U.S. patent application number 17/448488 was filed with the patent office on 2022-03-10 for pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester.
This patent application is currently assigned to LUMOSA THERAPEUTICS CO., LTD.. The applicant listed for this patent is LUMOSA THERAPEUTICS CO., LTD., SHANGHAI LUMOSA THERAPEUTICS CO., LTD.. Invention is credited to David Chih-Kuang CHOU, Jin-Ding HUANG, Shu-Wen KUO, Chan-Jung LI, Yu-En TIEN, Shin-Jr TSAI.
Application Number | 20220071987 17/448488 |
Document ID | / |
Family ID | 79910035 |
Filed Date | 2022-03-10 |
United States Patent
Application |
20220071987 |
Kind Code |
A1 |
LI; Chan-Jung ; et
al. |
March 10, 2022 |
PHARMACEUTICAL FORMULATIONS FOR SUSTAINED RELEASE OF SEBACOYL
DINALBUPHINE ESTER
Abstract
The present invention relates to injectable, extended-release,
pharmaceutical formulations comprising a nalbuphine ester prodrug
homogenously dissolved in a solution comprising a pharmaceutically
acceptable oil and an oil-miscible retaining solvent, as well as
manufacturing processes and medical uses of the formulations. The
invention further provides methods for adjusting the duration of
action of the formulations by varying the ratio of the
pharmaceutically acceptable oil and the oil-miscible retaining
solvent.
Inventors: |
LI; Chan-Jung; (Taipei,
TW) ; CHOU; David Chih-Kuang; (Palo Alto, CA)
; HUANG; Jin-Ding; (Taipei, TW) ; TSAI;
Shin-Jr; (New Taipei City, TW) ; KUO; Shu-Wen;
(Taipei, TW) ; TIEN; Yu-En; (Taipei, TW) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LUMOSA THERAPEUTICS CO., LTD.
SHANGHAI LUMOSA THERAPEUTICS CO., LTD. |
Taipei
Shanghai |
|
TW
CN |
|
|
Assignee: |
LUMOSA THERAPEUTICS CO.,
LTD.
SHANGHAI LUMOSA THERAPEUTICS CO., LTD.
|
Family ID: |
79910035 |
Appl. No.: |
17/448488 |
Filed: |
September 22, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16793465 |
Feb 18, 2020 |
|
|
|
17448488 |
|
|
|
|
16195187 |
Nov 19, 2018 |
|
|
|
16793465 |
|
|
|
|
15166403 |
May 27, 2016 |
10183018 |
|
|
16195187 |
|
|
|
|
14723996 |
May 28, 2015 |
|
|
|
15166403 |
|
|
|
|
62255805 |
Nov 16, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 31/485 20130101; A61K 9/0019 20130101; A61K 47/44
20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 47/44 20060101 A61K047/44; A61K 47/14 20060101
A61K047/14; A61K 9/00 20060101 A61K009/00 |
Claims
1. A pharmaceutical formulation comprising a nalbuphine ester
prodrug dissolved in a pharmaceutically acceptable oil and an
oil-miscible retaining solvent, wherein the concentration of the
nalbuphine ester prodrug in the formulation is greater than the
solubility of the nalbuphine ester prodrug when added to a mixture
of the pharmaceutically acceptable oil and the oil-miscible
retaining solvent, and/or wherein the weight ratio of the
oil-miscible retaining solvent to the pharmaceutically acceptable
oil is equal to or greater than about 1.1:1.
2. The pharmaceutical formulation of claim 1, wherein the
nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE).
3. The pharmaceutical formulation of claim 2, wherein the
solubility of SDE in the oil-miscible retaining solvent is equal to
or greater than about 100 mg/mL.
4. The pharmaceutical formulation of claim 2, wherein the
concentration of SDE in the formulation is equal to or greater than
70 mg/mL.
5. The pharmaceutical formulation of claim 1, wherein the
pharmaceutically acceptable oil is soybean oil, peanut oil, sesame
oil, or a mixture thereof; and the oil-miscible retaining solvent
is benzyl benzoate, benzyl alcohol, or a mixture thereof.
6. The pharmaceutical formulation of claim 5, wherein the
pharmaceutically acceptable oil is sesame oil and the oil-miscible
retaining solvent is benzyl benzoate.
7. The pharmaceutical formulation of claim 6, wherein the weight
ratio of benzyl benzoate to sesame oil is about 1-3:1.
8. The pharmaceutical formulation of claim 6, wherein the weight
ratio of benzyl benzoate to sesame oil is about 0.8-1.2:1.
9. The pharmaceutical formulation of claim 6, wherein the weight
ratio of benzyl benzoate to sesame oil is about 0.65-2:1.
10. The pharmaceutical formulation of claim 6, wherein the
concentration of SDE in the formulation is about 75 mg/mL, and the
weight ratio of benzyl benzoate to sesame oil is about 1.12:1.
11. The pharmaceutical formulation of claim 6, wherein the
concentration of SDE in the formulation is about 80 mg/mL, and the
weight ratio of benzyl benzoate to sesame oil is about 1.18:1.
12. The pharmaceutical formulation of claim 6, wherein the duration
of action of the pharmaceutical formulation is equal to or greater
than about 5 days.
13. The pharmaceutical formulation of claim 6, wherein the release
period of the pharmaceutical formulation is equal to or greater
than about 14 days.
14. The pharmaceutical formulation of claim 1, wherein the
formulation is suitable for administration by intramuscular or
subcutaneous injection.
15. The pharmaceutical formulation of claim 1, wherein the
concentration of the nalbuphine ester prodrug is greater than the
solubility of the nalbuphine ester prodrug when added to the
mixture of the pharmaceutically acceptable oil and the oil-miscible
retaining solvent.
16. The pharmaceutical formulation of claim 15, wherein the
nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE); the
pharmaceutically acceptable oil is sesame oil and the oil-miscible
retaining solvent is benzyl benzoate; the weight ratio of benzyl
benzoate to sesame oil is about 0.8-1.2:1; and the concentration of
SDE in the formulation is greater than about 70 mg/mL.
17. The pharmaceutical formulation of claim 1, wherein the weight
ratio of the oil-miscible retaining solvent to the pharmaceutically
acceptable oil is equal to or greater than about 1.1:1.
18. The pharmaceutical formulation of claim 17, wherein the
nalbuphine ester prodrug is sebacoyl dinalbuphine ester (SDE); the
pharmaceutically acceptable oil is sesame oil and the oil-miscible
retaining solvent is benzyl benzoate; the weight ratio of benzyl
benzoate to sesame oil is about 1.1-3:1; and the concentration of
SDE in the formulation is greater than about 70 mg/mL.
19. A method for preparing a pharmaceutical formulation, the method
comprising the steps of: (1) dissolving a nalbuphine ester prodrug
in an oil-miscible retaining solvent; and (2) mixing the solution
resulting from step (1) with a pharmaceutically acceptable oil to
give a homogenous solution, wherein the formulation is suitable for
administration by injection.
20. The method of claim 19, wherein the nalbuphine ester prodrug is
dissolved in the solution resulting from step (2) at a
concentration greater than the solubility of the nalbuphine ester
prodrug when added to a mixture of the oil-miscible retaining
solvent and the pharmaceutically acceptable oil.
21. The method of claim 19, wherein the nalbuphine ester prodrug is
sebacoyl dinalbuphine ester (SDE).
22. The method of claim 21, wherein the solubility of SDE in the
oil-miscible retaining solvent is equal to or greater than about
100 mg/mL.
23. The method of claim 21, wherein the concentration of SDE in the
formulation is greater than about 70 mg/mL.
24. The method of claim 19, wherein the pharmaceutically acceptable
oil is soybean oil, peanut oil, sesame oil, or a mixture thereof;
and the oil-miscible retaining solvent is benzyl benzoate, benzyl
alcohol, or a mixture thereof.
25. The method of claim 24, wherein the pharmaceutically acceptable
oil is sesame oil and the oil-miscible retaining solvent is benzyl
benzoate.
26. The method of claim 25, wherein the weight ratio of benzyl
benzoate to sesame oil is about 0.8-1.2:1.
27. The method of claim 19, wherein the formulation is suitable for
administration by intramuscular or subcutaneous injection.
28. A method for treating pain, comprising administering a
therapeutically effective amount of the pharmaceutical formulation
of claim 8 to a subject in need thereof, wherein the pharmaceutical
formulation is administered by intramuscular injection 6-36 hours
prior to the onset of pain symptoms.
29. The method of claim 28, wherein the onset of pain symptoms is
during or after a surgical operation on the subject.
30. The method of claim 28, wherein the pharmaceutical formulation
is administered to deliver a total dose of up to about 160 mg of
SDE.
31. A pharmaceutical formulation comprising a nalbuphine ester
prodrug and a release-controlling solution, wherein the formulation
is suitable for administration by injection and releases the
nalbuphine ester prodrug in an extended manner.
32. The pharmaceutical formulation of claim 31, wherein the
release-controlling solution comprises a pharmaceutically
acceptable oil and an oil-miscible retaining solvent.
33. The pharmaceutical formulation of claim 32, wherein the
pharmaceutically acceptable oil is soybean oil, peanut oil, sesame
oil, or a mixture thereof; and the oil-miscible retaining solvent
is benzyl benzoate, benzyl alcohol, or a mixture thereof.
34. The pharmaceutical formulation of claim 32, wherein the weight
ratio of the oil-miscible retaining solvent to the pharmaceutically
acceptable oil is greater than about 1, and the duration of action
of the pharmaceutical formulation is equal to or greater than about
5 days and/or the release period of the pharmaceutical formulation
is equal to or greater than about 14 days.
35. The pharmaceutical formulation of claim 32, wherein the weight
ratio of the oil-miscible retaining solvent to the pharmaceutically
acceptable oil is less than about 1, and the duration of action of
the pharmaceutical formulation is less than about 6 days and/or the
release period of the pharmaceutical formulation is less than about
14 days.
36. A method for preparing an extended release formulation
comprising a nalbuphine ester prodrug with a predetermined release
period, comprising the steps of: (1) providing an oil-miscible
retaining solvent and a pharmaceutically acceptable oil, wherein
the weight ratio of the oil-miscible retaining solvent to the
pharmaceutically acceptable oil is adjusted based on the
predetermined release period, and (2) mixing the nalbuphine ester
prodrug with the oil-miscible retaining solvent and the
pharmaceutically acceptable oil, to give a homogeneously dissolved
solution.
37. The method of claim 36, wherein step (2) comprises first mixing
the nalbuphine ester prodrug with the oil-miscible retaining
solvent to give a clear solution, and then mixing the clear
solution with the pharmaceutically acceptable oil.
38. The method of claim 36, wherein step (2) comprises mixing the
nalbuphine ester prodrug with a mixture of the oil-miscible
retaining solvent and the pharmaceutically acceptable oil.
39. The method of claim 36, wherein the predetermined release
period is greater than about 14 days, and the weight ratio of the
oil-miscible retaining solvent to the pharmaceutically acceptable
oil is greater than about 1.
40. The method of claim 36, wherein the predetermined release
period is less than about 14 days, and the weight ratio of the
oil-miscible retaining solvent to the pharmaceutically acceptable
oil is less than about 1.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/166,403, filed May 27, 2016, which is a
continuation-in-part of U.S. patent application Ser. No.
14/723,996, filed May 28, 2015, and also claims priority to U.S.
Provisional Application No. 62/255,805, filed Nov. 16, 2015. These
references are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to pharmaceutical
compositions. More particularly, the present invention relates to
extended release formulations of nalbuphine ester prodrugs such as
sebacoyl dinalbuphine ester ("SDE").
BACKGROUND OF THE INVENTION
[0003] Opioids have been widely regarded as the most effective
drugs for the treatment of pain, and the use of opioids in the
management of acute severe pain and chronic pain is considered the
standard of care. Prescription opioids are available as
immediate-release (IR) or extended release (ER) formulations.
Compared with IR formulations, ER formulations allow a controlled
release of the active agent to provide a prolonged plasma drug
level within the therapeutic window; ER formulations also provide a
lower maximum concentration (C.sub.max), fewer peak-to-trough
fluctuations, and less frequent dosing (J Multidiscip Healthc.
2013; 6: 265-280). However, the effective duration of most of the
current market available extended release opioids is less than 3
days. For example, nalbuphine is a short-acting drug with a
duration of action of 3-5 hours after being administered via
intravenous (IV), subcutaneous (SC), or intramuscular (IM)
injection. As such, frequent injections or administrations of
nalbuphine are needed for patients suffering from dramatic or
long-lasting pain.
[0004] U.S. Pat. No. 6,197,344 discloses several controlled release
suspension formulations for subcutaneous administration, each of
which comprises the opioid analgesic butorphanol in the form of
microparticles having an average particle size of from about 5 to
25 microns. It is stated that the suspension formulations can be
used to relieve pain for 12 to 24 hours. Furthermore, because the
particle sizes of butorphanol microparticles are too large, the
suspensions are considered not suitable for being administered by
intramuscular injection or for being sterilized by filtration.
[0005] U.S. Pat. No. 8,455,508 discloses an oil- and pH-controlled
buprenorphine-release formulation, which can be administered by
subcutaneous or intramuscular injection. The formulation is in the
form of an emulsion and needs to be prepared through several
sterilizing procedures during its manufacturing process, which is
time-consuming and not cost effective in large scale
production.
[0006] U.S. Pat. No. 6,225,321 discloses several extended release
formulations for intramuscularly administrating nalbuphine ester
prodrugs, e.g., sebacoyl dinalbuphine ester ("SDE"). The
formulations are prepared by mixing the nalbuphine ester prodrugs
with therapeutically injectable oils and excipients (such as methyl
paraben, propyl paraben, BHA, BHT, cremophore EL, pluronic,
solutol, or span). It is stated that a single dose of the
formulation could give an analgesic effect maintained for 4 to 5
days when the injection volume is 7.15 mL. However, 5 mL was
reported for adults as the maximum volume for a single
intramuscular injection. Large-volume injections (3 mL or greater)
are rarely administered clinically, and may cause serious injection
site irritation.
[0007] U.S. Pat. No. 6,703,398 discloses formulations for orally
administrating nalbuphine or nalbuphine ester. The oral
formulations are prepared by mixing nalbuphine or nalbuphine ester
with an oily substance, and a solubility-assisting agent. It is
stated that the solubility-assisting agent is used to improve
bioavailability and half-life of nalbuphine or nalbuphine ester.
However, the apparent half-life (t.sub.1/2) of nalbuphine from the
oral formulation was only about 24 hours, and it would require the
dosing interval of the oral formulation to be approximately every 8
to 12 hours to exert efficacy. Such a dosing frequency is not
practical or desirable for patients suffering from long-term or
severe pain, for example, post-surgical pain.
[0008] Although the use of emulsion or oil-based vehicles in
preparing extended release formulations of opioids is not unknown,
the complexity of sterilization and the limited solubility of
nalbuphine ester prodrugs in oily substances make it difficult to
achieve extended release formulations which can release nalbuphine
ester prodrugs in a well-controlled manner, can be administered to
patients in a low injection volume, and can be prepared by a simple
and cost-effective method, applicable in industrial scale
manufacturing. There is a need to prepare extended release
formulations with predetermined release periods by simple and cost
effective methods.
BRIEF SUMMARY OF THE INVENTION
[0009] The following presents a simplified summary of the invention
in order to provide the reader a basic understanding. This summary
is not an extensive overview of the invention. It is not intended
to, and does not, delineate the scope of the present invention.
Rather, its sole purpose is to present some concepts disclosed
herein in a simplified form as a prelude to the more detailed
description that is presented later.
[0010] In one aspect, the present disclosure provides
pharmaceutical formulations each comprising a nalbuphine ester
prodrug and a release-controlling solution, wherein the
formulations are suitable for administration by injection and
release the nalbuphine ester prodrug in an extended manner. In some
embodiments, the nalbuphine ester prodrug is homogenously dissolved
in the release-controlling solution. In some embodiments, the
release-controlling solution comprises an oil-miscible retaining
solvent and a pharmaceutically acceptable oil.
[0011] The present disclosure also provides pharmaceutical
formulations each comprising the nalbuphine ester prodrug dissolved
in the pharmaceutically acceptable oil and the oil-miscible
retaining solvent. In some embodiments, the concentration of the
nalbuphine ester prodrug in the formulation is greater than the
solubility of the nalbuphine ester prodrug when added to a mixture
of the pharmaceutically acceptable oil and the oil-miscible
retaining solvent. In some embodiments, the weight ratio of the
oil-miscible retaining solvent to the pharmaceutically acceptable
oil is equal to or greater than about 1.1:1. Such pharmaceutical
formulations may provide an extended release period of the
nalbuphine ester prodrug.
[0012] The inventors have discovered that by increasing the weight
ratio of the oil-miscible retaining solvent to the pharmaceutically
acceptable oil (the "retaining solvent/oil ratio"), the release
period of the nalbuphine ester prodrug from the formulation may be
extended. In some embodiments, the nalbuphine ester prodrug is
sebacoyl dinalbuphine ester (SDE). The pharmaceutically acceptable
oil may be a vegetable oil, for example, sesame oil, cottonseed
oil, castor oil or a mixture thereof. The oil-miscible retaining
solvent may be benzyl benzoate, benzyl alcohol, or a mixture
thereof. In some embodiments, the pharmaceutically acceptable oil
is sesame oil and the oil-miscible retaining solvent is benzyl
benzoate.
[0013] In some embodiments, the solubility of the prodrug, e.g.,
SDE, in the oil-miscible retaining solvent is equal to or greater
than about 100 mg/mL. For example, the solubility of SDE in the
oil-miscible retaining solvent may be equal to or greater than 300
mg/mL.
[0014] In some embodiments, the concentration of the prodrug, e.g.,
SDE, in the formulation is equal to or greater than about 70 mg/mL.
For example, the concentration of SDE in the formulation may be
about 70-300 mg/mL, 70-150 mg/mL, or about 70-100 mg/mL. In some
embodiments, the concentration of SDE in the formulation is about
75 mg/mL or about 80 mg/mL.
[0015] In some embodiments, the retaining solvent/oil ratio is
about 0.5 to about 19. In some embodiments, the retaining
solvent/oil ratio is equal to or greater than 1.1:1. For example,
the retaining solvent/oil ratio may be about 0.8-1.2:1, about
0.65-2:1, about 1-2:1, or about 1-3:1. In some embodiments, the
retaining solvent/oil ratio is about 1.12:1, about 1.18:1, about
0.65:1, about 2:1 or about 3:1.
[0016] In some embodiments, the concentration of SDE in the
formulation is about 70-80 mg/mL, and the weight ratio of benzyl
benzoate to sesame oil is about 1.1-1.2:1. In one embodiment, the
concentration of SDE in the formulation is about 75 mg/mL, and the
weight ratio of benzyl benzoate to sesame oil is about 1.12:1. In
one embodiment, the concentration of SDE in the formulation is
about 80 mg/mL, and the weight ratio of benzyl benzoate to sesame
oil is about 1.18:1.
[0017] In some embodiments, the concentration of the nalbuphine
ester prodrug in the formulation is greater than the solubility of
the nalbuphine ester prodrug when added to the mixture of the
pharmaceutically acceptable oil and the oil-miscible retaining
solvent. For example, the nalbuphine ester prodrug may be SDE; the
pharmaceutically acceptable oil may be sesame oil and the
oil-miscible retaining solvent may be benzyl benzoate; the weight
ratio of benzyl benzoate to sesame oil may be about 0.8-1.2:1; and
the concentration of SDE in the formulation may be greater than
about 70 mg/mL.
[0018] In some embodiments, the weight ratio of the oil-miscible
retaining solvent to the pharmaceutically acceptable oil is equal
to or greater than about 1.1:1. For example, the nalbuphine ester
prodrug may be SDE; the pharmaceutically acceptable oil may be
sesame oil and the oil-miscible retaining solvent may be benzyl
benzoate; the weight ratio of benzyl benzoate to sesame oil may be
about 1.1-3:1; and the concentration of SDE in the formulation may
be greater than about 70 mg/mL.
[0019] In some embodiments, the formulation is an extended or
sustained release formulation. In some embodiments, the present
formulation has a duration of action of equal to or greater than
about 5 days, or about 6 days. In some embodiments, the present
formulation has a release period of equal to or greater than about
10 days, about 12 days, or about 14 days. In some embodiments, the
retaining solvent/oil ratio is greater than about 1, and the
duration of action of the pharmaceutical formulation is equal to or
greater than about 5 days or about 6 days, and/or the release
period of the pharmaceutical formulation is equal to or greater
than about 10 days, about 12 days or about 14 days. In some
embodiments, the retaining solvent/oil ratio is less than about 1,
and the duration of action of the pharmaceutical formulation is
less than about 6 days, and/or the release period of the
pharmaceutical formulation is less than about 14 days.
[0020] The present formulations may be intramuscularly or
subcutaneously administered to a subject. In some embodiments, the
present formulation is suitable for administration by intramuscular
injection.
[0021] In some embodiments, the formulation further comprises
adding a solubilizing agent and/or a neutralizing agent.
[0022] In another aspect, the present invention provides a method
for preparing an extended release formulation comprising a
nalbuphine ester prodrug with a predetermined release period,
comprising providing an oil-miscible retaining solvent and a
pharmaceutically acceptable oil, wherein the weight ratio of the
retaining solvent to the oil is adjusted based on the predetermined
release period, and mixing the nalbuphine ester prodrug with the
retaining solvent and the oil to give a homogeneously dissolved
solution. In some embodiments, the step of mixing the prodrug with
the retaining solvent and the oil comprises mixing the prodrug with
the oil-miscible retaining solvent to give a clear solution, and
then mixing the clear solution with the pharmaceutically acceptable
oil. In some embodiments, the step of mixing the prodrug with the
retaining solvent and the oil comprises mixing the prodrug with a
mixture of the oil-miscible retaining solvent and the
pharmaceutically acceptable oil.
[0023] In some embodiments, the predetermined release period is
equal to or greater than about 10 days, about 12 days or about 14
days, and the retaining solvent/oil ratio is adjusted to greater
than about 1. For example, when a duration of action of equal to or
greater than about 5 or 6 days is intended for the present
formulation, the retaining solvent/oil ratio may be adjusted to
greater than about 1. When a duration of action of equal to or
greater than about 5 or 6 days, and/or a release period of equal to
or greater than 14 days, is intended for the present formulation,
the retaining solvent/oil ratio may be adjusted to greater than
about 1. In some embodiments, the predetermined release period is
less than about 14 days, and the retaining solvent/oil ratio can be
adjusted to less than about 1. In some embodiments, when a duration
of action of less than about 6 days, and/or a release period of
less than 14 days, is intended for the present formulation, the
retaining solvent/oil ratio can be adjusted to less than about
1.
[0024] The present invention also provides a method for preparing a
pharmaceutical formulation, comprising dissolving the nalbuphine
ester prodrug in the oil-miscible retaining solvent; and mixing the
resulting solution with the pharmaceutically acceptable oil to give
a homogenous solution, wherein the formulation is suitable for
administration by injection. In some embodiments, the nalbuphine
ester prodrug is dissolved in the formulation at a concentration
greater than the solubility of the nalbuphine ester prodrug when
added to a mixture of the oil-miscible retaining solvent and the
pharmaceutically acceptable oil.
[0025] In some embodiments, the nalbuphine ester prodrug is SDE. In
some embodiments, the solubility of the prodrug, e.g., SDE, in the
oil-miscible retaining solvent is equal to or greater than about
100 mg/mL. In some embodiments, the concentration of the prodrug,
e.g., SDE, in the formulation is greater than about 70 mg/mL. In
some embodiments, the pharmaceutically acceptable oil is soybean
oil, peanut oil, sesame oil, or a mixture thereof; and the
oil-miscible retaining solvent is benzyl benzoate, benzyl alcohol,
or a mixture thereof. For example, the oil may be sesame oil and
the retaining solvent may be benzyl benzoate. In some embodiments,
the weight ratio of benzyl benzoate to sesame oil is about
0.8-1.2:1. In some embodiments, the formulation is suitable for
administration by intramuscular or subcutaneous injection.
[0026] In some embodiments, the method can further comprise adding
a solubilizing agent and/or a neutralizing agent.
[0027] In some embodiments, the methods of the invention can
further include the step of filtering the resulting homogeneous
solution with a bacteria proof filter.
[0028] In another aspect, the present invention provides a method
of treating pain, comprise administering a therapeutically
effective amount of the pharmaceutical formulation of the invention
to a subject in need thereof. In some embodiments, the formulation
being administered substantially consists of SDE, sesame oil and
benzyl benzoate, wherein the weight ratio of benzyl benzoate to
sesame oil is about 0.8-1.2:1. In some embodiments, the
concentration of SDE in the formulation being administered is
greater than about 70 mg/mL.
[0029] In some embodiments, the formulation is administered by
intramuscular injection. In some embodiments, the formulation is
administered 6-36 hours prior to the onset of pain symptoms. In
some embodiments, the onset of pain symptoms is during or after a
surgical operation on the subject. In some embodiments, the
formulation is administered to deliver a total dose of up to about
160 mg of SDE.
[0030] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only, and are intended to provide further,
non-limiting explanation of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1A shows the accumulated dissolution profiles of R1,
AF3, AF1, AF4, R2, and N7 formulations.
[0032] FIG. 1B shows the accumulated dissolution profiles of N8 and
N9 formulations.
[0033] FIG. 2 shows the accumulated dissolution profiles of AF3,
AF1 and AF4 formulations.
[0034] FIG. 3 shows the plasma nalbuphine concentration in dogs
after intramuscular injection of AF3, AF1 and AF4 formulations
(total dose: 160 mg/dog).
[0035] FIG. 4 shows the log plasma nalbuphine concentration in dogs
after intramuscular injection of AF3, AF1 and AF4 formulations
(total dose: 160 mg/dog).
[0036] FIG. 5 shows the cumulative relative fraction absorbed
(CRFA)-time profiles of nalbuphine in dogs after intramuscular
injection of AF3, AF1 and AF4 formulations (total dose: 160
mg/dog).
[0037] FIG. 6 shows the accumulated dissolution profiles of AF1 and
F8 formulations.
[0038] FIG. 7 shows the mean plasma concentration-time profile of
nalbuphine after human subjects received a single intramuscular
injection of 17 mg Nubain.RTM. (Nalbuphine-HCl) or escalating doses
(75, 100, 125, and 150 mg) of the F8 formulation.
[0039] FIG. 8 shows the mean whole blood concentration-time profile
of nalbuphine after human subjects received a single intramuscular
injection of the F8 formulation (total dose: 150 mg/person).
[0040] FIG. 9 shows the distribution statistics of the consumption
of oral ketorolac through 48 hours after hemorrhoid operation on
subjects who received SDE prior to surgery or on subjects who
received placebo prior to surgery.
[0041] FIG. 10 shows the plot of adjusted VAS scores over time
through 0 hr to 7 days after hemorrhoid operation of mITT
population.
[0042] FIG. 11 shows the saturated concentration/solubility of SDE
in different solvent systems containing different alkyl
alcohols.
[0043] FIG. 12 shows the accumulated dissolution profiles of N1-N5
formulations.
[0044] FIG. 13 shows the accumulated dissolution profiles of N5, N7
and N10 formulations.
[0045] FIG. 14 shows the accumulated dissolution profiles of AF1,
N2, and F8 formulations.
[0046] FIG. 15 shows the accumulated dissolution profiles of N2,
N4, N13, and N14 formulations.
DETAILED DESCRIPTION OF THE INVENTION
[0047] The following detailed description and examples illustrate
certain embodiments of the present invention. Those of skill in the
art will recognize that there are numerous variations and
modifications of this disclosure that are encompassed by its scope.
Accordingly, the description of certain embodiments should not be
deemed as limiting.
[0048] As used herein, the term "extended release" or a similar
expression, for example, "sustained release" means that an active
pharmaceutical ingredient or prodrug thereof may be continuously
released from a drug formulation or pharmaceutical formulation over
an extended period of time after being administered (e.g., 24 hours
or longer, such as equal to or greater than 3 days, equal to or
greater than 5 days, equal to or greater than 6 days, equal to or
greater than 7 days, or equal to or greater than 14 days from
dosing). Other related terms include "released in a sustained
manner."
[0049] As used herein, the term "release period" means a period of
time during which an active ingredient or prodrug thereof is
available for absorption and pharmacological effect (e.g., to treat
pain) after administration.
[0050] As used herein, the term "duration of action" means the
length of time an active ingredient or prodrug thereof exhibits a
desired pharmacologic effect, e.g., an analgesic effect, after
administration. This is determined by the amount of time drug
concentration is at or above a minimum effective concentration.
[0051] As used herein, the term "pharmaceutically acceptable oil"
refers to an oil that may be used to prepare pharmaceutical
formulations containing an active ingredient, without the oil
causing an unacceptable adverse effect. As used herein, the term
"therapeutically injectable oil" refers to an oil that can be used
to prepare pharmaceutical formulations containing an active
ingredient, and the formulations later can be injected into a
patient for clinical or therapeutic use, without the oil causing an
unacceptable adverse effect. Thus, a "pharmaceutically acceptable
oil" may also refer to a "therapeutically injectable oil."
[0052] As used herein, the term "release-controlling solution"
refers to a solution that may be used to regulate or control the
release rate or release period of an active ingredient or prodrug
thereof from a formulation.
[0053] As used herein, the term "oil-miscible retaining solvent"
refers to an organic solvent that is miscible with oil and may be
used to slow the release of an active ingredient or prodrug thereof
in a formulation so as to modify the rate of drug delivery or to
modify the solubility of the drug in the pharmaceutically
acceptable oil. Dissolving the drug or pro-drug thereof in the
oil-miscible retaining solvent before the pharmaceutically
acceptable oil is added may allow for a concentration of drug or
prodrug thereof in the formulation that is higher than the
solubility of the drug or prodrug when it is added to a pre-made
mixture of the oil and the retaining solvent.
[0054] As used herein, the term "solubilizing agent" means a
substance that may be used to increase the solubility of an active
ingredient or prodrug thereof in a liquid formulation, and is
miscible with the liquid formulation.
[0055] As used herein, the term "neutralizing agent" means a
substance that may be used to neutralize an acid generated during
or after administration of a drug formulation.
[0056] As used herein, the word "dissolve" (e.g., as in fully
dissolve) or "dissolved" means that a non-aqueous substance (e.g.,
a solid) becomes or causes to become incorporated into a liquid so
as to form a homogeneous solution.
[0057] As used herein, the term "homogenously dissolved" means that
a non-liquid (e.g., a solid or amorphous) compound is completely
dissolved in a solvent, or a solvent system or mixture, to give a
homogenous solution which, for example, does not contain particles
or precipitates of the compound to be dissolved.
[0058] As used herein, the terms "suitable for injection" or
"suitable for administration by injection" mean that a
pharmaceutical composition is in such a form or state that makes it
clinically possible or ideal for administration by injection, e.g.,
subcutaneous injection, intravenous injection, or intramuscular
injection.
[0059] As used herein, the term "solubility" means the maximum
amount of a solute (e.g., an active ingredient or a prodrug
thereof) that can be dissolved in a given amount of a solvent at a
particular temperature. Unless otherwise specified, the
solubilities presented herein are at room temperature (e.g.,
25-28.degree. C.). The term "saturated concentration" refers to the
concentration at which no more of a solute will dissolve in a
solvent and additional amounts of solute will appear as a separate
phase (e.g., as a precipitate).
[0060] As used herein, the singular forms "a", "and", and "the" are
used herein to include plural referents unless the context clearly
dictates otherwise.
[0061] As used herein, the term "about" means within an acceptable
standard error of the mean when considered by one of ordinary skill
in the art. Other than in the operating/working examples, or unless
otherwise expressly specified, all of the numerical ranges,
amounts, values, and percentages such as those for quantities of
materials, durations of times, temperatures, operating conditions,
ratios of amounts, or reflection angles disclosed herein should be
understood as modified in all instances by the term "about." In the
context of the retaining solvent/oil ratio, of the concentration of
nalbuphine ester prodrug, or of time, for example, the amount of
time for each step of the disclosed methods, "about" as used herein
indicates that the calculation or the measurement of the value
allows some slight imprecision without having a substantial effect
on the chemical or physical attributes of the disclosed
formulations or methods. If, for some reason, the imprecision
provided by "about" is not otherwise understood in the art with
this ordinary meaning, then "about" as used herein indicates a
possible variation of up to 5% in the value.
[0062] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
the ordinary skill in the art to which this invention belongs.
[0063] Pharmaceutical Formulations
[0064] In one aspect, the present invention provides pharmaceutical
formulations each comprising a nalbuphine ester prodrug and a
release-controlling solution, wherein the formulations are suitable
for administration by injection and release the nalbuphine ester
prodrug in an extended or sustained manner. In some embodiments,
the nalbuphine ester prodrug is homogenously dissolved in the
release-controlling solution. The release-controlling solution may
comprise an oil-miscible retaining solvent and a pharmaceutically
acceptable oil.
[0065] The present disclosure also provides pharmaceutical
formulations each comprising the nalbuphine ester prodrug dissolved
in the pharmaceutically acceptable oil and the oil-miscible
retaining solvent. In some embodiments, the concentration of the
nalbuphine ester prodrug in the formulation is greater than the
solubility of the nalbuphine ester prodrug when added to a mixture
of the pharmaceutically acceptable oil and the oil-miscible
retaining solvent. In some embodiments, the weight ratio of the
oil-miscible retaining solvent to the pharmaceutically acceptable
oil is equal to or greater than about 1.1:1. Such pharmaceutical
formulations may provide an extended release period of the
nalbuphine ester prodrug.
[0066] The nalbuphine ester prodrug may show a better solubility in
an oily substance as compared with nalbuphine. For example, the
prodrug may be any of the nalbuphine polyester derivatives
disclosed in U.S. Pat. No. 6,225,321. In some embodiments, the
nalbuphine ester prodrug may be sebacoyl dinalbuphine ester
("SDE"). In some embodiments, the concentration of SDE in the
formulation is about 70-300 mg/mL, about 70-150 mg/mL, or about
70-100 mg/mL. For example, the concentration of SDE in the
formulation may be about 70 mg/mL, about 75 mg/mL, about 80 mg/mL,
about 100 mg/mL, or about 150 mg/mL.
[0067] In some embodiments, the solubility of the nalbuphine ester
prodrug in the retaining solvent is equal to or greater than about
100 mg/mL. In other embodiments, the oil-miscible retaining solvent
can dissolve the nalbuphine ester prodrug at a high concentration,
e.g., more than about 150 mg/mL, or more than about 300 mg/mL, and
is miscible with the pharmaceutically acceptable oil. In some
embodiments, the oil-miscible retaining solvent is benzyl benzoate,
benzyl alcohol, or any mixture thereof, and the nalbuphine ester
prodrug is SDE. The solubilities of SDE in benzyl benzoate and
benzyl alcohol are greater than 300 mg/mL and greater than 500
mg/mL, respectively.
[0068] The pharmaceutically acceptable oil may be a vegetable oil.
In some embodiments, the pharmaceutically acceptable oil may be
sesame oil, castor oil, cottonseed oil, soybean oil, corn oil,
sunflower oil, arachis oil, olive oil, or any mixture thereof. In
some embodiments, the oil is sesame oil, cottonseed oil, or castor
oil. For example, the oil may be sesame oil.
[0069] The oil-miscible retaining solvent may be an organic solvent
that is miscible with the pharmaceutically acceptable oil, for
example, benzyl benzoate, benzyl alcohol, or a mixture thereof. In
some embodiments, the retaining solvent is benzyl benzoate. For
example, the pharmaceutically acceptable oil may be sesame oil and
the oil-miscible retaining solvent may be benzyl benzoate.
[0070] The pharmaceutically acceptable oil is miscible with the
retaining solvent. When the formulation is administered into a
subject by subcutaneous or intramuscular injection, the oil and the
retaining solvent may form a matrix to retain the nalbuphine ester
prodrug, so as to release the prodrug from the formulation in an
extended/controlled manner. When the weight ratio of the retaining
solvent to the oil is increased, the release period of the prodrug
from the formulation may be extended or prolonged. Without wishing
to limit the invention to any particular theory or mechanism of
operation, it is believed that the oil-miscible retaining solvent
serves as the key element in the formulation to retain the prodrug
in the matrix.
[0071] As used herein, retaining solvent/oil ratios may be
expressed as either, for example, 3:1 or 3. For example, a
retaining solvent/oil ratio expressed as 0.5:1 is the same as a
retaining solvent/oil ratio expressed as 0.5. A range of retaining
solvent/oil ratios may be expressed as 1:1-3:1, 1-3:1 or 1-3, for
example.
[0072] By controlling/adjusting the retaining solvent/oil ratio,
the present formulations may regulate the release rate/release
period of the nalbuphine ester prodrug from the formulation. For
example, when the retaining solvent/oil ratio is adjusted to 3:1,
the formulation may show a release period significantly longer than
that of the formulation with a retaining solvent/oil ratio of
0.5:1. In some embodiments, when the retaining solvent/oil ratio is
adjusted to about 0.65, about 99% of the prodrug is released from
the formulation at 144 hours from dosing; when the retaining
solvent/oil ratio is adjusted to about 1, about 90% of the prodrug
is released from the formulation at 144 hours from dosing; when the
retaining solvent/oil ratio is adjusted to about 2, about 80% of
the prodrug is released from the formulation at 144 hours from
dosing. In some embodiments, when the retaining solvent/oil ratio
is adjusted to greater than about 1, the present formulation may
have a release period of equal to or greater than 10 days, 12 days
or 14 days. In some embodiments, when the retaining solvent/oil
ratio is adjusted to greater than about 1, the present formulation
may have a duration of action of equal to or greater than 5 days or
6 days.
[0073] In some embodiments, when the retaining solvent/oil ratio is
adjusted to greater than about 1, the present formulation may have
a release period of equal to or greater than 14 days or may have a
duration of action of equal to or greater than 6 days. In some
embodiments, when the retaining solvent/oil ratio is adjusted to
about 1-3 or about 1-2, the present formulation may have a duration
of action of equal to or greater than about 5 or 6 days, and/or a
release period of equal to or greater than about 10, 12 or 14 days.
In some embodiments, when the retaining solvent/oil ratio is
adjusted to less than about 1, the present formulation may have a
release period of less than 14 days, and/or a duration of action of
less than 6 days.
[0074] In some embodiments, the retaining solvent/oil ratio is
about 0.5 to about 19. In some embodiments, the retaining
solvent/oil ratio is about 0.65-8:1, about 0.65-3:1, about
0.65-2:1, about 1-8:1, about 1-3:1, about 1-2:1, or about
0.8-1.2:1. For example, the retaining solvent/oil ratio may be
about 0.5, 0.65, 0.8, 1, 1.12, 1.18, 1.2, 2, 3 or 8.
[0075] In some embodiments, the oil-miscible retaining solvent is
benzyl benzoate, benzyl alcohol, or any mixture thereof; the
nalbuphine ester prodrug is SDE; and the pharmaceutically
acceptable oil is sesame oil, cottonseed oil, castor oil, or any
mixture thereof. For example, the oil-miscible retaining solvent
may be benzyl benzoate, the nalbuphine ester prodrug may be SDE,
and the oil may be sesame oil, where the weight ratio of benzyl
benzoate to the oil (the "BB/oil ratio") may be about 0.5 to about
16. The present formulations when being prepared with the BB/oil
ratio of 16 may show a longer release period than as prepared with
the BB/oil ratio of 0.5. In some embodiments, the BB/oil ratio is
about 0.65-8:1, about 0.65-3:1, about 0.65-2:1, about 1-8:1, about
1-3:1, about 1-2:1, or about 0.8-1.2:1. For example, the BB/oil
ratio may be about 0.5, 0.65, 0.8, 1, 1.12, 1.18, 1.2, 2, 3 or 8.
In embodiments where the BB/oil ratio is adjusted to about 1:12,
the present formulation may have a release period of equal to or
greater than about 10 days, 12 days or 14 days, and/or a duration
of action of equal to or greater than about 5 days or 6 days. In
particular, when BB/oil ratio is adjusted to about 1:12, the
present formulation may have a release period of equal to or
greater than about 14 days, and/or have a duration of action of
equal to or greater than about 6 days.
[0076] In some embodiments, the oil-miscible retaining solvent is a
mixture of benzyl benzoate and benzyl alcohol. In some embodiments,
the combined weight ratio of benzyl benzoate and benzyl alcohol to
the pharmaceutically acceptable oil ("BB+BA/oil ratio") may be
0.5-19, about 0.82-19, about 0.5-16, about 0.65-8:1, about
0.65-3:1, about 1-8:1, or about 1-3:1. In some embodiments, the
BB+BA/oil ratio may be about 0.82:1 or about 19:1.
[0077] In some embodiments, the present formulation comprises SDE,
benzyl benzoate, and sesame oil, wherein the formulation is
administered to a subject by intramuscular injection, the weight
ratio of benzyl benzoate to sesame oil is greater than 1:1, the
concentration of SDE in the formulation is greater than 70 mg/mL,
and the duration of action of the formulation is equal to or
greater than 6 days.
[0078] In some embodiments, the pharmaceutical formulations of the
present invention are suitable for injection into a subject in need
thereof. It is known in the art that a formulation has to be a
homogeneous solution or a homogeneous suspension in order to be
qualified as an injectable formulation. More particularly, an
injectable suspension should contain at most 0.5-5.0% solids and
have an average particle size of less than 5 micrometers in order
to be used as a pharmaceutically acceptable suspension for
intramuscular injection (see R. M. Patel, Parenteral Suspension: an
Overview, Int. J. Curr. Pharm. Res., 2010, 2(3):3-13). In some
embodiments, the formulations of the present disclosure are
homogeneous and stable solutions and, therefore, are suitable for
administration by intramuscular injection. In some embodiments, the
nalbuphine ester prodrug is homogenously dissolved in the
formulation.
[0079] It should be understood that, due to the difference between
the solubility of SDE in the retaining solvent and in the oil, the
solubility of SDE is higher in formulations with higher retaining
solvent/oil ratios. For example, the solubilities of SDE in benzyl
benzoate and benzyl alcohol are greater than 300 mg/mL and greater
than 500 mg/mL, respectively, while the solubilities of SDE in
sesame oil, castor oil, and cottonseed oil are about 6 mg/mL, about
13 mg/mL, and about 6 mg/mL, respectively. Based on a series of
solubility tests conducted by the inventors, it was demonstrated
that when the weight ratio of benzyl benzoate to sesame oil is
about 1, the solubility (i.e., the saturated concentration) of SDE
when added to the mixture of benzyl benzoate and sesame oil is
about 60-65 mg/mL; when the weight ratio of benzyl benzoate to
sesame oil is about 1.1, the solubility of SDE when added to the
mixture of benzyl benzoate and sesame oil is about 70 mg/mL; when
the weight ratio of benzyl benzoate to sesame oil is about 1.5, the
solubility of SDE when added to the mixture of benzyl benzoate and
sesame oil is about 150 mg/mL; when the weight ratio of benzyl
benzoate to sesame oil is about 2.3, the solubility of SDE when
added to the mixture of benzyl benzoate and sesame oil is about 200
mg/mL; when the weight ratio of benzyl benzoate to sesame oil is
about 9, the solubility of SDE when added to the mixture of benzyl
benzoate and sesame oil is greater than 300 mg/mL.
[0080] In some embodiments, the concentration of the nalbuphine
ester prodrug in the formulation is greater than the solubility of
the nalbuphine ester prodrug when added to the mixture of the
pharmaceutically acceptable oil and the oil-miscible retaining
solvent. For example, the prodrug may be SDE, the retaining solvent
may be benzyl benzoate, the oil may be sesame oil, and the
retaining solvent/oil ratio, e.g., the BB/oil ratio, may be set to
about 1 or about 0.8-1.2:1, so as to give a predetermined release
period or a desired duration of action. In this case, the
concentration of SDE in the formulation may be increased from about
60-65 mg/mL (the solubility of SDE in the mixture of benzyl
benzoate and sesame oil with the BB/oil ratio of about 1) to about
70-100 mg/mL by using the following manufacturing process: a) fully
dissolving SDE in benzyl benzoate, and b) mixing the resulting
solution with sesame oil to give a homogenous solution. In this
preparative method of the present invention, SDE is first dissolved
in benzyl benzoate to form a clear solution which is then mixed
with sesame oil to give a homogeneous solution, by which a
homogenous and stable formulation having a BB/oil ratio of about
0.8-1.2:1 and a high concentration of SDE (such as 70-100 mg/mL)
can be prepared. The formulations prepared accordingly are stable
and have a long shelf-life, staying homogenous and free from
forming solid particles or precipitates even after being stored at
2-8.degree. C. for at least 24 months. Therefore, the formulations
are suitable for administration by intramuscular injection.
[0081] In some embodiments, the retaining solvent/oil ratio is
equal to or greater than about 1.1:1. For example, the prodrug may
be SDE, the retaining solvent may be benzyl benzoate, the oil may
be sesame oil, and the retaining solvent/oil ratio, e.g., the
BB/oil ratio, may be set to about 1.1, so as to give a
predetermined release period or a desired duration of action. In
some embodiments, the concentration of the nalbuphine ester prodrug
in the formulation is greater than the solubility of the nalbuphine
ester prodrug when added to the mixture of the pharmaceutically
acceptable oil and the oil-miscible retaining solvent and the
retaining solvent/oil ratio is equal to or greater than about
1.1:1.
[0082] In one embodiment, the nalbuphine ester prodrug is SDE; the
pharmaceutically acceptable oil is sesame oil; the oil-miscible
retaining solvent is benzyl benzoate; the weight ratio of benzyl
benzoate to sesame oil is about 1.1-3:1; and the concentration of
SDE in the formulation is greater than about 70 mg/mL.
[0083] In some embodiments, the retaining solvent/oil ratio is
equal to or greater than about 1.5:1. In some embodiments, the
concentration of the nalbuphine ester prodrug in the formulation is
greater than the solubility of the nalbuphine ester prodrug when
added to the mixture of the pharmaceutically acceptable oil and the
oil-miscible retaining solvent and the retaining solvent/oil ratio
is equal to or greater than about 1.5:1. In one embodiment, the
nalbuphine ester prodrug is SDE, the pharmaceutically acceptable
oil is sesame oil, and the oil-miscible retaining solvent is benzyl
benzoate.
[0084] It should be understood that when the BB/oil is increased,
for example, from about 1 to about 1.5, the solubility of SDE in
the formulation will be increased significantly, for example, from
about 60 mg/mL to about 150 mg/mL. When the formulation is intended
to be prepared with a SDE concentration greater than the solubility
of SDE when added to the mixture of benzyl benzoate and sesame oil,
the homogeneously dissolved solution can only be prepared by mixing
SDE with benzyl benzoate to form a clear solution, and then mixing
the clear solution with sesame oil. When the formulation is
intended to be prepared with a SDE concentration equal to or lower
than the solubility of SDE when added to the mixture of benzyl
benzoate and sesame oil, the homogeneously dissolved solution may
be given either by mixing SDE directly with the mixture of benzyl
benzoate and sesame oil, or by pre-dissolving SDE with benzyl
benzoate.
[0085] In some embodiments, the BB/oil ratio is equal to or greater
than about 1.1:1, and the concentration of SDE in the formulation
is greater than about 70 mg/mL. For example, the BB/oil ratio may
be about 1.1:1, and the concentration of SDE in the formulation may
be about 70-100 mg/mL.
[0086] In some embodiments, the nalbuphine ester prodrug is SDE;
the pharmaceutically acceptable oil is sesame oil and the
oil-miscible retaining solvent is benzyl benzoate; the weight ratio
of benzyl benzoate to sesame oil is about 0.8-1.2:1; and the
concentration of SDE in the formulation is greater than about 70
mg/mL.
[0087] In some embodiments, the concentration of SDE in the
formulation is about 70-80 mg/mL, and the weight ratio of benzyl
benzoate to sesame oil is about 1.1-1.2:1. In one embodiment, the
concentration of SDE in the formulation is about 75 mg/mL, and the
weight ratio of benzyl benzoate to sesame oil is about 1.12:1. In
one embodiment, the concentration of SDE in the formulation is
about 80 mg/mL, and the weight ratio of benzyl benzoate to sesame
oil is about 1.18:1.
[0088] In some embodiments, the formulations can further comprise a
solubilizing agent. The solubilizing agent may help to increase the
concentration of the nalbuphine ester prodrug in the formulation;
in the meantime, the solubilizing agent is miscible with the
release-controlling solution. For example, the solubilizing agent
may be an alkyl alcohol. When the alkyl alcohol is used
independently to dissolve the nalbuphine ester prodrug, the
solubility of the prodrug in the alkyl alcohol may be relatively
low. For example, the solubilities of SDE in ethanol, 1-propanol
and t-butanol are about 16 mg/mL, about 32 mg/mL, and about 19
mg/mL, respectively. However, in some embodiments, when the alkyl
alcohol is added into the present formulations, the solubility of
the prodrug in the formulations may be increased by at least 30%.
For example, the solubility of SDE in the formulations may be
increased from about 160 mg/mL to about 210 mg/mL when 10% by
weight of tert-Butanol is used to replace the corresponding amount
of benzyl benzoate in the formulations.
[0089] The solubilizing agent may be a C2-C6 alkyl alcohol or any
mixture thereof. The C2-C6 alkyl alcohol may be a linear or
branched alkyl alcohol. In some embodiments, the alkyl alcohol may
be a C2-C5 alkyl alcohol, such as ethanol, 1-propanol, isopropanol,
1-butanol, sec-butanol, isobutanol, tert-butanol, n-pentanol,
2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol,
3-methyl-2-butanol, 3-methyl-1-butanol, and/or
2,2-dimethyl-1-propanol. In some embodiments, the alkyl alcohol may
be ethanol, 1-propanol, 2-propanol, 1-butanol, and/or tert-butanol.
In some embodiments, the w/w % of the alkyl alcohol in the solvent
system (i.e., the sum of the alkyl alcohol, the retaining solvent
and the oil) is about 2.5-30%, for example, 2.5%, 5%, 10%, 15%, 20%
or 30%. In some embodiments, the w/w % of the alkyl alcohol in the
solvent system is about 10-20%. In some embodiments, the
solubilizing agent may be used to increase the solubility of
nalbuphine ester prodrug in the final formulations to more than 100
mg/mL, for example, more than 150, 200, 250, or 300 mg/mL. In some
embodiments, the solubilizing agent may be used to increase the
concentration of nalbuphine ester prodrug in the final formulations
by at least 30%.
[0090] It should be understood that the preparation of an
oil-containing formulation with a high concentration of SDE is
challenging due to the low solubility of SDE in the oil.
Clinically, 5 mL has been cited for human adults as the maximum
volume for a single IM injection. When preparing an injectable
extended release formulation of SDE, the longer the effective
release period is expected to be, the higher the drug load should
be. In the situation that the injection volume is limited to less
than 5 mL (even lower for adults with less muscle mass), the
concentration of SDE must be increased in order to increase the
drug load. The pre-dissolving of SDE in the retaining solvent and
the addition of the solubilizing agent, particularly ethanol, may,
respectively, significantly increase the solubility of SDE in the
formulation, by which a long-term release formulation of SDE with a
high drug-loading can be achieved.
[0091] In some embodiments, the pharmaceutical formulations of the
present invention each comprise SDE, the release-controlling
solution, and the solubilizing agent. In some examples, the
release-controlling solution comprises the pharmaceutically
acceptable oil selected from the group consisting of sesame oil,
castor oil, and cottonseed oil, and the oil-miscible retaining
solvent containing benzyl benzoate or benzyl alcohol. In some
examples, the solubilizing agent is an alkyl alcohol selected from
the group consisting of ethanol, 1-propanol, 2-propanol, 1-butanol,
and tert-butanol. In some examples, the w/w % of the
pharmaceutically acceptable oil in the solvent system (i.e., the
sum of the oil, the retaining solvent, and the solubilizing agent)
is about 5%, 10%, 20%, 30%, 40%, 45%, 50%, 55%, or 60%. In some
examples, the w/w % of the retaining solvent in the solvent system
is about 30%, 35%, 37.5%, 40%, 45%, 47.5%, 50%, 55%, 57.5%, 60%,
65%, 67.5%, 70%, 75%, 77.5%, 80%, or 85%. In some examples, the w/w
% of the solubilizing agent in the solvent system is about 2.5%,
5%, 10%, 15%, 20%, or 30%. In some examples, the concentration of
SDE in the formulation is above 100 mg/mL, and the solvent system
comprises about 2.5-30 w/w % of the alkyl alcohol. In some
examples, the concentration of SDE in the formulation is above 150
mg/mL, and the solvent system comprises about 5-30% of the alkyl
alcohol. In some examples, the concentration of SDE in the
formulation is above 200 mg/mL, and the solvent system comprises
about 10-20% of the alkyl alcohol. The formulation may be
administered into animals or humans by subcutaneous or
intramuscular injection.
[0092] The addition of the alkyl alcohol enables the present
formulations to be prepared at a higher SDE concentration while
showing excellent stability. In some embodiments, the present
pharmaceutical formulations are free from forming solid particles
or precipitates after being stored at 2-8.degree. C. for at least
24 hours. Moreover, the addition of the alcohol may help to
decrease the viscosity of the present formulations, so as to allow
an easier injection through a small gauge needle.
[0093] In some embodiments, the formulations may further comprise a
neutralizing agent, with or without a solubilizing agent. The
neutralizing agent may help in neutralizing the acid generated
during the conversion of nalbuphine ester prodrug to nalbuphine.
For example, when SDE is converted into nalbuphine, sebacoyl acid
will be generated. Accumulation of sebacoyl acid may cause
injection site irritation. The addition of a neutralizing agent may
help to neutralize sebacoyl acid so as to ease the local irritation
at the injection site. The neutralizing agent may be a
pharmaceutically acceptable basic salt. For example, the basic salt
may be a citrate salt, phosphate salt, carbonate salt, lactate
salt, tartrate salt, or succinate salt. In some embodiments, the
basic salt may be a sodium salt or a potassium salt. In some
embodiments, the basic salt may be trisodium citrate, disodium
phosphate, sodium bicarbonate, or sodium lactate.
[0094] In some embodiments, the pharmaceutical formulations of the
present invention each comprise SDE, the release-controlling
solution, the solubilizing agent, and the neutralizing agent.
[0095] The present pharmaceutical formulations may further comprise
suitable inactive ingredients, pharmaceutically or veterinary
acceptable carriers, including but not limited to viscosity
modifiers, coloring, and flavoring agents, etc.
[0096] Methods of Preparation
[0097] In some embodiments, the pharmaceutical formulations of the
present invention may be prepared without heating steps or
complicated mixing sequences.
[0098] The present invention also provides methods of preparing an
extended release formulation of nalbuphine ester prodrug with a
predetermined release period, each comprising: [0099] 1) providing
an oil-miscible retaining solvent and a pharmaceutically acceptable
oil, wherein the weight ratio of the oil-miscible retaining solvent
to the pharmaceutically acceptable oil (the "retaining solvent/oil
ratio") is adjusted based on the predetermined release period; and
[0100] 2) mixing the nalbuphine ester prodrug with the oil-miscible
retaining solvent and the pharmaceutically acceptable oil, to form
a homogeneously dissolved solution.
[0101] In some embodiments, the step of mixing the prodrug with the
retaining solvent and the oil comprises mixing the prodrug with a
mixture of the oil-miscible retaining solvent and the
pharmaceutically acceptable oil. For example, when the
predetermined release period is set to greater than 14 days, the
retaining solvent/oil ratio may be adjusted to greater than 1. For
example, the retaining solvent/oil ratio may be about 2. In one
embodiment, a release-controlling solution, i.e. the mixture of the
retaining solvent and the oil, comprising about 12 g of the
retaining solvent and about 6 g of the oil may be firstly prepared
and then mixed with about 1.6 g of the prodrug.
[0102] In some embodiments, the step of mixing the prodrug with the
retaining solvent and the oil comprises the steps of (a) dissolving
the nalbuphine ester prodrug in the oil-miscible retaining solvent
thereby giving a nalbuphine ester prodrug solution (a clear
solution), and (b) mixing the therapeutically acceptable oil with
the nalbuphine ester prodrug solution resulting from step (a) to
give a homogenously dissolved solution. In some embodiments, when
the predetermined release period is set to lower than 14 days, the
retaining solvent/oil ratio may be adjusted to lower than 1. For
example, the retaining solvent/oil ratio may be about 0.65. In one
embodiment, about 1.5 g of the prodrug may be dissolved in about 11
g of the retaining solvent to give the clear solution, and the
clear solution is then mixed with about 17 g of the oil. In some
embodiments, the concentration of the prodrug in the formulation is
higher than the solubility of the prodrug when added to the mixture
of the retaining solvent and the oil. For example, when the BB/oil
ratio is about 1.1, the SDE concentration in the formulation may be
about 75 mg/mL or about 80 mg/mL (the solubility of SDE when added
into the mixture of benzyl benzoate and sesame oil with a BB/oil
ratio of about 1.1 is about 70 mg/mL).
[0103] As described above, the nalbuphine ester prodrug is more
soluble in formulations with increased retaining solvent/oil
ratios, and the duration of drug release is longer for such
formulations. When a longer release period is desired, the
retaining solvent/oil ratio may be adjusted to a higher value,
where the solubility of the prodrug when added to the mixture of
the retaining solvent and the oil may be higher than the
concentration of the prodrug in the final formulation; accordingly,
such a formulation may be prepared either by directly mixing the
prodrug with the release-controlling solution (i.e. the mixture of
the retaining solvent and the oil), or by pre-dissolving the
prodrug in the retaining solvent. However, when a shorter release
period in expected, i.e., the retaining solvent/oil ratio is lower,
or the intended concentration of the prodrug in the final
formulation is equal to or greater than the saturated concentration
(i.e. the solubility of the prodrug when added to the mixture of
the retaining solvent and the oil), the formulation can be prepared
by pre-dissolving the prodrug in the retaining solvent, so that the
solubility of the prodrug in the formulation may be significantly
improved. As such, the concentration of the prodrug in the
resulting formulation may be greater than the solubility of the
prodrug when added to a solution of the retaining solvent and
oil.
[0104] Once the homogeneously dissolved solutions are formed by the
preparative methods of the present invention, i.e., either by
directly mixing the prodrug with the release-controlling solution
or by pre-dissolving the prodrug in the retaining solvent, they may
all be stable solutions. In some embodiments, the formulations
prepared by pre-dissolving SDE in benzyl benzoate and then mixing
with sesame oil are stable at 2-8.degree. C. for at 24 months, and
may remain homogeneous at about 0-4.degree. C. while not forming
precipitates or solid particles.
[0105] In some embodiments of the methods, the nalbuphine ester
prodrug is SDE.
[0106] In some embodiments, step (a) may further include stirring
the mixture of SDE and the oil-miscible retaining solvent for about
30 to 90 minutes, for example, for about 60 minutes. In some
embodiments, step (b) may further include stirring the mixture of
the resulting solution of step (a) and the oil for about 15 to 45
minutes, for example, for about 30 minutes. In some embodiments,
step (a) and step (b) may be conducted at room temperature. The
formulations of the present invention may be prepared without any
heating process or other commonly used techniques to cause SDE to
fully dissolve, by which a high purity of the resulting formulation
can be achieved. Moreover, in some embodiments, only a short period
of stirring is needed to prepare formulations of the present
invention. Accordingly, the formulations of the present invention
may be prepared in a more economical and convenient manner, which
is beneficial to large-scale production.
[0107] In some embodiments of the methods, the oil-miscible
retaining solvent may be benzyl benzoate, benzyl alcohol, or any
mixture thereof, and the pharmaceutically acceptable oil may be
sesame oil, cottonseed oil, castor oil, or any mixture thereof.
[0108] The present invention also provides a method for preparing a
pharmaceutical formulation, comprising dissolving the nalbuphine
ester prodrug in the oil-miscible retaining solvent; and mixing the
resulting solution with the pharmaceutically acceptable oil to give
a homogenous solution, wherein the formulation is suitable for
administration by injection. In some embodiments, the nalbuphine
ester prodrug is SDE; the concentration of SDE in the formulation
is greater than about 70 mg/mL; the weight ratio of benzyl benzoate
to sesame oil is about 0.8-1.2:1; and the formulation is suitable
for administration by intramuscular or subcutaneous injection.
[0109] In some embodiments, the retaining solvent may be benzyl
benzoate and the oil may be sesame oil, where the weight ratio of
benzyl benzoate to the oil (the "BB/oil ratio") may be about 0.5 to
about 16. In some embodiments, the BB/oil ratio is about 0.65 to
about 3. In some embodiments, the BB/oil ratio is about 0.65 to
about 2. In other embodiments, the BB/oil ratio is about 1-3 or
about 1-2. In some embodiments, when the release period is
predetermined to give a duration of action of about 5 or 6 days,
the BB/oil ratio may be adjusted to about 1.1. Accordingly, when
the release period is predetermined to give a duration of action of
more than 6 days, the BB/oil ratio may be adjusted to more than
about 1.1; and when the release period is predetermined to give a
duration of action of less than 6 days, the BB/oil ratio may be
adjusted to less than about 1.1.
[0110] The methods may each further comprise adding a solubilizing
agent and/or a neutralizing agent. In some embodiments, the
solubilizing agent and/or the neutralizing agent may be added to
the release-controlling solution before the mixing with the
prodrug. For example, the solubilizing agent and/or the
neutralizing agent may be added to the release-controlling
solution, and then mixed with the prodrug. Alternatively, the
formulations may be prepared by mixing the prodrug with the mixture
of the retaining solvent and the solubilizing agent and/or the
neutralizing agent first, and then mixing with the oil.
[0111] The pharmaceutically acceptable oils, the oil-miscible
retaining solvents, the solubilizing agents, and the neutralizing
agents used in the methods of the present invention are the same as
those described for the present formulations.
[0112] In some embodiments of the methods, the solubilizing agent
may be an alkyl alcohol, such as ethanol, 1-propanol, 2-propanol,
1-butanol, and/or tert-butanol; and the nalbuphine ester prodrug
may be SDE. In some embodiments, the solubilizing agent may be
ethanol. The addition of the alkyl alcohol may significantly
increase the solubility of SDE in the final formulations, by which
a high drug loading formulation with a long release period can be
achieved. In some embodiments, the alkyl alcohol may be used to
increase the concentration of SDE in the final formulations to more
than 100 mg/mL, for example, more than 150, 200, 250, or 300 mg/mL.
In some embodiments, the alkyl alcohol may be used to increase the
concentration of SDE in the final formulations by at least 30%. The
alkyl alcohol may be added into the release-controlling solution
before SDE is added into the solvent system. Alternatively, the
alkyl alcohol may be added into the retaining solvent before SDE is
mixed with the retaining solvent.
[0113] In some embodiments of the methods, the neutralizing agent
may be a basic salt selected from the group consisting of trisodium
citrate, disodium phosphate, sodium bicarbonate, and sodium
lactate. The basic salt may be added into the formulation before or
after mixing the prodrug with the release-controlling solution.
Alternatively, the basic salt may be added into the formulation
before or after the retaining solvent is mixed with the prodrug.
Alternatively, the neutralizing agent may be mixed with the
formulation prior to the administration of the present
formulation.
[0114] In some embodiments, the methods of the present invention
may further comprise filtering the homogenously dissolved solution
with a bacteria proof filter, such as a Millipore 0.22 .mu.m
filter. The formulations of the present invention are homogeneously
dissolved solutions without precipitates or solid particles, so
that they can be easily sterilized by filtration with full or
nearly full recovery of the drug.
[0115] Extended Release Periods/Lower Release Rates
[0116] In some embodiments, the present formulations provide
extended release periods of nalbuphine ester prodrugs. For example,
release rates/periods of nalbuphine ester prodrugs may be
demonstrated or estimated through in vitro dissolution experiments
designed to cause nalbuphine ester prodrug release from the
formulations at a higher rate than the actual release rate in a
living subject. When a formulation shows a lower dissolution rate
in the dissolution experiments, it is expected that the formulation
may have a longer release period (or a lower release rate) in a
living subject. The dissolution rate may be defined as the amount
of the prodrug, e.g., SDE, which goes into a dissolution medium
from the formulation per unit time under certain conditions of
interface, temperature and solvent composition. The dissolution of
the nalbuphine ester prodrug can be determined by carefully
dropping the formulation into a larger volume of a dissolution
medium. For example, the volume of formulation may be 50-150 .mu.l
and the volume of dissolution medium may be 200-1000 ml, for
example 500 ml. The dissolution medium may be a buffer with a
surfactant, for example phosphate-buffered saline with 1% tween 80
and a pH of 6.0 (PBST). The dissolution medium can then be stirred
and samples of the resulting medium can be withdrawn at
predetermined time intervals. Prior to termination of the
experiment, HCl can be added to the resulting medium to allow 100%
release of the nalphubine ester prodrug and a sample can be taken
and used as a reference point of 100% in calculating the release
rate of the nalbuphine ester prodrug. The nalbuphine ester prodrug
can be SDE. For example, the dissolution profile of a formulation
can be determined as described in Example 1.
[0117] In some embodiments, when the retaining solvent/oil ratio is
about 0.5, about 0.65, about 1, about 2, about 3, and about 16, the
time for releasing about 50% of the total amount of the nalbuphine
ester prodrug from the formulation into the in vitro medium may be
about 15-25 minutes, about 20-30 minutes, about 35-45 minutes,
about 50-60 minutes, about 85-95 minutes, and about 120-130
minutes, respectively. It is demonstrated that when the retaining
solvent/oil ratio is increased, the dissolution rate of the prodrug
from the formulation may be decreased. The lower in vitro
dissolution rate of a formulation may reflect a longer release
period in a living subject (or a lower in vivo release rate).
[0118] The release rates/periods of the present formulations, or
the aforesaid correlation between the in vitro dissolution rate and
the in vivo release period/release rate, may be further assessed or
verified by evaluating the in vivo availability and pharmacokinetic
parameters of nalbuphine after administration of a present
formulation to a living subject. For example, a nalbuphine ester
prodrug formulation of the present invention can be administered to
a living subject through an injection. The nalbuphine ester prodrug
can be SDE. In some embodiments, the injection may be subcutaneous.
In other embodiments, the injection may be intramuscular. The
subject may be an animal, for example a dog, cat, or rodent, or the
subject may be a human. Blood samples may be taken from the
subjects prior to formulation administration and at various time
points following administration of the formulation, such as over
the first 144 or 360 hours after administration. For example, blood
samples may be drawn at 1, 2, 6, 24, 36, 48, 60, 72, 96, 120 and
144 hours after administration. Alternatively, blood samples may be
drawn at 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours
after administration or at similar intervals after administration,
and at regular intervals for up to 12 days after administration.
The whole blood or plasma concentration of nalbuphine can then be
determined for the blood samples. For example, plasma and whole
blood concentrations of nalbuphine can be determined as described
in Examples 3 and 4.
[0119] In some embodiments, when the retaining solvent/oil ratio is
adjusted to about 0.65, about 99% of the prodrug may be released
from the formulation at 144 hours from dosing; when the retaining
solvent/oil ratio is adjusted to about 1, about 90% of the prodrug
may be released from the formulation at 144 hours from dosing; when
the retaining solvent/oil ratio is adjusted to about 2, about 80%
of the prodrug may be released from the formulation at 144 hours
from dosing. It is shown that when the retaining solvent/oil ratio
is increased, the in vivo release period of the formulation may be
extended or prolonged, which is consistent with the results
demonstrated by the in vitro dissolution experiments.
[0120] In some embodiments, when the retaining solvent/oil ratio is
adjusted to about 1, e.g., 1.12, the present formulation may have a
release period of equal to or greater than about 10 days, 12 days
and 14 days and a duration of action of equal to or greater than
about 5 or 6 days. In some embodiments, the retaining solvent/oil
ratio may be adjusted to lower than about 1, e.g., 0.65, to give a
formulation having a duration of action of less than 6 days, for
example, about 4 days. In other embodiments, the retaining
solvent/oil ratio may be adjusted to more than about 1.1, e.g., 2,
to give a formulation having a duration of action of equal to or
greater than about 5 days and 6 days, for example, more than 6
days.
[0121] In one embodiment, a pharmaceutical formulation of the
present invention is administered intramuscularly into a subject in
need thereof for pain relief and the plasma or whole blood
concentration of nalbuphine may reach no less than 1 ng/mL within
6-12 hours of dosing and this concentration may remain for equal to
or greater than 12 days from administration. In one embodiment, the
plasma or whole blood concentration of nalbuphine may reach no less
than 3 ng/mL within 12-24 hours of dosing and this concentration of
nalbuphine may be maintained for equal to or greater than 7 days
from dosing. In another embodiment, the plasma or whole blood
concentration of nalbuphine may reach no less than 3 ng/mL within
12-24 hours of dosing, and maintain at said concentration for equal
to or greater than 9 days from dosing.
[0122] Pharmacokinetic parameters may also be calculated from the
whole blood or plasma nalbuphine concentrations, for example, the
maximum observed nalbuphine concentration in the plasma or whole
blood (C.sub.max) may be determined. The time to C.sub.max
(T.sub.max), half-life (T.sub.1/2), mean residence time (MRT), and
the area under the curve (time zero to the last quantifiable
nalbuphine measurement (AUC.sub.0-t) and time zero extrapolated to
infinity (AUC.sub.0-inf)) may also be determined. For example,
plasma and whole blood concentrations of nalbuphine and the
pharmacokinetic parameters of the present formulations can be
determined as described in Examples 3 and 4.
[0123] After administration via intramuscular injection to a
subject, in some embodiments the formulations of the present
invention exhibit the following in vivo characteristics: (a) a peak
plasma level of nalbuphine occurs within 45-66 hours after
administration (T.sub.max); and (b) an average elimination
half-life (T.sub.1/2) of nalbuphine after administration is about
56-90 hours.
[0124] In some embodiments, the plasma or whole blood
concentrations of nalbuphine following administration may be used
to determine the onset of the analgesic effect and the duration of
action of the present formulations. For example, the obtained
plasma or whole blood concentrations of nalbuphine may be compared
to a concentration of plasma or whole blood nalbuphine that has
been reported to exhibit analgesic effects. In general, by
administration of a pharmaceutical formulation of this disclosure
via intramuscular injection, the onset of the analgesic effect may
take place in about 6 to 36 hours of dosing and the duration of
action may be about 6 to about 12 days. In some embodiments, the
duration of action may be equal to or greater than about 5 days,
about 6 days, about 9 days, or about 12 days. In some embodiments,
the duration of action may be equal to or greater than 3, 6, 9, 10,
12, or 14 days. In some embodiments, the duration of action of the
formulation is equal to or greater than about 5 or 6 days. In other
embodiments, the duration of action of the formulation is equal to
or greater than about 7 days. The time of onset for an analgesic
effect can depend on dosing, the individual's response, and the
type of pain relief sought.
[0125] In certain embodiments, the present formulation is prepared
with a BB/oil ratio of about 0.8-1.2, wherein the SDE concentration
is about 75 mg/mL. In some embodiments, such formulations may
maintain a blood concentration of nalbuphine at >3 ng/mL for
equal to or greater than about 6 days, or at >1 ng/mL for equal
to or greater than about 12 days, when a single dose of 150 mg of
SDE is administered. Formulations with an increased BB/oil ratio
may have a duration of action for more than 6 days. Similarly, if
the formulation is intended to provide a duration of action shorter
than 6 days, e.g., 3 or 5 days, the BB/oil ratio may be
decreased.
[0126] It should be understood that the duration of action of the
present formulation may depend not only on the retaining
solvent/oil ratio, but also the concentration of the prodrug in the
formulation, and the total dose being administered. The
concentration of the prodrug in the formulation, and the total dose
being administered may be adjusted per need, so as to provide an
effective blood concentration for a desired period.
[0127] Treatment of Pain
[0128] In another aspect, the present invention provides methods
for treating pain, comprising administering a therapeutically
effective amount of the pharmaceutical formulation of the present
invention to a subject in need thereof. In some embodiments, the
present invention provides methods for treating post-surgical pain
or other types of long-term pain by the present formulations. In
some embodiments, the pharmaceutical formulation is administered by
intramuscular or subcutaneous injection. Treatment of pain can be
evaluated by assessing a subject's assessment of pain on an
intensity scale. For example, the Visual Analog Scale (VAS) for
pain can be used to score a subject's pain intensity (Psychol Med.
1988 November; 18(4):1007-19). The pain VAS is a unidimensional
intensity scale on which the subject is asked to indicate his or
her level of pain intensity. For example, pain intensity may be
assessed started right before the first use of patient-controlled
analgesia (PCA), and at 1.+-.0.1, 2.+-.0.1, 3.+-.0.1, 4.+-.0.25,
8.+-.0.5, 12.+-.0.5, 16.+-.0.5, 20.+-.0.5, 24.+-.1, 28.+-.1,
32.+-.2, 36.+-.2, 40.+-.2, 44.+-.2, 48.+-.2 hours after the
surgery, and be assessed during Days 3-7 in the morning and
evening, as well as during special events such as bowel movements.
For example, the patient-controlled analgesic is ketorolac. In some
embodiments, the present formulations may be administered to a
subject prior to a surgical procedure. For example, the surgical
procedure may be a hemorrhoidectomy. In certain embodiments, the
present formulations may be administered 6-36 hours prior to
surgery. In some embodiments, 150 mg of SDE is administered prior
to surgery. Pain intensity can then be assessed following surgery,
for example for 48 hours after surgery. In some embodiments, pain
can be assessed with the VAS pain scale. In some embodiments,
subjects administered a present formulation have a lower VAS pain
score over 48 hours than subjects administered a placebo. For
example, evaluation of the treatment of pain can be determined as
described in Example 4.
[0129] Treatment of pain can also be assessed by evaluating a
subject's use of a post-surgical analgesic, i.e. a rescue medicine,
such as ketorolac. For example, the time of a subject's first use
of the post-surgical analgesic following surgery can be evaluated.
In some embodiments, subjects administered a present formulation
prior to surgery have a longer period of time before the
post-surgical analgesic use compared to subjects administered a
placebo. For example, treatment of pain can be assessed as
described in Example 4.
[0130] Treatment of pain can also be assessed by evaluating a
subject's effective blood concentration of nalbuphine after
administration of the present formulation. In some embodiments,
when the retaining solvent/oil ratio is increased, the time to
reach the effective blood concentration of nalbuphine may be
longer, thus the onset of action of the formulation may be slower.
Accordingly, the time to administer the formulation into a subject
in need may be adjusted per the desired onset of action of the
formulation. For example, when the retaining solvent/oil ratio is
about 0.65, about 1, or about 2, the blood concentration of
nalbuphine at 1 hour after administration may be about 28 ng/mL,
about 11 ng/mL, or about 7 ng/mL, respectively. In some
embodiments, for example, if the effective blood concentration of
nalbuphine in a living subject, e.g., a dog, is about 5 ng/mL, the
formulation having a retaining solvent/oil ratio of about 2 may be
administered to the subject about 1 hour prior to the onset of pain
symptom; while the formulation having a retaining solvent/oil ratio
of about 0.65 may be administered to the subject about 30 minutes
prior to the onset of pain symptom.
[0131] In some embodiments, the present methods for treating pain
comprises administering to a subject, e.g., a human, in need
thereof the formulation of the present invention having a retaining
solvent/oil ratio of about 0.8-1.2, e.g., about 1.12, at 6 to 36
hours prior to the onset of pain symptoms, wherein the formulation
is administered to the subject via intramuscular injection. In some
embodiments, the formulation having a retaining solvent/oil ratio
of about 1.12 may be administered 12 to 36 hours prior to the onset
of pain symptoms. In some other embodiments, the formulation having
a retaining solvent/oil ratio of about 1.12 may be administered 12
to 24 hours prior to the onset of pain symptoms. In some
embodiments, the concentration of SDE in the formulation is about
75 mg/mL, and such formulation is administered with a total dose of
up to 150 mg of SDE.
[0132] In some embodiments, the present methods for treating pain
comprises administering to a subject, e.g., a dog, in need thereof
the formulation of the present invention having a retaining
solvent/oil ratio of about 1.18. In one embodiment, the
concentration of SDE in the formulation is about 80 mg/mL, and such
formulation is administered with a total dose of up to 160 mg of
SDE.
[0133] In some embodiments, the present method is for treating
post-surgical pain, wherein the onset of pain symptom is during or
after a surgical operation on the subject. Examples of the surgical
operation include common types of general surgery, such as hernia
surgery, hemorrhoid surgery, abdominal surgery, obstetric and
gynecological surgery, plastic surgery, orthopedic surgery,
otolaryngology surgery, male genital procedures, and dental
surgery. In some embodiments, the surgical operation is hemorrhoid
surgery. In certain embodiments, the formulation having a retaining
solvent/oil ratio of about 1.12 is administered 12 to 36 hours
prior to the surgical operation. In some embodiments, the
formulation having a retaining solvent/oil ratio of about 1.12 is
administered 12 to 24 hours prior to the surgical operation. In
some embodiments, the formulation being administered contains SDE,
sesame oil and benzyl benzoate, where the weight ratio of benzyl
benzoate to sesame oil is about 0.8-1.2:1; and the concentration of
SDE in the formulation is about 75 mg/mL. In certain embodiments, a
formulation having a retaining solvent/oil ratio of about 1.12 is
administered to a human with a total dose of up to 150 mg of
SDE.
[0134] Another aspect of the present invention is to provide a
method of treating long-term pain, which includes administering to
a subject in need thereof via intramuscular injection a
pharmaceutical formulation of the present invention having a
retaining solvent/oil ratio of about 1.12 at 6-36 hours prior to
the onset of pain symptoms. Examples of the long-term pain include
labor pain, chronic back pain, and chronic joint pain. In some
embodiments, the formulation having a retaining solvent/oil ratio
of about 1.12 is administered about 12-36 hours prior to the onset
of pain symptoms. In certain embodiments, the formulation having a
retaining solvent/oil ratio of about 1.12 is administered with a
total dose of up to 150 mg of SDE.
[0135] In some embodiments, the formulation is prepared with a
retaining solvent/oil ratio of about 0.8-1.2 and a SDE
concentration of about 75 mg/mL, and is intramuscularly
administered with a total dose of up to about 150 mg of SDE. In
such case, the onset of action of the formulation may be within
about 6-36 hours, or about 12-36 hours, from dosing; and the
duration of action of the formulation may be about 6 days, about 7
days, or about 9 days. In other embodiments, the formulation is
prepared with a retaining solvent/oil ratio of about 0.65 and a SDE
concentration of about 50 mg/mL, and is intramuscularly
administered with a total dose of up to about 160 mg of SDE. In
other embodiments, the formulation is prepared with a retaining
solvent/oil ratio of about 2 and a SDE concentration of about 80
mg/mL, and is intramuscularly administered with a total dose of up
to about 160 mg of SDE.
[0136] In some embodiments, the formulation is administered at a
concentration of about 50-160 mg/ml, or about 70-100 mg/mL, with a
total administered dose of about 75-160 mg, or about 150-160 mg.
For example, the concentration may be about 50, 75, 80, 100, or 150
mg/mL; and the total dose may be about 75, 100, 125, 150, or 160
mg. In certain embodiments, the formulation is administered at a
concentration of about 75 mg/ml and a total dose of about 150 mg.
In other embodiments, the formulation is administered at a
concentration of about 50 mg/mL, or about 80 mg/ml, and a total
dose of about 160 mg.
EXAMPLES
Example 1. In Vitro Release Study of Present Formulations with
Various BB/Oil Ratio
[0137] (1) Preparation of the Present Formulations
[0138] Eight present formulations with various SDE concentrations
(50-150 mg/mL) and various weight ratios of benzyl benzoate to
sesame oil ("BB/oil ratio"), or the mixture of benzyl benzoate and
benzyl alcohol to sesame oil ("BB+BA/oil ratio") (0.5-19) were
prepared based on Table 1A and Table 1B. Among them, AF4, R2, N7
and N9 formulations were prepared according to the following Method
A.
[0139] Method A:
[0140] The solvent systems (i.e., the mixture of benzyl benzoate,
with or without benzyl alcohol, and sesame oil) were respectively
prepared by mixing each component with the predetermined volume
corresponding to the desired weight/weight percent (w/w %) listed
in Table 1A and Table 1B. The resulting solvent mixtures were
vortexed or stirred at room temperature to fully mix each
component. The predetermined amounts of SDE were respectively
weighed, based on the SDE concentrations listed in Table 1A and 1B,
and then added into volumetric flasks containing the corresponding
solvent mixtures. The resulting mixtures were fully mixed by
inverting and shaking the volumetric flasks to give the final
formulations.
[0141] R1, AF1, AF3 and N8 formulations were prepared according to
the following Method B.
[0142] Method B:
[0143] The predetermined amounts of SDE were respectively weighed,
based on the SDE concentrations listed in Table 1A and Table 1B,
and then added into benzyl benzoate, or the mixture of benzyl
benzoate and benzyl alcohol, of predetermined volume corresponding
to the desired weight/weight percent (w/w %) listed in Table 1A and
Table 1B. The resulting mixtures were mixed by vortexing or
stirring to fully dissolve SDE. Sesame oil of predetermined volume
was then added into the resulting mixtures of benzyl benzoate, or
the mixture of benzyl benzoate and benzyl alcohol, and SDE to give
the final formulations.
TABLE-US-00001 TABLE 1A The present formulations having various
BB/oil ratios Benzyl Sesame Sample benzoate oil SDE BB/oil No. (w/w
%) (w/w %) (mg/mL) ratio R1 33 67 50 0.5 AF3 39 61 50 0.65 AF1 54.2
45.8 80 1.18 AF4 67 33 80 2 R2 75 25 75 3 N7 94 6 150 16
TABLE-US-00002 TABLE 1B The present formulations having various BB
+ BA/oil ratios Benzyl benzoate + Sesame BB + Benzyl alcohol oil
SDE BA/oil (w/w %) (w/w %) (mg/mL) ratio N8 45 55 75 0.82 N9 95 5
150 19
[0144] (2) In Vitro Dissolution Experiment:
[0145] The following in vitro dissolution experiment and UPLC
analysis were performed on the formulations listed in Table 1A and
Table 1B.
[0146] The dissolution/release rate of SDE from each of the
formulations was respectively assessed by in vitro dissolution
experiment. The dissolution medium was a PBST buffer (pH6.0) with
0.1% tween 80. For each experiment, 500 mL medium was placed in a
600 mL beaker and the air bubble on the top was removed. 50-150
.mu.l of each SDE formulation listed in Table 1A and Table 1B was
respectively and carefully dropped into the medium (in each
experiment, the dropped formulation contained the same amount of
SDE, i.e. about 7.5 mg). The temperature of the medium was set at
room temperature (about 25-28.degree. C.), and the stir speed was
set at about 360 rpm. 5 mL of the resulting medium was withdrawn at
predetermined time intervals. 200 .mu.l 6N HCl was added into the
resulting medium 20 minutes before the termination point of the
experiment to allow 100% release of SDE at an acidic condition. 5
mL of the resulting medium at the termination point was collected
and taken as the reference point of 100% release in calculating the
dissolution rate of SDE at each of the time intervals.
[0147] UPLC Analysis
[0148] The concentration of SDE in each of the samples collected in
the in vitro dissolution experiment was determined by ultra
performance liquid chromatography (UPLC). Standard solutions were
prepared. UPLC analysis was conducted by using the ACQUITY UPLC
ethylene bridged hybrid (BEH) C18, 1.7 .mu.m, 2.1*50 mm column
under the following conditions:
TABLE-US-00003 Flow rate 0.1 mL/min Injection volume 10 .mu.l Run
time 15 minutes Detector UV 280 nm Column temperature 35.degree. C.
Sample temperature 15.degree. C. Mobile phase Buffer A*/methanol =
40/60 *Buffer A: acetate buffer.
[0149] The accumulated SDE dissolution profiles of each of the
formulations are plotted in FIG. 1A and FIG. 1B.
[0150] In FIG. 1A, it can be seen that when the BB/oil ratio is
increased from 0.5 to 16, the dissolution rate of SDE from the
formulation is decreased, i.e. the release period of SDE from the
formulation is extended. For example, when the BB/oil ratio was
about 0.5 (R1), the time required for releasing about 50% of the
total amount of SDE from the formulation into the in vitro medium
was about 15-25 minutes; when the BB/oil ratio was about 3 (R2),
the time required for releasing 50% of the total amount of SDE from
the formulation into the in vitro medium was about 85-95 minutes;
and when the BB/oil ratio was about 16 (N7), the time required for
releasing 50% of the total amount of SDE from the formulation into
the in vitro medium was about 120-130 minutes. In FIG. 1B, it can
be seen that the trend observed in FIG. 1A still exists when the
retaining solvent is the mixture of benzyl benzoate and benzyl
alcohol.
[0151] The results indicate that the in vitro release rate/release
period of SDE from the present formulations may be regulated or
controlled by the retaining solvent/oil ratio, e.g., the BB/oil
ratio, of the solvent system. When a longer release period is
intended, the retaining solvent/oil ratio in the formulation can be
increased per need.
[0152] Correlations between in vitro and in vivo data are often
used during pharmaceutical development in order to reduce
development time and optimize the formulation. Many studies
reported in the late '70s and early '80s established the basic
reliability of such correlations (Pharm. Res. 1990, 7, 975-982).
Various definitions of in vitro-in vivo correlation have been
proposed as a predictive mathematical model describing the
relationship between an in vitro property of an extended release
dosage form (usually the rate or extent of drug dissolution or
release) and a relevant in vivo response, e.g., plasma drug
concentration or amount of drug absorbed. Under this concept, it is
believed that when the retaining solvent/oil ratio of the present
formulations is increased, the formulation may have an
increased/prolonged in vivo release period.
Example 2 Comparison Between Method A and Method B
[0153] (1) Suspensions with Precipitates, Prepared by Method A when
the BB/Oil Ratio is about 1
[0154] Two samples (1 and 2) were prepared by directly adding SDE
into a mixture of sesame oil and benzyl benzoate (i.e., Method A of
Example 1). In Sample 1, 5.5 mL sesame oil and 4.5 mL benzyl
benzoate were first mixed to form an oily solvent mixture. 750 mg
of SDE was then added into the solvent mixture. The resultant
mixture was sonicated for at least 2 hours, left overnight at room
temperature, and then centrifuged for 10 minutes at 3000 rpm. The
upper clear solution was collected and then subjected to high
performance liquid chromatography (HPLC) analysis. Sample 2 was
prepared by following the process for preparing Sample 1 except
that the amount of SDE was changed to 1000 mg. For Samples 1 and 2,
the ratios of "the originally added weight of SDE" to "the volume
of benzyl benzoate and sesame oil" were 75 mg/mL and 100 mg/mL,
respectively. For both of Samples 1 and 2, suspensions with
precipitates were formed immediately after SDE was added into the
oily mixture. After being sonicated for over 2 hours and left
overnight at room temperature, visible solid particles of SDE were
still present in the resulting mixtures.
[0155] (2) Homogeneous Solutions, Prepared by Method B when the
BB/Oil Ratio is about 1
[0156] Four samples (3-6) were prepared according to Method B of
Example 1. Specifically, in Sample 3, 2.25 mL of benzyl benzoate
and 375 mg of SDE were first mixed and stirred to form a clear
solution. 2.75 mL of sesame oil was then added into the clear
solution to give a homogeneous solution (resulting SDE
concentration of 75 mg/mL; volume ratio of benzyl benzoate to
sesame oil being 45:55), such that the SDE is homogenously
dissolved in the solution. Sample 4 was prepared by following the
method for making Sample 3 except that 2 mL benzyl benzoate and 3
mL sesame oil were used (resulting SDE concentration of 75 mg/mL;
volume ratio of benzyl benzoate to sesame oil being 40:60). Sample
5 was prepared by following the method for making Sample 3 except
that 2.5 mL benzyl benzoate and 2.5 mL sesame oil were used
(resulting SDE concentration of 75 mg/mL; volume ratio of benzyl
benzoate to sesame oil being 50:50). Sample 6 was prepared by
following the process of making Sample 3 except that 500 mg SDE was
used (resulting SDE concentration of 100 mg/mL; volume ratio of
benzyl benzoate to sesame oil being 45:55). Samples 3-6 were then
subject to a freeze-thaw test to check their physical stabilities.
The freeze-thaw test was conducted by cooling each of the samples
at about 0-4.degree. C. for about 12 hours, warming each of the
cooled samples at room temperature for about 12 hours, and
sequentially repeating the cooling and warming steps twice. All of
Samples 3-6 stayed clear and homogeneous after the freeze-thaw
test. The resulting samples were centrifuged for 10 minutes at 3000
rpm. The upper solution of each sample was respectively collected
and then subjected to HPLC analysis.
[0157] (3) HPLC Analysis of Samples 1-6
[0158] The HPLC analysis was conducted using the column Waters
Xbridge RP18, 4.6 mm.times.250 mm, 3.5 .mu.m column (Part No.:
186003964) and the following conditions:
[0159] Flow rate: 0.6 ml/min
[0160] Injection volume: 10 .mu.l
[0161] Run Time: 70 minutes
[0162] Detector: UV wavelength 280 nm
[0163] Column temperature: 35.degree. C.
[0164] Sample temperature: 25.degree. C.
[0165] Gradient program:
TABLE-US-00004 Time (mins.) Mobile phase A % Mobile phase B % 0 50
50 30 30 70 60 30 70 62 50 50 70 50 50
[0166] Mobile phase A was an acetate buffer, and Mobile phase B was
methanol. 1.0 mL of each of the upper solutions from centrifuged
Samples 1-6 was collected and then diluted with acetonitrile to 100
mL. The resulting solutions were subjected to the HPLC analysis,
individually and separately. The results of the HPLC analysis were
used to calculate the concentration of dissolved SDE in centrifuged
Samples 1-6, and the data is summarized in Table 2.
TABLE-US-00005 TABLE 2 Comparison between the formulations prepared
by Method A and Method B. Added SDE Calculated SDE Sample BB/oil
concentration Concentration # ratio Appearance (mg/mL) (mg/mL)
Samples prepared according to Method A: 1 1.0:1 Suspension 75 60 2
1.0:1 Suspension 100 65 Samples prepared according to Method B: 3
1.0:1 Clear solution 75 73 4 0.8:1 Clear solution 75 76 5 1.2:1
Clear solution 75 78 6 1.0:1 Clear solution 100 102
[0167] In Table 2, the weight ratio of benzyl benzoate to sesame
oil is calculated by the following formula:
Weight ratio=Volume ratio*1.118/0.917
[0168] In the formula, 1.118 (g/cm.sup.3) represents the density of
benzyl benzoate, and 0.917 (g/cm.sup.3) represents the density of
sesame oil. "Added SDE concentration" represents the ratio of "the
originally added weight of SDE" to "the originally added volume of
benzyl benzoate and sesame oil." "Calculated SDE Concentration"
represents the calculated SDE concentration of Samples 1-6,
obtained by centrifuging each of the samples, and then analyzing
the resulting supernatants by HPLC.
[0169] It can be seen from Table 2 that, when the BB/oil ratio is
set to about 1, samples prepared according to Method A--i.e.,
Samples 1 and 2--were all in the form of suspension with
precipitates, while samples prepared according to Method B--i.e.,
Samples 3-6--were all in a homogeneous solution form. For Samples 1
and 2, the difference between "Added SDE concentration" and
"Calculated SDE Concentration" indicates that more than 20% of SDE
formed solid particles in the formulations, which had greatly
exceeded the limitation of "at most 0.5-5.0% solids" acceptable for
an intramuscular injection suspension (see R. M. Patel, Parenteral
Suspension: an Overview, Int. J. Curr. Pharm. Res., 2010, 2,
3:3-13). In addition, the visible solid particles indicated that
the average particle size of Samples 1 and 2 was much larger than 5
micrometer (i.e., the upper limit for a qualified intramuscular
injection suspension). Moreover, "Calculated SDE Concentration" of
Samples 1 and 2 indicated that the saturated concentration of SDE
in the formulations prepared by Method A, when the BB/oil ratio is
set to about 1, was around 60-65 mg/mL.
[0170] For Samples 3-6, it can be seen that the difference between
"Added SDE concentration" and "Calculated SDE Concentration" was
not significant, meaning the homogeneous formulations prepared by
Method B were stable even after being tested by three cycles of
freeze-thaw step. The above data also demonstrate that when the
weight ratio of benzyl benzoate to sesame oil was in the range of
about 0.8-1.2:1, the present formulations prepared by Method B can
be homogeneous and stable with an SDE concentration of 100 mg/mL or
less. In some embodiments, the present invention may form a
homogeneous and stable formulation, at the BB/oil ratio of about
0.8-1.2:1, having a SDE concentration of 70-100 mg/mL, for example,
75 mg/mL. The SDE concentration of more than 70 mg/mL allows the
injection volume to be greatly reduced, as compared with the
injection volume suggested by the prior art.
[0171] It should be understood that when the BB/oil ratio is
increased, for example, from about 1 to about 1.5, the solubility
of SDE in the mixture of BB and oil will be increased
significantly, for example, from about 60 mg/mL to about 150 mg/mL.
Therefore, a homogeneously dissolved formulation having a BB/oil
ratio of about 1.5 can be prepared by either Method A or Method B
if the intended SDE concentration is lower than 150 mg/mL. However,
when a formulation having a BB/oil ratio of about 1.5 needs to be
prepared with a SDE concentration of greater than 150 mg/mL, Method
B must be used to achieve a homogeneously dissolved
formulation.
Example 3. In Vitro and In Vivo (on Dogs) Studies of Present
Formulations
[0172] (1) Preparation of Present Formulations
[0173] Three SDE formulations (AF3, AF1, and AF4) were prepared
based on the concentrations and BB/oil ratios listed in Table 3.
AF4 was prepared according to Method A of Example 1; AF3 and AF1
were prepared according to Method B of Example 1.
TABLE-US-00006 TABLE 3 Present formulations for in vitro and in
vivo studies on dogs Benzyl Sesame Sample benzoate oil SDE BB/oil
No. (w/w %) (w/w %) (mg/mL) ratio AF3 39 61 50 0.65 AF1 54.2 45.8
80 1.18 AF4 67 33 80 2
[0174] (2) Stability of Present Formulation
[0175] AF3, AF1 and AF4 formulations were then subject to a
freeze-thaw test to check its physical stabilities. The freeze-thaw
test was conducted by cooling each of the samples at about
0-4.degree. C. for about 12 hours, warming each of the cooled
samples at room temperature for about 12 hours, and sequentially
repeating the cooling and warming steps twice. AF3, AF1, and AF4
formulations stayed clear and homogeneous after the freeze-thaw
test. The resulting samples were centrifuged for 10 minutes at 3000
rpm. The upper solution of each sample was respectively collected
and then subjected to UPLC analysis according to the method of
Example 1, except that the run time was 15 minutes and the sample
volume was 1 ul. "Added SDE concentration" and "Calculated SDE
Concentration" are the same as that defined in Example 2, except
that the upper solutions of AF3, AF1 and AF4 were analyzed by UPLC
rather than HPLC.
TABLE-US-00007 TABLE 4 UPLC analysis results of AF3, AF1 and AF4
formulations Added SDE Calculated SDE Sample BB/oil concentration
Concentration No. ratio Appearance (mg/mL) (mg/mL) AF3 0.65:1 Clear
solution 50 47 AF1 1.18:1 Clear solution 80 77 AF4 2:1 Clear
solution 80 79
[0176] In Table 4, it can be seen that the difference between
"Added SDE concentration" and "Calculated SDE Concentration" is not
significant, meaning the 3 formulations are homogeneous, and are
stable even after being subjected to three freeze-thaw cycles. The
three formulations are respectively prepared by Method A or Method
B to form a homogeneous solution without solid particles, and the
homogeneous solutions exhibit superior stability that can satisfy
commercial needs, such as being suitable for direct sterilization
by filtration and low temperature storage (shelf-life may be
prolonged when being stored at a lower temperature).
[0177] (3) In Vitro Dissolution Experiment
[0178] In vitro dissolution experiments and UPLC analyses were
performed, according to the processes disclosed in Example 1, on
AF3, AF1 and AF4 formulations. The accumulated SDE dissolution
profiles of each of the formulations are plotted in FIG. 2. It can
be seen from FIG. 2 that, when the BB/oil ratio is about 0.65, the
time required for releasing 50% of the total amount of SDE from AF3
formulation into the in vitro medium was about 20-30 minutes. When
the BB/oil ratio was about 1.18, the time required for releasing
50% of the total amount of SDE from AF1 formulation into the in
vitro medium was about 35-45 minutes. When the BB/oil ratio was
about 2, the time required for releasing 50% of the total amount of
SDE from AF4 formulation into the in vitro medium was about 50-60
minutes. This testing indicates that when the BB/oil ratio is
increased from 0.65 to 2, the in vitro dissolution rate of the
present formulation will be decreased.
[0179] (4) Determining the Effective Plasma Nalbuphine
Concentration for Analgesia in Dogs
[0180] In the Handbook of Veterinary Pain Management (2nd Edition,
2009), the potencies of nalbuphine and other opioid analgesics were
reported (page 167, Table 9-2). The duration of analgesia when
administrating nalbuphine at 0.5 mg/kg on dogs was reported to be
about 4 hours. Thus, the plasma concentration of nalbuphine at 4
hours after injection of the said dose of nalbuphine via
subcutaneous administration may be the lowest effective plasma
concentration of nalbuphine for analgesia on dogs. According to in
vivo experiments conducted by the inventors, the average plasma
concentrations of nalbuphine at 3 hours and 4 hours after
subcutaneously injected with 0.5 mg/kg nalbuphine were 9.9 ng/mL
and 5.2 ng/mL, respectively. Therefore, it may be regarded that the
effective plasma concentration of nalbuphine for analgesia in dog
is about 5 ng/mL.
[0181] (5) Intramuscular Administration of Present Formulations
into Dogs
[0182] An animal study was conducted to verify the correlation
between the in vitro dissolution rate and the in vivo release
rate/release period of the present formulations. Each of the AF3,
AF1, and AF4 formulations were separately administered to two male
Beagle dogs by intramuscular injection. The dose of SDE was 160 mg
for each dog, and the injection volumes varied according to the
drug concentration of each formulation (AF3: 3.2 mL, AF1 and AF4: 2
mL). The blood samples were drawn prior to the dosing, and at 1, 2,
6, 24, 36, 48, 60, 72, 96, 120 and 144 hours after dosing. The
plasma nalbuphine concentration of each sample was determined using
a liquid chromatography-mass spectroscopy/mass spectroscopy
(LC-MS/MS) system consisting of an AB API4000 triple-quadrupole
mass spectrometer coupled with Shimazdu LC-20AD and a CTC
AutoSampler.
[0183] The mean plasma concentration-time profiles of nalbuphine
from Day 1 to Day 6 for the three formulations are showed in FIG.
3, and the corresponding log concentration-time profiles are shown
in FIG. 4. Since SDE is rapidly converted into nalbuphine when
released from the formulation into the blood or tissues, the plasma
nalbuphine concentration is measured to represent the release
amount of SDE from the formulation.
[0184] The in vivo testing results of the AF3, AF1 and AF4
formulations on dogs are consistent with the trend we expect based
on the in vitro dissolution studies. It can be seen from FIG. 3
that when the BB/oil ratio is increased, the in vivo release period
of the formulation is extended or prolonged. More specifically, the
nalbuphine plasma concentrations at 144 hours (Day 6) after
administration of AF3, AF1 and AF4 are about 0.4 ng/mL, about 9.2
ng/mL and about 14.7 ng/mL, respectively. Based on an assumption
that the effective plasma concentration of nalbuphine for analgesia
on dog is about 5 ng/mL, AF3 formulation would not produce an
analgesic effect at 144 hours from dosing, while the AF1 and AF4
formulations would produce an analgesic effect for a period longer
than 144 hours from dosing. According to the result of dog
experiment, when the BB/oil ratio was adjusted to lower than about
1, e.g. 0.65, the formulation may have a duration of action of less
than 6 days, for example, about 4 days; when the BB/oil ratio was
adjusted to greater than about 1, e.g. 2, the formulation may have
a duration of action of equal to or greater than about 5, for
example, more than 6 days. Thus, an extended release formulation of
SDE with a predetermined release period can be prepared by
adjusting the BB/oil ratio of the formulation.
[0185] Furthermore, it can also be observed from FIG. 3 that when
the BB/oil ratio is increased, the release profile of the
formulation will be steadier, e.g. delayed onset and insignificant
burst release for AF4. The pharmacokinetic parameters are
summarized in Table 5. The T.sub.max of AF3, AF1 and AF4 are 21
hours, 24 hours and 84 hours, respectively. The C.sub.max of AF3,
AF1 and AF4 are 87.35 ng/mL, 82.90 ng/mL and 41.1 ng/mL,
respectively.
[0186] When the BB/oil ratios were about 0.65, about 1, and about
2, the blood concentrations of nalbuphine at 1 hour after
administration were about 28.4 ng/mL, about 11.0 ng/mL, and about
6.7 ng/mL, respectively. The results indicate that when the BB/oil
ratio is increased, the time to reach an effective blood
concentration of nalbuphine may be longer, thus the onset of action
of the formulation may be slower.
[0187] The following PK parameters support the conclusion that when
the BB/oil ratio is increased, the formulation may exhibit a
release profile with a longer release period, a lower maximum
concentration (C.sub.max) and a longer time to peak blood
concentration level (T.sub.max), as compared with a formulation
having a lower BB/oil ratio.
TABLE-US-00008 TABLE 5 Pharmacokinetic parameters after IM
injection of AF3, AF1 and AF4 formulations Formulation AF3 AF1 AF4
Injection volume (mL) 3.2 2 2 Average BW(kg) 8.85 9.29 7.9 Average
Dose(mg/kg) 18.13 17.24 20.2 T.sub.max (hr) 21.00 24.00 84.0
C.sub.max (ng/mL) 87.35 82.90 41.1 T.sub.1/2 12.69 41.14 38.99
AUC.sub.last (hr*ng/mL) 4555.63 5030.93 4075.7
AUC.sub.INF.sub.--.sub.pred (hr*ng/mL) 4563.35 5577.12 4978.4
[0188] By using the Wegner-Nelson method, the average plasma
concentration versus time curve was transformed into the cumulative
relative fraction absorbed (CRFA) versus time curve. Under the
assumption that Ab.sup..infin. (total amount of drug absorbed at
t=0.about..infin.) of each formulation is 100% and the elimination
half-life of nalbuphine after i.v. dosing in dogs is about 1.2 hour
(Biopharm Drug Dispos. 1985 October-December; 6(4):413-21.), the
CRFA versus time curve of each formulation is plotted in FIG. 5. In
FIG. 5, when the BB/oil ratio is about 0.65, about 99% of
Ab.sup..infin. is absorbed at 144 hours after administration (AF3);
when the BB/oil ratio is about 1.18, about 91% of Ab.sup..infin. is
absorbed at 144 hours after administration (AF1); when the BB/oil
ratio is about 2, about 82% of Ab.sup..infin. is absorbed at 144
hours after administration (AF4). By applying this model, it can be
projected that when the BB/oil ratio of the formulation is
increased, the relative percentage of Ab.sup..infin. absorbed at
the same time point will be lower, which indicates that the
formulation with a higher BB/oil ratio may release the dose depot
for a longer period of time.
[0189] The above experimental results all indicate that the in
vitro dissolution profiles of the present formulations are
correlated to the in vivo release profiles of the formulations. The
in vivo release rate/release period of the present formulation can
be controlled or regulated by the BB/oil ratio.
Example 4. In Vitro and In Vivo (on Humans) Studies of Present
Formulations
[0190] (1) Preparation of Present Formulations, by Method B of
Example 1
[0191] About 600 g of SDE was mixed with about 4025 g of benzyl
benzoate. The resulting mixture was stirred at 300 rpm for 60
minutes to give a clear solution. About 3591 g of sesame oil was
added into the clear solution, and then stirred at 300 rpm for
about 30 minutes. The resulting solution was subjected to
filtration sterilization by using Millipore 0.22 .mu.m filters. The
final formulation (F8) had an SDE concentration of about 75 mg/mL,
and the weight ratio of benzyl benzoate to sesame oil was about
1.12:1 (Table 6).
TABLE-US-00009 TABLE 6 F8 formulation Benzyl Sesame Sample benzoate
oil SDE BB/oil No. (w/w %) (w/w %) (mg/mL) ratio F8 53 47 75
1.12
[0192] The F8 formulation thus obtained was a homogeneous solution
without solid particles, thereby suitable for being sterilized
directly by filtration and suitable for large scale production.
[0193] (2) In Vitro Dissolution Experiment
[0194] In vitro dissolution experiments and UPLC analyses were
performed, according to processes disclosed in Example 1, on the F8
formulation. The accumulated SDE dissolution profiles of the F8
formulation and the AF1 formulation are plotted in FIG. 6. It can
be seen from FIG. 6 that the dissolution profiles of F8 and AF1
formulations are similar as their BB/oil ratios are similar. When
the BB/oil ratio is about 1.1-1.2, the time required for releasing
50% of the total amount of SDE from the formulation into the in
vitro medium was about 30-40 minutes.
[0195] In view of the duration of action results obtained with AF1
in dogs described above and the similar in vitro dissolution
profiles for F8 and AF1, a similar duration of action (i.e. greater
than 6 days) with F8 was expected humans.
[0196] (3) Phase 1 Clinical Study
[0197] A Phase I clinical trial was conducted with the F8
formulation in healthy volunteers. It was designed to evaluate
safety and local tolerability and assess the pharmacokinetics of
SDE following single dose intramuscular injection. The study
enrolled a total of 28 healthy male subjects. All subjects were
randomized to 5 cohorts. Cohort 1 (N=4) was treated with single
dose Nubain.RTM. 17 mg (0.85 mL) via intramuscular injection.
Cohorts 2-5 (N=6) were either treated with placebo (N=2) or treated
with single dose SDE (N=4) at 75 mg (1 mL), 100 mg (1.33 mL), 125
mg (1.67 mL), and 150 mg (2 mL), respectively. Overall, the
escalating doses of SDE up to 150 mg were well tolerated. All
adverse events (AEs) were mild. No significant difference was found
among the SDE and placebo groups in the number of AEs, the number
of subjects with AEs, the severity of AEs, and AE relatedness.
[0198] Blood was collected from all 28 subjects who were treated
with Nubain.RTM., the F8 formulation, or placebo. Heparinized blood
samples were obtained before and at various time points following
single dose administration of study medication. Nalbuphine from
Nubain.RTM. or the F8 formulation were detected and quantitated
using the validated LC/MS/MS method. The subsequent analysis of the
data involved non-compartmental pharmacokinetics analysis, i.e.,
C.sub.max, T.sub.max, AUC.sub.0-t, AUC.sub.0-inf, and T.sub.1/2.
Since SDE is rapidly converted to nalbuphine in the blood, the
pharmacokinetic parameters of nalbuphine were calculated using a
non-compartment model and actual time vs. plasma concentrations of
nalbuphine (Table 7).
[0199] The pharmacokinetics of nalbuphine following the
administration of the F8 formulation appeared to be
dose-proportional. The highest mean C.sub.max and AUC.sub.0-inf
were found at 150 mg SDE and were 9.81 ng/mL and 1353.16 ng*hr/mL,
respectively. Plasma nalbuphine reached C.sub.max within 45-66
hours (T.sub.max) after IM administration of 75, 100, 125, and 150
mg SDE.
[0200] The average elimination half-life (T.sub.1/2) of nalbuphine
after IM administration of Nubain.RTM. (cohort 1) was about 4 h.
Following intramuscular injection of the F8 formulation with a
total dose ranging from 75 mg to 150 mg, the mean apparent
T.sub.1/2 of nalbuphine ranged from about 56 to 90 hours. The
longer apparent half-life was most likely due to slow and prolonged
absorption of SDE/nalbuphine from the IM injection site.
TABLE-US-00010 TABLE 7 Pharmacokinetic parameters after single IM
injection of 17 mg Nubain .RTM. (NH) or escalating doses of F8
formulation. AUC.sub.0-t AUC.sub.0-inf Treatment/ C.sub.max
T.sub.max (hr*ng/ (hr*ng/ T.sub.1/2 Dose (ng/mL) (hr) mL) mL) (hr)
NH Mean 85.73 0.25 171.74 174.16 4.06 17 mg SD 18.61 0 15.99 15.53
1.13 SDE Mean 5.45 66 647.84 692.27 55.75 75 mg SD 0.85 22.98 96.95
114.00 5.54 SDE Mean 5.65 66 811.34 936.17 85.45 100 mg SD 1.50
40.99 145.69 176.27 29.70 SDE Mean 7.31 45 1047.45 1219.71 89.83
125 mg SD 1.79 24.74 205.77 263.16 24.74 SDE Mean 9.81 60 1214.98
1353.16 73.4 150 mg SD 2.94 13.86 155.93 137.55 30.74
[0201] FIG. 7 shows the plasma concentrations of nalbuphine
following administration of various dose of the F8 formulation and
of one dose of Nubain.RTM.. The plasma concentrations of nalbuphine
were above 1 ng/mL or 3 ng/mL for at least 220 or 120 hours,
respectively, in all 16 subjects receiving 75-150 mg SDE in the F8
formulation. However, following intramuscular injection of
Nubain.RTM. 17 mg, the plasma concentrations of nalbuphine remained
above 1 ng/mL or 3 ng/mL for only 16 or 8 hours, respectively.
Under the assumption that the effective plasma concentration of
nalbuphine for analgesia in moderate to severe pain is greater than
1 ng/mL, more preferably greater than 3 ng/mL (Can J Anaesth. 1991
March; 38(2):175-82; European Journal of Clinical Pharmacology
1987, Volume 33, Issue 3, pp 297-301), the duration of action of a
single injection of the F8 formulation would be much longer than
that covered by a single injection of Nubain.RTM.. In the cohort
receiving 125 mg SDE, the mean plasma concentration of nalbuphine
was above 3 ng/mL between 12 to 168 hours of dosing, which
indicated that the duration of action was about 6.5 days
(168-12=156 hours=6.5 days). In the cohort receiving 150 mg SDE,
the mean plasma concentration of nalbuphine was above 3 ng/mL
between 24 to 168 hours of dosing, and was above 1 ng/mL between 6
to 288 hours of dosing, which indicated that the duration of action
was about 6-12 days (168-24=144 hours=6 days; 288-6=282 hours=11.75
days). For some individuals, the plasma concentrations of
nalbuphine were above 3 ng/mL between 12 to 216 hours of dosing,
which indicated that the duration of action was about 8.5 days
(216-12=204 hours=8.5 days). This indicates that the F8 formulation
may be administered to a patient at 6 to 36 hours prior to the
onset of pain symptoms. For example, the onset of pain symptoms is
during or after a surgical operation. Accordingly, the F8
formulation may be administered to a patient at 6 to 36 hours prior
to a surgical operation, and may effectively relieve pain during
and immediately after the surgical operation. For example, the F8
formulation may be administered at 12-36 hours or 12-24 hours prior
to the surgical operation.
[0202] (4) Bioavailability Study
[0203] A bioavailability study with the F8 formulation and
Bain.RTM. (Nalbuphine HCl IM injection) was conducted on healthy
volunteers. A total of twelve subjects completed the crossover
study. Each subject received a single dose of reference drug
(Bain.RTM., Nalbuphine HCl IM injection, 10 mg/mL.times.2 mL) in
period I and the F8 formulation (SDE IM injection, 75 mg/mL.times.2
mL) in period II. There was a minimum 5-day washout period between
period I and period II. In period I, the blood samples were drawn
prior to the dosing, and 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,
12, and 24 hours after dosing. In period II, the blood samples were
drawn prior to the dosing, and 6, 12, 24, 48, 60, 72, 96, 120, 168,
216, 288 and 360 hours after dosing.
[0204] The whole blood concentrations of nalbuphine in the samples
were determined by LC-MS/MS. AUC.sub.0-t, AUC.sub.0-inf, C.sub.max,
T.sub.max, T.sub.1/2, and MRT for nalbuphine in whole blood were
determined by non-compartment methods. In addition, relative
bioavailability of SDE compared to Nalbuphine (Bain.RTM.) was
calculated.
[0205] No serious adverse events occurred during this study.
Pharmacokinetic parameters of nalbuphine for Bain.RTM. and the F8
formulation are presented as mean.+-.the standard deviation (SD) in
Table 8.
TABLE-US-00011 TABLE 8 Pharmacokinetic parameters of nalbuphine for
Nalbuphine (Bain .RTM.) and the F8 formulation. AUC.sub.0-t
AUC.sub.0-inf C.sub.max Treatment/ (ng/ (ng/ (ng/ T.sub.max MRT
T.sub.1/2 Dose mL*h) mL*h) mL) (h) (h) (h) Bain .RTM. Mean 319.3
323.0 115.45 0.40 4.15 4.03 20 mg SD 85.3 86.5 56.45 0.13 0.61 0.54
SDE Mean 1687.4 1832.0 15.40 64.00 149.38 83.16 150 mg SD 385.6
402.2 6.42 9.34 69.07 46.45
[0206] FIG. 8 shows the mean whole blood concentration-time
profiles of nalbuphine after subjects received the F8 formulation
from 0 to 360 hours of dosing in period II described above. In this
bioavailability study, the mean whole blood concentration of
nalbuphine was above 3 ng/mL between 24 to 168 hours of dosing,
which indicated that the duration of action was about 6 days (Table
9). The result is consistent with the finding in the cohort
receiving 150 mg SDE of Phase 1 study (plasma concentration of
nalbuphine). For some individuals, the whole blood concentrations
of nalbuphine were above 3 ng/mL between 12 to 216 hours of dosing,
which indicated that the duration of action was about 8.5 days. In
addition, the mean whole blood concentration of nalbuphine was
above 1 ng/mL between 6 to 288 hours of dosing, which indicated
that the duration of action was about 12 days.
TABLE-US-00012 TABLE 9 Mean whole blood concentration-time data of
nalbuphine for the F8 formulation Time (h) Mean (ng/mL) SD 0 -- --
6 1.09 0.39 12 2.04 0.94 24 5.03 2.55 48 11.83 5.51 60 13.39 5.87
72 14.12 6.49 96 9.17 3.15 120 6.48 1.67 168 4.33 1.19 216 2.51
1.10 288 1.44 0.98 360 0.81 0.78
[0207] The relative bioavailability (F) of nalbuphine from the F8
formulation to nalbuphine from Bain.RTM. was about 86.2.+-.12.1(%).
In addition, the mean absorption time (MAT) and absorption rate
(Ka) of nalbuphine from the F8 formulation were about 145.2.+-.69.1
hour and about 0.0081.+-.0.0030 h.sup.-1, respectively. The
bioavailability study shows that the duration of action of the
present formulation may be equal to or greater than 6 days when the
BB/oil ratio is set to about 1.12. On some individuals, the
duration of action of the present formulation may be about 5
days.
[0208] By correlating the dog study results (Example 3) with the
human study results, it can be concluded that when the formulation
having a BB/oil ratio of less than 1, e.g., about 0.65, is
administered to a human subject via IM injection, the duration of
action of the formulation may be less than 6 days; while when the
formulation having a BB/oil ratio of more than 1, e.g., about 2, is
administered to a human subject via IM injection, the duration of
action of the formulation may be greater than 6 days. Accordingly,
the present invention may provide extended release formulations of
SDE with various release periods by adjusting the BB/oil ratio. For
example, when a longer duration of action is intended (e.g. 1 or 2
weeks, or longer), the BB/oil ratio may be set to about 1 or
greater than 1, for example, 2 or 3; and when a shorter duration of
action is intended (e.g. 3 or 4 days), the BB/oil ratio may be set
to less than 1, for example, 0.5 or 0.65.
[0209] (5) Phase 2/3 Clinical Study
[0210] A random, placebo-controlled, single dose, parallel design,
phase 2/3 study was conducted with 209 male and female patients to
assess the safety and efficacy of the intramuscular injection of F8
formulation in the treatment of postoperative pain following
hemorrhoidectomy.
[0211] The subjects were divided into two groups, of which Group 1
(n=103) was treated with a single dose of intramuscular SDE 150 mg
(2 mL), and Group 2 (n=106) was treated with a single dose of
intramuscular placebo (2 mL). All subjects were given a single dose
of SDE or placebo via intramuscular injection 24.+-.12 hours before
hemorrhoid surgery. The subjects were allowed to take rescue
medication and monitored for 7 days after dosing. Statistical
analyses were performed on the data to compare the two groups.
[0212] The primary efficacy endpoint was pain assessment calculated
as the area under the curve of VAS pain intensity scores through 48
hours after surgery. The secondary efficacy endpoints included pain
assessment measured with VAS; time from the end of operation to the
first rescue medication dosing; the consumption of oral ketorolac.
Pain intensity was assessed right before the first use of PCA
ketorolac, and at 1.+-.0.1, 2.+-.0.1, 3.+-.0.1, 4.+-.0.25,
8.+-.0.5, 12.+-.0.5, 16.+-.0.5, 20.+-.0.5, 24.+-.1, 28.+-.1,
32.+-.2, 36.+-.2, 40.+-.2, 44.+-.2, 48.+-.2 hours after the
surgery, and was assessed during Days 3-7 in the morning and
evening, as well as during special events such as bowel
movements.
[0213] For the calculation of AUC, data were imputed with the use
of the windowed worst observation carried forward plus last
observation carried forward method. For subjects who used rescue
medication for pain relief, their VAS scores recorded within the
window of ketorolac medication (6 hours, which is one half-life of
ketorolac) were replaced by the "worst" observation (i.e., the
highest score before taking ketorolac), hereafter called "adjusted
VAS scores."
[0214] The AUC.sub.0-24 and AUC.sub.0-48 of the mean adjusted VAS
scores of SDE and placebo groups were calculated by using the
trapezoidal method and summarized in Table 10.
TABLE-US-00013 TABLE 10 Statistical analysis of AUC.sub.0-24 and
AUC.sub.0-48 by treatment after hemorrhoid operation. SDE - Placebo
Mean .+-. SD LS-mean p- Population SDE Placebo [95% CI].sup.1
value.sup.2 mITT N 103 106 AUC.sub.0-24 109.42 .+-. 126.71 .+-.
-16.86 0.0201* 55.04 49.22 [-31,05; -2.67] AUC.sub.0-48 209.93 .+-.
253.53 .+-. -42.20 0.0052* 111.26 108.49 [-71,68; -12.71] *mITT
population: modified Intention-To-Treat population
[0215] The AUC.sub.0-48 of the SDE group showed statistically
significant superiority against placebo group in mITT population
(209.93.+-.111.26 vs. 253.53.+-.108.49, p=0.0052). The distribution
statistics for the amount of oral ketorolac consumption after 48
hours post-operation by treatment was graphed as the box plot
presented in FIG. 9. Both the mean and median consumption of oral
ketorolac were lower in SDE group (Mean: 51.36 mg, Median: 40.00
mg) than those in the placebo group (Mean: 73.30 mg, Median: 80.00
mg).
[0216] Furthermore, the time of the first use of post-surgical
analgesic from post-operation was assessed and the results of
distribution statistics are summarized in Table 11. Longer periods
of time for the first use of post-operational analgesic in SDE
groups were observed. The mean time period of SDE group (12.57
hours) was prolonged, compared to that of the placebo group (4.93
hours).
TABLE-US-00014 TABLE 11 Distribution statistics of time (hour) for
the first use of post-operational analgesic by treatment Population
SDE Placebo Overall mITT (N) 103 106 209 NObs.sup.1 87 99 186 Mean
(SD) 12.57 (1.68) 4.93 (0.47) 9.68 (1.01) Q1 [95% CI].sup.2 2.27
[1.32; 2.78] 1.43 [0.98; 1.90] 1.80 [1.23; 2.22] Median [95%
CI].sup.2, 3 4.42 [3.47; 5.80] 3.28 [2.33; 4.73] 4.23 [3.03; 4.75]
Q3 [95% CI].sup.2 11.25 [8.33; 45.65] 6.52 [5.67; 7.60] 7.95 [6.60;
10.63]
[0217] In summary, the trends of VAS scores for pain intensity
measured over time through 48 hours post-operation, the time from
the end of operation to the first rescue medication dosing and the
consumption of oral ketorolac within 48 hours were consistent. All
these clinical results indicated that the F8 formulation may be
administered to a patient prior to a hemorrhoid operation, and may
effectively relieve pain immediately after the hemorrhoid
operation.
[0218] FIG. 10 shows the plot of adjusted VAS scores over time
through 0 hr to 7 days after hemorrhoid operation of mITT
population. The adjusted AUC.sub.0-final of the mean VAS scores for
SDE and placebo groups were calculated by using the trapezoidal
method and summarized in Table 12. The AUC.sub.0-final of mean
adjusted VAS scores of pain intensity of the SDE group showed
statistically significant superiority against the placebo group in
mITT population (630.79.+-.350.90 vs. 749.94.+-.353.72, p=0.0165).
In addition, the adjusted VAS score of pain intensity in the SDE
group was lower at beginning of the assessment measured the first 1
hour and at Day 7 morning after hemorrhoid operation (see the first
and the last data point of FIG. 10). The adjusted VAS score of the
SDE group was lower than the placebo group throughout the 7 days
after the hemorrhoid operation. Accordingly, the F8 formulation may
be administered to a patient prior to a hemorrhoid operation, and
may effectively relieve pain immediately after the hemorrhoid
operation with the duration of action persisting for at least about
5 or 6 days.
TABLE-US-00015 TABLE 12 Statistical analysis of AUC.sub.0-final
(based on adjusted VAS scores) by treatment after hemorrhoid
operation SDE - Placebo Mean .+-. SD LS-mean Population SDE Placebo
[95% CI].sup.1 p-value.sup.2 mITT N 103 106 AUC.sub.0-final 630.79
.+-. 749.94 .+-. -115.20 0.0165* 350.90 353.72 [-209.153;
-21.26]
Example 5. Stability Data of the Present Formulation
[0219] The F8 formulation prepared according to Example 4 was
stored at 2-8.degree. C. for 24 months. The formulation remained as
a clear and lightly yellow oily solution for the whole period of 24
months. In the meantime, the formulation was tested periodically by
HPLC to determine its Assay (Table 13).
TABLE-US-00016 TABLE 13 Assay of the F8 formulation at 2-8.degree.
C. for 24 months. Time of sampling Assay by HPLC (month) (% of
target) 0 104.3% 6 105.2% 12 101.7% 18 101.7% 24 101.3%
[0220] It can be seen from Table 13 that the F8 formulation is
stable for storage at 2-8.degree. C. for at least 24 months. The
freeze-thaw test conducted in Example 2 also demonstrates that the
formulation of the present invention can remain homogeneous at
about 0-4.degree. C. while not forming precipitates or solid
particles when being returned to room temperature. The stability
testing results indicate that the formulation, having a SDE
concentration (about 75 mg/mL) higher than the original
solubility/saturated concentration (about 60 mg/mL), prepared by
Method B can exhibit superior stability to satisfy commercial
needs, e.g. long shelf-life under low-temperature storage.
[0221] In another example, the F8 formulation was respectively
stored at 5, 25 and 40.degree. C. for 6 months. Samples collected
from each group were tested periodically by HPLC to determine the
formation of degradation products (Table 14).
TABLE-US-00017 TABLE 14 Stability of the F8 formulation at 5, 25,
and 40.degree. C. for 6 months Total impurities by HPLC Time of
sampling Stored Stored Stored (month) at 5.degree. C. at 25.degree.
C. at 40.degree. C. 0 0.37% 0.37% 0.37% 1 0.42% 0.45% 0.47% 3 0.39%
0.50% 0.85% 6 0.38% 0.65% 1.66%
[0222] It can be seen from Table 14 that when stored at 25.degree.
C. or 40.degree. C., the F8 formulation generated more impurities.
This indicates that the formulation is more suitable to be stored
at a temperature lower than room temperature. Since the formulation
of the present invention can remain homogeneous and stable at
2-8.degree. C. while not forming solid particles when returned to
room temperature, its shelf-life can be further prolonged by being
stored at a lower temperature.
Example 6. Improvement of SDE Solubility in Various Solvent Systems
Containing Different Alkyl Alcohols as the Solubilizing Agent
[0223] (1) Solubility Test of SDE Solutions
[0224] Table 15 shows the compositions of the tested solvent
systems by weight/weight percent (w/w %). The solvent systems each
comprise sesame oil, benzyl benzoate and different alkyl alcohols
(i.e., ethanol, 1-propanol, 2-propanol, 1-butanol and
t-butanol).
[0225] Each of the solvent systems was prepared by mixing each
component with the exact volume (.mu.l) corresponding to the w/w %
listed in Table 15. About 500 .mu.l of each of the solvent systems
was prepared and was vortexed for 3 minutes or more to fully mix
each component. An appropriate amount of SDE was added into 250
.mu.l of each of the solvent systems and the resulting mixtures
were sonicated for 10 minutes. If the previously added SDE was
completely dissolved, an additional 4-8 mg of SDE was added into
the mixture and which was then sonicated for another 10 minutes.
The step of adding 4-8 mg of SDE was repeated until the mixture was
saturated to show undissolved SDE precipitates. All of the mixtures
were sonicated for at least 30 minutes, and then centrifuged to
collect the supernatants. The supernatants were treated with
acetonitrile and then subjected to UPLC analysis.
[0226] (2) UPLC Analysis
[0227] The SDE concentrations in the supernatants collected from
samples S1-S8 were respectively determined by UPLC according to the
method of Example 1, except that the run time was 15 minutes and
the sample volume was 1 ul.
[0228] The saturated SDE concentrations (i.e., solubility) for each
tested solvent systems are shown in Table 15. It is seen that the
addition of alkyl alcohols in the solvent systems can significantly
increase the SDE solubility, although the solubility of SDE in each
of the alcohols alone is rather low. The solubility of SDE in
ethanol, 1-propanol, or t-butanol is about 10-30 mg/mL (Table
16).
[0229] The solubility of SDE in the solvent systems may be
increased by at least 30% when there is 10% of alkyl alcohol
added.
TABLE-US-00018 TABLE 15 Effect of alkyl alcohol on increasing SDE
solubility in the present formulations Composition of the SDE Solu-
solvent system (w/w %) Solu- bility alcohol alco- sesame benzyl
bility Improve- No. type hol oil benzoate ( mg/mL) ment S1 NC* 0 40
60 159.8 -- S2 Ethanol 10 40 50 267.7 168% S3 1-Propanol 10 40 50
254.1 159% S4 2-Propanol 10 40 50 235.2 147% S5 1-Butanol 10 40 50
222.0 139% S6 tert-Butanol 10 40 50 211.2 132% *NC: Negative
control, i.e. no alcohol is added.
TABLE-US-00019 TABLE 16 The solubility of SDE in various solvents
Sample Solubility of SDE in No. Solvent the solvent (mg/mL) 1
Benzyl benzoate (BB) 373.44 2 Benzyl alcohol 583.13 4 Ethanol 15.86
5 1-Propanol 32.46 6 t-Butanol 19.46 11 Sesame oil 5.93
Example 7. Solubility of SDE in Solvent Systems Comprising
Different Types and Amounts of Alkyl Alcohols
[0230] Five groups of solvent systems containing 40% by weight of
sesame oil were respectively prepared according to the method of
Example 6 by using the compositions as listed in Table 17; and
among them, five different alcohols (i.e., ethanol, 1-propanol,
2-propanol, 1-butanol, and tert-butanol) were used in the five
groups. SDE was dissolved in each of the solvent systems till
saturation by following the method of Example 6. The SDE
concentrations in the supernatants collected from each of the
samples (i.e. the saturated SDE concentration, or SDE solubility)
were respectively determined by UPLC using the method of Example
6.
TABLE-US-00020 TABLE 17 Solvent systems with various types and
amounts of alcohols Components of the solvent system (w/w %) Sesame
oil Alcohol * Benzyl benzoate 40 0 60 40 2.5 57.5 40 5 55 40 10 50
40 20 40 40 30 30 40 40 20 * Ethanol, 1-propanol, 2-propanol,
1-butanol, and tert-butanol were used in the five groups,
respectively.
[0231] The UPLC analysis results are divided into the five groups
to illustrate the effect of changing the alcohol on the SDE
solubility, as depicted in FIG. 11. It can be seen from FIG. 11
that when ethanol is replaced by 1-propanol, 2-propanol, 1-butanol,
or tert-butanol, the trends of solubility improvement observed are
similar. For C.sub.2-C.sub.4 alcohols, when 2.5-30% by weight of
the alcohol is added into the solvent system, the solubility of SDE
can be significantly increased; and when about 10-20% by weight of
the alcohol is added into the solvent system, the SDE solubility
can be maximized.
Example 8. In Vitro Release Study of Present Formulations
Containing Various Alkyl Alcohols
[0232] (1) Preparation of Present Formulations
[0233] Five present formulations were prepared according to Method
A of Example 1 (i.e., mixing the alkyl alcohol, BB and oil, then
adding SDE) by using various solvent systems as listed in Tables
18. The solubility of SDE in formulations comprising an
oil-miscible retaining solvent and a pharmaceutically acceptable
oil may be significantly increased by adding an alkyl alcohol. As
such, Method A is sufficient to prepare a homogenous
alcohol-containing formulation having a SDE concentration that is
greater than the SDE solubility of the formulation without the
alcohol, as long as the intended concentration of SDE in the
alcohol-containing formulation is lower than the saturated
concentration.
[0234] For the five formulations listed in Table 18, each
formulation contains 10% ethanol and the BB/oil ratio ranges from
0.5 to 16.
TABLE-US-00021 TABLE 18 The present formulations with ethanol, at
various BB/oil ratios Benzyl Sesame Sample Ethanol benzoate oil SDE
BB/oil No. (w/w %) (w/w %) (w/w %) (mg/mL) ratio N1 10 30 60 75 0.5
N2 10 45 45 150 1 N3 10 67.5 22.5 150 3 N4 10 80 10 150 8 N5 10 85
5 150 16
[0235] (2) In Vitro Dissolution Experiment
[0236] In vitro dissolution experiments and UPLC analyses were
performed according to the method of Example 1. The accumulated SDE
dissolution profiles of the five formulations listed in Tables 18
are plotted in FIG. 12.
[0237] In FIG. 12, it can be seen that the trend observed in FIG. 1
remains when ethanol is added into the formulations (N1-N5 of Table
18).
[0238] The presence or absence of an alkyl alcohol in the present
formulation does not significantly affect the correlation between
the dissolution/release rate and the BB/oil ratio, though the
addition of the alcohol can significantly improve the solubility of
SDE in the formulation so as to give a homogeneous formulation
having a SDE concentration higher than that possible for the
formulation without the alcohol.
Example 9. In Vitro Release Study of Present Formulations with or
without Alkyl Alcohol
[0239] (1) Preparation of Formulations
[0240] Six formulations were prepared using various solvent systems
as listed in Tables 19-20. Among them, formulations F8 and AF1 were
prepared according Method B of Example 1, and the remaining
formulations were prepared according to Method A of Example 1 (i.e.
mixing the alkyl alcohol, BB and oil, then adding SDE).
[0241] For the three formulations listed in Table 19, the BB/oil
ratios are all 16. For the N5 and N10 formulations, ethanol and
1-butanol were respectively added in the formulations. For the N7
formulation, there was no alcohol used in the formulation.
[0242] For the three formulations listed in Table 20, the BB/oil
ratios are all about 1. For the N2 formulation, ethanol was added
in the formulation, and for the F8 and AF1 formulations, there were
no alcohol used in the formulations.
TABLE-US-00022 TABLE 19 The present formulations with/without
alcohols, at the BB/oil ratio of 16 Components of the solvent
system (w/w %) Sample Alcohol Alco- Benzyl Sesame SDE BB/oil No.
type hol benzoate oil (mg/mL) ratio N7 -- 0 94 6 150 16 N5 Ethanol
10 85 5 150 16 N10 1-butanol 10 85 5 150 16
TABLE-US-00023 TABLE 20 The present formulations with/without
alcohols, at the BB/oil ratio of about 1 Components of the solvent
system (w/w %) Sample Benzyl Sesame SDE BB/oil No. Ethanol benzoate
oil (mg/mL) ratio F8 0 53 47 75 1.12 AF1 0 54.2 45.8 80 1.18 N2 10
45 45 150 1
[0243] (2) In Vitro Dissolution Experiment
[0244] In vitro dissolution experiments and UPLC analyses were
performed, according to the method of Example 1, on the
formulations listed in Tables 19-20. The accumulated SDE
dissolution profiles of the eight formulations of Tables 19 and 20
are plotted in FIGS. 13-14, respectively. As shown in FIGS. 13-14,
the presence or absence of an alkyl alcohol, does not significantly
affect the dissolution rate of SDE from the formulation as long as
the BB/oil ratio remains the same or similar. When the BB/oil ratio
is set to about 16, the times required for releasing 50% of the
total amount of SDE from the four formulations into the in vitro
medium are all about 100-120 minutes (N7, N5 and N10 of Table 19).
When the BB/oil ratio is set to about 1, the times required for
releasing 50% of the total amount of SDE from the three
formulations into the in vitro medium are all about 20-50 minutes
(F8, AF1, and N2 of Table 20).
[0245] The results show that the presence or absence of an alkyl
alcohol does not significantly affect the dissolution/release rate
of the present formulations as long as the BB/oil ratio remains the
same or similar.
Example 10. In Vitro Release Study of Formulations Containing
Different Oils
[0246] (1) Preparation of Formulations
[0247] Four formulations were prepared according to Method A of
Example 1 by using different solvent systems as listed in Table 21
(i.e., mixing ethanol, BB and the oil, then adding SDE). For the N2
and N14 formulations, the BB/oil ratios are about 1; while for the
N4 and N13 formulations, the BB/oil ratios are about 8. In the N2
and N4 formulation, the oil used is sesame oil; and in the N14 and
N13 formulation, the oil used is castor oil.
TABLE-US-00024 TABLE 21 The formulations with different oils
Components of the solvent system (w/w %) Sample Oil Benzyl SDE
BB/oil No. Type Oil Ethanol benzoate (mg/mL) ratio N2 sesame oil 45
10 45 150 1 N14 castor oil 45 10 45 150 1 N4 sesame oil 10 10 80
150 8 N13 castor oil 10 10 80 150 8
[0248] (2) In Vitro Dissolution Experiment
[0249] In vitro dissolution experiments and UPLC analyses were
performed, according to the method in Example 1, on the four
formulations. The accumulated SDE dissolution profiles of the four
formulations are plotted in FIG. 15.
[0250] As shown in FIG. 15, when the oil used is sesame oil and the
BB/oil ratio is set to 1, the time required for releasing about 50%
of the total amount of SDE from the formulation into the in vitro
medium is about 30-40 minutes (N2); and when the oil used is castor
oil and the BB/oil ratio is set to 1, the time required for
releasing 50% of the total amount of SDE from the formulation into
the in vitro medium is about 100-120 minutes (N14). On the other
hand, when the oil used is sesame oil and the BB/oil ratio is set
to 8, the time required for releasing about 50% of the total amount
of SDE from the formulation into the in vitro medium is about 70-90
minutes (N4); and when the oil used is castor oil and the BB/oil
ratio is set to 8, the time required for releasing 50% of the total
amount of SDE from the formulation into the in vitro medium is
about 120-140 minutes (N13).
[0251] It can be seen from FIG. 15 that the dissolution profiles of
the N2 and N14 formulations are quite similar though the
dissolution rate can be further decreased by using castor oil to
replace sesame oil. This pattern is also seen with the comparison
between N4 and N13 formulations. This is to say that to replace
sesame oil by another pharmaceutical acceptable oil in the present
formulation will not significantly affect the correlation between
the release period and the BB/oil ratio, i.e., the higher BB/oil
ratio, the longer the release period of the formulation.
Furthermore, using castor oil to replace with sesame oil may
further prolong the release period of the formulation.
* * * * *