17HP can be formulated into oral
compositions and oral dosage forms thereof with higher percent w/w
loading of the ester. For example, we have found that when one or
more solubilizing agents such as for example, benzyl alcohol,
benzyl benzoate etc., is incorporated in the composition, a
significant amount (i.e. greater than 12% w/w) of the ester of 17HP
can be solubilized in the composition or dosage form. The increased
drug loading in the compositions and dosage forms of the current
inventions, can provide avid advantages including but not limited
to reduced size or volume of the unit dosage (i.e., tablet,
capsule, syrup, elixir, beverage, etc.), reduced number of dosage
units to be taken per single administration, improved patient
compliance etc., because patients typically can take fewer number
of dosage units per day in order to get a sufficient dose to
provide the desired efficacy. In a separate aspect, it was also
surprisingly found that an effective bioavailability of the ester
of 17HP can be provided by the compositions of the current
inventions which when dispersed in an aqueous medium, provide clear
or colloidal to hazy or unclear dispersions having partially or
fully solubilized drug in the dispersions.
[0010] It was also found that the compositions of current invention
facilitate production of solid dosage forms such as tablets,
caplets, granules, beads, particulates etc., which can solve the
drawbacks of having the 17HP ester in a liquid solution form in the
dosage unit. This eliminates a number of undesirable
inconveniences, such as specialized manufacturing process and/or
equipment, poor chemical and/or physical stability of the ester
typical to liquid solutions due to the nature of the ester or
solvents used, and so-on.
[0011] All the oral dosage forms of the present inventions having
the drug in the form of solution, suspension, particulates, etc.,
can be produced by conventional methods of processing and
manufacture known in the art.
[0012] The present invention provides for compositions and oral
dosage forms containing esters of 17HP as well as related methods.
The compositions and oral dosage forms can be formulated to include
a therapeutically effective amount of an ester of 17HP and a
pharmaceutically acceptable carrier. In one embodiment, a
pharmaceutically acceptable oral dosage form for pregnancy support
and non-pregnancy support is provided. The pharmaceutically
acceptable oral dosage can include a therapeutically effective
amount of an ester of 17HP and a pharmaceutically acceptable
carrier. The oral dosage form can, when measured using a USP
Type-II dissolution apparatus in 900 mL of deionized water with
0.5% (w/v) of sodium lauryl sulfate at 50 RPM at 37.degree. C.,
release at least 20 wt % of the dose of the ester of 17HP after 60
minutes.
[0013] In yet a further embodiment, a pharmaceutically acceptable
oral dosage form for pregnancy or non-pregnancy support is
provided. The pharmaceutically acceptable oral dosage can include a
therapeutically effective amount of an ester of 17HP and a
pharmaceutically acceptable carrier. The oral dosage form can, when
measured using a USP Type-II dissolution apparatus in 900 mL of
deionized water with 0.5% (w/v) of sodium lauryl sulfate at 50 RPM
at 37.degree. C., release at least 20 wt % more 17HP ester after 60
minutes than an equivalently dosed oral dosage form without the
carrier.
[0014] In some aspects, the oral dosage forms of the present
invention can be used to treat pregnant female subjects who are at
risk of preterm birth. Such methods of treatment may include the
step of orally administering to the female subject the oral
pharmaceutical composition. In some aspects, the dosage amount is
an amount sufficient to provide an intended therapeutic effect. In
another embodiment, the oral dosage forms can be administered to
subjects in need thereof. The administration of the oral dosage
form can treat at least one condition selected from preterm labor,
preterm birth, infertility and miscarriage. The conditions and the
relative treatment can be based on their primary and secondary
outcome measurements associated with the administration of the
ester of 17HP.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a plot of the in vitro release profile of a
17-hydroxyprogesterone caproate containing oral dosage form in
accordance with an embodiment of the present invention compared to
a carrier-free dose of 17-hydroxyprogesterone caproate.
[0016] FIG. 2 is a plot of the in vitro release profiles of
17-hydroxyprogesterone containing oral dosage forms in accordance
with an embodiment of the present invention.
[0017] FIG. 3 is a plot of the in vitro release profiles of
17-hydroxyprogesterone containing oral dosage forms in accordance
with an embodiment of the present invention.
[0018] FIG. 4 is a plot of pharmacokinetics in accordance with
embodiments described herein and Example 55.
[0019] FIG. 5 is a plot of XRD data in accordance with embodiments
described here in and Example 56.
[0020] Reference will now be made to the exemplary embodiments
illustrated, and specific language will be used herein to describe
the same. It will nevertheless be understood that no limitation of
the scope of the invention is thereby intended.
DETAILED DESCRIPTION OF EXAMPLE EMBODIMENT(S)
[0021] Before the present oral dosage forms and methods for the
delivery and use of 17-hydroxyprogesterone esters 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.
[0022] It should be noted that, as used in the written description,
the singular forms "a," "an," and, "the" include express support
for 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.
[0023] Definitions
[0024] As used herein, "drug," "active agent," "bioactive agent,"
"pharmaceutically active agent," "therapeutically active agent" and
"pharmaceutical," may be used interchangeably to refer to an agent
or substance that has measurable specified or selected physiologic
activity when administered to a subject in a significant or
effective amount. It is to be understood that the term "drug" is
expressly encompassed by the present definition as many drugs and
prodrugs are known to have specific physiologic activities. These
terms of art are well-known in the pharmaceutical and medicinal
arts. Further, when these terms are used, or when a particular
active agent is specifically identified by name or category, it is
understood that such recitation is intended to include the active
agent per se, as well as pharmaceutically acceptable salts, esters
or compounds significantly related thereto, including without
limitation, prodrugs, active metabolites, isomers, and the
like.
[0025] As used herein, the term "recurrent" is used to refer to a
repeat or re-occurrence of at least one incidence like
"miscarriage", "preterm birth" or "preterm labor" or "multifetal
gestation" or any like medical situation in reference with or
without same partner, with or without previous live birth.
[0026] As used herein, the term "treatment" when used in
conjunction with the administration of a 17-hydroxyprogesterone
ester, refers to the administration of the 17-hydroxyprogesterone
ester to subjects who are either asymptomatic or symptomatic. In
other words, "treatment" can refer to the act of reducing or
eliminating a condition (i.e. symptoms manifested), or it can refer
to prophylactic treatment, (i.e. administering to a subject not
manifesting symptoms in order to prevent their occurrence). Such
prophylactic treatment can also be referred to as prevention of the
condition, preventative action, preventative measures, etc.
[0027] As used herein, the term "ester" represents compounds
produced by reaction between acids and alcohols with the
elimination of water. As described herein, the term "ester" can
also represent the class of organic compounds corresponding to the
inorganic salts formed from an organic acid and an alcohol. In one
aspect, the "ester of 17-hydroxyprogesterone" can be the caproate
ester, but can also represent esters of the longer chain fatty
acids such as undecanoic acid and higher, that typically get
lymphatically absorbed and avoid first pass hepatic metabolism for
improved efficacy or safety.
[0028] 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.
[0029] The terms "pharmaceutically acceptable carrier" or "carrier"
are used interchangeably and refer to a pharmaceutically acceptable
substance that enables a pharmaceutical composition and/or a dosage
form of an ester of 17-hydroxyprogesterone. Further, in some
aspects, the carrier is an element or ingredient that can be varied
for the alteration of release rate and/or extent of the active
agent, for example an ester of 17-hydroxyprogesterone, 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 determines, controls, or contributes, at least
in part, to the release of an ester of 17-hydroxyprogesterone from
a pharmaceutical oral composition and/or dosage form, when tested
using a USP Type II apparatus in about 900 mL of simulated
intestinal fluid (according to USP, SIF, without enzyme) having
0.5% w/w sodium lauryl sulfate at about 37.degree. C. and 50
rpm.
[0030] In another embodiment, the composition or dosage form
provides a release of the ester of 17-hydroxyprogesterone such that
when tested using a USP Type II apparatus in about 900 mL of
simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at
about 37.degree. C. and 50 rpm, at least 20% more the ester of
17-hydroxyprogesterone is released after the first 60 minutes
compared to an equivalent dose an ester of 17-hydroxyprogesterone
oral dosage form without the pharmaceutically acceptable carrier.
In another particular embodiment, the composition or the dosage
form releases at least 40% more of the ester of
17-hydroxyprogesterone after the first 60 minutes compared to an
equivalent dose an ester of 17-hydroxyprogesterone oral dosage form
without the pharmaceutically acceptable carrier.
[0031] It should be noted that the release of the ester of
17-hydroxyprogesterone from the composition or the dosage form can
be tested in a suitable solubilizing medium or a non-solubilizing
aqueous medium at about 37.degree. C., in a USP Type II apparatus
at 50 rpm. For example, aqueous medium can be water, simulated
gastric fluid (SGF) with or without enzyme, simulated intestinal
fluid (SIF) with or without enzyme, a hydro-alcoholic solution, a
surfactant solution and the like. The aqueous medium can be used
for the purpose of determining the release rate and/or extent of
the ester of 17-hydroxyprogesterone from the compositions or the
dosage forms. The aqueous medium can be a non-solubilizing aqueous
medium (for example, having low or no surfactant in the medium) for
the entire amount of the ester present in the composition or the
dosage form. In one embodiment, the non-solubilizing aqueous medium
can solubilize about 90% or less of the amount of ester present in
the composition or dosage form. In another embodiment, the
non-solubilizing aqueous medium can solubilize about 80% or less,
about 70% or less, about 60% or less, about 50% or less, about 30%
or less, or about 20% or less of the total amount of the ester
present in the composition or dosage form.
[0032] Conversely, in another embodiment the aqueous medium is
capable of solubilizing substantially all of the ester of
17-hydroxyprogesterone present in the composition or dosage form.
In one embodiment, the aqueous medium can solubilize at least about
90% of the amount of the ester of 17-hydroxyprogesterone present in
the composition or dosage form. In a particular embodiment the
aqueous medium can solubilize about 1.5 times or more, about 3
times or more, 5 times or more of the amount of the ester
17-hydroxyprogesterone present in the composition or dosage
form.
[0033] 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 specific aspect, a subject is
a human. In another aspect, the subject is a female. In yet another
aspect, the oral dosage form of the current invention is for a
female requiring pregnancy support.
[0034] The term "oral administration" represents any method of
administration in which an active agent can be administered by
swallowing, chewing, or sucking or drinking an oral dosage form.
Such solid or liquid oral dosage forms are traditionally intended
to substantially release and or deliver the active agent in the
gastrointestinal tract beyond the mouth and/or buccal cavity.
Examples of solid dosage forms include conventional tablets,
multi-layer tablets capsules, caplets, etc., which do not
substantially release the drug in the mouth or in the oral
cavity.
[0035] As used herein, the terms "release" and "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.
[0036] As used herein, the term "lipophilic" when used in
combination with both solid and liquid lipophilic additives
(alternatively referred to hereinafter as "LA"), refers to
additives that "love oil" and generally have poor or no solubility
in water. "Lipophilic surfactants" (alternatively referred to
hereinafter as "LS") 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 (alternatively referred to hereinafter
as "HA"), refers to additives that "love water", and generally have
average or good solubility in water. "Hydrophilic surfactants"
(alternatively referred to hereinafter as "HS") are hydrophilic
additives that have significant surface active property and that
have HLB values of more than 10.
[0037] As used herein, the term "lipid" or lipid substance" when
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.
[0038] In some aspects of the present invention, the release of the
drug may be controlled release. As used herein, the term
"controlled release" represents the release of the drug from the
dosage form according to a predetermined profile. In some aspects,
the controlled release selected can be, intermediate, delayed,
extended, sustained, pulsatile, gastric, enteric or colonic. In
another aspect, combinations of the aforementioned release profiles
may be used in order to achieve specific delivery results, such as
an immediate release followed by a delayed and/or a sustained
release of the active agent.
[0039] As used herein, a composition or dosage form provides
"immediate release" when greater than about 90% of the drug is
released after the first 30 minutes, in a USP simulated gastric
fluid (SGF) with or without enzyme.
[0040] As used herein, the term "pregnancy support" when used to
describe the functionality of the oral compositions or dosage forms
of the present invention, can refer to providing exogenous
progestational support from inception through birth including, but
not limited to preterm birth, preterm labor, and miscarriage. The
pregnancy support can provide improved quality of the pregnancy for
the pregnant woman, the fetus, or both. Further, pregnancy support
can also include increased fertility for a woman trying to become
pregnant.
[0041] As used herein, the term "non-pregnancy" support when used
to describe the functionality of the oral compositions or dosage
forms of the present invention, can refer to conditions that
require exogenous supplementation of a progestogen agent to a
non-pregnant subject, such as a non-pregnant woman, including but
not limited to, delaying or preventing the occurrence of pregnancy,
preventing or treating conditions due to progesterone deficiencies
such as amenorrhea, fibroids, contraception, postpartum lactation
suppression, treatment of dysfunctional uterine bleeding,
endometriosis, endometrial hyperplasia, cervical hyperplasia,
hormone replacement therapy, treatment of hypoventilation,
prevention and treatment of osteoporosis, management of breast,
hypothyroidism, migraine headaches, pemporomandibular joint
syndrome, catamenial epilepsy, endometrial, and/or renal
carcinomas. In one embodiment, the term "non-pregnancy" support
when used to describe the functionality of the oral compositions or
dosage forms of the present invention can refer to conditions that
require exogenous supplementation of the progestogen agent of the
invention to a male human for example, to effect contraception, to
counter estogenic activity, etc. It should be noted that the
present compositions and dosage forms of the ester of the
17-hydroxyprogesterone may be administered alone or in combination
with other therapy. In another embodiment, the current invention
compositions and dosage forms of the ester of the
17-hydroxyprogesterone may be used to supplement, augment,
mitigate, treat, cure or prevent, or for providing prophylaxis in a
subject in need thereof.
[0042] 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.
[0043] 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.
[0044] 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 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.
Exemplary Embodiments
[0045] 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.
[0046] During pregnancy, it has been shown that serum progestogen,
including progesterone and 17-hydroxyprogesterone levels are
decreased in the pregnant female in cases of intrauterine death,
premature labor, threatened premature labor, premature rupture of
membranes, amnionitis and abruption of placenta. As discussed
above, it has been discovered that esters of 17-hydroxyprogesterone
have potential for use in pregnancy to treat and or prevent the
following conditions or occurrences: spontaneous abortion in women
who have had previous spontaneous abortion, history of recurrent
spontaneous abortion, previous stillbirth, previous premature
delivery (<37 weeks), previous premature (<37 weeks) rupture
of membranes or PROM, previous pregnancy related hypertension or
toxemia, previous abruption of placenta, threatened premature labor
or cerclage, multiple pregnancy, primary or secondary infertility,
congenital uterine anomaly or any other condition where endogenous
progestogen (e.g. progesterone) levels are lower than in normal
pregnancy.
[0047] Primary and secondary outcome measures can be used to
determine the need for and/or the effectiveness of ester of
17-hydroxyprogesterone supplementation therapy for pregnancy
related support to a particular subject and its direct or indirect
effect on the neonates. Typical primary and secondary outcome
measures for preterm birth and preterm labor include, without
limitation,
Primary Outcome Measures (Maternal):
[0048] 1. Perinatal mortality [0049] 2. Preterm birth (less than 32
weeks' gestation) [0050] 3. Preterm birth (less than 34 weeks'
gestation) [0051] 4. Preterm birth (less than 37 weeks' gestation)
[0052] 5. Major neuro-developmental handicap at childhood follow
up
Secondary Outcome Measures (Maternal):
[0052] [0053] 1. Threatened preterm labor [0054] 2. Pre-labor
spontaneous rupture of membranes [0055] 3. Adverse drug reaction
[0056] 4. Pregnancy prolongation (interval between randomization
and birth) [0057] 5. Mode of birth [0058] 6. Number of antenatal
hospital admissions [0059] 7. Satisfaction with the therapy [0060]
8. Use of tocolysis
Secondary Outcome Measures (Infant):
[0060] [0061] 1. Birth before 37 completed weeks [0062] 2. Birth
before 34 completed weeks [0063] 3. Birth before 32 completed weeks
[0064] 4. Birth before 28 completed weeks [0065] 5. Birth weight
less than the third centile for gestational age [0066] 6. Birth
weight less than 2500 grams [0067] 7. Apgar score of less than
seven at five minutes [0068] 8. Respiratory distress syndrome
[0069] 9. Use of mechanical ventilation [0070] 10. Duration of
mechanical ventilation [0071] 11. Intraventricular
hemorrhage--grades III or IV [0072] 12. Periventricular
leucomalacia [0073] 13. Retinopathy of prematurity [0074] 14.
Retinopathy of prematurity--grades III or IV [0075] 15. Chronic
lung disease [0076] 16. Necrotizing enterocolitis [0077] 17.
Neonatal sepsis [0078] 18. Fetal death [0079] 19. Neonatal death
[0080] 20. Admission to neonatal intensive care unit [0081] 21.
Neonatal length of hospital stay [0082] 22. Teratogenic effects
(including virilisation in female infants)
Secondary Outcome Measures (Child):
[0082] [0083] 1. Major sensorineural disability (defined as any of
legal blindness, sensorineural deafness requiring hearing aids,
moderate or severe cerebral palsy, or developmental delay or
intellectual impairment) [0084] 2. Developmental delay [0085] 3.
Intellectual impairment [0086] 4. Motor impairment [0087] 5. Visual
impairment [0088] 6. Blindness [0089] 7. Deafness [0090] 8. Hearing
impairment [0091] 9. Cerebral palsy [0092] 10. Child behavior
[0093] 11. Child temperament [0094] 12. Learning difficulties
[0095] 13. Growth assessments at childhood follow up (weight, head
circumference, length, skin fold thickness)
In-Vitro Fertilization
1. Primary Outcome Measures:
[0095] [0096] 1.1. Pregnancy Rate [0097] 1.2. Live birth [0098]
1.3. Ongoing pregnancy rate [0099] 1.4. Clinical pregnancy, defined
as ultrasound evidence of fetal heart activity at 6-8 weeks of
gestation [0100] 1.5. Fetus Vitality measured by heart beat [0101]
1.6. Rate of complete abortion 24-48 hrs after receiving medical
treatment for early pregnancy failure.
2. Secondary Outcome Measures:
[0101] [0102] 2.1. Clinical pregnancy [0103] 2.2. Cycle
Cancellation Rates [0104] 2.3. Number of Oocytes Generated [0105]
2.4. Number of Embryos Generated [0106] 2.5. Serum hormonal
evaluation [0107] 2.6. Follicular fluid evaluation [0108] 2.7. Peak
estradiol level [0109] 2.8. Ampules of gonadotropins required
during ovarian stimulation [0110] 2.9. Number of days of ovarian
stimulation [0111] 2.10. Number of oocytes retrieved [0112] 2.11.
Number of embryos transferred [0113] 2.12. Number of embryos frozen
[0114] 2.13. Embryo grade [0115] 2.14. Implantation rate [0116]
2.15. Miscarriage rate [0117] 2.16. Pregnancy outcome [0118] 2.17.
rate of complete abortion at one week, time to expulsion of
products of conception, correlation of abortion rates to serum
17-hydroxyprogesterone levels and type of pregnancy failure, number
of bleeding days and patient satisfaction [0119] 2.18. Ovarian
Response [assessed upon completion of the controlled ovarian
stimulation and the egg collection procedures]
Miscarriage
1. Primary Outcomes
[0119] [0120] 1.1. Miscarriage [0121] 1.2. Early miscarriage up to
12 weeks [0122] 1.3. Miscarriage later than 12 weeks and less than
23 weeks [0123] 1.4. Cytokine ratio IFN/IL-10 [0124] 1.5. Clinical
pregnancy rate at 8 weeks and 12 weeks of pregnancy
2. Secondary Outcomes
[0124] [0125] 2.1. Mother [0126] a. Pain relief (threatened
miscarriage) [0127] b. Severity of `morning sickness`--intensified
headache [0128] c. nausea, breast tenderness [0129] d. reported
thromboembolic events [0130] e. Thrombolytic events [0131] f.
depression; [0132] g. admission to special care unit [0133] h.
subsequent fertility. [0134] i. PIBF level [0135] j. Uterine
contraction frequency [0136] 2.2. Child [0137] a. Preterm birth;
[0138] b. stillbirth; [0139] c. neonatal death; [0140] d. low
birthweight less than 2500 g [0141] e. fetal genital abnormalities;
[0142] f. teratogenic effects (impairing normal fetal development);
[0143] g. admission to special care unit. [0144] 2.3. General
[0145] a. Intrauterine fetal death [0146] b. Still birth [0147] c.
Fetal [0148] d. Exploratory analysis of pregnancy outcome by
monitoring biochemical and clinical pregnancy parameters, weekly
evaluation of serum progesterone [0149] e. live birth rate, cycle
cancellation rate, rate of spontaneous abortion, rate of
biochemical pregnancy, rate of ectopic pregnancy
[0150] Several biomarkers have been implicated in predicting
preterm birth (PTB). Among symptomatic women, the likelihood ratio
(LR+) for the prediction of PTB is known to be greater than 10
using amniotic fluid (AF) interleukin-6 (IL-6), AF Ureaplasma
urealyticum, as well as a multi-marker consisting of cervical IL-6,
cervical IL-8, and cervical length (CL). The LR+ is also known to
be between 5 and 10 for serum C-reactive protein (CRP). An LR+
between 2.5 and 5 was recorded for serum corticotropin-releasing
hormone (CRH), cervical IL-6, serum relaxin.
[0151] In asymptomatic women, AFU urealyticum and a multimarker
consisting of five individual markers [fFN, CL, serum
alpha-fetoprotein (AFP), serum alkaline phosphatase, and serum
granulocyte colony-stimulating factor (G-CSF)] predict PTB with an
LR+ greater than 10. The LR+ was between 5 and 10 for serum relaxin
and CL. LRs+ recorded for serum alkaline phosphatase, salivary
estriol, serum CRH, serum G-CSF, cervical IL-6, AF IL-6, cervical
fFN, AFP, and chlamydia all ranged between 2.5 and 5. Finally, an
LR+ below 2.5 has been documented for serum ferritin, serum CRP,
BV, and cervical ferritin.
[0152] Miscarriages and possible miscarriages can be categorized in
several ways: A) threatened or possible miscarriage -when any
bleeding from the uterus occurs before 20 weeks, but the cervix is
closed and the fetus is alive; B) Inevitable abortion or
miscarriage (inevitable--meaning it cannot be stopped, particularly
if there is bleeding from the uterus and the cervix is opening
prior to 20 weeks, but neither the fetus nor placenta have passed
out of the woman's body)--the membranes around the fetus may or may
not have ruptured (broken); C) Incomplete abortion or
miscarriage--when a portion of the fetus or placenta has passed out
of the uterus prior to 20 weeks gestation while some of the
placenta or fetus remains in the uterus; D) Complete
miscarriage--complete expulsion of all the membranes around the
fetus and the placenta and the cervix closes prior to 20 weeks; E)
Missed abortion or miscarriage--death of the fetus prior to 20
weeks gestation with neither the fetus nor the placenta having been
expelled from the uterus; F) Recurrent miscarriage--a woman is said
to have recurrent miscarriage after she has already had two or more
miscarriages in a row; G) Blighted ovum or an-embryonic
gestation--occurs when a gestational sac forms inside the uterus,
but no fetus is present after seven weeks.
[0153] Threatened miscarriage, as demonstrated by low endogenous
progesterone or 17-hydroxyprogesterone, or vaginal bleeding with or
without abdominal cramps within 26 weeks of conception, is a common
complication of pregnancy. It occurs in about 20% of recognized
pregnancies. Risk of miscarriage is increased in older women and
those with a history of miscarriage.
[0154] It has been shown that low serum levels of progestogen
(progesterone or 17 HP) or human chorionic gonadotropin (hCG) are a
risk factor for miscarriage. Threatened miscarriage causes
considerable stress and anxiety for a pregnant woman. Because
esters of 17-hydroxyprogesterone interact with the progesterone
receptor, it is believed that treatment with esters of
17-hydroxyprogesterone can be designed based on progesterone
levels. One diagnostic criterion is low serum progesterone, but
levels vary widely during early pregnancy and any later decline may
be attributed to a dysfunctioning placenta. Nevertheless, luteal
support is widely used for the management of threatened
miscarriage. First trimester pregnancies show risk of miscarriage
with declining serum progesterone levels. Levels of <5 ng/ml
were associated with a spontaneous miscarriage in 86% of cases
compared with only 8% at levels of 20-25 ng/ml. A threshold value
of 14 ng/ml has been reported to differentiate between the viable
and non-continuing pregnancies. Other maternal serum biomarkers
such as Tumor marker CA-125, Inhibin A, Anandamide and progesterone
induced blocking factor (PIBF) are also good indicators of
miscarriage risk.
[0155] In one embodiment, the compositions of the present invention
are intended to provide an increase in the baseline endogenous
progesterone and/or 17-hydroxyprogesterone. In a particular
embodiment, the increase in the baseline endogenous progesterone
can be greater than 10%. Progestogens also have a direct
pharmacological effect by reducing the synthesis of prostaglandins,
thereby relaxing uterine smooth musculature and preventing
inappropriate contractions that may result in miscarriage.
[0156] Although the oral dosage forms and methods of the present
invention can be used in most female subjects, patients most
suitable for receiving oral 17-hydroxyprogesterone ester of this
invention are the ones that have one or more of the following
conditions, symptoms, and/or needs: 1) are in need of an
anti-inflammatory; 2) are progesterone deficient with base line
progesterone in early (first trimester) pregnancy of
C.sub.avg<14 ng/ml or baseline progesterone levels, C.sub.avg of
less than 50 ng/ml in late (second and third trimester) pregnancy;
3) have genetic variation of the SERPINH1 gene that cause to
produce a reduced amount of the protein, collagen, which may lead
to weakened fetal membranes; 4) have a genetic variant of the
Prolylcarboxypeptidase gene associated with preeclampsia; 5) have
certain bacterial infections (bacterial vaginosis) including
Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis,
and Peptostreptococcus and Bacteroides species; 6) have abnormal
amniotic fluid metabolome (the sum of all metabolic processes
occurring in the amniotic fluid) indicating risk for prematurity;
7) have had above average total phthalate exposure; 8) abnormal
prepregnancy body mass index; 9) have inflammatory milieu of the
vagina in early pregnancy; 10) have increased maternal plasma
urocortin levels; 11) show increased uterine activity as noted by
Home Uterine Activity Monitoring; 12) test positive to salivary
estriol levels predicting preterm delivery; 13) show alarming fetal
Fibronectin Screening (fFS) results; 14) show unusual cervical
shortening relative to gestational age as measured by cervical
ultrasonography, or transvaginal ultrasound or digital examination
with/without use of Cervilenz.TM.; 15) show unusual maternal serum
bio markers such as Tumour marker CA-125, or Inhibin A, or
Anandamide or Progesterone Induced Blocking factor (PIBF); 16) have
unbalanced ratio of Th-1 cytokines to Th-2 cytokines such as IFN to
IL-10.
[0157] Besides maintaining pregnancy, other potential uses of the
ester of 17-hydroxyprogesterone containing oral dosage forms of the
present invention include, but are not limited to: a) preventing
estrogen dominance; b) stimulating new bone formation and
prevent/reverse osteoporosis; c) providing the precursor for
adrenal cortex hormones (corticosteroids); d) treating variety of
skin problems such as acne in adult women, seborrhea, rosacea,
psoriasis, and keratosis; e) promoting myelin sheath production to
protect nerve fibers and speed nerve signals; f) managing
depression that accompany PMS, menopause, postpartum depression,
etc.; g) protecting from brain/spinal cord injury, stroke, and/or
hemorrhage.
[0158] In one embodiment, the present invention provides for oral
dosage forms containing esters of 17-hydroxyprogesterone as well as
related methods. The oral dosage forms can be formulated for
pregnancy support and can include a therapeutically effective
amount of an ester of 17-hydroxyprogesterone and a pharmaceutically
acceptable carrier. The oral dosage form can, when measured using a
USP Type-II dissolution apparatus in 900 mL of deionized water with
0.5 (w/v) of sodium lauryl sulfate at 50 RPM at 37.degree. C.,
release at least 20 wt % of the dose of the ester of
17-hydroxyprogesterone after 60 minutes. In yet a further
embodiment, the oral dosage form can, when measured using a USP
Type-II dissolution apparatus in 900 mL of deionized water with 0.5
(w/v) of sodium lauryl sulfate at 50 RPM at 37.degree. C., release
at least 20 wt % more 17-hydroxyprogesterone ester after 60 minutes
than an equivalently dosed oral dosage form without the
carrier.
[0159] A number of 17-hydroxyprogesterone esters can be used in the
compositions and oral dosages of the present invention. Examples of
specific acceptable esters of 17-hydroxyprogesterone include
without limitation, acetate esters of 17-hydroxyprogesterone,
caproate esters of 17-hydroxyprogesterone, undecanoate esters of
17-hydroxyprogesterone, and the like and combinations thereof.
Other pharmacologically active and acceptable esters of
17-hydroxyprogesterone may also be prepared and used in accordance
with the embodiments of the present invention so long as they
provide the desired support in pregnancy and/or non-pregnancy
conditions.
[0160] The ester of 17-hydroxyprogesterone can be present in the
compositions and oral dosage forms of the present disclosure in a
variety of forms. In one embodiment, the ester of
17-hydroxyprogesterone can be present in particulate form. The
particulate form can have a mean diameter of about 50 .mu.m or
less. The particulate form can have a mean diameter of about 25
.mu.m or less. In another embodiment, the particulate form can have
a mean diameter of about 1 .mu.m or less. In another embodiment,
the ester of 17-hydroxyprogesterone can be present in a fully
solubilized form. In another embodiment, the ester of
17-hydroxyprogesterone can be present in a partially solubilized
form. In another embodiment, a portion of the ester of
17-hydroxyprogesterone present in the composition and/or dosage
form can be present in particulate or unsolubilzied form. In some
embodiments, the ester of 17-hydroxyprogesterone can be present in
both solubilized form as well as in particulate form.
[0161] In some embodiments, the carrier of the compositions or oral
dosage forms of the present invention can act to facilitate the
delivery, release, and/or bioavailability of the ester of
17-hydroxyprogesterone. In certain aspects, the carrier can be one
or a mixture of two or more compounds. The carrier can include at
least one of a lipophilic and/or a hydrophilic component additive.
The lipophilic and hydrophilic additives that can be used in the
compositions of the invention can be selected from a variety of
classes of the pharmaceutical aids including, but not limited to,
absorbents, acids, adjuvants, anticaking agent, antitacking agents,
antifoamers, anticoagulants, antimicrobials, antioxidants,
antiphlogistics, astringents, antiseptics, bases, binders,
bufferants, chelating agents, sequestrants, celluloses, coagulants,
coating agents, colorants, dyes, pigments, complexing agents,
crystal growth regulators, denaturants, desiccants, drying agents,
dehydrating agents, diluents, disintegrants, dispersants,
emollients, emulsifiers, encapsulants, enzymes, extenders, fillers,
flavor masking agents, flavorants, fragrances, gelling agents,
glidants hardeners, stiffening agents, humectants, lubricants,
moisturizers, pH control agents, plasticizers, soothing agents,
demulcents, retarding agents, spreading agents, stabilizers,
suspending agents, sweeteners, thickening agents, consistency
regulators, surfactants, opacifiers, polymers, preservatives,
antigellants, rheology control agents, softeners, solubilizers;
solvents tonicifiers, viscosity modulators UV absorbers, or
combinations thereof. In some embodiments additives from multiple
classes or types can be used.
[0162] Non-limiting examples of compounds that can form all or a
part of the carrier are set forth in the following lists which have
been organized in general categories. It is to be understood that
the categories are not intended to limit the particular carrier
compounds, but are simply present for ease of organization and
presentation. With this in mind, example carrier compounds can
include one or more of the following:
[0163] Triglycerides such as Aceituno oil; Almond oil; Arachis oil;
Babassu oil; Blackcurrant seed oil; Borage oil; Canola oil (Lipex
108 (Abitec)); Castor oil; Cocoa butter; Coconut oil (Pureco 76
(Abitec)); Coffee seed oil); Corn oil; Cottonseed oil; Crambe oil;
Cuphea species oil; Evening primrose oil; Grapeseed oil; Groundnut
oil; Hemp seed oil; Illipe butter; Kapok seed oil; Linseed oil;
Menhaden oil; Mowrah butter; Mustard seed oil; Oiticica oil; Olive
oil; Palm oil; Palm kernel oil; Peanut oil; Poppy seed oil;
Rapeseed oil; Rice bran oil; Safflower oil; Sal fat; Sesame oil;
Shark liver oil; Shea nut oil; Soybean oil; Stillingia oil;
Sunflower oil; Tall oil; Tea sead oil; Tobacco seed oil; Tung oil
(China wood oil): Vernonia oil; Wheat germ oil; Hydrogenated castor
oil (Castorwax); Hydrogenated coconut oil (Pureco 100 (Abitec));
Hydrogenated cottonseed oil (Dritex C (Abitec)); Hydrogenated palm
oil (Dritex PST (Abitec); Softisan154 (Huls)); Hydrogenated soybean
oil (Sterotex HM NF (Abitec); Dritex S (Abitec)); Hydrogenated
vegetable oil (Sterotex NF (Abitec): Hydrokote M (Abitec));
Hydrogenated cottonseed and caster oil (Sterotex K (Abitec));
Partially hydrogenated soybean oil (Hydrokote APS (Abitec));
Partially soy and cottonseed oil (Apex B (Abitec)); Glyceryl
tributyrate (Sigma); Glyceryl tricaproate (Sigma); Glyceryl
tricaprylate (Sigma); Glyceryl tricaprate (Captex 1000 (Abitec));
Glyceryl trundecanoate (Captex 8227 (Abitec)); Glyceryl trilaurate
(Sigma); Glyceryl trimyristate (Dynasan 114 (Huls)); Glyceryl
tripalmitate (Dynasan 116 (Huls)); Glyceryl tristearate (Dynasan
118 (Huls)); Glyceryl triarcidate (Sigma); Glyceryl trimyristoleate
(Sigma); Glyceryl tripalmitoleate (Sigma); Glyceryl trioleate
(Sigma); Glyceryl trilinoleate (Sigma); Glyceryl
tricaprylate/caprate (Captex 300 (Abitec); Captex 355 (Abitec);
Miglyol 810 (Huls); Miglyol 812 (Huls)); Glyceryl
tricaprylate/caprate/laurate (Captex 350 (Abitec)); Glyceryl
tricaprylate/caprate/linoleate (Captex 810 (Abitec); Miglyol 818
(Huls)); Glyceryl tricaprylate/caprate/stearate (Softisan 378
(Huls); (Larodan); Glyceryl tricaprylate/laurate/stearate
(Larodan); Glyceryl 1,2-caprylate-3-linoleate (Larodan); Glyceryl
1,2-caprate-3-stearate (Larodan); Glyceryl 1,2-laurate-3-myristate
(Larodan); Glyceryl 1,2-myristate-3-laurate (Larodan); Glyceryl
1,3-palmitate-2-butyrate (Larodan); Glyceryl 1,3-stearate-2-caprate
(Larodan); Glyceryl 1,2-linoleate-3-caprylate (Larodan), mixtures
and derivatives thereof. Fractionated triglycerides, modified
triglycerides, synthetic triglycerides, and mixtures of
triglycerides are also within the scope of the invention.
[0164] PEG-Fatty Acid Monoester Surfactants (listed as compound
name (common commercial product name (supplier) (HLB)): PEG 4-100
monolaurate (Crodet L series (Croda) (>9)); PEG 4-100 monooleate
(Crodet O series (Croda) (>8)); PEG 4-100 monostearate (Crodet S
series (Croda), Myrj Series (Atlas/ICI) (>6)); PEG 400
distearate (Cithrol 4DS series (Croda) (>10)); PEG 100, 200, 300
monolaurate (Cithrol ML series (Croda) (>10)); PEG 100, 200, 300
monooleate (Cithrol MO series (Croda) (>10)); PEG 400 dioleate
(Cithrol 4DO series (Croda) (>10)); PEG 400-1000 monostearate
(Cithrol MS series (Croda) (>10)); PEG-1 stearate (Nikkol
MYS-1EX (Nikko), Coster K1 (Condea) (2)); PEG-2 stearate (Nikkol
MYS-2 (Nikko) (4)); PEG-2 oleate (Nikkol MYO-2 (Nikko) (4.5));
PEG-4 laurate (Mapeg.RTM. 200 ML (PPG), Kessco.RTM. PEG 200 ML
(Stepan), LIPOPEG 2 L(LIPO Chem.) (9.3)); PEG-4 oleate (Mapeg.RTM.
200 MO (PPG), Kessco.RTM. PEG 200 MO (Stepan) (8.3)); PEG-4
stearate (Kessco.RTM. PEG 200 MS (Stepan), Hodag 20 S (Calgene),
Nikkol MYS-4 (Nikko) (6.5)); PEG-5 stearate (Nikkol TMGS-5 (Nikko)
(9.5)); PEG-5 oleate (Nikkol TMGO-5 (Nikko) (9.5)); PEG-6 oleate
(Algon OL 60 (Auschem SpA), Kessco.RTM. PEG 300 MO (Stepan), Nikkol
MYO-6 (Nikko), Emulgante A6 (Condea) (8.5)); PEG-7 oleate (Algon OL
70 (Auschem SpA) (10.4)); PEG-6 laurate (Kessco.RTM. PEG300 ML
(Stepan) (11.4)); PEG-7 laurate (Lauridac 7 (Condea) (13)); PEG-6
stearate (Kessco.RTM. PEG300 MS (Stepan) (9.7)); PEG-8 laurate
(Mapeg.RTM. 400 ML (PPG), LIPOPEG 4DL(Lipo Chem.) (13)); PEG-8
oleate (Mapeg.RTM. 400 MO (PPG), Emulgante A8 (Condea) (12)); PEG-8
stearate (Mapeg.RTM. 400 MS (PPG), Myrj 45 (12)); PEG-9 oleate
(Emulgante A9 (Condea) (>10)); PEG-9 stearate (Cremophor S9
(BASF) (>10)); PEG-10 laurate (Nikkol MYL-10 (Nikko), Lauridac
10 (Croda) (13)); PEG-10 oleate (Nikkol MYO-10 (Nikko) (11));
PEG-12 stearate (Nikkol MYS-10 (Nikko), Coster K100 (Condea) (11));
PEG-12 laurate (Kessco.RTM. PEG 600 ML (Stepan) (15)); PEG-12
oleate (Kessco.RTM. PEG 600 MO (Stepan) (14)); PEG-12 ricinoleate
(CAS #9004-97-1) (>10)); PEG-12 stearate (Mapeg.RTM. 600 MS
(PPG), Kessco.RTM. PEG 600 MS (Stepan) (14)); PEG-15 stearate
(Nikkol TMGS-15 (Nikko), Koster K15 (Condea) (14)); PEG-15 oleate
(Nikkol TMGO-15 (Nikko) (15)); PEG-20 laurate (Kessco.RTM. PEG 1000
ML (Stepan) (17)); PEG-20 oleate (Kessco.RTM. PEG 1000 MO (Stepan)
(15)); PEG-20 stearate (Mapeg.RTM. 1000 MS (PPG), Kessco.RTM. PEG
1000 MS (Stepan), Myrj 49 (16)); PEG-25 stearate (Nikkol MYS-25
(Nikko) (15)); PEG-32 laurate (Kessco.RTM. PEG 1540 ML (Stepan)
(16)); PEG-32 oleate (Kessco.RTM. PEG 1540 MO (Stepan) (17));
PEG-32 stearate (Kessco.RTM. PEG 1540 MS (Stepan) (17)); PEG-30
stearate (Myrj 51 (>10)); PEG-40 laurate (Crodet L40 (Croda)
(17.9)); PEG-40 oleate (Crodet O40 (Croda) (17.4)); PEG-40 stearate
(Myrj 52, Emerest.RTM. 2715 (Henkel), Nikkol MYS-40 (Nikko)
(>10)); PEG-45 stearate (Nikkol MYS-45 (Nikko) (18)); PEG-50
stearate (Myrj 53 (>10)); PEG-55 stearate (Nikkol MYS-55 (Nikko)
(18)); PEG-100 oleate (Crodet O-100 (Croda) (18.8)); PEG-100
stearate (Myrj 59, Ariacel 165 (ICI) (19)); PEG-200 oleate (Albunol
200 MO (Taiwan Surf) (>10)); PEG-400 oleate (LACTOMUL (Henkel),
Albunol 400 MO (Taiwan Surf) (>10)); PEG-600 oleate (Albunol 600
MO (Taiwan Surf) (>10)); and combinations thereof.
[0165] PEG-Fatty Acid Diesters (listed as compound name (common
commercial product name (supplier) (HLB)): PEG-4 dilaurate
(Mapeg.RTM. 200 DL (PPG), Kessco.RTM. PEG 200 DL (Stepan), LIPOPEG
2-DL (Lipo Chem.) (7)); PEG-4 dioleate (Mapeg.RTM. 200 DO (PPG),
(6)); PEG-4 distearate (Kessco.RTM. 200 DS (Stepan) (5)); PEG-6
dilaurate (Kessco.RTM. PEG 300 DL (Stepan) (9.8)); PEG-6 dioleate
(Kessco.RTM. PEG 300 DO (Stepan) (7.2)); PEG-6 distearate
(Kessco.RTM. PEG 300 DS (Stepan) (6.5)); PEG-8 dilaurate
(Mapeg.RTM. 400 DL (PPG), Kessco.RTM. PEG 400 DL (Stepan), LIPOPEG
4 DL (Lipo Chem.) (11)); PEG-8 dioleate (Mapeg.RTM. 400 DO (PPG),
Kessco.RTM. PEG 400 DO (Stepan), LIPOPEG 4 DO (Lipo Chem.) (8.8));
PEG-8 distearate (Mapeg.RTM. 400 DS (PPG), CDS 400 (Nikkol ) (11));
PEG-10 dipalmitate (Polyaldo 2PKFG (>10)); PEG-12 dilaurate
(Kessco.RTM. PEG 600 DL (Stepan) (11.7)); PEG-12 distearate
(Kessco.RTM. PEG 600 DS (Stepan) (10.7)); PEG-12 dioleate
(Mapeg.RTM. 600 DO (PPG), Kessco.RTM. 600 DO (Stepan) (10)); PEG-20
dilaurate (Kessco.RTM. PEG 1000 DL (Stepan) (15)); PEG-20 dioleate
(Kessco.RTM. PEG 1000 DO (Stepan) (13)); PEG-20 distearate
(Kessco.RTM. PEG 1000 DS (Stepan) (12)); PEG-32 dilaurate
(Kessco.RTM. PEG 1540 DL (Stepan) (16)); PEG-32 dioleate
(Kessco.RTM. PEG 1540 DO (Stepan) (15)); PEG-32 distearate
(Kessco.RTM. PEG 1540 DS (Stepan) (15)); PEG-400 dioleate (Cithrol
4DO series (Croda) (>10)); PEG-400 distearate (Cithrol 4DS
series (Croda) (>10)); and combinations thereof.
[0166] PEG-Fatty Acid Mono- and Di-ester Mixtures (listed as
compound name (common commercial product name (supplier) (HLB)):
PEG 4-150 mono, dilaurate (Kessco.RTM. PEG 200-6000 mono, dilaurate
(Stepan))); PEG 4-150 mono, dioleate (Kessco.RTM. PEG 200-6000
mono, dioleate (Stepan))); PEG 4-150 mono, distearate (Kessco.RTM.
200-6000 mono, distearate (Stepan)), and combinations thereof.
[0167] Polyethylene Glycol Glygerol Fatty Acid Esters (listed as
compound name (common commercial product name (supplier) (HLB)):
PEG-20 glyceryl laurate (Tagat.RTM. L (Goldschmidt) (16)); PEG-30
glyceryl laurate (Tagat.RTM. L2 (Goldschmidt) (16)); PEG-15
glyceryl laurate (Glycerox L series (Croda) (15)); PEG-40 glyceryl
laurate (Glycerox L series (Croda) (15)); PEG-20 glyceryl stearate
(Capmul.RTM. EMG (ABITEC), (13)); (Aldo.RTM. MS-20 KFG (Lonza)));
PEG-20 glyceryl oleate (Tagat .RTM. 0 (Goldschmidt) (>10));
PEG-30 glyceryl oleate (Tagat .RTM. 02 (Goldschmidt) (>10)); and
combinations thereof.
[0168] Alcohol-oil Transesterification Products (listed as compound
name (common commercial product name (supplier) (HLB)): PEG-3
castor oil (Nikkol CO-3 (Nikko) (3)); PEG-5, 9, and 16 castor oil
(ACCONON CA series (ABITEC) (6-7)); PEG-20 castor oil (Emalex C-20
(Nihon Emulsion), Nikkol CO-20 TX (Nikko) (11)); PEG-23 castor oil
(Emulgante EL23 (>10)); PEG-30 castor oil (Emalex C-30 (Nihon
Emulsion), Alkamuls.RTM. EL 620 (Rhone-Poulenc), Incrocas 30
(Croda) (11)); PEG-35 castor oil (Cremophor EL and EL-P (BASF),
Emulphor EL, Incrocas-35(Croda), Emulgin RO 35 (Henkel))); PEG-38
castor oil (Emulgante EL 65 (Condea))); PEG-40 castor oil (Emalex
C-40 (Nihon Emulsion), Alkamuls.RTM. EL 719 (Rhone-Poulenc) (13));
PEG-50 castor oil (Emalex C-50 (Nihon Emulsion) (14)); PEG-56
castor oil (Eumulgin.RTM. PRT 56 (Pulcra SA) (>10)); PEG-60
castor oil (Nikkol CO-60TX (Nikko) (14)); PEG-100 castor oil
(Thornley (>10)); PEG-200 castor oil (Eumulgin.RTM. PRT 200
(Pulcra SA) (>10)); PEG-5 hydrogenated castor oil (Nikkol HCO-5
(Nikko) (6)); PEG-7 hydrogenated castor oil (Simusol.RTM. 989
(Seppic), Cremophor WO7 (BASF) (6)); PEG-10 hydrogenated castor oil
(Nikkol HCO-10 (Nikko) (6.5)); PEG-20 hydrogenated castor oil
(Nikkol HCO-20 (Nikko) (11)); PEG-25 hydrogenated castor oil
(Simulson.RTM. 1292 (Seppic), Cerex ELS 250 (Auschem SpA) (11));
PEG-30 hydrogenated castor oil (Nikkol HCO-30 (Nikko) (11)); PEG-40
hydrogenated castor oil (Cremophor RH 40 (BASF), Croduret (Croda),
Emulgin HRE 40 (Henkel) (13)); PEG-45 hydrogenated castor oil
(Cerex ELS 450 (Auschem Spa) (14)); PEG-50 hydrogenated castor oil
(Emalex HC-50 (Nihon Emulsion) (14)); PEG-60 hydrogenated castor
oil (Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) (15)); PEG-80
hydrogenated castor oil (Nikkol HCO-80 (Nikko) (15)); PEG-100
hydrogenated castor oil (Nikkol HCO-100 (Nikko) (17)); PEG-6 corn
oil (Labrafil.RTM. M 2125 CS (Gattefosse) (4)); PEG-6 almond oil
(Labrafil.RTM. M 1966 CS (Gattefosse) (4)); PEG-6 apricot kernel
oil (Labrafil.RTM. M 1944 CS (Gattefosse) (4)); PEG-6 olive oil
(Labrafil.RTM. M 1980 CS (Gattefosse) (4)); PEG-6 peanut oil
(Labrafil.RTM. M 1969 CS (Gattefosse) (4)); PEG-6 hydrogenated palm
kernel oil (Labrafil.RTM. M 2130 BS (Gattefosse) (4)); PEG-6 palm
kernel oil (Labrafil.RTM. M 2130 CS (Gattefosse) (4)); PEG-6
triolein (Labrafil.RTM. M 2735 CS (Gattefosse) (4)); PEG-8 corn oil
(Labrafil.RTM. WL 2609 BS (Gattefosse) (6-7)); PEG-20 corn
glycerides (Crovol M40 (Croda) (10)); PEG-20 almond glycerides
(Crovol A40 (Croda) (10)); PEG-25 trioleate (TAGAT.RTM. TO
(Goldschmidt) (11)); PEG-40 palm kernel oil (Crovol PK-70
(>10)); PEG-60 corn glycerides (Crovol M70(Croda) (15)); PEG-60
almond glycerides (Crovol A70 (Croda) (15)); PEG-4 caprylic/capric
triglyceride (Labrafac.RTM. Hydro (Gattefosse), (4-5)); PEG-8
caprylic/capric glycerides (Labrasol (Gattefosse),Labrafac CM 10
(Gattefosse) (>10)); PEG-6 caprylic/capric glycerides
(SOFTIGEN.RTM. 767 (Huls), Glycerox 767 (Croda) (19)); Lauroyl
macrogol-32 glyceride (GELUCIRE 44/14 (Gattefosse) (14)); Stearoyl
macrogol glyceride (GELUCIRE 50/13 (Gattefosse) (13)); Mono, di,
tri, tetra esters of vegetable oils and sorbitol (SorbitoGlyceride
(Gattefosse) (<10)); Pentaerythrityl tetraisostearate (Crodamol
PTIS (Croda) (<10)); Pentaerythrityl distearate (Albunol DS
(Taiwan Surf.) (<10)); Pentaerythrityl tetraoleate (Liponate
PO-4 (Lipo Chem.) (<10)); Pentaerythrityl tetrastearate
(Liponate PS-4 (Lipo Chem.) (<10)); Pentaerythrityl
tetracaprylate/tetracaprate (Liponate PE-810 (Lipo Chem.), Crodamol
PTC (Croda) (<10)); Pentaerythrityl tetraoctanoate (Nikkol
Pentarate 408 (Nikko))); and combinations thereof.
[0169] Polyglycolized Fatty Acids: (listed as compound name (common
commercial product name (supplier) (HLB)): Polyglyceryl-2 stearate
(Nikkol DGMS (Nikko) (5-7)); Polyglyceryl-2 oleate (Nikkol DGMO
(Nikko) (5-7)); Polyglyceryl-2 isostearate (Nikkol DGMIS (Nikko)
(5-7)); Polyglyceryl-3 oleate (Caprol .RTM. 3GO (ABITEC), Drewpol
3-1-0 (Stepan) (6.5)); Polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O
(Nikko) (5-7)); Polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S
(Nikko) (5-6)); Polyglyceryl-6 oleate (Drewpol 6-1-O (Stepan),
Nikkol Hexaglyn 1-O (Nikko) (9)); Polyglyceryl-10 laurate (Nikkol
Decaglyn 1-L (Nikko) (15)); Polyglyceryl-10 oleate (Nikkol Decaglyn
1-O (Nikko) (14)); Polyglyceryl-10 stearate (Nikkol Decaglyn 1-S
(Nikko) (12)); Polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15
(Nikko) (>8)); Polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN
(Nikko) (12)); Polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O
(Nikko) (<10)); Polyglyceryl-3 dioleate (Cremophor GO32 (BASF)
(<10)); Polyglyceryl-3 distearate (Cremophor GS32 (BASF)
(<10)); Polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-O (Nikko)
(<10)); Polyglyceryl-6 dioleate (Caprol.RTM. 6G20 (ABITEC);
Hodag PGO-62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse) (8.5));
Polyglyceryl-2 dioleate (Nikkol DGDO (Nikko) (7)); Polyglyceryl-10
trioleate (Nikkol Decaglyn 3-O (Nikko) (7)); Polyglyceryl-10
pentaoleate (Nikkol Decaglyn 5-O (Nikko) (3.5)); Polyglyceryl-10
septaoleate (Nikkol Decaglyn 7-O (Nikko) (3)); Polyglyceryl-10
tetraoleate (Caprol.RTM. 10G4O (ABITEC); Hodag PGO-62 (CALGENE),
Drewpol 10-4-O (Stepan) (6.2)); Polyglyceryl-10 decaisostearate
(Nikkol Decaglyn 10-IS (Nikko) (<10)); Polyglyceryl-101
decaoleate (Drewpol 10-10-O (Stepan), Caprol 10G100 (ABITEC),
Nikkol Decaglyn 10-O (3.5)); Polyglyceryl-10 mono, dioleate
(Caprol.RTM. PGE 860 (ABITEC) (11)); Polyglyceryl polyricinoleate
(Polymuls (Henkel) (3-20)); and combinations thereof.
[0170] Propylene Glycol Fatty Acid Esters: (listed as compound name
(common commercial product name (supplier) (HLB)): Propylene glycol
monocaprylate (Capryol 90 (Gattefosse), Nikkol Sefsol 218 (Nikko)
(<10)); Propylene glycol monolaurate (Lauroglycol 90
(Gattefosse), Lauroglycol FCC (Gattefosse) (<10)); Propylene
glycol oleate (Lutrol OP2000 (BASF) (<10)); Propylene glycol
myristate (Mirpyl (<10)); Propylene glycol monostearate (ADM
PGME-03 (ADM), LIPO PGMS (Lipo Chem.), Aldo.RTM. PGHMS (Lonza)
(3-4)); Propylene glycol hydroxy stearate (<10)); Propylene
glycol ricinoleate (PROPYMULS (Henkel) (<10)); Propylene glycol
isostearate (<10)); Propylene glycol monooleate (Myverol P-O6
(Eastman) (<10)); Propylene glycol dicaprylate/dicaprate
(Captex.RTM. 200 (ABITEC), Miglyol.RTM. 840 (Huls), Neobee.RTM.
M-20 (Stepan) (>6)); Propylene glycol dioctanoate (Captex.RTM.
800 (ABITEC) (>6)); Propylene glycol caprylate/caprate (LABRAFAC
PG (Gattefosse) (>6)); Propylene glycol dilaurate (>6));
Propylene glycol distearate (Kessco.RTM. PGDS (Stepan) (>6));
Propylene glycol dicaprylate (Nikkol Sefsol 228 (Nikko) (>6));
Propylene glycol dicaprate (Nikkol PDD (Nikko) (>6)); and
combinations thereof.
[0171] Mixtures of Propylene Glycol Esters and Glycerol-Esters:
(listed as compound name (common commercial product name (supplier)
(HLB)): Oleic (ATMOS 300, ARLACEL 186 (ICI) (3-4)); Stearic (ATMOS
150 (3-4)); and combinations thereof.
[0172] Mono- and Diglycerides: (listed as compound name (common
commercial product name (supplier) (HLB)): Monopalmitolein (C16:1)
(Larodan) (<10)); Monoelaidin (C18:1) (Larodan) (<10));
Monocaproin (C6) (Larodan) (<10)); Monocaprylin (Larodan)
(<10)); Monocaprin (Larodan) (<10)); Monolaurin (Larodan)
(<10)); Glyceryl monomyristate (C14) (Nikkol MGM (Nikko) (3-4));
Glyceryl monooleate (C18:1) (PECEOL (Gattefosse), Hodag GMO-D,
Nikkol MGO (Nikko) (3-4)); Glyceryl monooleate (RYLO series
(Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO.RTM.
MO FG (Lonza), Kessco GMO (Stepan), MONOMULS.RTM. series (Henkel),
TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80
(Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol(Eastman) (3-4));
Glycerol monooleate/linoleate (OLICINE (Gattefosse) (3-4));
Glycerol monolinoleate (Maisine (Gattefosse), MYVEROL 18-92,
Myverol 18-06 (Eastman) (3-4)); Glyceryl ricinoleate (Softigen.RTM.
701 (Huls), HODAG GMR-D (Calgene), ALDO.RTM. MR (Lonza) (6));
Glyceryl monolaurate (ALDO.RTM. MLD (Lonza), Hodag GML (Calgene)
(6.8)); Glycerol monopalmitate (Emalex GMS-P (Nihon) (4)); Glycerol
monostearate (Capmul.RTM. GMS (ABITEC), Myvaplex (Eastman),
IMWITOR.RTM. 191 (Huls), CUTINA GMS, Aldo.RTM. MS (Lonza), Nikkol
MGS series(Nikko) (5-9)); Glyceryl mono-,dioleate (Capmul.RTM.
GMO-K (ABITEC) (<10)); Glyceryl palmitic/stearic (CUTINA MD-A,
ESTAGEL-G18 (<10)); Glyceryl acetate (Lamegin.RTM. EE (Grunau
GmbH) (<10)); Glyceryl laurate (Imwitor.RTM. 312 (Huls),
Monomuls.RTM. 90-45 (Grunau GmbH), Aldo.RTM. MLD (Lonza) (4));
Glyceryl citrate/lactate/oleate/linoleate (Imwitor.RTM. 375 (Huls)
(<10)); Glyceryl caprylate (Imwitor.RTM. 308 (Huls), Capmul.RTM.
MCMC8 (ABITEC) (5-6)); Glyceryl caprylate/caprate (Capmul.RTM. MCM
(ABITEC) (5-6)); Caprylic acid mono,diglycerides (Imwitor.RTM. 988
(Huls) (5-6)); Caprylic/capric glycerides (Imwitor.RTM. 742 (Huls)
(<10)); Mono-and diacetylated monoglycerides (Myvacet.RTM. 9-45,
Myvacet.RTM. 9-40, Myvacet.RTM. 9-08 (Eastman), Lamegin.RTM.
(Grunau) (3.8-4)); Glyceryl monostearate (Aldo.RTM. MS, Arlacel 129
(ICI), LIPO GMS (Lipo Chem.), Imwitor.RTM. 191 (Huls), Myvaplex
(Eastman) (4.4)); Lactic acid esters of mono,diglycerides (LAMEGIN
GLP (Henkel) (<10)); Dicaproin (C6) (Larodan) (<10); Dicaprin
(C10) (Larodan) (<10); Dioctanoin (C8) (Larodan) (<10);
Dimyristin (C14) (Larodan) (<10); Dipalmitin (C16) (Larodan)
(<10); Distearin (Larodan) (<10); Glyceryl dilaurate (C12)
(Capmul.RTM. GDL (ABITEC) (3-4)); Glyceryl dioleate (Capmul.RTM.
GDO (ABITEC) (3-4)); Glycerol esters of fatty acids (GELUCIRE 39/01
(Gattefosse), GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06
(Gattefosse) (1 6)); Dipalmitolein (C16:1) (Larodan) (<10); 1,2
and 1,3-diolein (C18:1) (Larodan) (<10); Dielaidin (C18:1)
(Larodan) (<10); Dilinolein (C18:2) (Larodan) (<10); and
combinations thereof.
[0173] Sterol and Sterol Derivatives: (listed as compound name
(common commercial product name (supplier) (HLB)): Cholesterol,
sitosterol, lanosterol (<10)); PEG-24 cholesterol ether (Solulan
C-24 (Amerchol) (>10)); PEG-30 cholestanol (Nikkol DHC (Nikko)
(>10)); Phytosterol (GENEROL series (Henkel) (<10)); PEG-25
phyto sterol (Nikkol BPSH-25 (Nikko) (>10)); PEG-5 soya sterol
(Nikkol BPS-5 (Nikko) (<10)); PEG-10 soya sterol (Nikkol BPS-10
(Nikko) (<10)); PEG-20 soya sterol (Nikkol BPS-20 (Nikko)
(<10)); PEG-30 soya sterol (Nikkol BPS-30 (Nikko) (>10)); and
combinations thereof.
[0174] Polyethylene Glycol Sorbitan Fatty Acid Esters: (listed as
compound name (common commercial product name (supplier) (HLB)):
PEG-10 sorbitan laurate (Liposorb L-10 (Lipo Chem.) (>10));
PEG-20 sorbitan monolaurate (Tween-20 (Atlas/ICI), Crillet 1
(Croda), DACOL MLS 20 (Condea) (17)); PEG-4 sorbitan monolaurate
(Tween-21 (Atlas/ICI), Crillet 11 (Croda) (13)); PEG-80 sorbitan
monolaurate (Hodag PSML-80 (Calgene); T-Maz 28 (>10)); PEG-6
sorbitan monolaurate (Nikkol GL-1 (Nikko) (16)); PEG-20 sorbitan
monopalmitate (Tween-40 (Atlas/ICI), Crillet 2 (Croda) (16));
PEG-20 sorbitan monostearate (Tween-60 (Atlas/ICI), Crillet 3
(Croda) (15)); PEG-4 sorbitan monostearate (Tween-61 (Atlas/ICI),
Crillet 31 (Croda) (9.6)); PEG-8 sorbitan monostearate (DACOL MSS
(Condea) (>10)); PEG-6 sorbitan monostearate (Nikkol TS106
(Nikko) (11)); PEG-20 sorbitan tristearate (Tween-65 (Atlas/ICI),
Crillet 35 (Croda) (11)); PEG-6 sorbitan tetrastearate (Nikkol GS-6
(Nikko) (3)); PEG-60 sorbitan tetrastearate (Nikkol GS-460 (Nikko)
(13)); PEG-5 sorbitan monooleate (Tween-81 (Atlas/ICI), Crillet 41
(Croda) (10)); PEG-6 sorbitan monooleate (Nikkol TO-106 (Nikko)
(10)); PEG-20 sorbitan monooleate (Tween-80 (Atlas/ICI), Crillet 4
(Croda) (15)); PEG-40 sorbitan oleate (Emalex ET 8040 (Nihon
Emulsion) (18)); PBG-20 sorbitan trioleate (Tween-85 (Atlas/ICI),
Crillet 45 (Croda) (11)); PEG-6 sorbitan tetraoleate (Nikkol GO-4
(Nikko) (8.5)); PEG-30 sorbitan tetraoleate (Nikkol GO-430 (Nikko)
(12)); PEG-40 sorbitan tetraoleate (Nikkol GO-440 (Nikko) (13));
PEG-20 sorbitan monoisostearate (Tween-120 (Atlas/ICI), Crillet 6
(Croda) (>10)); PEG sorbitol hexaoleate (Atlas G-1086 (ICI)
(10)); PEG-6 sorbitol hexastearate (Nikkol GS-6 (Nikko) (3)); and
combinations thereof.
[0175] Polyethylene Glycol Alkyl Ethers: (listed as compound name
(common commercial product name (supplier) (HLB)): PEG-2oleyl
ether, oleth-2(Brij 92/93 (Atlas/ICI) (4.9)); PEG-3 oleyl ether,
oleth-3 (Volpo 3 (Croda) (<10)); PEG-5 oleyl ether, oleth-5
(Volpo 5 (Croda) (<10)); PEG-10 oleyl ether, oleth-10 (Volpo 10
(Croda), Brij 96/97 (Atlas/ICI) (12)); PEG-20 oleyl ether, oleth-20
(Volpo 20 (Croda), Brij 98/99 (Atlas/ICI) (15)); PEG-4 lauryl
ether, laureth-4 (Brij 30 (Atlas/ICI) (9.7)); PEG-9 lauryl ether
(>10)); PEG-23 lauryl ether, laureth-23 (Brij 35 (Atlas/ICI)
(17)); PEG-2 cetyl ether (Brij 52 (ICI) (5.3)); PEG-10 cetyl ether
(Brij 56 (ICI) (13)); PEG-20 cetyl ether (BriJ 58 (ICI) (16));
PEG-2 stearyl ether (Brij 72 (ICI) (4.9)); PEG-10 stearyl ether
(Brij 76 (ICI) (12)); PEG-20 stearyl ether (Brij 78 (ICI) (15));
PEG-100 stearyl ether (Brij 700 (ICI) (>10)); and combinations
thereof.
[0176] Sugar Esters: (listed as compound name (common commercial
product name (supplier) (HLB)): Sucrose distearate (SUCRO ESTER 7
(Gattefosse), Crodesta F-10 (Croda) (3)); Sucrose
distearate/monostearate (SUCRO ESTER 11 (Gattefosse), Crodesta
F-110 (Croda) (12)); Sucrose dipalmitate (7.4)); Sucrose
monostearate (Crodesta F-160 (Croda) (15)); Sucrose monopalmitate
(SUCRO ESTER 15 (Gattefosse) (>10)); Sucrose monolaurate
(Saccharose monolaurate 1695 (Mitsubisbi-Kasei) (15)); and
combinations thereof.
[0177] Polyethylene Glycol Alkyl Phenols: (listed as compound name
(common commercial product name (supplier) (HLB)): PEG-10-100 nonyl
phenol (Triton X series (Rohm & Haas), Igepal CA series (GAF,
USA), Antarox CA series (>10)); (GAF, UK); PEG-15-100 octyl
phenol ether (Triton N-series (Rohm & Haas), Igepal CO series
(GAF, USA), Antarox CO series (GAF, UK) (>10)); and combinations
thereof.
[0178] Polyethylene-Polyoxypropylene Block Copolymers
(AKA--"poloxamer"): These polymers have the formula:
HO(C<2>H<4>O)<a>(C<3>H<6>O)<b>(C<2-
>H<4>O)<a>H where "a" and "b" denote the number of
polyoxyethylene and polyoxypropylene units, respectively. The
compounds are listed by generic name, with the corresponding "a"
and "b" values. POE-POP Block Copolymers)); (a, b values in));
(HO(C<2>H<4>O)<a>)); (COMPOUND
(C<3>H<6>O)<b>(C<2>H<4>O)<a>H
(HLB)); (Poloxamer 105 (a=11 (b=16 (8)); (Poloxamer 108 (a=46 (b=16
(>10)); (Poloxamer 122 (a=5 (b=21 (3)); (Poloxamer 123 (a=7
(b=21 (7)); (Poloxamer 124 (a=11 (b=21 (>7)); (Poloxamer 181
(a=3 (b=30)); (Poloxamer 182 (a=8 (b=30 (2)); (Poloxamer 183 (a=10
(b=30)); (Poloxamer 184 (a=13 (b=30)); (Poloxamer 185 (a=19
(b=30)); (Poloxamer 188 (a=75 (b=30 (29)); (Poloxamer 212 (a=8
(b=35)); (Poloxamer 215 (a=24 (b=35)); (Poloxamer 217 (a=52
(b=35)); (Poloxamer 231 (a=16 (b=39)); (Poloxamer 234 (a=22
(b=39)); (Poloxamer 235 (a=27 (b =39)); (Poloxamer 237 (a=62 (b=39
(24)); (Poloxamer 238 (a=97 (b=39)); (Poloxamer 282 (a=10 (b=47));
(Poloxamer 284 (a=21 (b=47)); (Poloxamer 288 (a=122 (b=47
(>10)); (Poloxamer 331 (a=7 (b=54 (0.5)); (Poloxamer 333 (a=20
(b=54)); (Poloxamer 334 (a=31 (b=54)); (Poloxamer 335 (a=38
(b=54)); (Poloxamer 338 (a=128 (b=54)); (Poloxamer 401 (a=6
(b=67)); (Poloxamer 402 (a=13 (b=67)); (Poloxamer 403 (a=21
(b=67)); (Poloxamer 407 (a=98 (b=67)); and combinations
thereof.
[0179] Sorbitan Fatty Acid Esters: (listed as compound name (common
commercial product name (supplier) (HLB)): Sorbitan monolaurate
(Span-20 (Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) (8.6));
Sorbitan monopalmitate (Span-40 (Atlas/ICI), Crill 2 (Croda),
Nikkol SP-10 (Nikko) (6.7)); Sorbitan monooleate (Span-80
(Atlas/ICI), Crill 4 (Croda), Crill 50 (Croda) (4.3)); Sorbitan
monostearate (Span-60 (Atlas/ICI), Crill 3 (Croda), Nikkol SS-10
(Nikko) (4.7)); Sorbitan trioleate (Span-85 (Atlas/ICI), Crill 45
(Croda), Nikkol SO-30 (Nikko) (4.3)); Sorbitan sesquioleate
(Arlacel-C (ICI), Crill 43 (Croda), Nikkol SO-15 (Nikko) (3.7));
Sorbitan tristearate (Span-65 (Atlas/ICI) Crill 35 (Croda), Nikkol
SS-30 (Nikko) (2.1)); Sorbitan monoisostearate (Crill 6 (Croda),
Nikkol SI-10 (Nikko) (4.7)); Sorbitan sesquistearate (Nikkol SS-15
(Nikko) (4.2)); and combinations thereof.
[0180] Lower Alcohol Fatty Acid Esters: (listed as compound name
(common commercial product name (supplier) (HLB)): Ethyl oleate
((Crodamol EO (Croda), Nikkol EOO (Nikko) (<10)); Isopropyl
myristate (Crodamol IPM (Croda) (<10)); Isopropyl palmitate
(Crodamol IPP (Croda) (<10)); Ethyl linoleate (Nikkol VF-E
(Nikko) (<10)); Isopropyl linoleate (Nikkol VF-IP (Nikko)
(<10)); and combinations thereof.
[0181] Ionic Surfactants: (listed as compound name (HLB) Fatty acid
salts (>10)); Sodium caproate; Sodium caprylate; Sodium caprate;
Sodium laurate; Sodium myristate)); Sodium myristolate; Sodium
palmitate; Sodium palmitoleate; Sodium oleate (18); Sodium
ricinoleate)); Sodium linoleate; Sodium linolenate; Sodium
stearate; Sodium lauryl sulfate (40); Sodium tetradecyl sulfate;
Sodium lauryl sarcosinate; Sodium dioctyl sulfosuccinate; Bile
Salts (>10); Sodium cholate; Sodium taurocholate; Sodium
glycocholate; Sodium deoxycholate; Sodium taurodeoxycholate; Sodium
glycodeoxycholate; Sodium ursodeoxycholate; Sodium
chenodeoxycholate; Sodium taurochenodeoxycholate; Sodium glyco
cheno deoxycholate; Sodium cholylsarcosinate; Sodium N-methyl
taurocholate; and combinations thereof.
[0182] Phospholipids: such as Egg/Soy lecithin (Epikuron.TM.;
Ovothin.TM.); Lyso egg/soy lecithin; Hydroxylated lecithin;
Lysophosphatidylcholine; Cardiolipin; Sphingomyelin;
Phosphatidylcholine; Phosphatidyl ethanolamine; Phosphatidic acid;
Phosphatidyl glycerol; Phosphatidyl serine, and combinations
thereof.
[0183] Phosphoric Acid Esters: Diethanolammonium polyoxyethylene-10
oleyl ether phosphate; Esterification products of fatty alcohols or
fatty alcohol ethoxylates with phosphoric acid or anhydride.
[0184] Carboxylates, such as: Ether carboxylates (by oxidation of
terminal OH group of fatty alcohol ethoxylates) Succinylated
monoglycerides; Sodium stearyl fumarate; Stearoyl propylene glycol
hydrogen succinate; Mono/diacetylated tartaric acid esters of mono-
and diglycerides; Citric acid esters of mono-, diglycerides;
Glyceryl-lacto esters of fatty acids; and combinations thereof.
[0185] Acyl lactylates such as: lactylic esters of fatty acids;
calcium/sodium stearoyl-2-lactylate; calcium/sodium stearoyl
lactylate; alginate salts like sodium alginate, calcium alginate
and others; and combinations thereof.
[0186] Hydrophilic Polymers such as: carboxyvinyl polymer,
polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid
copolymers, macrogol, starch, gelatin, dextrin, pullulan, agar,
acacia, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl
alcohol), poly(ethylene-co-vinyl alcohol), poly(acrylic acid),
poly(ethylene-co-acrylic acid), poly(ethyloxazoline), poly(vinyl
pyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poly(maleic
acid), poly(ethylene-co-maleic acid), poly(acrylamide), or
poly(ethylene oxide)-co-poly(propylene oxide); block copolymers,
graft copolymers of lactic acid, glycolic acid,
epsilon-caprolactone, lactic-co-glycolic acid oligomers,
trimethylene carbonate, anhydrides, and amino acids acrylates,
benzoquinones, naphthoquinones and the like;
N-vinylpyrrolidone-co-vinyl alcohol, poly(ethylene-co-vinyl
alcohol); acrylic or methacrylic acid copolymers; carbomers,
Chitosan, methacrylates (Eudragits), and combinations thereof.
[0187] Acids such as: acetic acid, hydrochloric acid, hydrobromic
acid, hydriodic acid, phosphoric acid, sulfuric acid, nitric acid,
acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an
amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid,
carbonic acid, citric acid, fatty acid, formic acid, fumaric acid,
gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic
acid, maleic acid, methanesulfonic acid, oxalic acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic
acid, salicylic acid, stearic acid, succinic acid, tannic acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid,
salts thereof, and mixtures thereof.
[0188] Bases such as: amino acids, amino acid esters, ammonium
hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen
carbonate, aluminum hydroxide, calcium carbonate, magnesium
hydroxide, magnesium aluminum silicate, synthetic aluminum
silicate, synthetic hydrotalcite, magnesium aluminum hydroxide,
diisopropylethylamine, ethanolamine, ethylenediamine,
triethanolamine, triethylamine, triisopropanolamine, and mixtures
of combinations thereof.
[0189] Chelating Agents such as: Sodium EDTA, Dieditate Sodium, and
mixtures or combinations thereof. Complexing Agents such as:
Hydroxypropyl Cyclodextrin, Hydroxy propyl beta Cyclodextrin,
sulfabutyl ether cyclodextrin, and mixtures and combinations
thereof. Salts such as: salts of acids, bases, salts of fatty
acids, fatty acid glycerides, Salts of bile acids, and mixtures and
combinations thereof.
[0190] Amides such as: for example 2-pyrrolidone, 2-piperidone,
epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone,
N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide,
polyvinylpyrrolidone and the like.
[0191] Alcohols such as: ethanol, isopropanol, butanol, benzyl
alcohol, ethylene glycol, propylene glycol, glycerol, sorbitol,
mannitol, dimethyl isosorbide, polyethylene glycol, fatty acid
alcohol, vinyl alcohol polypropylene glycol, polyvinylalcohol,
tocopherols, cellulose cyclodextrins, other derivatives, forms,
mixtures thereof, or the like.
[0192] Glycerols and Propylene Glycols such as: glycerine,
propylene glycol, polypropylene glycol, polypropylene oxides, and
mixtures thereof. Polyethylene Glycol (PEG) such as: PEG 300, PEG
400, PEG 4000, PEG 6000, PEG 8000, PEG 20000, and combinations
thereof.
[0193] Esters such as: ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
epsilon-caprolactone and isomers thereof, delta-valerolactone and
isomers thereof, beta-butyrolactone and isomers thereof; dimethyl
acetamide, dimethyl isosorbide, N-methyl pyrrolidones,
monooctanoin, diethylene glycol monoethyl ether, or the like.
[0194] Bile acids such as: cholate, taurocholate, glycocholate,
deoxycholate, taurodeoxycholate, chenodeoxycholate,
glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate,
ursodeoxycholate, lithocholate, tauroursodeoxycholate,
glycoursodeoxycholate, cholylsarcosine).
[0195] Celluloses such as: microcrystalline cellulose, ethyl
cellulose (EC), methylethyl cellulose (MEC), carboxymethyl
cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl
cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate
(CA), cellulose propionate (CPr), cellulose butyrate (CB),
cellulose acetate butyrate (CAB), cellulose acetate phthalate
(CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl
cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP),
hydroxypropyl methyl cellulose acetate succinate (HPMCAS),
hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and
ethylhydroxy ethylcellulose (EHEC), various grades of low viscosity
(MW less than or equal to 50,000 daltons) and high viscosity (MW
greater than 50,000 daltons) HPMC, and combinations thereof.
[0196] Cellulose Esters such as: Cellulose acetate, Cellulose
Acetate Butyrate, Cellulose acetate phthalate, Hydroxypropyl
methylcellulose phthalate, and combinations thereof.
[0197] Mucoadhesive Polymers such as for example tocopherols such
as for example tocopherol, tocopherol acetate, tocopherol
succinate, and combinations thereof.
[0198] Amino Acids and Modified Amino acids such as: aminoboronic
acid derivatives, n-acetylcysteine, and mixtures thereof.
[0199] Sugars such as: maltose, sucrose, dextrose, lactose,
fructose, mannitol, sucralose, fructalose, trehelose, dextrose,
maltodextrose, and combinations thereof.
[0200] Sugar Alcohols such as: mannitol, xylitol, sorbitol,
combinations thereof, and the like
[0201] Osmotic agents such as: Hydrophilic vinyl and acrylic
polymers, polysaccharides such as calcium alginate, polyethylene
oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG),
poly(2-hydroxyethyl methacrylate), poly(acrylic) acid,
poly(methacrylic) acid, polyvinylpyrrolidone (PVP) and crosslinked
PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP
copolymers with hydrophobic monomers such as methyl methacrylate,
vinyl acetate, and the like, hydrophilic polyurethanes containing
large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl
cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl
methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carbox
cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan
gum, and sodium starch glycolate and the like.
[0202] Other carriers such as: dibasic calcium phosphate,
croscarmellose sodium, sodium starch glycolate, sodium alginate,
phospholipids, lecithins, proteins (e.g., collagen, gelatin, Zein,
gluten, mussel protein, lipoprotein); carbohydrates (e.g.,
alginates, carrageenan, cellulose derivatives, pectin, starch);
gums (e.g., xanthan gum, gum Arabic, gum tragacanth, gum acacia);
spermaceti; natural or synthetic waxes; carnuaba wax; fatty acids
(e.g., stearic acid, hydroxystearic acid); Magnesium stearate,
calcium stearate, titanium dioxide, polyacrylic acid, silicates,
magnesium aluminum silicates, siloxanes, mimeticones, paraffins,
fatty alcohols; dibutyl phthalate; dibutyl sebacate; diethyl
phthalate; dimethyl phthalate; triethyl citrate; butyl and glycol
esters of fatty acids; mineral oil; cetyl alcohol; stearyl alcohol;
camphor oil; triethyl citrate, shellacs, benzalkonium chloride,
methyl paraben, propyl paraben, sodium benzoate and the like.
[0203] In one embodiment, the pharmaceutical composition or oral
dosage form can be formulated to include at least one of the
following preferred carriers: citric acid, maleic acid, tartaric
acid, ascorbic acid, lactic acid, and salts thereof,potassium
hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium
carbonate, silicon dioxide, magnesium aluminum silicate,
triethylamine, fatty acid glycerides, pyrrolidone,
polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol,
propylene glycol, polyethylene glycol, triethylcitrate, triacetin,
benzyl benzoate, bile acid, salts of bile acid, ethyl cellulose,
hydroxypropyl ethyl cellulose, cellulose esters, carbomer,
methacrylates, polyvinyl alcohol, gelatin, distearin,
monopalmitolein tocopherol, tocopherol succinate, corn oil, olive
oil, peanut oil, safflower oil, sesame oil, soybean oil,
hydrogenated castor oil, glyceryl tricaprate, glyceryl
trilinoleate, glyceryl tricaprylate/caprate, glyceryl
tricaprylate/caprate/linoleate, saturated polyglycolized
glycerides, linoleic glycerides, caprylic/capric glycerides, capric
acid, caprylic acid, palmitic acid, Lauric acid, stearic acid,
linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid,
docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate,
glyceryl monolaurate, glycerol monostearate, glyceryl distearate,
glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate,
PEG-6 corn oil, PEG-6 apricot kernel oil, stearoyl macrogol
glyceride, PEG-20 sorbitan monostearate, PEG-40 hydrogenated castor
oil,PEG -35 castor oil, sodium oleate, sodium lauryl sulfate,
sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate,
polyglyceryl-3 oleate, polyglyceryl-10 oleate, polyglyceryl-6
dioleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer
108, poloxamer 182, propylene glycol monocaprylate, propylene
glycol monolaurate, propylene glycol dicaprylate/dicaprate,
propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan
monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan
sesquioleate, sorbitan sesquistearate, maltose, sucrose, fructose,
mannitol, xylitol, and combinations thereof.
[0204] In one embodiment, the pharmaceutical compositions or oral
dosage forms of the present invention can be formulated to include
a hydrophilic additive. In another embodiment, the hydrophilic
additive can be a hydrophilic surfactant. In one embodiment, when
the hydrophilic additive includes a hydrophilic surfactant, the
hydrophilic surfactant does not appreciably solubilize the ester of
17-hydroxyprogesterone. Non-limiting examples of hydrophilic
additives include salts of citric acid, maleic acid, tartaric acid,
acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium
hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium
carbonate, silicon dioxide, magnesium aluminum silicate,
hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile
acids, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl
alcohol, glycerol, propylene glycol, polyethylene glycol methyl
cellulose, hydroxypropyl methyl cellulose, cellulose ssters,
carbomer, chitosan, methacrylates,polyvinyl alcohol, gelatin, PEG-8
caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl
macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor
oil, sodium oleate, sodium lauryl sulfate, sodium lauryl
sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20
oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate,
PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl
oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate,
PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10
mono, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose,
fructose, mannitol, xylitol, and combinations thereof.
[0205] In another particular embodiment, the carrier can include a
hydrophilic surfactant that is an ionic or non-ionic surfactant.
Non-limiting examples of hydrophilic surfactants include proteins,
gelatin, salts of bile acids, PEG-8 caprylic/capric glycerides,
lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40
hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium
lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl
sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate,
PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate,
PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan
laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate,
polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poloxamer
188, poloxamer 108, and combinations thereof.
[0206] In one embodiment, the hydrophilic additive can be free of
hydrophilic surfactants, and can be citric acid, maleic acid,
tartaric acid, acetic acid, ascorbic acid, benzoic acid, lactic
acid, potassium hydroxide, sodium hydroxide, sodium hydrogen
carbonate, calcium carbonate, silicon dioxide, magnesium aluminum
silicate, hydroxypropyl cyclodextrin, pyrrolidone,
polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol,
propylene glycol, polyethylene glycol, methyl cellulose,
hydroxypropyl methyl cellulose, cellulose esters, carbomer,
chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose,
sucrose, fructose, mannitol, xylitol, and combinations thereof.
[0207] In another embodiment, the carrier of the pharmaceutical
compositions or oral dosage forms can include a lipophilic
additive. Non-limiting examples of lipophilic additives include
tributylcitrate, triethylcitrate, triacetin, ethyl cellulose,
cellulose esters, cellulose acetate, cellulose acetates butyrate,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, tocopherol, tocopherol acetate, tocopherol succinate,
corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean
oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl
trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl
tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate,
glyceryl tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, saturated polyglycolized glycerides
linoleic glycerides, caprylic/capric glycerides capric acid,
caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic
acid, oleic acid, arachidonic acid, eicosapentaenoic acid,
docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate,
glyceryl monolaurate, glycerol monostearate, glyceryl distearate,
glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate,
distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn
oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride,
PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate,
polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182,
propylene glycol monocaprylate, propylene glycol monolaurate,
propylene glycol dicaprylate/dicaprate, propylene glycol
caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,
sorbitan sesquistearate, and combinations thereof. In one
embodiment, the carrier of the current invention can include at
least 50 wt % of lipophilic additive.
[0208] In a particular embodiment, the lipophilic additive is at
least one agent selected from tributylcitrate, triethylcitrate,
triacetin, ethyl cellulose, cellulose esters, cellulose acetate,
cellulose acetates butyrate, cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol
acetate, tocopherol succinate, triglycerides, corn oil, olive oil,
peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated
castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl
trioleate, glyceryl trilinoleate, glyceryl tricaprylate/caprate,
glyceryl tricaprylate/caprate/laurate, glyceryl
tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, saturated polyglycolized glycerides
linoleic glycerides, caprylic/capric glycerides, capric acid,
caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic
acid, oleic acid, arachidonic acid, eicosapentaenoic acid,
docosahexaenoic acid, glyceryl distearate, glyceryl
palmitostearate, distearin, tristearin, paraffin oil, bess wax,
animal fat, phytosterol, cholesterol, shellac and combinations
thereof.
[0209] In a particular embodiment, the lipophilic additive is a
triglyceride. Non-limiting examples of triglycerides suitable for
this invention include corn oil, olive oil, peanut oil, palm oil,
coconut oil, arachis oil, safflower oil, sesame oil, soybean oil,
castor oil, primrose oil, cotton seed oil, vegetable oil, borage
oil, linseed oil, flax seed oil, omega oils, partially or fully
hydrogenated castor oil, fish oil, shark oil, whale oil, seal oil,
glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate,
glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl
tricaprylate/caprate/laurate, glyceryl
tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, saturated polyglycolized glycerides
linoleic glycerides, caprylic/capric glycerides, tristearin and the
like, and combinations thereof
[0210] In one embodiment, the lipophilic additive can be free of
lipophilic surfactants. In one particular embodiment, the carrier
is a lipophilic surfactant. Non-limiting examples of lipophilic
surfactants suitable for this invention include tributylcitrate,
triethylcitrate, triacetin, ethyl cellulose, cellulose esters,
cellulose acetate, cellulose acetates butyrate, benzyl benzoate,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, tocopherol, tocopherol acetate, tocopherol succinate,
corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean
oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl
trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl
tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate,
glyceryl tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, saturated polyglycolized glycerides
linoleic glycerides, caprylic/capric glycerides capric acid,
caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic
acid, oleic acid, arachidonic acid, eicosapentaenoic acid,
docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate,
glyceryl monolaurate, glycerol monostearate, glyceryl distearate,
glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate,
distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn
oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride,
PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate,
polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182,
propylene glycol monocaprylate, propylene glycol monolaurate,
propylene glycol dicaprylate/dicaprate, propylene glycol
caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,
sorbitan sesquistearate, and combinations thereof.
[0211] In another particular embodiment, the compositions or dosage
form of the present invention can be free of triglycerides, or
substantially free of triglycerides. Thus, in one embodiment, the
present invention does not include lipophilic or hydrophilic
additive, which contain triglycerides as an intended or added
component. However, it should be appreciated that the present
invention does not exclude the use of lipophilic or hydrophilic
additives, which contain small amounts of triglycerides as
impurities or as unreacted starting material. It is expected that
when such lipophilic or hydrophilic additive is used in the
compositions of the present invention, the total triglyceride
content does not exceed 5% by weight of the composition or dosage
form. Thus, "substantially triglyceride-free" should be understood
as meaning free of added triglycerides, and the triglyceride
impurity from the lipophilic or hydrophilic additives constitute
about 5%, or less than 5%, less than 2%, or preferably 0%
(triglyceride free), by weight of the composition. Further, the
present invention does not exclude lipophilic or hydrophilic
additives that are derivatives of triglycerides, such as for
example polyethylene glycol or propylene glyocol derivatives of
triglycerides; while these derivatized triglycerides may have
surfactant properties, the triglycerides are not surfactants by
themselves.
[0212] Non-limiting examples of such lipophilic additives include
tributylcitrate, triethylcitrate, triacetin, ethyl cellulose,
cellulose esters, cellulose acetate, cellulose acetates butyrate,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, tocopherol, tocopherol acetate, tocopherol succinate,
saturated polyglycolized glycerides linoleic glycerides,
caprylic/capric glycerides capric acid, caprylic acid, palmitic
acid, lauric acid, stearic acid, linoleic acid, oleic acid,
arachidonic acid, eicosapentaenoic acid, benzyl benzoate,
docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate,
glyceryl monolaurate, glycerol monostearate, glyceryl distearate,
glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate,
distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn
oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride,
PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate,
polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182,
propylene glycol monocaprylate, propylene glycol monolaurate,
propylene glycol dicaprylate/dicaprate, propylene glycol
caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,
sorbitan sesquistearate, and combinations thereof.
[0213] In some embodiments, the carrier of the current invention
can include a control release agent. In a particular embodiment,
the control release agent can be selected from the group consisting
of the said hydrophilic additives or lipophilic additives or a
mixture thereof. In another particular embodiment, the compositions
or dosage forms of the present invention can be free of lipophilic
surfactant. In another particular embodiment, the compositions or
dosage form of the present invention can be free of lipophilic
additive.
[0214] As discussed above, in some embodiments, the pharmaceutical
compositions and the oral dosage forms of the present disclosure
can include at least one hydrophilic additive and at least one
lipophilic additive. In one embodiment, when both a hydrophilic
additive and a lipophilic additive are present, they can be present
at a lipophilic additive to hydrophilic additive ratio of about
99:1 to about 1:99. In one embodiment, the lipophilic additive to
hydrophilic additive ratio can be about 95:5 to about 5:95. In
another embodiment, the lipophilic additive to hydrophilic additive
ratio can be about 90:10 to about 10:90. In one embodiment, the
lipophilic additive to hydrophilic additive ratio can be of about
90:10 to about 1:99. In another specific embodiment, the lipophilic
additive to hydrophilic additive ratio can be of about 80:20 to
about 20:80. In another specific embodiment, the lipophilic
additive to hydrophilic additive ratio can be of about 70:30 to
about 30:70. In another specific embodiment, the lipophilic
additive to hydrophilic additive ratio can be of about 60:40 to
about 40:60. In another specific embodiment, the lipophilic
additive to hydrophilic additive ratio can be about 50:50.
[0215] In an additional embodiment, when both a hydrophilic
surfactant and a lipophilic additive are present, they can be
present in amounts such that when 1 part by weight of the mixture
of the hydrophilic surfactant and lipophilic additive is mixed 99
parts of an aqueous diluent, the dispersion so obtained so obtained
can be colloidal, hazy or unclear. For example, the aqueous diluent
used for dispersion is either water or 0.5% w/v sodium lauryl
sulfate in water. In a specific embodiment, the dispersion can
exhibit an absorbance greater than 0.1 when determined using a
spectrophotometer at 400 nm. In another specific embodiment, the
absorbance is greater than 0.3 at 400 nm. In another embodiment,
the mean particle size of the dispersion is about 60 nm or more. In
another specific embodiment, the mean particle size of the
dispersion is about 100 nm or more. In another specific embodiment,
the mean particle size of the dispersion is about 150 nm or more.
In yet another specific embodiment, the mean particle size of the
dispersion is about 200 nm or more. In yet another specific
embodiment, the mean particle size of the dispersion is about 250
nm or more. For example, the aqueous diluent used for dispersion is
either water or 0.5% w/v sodium lauryl sulfate in water. For the
purpose of this invention, the dispersion is deemed clear if it
appears clear to the naked eye. In one embodiment, the dispersion
can be clear.
[0216] In one embodiment, the carrier can be present in an amount
sufficient to solubilize the ester of 17 hydroxyprogesterone. In
some aspects, the carrier of the present invention aids in
solubilizing a significant amount of the ester of
17-hydroxyprogesterone in the composition. In one embodiment, the
carrier can solubilize 20 wt % or more of the amount of the ester
of 17-hydrxoyprogesterone. In another embodiment, the carrier can
aid loading of greater than about 10% w/w of the ester in the
composition and/or dosage form. In another embodiment, the loading
achieved by the carrier can be greater than about 12% w/w of the
composition and/or dosage form. In another embodiment, the loading
achieved by the carrier can be greater than about 15% w/w of the
composition and/or dosage form. In another embodiment, the loading
attained by inclusion of the carrier can be greater than about 18%
w/w of the composition and/or dosage form. In further embodiments,
the loading attained by inclusion of the carrier can be greater
than about 20%; greater than about 25%, greater than about 30%,
greater than about 35%, greater than about 40%, greater than about
50%, greater than about 60%, greater than about 75%, or greater
than about 90%, with each percentage based on w/w of the
composition and/or dosage form.
[0217] In one embodiment, the carrier can include benzyl alcohol,
benzyl benzoate, mixtures thereof. In another embodiment, the
carrier can include benzyl alcohol, benzyl benzoate, or mixtures
thereof and the amount of the ester of 17-hydroxyprogesterone can
be between about 5 to about 80% w/w of the total composition. In
one embodiment, when the carrier includes benzyl alcohol, benzyl
benzoate, or mixtures thereof, the amount of the ester of
17-hydroxyprogesterone can be between about 5 to about 80% w/w of
the total composition. In one embodiment, the amount of the ester
of 17-hydroxyprogesterone can be between 5% to about 60% w/w of the
total composition. In another specific embodiment, when the carrier
includes benzyl alcohol, benzyl benzoate, or mixtures thereof, the
amount of the ester of 17-hydroxyprogesterone can be between about
5 to about 40% w/w of the total composition. In another specific
embodiment, when the carrier includes benzyl alcohol, benzyl
benzoate, or mixtures thereof, the amount of the ester of
17-hydroxyprogesterone can be between about 5 to about 30% w/w of
the total composition. In another specific embodiment, when the
carrier includes benzyl alcohol, benzyl benzoate, or mixtures
thereof, the amount of the ester of 17-hydroxyprogesterone can be
between about 5 to about 25% w/w of the total composition. In one
specific embodiment, when the carrier includes benzyl alcohol,
benzyl benzoate, or mixtures thereof, the ester of
17-hydroxyprogesterone can be fully solubilized in the composition
and/or the dosage form. In another specific embodiment, the ester
of 17-hydroxyprogesterone can be partially solubilized in the
dosage form. In another specific embodiment, the ester of
17-hydroxyprogesterone can be 17-hydroxyprogesterone caproate.
[0218] In one embodiment the ratio of the amount of the ester of
17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol
and benzyl benzoate present in the composition or oral dosage form
can be about 1:0.01 (W/W) to about 1:5 (W/W). In another
embodiment, the ratio can be about 1:0.01 (W/W) to about 1:3.5
(W/W). In another embodiment, the ratio of the amount of the ester
of 17-hydroxyprogesterone to the sum of the amounts of benzyl
alcohol and benzyl benzoate present in the composition or oral
dosage form can be about 1:0.01 (W/W) to about 1:2.5 (W/W). In
another embodiment, the ratio of the amount of the ester of
17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol
and benzyl benzoate present in the composition or oral dosage form
can be about 1:0.01 to about 1:2 (W/W).
[0219] In one embodiment, the pharmaceutical composition or unit
dosage form described herein having an ester of
17-alpha-hydroxyprogesterone is particle size physically stable.
The term "particle size physically stable" means that, on storage,
there is no evidence of substantial particle growth or
agglomeration of the API particles. Substantial particle growth or
agglomeration refers to an increase in particle size of greater
than 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, or 300%. One
particular apparatus that can be used is the Sympatec Dry
Dispersion Size Analyser. The term "particle agglomeration
inhibitor" refers to agents, which are used to stabilize an API in
order to reduce or prevent the API from agglomerating or
aggregating. A stabilizing agent generally reduces the cohesion
between particles and prevents fine particles becoming attached to
each other. Stabilizing agents include metal stearates such as
magnesium stearate and calcium stearate, ionic and non-ionic
surfactants, and polymers such as cellulose ethers, PVP or PVA.
Typically, a particle agglomeration inhibitor can be included in an
amount to provide particle size stability.
[0220] Other particle agglomeration inhibitors, include, but are
not limited to, povidone, crosslinked PVP (crospovidone), cross
linked carmellose (croscarmellose), sodium starch glycolate,
Povidone (PVP), Povidone K12, Povidone K17, Povidone K25, Povidone
K29/32 and Povidone K30, stearic acid, magnesium stearate, calcium
stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc
stearate, sodium stearate or lithium stearate, other solid state
fatty acids such as oleic acid, lauric acid, palmitic acid, erucic
acid, behenic acid, or derivatives (such as esters and salts),
Amino acids such as leucine, isoleucine, lysine, valine,
methionine, phenylalanine, aspartame or acesulfame K.
[0221] In one embodiment, the pharmaceutical composition or unit
dosage form described herein having an ester of
17-alpha-hydroxyprogesterone is crystallization stable. The term
"crystallization stable" means that, on storage, there is no
evidence of substantial crystallization of the API particles.
Substantial crystallization refers to an increase in crystalline
particle size of greater than 10%, 20%, 30%, 40%, 50%, 75%, 100%,
150%, 200%, or 300%. In one aspect, the pharmaceutical composition
or unit dosage form described herein having an ester of
17-alpha-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) has a crystallization inhibitor. The term
"crystallization inhibitor," as used herein, means an agent that
facilitates prevention of crystallization of the API. Examples of
crystallization inhibitors include, but are not limited to
polyvinylpyrrolidone (PVP or povidone), including homo- and
copolymers of polyvinylpyrrolidone and homopolymers or copolymers
of N-vinylpyrrolidone; crospovidone; gums; cellulose derivatives
(e.g., HPMC polymers, hydroxypropyl cellulose, ethyl cellulose,
hydroxyethylcellulose, sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, sodium carboxymethyl cellulose); dextran;
acacia; homo- and copolymers of vinyllactam, and mixtures thereof;
cyclodextrins; gelatins; hypromellose phthalate; sugars; sugar
alcohols including mannitol; polyhydric alcohols; polyethylene
glycol (PEG); polyethylene oxides; polyoxyethylene derivatives;
polyvinyl alcohol; propylene glycol derivatives and the like, SLS,
Tweens, Eudragits (methacrylic acid copolymers); and combinations
thereof; amino acids such as prolin.Included herein are methods of
manufacturing pharmaceutical composition that reduce API particle
agglomeration or crystallization. Such methods include co-milling,
co-micronization, co-nanosizing, and/or solid solution.
[0222] The pharmaceutical compositions and oral dosage forms can be
formulated and delivered in a variety of solid or liquid dosage
forms. Non-limiting examples of such dosage forms include powder,
granulate, particulate, bead, pellet, sprinkle, suspension,
solution, tablet, capsule, and combinations thereof. In one
embodiment, the pharmaceutical composition or oral dosage form can
be in the form of a capsule. In another embodiment, the
pharmaceutical composition or oral dosage form can be in the form
of a tablet. In one embodiment, the dosage form is a hard or a soft
capsule. The capsule can be made of conventional capsule shell
materials known in the art; such materials can include, but are not
limited to gelatins, celluloses, starches, methacrylates,
carrageenans, polyvinyl alcohols, and the like. In another
embodiment, the capsule is an immediate release dosage form. In yet
another embodiment, the capsule is a controlled release dosage
form. In another embodiment, the tablet is an immediate release
dosage form. In another embodiment, the tablet is a controlled
release dosage form.
[0223] In one embodiment, the volume of the capsule can be about
1.5 mL or less. In another embodiment, the volume of capsule can be
about 1.2 mL or less. In one particular embodiment, the volume of
the capsule can be about 0.8 mL or less. In another embodiment, the
ratio of the weight of fill material encapsulated within the
capsule to the capsule volume can be between about 0.3 g/mL to
about 3.5 g/mL. In a particular embodiment, the ratio can be
between 0.6 g/mL to about 2.5 g/mL. In another particular
embodiment, the ratio can be between 0.6 g/mL to about 1.2
g/mL.
[0224] In another embodiment, the pharmaceutical capsule oral
dosage form of the current invention can have a ratio of the amount
of the ester of 17-hydroxyprogesterone in the composition to the
fill volume of the capsule between about 0.02 g/mL to about 0.8
g/mL. In another embodiment, the ratio can be between about 0.02
g/mL to about 0.7 g/mL. In a specific embodiment, the ratio can be
between about 0.02 g/mL to about 0.5 g/mL. In another specific
embodiment, the ratio can be between about 0.05 g/mL to about 0.5
g/mL. In another specific embodiment, the ratio can be between
about 0.05 g/mL to about 0.35 g/mL. In another specific embodiment,
the ratio can be between about 0.05 g/mL to about 0.3 g/mL. In
another specific embodiment, the ratio can be between about 0.1
g/mL to about 0.25 g/mL.
[0225] The oral dosage forms of the present invention can be
formulated to include an amount of an ester of
17-hydroxyprogesterone equivalent to about 10 mg to about 800 mg of
17-hydroxyprogesterone. In one embodiment, the oral dosage form can
be formulated to include an amount of ester of
17-hydroxyprogesterone equivalent to 20 mg to about 400 mg of
17-hydroxyprogesterone. The pharmaceutical composition and oral
dosage forms of the present invention can be formulated to be
administered to a subject in order to provide a daily dose of the
ester of 17-hydroxyprogesterone that is equivalent to about 40 mg
to about 3200 mg of 17-hydroxyprogesterone. In one embodiment, the
oral dosage form can be a capsule and the capsule includes from
about 10 mg to about 300 mg17-hydroxyprogesterone caproate. In
another embodiment, the oral dosage form can be a tablet and the
tablet includes from about 20 mg to about 800 mg of
17-hydroxyprogesterone caproate. In another embodiment, the oral
dosage form includes from about 20 mg to about 1200 mg of
17-hydroxyprogesterone caproate. In another embodiment, the oral
dosage form can be a tablet and the tablet includes from about 100
mg to about 1000 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 200 mg to
about 900 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 300 mg to
about 900 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 350 mg to
about 800 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 400 mg to
about 800 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 100 mg to
about 400 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 150 mg to
about 350 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 200 mg to
about 375 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 200 mg to
about 475 mg of 17-hydroxyprogesterone caproate. In another
embodiment, the oral dosage form includes from about 525 mg to
about 850 mg of 17-hydroxyprogesterone caproate. In order to
provide a desired daily dose, the pharmaceutical compositions and
oral dosage forms can be formulated to be administered at various
dosing intervals. In one embodiment, the compositions or oral
dosage forms can be formulated for administration about once every
8 hours. In one embodiment, the compositions or oral dosage forms
can be formulated for administration about three times a day. In
another embodiment, the compositions or oral dosage forms can be
formulated for administration to a subject, such as a human
subject, once every 6 hours. In one embodiment, the compositions or
oral dosage forms can be formulated for administration about four
times a day. In another embodiment, the compositions or oral dosage
forms can be formulated for administration about once every 12
hours. In one embodiment, the compositions or oral dosage forms can
be formulated for administration about two times a day. In yet a
further embodiment, the compositions or oral dosage forms can be
formulated for administration about once every 24 hours. In one
embodiment, the compositions or oral dosage forms can be formulated
for administration about once a day. The amount of 17 HPC per
dosage form are as provided in the previous paragraph which can be
administered as one, two, three, or four unit dosage forms per dose
(e.g., each time).
[0226] In one embodiment, the oral pharmaceutical compositions
comprising 17 HPC and a pharmaceutically acceptable carrier when
used to treat a female for one or more of the conditions described
herein yields improved efficacy as compared to administration of
placebo.
[0227] In one aspect, the oral dosage forms of the present
invention can be used to treat pregnant female subjects who are at
risk of preterm birth. The methods of treatment include the step of
orally administering to the female subject the oral pharmaceutical
composition. In another embodiment, the oral dosage forms can be
administered to subjects in need thereof.The administration of the
oral dosage form can treat at least one condition selected from
preterm labor, preterm birth, infertility and miscarriage. In one
embodiment, the subject receiving administration of the
pharmaceutical composition or oral dosage form can be experiencing
or be at risk of at least two of: singleton pregnancy, history of
preterm labor and/or preterm birth, history of preterm delivery,
shortened cervix, and effaced cervix, history of more at least one
miscarriage, and history of multifetal gestation. The conditions
and the relative treatment can be based on their primary and
secondary outcome measurements associated with the administration
of the ester of 17-hydroxyprogesterone.
[0228] In one embodiment, upon single administration to a human
subject, the pharmaceutical compositions or oral dosage forms of
the present invention comprising an ester of 17-hydroxyprogesterone
can provide a 17-hydroxyprogesterone equivalent C.sub.avg-24h
greater than about 0.7 ng/mL. In another embodiment, the oral
dosage form or the composition can provide a C.sub.avg-24h of
17-hydroxyprogesterone equivalent greater than about 10 ng/mL. In
another embodiment, the oral dosage form or the composition can
provide a C.sub.avg-24h of 17-hydroxyprogesterone equivalent
greater than about 30 ng/mL. In another embodiment, the oral dosage
form or the composition can provide a C.sub.avg-24h of
17-hydroxyprogesterone equivalent greater than about 50 ng/mL. In
yet a further embodiment, the oral dosage form or the composition
can provide a C.sub.avg-24h of 17-hydroxyprogesterone equivalent
greater than about 100 ng/mL. In one embodiment, the said
17-hydroxyprogesterone equivalent C.sub.avg-24h is determined by an
HPLC-MS/MS method of analysis of the plasma, serum or blood samples
collected following the oral administration.
[0229] In one embodiment, upon single administration to a human
subject, the pharmaceutical compositions or oral dosage forms of
the present invention comprising an ester of 17-hydroxyprogesterone
can provide a 17-hydroxyprogesterone equivalent C.sub.avg-24h
greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 1. 2.0, 3.0, 5.0,
10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0 or 75.0
ng/mL (or within a range defined by any two of these values). In
one embodiment, the said 17-hydroxyprogesterone equivalent
C.sub.avg-24h is determined by an HPLC-MS/MS method of analysis of
the plasma, serum or blood samples collected following the oral
administration.
[0230] In one embodiment, upon single administration to a human
subject the pharmaceutical compositions or oral dosage forms of the
present invention comprising 17-hydroxyprogesterone caproate, can
provide a 17-hydroxyprogesterone caproate C.sub.avg-24h equal to
about 1.0 ng/mL or more. In another embodiment, the oral dosage
form or the composition can provide a 17-hydroxyprogesterone
caproate C.sub.avg-24h equal to about 20 ng/mL or more. In another
embodiment, the oral dosage form or the composition can provide a
17-hydroxyprogesterone caproate C.sub.avg-24h equal to about 50
ng/mL or more. In another embodiment, the oral dosage form or the
composition can provide a 17-hydroxyprogesterone caproate
C.sub.avg-24h equal to about 100 ng/mL or more. In one embodiment,
the said 17-hydroxyprogesterone caproate C.sub.avg-24h is
determined by an HPLC-MS/MS method of analysis of the plasma, serum
or blood samples collected following the oral administration.
[0231] In one embodiment, upon single administration to a human
subject the pharmaceutical compositions or oral dosage forms of the
present invention comprising 17-hydroxyprogesterone caproate, can
provide a 17-hydroxyprogesterone caproate C.sub.avg-24h greater
than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0,
15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0 or 75.0 ng/mL
(or within a range defined by any two of these values). In one
embodiment, the said 17-hydroxyprogesterone caproate C.sub.avg-24h
is determined by an HPLC-MS/MS method of analysis of the plasma,
serum or blood samples collected following the oral
administration.
[0232] It was surprisingly found that the compositions and/or
dosage forms of this invention provided significantly enhanced
bioavailability of 17-hydroxyprogesterone caproate as a function of
the oral dose of the 17 hydroxyprogesterone caproate administered
to a subject. Accordingly, the compositions or dosage forms of this
invention provide, upon single dose oral administration, an
AUC.sub.(0-24h) to dose ratio of about 10 or less, wherein the dose
is the amount in mg of the 17-hydroxyprogesterone caproate
administered. In one embodiment, the ratio of the
17-hydroxyprogesterone caproate AUC.sub.(0-24h) to dose of the
17-hydroxyprogesterone caproate administered can be about 0.2 ng*h
mL.sup.-1 mg.sup.-1 to about 10 ng*h mL.sup.-1 mg.sup.-1. In
another embodiment, the ratio of the 17-hydroxyprogesterone
caproate AUC.sub.(0-24h) to dose of the 17-hydroxyprogesterone
caproate administered can be about 0.3 ng*h mL.sup.-1 mg.sup.-1 to
about 7 ng*h mL.sup.-1 mg.sup.-1. In a specific embodiment, the
AUC.sub.(0-24h) to dose ratio is between about 0.5 and about 6 ng*h
mL.sup.-1 mg.sup.-1.
[0233] In another embodiment, in one aspect the compositions or
dosage forms of this invention provide, upon single dose oral
administration, an AUC.sub.(0-24h) to dose ratio of less than 10,
9, 8, 7, 6, 5, 4, 3, 2, or 1 , wherein the dose is the amount in mg
of the 17-hydroxyprogesterone caproate administered. In another
aspect the compositions or dosage forms of this invention provide,
upon single dose oral administration, an AUC.sub.(0-24h) to dose
ratio of greater than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1.75, 1.5, 1.25,
1 or 0.5, wherein the dose is the amount in mg of the
17-hydroxyprogesterone caproate administered. In one embodiment,
the ratio of the 17-hydroxyprogesterone caproate AUC.sub.(0-24h) to
dose of the 17-hydroxyprogesterone caproate administered can be
about 0.01 ng*h mL.sup.-1 mg.sup.-1 to about 5.0 ng*h mL.sup.-1
mg.sup.-1. In another embodiment, the ratio of the
17-hydroxyprogesterone caproate AUC.sub.(0-24h) to dose of the
17-hydroxyprogesterone caproate administered can be about 0.05 ng*h
mL.sup.-1 mg.sup.-1 to about 3.0 ng*h mL.sup.-1 mg.sup.-1. In a
specific embodiment, the AUC.sub.(0-24h) to dose ratio is between
about 0.1 and about 2.0 ng*h mL.sup.-1 mg.sup.-1. In a specific
embodiment, the AUC.sub.(0-24h) to dose ratio is between about 0.1
and about 1.5 ng*h mL.sup.-1 mg.sup.-1. In a specific embodiment,
the AUC.sub.(0-24h) to dose ratio is between about 0.1 and about
1.0 ng*h mL.sup.-1 mg.sup.-1. In a specific embodiment, the
AUC.sub.(0-24h) to dose ratio is between about 1.5 and about 10.0
ng*h mL.sup.-1 mg.sup.-1. In a specific embodiment, the
AUC.sub.(0-24h) to dose ratio is between about 2.0 and about 10.0
ng*h mL.sup.-1 mg.sup.-1. In a specific embodiment, the AUC
.sub.(0-24h) to dose ratio is between about 3.0 and about 10.0 ng*h
mL.sup.-1 mg.sup.-1. In a specific embodiment, the AUC .sub.(0-24h)
to dose ratio is between about 4.0 and about 10.0 ng*h mL.sup.-1
mg.sup.-1. In a specific embodiment, the AUC .sub.(0-24h) to dose
ratio is between about 5.0 and about 10.0 ng*h mL.sup.-1 mg.sup.-1.
In a specific embodiment, the AUC .sub.(0-24h) to dose ratio is
between about 6.0 and about 10.0 ng*h mL.sup.-1 mg.sup.-1. In a
specific embodiment, the AUC .sub.(0-24h) to dose ratio is between
about 7.0 and about 10.0 ng*h mL.sup.-1 mg.sup.-1.
[0234] In one embodiment, an oral dosage form having
17-hydroxyprogesterone caproate, upon single dose administration to
a human provides at least 10% of the bioavailability of an
intramuscular injection of 17-hydroxyprogesterone caproate (e.g.,
250 mg of 17-hydroxyprogesterone caproate in castor oil (1 or 5 mL)
with or without benzyl alcohol or benzyl benzoate.)
[0235] In a specific embodiment, upon single administration of the
pharmaceutical compositions or oral dosage forms containing
17-hydroxyprogesterone caproate of the present invention to a human
subject under fed conditions, the oral dosage form or
pharmaceutical composition can provide a 17-hydroxyprogesterone
caproate C.sub.avg-24h of greater than about 1.0 ng/mL. In another
specific embodiment, the pharmaceutical compositions or oral dosage
forms containing 17-hydroxyprogesterone of the present invention
can provide a steady state 17-hydroxyprogesterone caproate
C.sub.avg-24h of greater than about 1.0 ng/mL, when administered to
a human subject under fed condition. In one embodiment, the said
C.sub.avg-24h is determined by an HPLC-MS/MS method of analysis of
the plasma, serum or blood samples collected following the
administration. In another embodiment, the compositions and oral
dosage forms disclosed herein can be orally administered with food
or without regards to the food or food content. In a specific
embodiment, the compositions and oral dosage forms containing
caproate ester of 17-hydroxyprogesterone as disclosed herein can be
orally administered with food or without regards to the food or
food content.
[0236] In another specific embodiment, the pharmaceutical
compositions or oral dosage forms containing 17-hydroxyprogesterone
of the present invention can provide a steady state
17-hydroxyprogesterone caproate C.sub.avg-24h of greater than about
0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0, 15.0, 20.0,
25.0, 30.0, 35.0, 40.0, 45.0, 50.0, 60.0 or 75.0 ng/mL, when
administered to a human subject under fed conditions (or within a
range defined by any two of these values).
[0237] In one embodiment, the oral dosage form can be orally
administered with food or under fed condition. In another
embodiment, the composition or oral dosage form can be administered
with a normal or standard meal. In a specific embodiment, the
composition or oral dosage form can be administered with a food or
meal, such as a meal that provides about 200 calories to about 1000
calories of energy. In another specific 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
3 g to about 50 g of fat. In yet a further embodiment, the meal can
provide 10 g to about 50 g of fat. In yet another embodiment, the
meal can provide about 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. In another embodiment, when
administering the oral dosage form, the total daily dose of the
ester of 17 HP administered to human female subject with food or
under fed condition is from about 20% to about 80% of the total
daily dose administered without meals, for a similar therapeutic
benefit. In a specific embodiment, the daily dose under fed
condition is from about 20% to about 60% of the total daily dose
administered without meals, for a similar therapeutic benefit. In
another embodiment, the composition or oral dosage form can be
administered without food or under fasted condition.
[0238] The oral bioavailability of the ester of
17-hydroxyprogesterone can be enhanced by using the said ester in
the form of fine particulate, for example milled, micronized or
nanosized etc, in the composition and/or the dosage form of the
current invention. Further, the oral bioavailability can be
enhanced by using the ester along with a carrier that aids the
release of at least 20% more of the ester from the composition or
dosage form when exposed to an aqueous medium compared to an
equivalent dose of the ester without the carrier of the current
invention. In a specific embodiment the oral bioavailability of the
caproate ester of 17-hydroxyprogesterone can be enhanced by using
the said ester in the form of fine particulate, for example milled,
micronized or nanosized or combinations thereof in the composition
and/or the dosage form of the current invention.
[0239] Accordingly, in one embodiment, the oral bioavailability of
the ester of 17-hydroxyprogesterone is at least 10% more for the
compositions or a dosage forms of the current invention that
releases at least 20% of the ester in an aqueous medium compared to
an equivalent dose of the ester present in an "untreated"
particulate form such as for example as unmilled or unmicronized
particulate forms. In another embodiment, the oral bioavailability
of the ester of 17-hydroxyprogesterone is at least 10% more for the
compositions or a dosage forms of the current invention that
releases at least 20% more of the ester from the composition or
dosage form when exposed to an aqueous medium compared to an
equivalent dose of the ester without the carrier of the current
invention. In a specific embodiment, the said ester is
17-hydroxyprogesterone caproate.
[0240] The ester of 17-hydroxyprogesterone can be a substrate to
the P-glycoproteins (P-gp) the efflux transporter systems. Hence,
in one embodiment, the oral bioavailability can be enhanced by at
least 10% by co-administering the ester of 17-hydroxyprogesterone
of the current invention with an effective amount of P-gp and/or
CYP3A4 inhibiting agents e.g., star fruit, grape fruit juice,
bergamottin, cafestol (as in unfiltered coffee), ketoconazole,
erythromycin, mibefradil, loperamide etc.
[0241] In a further aspect, the oral pharmaceutical compositions or
the oral dosage forms of the ester of 17-hydroxyprogesterone
according to the current invention can be used for providing luteal
support for a subject in need thereof. In one embodiment, the oral
composition or the oral dosage form can be formulated to enable
modulation or titration of the dose and/or dosing regimen of the
ester of 17-hydroxyprogesterone for providing effective luteal
support to a subject in need thereof. In one particular embodiment,
the dose of the ester of 17-hydroxyprogesterone in the form of oral
compositions or dosage forms of the present invention may be
modulated or titrated to provide effective luteal support as needed
at the during early pregnancy. In another particular embodiment,
the dose of the ester of 17-hydroxyprogesterone in the form of oral
compositions or dosage forms of the present invention may be
modulated or titrated to provide effective luteal support as needed
based on the body mass index (BMI) of the subject. In another
particular embodiment, the dose of the ester of
17-hydroxyprogesterone in the form of oral compositions or dosage
forms of the present invention may be modulated or titrated to
provide effective luteal support as needed based on the race or
ethnicity of the subject.
[0242] An example of the dose modulation or titration can be based
on the total dose per day, and can include administration of a
higher initial loading dose or bolus dose, followed by a lower
effective standard dose. Similarly, the dose modulation or
titration can be based on the total dose per week and can include
administration of a higher initial loading dose or bolus dose in
the initial days of the week followed by a lower effective standard
dose in the later days of the week. The dosing regimen can include
ramping up of (i.e. progressive increments) the daily dose in
accordance with the progression of pregnancy. In a specific
embodiment the ester is 17-hydroxyprogesterone caproate.
[0243] In another embodiment, the daily oral dose administered with
food of 17-hydroxyprogesterone caproate is from about 40 mg to
about 5000 mg. In another embodiment, the daily oral dose is from
about 40 mg to about 4000 mg. In another embodiment, the daily oral
dose is from about 80 mg to about 4000 mg. In another embodiment,
the daily oral dose is from about 150 mg to about 4000 mg. In
another embodiment, the daily oral dose is from about 250 mg to
about 4000 mg. In another embodiment, the daily oral dose of is
from about 500 mg to about 4000 mg. In another embodiment, the
daily oral dose is from about 750 mg to about 4000 mg. In another
embodiment, the daily oral dose is from about 1000 mg to about 4000
mg. In another embodiment, the daily oral dose is from about 1200
mg to about 4000 mg. In another embodiment, the daily oral dose is
from about 1500 mg to about 4000 mg. In another embodiment, the
daily oral dose is from about 1500 mg to about 3000 mg. In another
embodiment, the daily oral dose is from about 1000 mg to about 2000
mg. In another embodiment, the daily oral dose is from about 200 mg
to about 2000 mg. In another embodiment, the daily oral dose is
from about 400 mg to about 2000 mg. In another embodiment, the
daily oral dose is from about 800 mg to about 2000 mg.
[0244] In yet another embodiment, the total daily dose of 17 HPC
administered to a human subject in milligrams is about 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,
125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,
138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,
190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,
203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215,
216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,
229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280,
281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,
294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,
307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,
320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332,
333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345,
346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,
359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371,
372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384,
385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397,
398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410,
411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423,
424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436,
437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,
450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462,
463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475,
476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488,
489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501,
502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514,
515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527,
528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,
541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553,
554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566,
567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,
580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592,
593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605,
606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618,
619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631,
632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644,
645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657,
658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670,
671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,
684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696,
697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709,
710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722,
723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735,
736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,
749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761,
762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774,
775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787,
788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800,
801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813,
814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826,
827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839,
840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852,
853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865,
866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878,
879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891,
892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904,
905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917,
918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930,
931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943,
944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956,
957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969,
970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982,
983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995,
996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007,
1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018,
1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029,
1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040,
1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051,
1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062,
1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073,
1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084,
1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,
1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106,
1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117,
1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,
1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139,
1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150,
1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161,
1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172,
1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183,
1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194,
1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205,
1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216,
1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227,
1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238,
1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249,
1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260,
1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271,
1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282,
1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293,
1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304,
1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315,
1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326,
1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337,
1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348,
1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359,
1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370,
1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381,
1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392,
1393, 1394, 1395, 1396, 1397, 1398, 1399, or 1400 (or within a
range defined by any two of these values). According to one aspect
of this embodiment, the 17 HPC is administered one, two or three
times a day as one, two, three or four unit dosage forms (e.g., up
to 12 unit dosage forms per day) to yield the total daily dose
provided in this paragraph. In some aspects, the total daily dose
can provide a 17-hydroxyprogesterone caproate C.sub.avg-24h of
greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human
subject (female or pregnant female) once, twice or three times
daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms. In one
aspect, the daily dose is from 525 mg per day to about 1400 mg per
day. In one aspect, the daily dose is from 800 mg per day to about
1400 mg per day. In one aspect, the daily dose is from 900 mg per
day to about 1200 mg per day. According to one aspect of this
embodiment, the daily dose is provided by one or more unit dosage
form, which is a tablet, capsule, solution, suspension, or sprinkle
for oral administration. According to one aspect of this
embodiment, the unit dosage form has a surfactant e.g., at least 1,
2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic
surfactant. According to another aspect of this embodiment, the
unit dosage form has one or more of (1) a lipophilic additive, (2)
a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6)
one or more other pharmaceutically acceptable excipients. According
to one aspect of this embodiment, the unit dosage form has a
lipophilic additive, binder, a diluent, a disintegrant or a
combination thereof individually or together in an amount of e.g.,
at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or
within a range defined by any two of these values.)
[0245] In yet another embodiment, the total daily dose of 17 HPC
administered to a human subject in milligrams is about 500, 501,
502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514,
515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527,
528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,
541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553,
554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566,
567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,
580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592,
593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605,
606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618,
619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631,
632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644,
645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657,
658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670,
671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,
684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696,
697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709,
710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722,
723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735,
736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,
749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761,
762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774,
775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787,
788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800,
801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813,
814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826,
827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839,
840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852,
853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865,
866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878,
879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891,
892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904,
905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917,
918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930,
931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943,
944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956,
957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969,
970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982,
983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995,
996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007,
1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018,
1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029,
1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040,
1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051,
1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062,
1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073,
1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084,
1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,
1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106,
1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117,
1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,
1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139,
1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150,
1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161,
1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172,
1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183,
1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194,
1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205,
1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216,
1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227,
1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238,
1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249,
1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260,
1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271,
1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282,
1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293,
1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304,
1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315,
1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326,
1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337,
1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348,
1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359,
1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370,
1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381,
1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392,
1393, 1394, 1395, 1396, 1397, 1398, 1399, or 1400 (or within a
range defined by any two of these values). According to one aspect
of this embodiment, the 17 HPC is administered one, two or three
times a day as one, two, three or four unit dosage forms (e.g., up
to 12 unit dosage forms per day) to yield the total daily dose
provided in this paragraph. In some aspects, the total daily dose
can provide a 17-hydroxyprogesterone caproate C.sub.avg-24h of
greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human
subject (female or pregnant female) once, twice or three times
daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms. In one
aspect, the daily dose is from 525 mg per day to about 1400 mg per
day. In one aspect, the daily dose is from 800 mg per day to about
1400 mg per day. In one aspect, the daily dose is from 900 mg per
day to about 1200 mg per day. According to one aspect of this
embodiment, the daily dose is provided by one or more unit dosage
form, which is a tablet, capsule, solution, suspension, or sprinkle
for oral administration. According to one aspect of this
embodiment, the unit dosage form has a surfactant e.g., at least 1,
2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic
surfactant. According to another aspect of this embodiment, the
unit dosage form has one or more of (1) a lipophilic additive, (2)
a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6)
one or more other pharmaceutically acceptable excipients. According
to one aspect of this embodiment, the unit dosage form has a
lipophilic additive, binder, a diluent, a disintegrant or a
combination thereof individually or together in an amount of e.g.,
at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or
within a range defined by any two of these values.)
[0246] In yet another embodiment, the total daily dose of 17 HPC
administered to a human subject in milligrams is about 800, 801,
802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814,
815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827,
828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840,
841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,
854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866,
867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879,
880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892,
893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905,
906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,
919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931,
932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944,
945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957,
958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970,
971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983,
984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996,
997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007,
1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018,
1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029,
1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040,
1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051,
1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062,
1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073,
1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084,
1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,
1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106,
1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117,
1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,
1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139,
1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150,
1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161,
1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172,
1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183,
1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194,
1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205,
1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216,
1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227,
1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238,
1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249,
1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260,
1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271,
1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282,
1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293,
1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304,
1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315,
1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326,
1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337,
1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348,
1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359,
1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370,
1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381,
1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392,
1393, 1394, 1395, 1396, 1397, 1398, 1399, or 1400 (or within a
range defined by any two of these values). According to one aspect
of this embodiment, the 17 HPC is administered one, two or three
times a day as one, two, three or four unit dosage forms (e.g., up
to 12 unit dosage forms per day) to yield the total daily dose
provided in this paragraph. In some aspects, the total daily dose
can provide a 17-hydroxyprogesterone caproate C.sub.avg-24h of
greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to a human
subject (female or pregnant female) once, twice or three times
daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms. In one
aspect, the daily dose is from 525 mg per day to about 1400 mg per
day. In one aspect, the daily dose is from 800 mg per day to about
1400 mg per day. In one aspect, the daily dose is from 900 mg per
day to about 1200 mg per day. According to one aspect of this
embodiment, the daily dose is provided by one or more unit dosage
form, which is a tablet, capsule, solution, suspension, or sprinkle
for oral administration. According to one aspect of this
embodiment, the unit dosage form has a surfactant e.g., at least 1,
2, 3, 4, 5, 10, 15, 20, 30, 40, or 50 mg of a non-ionic or ionic
surfactant. According to another aspect of this embodiment, the
unit dosage form has one or more of (1) a lipophilic additive, (2)
a diluent (3) a binder (4) a disintegrant, (5) a lubricant and (6)
one or more other pharmaceutically acceptable excipients. According
to one aspect of this embodiment, the unit dosage form has a
lipophilic additive, binder, a diluent, a disintegrant or a
combination thereof individually or together in an amount of e.g.,
at least 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 mg (or
within a range defined by any two of these values.)
[0247] In again another embodiment, a unit dosage form (e.g.,
tablet, capsule, caplet etc.) is provided having a milligram amount
of 17 HPC of about 200, 201, 202, 203, 204, 205, 206, 207, 208,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234,
235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247,
248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260,
261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273,
274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286,
287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299,
300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312,
313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325,
326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338,
339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351,
352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364,
365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377,
378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390,
391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403,
404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416,
417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429,
430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442,
443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455,
456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468,
469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481,
482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494,
495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507,
508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520,
521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533,
534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546,
547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559,
560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572,
573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585,
586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598,
599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611,
612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624,
625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637,
638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650,
651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,
664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676,
677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689,
690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702,
703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715,
716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728,
729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741,
742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754,
755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767,
768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780,
781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793,
794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806,
807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819,
820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,
833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845,
846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858,
859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871,
872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884,
885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897,
898, 899, or 900 (or within a range defined by any two of these
values). In some aspects, the the oral dosage form or
pharmaceutical composition can provide a 17-hydroxyprogesterone
caproate C.sub.avg-24h of greater than about 0.1, 0.5 or 1.0 ng/mL
when admistered to a human subject (female or pregnant female) once
or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage
forms. In one aspect, the release of of 17 HPC from the unit dosage
form is tested using a USP Type II apparatus at 50 or 100 rpm in
about 1000 mL of from about 2% to about 16% (e.g., 2%, 4%, 6%, 8%,
10%, 12%, 14% or 16%) Triton X-100 solution in water at a specific
temperature e.g., 20.0, 37.0 or 40.0.degree. C. (.+-.0.5). In a
specific aspect, the unit dosage form release greater than 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at one hour. According to
one aspect of this embodiment, the unit dosage form has a
surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, or 50
mg of a non-ionic or ionic surfactant. According to another aspect
of this embodiment, the unit dosage form has one or more of (1) a
lipophilic additive, (2) a diluent (3) a binder (4) a disintegrant,
(5) a lubricant and (6) one or more other pharmaceutically
acceptable excipients. According to one aspect of this embodiment,
the unit dosage form has a lipophilic additive, binder, a diluent,
a disintegrant or a combination thereof individually or together in
an amount of e.g., at least 10, 20, 30, 40, 50, 100, 150, 200, 300,
400, or 500 mg (or within a range defined by any two of these
values.)
[0248] In again another embodiment, a unit dosage form (e.g.,
tablet, capsule, caplet etc.) is provided having a milligram amount
of 17 HPC of about 300, 301, 302, 303, 304, 305, 306, 307, 308,
309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,
322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334,
335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,
361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373,
374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386,
387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399,
400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412,
413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425,
426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438,
439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451,
452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464,
465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477,
478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490,
491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503,
504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,
517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529,
530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542,
543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555,
556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568,
569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581,
582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594,
595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607,
608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,
621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633,
634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646,
647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659,
660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672,
673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685,
686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698,
699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711,
712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724,
725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737,
738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,
751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763,
764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776,
777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789,
790, 791, 792, 793, 794, 795, 796, 797, 798, 799 or 800(or within a
range defined by any two of these values). In some aspects, the the
oral dosage form or pharmaceutical composition can provide a
17-hydroxyprogesterone caproate C.sub.avg-24h of greater than about
0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or
pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 unit dosage forms. In one aspect, the release of of 17 HPC
from the unit dosage form is tested using a USP Type II apparatus
at 50 or 100 rpm in about 1000 mL of from about 2% to about 16%
(e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14% or 16%) Triton X-100 solution
in water at a specific temperature e.g., 20.0, 37.0 or 40.0.degree.
C. (.+-.0.5). In a specific aspect, the unit dosage form release
greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at
one hour. According to one aspect of this embodiment, the unit
dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15,
20, 30, 40, or 50 mg of a non-ionic or ionic surfactant. According
to another aspect of this embodiment, the unit dosage form has one
or more of (1) a lipophilic additive, (2) a diluent (3) a binder
(4) a disintegrant, (5) a lubricant and (6) one or more other
pharmaceutically acceptable excipients. According to one aspect of
this embodiment, the unit dosage form has a lipophilic additive,
binder, a diluent, a disintegrant or a combination thereof
individually or together in an amount of e.g., at least 10, 20, 30,
40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range
defined by any two of these values.)
[0249] In again another embodiment, a unit dosage form (e.g.,
tablet, capsule, caplet etc.) is provided having a milligram amount
of 17 HPC of about 450, 451, 452, 453, 454, 455, 456, 457, 458,
459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471,
472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484,
485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497,
498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510,
511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523,
524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536,
537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549,
550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562,
563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575,
576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588,
589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601,
602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614,
615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627,
628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640,
641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653,
654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,
667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679,
680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692,
693, 694, 695, 696, 697, 698, 699, or 700. In some aspects, the the
oral dosage form or pharmaceutical composition can provide a
17-hydroxyprogesterone caproate C.sub.avg-24h of greater than about
0.1, 0.5 or 1.0 ng/mL when admistered to a human subject (female or
pregnant female) once or twice daily as 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 unit dosage forms. In one aspect, the release of of 17 HPC
from the unit dosage form is tested using a USP Type II apparatus
at 50 or 100 rpm in about 1000 mL of from about 2% to about 16%
(e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14% or 16%) Triton X-100 solution
in water at a specific temperature e.g., 20.0, 37.0 or 40.0.degree.
C. (.+-.0.5). In a specific aspect, the unit dosage form release
greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at
one hour. According to one aspect of this embodiment, the unit
dosage form has a surfactant e.g., at least 1, 2, 3, 4, 5, 10, 15,
20, 30, 40, or 50 mg of a non-ionic or ionic surfactant. According
to another aspect of this embodiment, the unit dosage form has one
or more of (1) a lipophilic additive, (2) a diluent (3) a binder
(4) a disintegrant, (5) a lubricant and (6) one or more other
pharmaceutically acceptable excipients. According to one aspect of
this embodiment, the unit dosage form has a lipophilic additive,
binder, a diluent, a disintegrant or a combination thereof
individually or together in an amount of e.g., at least 10, 20, 30,
40, 50, 100, 150, 200, 300, 400, or 500 mg (or within a range
defined by any two of these values.)In one particular embodiment
the oral dosage form of the current invention comprises a
therapeutically effective amount of an ester of
17-hydroxyprogesterone, wherein, when measured using a USP Type-II
dissolution apparatus in 900 mL of deionized water with 0.5% (w/v)
of sodium lauryl sulfate at 50 RPM at 37.degree. C., the oral
dosage form releases at least 20 wt % of the dose of the ester of
17-hydroxyprogesterone after 60 minutes, In another particular
embodiment, the dosage form releases at least about 40 wt % of the
dose of the ester of 17-hydroxyprogesterone after 60 minutes. In
another particular embodiment, the dosage form releases at least
about 50 wt % of the dose of the ester of 17-hydroxyprogesterone
after 60 minutes. In another particular embodiment, the dosage form
releases at least about 70 wt % of the dose of the ester of
17-hydroxyprogesterone after 60 minutes. In a specific embodiment
the ester is 17-hydroxyprogesterone caproate. In another
embodiment, the dosage form is administered with food.
[0250] Following oral administration of the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) in
the form of the composition or dosage form the present invention,
its concentration in the serum, plasma or blood of the subject may
be determined by analytical techniques based on radio-immunoassay
(MA), high performance liquid chromatography--Mass Spectroscopy
(HPLC-MS/MS) and the like. Accordingly, the plasma or blood levels
for the ester may be different. It has to be understood that any
relative comparisons of blood plasma levels of any compound should
be made with the same assay methodology, or corrections must be
made to adjust for discrepancy for assay specificity.
[0251] Accordingly, in one embodiment, the 17-hydroxyprogesterone
caproate compositions or dosage forms of the present invention can
provide a mean steady state 17-hydroxyprogesterone caproate mean
C.sub.max from about 10 ng/mL to about 800 ng/mL, wherein the
plasma 17-hydroxyprogesterone caproate is determined by HPLC-MS/MS
method. In a particular embodiment, the compositions or dosage
forms provides a mean steady state 17-hydroxyprogesterone caproate
mean C.sub.max from about 10 ng/mL to about 400 ng/mL.
[0252] In further embodiment, the 17-hydroxyprogesterone caproate
compositions or oral dosage forms of the present invention can
provide a 17-hydroxyprogesterone caproate mean steady state
C.sub.min of about 1 ng/mL or more. The plasma concentrations of
the 17-hydroxyprogesterone caproate can be determined by HPLC-MS/MS
method. In one embodiment, the compositions or oral dosage forms
can provide a 17-hydroxyprogesterone caproate mean steady state
C.sub.min greater than about 10 ng/mL. In another embodiment, the
composition or oral dosage forms can provide a
17-hydroxyprogesterone caproate mean steady state C.sub.min greater
than about 20 ng/mL, or greater than about 40 ng/ml, greater than
about 60 ng/mL, or greater than about 80 ng/mL. In one specific
embodiment, the composition or oral dosage form can provide a mean
steady state of about 1 to about 60 ng/mL. In another specific
embodiment, the composition or dosage form can provide a mean
steady state C.sub.min of about 1 ng/mL to about 20 ng/mL.
[0253] In further embodiment, the 17-hydroxyprogesterone caproate
compositions or oral dosage forms or method described herein can
provide a 17-hydroxyprogesterone caproate mean steady state
C.sub.min of greater than about 0.001, 0.01, 0.05, 0.1, 0.5, 1, 2,
3, 4, 5, 6, 7, 8, 9 or 10 ng/mL (or within a range defined by any
two of these values). The plasma concentrations of the
17-hydroxyprogesterone caproate can be determined by HPLC-MS/MS
method. In one aspect, the Cmin range occurs for less than 4 hours,
3, hours, 2 hours or 0.5 hours per day. In one aspect, the Cmin
values in this paragraph are threshold values for which the patient
does not have values lower than these values or ranges for more
than 4 hours, 3, hours, 2 hours, 0.5 hours or 0.25 hours per
day.
[0254] Accordingly, the oral dosage form of 17-hydroxyprogesterone
caproate of the present invention can be an immediate release
dosage form. In a separate embodiment, the oral dosage form of the
17-hydroxyprogesterone caproate of the present invention can be a
controlled release dosage form. In another specific embodiment,
dosage form can include 17-hydroxyprogesterone caproate in the form
of both immediate release and controlled release fractions,
preferably extended or delayed release.
[0255] Consequently, the controlled release 17-hydroxyprogesterone
caproate compositions or dosage forms of the present invention can
provide a fluctuation in the 17-hydroxyprogesterone caproate levels
less than about 795 ng/mL, wherein the fluctuation is determined by
the difference of the mean steady state C.sub.max and the mean
steady state C.sub.min of 17-hydroxyprogesterone caproate in plasma
or serum or blood, upon oral administration.
[0256] In another embodiment, 17-hydroxyprogesterone caproate
compositions or dosage forms of the present invention can provide a
fluctuation in the 17-hydroxyprogesterone caproate levels less than
about 2000, 1500, 1000, 900, 800, 700, 600, 500, 400, 300, 200,
175, 150, 140, 130, 120, 110 or 100 ng/mL, wherein the fluctuation
is determined by the difference of the mean steady state C.sub.max
and the mean steady state C.sub.min of 17-hydroxyprogesterone
caproate in plasma or serum or blood, upon oral administration.
[0257] In another embodiment, 17-hydroxyprogesterone caproate
compositions or dosage forms of the present invention can provide a
fluctuation in the 17-hydroxyprogesterone caproate levels greater
than about 1, 10, 15, 25, 50, 75, 100, 200, 300 or 400 ng/mL,
wherein the fluctuation is determined by the difference of the mean
steady state C.sub.max and the mean steady state C.sub.min of
17-hydroxyprogesterone caproate in plasma or serum or blood, upon
oral administration. In an aspect of the fluctuation embodiments,
the fluctuation falls within a range defined by any two of the
values in the greater than and less than embodiments.
[0258] In a another particular aspect, the oral pharmaceutical
compositions and/or dosage forms of 17-hydroxyprogesterone caproate
of the current invention can be used for the treatment of one or
more of the conditions selected from the group consisting of
habitual abortion, recurrent abortion, threatened abortion,
post-partum after pains, endometrial cancer, management of primary
and secondary amenorrhea, infertility due to corpus luteum
insufficiency, deficiency of progestogen, cervical insufficiency,
cervical incompetency, and abnormal uterine bleeding. In a further
embodiment, the oral pharmaceutical compositions and/or dosage
forms of 17-hydroxyprogesterone caproate of the current invention
can be used for testing endogenous estrogen production, and for the
production of secretory endometrium and desquamation.
[0259] In another embodiment, the oral pharmaceutical compositions
and/or dosage forms of 17-hydroxyprogesterone caproate of the
current invention can be used along with omega-3 fatty acid
supplementation to treat symptomatic preterm labor patients. In a
particular embodiment, the current invention compositions and/or
dosage forms may include at least one omega fatty acid. In another
particular embodiment, the current invention compositions and/or
dosage form may include omega-3, omega-6 or omega-9 fatty acid or
mixtures thereof.
[0260] In one embodiment, a method is provided for treating a
pregnant female based on gestational age. The method involves
treating a pregnant female with a pharmaceutically composition
formulated for oral administration comprising 17 HPC and a
pharmaceutically acceptable carrier with an initial gestational age
daily dose of 17 HPC. The initial gestational age daily dose of 17
HPC is selected or determined based on gestational age. For
example, initiation of treatment of a pregnant female with a
gestational age of 20 weeks involves a daily dose of 17 HPC
appropriate for this gestational age. Initiation of treatment of a
pregnant female with a gestational age of 26 weeks involves a daily
dose appropriate for this gestational age. The initial gestational
age daily dose for 20 weeks gestational age and 26 weeks
gestational age can be the same or differ (a non-limiting example
is that a 20 week initial gestational age daily dose can be e.g.,
550 mg 17 HPC per day orally whereas a 20 week initial gestational
age daily dose can be e.g., 750 mg 17 HPC per day orally).
Gestational age can be determined by any appropriate method
including directly calculating the days since the beginning of the
last menstrual period, early obstetric ultrasound, and the like. A
pregnant female being treated with an initial gestational age daily
dose of 17 HPC can be maintained on the same daily dose of 17 HPC
throughout the pregnancy or have a daily dose alteration based on a
later gestational age. For example, the initial gestational age
daily dose can be between 10 mg to 1500 mg per day orally and after
1 day, 2 days, 3, days, 5 days, 7 days, 10 days, 14 days, 18 days,
21 days or more on the initial gestational age daily dose, the dose
can be adjusted within plus/minus 5 mg to 1495 mg per day orally
which is a referred to as a second gestational age daily dose.
Likewise, the second gestational age daily dose can be adjusted
after 1 day, 2 days, 3, days, 5 days, 7 days, 10 days, 14 days, 18
days, 21 days or more on the second gestational age daily dose, the
dose can be adjusted within plus/minus 5 mg to 1495 mg per day
orally of the second gestational age daily dose--this new daily
dose is referred to as the third gestational age daily dose.
Alternatively, the gestational age treatment can be based on IM
injection. For example, 17 HPC is formulated as an IM injection and
the amount of 17 HPC administered via the IM route is based on the
gestational age. For example, the oil can be castor oil or another
suitable vegetable oil (e.g., corn oil, cottonseed oil, olive oil,
peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,
hydrogenated vegetable oils, hydrogenated soybean oil, and
medium-chain triglycerides of coconut oil and palm seed oil)). The
formulation can include one or more of benzyl benzoate, benzyl
alcohol. The formulation can include a surfactant (e.g., non-ionic
surfactant) or more or more other optional additives. The initial
gestational dose and second gestational age doses of 17 HPC are
within the range of about 50 mg to 1000 mg per week (or e.g., 100
mg to 2000 mg every two weeks or 200 mg to 4000 mg per month). The
dose is then adjusted based on gestational are as general described
above although the dose changes correlate to about 25 mg or less,
50 mg or less, 100 mg or less or 200 mg or less per week of IM 17
HPC.
[0261] In one embodiment, a method of administering 17 HPC to a
female is provided. The method involves administering to or
treating a female with a pharmaceutical composition formulated for
oral administration comprising 17 HPC and a pharmaceutically
acceptable carrier with an initial daily dose of 17 HPC. Typically,
the initial daily dose of 17 HPC is in the range of 10 mg to 1500
mg per day. After a period of time e.g., 1 day, 2 days, 3, days, 5
days, 7 days, 10 days, 14 days, 18 days, 21 days or more, a
biomarker from the female being treated is measured or the level of
the biomarker is determined. If the biomarker is within a
maintenance target range, then the female continues to receive the
same daily dose. If the biomarker is within an up-titration target
range, then the female is administered a second daily dose that is
greater than the initial daily dose. If the biomarker is within a
down-titration target range, then the female is administered a
second daily dose that is less than the initial daily dose.
Typically, the daily dose changes between the initial and second
daily doses are within plus/minus 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, or 90% of each other. Alternatively, an up-titration or
down titration can be a change from the initial daily dose of about
10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80
mg 80-90 mg, 90-100 mg, 100-125 mg, 125-150 mg, 150-175 mg or
175-200 mg (or 200-225 mg, 225-250 mg, 250-300 mg, 300-325 mg,
325-350 mg, 350-400 mg, 400-425 mg, 425-450 mg, or 450-500 mg). The
biomarker used to determine titration can be any appropriate
biomarker. For example, the biomarker can be an efficacy biomarker,
a safety biomarker or a combination thereof. The biomarker can be
17 HPC or a metabolite thereof. 17 HPC or a metabolite thereof can
be serum 17 HPC or metabolite thereof, urinary 17 HPC or a
metabolite thereof, salivary 17 HPC or a metabolite thereof. The
biomarker can be a steroid e.g., progesterone or a metabolite
thereof (serum, salivary, urinary). The biomarker can be any
biomarker specified in this application or otherwise useful for
determining titrations. In one specific example, the titration
biomarker is serum 17 HPC (a pharmacokinetic parameter). For
example, if the serum 17 HPC (e.g., C.sub.avg, C.sub.min, C.sub.max
or any other pharmacokinetic parameter and particularly described
herein) is below a minimum target threshold, the daily dose of 17
HPC daily dose can be increased, if the serum 17 HPC is above a
maximum target threshold, then the 17 HPC daily dose can be
decreased, or if the serum 17 HPC is within a target range that is
deemed sufficient, then the daily dose can be maintained. In one
aspect, the target is can provide a 17-hydroxyprogesterone caproate
C.sub.avg-24h greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5,
2.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0
60.0, 75.0 or 100 ng/mL (or alternatively less than any of these
values or alternatively within a range defined by any two of these
values). In one aspect, the said 17-hydroxyprogesterone caproate
C.sub.avg-24h is determined by an HPLC-MS/MS method of analysis of
the plasma, serum or blood samples collected following the oral
administration. In one aspect, the oral pharmaceutical composition
comprises 17-hydroxyprogesterone caproate and a pharmaceutically
acceptable carrier, wherein, when measured using a USP Type-II
dissolution apparatus in 900 mL of simulated intestinal fluid
having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37.degree. C.,
at least 20% of the 17-hydroxyprogesterone caproate is released
from the oral composition at 60 minutes. In one aspect, the oral
pharmaceutical composition comprises: 17-hydroxyprogesterone
caproate, and a pharmaceutically acceptable carrier including at
least a hydrophilic surfactant. In one aspect, the oral
pharmaceutical composition, comprises: 17-hydroxyprogesterone
caproate having a mean particulate diameter of about 50 micron or
less, and a pharmaceutically acceptable carrier including at least
a hydrophilic surfactant. In one aspect, the oral pharmaceutical
composition comprises: 17-hydroxyprogesterone caproate having a
mean particulate diameter of about 50 micron or less, and a
pharmaceutically acceptable carrier including at least a
hydrophilic surfactant wherein, when measured using a USP Type-II
dissolution apparatus in 900 mL of simulated intestinal fluid
having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37.degree. C.,
at least 20% of the 17-hydroxyprogesterone caproate is released
from the oral composition at 60 minutes. In one aspect, the oral
pharmaceutical composition comprises: 17-hydroxyprogesterone
caproate having a mean particulate diameter of about 50 micron or
less, and a pharmaceutically acceptable carrier including at least
a hydrophilic surfactant; wherein the amount of the
17-hydroxyprogesterone caproate is from about 5% to about 80% w/w
of the total composition; and wherein, when measured using a USP
Type-II dissolution apparatus in 900 mL of simulated intestinal
fluid having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37.degree.
C., at least 20% of the 17-hydroxyprogesterone caproate is released
from the oral composition at 60 minutes. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant,
which is an ionic hydrophilic surfactant. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant,
which is a non-ionic hydrophilic surfactant. In one aspect, the
oral pharmaceutical composition comprises a hydrophilic surfactant,
which is a poloxamer, a polyethylene glycol sorbitan fatty acid
ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol
fatty acid ester or a combination thereof. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant,
which is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a
lecithin, a bile salt or a combination thereof. In one aspect, the
oral pharmaceutical composition further comprises
polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose,
magnesium stearate, silicon dioxide, stearic acid, mannitol, a
polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a
polyethylene glycol copolymer, a methacrylic acid copolymer, or a
combination thereof. In one aspect, the oral pharmaceutical
composition is formulated as a powder, granulate, particulate,
bead, pellet, sprinkle, suspension, solution, tablet, capsule, or a
combination thereof. In one aspect, the oral pharmaceutical
composition is formulated as a capsule. In one aspect, the oral
pharmaceutical composition is formulated as a tablet. In one
aspect, the oral pharmaceutical composition comprises an amount of
17-hydroxyprogesterone caproate equivalent to from about 20 mg to
about 400 mg of 17-hydroxyprogesterone. In one aspect, the oral
pharmaceutical composition has from about 20 mg to about 800 mg
17-hydroxyprogesterone caproate. In one aspect, the oral
pharmaceutical composition has from about 10 mg to about 300 mg
17-hydroxyprogesterone caproate. As shown in Example 58, There was
a good correlation of C.sub.max to C.sub.avg and C.sub.avg to
pre-dose C value which enables single point titration (e.g., based
on serum or plasma 17 HPC levels at a single time point with 0-12
hours after single dose administration at steady state (e.g., at
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,
8.5, 9, 9.5, 10, 10.5, 11, or 11.5 hours after single dose
administration (or within a range defined by any two of these
values, or within a range of within 0.5 h or 1 h of any one of
these values))). For example, a pregnant female at risk for preterm
birth is administered orally, a pharmaceutical composition (e.g.,
as described herein), in an initial dosing regimen, until steady
state is achieved (e.g., 5 or more days, 6 or more days, 7 or more
days). The initial dosing regimen (or alternatively after titration
can be) can be e.g., 400 mg per day, 450 mg per day, 500 mg per
day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per
day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per
day, 950 mg per day, 1000 mg per day, 1150 mg per day, 1200 mg per
day, 1250 mg per day, 1300 mg per day, 1350 mg per day, 1400 mg per
day, 1450 mg per day, 1500 mg per day, 1550 mg per day, 1600 mg per
day, 1650 mg per day, 1700 mg per day, 1750 mg per day, 1800 mg per
day, 1850 mg per day, 1900 mg per day, 1950 mg per day or 2000 mg
per day (or within a range defined by any two of these values, or
within a range of within 50 mg or 100 mg of any one of these
values) e.g., on a once, twice, thrice, or four times a day dosing
regime. After single dose administration at steady state, the
plasma or serum 17 HPC in the subject is determined and if the
levels are too low, the daily dose is increased, if the levels are
too high, the daily dose is increased or if they levels are
appropriate, the daily dose is maintained. The pharmaceutical
composition can delivery the daily dose in e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 unit dosage forms per
day.
[0262] In one embodiment, the pharmaceutical compositions
containing 17 HPC are for use in conditions associated with preterm
labor. Thus, in some aspects, a method for treating preterm labor
or a condition associated with preterm labor is provided. The
method involves orally administering a pharmaceutical composition
comprising 17 HPC and a pharmaceutically acceptable carrier to a
pregnant female experiencing preterm labor, at risk for preterm
labor or after preterm labor. The method and oral pharmaceutical
composition can reduce the risk of preterm labor, reduce the risk
of preterm birth as a result of preterm labor, provide tocolytic
effect, improve tocolysis, provide maintenance tocolysis, reduce
preterm birth, reduce the risk of miscarriage, improve neonatal
outcome, prolong gestation, improve postnatal outcome, improve
maternal outcome, improve Bayley Scales of Infant Development
Scores (including one or more of motor (fine, gross or both),
language (receptive, expressive or both), and cognitive
development), improve scores on Social-Emotional Adaptive Behavior
Questionnaire, or a combination thereof. The pharmaceutical
composition and method of this embodiment can improve neonatal
outcomes including birth weight gestational age or both. The
pharmaceutical composition and method of this embodiment can
improve maternal, infant and child outcomes as described elsewhere
herein.
[0263] Preterm labor refers to regular contractions of the uterus
that result in changes in the cervix that occur before 37 weeks of
pregnancy. Changes in the cervix include effacement (e.g., the
cervix thins out) and dilation (e.g., the cervix opens so that the
fetus can enter the birth canal). In one aspect, preterm labor is
diagnosed by transvaginal ultrasound, fetal fibronectin in vaginal
discharge or both. Accordingly, in one aspect, a pregnant female
experiencing preterm labor is administered an oral pharmaceutical
composition having 17 HPC and a pharmaceutically acceptable
carrier. In another aspect, a method for improving one or more of
maternal, infant and child outcomes is provided. The method
involves administering to a female that recently experienced
preterm labor e.g., within 3 weeks, 2 weeks, 1 week, 6 days, 5
days, 4 days, 3 days, 2 days, or 1 day an oral pharmaceutical
composition having 17 HPC and a pharmaceutically acceptable
carrier. The pregnant female can have had the preterm labor stop,
subside or lessen without pharmaceutical intervention or
alternatively the preterm labor was treated medically with a
pharmaceutical intervention. In one aspect, the pharmaceutical
intervention is magnesium sulfate or a tocolytic. The daily dose of
17 HPC and per unit dosage are as described herein. In a specific
aspect, the daily dose of 17 HPC ranges from about 550 mg to about
1600 mg. In another specific aspect, the unit dosage forms comprise
from about 250 mg to about 800 mg of 17 HPC.
[0264] In one embodiment, a combination therapy is provided,
comprising oral 17 HPC and a second agent. The second agent can be
a pharmaceutical agent, a vitamin, a mineral, supplement, etc.
[0265] In one aspect, a combination therapy is provided, comprising
oral 17 HPC and a compound chosen from a progestogen, a
corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or
a combination thereof. The combination therapy, in some aspects,
involves a co-formulation of oral 17 HPC and a compound chosen from
a progestogen, a corticosteroid, a tocolytic, an antibiotic, a
vitamin D compound or a combination thereof. According to this
aspect, the co-formulation is orally administered to a subject in
need thereof. For example, a co-formulation of (1) 17 HPC, (2) one
or more of a progestogen, a corticosteroid, a tocolytic, an
antibiotic, a vitamin D compound and (3) a pharmaceutically
acceptable carrier is administered to a pregnant female. The
combination therapy, in some aspects, involves a co-administration
of oral 17 HPC and a compound chosen from a progestogen, a
corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or
a combination thereof. Co-administration refers to oral
administration of 17 HPC and enteral, parenteral or topical
administration of one or more of a progestogen, a corticosteroid, a
tocolytic, an antibiotic and a vitamin D compound.
[0266] In one aspect, a combination therapy is provided, comprising
oral 17 HPC and a compound chosen from an antenatal corticosteroid,
beta-adrenergic receptor agonist, a calcium channel blocker,
magnesium sulfate, an NSAID, an oxytocin antagonist or a
combination thereof. The pharmaceutical compositions and methods of
this embodiment can improve maternal, infant and child outcomes as
described elsewhere herein.
[0267] The pharmaceutical compositions comprising 17 HPC and a
pharmaceutically acceptable carrier can be co-formulated or
co-administered with prenatal vitamins or supplements and the like.
For example, the pharmaceutical compositions described herein can
be co-administered or co-formulated with A, B3, B6, C, D, folic
acid, calcium, iron, magnesium, manganese, phosphorus, potassium,
sodium, zinc, omega-3, eicosapentaenoic acid (EPA), docosahexaenoic
(DHA) or a combination thereof. For example one or more of, 400
micrograms (mcg) of folic acid, 400 IU of vitamin D, 200 to 300 mg
of calcium, 65-75 mg of vitamin C, 2-4 mg of thiamine, 1-3 mg of
riboflavin, 14-25 mg of niacin, 4-8 mcg of vitamin B12, 8-12 mg of
vitamin E, 13-17 mg of zinc, 15-19 mg of iron, 140-160 micrograms
of iodine can be co-administered with the pharmaceutical
compositions comprising 17 HPC and a pharmaceutically acceptable
carrier described herein. Co-administration does not necessarily
mean that the compositions are administered at the same time. For
example, the prenatal vitamins can be administered once-a-day (or
more) and a different time of day than the 17 HPC containing
compositions (which could be administered e.g., two time or three
times daily).
[0268] In one embodiment, compositions and methods for treating a
pregnant female is provided. According to this embodiment, a
therapy comprising vitamin D and oral 17 HPC is provided. In one
aspect, the therapy comprises administration of oral 17 HPC and
oral vitamin D to a pregnant female. The daily dose of 17 HPC and
per unit dosage are as described herein. In a specific aspect, the
daily dose of 17 HPC ranges from about 550 mg to about 1600 mg. In
another specific aspect, the unit dosage forms comprise from about
250 mg to about 800 mg of 17 HPC. In one aspect, the daily dose of
vitamin D is 200 IU per day or more. In another aspect, the daily
dose of vitamin D is 400 IU per day or more. In another aspect, the
daily dose of vitamin D is 600 IU per day or more. In another
aspect, the daily dose of vitamin D is 800 IU per day or more. In
another aspect, the daily dose of vitamin D is 1000 IU per day or
more. In another aspect, the daily dose of vitamin D is 1500 IU per
day or more. In another aspect, the daily dose of vitamin D is 2000
IU per day or more. In another aspect, the daily dose of vitamin D
is 3000 IU per day or more. In another aspect, the daily dose of
vitamin D is 4000 IU per day or more. In another aspect, the daily
dose of vitamin D is 5000 IU per day or more. In another aspect,
the daily dose of vitamin D is 4000 IU per day or more. In another
aspect, the daily dose of vitamin D is 6000 IU per day or more. In
another aspect, the daily dose of vitamin D is from 450 to 8000 IU
per day or more. In another aspect, the daily dose of vitamin D is
from 450 to 3000 IU per day or more. In another aspect, the daily
dose of vitamin D is from 450 to 2000 IU per day or more. In
another aspect, the daily dose of vitamin D is from 450 to 2000 IU
per day or more. In one aspect, the daily dose of vitamin D is
based at least in part on first, second, or third trimester serum
vitamin D levels of the pregnant female. For example, in one
aspect, the dose of vitamin D is chosen such that the level of
serum vitamin D falls within the range of about 50 to about 75
nmol/L. In another aspect, the dose of vitamin D is chosen such
that the level of serum vitamin D is greater than about 50 nmol/L.
In another aspect, the dose of vitamin D is chosen such that the
level of serum vitamin D falls is greater than about 75 nmol/L. In
another aspect, the dose of vitamin D is chosen such that the level
of serum vitamin D is greater than about 100 nmol/L. In another
aspect, the dose of vitamin D is chosen such that the level of
serum vitamin D is greater than about 125 nmol/L. In another
aspect, the dose of vitamin D is chosen such that the level of
serum vitamin D is greater than about 150 nmol/L. In another
aspect, the dose of vitamin D is chosen such that the level of
serum vitamin D is greater than about 175 nmol/L. In one aspect,
the daily dose of vitamin D is chosen such that the level of serum
vitamin D falls within a range of about 50 nmol/L to about 200
nmol/L. In another aspect, the dose of vitamin D is chosen such
that the level of serum vitamin D is greater than about 500, 400,
300 or 200 nmol/L. In one aspect, the serum level of the pregnant
female is titrated into a selected range or value. For example, the
pregnant female is administered a dose of vitamin D, e.g., 200 IU
per day and it is determined that this daily dose has not provided
her with sufficient vitamin D. The dose can then be increased,
e.g., by 50 IU or more, 100 IU or more, 200 IU or more, 300 IU or
more, until the desired target vitamin D level is reached.
Alternatively, the vitamin D daily dose can be down-titrated into
the target range in a similar manner. In one aspect, the serum
vitamin D is 25-hydroxyvitamin D (the target serum vitamin D levels
or ranges are for 25-hydroxyvitamin D). In one aspect, the
pharmaceutical composition that is administered comprises
cholecalciferol or ergocalciferol. In one aspect, the
pharmaceutical composition that is administered comprises
alfacalcidol, calcifediol, calcitriol, dihydrotachysterol or
combination thereof. In one aspect, the pharmaceutical composition
that is administered comprises cholecalciferol, alfacalcidol,
calcifediol, calcitriol, dihydrotachysterol or a combination
thereof and 17 HPC. In one aspect, the amount of vitamin D
administered is in addition to that being provided by prenatal
vitamins or supplements to the pregnant female. In one aspect, the
pharmaceutical composition that is administered comprises at least
50 IU cholecalciferol and at least 50 mg 17 HPC. In one aspect, the
pharmaceutical composition that is administered comprises 50 IU to
400 IU cholecalciferol and 100 mg to 450 mg 17 HPC. In one aspect,
the combination composition is formulated for parenteral
administration. In another aspect, the combination composition is
formulated for oral administration. In one aspect, the daily
comprises at least 200 IU cholecalciferol and at least 200 mg 17
HPC. In one aspect, the daily dose comprises 200 IU to 4000 IU
cholecalciferol and 400 mg to 1600 mg 17 HPC. In one aspect, the
daily dose comprises 200 IU to 4000 IU cholecalciferol and 550 mg
to 1600 mg 17 HPC. The method and composition according to this
embodiment provide one or more of an improvement in maternal,
infant and child outcomes with respect to a pregnant female. In one
aspect, pregnant female is at risk for preterm birth due to
previous low birth weight or preterm delivery, multiple 2nd
trimester spontaneous abortion, exposure to tobacco smoke or
tobacco smoke residue, use of smokeless tobacco, substance use or
abuse or dependence, alcohol use or abuse or dependence, stress,
anxiety, depression, short stature, poor nutritional status,
insufficient weight gain during pregnancy, low prepregnancy
weight/low body mass index, advanced maternal age, low
socio-economic status, prior first trimester induced abortion,
familial and intergenerational factors, history of infertility,
nulliparity, placental abnormalities, cervical and uterine
anomalies, gestational bleeding, intrauterine growth restriction,
in utero diethylstilbestrol exposure, multiple gestations, infant
sex (e.g., fetal male), urogenital infections, preeclampsia or a
combination thereof.
[0269] In one embodiment, a therapy is provided comprising
intramuscular injection of vitamin D and 17 HPC to a pregnant
female. According to one aspect of this embodiment, a pregnant
female is administered from 100 mg/mL to 500 mg/mL of 17 HPC per
week and from 10,000 IU to 300000 IU cholecalciferol per week.
According to one aspect of this embodiment, a pregnant female is
administered from 100 mg/mL to 500 mg/mL of 17 HPC per week and
from 10,000 IU to 100000 IU cholecalciferol per week. According to
one aspect of this embodiment, a pregnant female is administered
from 100 mg to 500 mg of 17 HPC per week and from 10,000 IU to
50000 IU cholecalciferol per week. In one aspect, the vitamin D and
17 HPC are coformulated for IM injection. In another aspect, the
vitamin D and 17 HPC are formulated separately. The values
described in this embodiment can be for one week, two weeks, three
weeks or more. For example, a two week dose can be provides which
would be twice the dose of the one week dose. According to one
aspect of this embodiment, a pregnant female is administered from a
dose of about 200 mg to 300 mg (e.g., 1 mL of 250 mg/mL 17 HPC) of
17 HPC per week and a dose of from 10,000 IU to 50000 IU
cholecalciferol per week. The 17 HPC, cholecalciferol, or both can
be formulated for IM injection in a vehicle having an oil suitable
for IM injection and optionally a solubilizer. For example, the oil
can be castor oil or another suitable vegetable oil (e.g., corn
oil, cottonseed oil, olive oil, peanut oil, peppermint oil,
safflower oil, sesame oil, soybean oil, hydrogenated vegetable
oils, hydrogenated soybean oil, and medium-chain triglycerides of
coconut oil and palm seed oil)). The formulation can include one or
more of benzyl benzoate, benzyl alcohol. The formulation can
include a surfactant (e.g., non-ionic surfactant) or more or more
other optional additives.
[0270] Examples of beta-adrenergic receptor agonist include, but
are not limited to, fenoterol, terbutaline, salbutamol, and
nifedipine. Examples of NSAIDs include, but are not limited to,
indomethacin, ketorolac and sulindac. An example of a calcium
channel blocker includes, but is not limited to, nifedipine. An
example of an oxytocin antagonist includes, but is not limited to,
atosiban. Examples of antenatal corticosteroids include, but are
not limited to, betamethasone and dexamethasone. Examples of
antibiotics include, but are not limited to ampicillin and
penicillin. Examples of vitamin D compounds include, but are not
limited to, cholecalciferol and ergocalciferol. Examples of
progestogens include, but are not limited to, progesterone and
dydrogesterone.
[0271] Nifedipine can be administered at e.g., an initial oral dose
of 20 mg followed by 10-20 mg three to four times daily, adjusted
according to uterine activity for up to 48 hours. Total doses above
60 mg appear to be associated with increased adverse events.
Atosiban can be administered e.g., as an initial bolus dose of 6.75
mg over 1 minute, followed by an infusion of 18 mg/hour for 3
hours, then 6 mg/hour for up to 45 hours (to a maximum of 330
mg).
[0272] In one embodiment, a method of treatment is provided that
involves orally administering to a pregnant female a pharmaceutical
composition having 17 HPC and a pharmaceutically acceptable carrier
where the preganant female is at risk for preterm birth due to
previous low birth weight or preterm delivery, multiple 2nd
trimester spontaneous abortion, exposure to tobacco smoke or
tobacco smoke residue, use of smokeless tobacco, substance use or
abuse or dependence, alcohol use or abuse or dependence, stress,
anxiety, depression, short stature, poor nutritional status,
insufficient weight gain during pregnancy, low prepregnancy
weight/low body mass index, advanced maternal age, low
socio-economic status, prior first trimester induced abortion,
familial and intergenerational factors, history of infertility,
nulliparity, placental abnormalities, cervical and uterine
anomalies, gestational bleeding, intrauterine growth restriction,
in utero diethylstilbestrol exposure, multiple gestations, infant
sex, urogenital infections, preeclampsia or a combination
thereof.
[0273] The ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is provided herein which is
crystalline. The crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) can be a particular crystal form,
a solvate of a crystal form, a polymorph, a pseudopolymorph, a
pharmaceutically acceptable solvate, or a hydrate. In a specific
aspect, the crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is a crystal form substantially
free of other crystal forms of ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate). In another specific
aspect, the crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is substantially free of amorphous
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate).
[0274] In a related aspect, amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
provided which is substantially free of crystalline ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
[0275] Ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is provided herein having a
particular size characteristic. For example provided herein is
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) which is not-milled or is milled, micronized or
nanosized. In specific aspects, ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) is provided wherein the
particle size is less than 200 nm ("nanometer"), from 200 to 500
nm, from 500 to 1000 nm, from 1 to 50 .mu.m ("micrometer"), from 50
to 250 .mu.m, from 250 to 500 .mu.m, from 500 to 1000 .mu.m, or
greater than 1000 .mu.m. In another aspect, the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
having a d.sub.50 of greater than 1000 .mu.m, from 355 to 1000
.mu.m, from 180 to 355 .mu.m, from 125 to 180 .mu.m, 90 to 125
.mu.m 1 to 90 .mu.m, or less than 1 .mu.m. In one specific aspect,
the mean particle size of ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is from 1 to 40 .mu.m, from 1 to
30 .mu.m, or from 1 to 25 .mu.m. In another related aspect, the
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate has a D.sub.10, D.sub.50, or D.sub.90 that is less than
200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50
.mu.m, from 50 to 250 .mu.m, from 250 to 500 .mu.m, from 500 to
1000 .mu.m, or greater than 1000 .mu.m. In one particular aspect,
the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) having a particular size or size characteristics is
crystalline ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate). In another particular aspect, the
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) having a particular size or size characteristics is a
crystal form of the ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate) substantially free of other
crystal forms of the ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). In yet another, the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
having a particular size or size characteristics is amorphous ester
of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate).
In yet another, the ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) having a particular size or size
characteristics is amorphous ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) substantially free of crystalline
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate).
[0276] Pharmaceutical compositions are provided herein having or
prepared from ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) as described in the paragraphs
above. For example, the pharmaceutical composition is prepared from
or has ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) and one or more pharmaceutically
acceptable excipients or carriers. The pharmaceutical composition
described herein can comprise or be prepared from crystalline ester
of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate),
amorphous ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate), or a combination thereof. The
pharmaceutical composition comprises or is prepared from a
particular crystal form, a solvate of a crystal form, a polymorph,
a pseudopolymorph, a pharmaceutically acceptable solvate, or a
hydrate of crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). Alternatively, the pharmaceutical
composition is prepared from or comprises amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). In
some aspects, the pharmaceutical composition comprises or is
prepared ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate) where the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
not-milled or is milled, micronized or nanosized. Is specific
aspects, the pharmaceutical composition comprises or is prepared
from an ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) wherein the mean particle size of
the API is less than 200 nm, from 200 to 500 nm, from 500 to 1000
nm, from 1 to 50 .mu.m, from 50 .mu.m to 250 .mu.m, from 250 .mu.m
to 500 .mu.m, from 500 .mu.m to 1000 .mu.m, or greater than 1000
.mu.m. In one specific aspect, the mean particle size of ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
from 1 to 40 .mu.m, from 1 to 30 .mu.m, from 1 to 25 .mu.m, from 1
to 20 .mu.m, from 1 to 15 .mu.m, or from 1 to 10 .mu.m. In another
aspect, the pharmaceutical composition comprises or is prepared
from an ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) having a d.sub.50 of greater than
1000 .mu.m, from 355 to 1000 .mu.m, from 180 to 355 .mu.m, from 125
to 180 .mu.m, from 90 to 125 .mu.m, from 1 to 90 .mu.m, from 1 to
40 .mu.m, from 1 to 30 .mu.m, or from 1 to 25 .mu.m, or less than 1
.mu.m. In another related aspect, the pharmaceutical composition
comprises or is prepared from ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) having a D.sub.10,
D.sub.50, or D.sub.90 that is less than 200 nm, from 200 to 500 nm,
from 500 to 1000 nm, from 1 to 50 .mu.m, from 50 to 250 .mu.m, from
250 to 500 .mu.m, from 500 to 1000 .mu.m, or greater than 1000
.mu.m. In some specific aspects, the pharmaceutical composition of
this paragraph is formulated for topical, enteral or parenteral
administration. In some aspects, the pharmaceutical composition of
this paragraph is formulated for buccal, sublingual, or sublabial
administration. In some specific aspects, the pharmaceutical
composition of this paragraph is formulated for nasal, rectal or
vaginal administration. In some specific aspects, the
pharmaceutical composition of this paragraph is formulated for
intravenous, subcutaneous, intramuscular, intradermal, intraspinal,
intrathecal, or intra-arterial administration. In some specific
aspects, the pharmaceutical composition of this paragraph is
formulated as a sprinkle liquid, solution, suspension, dispersion,
solid, semi-solid, a gel, a lotion, paste, foam, spray, suspension,
dispersion, syrup, or ointment. In some specific aspects, the
pharmaceutical composition of this paragraph is formulated as a
tincture, patch, injectable, or oral dosage form. In some aspects,
the pharmaceutical composition of this paragraph comprises
solubilized or partially solubilized ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate). In
one aspect, the pharmaceutical composition or unit dosage forms is
suitable for oral administration (e.g., capsule or tablet).
[0277] D values like D10, D50 or D90 refer the the size of
particles e.g., a D10 of 5 micron refers to 10% of the particles
having a size of 5 micron or less; a D90 of 17 micron refers to 90%
of the particles having a particle size of less than 17 micron.
[0278] Solid state API, e.g., solid state ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate)
described herein, can exist in different crystalline forms as well
as in non-crystalline forms. A non-crystalline solid API is
referred to herein as an "amorphous form," which is a disordered
arrangement of API molecules. Different crystalline forms of the
API, e.g., of a specific ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate), arise from different packing of
the ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) molecules in the solid state, resulting in different
crystal symmetries and/or unit cell parameters. Crystalline forms
are identified or characterized by any suitable methods e.g., x-ray
diffraction (see, e.g., Remington's Pharmaceutical Sciences, 18th
ed., Mack Publishing, Easton Pa., p 173 (1990); The United States
Pharmacopeia, 23rd ed., pp. 1843-1844 (1995)). Such different
crystalline forms are referred to herein as "polymorphic forms" or
"non-solvated forms," which means that they are essentially free of
residual solvents e.g., organic solvents. If the substances
incorporate stoichiometric or non-stoichiometric amounts of water
("hydrate" as used herein), or any other solvent ("solvate" as used
herein), in the crystal structure, these are referred to herein as
a "pseudopolymorphic form."
[0279] The term "amorphous form" as used herein in connection with
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) that is a non-crystalline solid (i.e not in a crystalline
form), which is a disordered arrangements of ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
molecules. Typically, amorphous ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) has no long-range periodic
atomic structure as determined by X-ray powder diffraction (MOD or
XRD). The XRPD pattern of amorphous ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) appears as a halo with no
distinctive peaks. Amorphous material for some compounds can be
obtained by a number of methods known in the art, including, but
not limited to, heating, melt cooling, rapid melt cooling, solvent
evaporation, rapid solvent evaporation, desolvation, sublimation,
grinding, cryo-grinding or freeze-drying.
[0280] The term "crystal" as used herein refers to a solid
structure, typically formed by a solidification of an API, that
generally has a regular atomic structure (characteristic shapes and
cleavage planes formed by the arrangement of molecules in a pattern
referred to as a "lattice").
[0281] The term "seeding" as used herein refers to starting or
promoting a crystallization event using a small amount of
material.
[0282] Crystalline forms of a substance can be obtained by a number
of techniques, as is known in the art. Exemplary techniques for
obtaining, producing, or manufacturing crystalline forms of ester
of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
include e.g., melt recrystallization, melt cooling, solvent
recrystallization, recrystallization in confined spaces such as,
e.g., in nanopores or capillaries, recrystallization on surfaces or
templates such as, e.g., on polymers, recrystallization in the
presence of additives, such as, e.g., co-crystal counter-molecules,
desolvation, dehydration, rapid evaporation, rapid cooling, slow
cooling, vapor diffusion, sublimation, grinding and solvent-drop
grinding. In some aspect, the crystalline form of ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) is
generated from recrystallization of solid API from a solvent. In
one aspect, the solvent (for crystallization or recrystallization)
is an alcohol (e.g., ethanol, methanol, or propanol), fatty acid
(e.g., oleic acid, linoleic acid, or linoleic acid), alkane (e.g.,
hexane, heptane, pentane, or halogenated alkane), oil (e.g.,
vegetable oil, castor oil, or hydrogeneated oil), an ester, or any
other suitable solvent (e.g., pyridine, benzene, or toluene). In
one aspect, the crystalline form of ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) is generated from
recrystallization of solid API from a solvent in the presence of a
seeding agent. In one aspect, the seeding agent is a steroid. In
one aspect, the seeding agent is a derivative of 17 HPC. In one
aspect, the seeding agent is an ester of 17-hydroxyprogesterone
that is not the caproate ester.
[0283] Typically, crystalline forms of a specific ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate) can
be distinguished from each other by one or more physical or
analytical properties such as rate of dissolution, infrared or
raman spectroscopy, x-ray diffraction techniques such as single
crystal and powder diffraction techniques, solid state-NMR
(SS-NMR), thermal techniques such as melting point, differential
thermal analysis (DTA), differential scanning calorimetry (DSC),
thermal gravimetric analysis (TGA) and other methods as disclosed
elsewhere in the specification or available to the skilled artisan.
Other methods to characterize or distinguish a pseudopolymorph from
another isostructural polymorph, pseudopolymorph, desolvate or
anhydrate include elemental analysis, Karl-Fisher titration,
dynamic vapor sorption analysis, thermogravimetric-infrared
spectroscopic analysis (TG-IR), residual solvent gas
chromatography, 1H-NMR etc.
[0284] Thus, in one embodiment, an ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) is provided which has one
or more advantageous properties compared to other forms such as
chemical, crystalline, or polymorphic purity, increased
crystallinity, flowability, solubility, dissolution rate,
bioavailability, morphology or crystal habit, specific surface and
pycnometric density, bulk/tap density, stability (e.g., such as
chemical stability as well as thermal and mechanical stability with
respect to polymorphic conversion), stability towards hydration
and/or storage stability, a lower degree of hygroscopicity, low
content of residual solvent(s) and advantageous processing and
handling characteristics such as compressibility and bulk density.
The ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) is crystalline, non-crystalline, or a mixture thereof. In
specific aspects of this embodiment, the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) in
solid state form has unexpectedly improved dissolution, solubility,
bioavailability, bioactivity, fluctuation index, processing,
manufacturing, storage, taste, color, aggregates or granules.
[0285] In one embodiment, solid state ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
provided. In one aspect of this embodiment, the ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
crystalline or non-crystalline ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate), or a mixture thereof. In a
specific aspect, the solid state API is amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). The
solid state API is particularly suitable for administration to a
human. In one aspect, the solid state API is a specific crystalline
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) form (e.g., substantially similar to that characterized
in the Examples and figures by XRD. In a specific aspect, the solid
state API is crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) having 50%, 40%, 30%, 20%, 10%,
5%, 2%, or 1% or less by total weight amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). In
another aspect, the solid state API is a solvate or a
pseudopolymorph of ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate). In another aspect, the solid
state API is a polymorph of ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). In another aspect, the solid
state API is a hydrate of ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). In yet another aspect, the solid
state API is crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) form having 50%, 40%, 30%, 20%,
10%, 5%, 2%, or 1% or less by total weight of API of other
crystalline forms of ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate). In one aspect, the solid state
API is a crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) having a melting point in the
range of 110 to 130.degree. C., 115 to 125.degree. C., 117 to
124.degree. C., as determined by differential scanning calorimetry.
In one aspect, the solid state API has a melting point as
determined by differential scanning calorimetry characteristic of a
single crystal form or non-amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). In
one aspect, the solid state API is crystalline ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate)
having 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18
or more peaks as determined by XRD corresponding to those in FIG. 5
(one aspect, the peaks are chosen from the 7 tallest peaks in the
reference spectrum). In again yet another aspect, the solid state
API is ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone
caproate) having 50%, 40%, 30%, 20%, 10%, 5%, 2%, or 1% or less by
total weight of crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). In one aspect, the solid state
API is crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) which is not milled or is milled,
micronized, or nanosized. In one aspect, the solid state API is
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) having a D.sub.50 of greater than 1000 .mu.m, from 355 to
1000 .mu.m, from 180 to 355 .mu.m, from 125 to 180 .mu.m, from 90
to 125 .mu.m, from 1 to 90 .mu.m, or less than 1 .mu.m. In one
aspect, the solid state API is ester of 17hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) having a particle size of
less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1
to 50 .mu.m, from 50 .mu.m to 250 .mu.m, from 250 .mu.m to 500
.mu.m, from 500 .mu.m to 1000 .mu.m, or greater than 1000 .mu.m. In
one aspect, the solid state API is ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) having a D.sub.10,
D.sub.50, or D.sub.90 that is less than 200 nm, from 200 to 500 nm,
from 500 to 1000 nm, from 1 to 50 .mu.m, from 50 to 250 .mu.m, from
250 to 500 .mu.m, from 500 to 1000 .mu.m, or greater than 1000
.mu.m. In one aspect, the solid state ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is a
composition having greater than 1 g, 2 g, 50 g, 500 g, 1 kg, 10 kg,
50 kg, 100 kg, 200 kg, 500 kg, 1000 kg, 2000 kg, 5000 kg, or 10,000
kg solid state ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). In one aspect, the release
profile of the ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) does not change substantially as a
function of time.
Production of Amorphous API or Different Crystal Forms of Solid
State API
[0286] Described herein are different forms of API, particularly
ester of 17-hydroxyprogesterone (e.g 17-hydroxyprogesterone
caproate). The identification of different forms of API yields new,
improved properties related to the use of the API.
[0287] A number of different forms, including crystalline forms of
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) may exist. Crystalline ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) may be produced according
to the Figures and as described herein or by other methods
available to the ordinary skilled artisan in view of this
disclosure to obtain solid state forms having desirable
properties.
[0288] Amorphous ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is another solid state API form. A
number of techniques are available for preparing amorphous ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). For
example, flash evaporation, lyophilization, quench cooling of the
melt, spray drying, grinding, supercritical fluids are non-limiting
techniques that can be used to make amorphous API. In some aspects,
the amorphous ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is metastable.
Experimental Instrumentation and Conditions for Analyzing Solid
State API
[0289] A variety of techniques may be used to identify or
characterize solid state API, particularly solid state ester of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone caproate).
Fourier Transform-Raman Spectroscopy ("FT-Raman") is useful for
characterizing and identify solid state forms of (ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate). For
example, different solid API forms may be characterized using a
Bruker RFS100 instrument, with Nd:YAG 1064 nm excitation, 300 mW
laser power, Ge detector, using 64 scans over the range of 25-3500
cm.sup.-1, and with 2 cm.sup.-1 resolution. As is understood by the
ordinary skilled artisan, the parameters and instrumentation for
FT-Raman may be modified depending on the instrument, the solid
state API and goal(s) of the analysis.
[0290] Another useful technique for characterization is Power X-ray
Diffraction ("XRD"). XRD can be performed with a Bruker D8 Advance
X-ray diffractometer with CuK.alpha.-radiation. The standard
measuring conditions are e.g., tube power 35 kV/45 mA; step size
0.017.degree. (2.theta.); step time 105.+-.5 sec; scanning range
2.degree. -50.degree. (2.theta.); divergence slit equal to variable
V12; sample rotation; a Vantec1 detector; the opening angle
3.degree.; channel number 360.+-.10; the y-axis shows the value
intensity/number of active detector channels/sec; silicon single
crystal sample holders; and the sample dimensions depth/diameter
was 0.1 mm/.sup..about.12 mm. As is understood by the ordinary
skilled artisan, the parameters and instrumentation for PDXR may be
modified depending on the instrument, the solid state API and
goal(s) of the analysis. In one embodiment, the solid state ester
of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
is crystalline or substantially crystalline as indicated by XRD. An
example of an XRD spectra is shown in FIG. 6 for crystalline or
substantially crystalline ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate). FIG. 5 hows well defined peaks
corresponding to crystalline or substantially crystalline ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) with
little or no amorphous API (as indicated by the absence of an
"amorphous halo" in the spectra in the 20-40 degree 2.theta.
range). In one aspect, the solid state API described herein has 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more of the peaks that
corresponds to those in FIG. 5 (in one aspect these peaks are
chosen from the 7 tallest peaks in the reference spectrum).
Thermogravimetric-Fourier transform Infrared Spectroscopy
("TG-FTIR") can also be used to characterize or analyze solid state
API. For example, TG-FTIR can be performed with a Netzsch
Thermo-Microbalance TG 209 coupled with a Bruker FT-IR Spectrometer
Vector 22, using an aluminum crucible (open or with a microhole),
under a nitrogen atmosphere, and e.g., at a heating rate of
10.degree. C./min over the range of 25.degree. C. to 350.degree. C.
As is understood by the ordinary skilled artisan, the parameters
and instrumentation for TG-FITR may be modified depending on the
instrument, the solid state API and goal(s) of the analysis.
[0291] Characterization/Analysis of API can also be performed using
Differential Scanning calorimetry ("DSC"). For example, DSC can be
performed with a Perkin Elmer Differential Scanning calorimeter,
using closed gold crucibles, a heating rate of 10.degree. C.
min.sup.-1 or 20.degree. C. min.sup.-1 over a range from 0.degree.
C. to 300.degree. C. (or e.g., over a range from 5.degree. C. to
250.degree. C.). As is understood by the ordinary skilled artisan,
the parameters and instrumentation for DSC may be modified
depending on the instrument, the solid state API and goal(s) of the
analysis.
[0292] Thus, in yet another embodiment, a solid state API, e.g.,
ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate), is provided which has a melting point in the range of
about 50 to 300.degree. C., as determined by DSC. In a more
specific embodiment, a solid state API is provided which has a
melting point in the range of about 50 to 200.degree. C., as
determined by DSC. In another specific embodiment, a solid state
API is provided which has a melting point in the range of about 100
to 150.degree. C., as determined by DSC. In one aspect of this
embodiment, the melting point of the solid state API is
characteristic of a single physical form of API e.g., a single
crystalline form or amorphous API.
[0293] In yet another embodiment, a pharmaceutical composition or
unit dosage form having a solid state API (e.g., ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate) is
provided where the API in the pharmaceutical composition has a
melting point in the range of about 50 to 150.degree. C., as
determined by DSC. The pharmaceutical composition or unit dosage
form of this embodiment comprises or is prepared from solid state
API and one or more pharmaceutically acceptable carriers. In a more
specific embodiment, a pharmaceutical composition is provided
having or prepared from solid state API where the solid state API
starting material has a melting point in the range of about 85 to
145.degree. C., as determined by DSC. In a more specific
embodiment, a pharmaceutical composition is provided having or
prepared from solid state API where the solid state starting
material has a melting point in the range of about 110 to
130.degree. C., 115 to 125.degree. C., 117 to 124.degree. C., as
determined by DSC. In a specific embodiment, a pharmaceutical
composition is provided having or prepared from solid state which
has a melting point of API in the range of about 115 to 125.degree.
C., as determined by DSC. In one aspect of this embodiment, the
melting point of the pharmaceutical composition or unit dosage form
does not have a peak corresponding to the melting point peak of the
API from which it was prepared as determined by DSC. For example,
the melting point of the starting solid state API is in the range
of 115 to 125.degree. C. and when the melting point of the
pharmaceutical composition comprising the API is determined the
melting point peak in the range of 115 to 125.degree. C.
disappears, is diminished or substantially diminished. Dynamic
Vapor Sorption (DVS) analysis is another technique for
characterizing and analyzing API. For example, DVS can be performed
with a Surface Measurement Systems DVS-1 water vapor sorption
analyzer. The experiments can be run by placing the sample on a
quartz holder on top of a microbalance, and allowing the sample to
equilibrate at 50% relative humidity (r.h.) before starting the
pre-defined humidity program. The program can proceed e.g., in the
following steps: 1 hour at 50% r.h.; 50% to 0% r.h. at a rate of 5%
r.h. change per hour; 5 hours at 0% r.h; 0% r.h to 96% r.h. at 5%
r.h change per hour; 5 hours at 95% r.h.; 95% r.h. to 50% r.h. at a
rate of 5% r.h. change per hour, and followed by one hour at 50%
r.h. As is understood by the ordinary skilled artisan, the
parameters and instrumentation for DVS may be modified depending on
the instrument, the solid state API and goal(s) of the
analysis.
[0294] High performance liquid chromatography (HPLC) is also useful
for analyzing or characterizing API. In some of the embodiments,
the purity of the amorphous form of ester of 17-hydroxyprogesterone
(e.g., 17-hydroxyprogesterone caproate) as measured by high
pressure liquid chromatography is greater than about 90%, about
90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about
93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about
95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about
98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% total
area under the curve as observed at a suitable wavelength e.g.,
about 240 nm or about 242 nm. In some embodiments, the amorphous
form of ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is about 100.0% pure as measured
by HPLC as area under the curve as observed at a suitable
wavelength, e.g., at a wavelength of from about 200 nm to about 300
nm, e.g., about 240 nm or 242 nm.
[0295] In some of the embodiments, the purity of a crystalline form
of ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) as measured by HPLC is greater than about 90%, about
90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about
93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about
95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about
98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% total
area under the curve as observed at a suitable wavelength e.g.,
about 240 nm or about 242 nm. In some embodiments of the invention,
a crystalline form of ester of 17-hydroxyprogesterone (e.g.,
17-hydroxyprogesterone caproate) is about 100.0% pure as measured
by HPLC as area under the curve as observed at a suitable
wavelength, e.g., at a wavelength of from about 200 nm to about 300
nm, e.g., about 240 nm or 242 nm.
[0296] As is understood by the ordinary skilled artisan, solid
state NMR and other techniques can be used to analyze or
characterize solid API and forms thereof in view of this
disclosure.
Production of Different Sizes of Solid State API
[0297] Composition having different particles sizes or
distributions of particles sizes can be produced by any suitable
method. Micronization techniques can be based on friction to reduce
particle size; such methods include milling, bashing and grinding.
Another technique of producing different sized API particles
involves supercritical fluids where the API is dissolved in a
solvent at high temperature and pressure and they sprayed out of a
nozzle, causing the formation of API particles of particular sizes
or within particular size ranges/distributions. Some basic
supercritical fluid techniques are RESS process (Rapid Expansion of
Supercritical Solutions), the SAS method (Supercritical
Anti-Solvent) and the PGSS method (Particles from Gas Saturated
Solutions).
Particle Size and Morphology Analysis
[0298] Solid state API particles can be analyzed by a number of
techniques. For example, Particle size can analyzed by photon
correlation spectroscopy (PCS) using a Malvern ZetaSizer 2000 HS
(Malvern Instruments, Malvern, UK). The measuring mode applied can
be e.g., Contin-Auto mode. PCS yields the mean diameter of the bulk
population (z-average) and a polydispersity index (PI) ranging from
0 (monodisperse) through 0.10-0.20 (relatively monodisperse)
to>0.5 for a broad size distribution. The measuring range of PCS
is approximately 3 nm-3 .mu.m. As is understood by the ordinary
skilled artisan, the parameters and instrumentation for PCS may be
modified depending on the instrument, the solid state API and
goal(s) of the analysis.
[0299] Solid state API can also be analyzed by electron microscopy.
Solid particles are deposited on metallic stubs then placed in
liquid nitrogen and dried under vacuum. The freeze-dried particles
are coated uniformly with gold. All samples are examined for
morphology and surface properties using a scanning electron
microscope (e.g., Joel, SEM, JSM-25 SII, Tokyo, Japan). Particle
size, polydispersity index and zeta potential were initially
measured by a laser particle size analyser (Submicron Particle Size
Analyser 90 plus, Brookhaven Instrument Co., Holtsville, N.Y.,
USA). An aliquot of solid state API particles can be diluted with
e.g., 3 ml of deionized water. The diluted API samples are loaded
into a 4 ml cuvette and the particle size and zeta potential
measurement can be conducted at e.g., ambient temperature. As is
understood by the ordinary skilled artisan, the parameters and
instrumentation for electron microscopy may be modified depending
on the instrument, the solid state API and goal(s) of the
analysis.
[0300] The particle size can also be estimated by XRD e.g., by
applying the Sherrer equation which relates the size particles
(e.g., crystal particles or crystallites), in a solid to the
broadening of a peak in a diffraction pattern.
Release Profile of Solid State API
[0301] In one embodiment, the release profile (e.g., a profile
comprising 2, 3, 4, 5, or 6 or more time points each at least 5,
10, or 15 minutes apart or a single time point) of solid state
ester of 17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone
caproate) API does not change substantially as a function of
storage time. In one aspect, the release profile of solid state
17-HPC does not substantially change over a period of 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one aspect,
the release profile of solid state 17-HPC does not substantially
change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, or 16 months. In one aspect, the release profiles is tested
using a USP type 2 apparatus at 100 rpm in about 1000 mL 8%, 12% or
16% Triton X-100 solution in water at a specific temperature e.g.,
20.0, 37.0 or 40.0.degree. C. (.+-.0.5). In one aspect, a release
profile that does not substantially change over a period of time
refers to a release profile that changes by less than plus/minus
50%, 40%, 30%, 20%, or 10% or less of amount ester of
17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone caproate)
released at one or more specific time point under specific
conditions.
Exemplary Pharmaceutical Compositions and Unit Dosage Forms
[0302] The pharmaceutical compositions and oral dosage forms (e.g.,
capsule or tablet) described herein prepared from or comprising
solid ester of 17-hydroxyprogesterone (e.g., 17-hydroxyprogesterone
caproate) API can include a variety of pharmaceutically acceptable
carriers or excipeints known in the art. Exemplary pharmaceutical
compositions and unit dosage forms are given below in Tables A-E.
These Tables describe various formulations containing 17 HPC. In
one embodiment, the pharmaceutical composition or oral dosage form
includes 17 HPC and a carrier. According to one aspect of this
embodiment, the carrier can include a surfactant. In one aspect,
the surfactant is a lipophilic or hydrophilic surfactant. In one
aspect, the surfactant is an ionic or non-ionic surfactant. In yet
another aspect, the pharmaceutical composition includes 17 HPC and
one or more of: a diluent, filler, binder, adhesive, disintegrant,
lubricant, anti-oxidant, surfactant, colorant, flavorant, coating
agent, solvent, and water. In another aspect, the pharmaceutical
composition or unit dosage form includes (1) 17 HPC, (2) a diluent
and (3) one or more other pharmaceutically acceptable excipients.
In another aspect, the pharmaceutical composition or unit dosage
form includes (1) 17 HPC, (2) a binder and (3) one or more other
pharmaceutically acceptable excipients. In another aspect, the
pharmaceutical composition or unit dosage form includes (1) 17 HPC,
(2) a disintegrant and (3) one or more other pharmaceutically
acceptable excipients. In another aspect, the pharmaceutical
composition or unit dosage form includes (1) 17 HPC, (2) a
lubricant and (3) one or more other pharmaceutically acceptable
excipients. In another aspect, the pharmaceutical composition or
unit dosage form includes (1) 17 HPC, (2) a diluent (3) a binder
and (4) one or more other pharmaceutically acceptable excipients.
In another aspect, the pharmaceutical composition or unit dosage
form includes (1) 17 HPC, (2) a diluent (3) a disintegrant and (4)
one or more other pharmaceutically acceptable excipients. In
another aspect, the pharmaceutical composition or unit dosage form
includes (1) 17 HPC, (2) a diluent (3) a lubricant and (4) one or
more other pharmaceutically acceptable excipients. In another
aspect, the pharmaceutical composition or unit dosage form includes
(1) 17 HPC, (2) a binder (3) a disintegrant and (4) one or more
other pharmaceutically acceptable excipients. In another aspect,
the pharmaceutical composition or unit dosage form includes (1) 17
HPC, (2) a binder (3) a lubricant and (4) one or more other
pharmaceutically acceptable excipients. In another aspect, the
pharmaceutical composition or unit dosage form includes (1) 17 HPC,
(2) a disintegrant (3) a lubricant and (4) one or more other
pharmaceutically acceptable excipients. In another aspect, the
pharmaceutical composition or unit dosage form includes (1) 17 HPC,
(2) a diluent (3) a binder (4) a disintegrant and (5) one or more
other pharmaceutically acceptable excipients. In another aspect,
the pharmaceutical composition or unit dosage form includes (1) 17
HPC, (2) a diluent (3) a binder (4) a lubricant and (5) one or more
other pharmaceutically acceptable excipients. In another aspect,
the pharmaceutical composition or unit dosage form includes (1) 17
HPC, (2) a diluent (3) a disintegrant (4) a lubricant and (5) one
or more other pharmaceutically acceptable excipients. In another
aspect, the pharmaceutical composition or unit dosage form includes
(1) 17 HPC, (2) a binder (3) a disintegrant (4) a lubricant and (5)
one or more other pharmaceutically acceptable excipients. In
another aspect, the pharmaceutical composition or unit dosage form
includes (1) 17 HPC, (2) a diluent (3) a binder (4) a disintegrant,
(5) a lubricant and (5) one or more other pharmaceutically
acceptable excipients. In some aspects of this embodiment, the
pharmaceutical composition or oral dosage forms are as described
below in Tables A-E. In some aspects, the 17 HPC is present in the
pharmaceutical composition or unit dosage form in an amount ranging
from about 1 mg to about 1200 mg, In some aspects, the 17 HPC is
present in the pharmaceutical composition or unit dosage form in an
amount ranging from about 10 mg to about 1000 mg, In some aspects,
the 17 HPC is present in the pharmaceutical composition or unit
dosage form in an amount ranging from about 100 mg to about 900 mg,
In some aspects, the 17 HPC is present in the pharmaceutical
composition or unit dosage form in an amount ranging from about 200
mg to about 800 mg, In some aspects, the 17 HPC is present in the
pharmaceutical composition or unit dosage form in an amount ranging
from about 300 mg to about 700 mg, In some aspects, the 17 HPC is
present in the pharmaceutical composition or unit dosage form in an
amount ranging from about 350 mg to about 700 mg, In some aspects,
the 17 HPC is present in the pharmaceutical composition or unit
dosage form in an amount ranging from about 400 mg to about 700 mg,
In some aspects, the 17 HPC is present in the pharmaceutical
composition or unit dosage form in an amount ranging from about 450
mg to about 650 mg, In some aspects, the 17 HPC is present in the
pharmaceutical composition or unit dosage form in an amount ranging
from about 500 mg to about 600 mg, Typically, the total weight of
the unit dosage forms described in the following Tables (or
elsewhere in the specification) is greater than 10 mg and less than
2000 mg. In some aspects, the unit dosage forms (e.g., tablet,
caplet, capsule, etc.) as described in the Tables below have a
total weight of from 10-100 mg, 100-200 mg, 200-300 mg, 300-400 mg,
500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, 900-1000 mg,
1000-1100 mg, 1100-1200 mg, 1200-1300 mg, 1300-1400 mg, 1400-1500
mg, 1500-1600 mg 1600-1700 mg, 1700-1800 mg, 1800-1900 mg, or
1900-2000 mg. In some aspects, the loading of the 17 HPC in the
pharmaceutical compositions and unit dosage forms described in the
Tables below is greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 75%, 80%, 85%, 90%, or 95% (or within any range
defined by any two of these value (e.g., 30%-75% or 45%-65%,
etc.)). Loading is the mg amount of 17 HPC/total mg amount of the
unit dosage form or pharmaceutical composition multiplied by 100.
In one aspect, the 17 HPC is present in particulate form, partially
solubilized, fully solubilized, or amorphous form. In one aspect,
the 1 HPC is present as crystalline particulate form. In one
aspect, the crystalline particulate form of 17 HPC has a D.sub.50
of from 1000-750, 750-500, 500-250, 250-200, 200-150, 150-100, or
100-50 microns. In one aspect, the crystalline particulate form of
17 HPC has a D.sub.50 of from 50-40, 40-30, 30-20, 20-10, or 10-1
microns. In one aspect, the crystalline particulate form of 17 HPC
has a D.sub.50 of from 1000-750, 750-500, 500-250, 250-200,
200-150, 150-100, or 100-50 nanometers. In some aspects of this
embodiment, the pharmaceutical composition or unit dosage form is a
powder, granulate, particulate, bead, pellet, sprinkle, suspension,
solution, tablet, caplet, capsule, or a combination thereof. In
some aspects of this embodiment, the pharmaceutical composition or
unit dosage form is a matrix tablet. In some aspects of this
embodiment, the pharmaceutical composition or unit dosage form is a
coated or uncoated tablet. In some aspects of this embodiment, the
pharmaceutical composition or unit dosage form is immediate release
or controlled release. In some aspects, the controlled release
selected can be, intermediate, delayed, extended, sustained,
pulsatile, gastric, enteric or colonic. In some aspects of this
embodiment, the pharmaceutical composition of unit dosage form is
administered once, twice or three time a day to an individual in
need of treatment (e.g., a pregnant female). In yet another aspect,
the pharmaceutical composition or dosage form is administered with
food. In some aspects, the the oral dosage form or pharmaceutical
composition can provide a 17-hydroxyprogesterone caproate C.sub.avg
-24h of greater than about 0.1, 0.5 or 1.0 ng/mL when admistered to
a human subject (female or pregnant female) once or twice daily as
1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms. In some aspects
of this embodiment, the 17-hydroxyprogesterone caproate
compositions or dosage forms can provide a fluctuation in the
17-hydroxyprogesterone caproate levels less than about 2000, 1500,
1000, 900, 800, 700, 600, 500, 400, 300, 200, 175, 150, 140, 130,
120, 110 or 100 ng/mL, or greater than about 1, 10, 15, 25, 50, 75,
100, 200, 300 or 400 ng/mL (or within a range as defined by any two
of these values) wherein the fluctuation is determined by the
difference of the mean steady state C.sub.max and the mean steady
state C.sub.min of 17-hydroxyprogesterone caproate in plasma or
serum or blood, upon oral administration. In a specific aspect, the
AUC.sub.(0-24h) to dose ratio is between about 1.5 and about 10.0
ng*h mL.sup.-1 mg.sup.-1. In a specific aspect, the AUC
.sub.(0-24h) to dose ratio is between about 2.0 and about 10.0 ng*h
mL.sup.-1 mg.sup.-1. In a specific aspect, the AUC .sub.(0-24h) to
dose ratio is between about 3.0 and about 10.0 ng*h mL.sup.-1
mg.sup.-1. In a specific aspect, the AUC.sub.(0-24h) to dose ratio
is between about 4.0 and about 10.0 ng*h mL.sup.-1 mg.sup.-1. In a
specific aspect, the AUC .sub.(0-24h) to dose ratio is between
about 5.0 and about 10.0 ng*h mL.sup.-1 mg.sup.-1. In a specific
aspect, the AUC .sub.(0-24h) to dose ratio is between about 6.0 and
about 10.0 ng*h mL.sup.-1 mg.sup.-1. In a specific aspect, the AUC
.sub.(0-24h) to dose ratio is between about 7.0 and about 10.0 ng*h
mL.sup.-1 mg.sup.-1.
TABLE-US-00001 TABLE A 17HPC + Carrier Composition (% w/w)
Ingredients A B C 17-a-Hydroxyprogesterone 1-99 -- -- Caproate
(particle size >50 .mu.m) 17-a-Hydroxyprogesterone -- 1-99 --
Caproate (micronized: <15 .mu.m or nanosized: <1 .mu.m)
17-a-Hydroxyprogesterone -- -- 1-99 Caproate (milled, <50 .mu.m)
Carrier 1-99 1-99 1-99 Granulating solvent qs qs qs % Release in 1
hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
TABLE-US-00002 TABLE A1 Exemplary Composition of Surfactants, When
Present, in Carriers Composition in Carriers (% w/w) Surfactant AS1
AS2 AS3 BS1 BS2 BS3 CS1 CS2 CS3 Lipophilic additive (e.g. 100 --
5-95 100 -- 5-95 100 -- 5-95 lipophilic surfactant) Hydrophilic
additive -- 100 5-95 -- 100 5-95 -- 100 5-95 (e.g. hydrophilic
surfactant) AS: A composition in Table A + Surfactant BS: B
composition in Table A + Surfactant CS: C comuosition in Table A +
Surfactant
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00003 TABLE A2 Exemplary Composition of Carrier
Composition in Carrier component carriers (% w/w) Diluent/filler
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Binder/adhesive (e.g. cellulose derivatives, starch, 1-50
gelatin) Disintegrant (e.g. cellulose derivatives, 1-20
crospovidone, starch) Lubricant/glidant (e.g. magnesium stearate,
0-5 colloidal silicon dioxide) Anti-oxidant 0-50 Surfactant 0-95
Colorant 0-5 Flavor 0-5 Coating agent 0-5 Solvent 0-60 Water
0-40
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00004 TABLE B1 Drug + Diluent + Carriers Except Diluents
Composition (% w/w) Ingredients A2A B2A C2A
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Carriers except diluents 1-50 1-50 1-50 Granulating
solvent qs qs qs % Release in 1 hrs .gtoreq.20 .gtoreq.20
.gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00005 TABLE B2 Drug + Binder + Carriers Except Binders
Composition (% w/w) Ingredients A2B B2B C2B
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Binder/adhesive (e.g.
cellulose 1-50 1-50 1-50 derivatives, starch, gelatin) Carriers
except binders 1-50 1-50 1-50 Granulating solvent qs qs qs %
Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00006 TABLE B3 Drug + Disintegrant + Carriers Except
Disintegrants Composition (% w/w) Ingredients A2C B2C C2C
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Disintegrant (e.g.
cellulose 1-20 1-20 1-20 derivatives, crospovidone, starch)
Carriers except disintegrants 1-80 1-80 1-80 Granulating solvent qs
qs qs % Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00007 TABLE B4 Drug + Lubricant + Carriers Except
Lubricants Composition (% w/w) Ingredients A2D B2D C2D
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Lubricant/glidant (e.g. 0-5
0-5 0-5 magnesium stearate, colloidal silicon dioxide) Carriers
except lubricants 1-95 1-95 1-95 Granulating solvent qs qs qs %
Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00008 TABLE C1 Drug + Diluent + Binder + Carriers
Composition (% w/w) Ingredients A3A B3A C3A
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Binder/adhesive (e.g. cellulose 1-50 1-50 1-50
derivatives, starch, gelatin) Carriers 1-50 1-50 1-50 Granulating
solvent qs qs qs % Release in 1 hrs .gtoreq.20 .gtoreq.20
.gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00009 TABLE C2 Drug + Diluent + Disintegrant + Carriers
Composition (% w/w) Ingredients A3B B3B C3B
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Disintegrant (e.g. cellulose 1-20 1-20 1-20 derivatives,
crospovidone, starch) Carriers 1-50 1-50 1-50 Granulating solvent
qs qs qs % Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00010 TABLE C3 Drug + Diluent + Lubricant + Carriers
Composition (% w/w) Ingredients A3C B3C C3C
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Lubricant/glidant (e.g. 0-5 0-5 0-5 magnesium stearate,
colloidal silicon dioxide) Carriers 1-50 1-50 1-50 Granulating
solvent qs qs qs % Release in 1 hrs .gtoreq.20 .gtoreq.20
.gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00011 TABLE C4 Drug + Binder + Disintegrant + Carriers
Composition (% w/w) Ingredients A3D B3D C3D
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Binder/adhesive (e.g.
cellulose 1-50 1-50 1-50 derivatives, starch, gelatin) Disintegrant
(e.g. cellulose 1-20 1-20 1-20 derivatives, crospovidone, starch)
Carriers 1-50 1-50 1-50 Granulating solvent qs qs qs % Release in 1
hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00012 TABLE C5 Drug + Binder + Lubricant + Carriers
Composition (% w/w) Ingredients A3E B3E C3E
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Binder/adhesive (e.g.
cellulose 1-50 1-50 1-50 derivatives, starch, gelatin)
Lubricant/Glidant (e.g. 1-5 1-5 1-5 magnesium stearate, colloidal
silicon dioxide) Carriers 1-50 1-50 1-50 Granulating solvent qs qs
qs % Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
[0303] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00013 TABLE C6 Drug + Disintegrant + Lubricant + Carriers
Composition (% w/w) Ingredients A3F B3F C3F
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Disintegrant (e.g.
cellulose 1-20 1-20 1-20 derivatives, crospovidone, starch)
Lubricant/Glidant (e.g. 1-5 1-5 1-5 magnesium stearate, colloidal
silicon dioxide) Carriers 1-75 1-75 1-75 Granulating solvent qs qs
qs % Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00014 TABLE D1 Drug + Diluent + Binder + Disintegrant +
Carriers Composition (% w/w) Ingredients A4A B4A C4A
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Binder/adhesive (e.g. cellulose 1-50 1-50 1-50
derivatives, starch, gelatin) Disintegrant (e.g. cellulose 1-20
1-20 1-20 derivatives, crospovidone, starch) Carriers 1-50 1-50
1-50 Granulating solvent qs qs qs % Release in 1 hrs .gtoreq.20
.gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00015 TABLE D2 Drug + Diluent + Binder + Lubricant +
Carriers Composition (% w/w) Ingredients A4B B4B C4B
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Binder/adhesive (e.g. cellulose 1-50 1-50 1-50
derivatives, starch, gelatin) Lubricant/Glidant (e.g. 0-5 0-5 0-5
magnesium stearate, colloidal silicon dioxide) Carriers 1-50 1-50
1-50 Granulating solvent qs qs qs % Release in 1 hrs .gtoreq.20
.gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00016 TABLE D3 Drug + Diluent + Disintegrant + Lubricant +
Carriers Composition (% w/w) Ingredients A4C B4C C4C
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Disintegrant (e.g. cellulose 1-20 1-20 1-20 derivatives,
crospovidone, starch) Lubricant/Glidant (e.g. 0-5 0-5 0-5 magnesium
stearate, colloidal silicon dioxide) Carriers 1-50 1-50 1-50
Granulating solvent qs qs qs % Release in 1 hrs .gtoreq.20
.gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00017 TABLE D4 Drug + Binder + Disintegrant + Lubricant +
Carriers Composition (% w/w) Ingredients A4D B4D C4D
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Binder/adhesive (e.g.
cellulose 1-50 1-50 1-50 derivatives, starch, gelatin) Disintegrant
(e.g. cellulose 1-20 1-20 1-20 derivatives, crospovidone, starch)
Lubricant/Glidant (e.g. 0-5 0-5 0-5 magnesium stearate, colloidal
silicon dioxide) Carriers 1-50 1-50 1-50 Granulating solvent qs qs
qs % Release in 1 hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00018 TABLE E Drug + Diluent + Binder + Disintegrant +
Lubricant + Carriers Composition (% w/w) Ingredients A5A B5A C5A
17-a-Hydroxyprogesterone 1-99 -- -- Caproate (particle size >50
.mu.m) 17-a-Hydroxyprogesterone -- 1-99 -- Caproate (micronized:
<15 .mu.m or nanosized: <1 .mu.m) 17-a-Hydroxyprogesterone --
-- 1-99 Caproate (milled, <50 .mu.m) Diluent/filler 1-50 1-50
1-50 (e.g. lactose, starch, glucose, magnesium salt, potassium
chloride) Binder/adhesive (e.g. cellulose 1-50 1-50 1-50
derivatives, starch, gelatin) Disintegrant (e.g. cellulose 1-20
1-20 1-20 derivatives, crospovidone, starch) Lubricant/Glidant
(e.g. 0-5 0-5 0-5 magnesium stearate, colloidal silicon dioxide)
Carriers 1-50 1-50 1-50 Granulating solvent qs qs qs % Release in 1
hrs .gtoreq.20 .gtoreq.20 .gtoreq.20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0304] As indicated in the Tables above, pharmaceutical
compositions or unit dosage forms described herein can release
greater than 20% of the 17 HPC at one hour when tested under
appropriate conditions. The selection of conditions depends on a
number of factors that the skilled artisan is aware of In one
aspect, the release of 17 HPC is tested with a USP Type II
Dissolution Apparatus using a specific aqueous media. In one
aspect, the specific aqueous media is one in which provides sink
conditions for the amount of 17 HPC in the pharmaceutical
composition or unit dosage form. Sink conditions refers to the
ability of the aqueous media to completely dissolve all of the 17
HPC and is determined by the solubility of 17 HPC in that
particular aqueous media. In one specific aspect, the release is
determined in 2.times., 3.times., 4.times., 5.times., 6.times.,
7.times., 8.times., or 10.times. or more sink conditions. For
example, 2.times. refers to the ability of the media to dissolve
twice the total amount of the 17 HPC in the pharmaceutical
composition or unit dosage form (if the solubility of 17 HPC was 1
mg/mL in a particular aqueous media and 1000 mL than that would be
2.times. for 500 mg of 17 HPC; 4.times. for 250 mg 17 HPC, etc.).
In one aspect, the aqueous media has 0.5% (w/w) sodium lauryl
sulfate. In another aspect, the aqueous media is simulated
intestinal fluid having 0.5% w/w sodium lauryl sulfate. In another
aspect, the aqueous media is 900 mL simulated intestinal fluid
having 0.5% w/w sodium lauryl sulfate. In one aspect, the release
is tested using a USP Type II apparatus at 50 or 100 rpm in about
1000 mL 8%, 12% or 16% Triton X-100 solution in water at a specific
temperature e.g., 20.0, 37.0 or 40.0.degree. C. (.+-.0.5).
EXAMPLES
[0305] 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 or mentioned, all the compositions provided in the
examples are with respect to %w/w of the final composition. Note
that with the exception of the compositions listed in Examples 1,
7, 10, 17 and 36, the 17-hydroxyprogesterone caproate of all other
example compositions can be in either treated (milled, micronized,
or nanosized) or untreated form. The 17-hydroxyprogesterone
Caproate in compositions 1, 7, 10, 17 and 36 are untreated for size
reduction (i.e., unmilled, non-micronized, un-micronized or
non-nanosized), and have an average particle size greater than 50
micrometers. The dosage forms of corresponding Examples were tested
for release of the 17-hydroxyprogesterone caproate using a USP Type
II apparatus, 50 rpm in 900 mL of simulated intestinal fluid having
0.5% w/w sodium lauryl sulfate at 37.degree. C. The percent of the
17-hydroxyprogesterone caproate released from each composition was
analyzed using HPLC.
Examples 1-6
17-Hydroxyprogesterone Caproate Compositions
[0306] 17-hydroxyprogesterone caproate compositions as recited in
Examples 1 through 6 are prepared by using the respective
components shown in Table I. Example 1 is the untreated crystalline
form of 17-hydroxyprogesterone caproate filled into hard gelatin
capsule. Example 2 is micronized 17-hydroxyprogesterone caproate
without a carrier filled into hard gelatin capsule. Examples 3-6,
are prepared as follows: The required quantities of each of the
components of the respective composition, except
17-hydroxyprogesterone caproate 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 17-hydroxyprogesterone caproate 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
17-hydroxyprogesterone caproate dose required. The capsules are
allowed to solidify at room temperature and then banded, and
packaged into HDPE bottles and sealed with a lid.
[0307] The 17-hydroxyprogesterone caproate released within 60
minutes from each of the compositions using the aforementioned
dissolution testing parameters are shown in Table I. Moreover, FIG.
1 shows the comparative release of Examples 1 and 2 over a duration
of 2 hours. It should be noted that the Examples 1 & 2
(17-hydroxyprogesterone caproate without a carrier) and Examples 3
to 6 (17-hydroxyprogesterone caproate admixed with at least one
carrier) can be used for comparison purposes to help illustrate the
advantages of the compositions and dosage forms of the current
invention.
TABLE-US-00019 TABLE I Example No. 1 2 3 4 5 6 Ingredients
Composition in % w/w. 17-hydroxyprogesterone 100 100* 12 15 11 18
caproate Lipophilic additive: -- -- 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 60 mins <10 >70 >70 >70 >70 >70
*micronized 17-hydroxyprogesterone caproate (approximate particle
size distribution: d100% <25 .mu.m; d50% <15 .mu.m)
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0308] The aqueous dispersion of the mixture that includes a
lipophilic additive and a hydrophilic surfactant, if present, of
the Examples 3 to 6 of Table-I can be hazy to non-clear when viewed
with a naked eye. Their absorbance at 400 nm can be greater than
0.1, or greater than 0.3, and/or the particle size of the
dispersion can be greater than 100 nm. In some aspects, the average
particle size of the dispersion may be greater than 250 nm. Each of
the aqueous dispersions is prepared by mixing 1 part of the mixture
of the additives of the corresponding example and 99 parts of an
aqueous diluent. The compositions of Example 3-6 may be prepared by
mixing the additives the 17 hydroxyprogesterone caproate to get a
homogenous solution or suspension. If required, the mixture may be
heated (for example, to about 40.degree. C. to about 80.degree. C.)
to get a solution or to achieve a homogenous suspension. The
mixture can be disposed into a capsule. The dosage form of Example
1 and 2 has 17-hydroxyprogesterone caproate in the solid
unmicronized and micronized particulate form respectively. The
17-hydroxyprogesterone caproate can be fully solubilized (as in
case of Example 3) or partially solubilized (as in case of Examples
5 and 6). The formulations of Table I, if liquid, can be also
formulated to be a solid dosage form by filling either as is, or
admixed with a solidification aid, into a capsule. Alternatively,
they can be formulated into tablets by using appropriate tableting
aids.
Examples 7-10
17-Hydroxyprogesterone Caproate Compositions
[0309] 17-hydroxyprogesterone caproate compositions of Examples 7
through 10 can be prepared by using the ingredients shown in Table
II and attain the release performance indicated.
TABLE-US-00020 TABLE II Example No. 7 8 9 10 Ingredients
Composition in % w/w. 17-hydroxyprogesterone 90-99 -- -- 90-99
caproate (particle size >50 .mu.m) 17-hydroxyprogesterone --
70-80 -- -- caproate micronized* 17-hydroxyprogesterone -- -- 70-80
-- caproate (milled) Lactose 1-10 1-20 1-20 30 Povidone K30 3-6 3-6
3-6 3-6 Organic granulating -- 0 or 0 or q.s*** solvent (example,
q.s*** q.s***- .sup. alcohol)** % release in 60 mins <15 >50
>50 >30 *may be substituted with nanomilled or nanosized
17-hydroxyprogesterone caproate. **removed substantially during
drying process ***Quantity sufficient for wet granulation process
or for in situ formation/precipitation of fast releasing solid
17-hydroxyprogesterone caproate
[0310] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0311] It should be noted that the compositions of Examples 7 to 10
can be formulated to provide granules for compression into a tablet
or filling in a capsule, sachet etc., with the inclusion of
appropriate pharmaceutical aids such as diluents, binder,
disintegrant, lubricants, flavor, etc.
[0312] Unlike Example 1 and 7, the 17-hydroxyprogesterone caproate
release profile of Examples 8, 9 and 10, shown in Table II,
illustrate the advantages of the smaller particle size of
17-hydroxyprogesterone caproate. These Examples further illustrate
the advantages of various manufacturing processes, such as
granulation, which yield solid compositions with appropriate
17-hydroxygprogesterone caproate release profiles. In some
embodiments, the caproate ester in the compositions of examples in
Table II can be substituted with other esters of
17-hydroxyprogesterone, such as acetate or undecanoate.
Example 11
17-Hydroxyprogesterone Caproate Coated Tablets
[0313] 17-hydroxyprogesterone caproate tablets of Example 7 through
10 can be further coated with a coating solution having typical
composition set forth in Table III, using conventional tablet
coating procedures known in the art to a weight gain of about 3 to
6%.
TABLE-US-00021 TABLE III Ingredients Composition in % w/w Polymer
(for e.g. 8.0 Hypromellose, Methocel E 5) Plasticizer (e.g.
Polyethylene 0.6 glycol, NF 8000) Coating Solvent 54.8 (e.g.
Ethanol) Coating Solvent 36.6 Water
[0314] The coating polymer can be selected based on the need for a
specific functionality to be imparted to the dosage form. For
example film coating, taste masking, enteric coating protective
coating, sustained release coating and so on can all be used.
Unlimited examples of the polymers for use in such coatings include
hypromellose, polyethylene glycol, povidone, sugars, ethyl
celluloses, methacrylates, cellulose phthalates etc. Many
conventional coating aids such as talc, starch, plasticizers,
opacifiers, colors, flavors etc. can also be used along with
coating polymers or sugars. The coating solvents can be suitably
varied based on the coating polymer or sugar being applied.
Examples 12
17-Hydroxyprogesterone Caproate Compositions
[0315] Table IV shows the 17-hydroxyprogesterone caproate
compositions of Examples 12-17 that can be prepared by using the
components set forth therein and the method similar to that
described for Examples 3-6. The release of 17-hydroxyprogesterone
caproate from the dosage form is also shown in Table IV.
TABLE-US-00022 TABLE IV Example No. 12 13 14 15 16 17 Ingredients
Composition % w/w 17-hydroxyprogesterone caproate 15 15 14 15 22 25
Lipophilic Additive . . . -- 85 -- -- -- -- (example Glyceryl
Caprylate/Caprate (Capmul .RTM.MCM) Lipophilic Additive (e.g . . .
Capric Acid) 85 -- -- -- -- -- Lipophilic Additive (e.g Glyceryl --
73 65 3 5 Monolinoleate) Hydrophilic Additive (e.g. Polyoxyl -- --
13 15 -- -- 40 Hydrogenated Castor Oil) Hydrophilic Additive (e.g.
Polyoxyl 35 -- -- -- -- -- 22 Castor Oil) Lipophilic Additive (e.g
Glyceryl -- -- -- 5 -- -- Palmitostearate; Glyceryl distearate,
Precirol .RTM. ATO 5) Hydrophilic Additive (e.g. -- -- -- -- 22 --
Tocopherol Polyethylene Glycol Succinate) Lipophilic Additive (e.g
Vitamin E; -- -- -- -- 35 48 d,l-.alpha.-tocopherol) Hydrophilic
Additive (e.g. Hypromellose -- -- -- -- 18 -- (4,000 cPs) % release
in 60 mins >40 >40 >40 >40 >30 >40
[0316] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0317] The aqueous dispersion of the mixture of lipophilic additive
and the hydrophilic surfactant, if present, in the examples shown
in Table-IV can be hazy to non-clear when viewed with the naked
eye. Their absorbance at 400 nm can be greater than 0.1, or greater
than 0.3, and/or the particle size of the dispersion can be greater
than 100 nm. In some aspects, the mean particle size of the
dispersion may be greater than 250 nm. Each of the aqueous
dispersions is prepared by mixing 1 part of the mixture of the
additives of the corresponding example and 99 parts of an aqueous
diluent.
[0318] The compositions of Table IV, if liquid, can be formulated
to be solid dosage forms by filling into a capsule either as is, or
admixed with a solidification aid such as polyethylene glycol,
glyceryl distearate, wax and the like. It should be noted that
these compositions can also be formulated to obtain granules for
compression into a tablet or filling into a capsule, sachet etc.,
with the inclusion of appropriate pharmaceutical aids such as
diluents, binders, disintegrants, lubricants, flavors, etc.
[0319] The 17-hydroxyprogesterone caproate in the compositions of
examples in Table IV can in some embodiments be substituted with
other esters of 17-hydroxyprogesterone, such as
17-hydroxyprogesterone acetate or 17-hydroxyprogesterone
undecanoate.
Examples 18-23
17-Hydroxyprogesterone Caproate Compositions
[0320] Table V shows various 17-hydroxyprogesterone caproate
compositions as recited in Examples 18-23 that can be prepared
using the components set forth therein.
TABLE-US-00023 TABLE V Example No. 18 19 20 21 22 23 INGREDIENT
Composition % w/w 17-hydroxyprogesterone 9 7 6 8 8 6 caproate
Hydrophilic Surfactant 1 1 1 4 1 1 (e.g. Tween 80) Hydrophilic
Surfactant 4 4 3 1 4 3 (e.g. Sodium Lauryl Sulfate) Hydrophilic
Polymer -- 15 26 5 -- 25 (e.g. HPMC) Enteric Polymer -- -- -- -- --
4 (e.g. Eudragit) Hydrophobic Polymer -- -- -- -- 5 -- (e.g. Ethyl
Cellulose) Diluents/Processing Aids 86 73 64 82 82 61 Total 100 100
100 100 100 100
Table VI shows various specific embodiments of different dosage
forms (DF-1 to DF-9) containing 17-hydroxyprogesterone caproate
that can be achieved by various combinations of the compositions
shown in Table V.
[0321] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
TABLE-US-00024 TABLE VI Dosage Form Composition DF-1 DF-2 DF-3 DF-4
DF-5 DF-6 DF-7 DF-8 DF-9 Example No. Composition % w/w 18 100 50 50
50 30 -- -- 30 50 19 -- 50 -- -- -- -- -- -- -- 20 -- -- 50 -- --
100 -- 30 -- 21 -- -- -- 50 -- -- -- 40 50 22 -- -- -- -- -- -- 100
-- -- 23 -- -- -- -- 70 -- -- -- -- Total 100 100 100 100 100 100
100 100 100
[0322] Additional tableting methods known in the art can be used
can be applied to the above exemplified compositions. [0323]
Excipients shown are exemplary of classes of excipients that can be
used [0324] The form of the drug can be interchanged with other
forms such as micronized, sieved, milled, amorphous, nano, etc. The
above dosage forms DF-1 to DF-9 can be single or multiple
particulate units in a capsule or as single or multiple particulate
units compressed into a single tablet or multi-layer tablets.
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Examples 24-28
17-Hydroxyprogesterone Caproate Compositions
[0325] Table VII shows 17-hydroxyprogesterone caproate compositions
as recited in Examples 24-28 that can be prepared using the
components set forth therein, and their release performance.
TABLE-US-00025 TABLE VII Example No. 24 25 26 27 28 INGREDIENT
Composition (mg per dosage form) 17-hydroxyprogesterone 50 50 50 50
50 Hydrophilic Surfactant 2.5 2.5 2.5 2.5 2.5 (e.g. Tween 80)
Hydrophilic Surfactant 12.5 12.5 12.5 12.5 12.5 (e.g. Sodium Lauryl
Sulfate) Hydrophilic Polymer 125 65 90 -- 3 (e.g. HPMC) Enteric
Polymer -- -- -- -- 5 (e.g. Eudragit) Coating Processing Aids -- --
-- -- 2 (e.g. Plasticizer, Anti-sticking agent) Diluents/Processing
Aids 25 25 35 35 35 (e.g. binder, disintegrant, diluent, glidant,
lubricant) Total 215 155 190 100 110 % Release in 60 minutes >25
>40 >40 100 >30
[0326] Additional tableting methods known in the art can be used
can be applied to the above exemplified compositions. [0327]
Excipients shown are exemplary of classes of excipients that can be
used, processing aids like binders, disintegrants, diluents,
glidants, lubricants and coating aids commonly known in the art can
be used. [0328] The form of the drug can be interchanged with other
forms such as micronized, sieved, milled, amorphous, nano, etc.
[0329] The above dosage forms can be single or multiple particulate
units in a capsule or as single or multiple particulate units
compressed as a monolithic/matrix tablet or multi-layer tablets For
Example 28 the dosage form is first exposed to about 250 mL
simulated gastric fluid (SGF) without enzyme for the first 30
minutes, followed by exposure to 900 mL of 0.5 wt % SLS in water at
having pH about 6.8.
[0330] According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 100 mg to 495 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 150 to 450 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 200 mg to 490
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Examples 29-35
17-Hydroxyprogesterone Caproate Compositions
[0331] Table VIII shows 17-hydroxyprogesterone caproate
compositions and release data within 60 min for Examples 29-35 that
can be prepared by using components set forth therein and the
method similar to that described for Examples 12-17. Furthermore,
FIGS. 2 and 3 show the release profile over the course of two hours
for Examples 31 and 34 in comparison to Example 1 respectively.
TABLE-US-00026 TABLE VIII Example No. 29 30 31 32 33 34 35
Ingredients Composition % w/w 17-hydroxyprogesterone caproate 25 20
7 7 8 16 25 Lipophilic Additive 48 45 -- -- -- 29 53 (e.g. Benzyl
benzoate) Hydrophilic Additive 2 2 -- -- -- -- 2 (e.g. Benzyl
alcohol) Lipophilic Additive (e.g. Castor Oil) 25 23 -- -- -- -- --
Lipophilic Additive -- -- -- -- 67 -- (e.g. Corn glycerides)
Lipophilic Additive (e.g. Glyceryl -- -- 51 48 -- 17 --
Caprylate/Caprate; Capmul .RTM.MCM) Lipophilic Additive -- -- -- --
-- -- -- (e.g. Capric Acid) Hydrophilic Additive (e.g Polyoxyl --
10 42 40 25 38 10 40 Hydrogenated Castor Oil) Hydrophilic Additive
-- -- -- 5 -- -- 10 (e.g Polyethylene glycol 8000) % release in 60
mins >25 >25 >90* >80 >60 >60 >25 *% released
in 30 minutes
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0332] The above compositions can be formulated to exhibit
immediate or controlled release profiles. The aqueous dispersion of
the mixture of the lipophilic additive and the hydrophilic
surfactant, if present, in the examples of Table-VIII can be hazy
to non-clear when viewed with the naked eye. Their absorbance at
400 nm are greater than 0.1, in some cases greater than 0.3, and/or
the average particle size of the dispersion may be greater than 100
nm in some aspects. In other aspects, the average particle size of
the dispersion can be greater than 250 nm. Each of the aqueous
dispersions is prepared by mixing 1 part of the mixture of the
additives and surfactants of the corresponding example and 99 parts
of an aqueous diluent.
[0333] As can be seen from the above Examples 29, 30 and 35 by
using benzyl benzoate and/or benzyl alcohol, a higher drug loading
(e.g.>20% w/w 17-hydroxyprogesterone caproate) with desired
release characteristics can be achieved. The 17-hydroxyprogesterone
caproate can remain fully solubilized (Examples 29, 30, 31, and 33)
or can be partially solubilized (Examples 32, 34 and 35) in the
compositions. Further, when viewed with the naked eye the aqueous
dispersion of the mixtures having a lipophilic additive and the
hydrophilic surfactant, if present, as recited in Examples 29-31
and 33-35 can be hazy to non-clear. In some cases, their absorbance
at 400 nm is greater than 0.1, or even greater than 0.3. Further
the average particle size of the dispersion can be greater than 100
nm, or even greater than 250 nm. Each of the aqueous dispersions is
prepared by mixing 1 part of the mixture of the additives and
surfactants of the corresponding example and 99 parts of an aqueous
diluent.
[0334] The 17-hydroxyprogesterone caproate in the compositions of
examples in Table VIII can in some aspects substituted with other
esters of 17-hydroxyprogesterone, such as 17-hydroxyprogesterone
acetate or 17-hydroxyprogesterone undecanoate.
[0335] The compositions of example 3, 31, 32, 33, and 34 can in
some aspects, also be administered as oral liquid. These
compositions can also be administered orally after appropriate
admixture/dilution with diluent such as water, milk, fruit juices,
beverages and the like just before administration.
[0336] In certain embodiments, the contents of the above
compositions can be adsorbed on some diluents and additional
excipients and can be compress into tablet.
Example 36
17-Hydroxyprogesterone Caproate Tablets
[0337] 17-hydroxyprogesterone caproate containing granules for
tableting having the components set forth in Table IX can be
prepared by wet granulation methods. Accordingly,
17-hydroxyprogesterone caproate, 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 sized/screened, lubricated with Aerosil 200 and magnesium
stearate, and compressed into tablets.
TABLE-US-00027 TABLE IX Ingredients Composition in % w/w
17-hydroxyprogesterone caproate (untreated) 28 Microcrystalline
Cellulose (Avicel PH 102) 52.5 Croscarmellose sodium 10
Pregelatinized starch (Starch1500) 8 Colloidal silicon dioxide
(Aerosil 200) 0.5 Magnesium stearate 1
[0338] The tablets of Example 36 exhibit less than 20%
17-hydroxyprogesterone caproate released in the first 60 minutes
when tested using a USP Type II apparatus, 50 rpm in 900 mL of
simulated intestinal fluid having 0.5% w/w sodium lauryl sulfate at
37.degree. C. Whereas, when the micronized 17-hydroxyprogesterone
caproate (with particle size d100% being about 50 .mu.m or less)
with or without surfactant is used in the above formula, at least
40% release of 17-hydroxyprogesterone caproate may be observed
after the 60 minute time-point.
Examples 37-42
17-Hydroxyprogesterone Caproate Compositions
[0339] Examples 37-39 of Table X have hydrophilic additives as
carriers. The Examples 37, 38 and 39 therein are prepared by wet
granulation process with organic solvent such as ethanol or
ethanol-water as the granulating liquid. Partial or full amounts of
some of hydrophilic additives therein (e.g. povidones, pluronics,
surfactants etc.) can be dissolved in the granulating liquid.
Optionally the ester of 17-hydroxyprogesterone (e.g.
17-hydroxyprogesterone caproate) can be solubilized or suspended in
the granulating liquid. This granulating liquid can then be poured
over the adsorbing hydrophilic carriers (e.g. celluloses, Lactose
etc.) with low shear mixing. The granules can be dried under a
gentle current of air at room temperature. The dried granules are
passed through ASTM #40 mesh and filled into appropriate size
capsules or compressed into tablets according to the required
17-hydroxyprogesterone caproate strength per unit dosage form.
[0340] 17-hydroxyprogesterone caproate compositions of Examples
40-42 can be prepared by using the components set forth in Table X
and according to the following method: The required quantities of
the respective inactive component and the 17-hydroxyprogesterone
caproate, are 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 homogenous mixture. A predetermined weight of the resulting
mixture is disposed into hard gelatin capsule and allowed to
solidify at room temperature.
[0341] The dosage forms of each Example 37-42 are tested for
release of the 17-hydroxyprogesterone caproate using a USP Type II
apparatus, at 50 rpm in 900 mL of simulated intestinal fluid having
0.5% w/w sodium lauryl sulfate at 37.degree. C. The percent of the
17-hydroxyprogesterone caproate released from each composition is
analyzed using HPLC. The results of the release testing are also
shown in Table X.
[0342] It should be noted that the compositions of Examples 37-42
can be formulated to achieve tablet dosage forms with the inclusion
of appropriate conventional tableting aids such as diluents,
binders, disintegrants, lubricants, etc. as needed.
TABLE-US-00028 TABLE X Example No. 37 38 39 40 41 42 Ingredients
Composition in % w/w 17-hydroxyprogesterone 45 40 40 75 34 60
caproate PEG 8000 USP -- -- -- 10 29 40 Sodium Lauryl sulfate 10 9
9 10 -- -- Microcrystalline 45 40 37 -- -- -- Cellulose*, Pluronic
F 68 0 11 11 -- -- -- Polyvinylpyrrolidone 0 0 3 5 37 -- (Povidone
K 30) % release in 60 mins >40 >40 >40 >40 >40
>30 *Magnesium alumnometasilicate (Neuslin .RTM.), lactose and
other similar substances can be used/calcium silicate
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
[0343] The in vitro 17-hydroxyprogesterone caproate release
performance of Examples 37 to 42 can be seen to be superior over
the release performance of the Example 36. It should be noted that
in the above-recited compositions, appropriate amounts of typical
pharmaceutical aids such as glidants, lubricants, anti-adherents,
disintegrants and the like, can be incorporated as needed. Further,
suitable amounts of hydrophilic release modifying agents (e.g.
hypromellose, Eudragits etc.) may also be incorporated as needed in
the compositions of Examples 37 to 42. Also, in some particular
cases, when the dosage form of the Examples 37 to 42 is a tablet,
appropriate functional coatings may be applied as required. It
should also be noted that in some aspects the example compositions
of Table X can be substituted with other esters of
17-hydroxyprogesterone (e.g. 17-hydroxyprogesterone acetate,
17-hydroxyprogesterone undecanoate, etc.)
Examples 43 and 44
17-Hydroxyprogesterone Caproate Compositions
[0344] 17-hydroxyprogesterone caproate compositions as recited in
Examples 43 and 44 were prepared by using the components set forth
in Table XI. Each of the compositions was prepared by incorporating
17-hydroxyprogesterone caproate in the molten mixture of the
corresponding inactive components taken in a stainless steel
container at about 35.degree. C. to 70.degree. C. with gentle
stirring to get a free-flowing liquid mixture. A predetermined
weight of the resulting liquid mixture is disposed into hard or
soft gelatin capsule shells 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 an ASTM mesh #30 to get granular
particulates, which can be further filled in hard gelatin capsules
or compressed into tablets.
[0345] Each of the compositions is tested for release of the
17-hydroxyprogesterone caproate using a USP Type II apparatus, at
50 rpm in 900 mL of simulated intestinal fluid having 0.5% w/w
sodium lauryl sulfate at 37.degree. C. The percent of the
17-hydroxyprogesterone caproate released from each composition is
analyzed using HPLC. The results of the release testing are also
shown in Table XI.
TABLE-US-00029 TABLE XI Example No. 43 44 Ingredients Composition
in % w/w 17-hydroxyprogesterone caproate 20 80 Lipophilic additive:
80 20 (e.g., Glycerol esters of C.sub.12-C.sub.18 fatty acids) %
release in 60 mins >30% >30%
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 45
17-Hydroxyprogesterone Caproate Spray Dried Multiparticulates
[0346] 17-hydroxyprogesterone caproate multiparticulates can be
prepared as follows: 15 g of a milled or micronized
17-hydroxyprogesterone caproate and lactose, mixture (95:5 w/w),
are passed through ASTM mesh #60 sieve and added under mixing to
about 250 mL of a 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 a 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 17-hydroxyprogesterone caproate
composition can have a compositional makeup of about 53 wt %
17-hydroxyprogesterone caproate, about 2.8 wt % lactose and about
44.2 wt % povidone K17.
[0347] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 46-50
17-Hydroxyprogesterone Caproate Compositions
[0348] A mixture of 17-hydroxyprogesterone caproate and the
corresponding 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 is 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 compositions for
melt-extrusion are indicated in Table XII. These dosage forms can
release 40% or more 17-hydroxyprogesterone caproate in about first
60 minutes. It should be noted that the 17-hydroxyprogesterone
caproate compositions of Table XII can be further formulated to
include one or more 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-00030 TABLE XII Example No. 46 47 48 49 50 Ingredients
Composition in %w/w 17-hydroxyprogesterone caproate 70 40 50 80 60
Polyethylene glycol 8000 USP 10 -- 20 15 20 (Glyceryl distearate
GDS, 10 40 20 -- -- Precirol ATO 5) Stearic acid 10 20 10 --
Cholesterol -- -- -- 5 20
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 51
17-Hydroxyprogesterone Caproate Compositions Produced by
Co-Milling
[0349] A 17-hydroxyprogesterone caproate containing composition can
be prepared by co-milling (or co-grinding) 80 g
17-hydroxyprogesterone caproate along with 15 g PVP K 17 and 5 g of
sodium lauryl sulfate 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, 50 rpm in 900 mL of simulated intestinal fluid
having 0.5% w/w sodium lauryl sulfate at 37.degree. C.
[0350] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 52
17-hydroxyprogesterone caproate loaded pellets
[0351] 17-hydroxyprogesterone caproate coated pellets are prepared
using the ingredients set forth in Table XIII A spraying solution
of the coating materials can be prepared by dissolving 25 g of
17-hydroxyprogesterone caproate, 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 conventional coating pan.
After all the spray solution is loaded on the spheres, it can be
dried under a 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 17-hydroxyprogesterone caproate
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.
[0352] 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 17-hydroxyprogesterone caproate in the
spray solution, pellets of different drug loading can be
achieved.
TABLE-US-00031 TABLE XIII Ingredients Composition in % w/w
17-hydroxyprogesterone caproate 25 Pluronic F 68 6
Polyvinylpyrrolidone K 30 5 Dehydrated Alcohol 250 mL
Microcrystalline cellulose spheres Celsphere .RTM.) 64
According to one aspect, the formulations (e.g., unit dosage forms)
in the above table have from about 100 mg to 495 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 150 to 450 mg of 17 HPC.
According to another aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 200 mg to 490 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 505 mg to 850 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 53
17-Hydroxyprogesterone Caproate Suspension Compositions
[0353] A homogenous suspension of 17-hydroxyprogesterone caproate
prepared in a liquid vehicle having at least one non-solvent can be
made by conventional processes known in the art. The suspension can
be dosed as a conventional oral liquid or a known volume of the
suspension may be encapsulated. Pharmaceutical aids such suspending
agents, thickening agents or viscosity modifiers, wetting agents,
etc., known in the art can be used to achieve homogenous suspension
of the drug in the liquid vehicle.
[0354] According to one aspect, the formulations (e.g., unit dosage
forms) in the above table have from about 100 mg to 495 mg of 17
HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 150 to 450 mg of
17 HPC. According to another aspect, the formulations (e.g., unit
dosage forms) in the above table have from about 200 mg to 490 mg
of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 505 mg to 850
mg of 17 HPC. According to another aspect, the formulations (e.g.,
unit dosage forms) in the above table have from about 400 mg to 600
mg of 17 HPC.
Example 54
17-Hydroxyprogesterone Caproate Composition in Vivo Evaluation:
[0355] A preliminary pharmacokinetic evaluation upon oral
administration of 17-hydroxyprogesterone caproate of the current
invention was carried out in male dogs. A single oral dose of 30
mg/kg and 5 mg/kg of 17-hydroxyprogesterone caproate formulated in
a accordance with exemplary formulations of the present invention
were used for relative bioavailability study in a fed state,
compared with an intramuscular dose of 6.4 mg/kg (composition
similar to commercially available Intramuscular Injection,
Makena.RTM.) as positive control.
[0356] The post-dose blood levels of 17-hydroxyprogesterone
caproate were monitored for 24 hours after oral dosing and for 192
hours after intramuscular injection dosing. About 2 mL of blood was
drawn from the jugular, cephalic, or saphenous veins immediately
before the dose was administered and at pre-determined intervals
post-dose. At each time point, the blood sample was collected in a
vacutainer tubes and centrifuged at about 3200 rpm for
approximately 10 minutes at about 5.degree. C. The serum obtained
was analyzed by HPLC-MS/MS for 17-hydroxyprogesterone caproate. The
results of the 17-hydroxyprogesterone caproate concentration in the
samples are shown in Table-XIV below:
TABLE-US-00032 TABLE-XIV Exemplary Oral Dosage formulations of the
present invention IM Injection Dose Administered 30 mg/kg 5 mg/kg
6.4 mg/kg Mean C.sub.last (ng/mL) 4.51 0.28 2.54 C.sub.avg (ng/mL)
74 2.5 8 Mean AUC.sub.0-last (ng*h/mL) 1767 60 1546 AUC(ng*h
mL.sup.-1).sub.0-24 h/Dose 5.8 1.0 -- (mg) Ratio
[0357] Contrary to reports in the literature we surprisingly found
that oral compositions of the present invention provided
significant blood levels (C.sub.avg) of 17-hydroxyprogesterone
caproate upon oral administration.
Example 55
Clinical Trial in Pregnant Women
[0358] Formulations (e.g., oral dosage forms like those described
herein) were used in a Phase 1b open-label study that enrolled
eight healthy, pregnant women at 16 to 18 weeks gestation. All
subjects received three treatments in sequence. In period one,
subjects received two doses of 400 mg with oral dosage forms like
those described herein. administered 12 hours apart. In period two,
subjects received two doses of 800 mg oral with dosage forms like
those described herein, administered 12 hours apart. In period
three, subjects were given 250 mg of HPC via intramuscular
injection (marketed product Makena.RTM.). Blood samples were
collected periodically over 24 hours following oral dosing and over
28 days following the IM dose.
[0359] The maximum concentration ("Cmax") and the area under the
curve ("AUC") for the oral treatments are shown in Table below.
TABLE-US-00033 TABLE Single Dose Pharmacokinetic Parameters Dosing
Regimen (BID) C.sub.max (ng/ml) AUC.sub.0-24 (ng h/ml) (N = 7)
[range] [range] 400 mg 21.3 156 [11.5-36.2] [81-234] 800 mg 63.2
577 [37.8-144] [323-1365]
Results from this study demonstrate significant HPC absorption
following oral administration in healthy pregnant women.
Additionally, there was a more than dose proportional increase in
exposure with the 800 mg dose.
[0360] Steady state pharmacokinetic parameters for oral and IM
dosing regimens were simulated based on single dose data and the
Cmax and AUC values are shown in the table below.
TABLE-US-00034 TABLE Simulated Steady State Pharmacokinetic
Parameters Products/Dosing Regimen C.sub.ss, max (ng/ml) AUC.sub.SS
(ng h/ml).sup.# (N = 7) [range] [range] 17HPC/400 mg BID 21.6 1074
[12.1-36.2] [82-229] 17HPC/800 mg BID 71.1 4058 [43.8-144.1]
[311-1100] Intramuscular injection/ 13.0 1817 250 mg 17HPC weekly
[6.5-29.4] [805-3904] .sup.#AUCss calculated for post steady state
1 week duration
Based on the results shown in the Table above, oral dosing between
400 and 800 mg twice a day is expected to be comparable to the
marketed 250 mg weekly IM product.
[0361] The simulated steady state PK parameters for oral and IM
dosing from this were compared to simulated steady state data from
previously reported results from Phase 1a study (in non-pregnant
women (see Table 3).
TABLE-US-00035 TABLE 3 Bioavailability in pregnant and non-pregnant
women AUC.sub.SS (ng h/ml).sup.# LPCN 1107/ Intramuscular Relative
Study population 400 mg Injection/ bioavailability (N) BID Oral 250
mg weekly [oral/IM] Pregnant women (7) 1074 1817 59% Non-pregnant
1348 2468 55% women (10) .sup.#AUCss calculated for post steady
state 1 week duration
[0362] Based on the results shown in the table above, relative
bioavailability of oral to IM dosing was similar between pregnant
and non-pregnant women. Results from these studies are illustrated
in FIG. 4.
Example 56
Powder X-ray Diffraction
[0363] The PXRD (Powder X-Ray Diffraction (or XRD)) measurement of
17-HPC products was conducted using a Philips X'Pert X-Ray
Diffractometer. The geometry for the measurement was the standard
Bragg-Brentano .theta.-2.theta. geometry using a Seifert MZ IV
goniometer at room temperature. Standard sample holders (22 mm
diameter) were carefully filled with the powder samples. The XRPD
patterns were recorded using CuKa radiation (.lamda.=1.5406 .ANG.)
and the following measurement conditions.
[0364] 1. Tube tension: 45 kV
[0365] 2. Tube current: 40 mA
[0366] 3. Scan Axis: Gonio
[0367] 4. Start Position [.degree.2Th.]: 2.0125
[0368] 5. End Position [.degree.2Th.]: 54.9875
[0369] 6. Step Size [.degree.2Th.]: 0.0250
[0370] 7. Scan Step Time [s]: 0.5000
[0371] 8. Scan Type: Continuous
Sample preparation
[0372] About 1 g of each micronized powdered 17-HPC API (Active
Pharmaceutical Ingredient), placebo tablet and 17-HPC GMP tablet
product sample were prepared for the PXRD measurement. The powdered
API was used without modification. All tablets (placebo and 17-HPC
containing tablet products) were ground to fine powder using a
mortar and pestle set. All tablets were stored at 25.degree. C. and
60% RH. The placebo tablet and 17-HPC tablet were stored for 2 and
3/4 months after manufactured.
[0373] FIG. 5 shows the PXRD spectrograms measured for 17-HPC in
Tablet (top), micronized 17-HPC API (middle), and 17-HPC reference
peaks (bottom). FIG. 5 shows XRD Spectrograph measured for 17-HPC
products. In FIG. 5, the top spectrogram was obtained from 17-HPC
in tablet, the middle was from micronized 17-HPC API, and the
bottom was from 17-HPC reference XRD Peaks. The top spectrogram
(17-HPC in tablet) in FIG. 5 was calibrated by subtracting data
obtained from the placebo tablet from data obtained from the 17-HPC
GMP tablet. The 17-HPC reference XRD spectrogram was obtained from
publically available data or databases. The peak patterns of 17-HPC
molecules in the final tablet form (Top spectrogram in FIG. 5) were
identical to the patterns of the micronized 17-HPC API (Middle
spectrogram in FIG. 5). As a result of comparison with the
reference patterns (Bottom spectrogram in FIG. 5), it is concluded
that 17-HPC in the final tablet form and API are identical
crystalline forms without any polymorphism or phase change.
Example 57
Exemplary Formulations Containing 17 HPC
TABLE-US-00036 [0374] TABLE XVII Composition in % w/w or [mg] 1.
Ingredients A1 A2 A3 A4 A5 A6 17-Hydroxyprogesterone Caproate* 10 7
12 17 19 20 [20] [50] [96] [133] [150] [200] Carrier 90 93 82 83 81
80 [180] [665] [656] [667] [650] [800] Solvent 6 [48] Total 100 100
100 100 100 100 [200] [715] [800] [800] [800] [1000] *Can be
unmilled (particle size: PS >50 .mu.m), milled (25 .mu.m < PS
< 50 .mu.m, or 15 .mu.m < PS < 25 .mu.m), micronized (1
.mu.m < PS < 15 .mu.m), or nanosized (PS <1 .mu.m). or
Composition in % w/w or [mg] Ingredients A1 A2 A3 A4 A5 A6
17-Hydroxyprogesterone Caproate* 10 7 12 17 19 20 [20] [50] [96]
[133] [150] [200] Carrier: Lipophilic additive (e.g. 90 51 75 75 69
70 Glyceryl monolinoleate, [180] [365] [600] [600] [555] [700]
Glyceryl caprylate/caprate, etc) Hydrophilic additive (e.g. 42 7 6
6 5 Cremophor, PEG) [300] [56] [51] [45] [50] Flow aid/disintegrant
2 (e.g. Colloidal Silicon [16] Dioxide, Stearic acid, Magnesium
stearate) Non-ionic surfactant (e.g. 6 Tween, Span, etc) [50]
Anionic surfactant 5 (e.g. Sodium Lauryl [50] Sulfate, etc) Solvent
(e.g. Benzyl Benzoate, 6 Benzyl alcohol, water, etc) [48] Total 100
100 100 100 100 100 [200] [715] [800] [800] [800] [1000]
TABLE-US-00037 TABLE XVIII Composition in % w/w or [mg] Ingredients
B1 B2 B3 B4 B5 B6 17-Hydroxyprogesterone 26 31 33 33 35 40
Caproate* [150] [200] [250] [300] [400] [450] Carrier 25 69 67 67
65 60 [143] [450] [500] [667] [750] [675] Solvent 49 [282] Total
100 100 100 100 100 100 [575] [650] [750] [910] [1150] [1125]
Composition in % w/w or [mg] Ingredients B1 B2 B3 B4 B5 B6
17-Hydroxyprogesterone Caproate* 26 31 33 33 35 40 [150] [200]
[250] [300] [400] [450] Lipophilic additive (e.g. Glyceryl
monolinoleate, 13 61 27 Glyceryl caprylate/caprate, [75] [400]
[200] etc) Hydrophilic additive (e.g. 12 27 Cremophor, PEG) [68]
[200] Disintegrant (e.g. Ac-di-sol, 16 30 25 Carrier Crospovidone,
etc) [140] [345] [281] EASYtab SP** 51 30 30 (Binder/flow [460]
[345] [338] aid/disintegrant) Non-ionic Surfactant (e.g. 13 5
Polysorbate, Span, etc) [100] [56] Anionic Surfactant 8 5 (e.g.
Sodium Lauryl Sulfate, [50] [60] etc) Solvent (e.g. Benzyl
Benzoate, 49 Benzyl alcohol, water, etc) [282] Total 100 100 100
100 100 100 [575] [650] [750] [910] [1150] [1125] *Can be unmilled
(particle size:PS > 50 .mu.m), milled (25 .mu.m < PS < 50
.mu.m, or 15 .mu.m < PS < 25 .mu.m), micronized (1 .mu.m <
PS < 15 .mu.m), or nanosized (PS < 1 .mu.m). or **Commercial
all-in-one excipient composite consisting of microcrystalline
cellulose (95.0-98.0%), colloidal silicon dioxide (1.5-2.5%),
sodium starch glycolate (0.5-2.0%), and sodium stearyl fumarate
(0.3-1.0%).
TABLE-US-00038 TABLE XIX Composition in % w/w or [mg] Ingredients
C1 C2 C3 C4 C5 C6 17-Hydroxyprogesterone Caproate* 46 49 55 58 65
75 [600] [850] [800] [700] [500] [150] Carrier 54 51 45 42 35 25
[700] [900] [650] [500] [265] [50] Solvent qs qs qs qs qs qs Total
100 100 100 100 100 100 [1300] [1750] [1450] [1200] [765] [200]
*Can be unmilled (particle size: PS >50 .mu.m), milled (25 .mu.m
< PS < 50 .mu.m, or 15 .mu.m < PS < 25 .mu.m),
micronized (1 .mu.m < PS < 15 .mu.m), or nanosized (PS <1
.mu.m). or Composition in % w/w or [mg] Ingredients C1 C2 C3 C4 C5
C6 17-Hydroxyprogesterone Caproate* 46 49 56 59 65 75 [600] [850]
[800] [700] [500] [150] Carrier: Diluent/filler 25 14 15 [325]
[245] [180] Binder/adhesive 20 20 7 [260] [355] [82] Disintegrant 8
4 16 3 10 1 [104] [70] [228] [38] [75] [2] Lubricant/glidant 1 1 1
[11] [15] [8] EASYtab SP 6 11 8 10 (Binder/flow [105] [155] [100]
[75] aid/disintegrant) Non-ionic Surfactant (e.g. 6 4 14
Polysorbate, Span, etc) [110] [50] [107] Anionic Surfactant 17 4 24
(e.g. Sodium Lauryl Sulfate, [242] [50] [48] etc) Solvent qs qs qs
qs qs qs Total 100 100 100 100 100 100 [1300] [1750] [1425] [1200]
[765] [200] and Composition in % w/w or [mg] Ingredients C7 C8 C9
C10 C11 C12 C13 C14 17- 49 44 50 47 52 48 49 54 Hydroxyprogesterone
[475] [500] [500] [550] [550] [575] [600] [600] Caproate* Carrier
51 56 50 53 48 52 51 46 [500] [625] [500] [675] [500] [625] [625]
[500] Solvent qs qs qs qs qs qs qs qs Total 100 100 100 100 100 100
100 100 [975] [1125] [1000] [1175] [1050] [1200] [1225] [1100] *Can
be unmilled (particle size: PS >50 mm), milled (25 mm < PS
< 50 mm, or 15 mm < PS < 25 mm), micronized (1 mm < PS
< 15 mm), or nanosized (PS <1 mm). or Composition in % w/w or
[mg] Ingredients C7 C8 C9 C10 C11 C12 C13 C14 17- 49 44 50 47 52 48
49 54 Hydroxyprogesterone [475] [500] [500] [550] [550] [575] [600]
[600] Caproate* Carrier: Disintegrant 17 20 17 19 16 16 19 10 [170]
[228] [170] [228] [170] [190] [228] [115] Lubricant/glidant 1 1 1
[10] [15] [10] EASYtab SP 28 14 28 13 27 20 12 25 [270] [155] [280]
[155] [280] [240] [147] [275] Non-ionic 5 5 Surfactant [50] [50]
(Tween, Span, etc) Anionic 22 5 21 5 15 20 5 Surfactant [242] [50]
[242] [50] [180] [240] [50] (Sodium lauryl sulfate, etc) Solvent qs
qs qs qs qs qs qs qs Total 100 100 100 100 100 100 100 100 [975]
[1125] [1000] [1175] [1050] [1200] [1225] [1100]
Example 58
Clinical Study
[0375] The study was an open-label, four-period, four-treatment,
randomized, single and multiple dose, PK study in pregnant women of
three dose levels of an oral pharmaceutical composition as
described herein (containing 17 HPC e.g., as described in the
Examples or elsewhere herein) and injectable HPC (Makenag.RTM.).
The study enrolled 12 healthy pregnant women (average age of 27
years) with a gestational age of approximately 16 to 19 weeks.
Subjects received three dose levels of the oral pharmaceutical
composition having 17 HPC (400 mg BID, 600 mg BID, or 800 mg BID)
in a randomized, crossover manner during the first three treatment
periods and then received five weekly injections of HPC during the
fourth treatment period. During each of the treatment periods with
the oral pharmaceutical composition having 17 HPC, subjects
received an oral single dose of 17 HPC on Day 1 followed by twice
daily administration from Day 2 to Day 8. Following completion of
the three treatment periods with the oral pharmaceutical
composition having 17 HPC, and a washout period, all subjects
received five weekly injections of HPC.
[0376] Average steady state 17 HPC levels (Cavg0-24) were
comparable or higher for all three oral doses than for injectable
HPC. HPC levels as a function of daily dose were linear for the
three doses with the oral pharmaceutical composition having 17 HPC.
Unlike the injectable HPC, steady state exposure was achieved for
all three doses with the oral pharmaceutical composition having 17
HPC, within seven days. The approved HPC injectable product is a
single fixed dose product that does not allow for dose
adjustments.
[0377] A previous literature study of 250 mg injectable HPC in
pregnant women reported that the lowest preterm birth rates were
seen when median HPC concentrations exceeded 6.4 ng/mL and that the
plasma concentrations of HPC ranged between 3.7 to 56 ng/mL with
the injectable HPC. With all three doses tested with the oral
pharmaceutical composition having 17 HPC, HPC exposure (Cavg0-24)
did not fall below 6.4 ng/ml in any study subject.
[0378] The oral pharmaceutical composition having 17 HPC was well
tolerated across the three dose levels. No adverse drug reactions,
serious adverse events, or deaths were reported during the study.
There was dose linearity and short duration to steady state
demonstrated in this study which unexpectedly allows dose
adjustments with the oral pharmaceutical composition having 17 HPC,
during the course of therapy (e.g., on a sufficient time scale) to
improve or modulate outcome. There was good correlation of Cmax to
Cavg and Cavg to pre-dose C value which enables single point
titration (e.g., based on serum or plasma 17 HPC levels at a single
time point with 0-12 hours after single dose administration at
steady state (e.g., at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,
6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, or 11.5 hours after
single dose administration (or within a range defined by any two of
these values, or within a range of within 0.5 h or 1 h of any one
of these values))).
[0379] For example, a pregnant female at risk for preterm birth is
administered orally, a pharmaceutical composition (e.g., as
described herein), in an initial dosing regimen, until steady state
is achieved (e.g., 5 or more days, 6 or more days, 7 or more days).
The initial dosing regimen can be e.g., 400 mg per day, 450 mg per
day, 500 mg per day, 550 mg per day, 600 mg per day, 650 mg per
day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per
day, 900 mg per day, 950 mg per day, 1000 mg per day, 1150 mg per
day, 1200 mg per day, 1250 mg per day, 1300 mg per day, 1350 mg per
day, 1400 mg per day, 1450 mg per day, 1500 mg per day, 1550 mg per
day, 1600 mg per day, 1650 mg per day, 1700 mg per day, 1750 mg per
day, 1800 mg per day, 1850 mg per day, 1900 mg per day, 1950 mg per
day or 2000 mg per day (or within a range defined by any two of
these values, or within a range of within 50 mg or 100 mg of any
one of these values) e.g., on a once, twice, thrice, or four times
a day dosing regime. After single dose administration at steady
state, the plasma or serum 17 HPC in the subject is determined and
if the levels are too low, the daily dose is increased, if the
levels are too high, the daily dose is increased or if they levels
are appropriate, the daily dose is maintained. The pharmaceutical
composition can delivery the daily dose in e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 unit dosage forms per day. In
one aspect, the oral pharmaceutical composition comprises
17-hydroxyprogesterone caproate and a pharmaceutically acceptable
carrier, wherein, when measured using a USP Type-II dissolution
apparatus in 900 mL of simulated intestinal fluid having 0.5% w/w
sodium lauryl sulfate at 50 RPM at 37.degree. C., at least 20% of
the 17-hydroxyprogesterone caproate is released from the oral
composition at 60 minutes.In one aspect, the oral pharmaceutical
composition, comprises: 17-hydroxyprogesterone caproate, and a
pharmaceutically acceptable carrier including at least a
hydrophilic surfactant. In one aspect, the oral pharmaceutical
composition, comprises: 17-hydroxyprogesterone caproate having a
mean particulate diameter of about 50 micron or less, and a
pharmaceutically acceptable carrier including at least a
hydrophilic surfactant. In one aspect, the oral pharmaceutical
composition, comprises: 17-hydroxyprogesterone caproate having a
mean particulate diameter of about 50 micron or less, and a
pharmaceutically acceptable carrier including at least a
hydrophilic surfactant wherein, when measured using a USP Type-II
dissolution apparatus in 900 mL of simulated intestinal fluid
having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37.degree. C.,
at least 20% of the 17-hydroxyprogesterone caproate is released
from the oral composition at 60 minutes. In one aspect, the oral
pharmaceutical composition, comprises: 17-hydroxyprogesterone
caproate having a mean particulate diameter of about 50 micron or
less, and a pharmaceutically acceptable carrier including at least
a hydrophilic surfactant; wherein the amount of the
17-hydroxyprogesterone caproate is from about 5% to about 80% w/w
of the total composition; and wherein, when measured using a USP
Type-II dissolution apparatus in 900 mL of simulated intestinal
fluid having 0.5% w/w sodium lauryl sulfate at 50 RPM at 37.degree.
C., at least 20% of the 17-hydroxyprogesterone caproate is released
from the oral composition at 60 minutes. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant which
is an ionic hydrophilic surfactant. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant which
is a non-ionic hydrophilic surfactant. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant which
is a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a
sorbitan fatty acid ester, a polyethylene glycol glycerol fatty
acid ester or a combination thereof. In one aspect, the oral
pharmaceutical composition comprises a hydrophilic surfactant,
which is sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a
lecithin, a bile salt or a combination thereof. In one aspect, the
oral pharmaceutical composition further comprises
polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose,
magnesium stearate, silicon dioxide, stearic acid, mannitol, a
polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a
polyethylene glycol copolymer, a methacrylic acid copolymer, or a
combination thereof. In one aspect, the oral pharmaceutical
composition is formulated as a powder, granulate, particulate,
bead, pellet, sprinkle, suspension, solution, tablet, capsule, or a
combination thereof. In one aspect, the oral pharmaceutical
composition is formulated as a capsule. In one aspect, the oral
pharmaceutical composition is formulated as a tablet. In one
aspect, the oral pharmaceutical composition comprises an amount of
17-hydroxyprogesterone caproate equivalent to from about 20 mg to
about 400 mg of 17-hydroxyprogesterone. In one aspect, the oral
pharmaceutical composition has from about 20 mg to about 800 mg
17-hydroxyprogesterone caproate. In one aspect, the oral
pharmaceutical composition has from about 10 mg to about 300 mg
17-hydroxyprogesterone caproate.
[0380] 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.
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