U.S. patent application number 15/266206 was filed with the patent office on 2017-01-12 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 Kumar Nachaegari, Mahesh V. Patel, Srinivasan Venkateshwaran.
Application Number | 20170007623 15/266206 |
Document ID | / |
Family ID | 47597718 |
Filed Date | 2017-01-12 |
United States Patent
Application |
20170007623 |
Kind Code |
A1 |
Giliyar; Chandrashekar ; et
al. |
January 12, 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 Kumar;
(Holladay, UT) ; Chidambaram; Nachiappan; (Sandy,
UT) ; Patel; Mahesh V.; (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: |
47597718 |
Appl. No.: |
15/266206 |
Filed: |
September 15, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15090800 |
Apr 5, 2016 |
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15266206 |
|
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|
14477771 |
Sep 4, 2014 |
9358298 |
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15090800 |
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13193571 |
Jul 28, 2011 |
8951996 |
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14477771 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/44 20130101;
A61P 5/30 20180101; A61P 9/10 20180101; A61K 9/14 20130101; A61K
9/4866 20130101; A61P 25/00 20180101; A61K 9/2031 20130101; A61K
2800/10 20130101; A61Q 11/00 20130101; A61K 9/1641 20130101; A61K
47/14 20130101; A61P 19/10 20180101; A61K 9/4858 20130101; A61K
47/12 20130101; A61K 9/1623 20130101; A61K 9/1652 20130101; A61K
9/1617 20130101; A61K 9/1635 20130101; A61P 17/00 20180101; A61P
17/10 20180101; A61K 9/2018 20130101; A61P 7/04 20180101; A61P
17/06 20180101; A61K 8/63 20130101; A61K 9/145 20130101; A61K
9/4841 20130101; A61K 47/26 20130101; A61P 5/00 20180101; A61P
17/08 20180101; A61P 15/06 20180101; A61K 47/32 20130101; A61P
15/08 20180101; A61P 15/12 20180101; A61P 25/24 20180101; A61K
47/20 20130101; A61K 9/0053 20130101; A61K 9/2054 20130101; A61P
15/00 20180101; A61K 31/57 20130101; A61K 47/22 20130101; A61K
9/2013 20130101; A61K 9/2059 20130101; A61K 47/10 20130101; A61K
9/1676 20130101 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61K 9/20 20060101 A61K009/20; A61K 9/48 20060101
A61K009/48; A61K 9/16 20060101 A61K009/16; A61K 9/00 20060101
A61K009/00 |
Claims
1. A oral pharmaceutical composition comprising: a therapeutically
effective amount of 17-hydroxyprogesterone caproate, and a
pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1, wherein the
composition is formulated for pregnancy support.
3. The pharmaceutical composition of claim 1, wherein the
17-hydroxyprogesterone caproate is present in the composition in
particulate form having a mean particulate diameter of about
50.mu.m or less.
4. The pharmaceutical composition of claim 1, wherein the carrier
includes benzyl benzoate, benzyl alcohol, or mixtures thereof.
5. The pharmaceutical composition of claim 4, wherein the amount of
the 17-hydroxyprogesterone caproate to the sum of the amounts of
benzyl benzoate and benzyl alcohol, in the oral dosage form is
about 1:0.01 (W/W) to about 1:5 (W/W).
6. The pharmaceutical composition of claim 1, wherein the amount of
the 17-hydroxyprogesterone caproate is from about 5% to about 80%
w/w of the total composition.
7. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is in the form of a capsule or a
tablet.
8. The pharmaceutical composition of claim 7, wherein the
composition is in the form of a capsule and the capsule includes
from about 30 mg to about 300 mg of 17-hydroxyprogesterone
caproate.
9. The pharmaceutical composition of claim 7, wherein the
composition is in the form of a tablet and the tablet includes from
about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate.
10. The pharmaceutical composition of claim 7, wherein the capsule
or tablet is a controlled release oral dosage form.
11. The pharmaceutical composition of claim 7, wherein the ratio of
the amount of 17-hydroxyprogesterone caproate in the composition to
the fill volume of the capsule is from about 0.02 g/mL to about 0.8
g/mL.
12. The pharmaceutical composition of claim 1, wherein the carrier
includes a hydrophilic additive.
13. The pharmaceutical composition of claim 1, wherein the carrier
includes a lipophilic additive.
14. The pharmaceutical composition of claim 12, wherein the carrier
includes a compound selected from the group consisting of 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, polyvinylpyrrolidone,
ethyl alcohol, benzyl alcohol, glycerol, propylene glycol,
polyethylene glycol, methyl cellulose, hydroxypropyl methyl
cellulose, 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.
15. The pharmaceutical composition of claim 12, wherein the carrier
includes a compound selected from the group consisting of 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,
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.
16. The pharmaceutical composition of claim 13, wherein the carrier
includes a compound selected from the group consisting of
tributylcitrate, triethylcitrate, triacetin, ethyl cellulose,
cellulose esters, cellulose acetate, cellulose acetates butyrate,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, tocopherol, tocopherol acetate, tocopherol succinate,
benzyl benzoate, 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.
17. The pharmaceutical composition of claim 13, wherein the carrier
includes a compound selected from the group consisting of
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, capric acid, caprylic acid, palmitic
acid, lauric acid, stearic acid, linoleic acid, oleic acid,
arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid,
ethyl oleate, and combinations thereof.
18. The pharmaceutical composition of claim 13, wherein the carrier
includes at least 50 wt % of a lipophilic additive.
19. The pharmaceutical composition of claim 1, wherein the carrier
includes at least one hydrophilic additive and at least one
lipophilic additive at a lipophilic additive to hydrophilic
additive ratio of about 90:10 to about 1:99.
20. A method of treating a pregnant female subject at risk of
preterm birth, comprising, administering to the female subject the
pharmaceutical composition of claim 1.
Description
PRIORITY DATA
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/090,800, filed Apr. 5, 2016, which is a
continuation of U.S. patent application Ser. No. 14/477,771, filed
on Sep. 4, 2014, now issued as U.S. Pat. No. 9,358,298, which is a
continuation of U.S. patent application Ser. No. 13/193,571, filed
on Jul. 28, 2011, now issued as U.S. Pat. No. 8,951,996, each of
which is incorporated herein by reference.
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 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 with injection of
17-hydroxyprogesterone caproate (e.g. Makena.RTM.) at once weekly
(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, NJEM 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
enable 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 have 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 a certain 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 a certain 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 a certain embodiment of the present invention.
[0018] 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)
[0019] 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.
[0020] It should be noted that, the singular forms "a," "an," and,
"the" include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to "an excipient" includes
reference to one or more of such excipients, and reference to "the
carrier" includes reference to one or more of such carriers.
DEFINITIONS
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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-hdroxyprogesterone 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.
[0029] 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-hydroxyprogesteron present in the composition or dosage
form.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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
undesirable 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] Invention
[0043] 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.
[0044] 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.
[0045] 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):
[0046] 1. Perinatal mortality
[0047] 2. Preterm birth (less than 32 weeks' gestation)
[0048] 3. Preterm birth (less than 34 weeks' gestation)
[0049] 4. Preterm birth (less than 37 weeks' gestation)
[0050] 5. Major neuro-developmental handicap at childhood follow
up
Secondary Outcome Measures (Maternal):
[0051] 1. Threatened preterm labor
[0052] 2. Pre-labor spontaneous rupture of membranes
[0053] 3. Adverse drug reaction
[0054] 4. Pregnancy prolongation (interval between randomization
and birth)
[0055] 5. Mode of birth
[0056] 6. Number of antenatal hospital admissions
[0057] 7. Satisfaction with the therapy
[0058] 8. Use of tocolysis
Secondary Outcome Measures (Infant):
[0059] 1. Birth before 37 completed weeks
[0060] 2. Birth before 34 completed weeks
[0061] 3. Birth before 32 completed weeks
[0062] 4. Birth before 28 completed weeks
[0063] 5. Birth weight less than the third centile for gestational
age
[0064] 6. Birth weight less than 2500 grams
[0065] 7. Apgar score of less than seven at five minutes
[0066] 8. Respiratory distress syndrome
[0067] 9. Use of mechanical ventilation
[0068] 10. Duration of mechanical ventilation
[0069] 11. Intraventricular hemorrhage--grades III or IV
[0070] 12. Periventricular leucomalacia
[0071] 13. Retinopathy of prematurity
[0072] 14. Retinopathy of prematurity--grades III or IV
[0073] 15. Chronic lung disease
[0074] 16. Necrotizing enterocolitis
[0075] 17. Neonatal sepsis
[0076] 18. Fetal death
[0077] 19. Neonatal death
[0078] 20. Admission to neonatal intensive care unit
[0079] 21. Neonatal length of hospital stay
[0080] 22. Teratogenic effects (including virilisation in female
infants)
Secondary Outcome Measures (Child):
[0081] 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) [0082] 2. Developmental delay [0083] 3. Intellectual
impairment [0084] 4. Motor impairment [0085] 5. Visual impairment
[0086] 6. Blindness [0087] 7. Deafness [0088] 8. Hearing impairment
[0089] 9. Cerebral palsy [0090] 10. Child behavior [0091] 11. Child
temperament [0092] 12. Learning difficulties [0093] 13. Growth
assessments at childhood follow up (weight, head circumference,
length, skin fold thickness)
In-Vitro Fertilization
[0094] 1. Primary Outcome Measures: [0095] 1.1. Pregnancy Rate
[0096] 1.2. Live birth [0097] 1.3. Ongoing pregnancy rate [0098]
1.4. Clinical pregnancy, defined as ultrasound evidence of fetal
heart activity at 6-8 weeks of gestation [0099] 1.5. Fetus Vitality
measured by heart beat [0100] 1.6. Rate of complete abortion 24-48
hrs after receiving medical treatment for early pregnancy
failure.
[0101] 2. Secondary Outcome Measures: [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
[0120] 1. Primary Outcomes [0121] 1.1. Miscarriage [0122] 1.2.
Early miscarriage up to 12 weeks [0123] 1.3. Miscarriage later than
12 weeks and less than 23 weeks [0124] 1.4. Cytokine ratio
IFN/IL-10 [0125] 1.5. Clinical pregnancy rate at 8 weeks and 12
weeks of pregnancy
[0126] 2. Secondary Outcomes [0127] 2.1. Mother [0128] a. Pain
relief (threatened miscarriage) [0129] b. Severity of `morning
sickness`--intensified headache [0130] c. nausea, breast tenderness
[0131] d. reported thromboembolic events [0132] e. Thrombolytic
events [0133] f. depression; [0134] g. admission to special care
unit [0135] h. subsequent fertility. [0136] i. FIEF level [0137] j.
Uterine contraction frequency [0138] 2.2. Child [0139] a. Preterm
birth; [0140] b. stillbirth; [0141] c. neonatal death; [0142] d.
low birthweight less than 2500 g [0143] e. fetal genital
abnormalities; [0144] f. teratogenic effects (impairing normal
fetal development); [0145] g. admission to special care unit.
[0146] 2.3. General [0147] a. Intrauterine fetal death [0148] b.
Still birth [0149] c. Fetal [0150] d. Exploratory analysis of
pregnancy outcome by monitoring biochemical and clinical pregnancy
parameters, weekly evaluation of serum progesterone [0151] e. live
birth rate, cycle cancellation rate, rate of spontaneous abortion,
rate of biochemical pregnancy, rate of ectopic pregnancy
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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. 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.
[0163] 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.
[0164] 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:
[0165] 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 AP5 (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.
[0166] PEG-Fatty Acid Monoester Surfactant (listed as compound name
(common commercial product name (supplier) (HLB)): PEG 4-100
monolaurate (Crodet L series (Croda) (>9)); PEG 4-100 monooleate
(Crodet 0 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 PEG300 ML (Stepan)
(11.4)); PEG-7 laurate (Lauridac 7 (Condea) (13)); PEG-6 stearate
(Kessco 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 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 040 (Croda) (17.4)); PEG-40 stearate (Myrj 52,
Emerest 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 0-100 (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.
[0167] PEG-Fatty Acid Diesters Ilisted 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
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.
[0168] 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.
[0169] Polyethylene Glycol Glygerol Fatty Acid Esters (listed as
compound name (common commercial product name (supplier) (HLB)):
PEG-20 glyceryl laurate (Tagat 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. O2 (Goldschmidt) (>10)); and
combinations thereof.
[0170] 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
(Simulsol.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 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.
[0171] 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 3GO (ABITEC), Drewpol 3-1-O
(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 G032 (BASF)
(<10)); Polyglyceryl-3 distearate (Cremophor GS32 (BASF)
(<10)); Polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0 (Nikko)
(<10)); Polyglyceryl-6 dioleate (Caprol 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 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 10G10O (ABITEC), Nikkol Decaglyn
10-O (3.5)); Polyglyceryl-10 mono, dioleate (Caprol PGE 860
(ABITEC) (11)); Polyglyceryl polyricinoleate (Polymuls (Henkel)
(3-20)); and combinations thereof.
[0172] 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 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 PGDS (Stepan) (>6));
Propylene glycol dicaprylate (Nikkol Sefsol 228 (Nikko) (>6));
Propylene glycol dicaprate (Nikkol PDD (Nikko) (>6)); and
combinations thereof.
[0173] 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.
[0174] 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 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
(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.
[0175] 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.
[0176] 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.
[0177] Polyethylene Glycol Alkyl Ethers: (listed as compound name
(common commercial product name (supplier) (HLB)): PEG-2 oleyl
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.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] 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
[0183] 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.
[0184] 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.
[0185] Phosphoric Acid Esters: Diethanolammonium polyoxyethylene-10
oleyl ether phosphate; Esterification products of fatty alcohols or
fatty alcohol ethoxylates with phosphoric acid or anhydride.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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.
[0192] Amides such as: for example 2-pyrrolidone, 2-piperidone,
.epsilon.-caprolactam, N-alkylpyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide, polyvinylpyrrolidone and the like.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] Bile acids such as: cholate, taurocholate, glycocholate,
deoxycholate, taurodeoxycholate, chenodeoxycholate,
glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate,
ursodeoxycholate, lithocholate, tauroursodeoxycholate,
glycoursodeoxycholate, cholylsarcosine) 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.
[0197] Cellulose Esters such as: Cellulose acetate, Cellulose
Acetate Butyrate, Cellulose acetate phthalate, Hydroxypropyl
methylcellulose phthalate, and combinations thereof.
[0198] Mucoadhesive Polymers such as for example tocopherols such
as for example tocopherol, tocopherol acetate, tocopherol
succinate, and combinations thereof.
[0199] Amino Acids and Modified Amino acids such as: aminoboronic
acid derivatives, n-acetylcysteine, and mixtures thereof.
[0200] Sugars such as: maltose, sucrose, dextrose, lactose,
fructose, mannitol, sucralose, fructalose, trehelose, dextrose,
maltodextrose, and combinations thereof.
[0201] Sugar Alcohols such as: mannitol, xylitol, sorbitol,
combinations thereof, and the like
[0202] 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.
[0203] 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.
[0204] 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.
[0205] 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 surfactants, 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.
[0206] In another particular embodiment, the carrier can be a
hydrophilic surfactant and can be 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.
[0207] 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.
[0208] 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.
[0209] 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.
[0210] 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
[0211] 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.
[0212] 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.
[0213] 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.
[0214] In some embodiments, the carrier of the current invention
can be a control release agent. In a particular embodiment, the
control release agent is 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.
[0215] 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.
[0216] In a separate 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.
[0217] 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.
[0218] 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.
[0219] 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).
[0220] 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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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 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 another embodiment, the compositions or oral dosage forms
can be formulated for administration about once every 12 hours. In
yet a further embodiment, the compositions or oral dosage forms can
be formulated for administration about once every 24 hours.
[0225] 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.
[0226] 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 equivalents 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 equivalents
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 equivalents 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 equivalents
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.
[0227] 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.
[0228] 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.
[0229] 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 condition, 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.
[0230] 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.
[0231] 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.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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
(17-hydroxyprogesterone caproate).
[0236] 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.
[0237] 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.
[0238] 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
(RIA), 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.
[0239] 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.
[0240] 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 C.sub.min 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.
[0241] 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
[0242] 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.
[0243] 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 in for testing endogenous estrogen production, and for
the production of secretory endometrium and desquamation.
[0244] 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.
EXAMPLES
[0245] 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
[0246] 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.
[0247] The 17-hydroxyprogesterone caproate released from each of
the compositions using the aforementioned dissolution testing
parameters are shown in Table I. 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-00001 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)
[0248] 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
[0249] 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-00002 TABLE II Example No. 7 8 9 10 Ingredients
Composition in % w/w. 17-hydroxyprogesterone caproate 90-99 -- --
90-99 (particle size >50 .mu.m) 17-hydroxyprogesterone caproate
-- 70-80 -- -- micronized* 17-hydroxyprogesterone caproate -- --
70-80 -- (milled) Lactose 1-10 1-20 1-20 30 Povidone K30 3-6 3-6
3-6 3-6 Organic granulating solvent -- 0 or 0 or q.s*** (example,
alcohol)** q.s*** q.s***-- % 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
[0250] 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.
[0251] 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
[0252] 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-00003 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
[0253] 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
17-Hydroxyprogesterone Caproate Compositions
[0254] 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-00004 TABLE IV Example No. 12 13 14 15 16 17 Ingredients
Composition % w/w 17-hydroxyprogesterone 15 15 14 15 22 25 caproate
Lipophilic Additive . . . -- 85 -- -- -- -- (example Glyceryl
Caprylate/Caprate (Capmul .RTM. MCM) Lipophilic Additive (e.g . . .
85 -- -- -- -- -- Capric Acid) Lipophilic Additive (e.g -- 73 65 3
5 Glyceryl Monolinoleate) Hydrophilic Additive (e.g. -- -- 13 15 --
-- Polyoxyl 40 Hydrogenated Castor Oil) Hydrophilic Additive (e.g.
-- -- -- -- -- 22 Polyoxyl 35 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 -- -- -- -- 35 48 E; d,l-.alpha.-tocopherol) Hydrophilic
Additive (e.g. -- -- -- -- 18 -- Hypromellose (4,000 cPs) % release
in 60 mins >40 >40 >40 >40 >30 >40
[0255] 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.
[0256] 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.
[0257] 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
[0258] 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-00005 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
[0259] 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.
TABLE-US-00006 TABLE VI Compo- sition Dosage Form Example DF-1 DF-2
DF-3 DF-4 DF-5 DF-6 DF-7 DF-8 DF-9 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
[0260] Additional tableting methods known in the art can be used
can be applied to the above exemplified compositions. [0261]
Excipients shown are exemplary of classes of excipients that can be
used [0262] 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.
Examples 24-28
17-Hydroxyprogesterone Caproate Compositions
[0263] 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-00007 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
[0264] Additional tableting methods known in the art can be used
can be applied to the above exemplified compositions. [0265]
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. [0266] The form of the drug can be interchanged with other
forms such as micronized, sieved, milled, amorphous, nano, etc.
[0267] 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.
Examples 29-35
17-Hydroxyprogesterone Caproate Compositions
[0268] Table VIII shows 17-hydroxyprogesterone caproate
compositions and release data 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.
TABLE-US-00008 TABLE VIII Example No. 29 30 31 32 33 34 35
Ingredients Composition % w/w 17-hydroxyprogesterone 25 20 7 7 8 16
25 caproate Lipophilic Additive 48 45 -- -- -- 29 53 (e.g. Benzyl
benzoate) Hydrophilic Additive 2 2 -- -- -- -- 2 (e.g. Benzyl
alcohol) Lipophilic Additive 25 23 -- -- -- -- -- (e.g. Castor Oil)
Lipophilic Additive -- -- -- -- 67 -- (e.g. Corn glycerides)
Lipophilic Additive -- -- 51 48 -- 17 -- (e.g. Glyceryl
Caprylate/Caprate; Capmul .RTM. MCM) Lipophilic Additive -- -- --
-- -- -- -- (e.g. Capric Acid) Hydrophilic Additive -- 10 42 40 25
38 10 (e.g Polyoxyl 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
[0269] 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.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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
[0274] 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-00009 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
[0275] 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
[0276] 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.
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.
[0277] 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.
[0278] 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-00010 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
[0279] 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
[0280] 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.
[0281] 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-00011 TABLE XI Example No. 43 44 Composition Ingredients
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%
Example 45
17-Hydroxyprogesterone Caproate Spray Dried Multiparticulates
[0282] 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.
Example 46-50
17-Hydroxyprogesterone Caproate Compositions
[0283] 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-00012 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, Precirol 10 40 20 -- -- ATO 5) Stearic acid 10 20 10 --
Cholesterol -- -- -- 5 20
Example 51
17-Hydroxyprogesterone Caproate Compositions Produced by
Co-Milling
[0284] 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.
Example 52
17-Hydroxyprogesterone Caproate Loaded Pellets
[0285] 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.
[0286] 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-00013 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
Example 53
17-Hydroxyprogesterone Caproate Suspension Compositions
[0287] 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.
Example 54
17-Hydroxyprogesterone Caproate Composition In Vivo Evaluation
[0288] 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.
[0289] 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-00014 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
[0290] 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.
[0291] 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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