U.S. patent application number 15/520946 was filed with the patent office on 2018-01-18 for injectable buprenorphine formulation.
The applicant listed for this patent is CAMURUS AB. Invention is credited to Ian HARWIGSSON, Markus JOHNSSON, Fredrik TIBERG.
Application Number | 20180015031 15/520946 |
Document ID | / |
Family ID | 52103459 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180015031 |
Kind Code |
A1 |
TIBERG; Fredrik ; et
al. |
January 18, 2018 |
INJECTABLE BUPRENORPHINE FORMULATION
Abstract
The present invention provides an injectable liquid formulation
with controlled release comprising: a) a lipid controlled-release
matrix comprising at least 50% triacyl lipids; b) at least one
oxygen containing organic solvent; c) at least 16% by weight of at
least one active agent selected from buprenorphine and salts
thereof, calculated as buprenorphine free base. The invention also
provides a method for the treatment of pain, for opioid maintenance
therapy or for the treatment of opioid dependence by detoxification
and/or maintenance or for the treatment or prophylaxis of the
symptoms of opioid withdrawal and/or cocaine withdrawal by
injecting such a liquid composition.
Inventors: |
TIBERG; Fredrik; (Lund,
SE) ; JOHNSSON; Markus; (Lund, SE) ;
HARWIGSSON; Ian; (Lund, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CAMURUS AB |
Lund |
|
SE |
|
|
Family ID: |
52103459 |
Appl. No.: |
15/520946 |
Filed: |
October 27, 2015 |
PCT Filed: |
October 27, 2015 |
PCT NO: |
PCT/EP2015/074901 |
371 Date: |
April 21, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 25/36 20180101; A61K 47/44 20130101; A61K 47/20 20130101; A61P
25/04 20180101; A61P 29/00 20180101; A61K 31/485 20130101; A61K
9/0024 20130101; A61K 47/12 20130101; A61K 47/22 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/20 20060101 A61K047/20; A61K 31/485 20060101
A61K031/485; A61K 47/12 20060101 A61K047/12; A61K 47/44 20060101
A61K047/44; A61K 47/22 20060101 A61K047/22 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 27, 2014 |
GB |
1419091.2 |
Claims
1-28. (canceled)
29. An injectable liquid formulation comprising: a) a lipid
controlled-release matrix comprising at least 50% triacyl lipids;
b) at least one oxygen containing organic solvent; c) at least 16%
by weight of at least one active agent selected from buprenorphine
and salts thereof, calculated as buprenorphine free base.
30. The injectable liquid formulation of claim 29, wherein the
formulation forms a controlled-release composition upon
administration to the body of a subject.
31. The injectable liquid formulation of claim 29, wherein the at
least one active agent selected from buprenorphine and salts
thereof is present at a level of greater than 21% (e.g., greater
than 30%, such as 31 to 50%) by weight buprenorphine (calculated as
buprenorphine free base).
32. The injectable liquid formulation of claim 29, wherein
component a) forms 10% to 60% of the total precursor formulation
and at least 50% of said component a) is formed of triacyl
lipids.
33. The injectable liquid formulation of claim 29, wherein 50% to
100%, preferably 60 to 90%, more preferably 70 to 90% of said lipid
controlled release matrix is formed of triacyl lipids.
34. The injectable liquid formulation of claim 29, wherein
component a) comprises at least 80% triglycerides.
35. The injectable liquid formulation of claim 29, wherein the
lipid controlled release formulation further comprises: i) at least
one neutral diacyl lipid ii) at least one tocopherol; and/or iii)
at least one phospholipid.
36. The injectable liquid formulation of claim 29, wherein
component a) comprises at least 50% by weight of triacyl lipids
comprising C16 to C20 acyl groups having zero, one or two
unsaturations, especially C16:0, C16:1, C18:0, C18:1, C18:2, C18:3
and/or C20:1 acyl groups.
37. The injectable liquid formulation of claim 29, wherein
component a) comprises at least 60% of triglycerides.
38. The injectable liquid formulation of claim 29, wherein
component a) comprises at least 60% of triacyl lipids having C16 to
C18 acyl groups with zero, one or two unsaturations.
39. The injectable liquid formulation of claim 29, wherein
component b) is present at 15 to 50% by weight of the precursor
formulation, preferably 25 to 40% by weight.
40. The injectable liquid formulation of claim 29, wherein
component b) comprises at least one amide and/or at least one
sulphoxide.
41. The injectable liquid formulation of claim 29, wherein
component b) comprises NMP, DMSO or mixtures thereof.
42. The injectable liquid formulation of claim 29 for
administration no more frequently than once every 28 days, such as
once every 28 to 32 days, once every 56 to 62 days, or once every
82 to 95 days.
43. The injectable liquid formulation of claim 29 having a dose in
the range 20 to 600 mg buprenorphine (calculated as free base)
particularly 30 to 300 mg, more preferably 40 to 140 mg.
44. The injectable liquid formulation of claim 29 having a dose in
the range 20 to 240 mg buprenorphine (calculated as free base) per
month of release duration and having a release duration of 1 to 4
months.
45. The injectable liquid formulation claim 29, wherein the
formulation is in ready-to-administer form.
46. The injectable liquid formulation of claim 29 having a
viscosity of 20 to 600 mPas at 20.degree. C., preferably 50 to 400
mPas at 20.degree. C., most preferably 60 to 300 mPas at 20.degree.
C.
47. The injectable liquid formulation of claim 29, wherein the
formulation is stable to storage in ready-to-administer form.
48. The injectable liquid formulation of claim 29, wherein the
ratio of triacyl lipid(s):phospholipid(s) (w/w) in the lipid
controlled-release matrix a) is in the range of 90:10 to 100:0,
preferably in the range of 95:5 to 100:0.
49. The injectable liquid formulation of claim 29, wherein the
level of phospholipid in the formulation as a whole is less than 8
wt.%, such as 6 wt % or less, or 4 wt % or less.
50. A controlled-release composition formed by administration to a
(preferably human) subject of an injectable liquid formulation of
claim 29.
51. The controlled-release composition of claim 50, wherein
following administration to said subject of an injectable liquid
formulation once monthly for at least 6 months, mean Cmin and Cmax
at a steady-state both fall within the range of between 0.3 ng/mL
to 12 ng/mL, preferably 0.4 ng/mL and 5 ng/mL, in a population of
at least 10 subjects.
52. The controlled-release composition of claim 50, wherein the
composition comprises: a) a lipid controlled-release matrix
comprising at least 50% triacyl lipids; b) optionally at least one
oxygen containing organic solvent; c) at least 16% by weight of at
least one active agent selected from buprenorphine and salts
thereof, calculated as buprenorphine free base; and d) optionally
at least one aqueous fluid.
53. A method of sustained delivery of buprenorphine to a human or
non-human animal body, said method comprising administering an
injectable liquid formulation comprising: a) a lipid
controlled-release matrix comprising at least 50% triacyl lipids;
b) at least one oxygen containing organic solvent; and c) at least
16% by weight of at least one active agent selected from
buprenorphine and salts thereof, calculated as buprenorphine free
base.
54. A method for the formation of a controlled-release composition
comprising exposing an injectable liquid formulation comprising: a)
a lipid controlled-release matrix comprising at least 50% triacyl
lipids; b) at least one oxygen containing organic solvent; and c)
at least 16% by weight of at least one active agent selected from
buprenorphine and salts thereof, calculated as buprenorphine free
base; to an aqueous fluid in vivo.
55. A method of treatment or prophylaxis of a human or non-human
animal subject comprising administration of an injectable liquid
formulation of claim 29.
56. A method of claim 55 for the treatment of pain, for opioid
maintenance therapy or for the treatment of opioid dependence by
detoxification and/or maintenance or for the treatment or
prophylaxis of the symptoms of opioid withdrawal and/or cocaine
withdrawal.
Description
[0001] The present invention relates to injectable formulations of
opioid agonists such as buprenorphine. In particular the invention
relates to injectable lipid formulations having the ability to form
controlled-release compositions upon injection.
BACKGROUND TO THE INVENTION
[0002] Many active pharmaceutical ingredients and other bioactive
agents exhibit a functional concentration window in vivo such that
blood plasma concentrations of active agent in particular range
will provide the desired effect. Concentrations below the
functional window are typically inactive or less effective and
concentrations above the functional window have the potential to
cause serious side-effects.
[0003] Opioid agonists are a prime example of pharmaceutical agents
for which adherence to an effective functional window, which may
vary significantly between patients and over time, is of great
importance. Opioids are indicated in many conditions including
treatment of pain and in various forms for treatment and
maintenance in opioid dependence. Insufficient dose, especially in
subject accustomed to opioids, can cause debilitating and
unpleasant withdrawal symptoms while excessive dose cause euphoria,
reinforcement of dependence and ultimately potentially fatal
respiratory depression.
[0004] A number of controlled release formulations which might
potentially be applied to opioid agents have been proposed.
Historically, most of these have relied on biodegradable polymers
such as poly-lactate, poly-glycolate and copolymers of these
moieties. More recently, some highly effective lipid-based depot
formulations have been proposed, such as the diacyl glycerol and
phospholipid formulations disclosed in WO2005/117830. Such lipid
formulations are highly effective. However, there remains a need
for simple alternative systems that can effectively deliver opioid
active agents over extended periods. It would be an advantage if
these could be provided with a smaller number of separate
constituents and particularly if these were highly biocompatible
and biotolerable.
[0005] The present inventors have now established that certain
opioids, particularly buprenorphine and its salts and derivatives,
can be delivered as a sustained-release injection in simple lipid
vehicles, providing a high concentration of the active agent is
used. Such formulations may be ineffective or inefficient at low
concentrations of buprenorphine but provide a much more desirable
release profile when the buprenorphine concentration is held above
around 16% by weight.
SUMMARY OF THE INVENTION
[0006] In a first aspect, the present invention therefore provides
an injectable liquid formulation comprising:
[0007] a) a lipid controlled-release matrix comprising at least 50%
triacyl lipids;
[0008] b) at least one oxygen containing organic solvent;
[0009] c) at least 16% by weight of at least one active agent
selected from buprenorphine and salts thereof, calculated as
buprenorphine free base.
[0010] Preferred triacyl lipids in all aspects and embodiments of
the present invention are triacyl glycerols (triglycerides).
[0011] Such injectable liquid formulations as described herein in
all aspects and embodiments of the invention typically form a
controlled-release composition upon administration to the body of a
subject. Such a subject may be a human or animal subject such as
any of those described herein.
[0012] The injectable liquid formulations described herein in all
aspects and embodiments of the invention typically have at least
one active agent selected from buprenorphine and salts thereof
present at a level of greater than 21% (e.g. greater than 30%, such
as 31 to 50%) by weight buprenorphine. Herein throughout, all
percentages of buprenorphine are calculated by weight as percentage
of buprenorphine free base in the complete formulation, unless
otherwise stated.
[0013] The injectable liquid formulations of the invention may be
administered to a suitable subject, particularly a mammalian
subject in thereby form a controlled-release formulation. In a
second aspect, the present invention therefore provides a
controlled-release composition formed by administration to a
(preferably human) subject of an injectable liquid formulation as
described in any of the aspects or embodiments disclosed herein.
Evidently, preferred formulations of the invention will result in
preferred controlled-release compositions.
[0014] The controlled-release compositions of the invention show
advantageous release profiles, particularly with regard to
maintaining plasma concentrations of buprenorphine within a
functional window for an extended period. Thus, following
administration to said subject of an injectable liquid (as
described in any embodiment herein) once monthly for at least 6
months, Cmin and Cmax (particularly the mean of each, taken in a
population of subjects typically comprising at least at least 10
subjects) at a steady-state both fall with the range of between 0.2
ng/mL to 12 ng/mL, preferably 0.4 ng/mL and 15 ng/mL.
[0015] In a further aspect, the invention also provides a method of
sustained delivery of buprenorphine to a human or non-human animal
body, said method comprising administering an injectable liquid
formulation comprising: [0016] a) a lipid controlled-release matrix
comprising at least 50% triacyl lipids; [0017] b) at least one
oxygen containing organic solvent; [0018] c) at least 16% by weight
of at least one active agent selected from buprenorphine and salts
thereof, calculated as buprenorphine free base.
[0019] Such formulations and compositions of the present invention
can be used in the treatment of any indication for which the
chronic administration of buprenorphine is suitable. In a
corresponding further aspect, the invention thus provides a method
of treatment or prophylaxis of a human or non-human animal subject
comprising administration of an injectable liquid formulation as
described in any aspect or embodiment of the invention. Such a
method may be for the treatment or prophylaxis of any suitable
condition, including for the treatment of pain, for opioid
maintenance therapy or for the treatment of opioid dependence by
detoxification and/or maintenance or for the treatment or
prophylaxis of the symptoms of opioid withdrawal and/or cocaine
withdrawal.
[0020] Correspondingly, in a yet further aspect, the present
invention provides an injectable liquid formulation or
controlled-release composition as described herein for use in
therapy. Such therapy may be for the treatment or prophylaxis of
any suitable condition, including for the treatment of pain, for
opioid maintenance therapy or for the treatment of opioid
dependence by detoxification and/or maintenance or for the
treatment or prophylaxis of the symptoms of opioid withdrawal
and/or cocaine withdrawal.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Highly effective lipid-based controlled-release formulations
have been disclosed over the last few years, including formulations
such as those of WO2005/117830 which comprise diacyl lipids and
phospholipids in appropriate mixtures so as to generate
formulations which change phase upon administration. This allows a
low-viscosity formulation to be injected and to generate a higher
viscosity depot composition in vivo which traps the active agent
and provides a slow-release effect. Such compositions are effective
for a broad range of active agents and rely primarily on the lipid
matrix to control the active agent release.
[0022] The present inventors, during their work with lipid-based
controlled-release formulations, have typically found that a lipid
mixture and a phase-change upon injection as described above is
generally necessary for controlled-release of most active agents.
There are, however, certain bioactive agents that, depending on the
therapeutic window (i.e. plasma concentration window where
treatment effects are realized and side effects are acceptable),
may be amenable to the use of simpler lipid formulations. The use
of simpler systems is always an advantage in medicine because this
reduces the number of components for which stringent sourcing and
quality-control procedures must be established. Simpler systems
also make the toxicological assessment and processes of regulatory
approval less complex, particularly where the remaining excipients
are generally regarded as safe (GRAS) or have an established record
of pharmaceutical use, e.g., previous use in registered injection
products.
[0023] It has now been established by the present inventors that
certain opioid active agents, particularly buprenorphine and
related compounds (salts and structural analogues thereof for
example) can be released in a controlled fashion from triacyl-lipid
containing formulations providing that the concentration of
buprenorphine compound ("buprenorphine" being used herein to
include all appropriate salts and structural analogues where
context allows) is above a certain threshold level.
[0024] The need for buprenorphine to be at a high concentration is
in itself unexpected because drug release in controlled-release
formulations is generally controlled by the carrier matrix. The
active agent will have the active role in the biological effect but
typically exhibits a passive role in the controlled-release.
Moreover, high concentrations of active agent will generally
interfere with the function of the controlled-release matrix and
thus the concentration of active agent will often be limited by the
disruptive effect that such an agent has upon the
controlled-release. The present case is quite the reverse of the
established norm and formulations having at least 16% buprenorphine
are found to provide more effective release than similar
formulations with a lower active-agent content.
[0025] The invention provides an injectable liquid formulation
comprising:
[0026] a) a lipid controlled-release matrix comprising at least 50%
triacyl lipids;
[0027] b) at least one oxygen containing organic solvent;
[0028] c) at least 16% by weight of at least one active agent
selected from buprenorphine and salts thereof, calculated as
buprenorphine free base.
[0029] In view of the positive effect that the buprenorphine
component has upon the controlled-release behaviour of this system,
the active agent (generally selected from buprenorphine, its
structural analogues and salts thereof) is present at a level of
greater than 16% in all aspects and embodiments of the invention.
This will preferably be greater than 21% (e.g. greater than 30%,
such as 31 to 50%) by weight buprenorphine (all calculated as
buprenorphine free base). Concentrations of up to 60% buprenorphine
may be used but preferably up to 50%, e.g. up to 45% will be
used.
[0030] The advantage of high buprenorphine concentrations is
illustrated in the attached FIG. 1. The Figure shows dose
normalized plasma concentrations of buprenorphine after
administration of a 33.8% formulation (A1) and a 1.06% formulation
(C1) to rats. It is evident from FIG. 1 that formulation A1
provides a much more sustained and stable release of buprenorphine
into blood plasma and has the potential to provide a much greater
duration of release, since the level does not change significantly
over the 14 day period of the experiment.
[0031] Another critical component in the liquid formulations and
controlled-release compositions of the invention is the lipid
matrix component a). In the injectable liquid formulations of all
embodiments of the invention, component a) typically forms 10% to
70% of the total precursor formulation. This may be 15% to 64% or
20 to 50% by weight.
[0032] In lipid component a), at least 50% of the lipids are formed
of triacyl lipids. Thus, generally 50% to 100% (such as at least
80%), preferably 60 to 90% or 60% to 95%, more preferably 70 to 90%
of said lipid controlled release matrix (component b)) is formed of
triacyl lipids. Component a) may consist essentially of triacyl
lipids (e.g. be 95% or more triacyl lipids).
[0033] The triacyl lipids forming part or all of component a) may
be any suitable triacyl lipid and will generally have a polar
"head" group and three non-polar "tail" groups. Typically these
will be joined by an ester moiety, although carbon-carbon bonds,
ethers, amides etc. may be used. Suitable polar head groups (for
the triacyl component and for any other lipids present) will
generally be non-ionic and include polyols such as glycerol,
diglycerol (and oligo/ploy glycerol such as 2 to 10 glycerols) and
sugar or carbohydrate moieties (such as mono-, di-, and
tri-saccharides including sorbitan, sorbitol, trehalose, inositol,
glucose, maltose and sucrose moieties and derivatives thereof) and
esters of polyols, such as acetate or succinate esters. Preferred
polar groups are glycerol and diglycerol, especially glycerol.
[0034] Suitable non-polar "tail" groups (for the triacyl component
and for any other lipids present) are typically C8 to C20 acyl
groups which may have one or more unsaturations in the carbon
chain. In one preferred embodiment, component a) may comprise
lipids (particularly triacyl lipids) with "medium chain" fatty acyl
components, such as C8 to C12 acyl chains (especially with zero,
one or two unsaturations). Such components may comprise some or all
of the triacyl lipid component, such as 1 to 100% of the triacyl
lipid component (e.g. 1 to 70% or 10 to 50%). Preferably such
components will comprise less than 50% of the triacyl lipids. In
another and more preferred embodiment, the triacyl lipid and any
other lipids present will comprise fatty acyl chains having 12 to
22 carbons, particularly C16 to C20 fatty acyl chains, especially
with zero, one or two unsaturations.
[0035] In one embodiment, in the injectable liquid formulation of
any aspect of the invention, component a) comprises at least 50% by
weight of triacyl lipids with such triacyl lipids comprising C16 to
C20 acyl groups having zero, one or two unsaturations. Among these,
especially preferred groups include C16:0, C16:1, C18:0, C18:1,
C18:2, C18:3 and/or 020:1 acyl groups.
[0036] In a further embodiment, the triacyl lipids of component a)
of the present invention will comprise not more than 25% of acyl
groups shorter than C12. That is to say, at least 75% of the acyl
groups of the triacyl components will be C12 or longer (typically
having zero, one or two unsaturations or a mixture thereof). This
may be at least 85% acyl groups of C12 or longer or at least 90%
acyl groups of C12 or longer.
[0037] In a further embodiment, the triacyl lipids of component a)
may comprise acyl groups wherein at least 25% of such acyl groups
are unsaturated (e.g. having 1, 2 or 3 unsaturations, preferably 1
or 2 unsaturations in the acyl chain). This will preferably be at
least 50% (e.g. 50 to 100% or 50 to 95%) unsaturated acyl moieties
and more preferably at least 75% unsaturated moieties in the
triacyl component (e.g. triacyl glycerol or others described
herein). In a similar embodiment, at least 50% by weight of triacyl
lipids in component a) may comprise at least 1 unsaturated acyl
moiety (e.g. at least one acyl moiety having 12 or more carbons in
the acyl chain and 1 or 2 unsaturations in that chain).
[0038] Some examples of non-polar groups suitable for use in
various embodiments of the present invention include caproyl
(C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0),
myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0),
palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl
(C18:1), ricinoleoyl (C18:1), linoleoyl (C18:2), linolenoyl
(C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl
(C24:9) groups. Thus, typical non-polar chains are based on the
fatty acids of natural ester lipids, including caproic, caprylic,
capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic,
oleic, elaidic, ricinoleic, linoleic, linolenic, arachidonic,
behenic or lignoceric acids, or the corresponding alcohols.
Preferable non-polar chains include palmitic, stearic, ricinoleic,
oleic and linoleic acids, particularly oleic acid.
[0039] In a further preferred embodiment, the injectable liquid
formulation of any aspect of the present invention may comprise at
least 60% of triacyl lipids having C16 to C18 acyl groups with
zero, one or two unsaturations. That is to say, of the triacyl
lipids present, at least 60% of the non-polar groups will be C16 to
C18, preferably, with zero, one or two unsaturations. The total
triacyl lipid (e.g. triacyl glycerol) component present will be as
indicated in any embodiment herein.
[0040] Triacyl lipids, such as triacyl glycerols, may be synthetic
but will typically be derived from natural sources. Many oils of
natural products are high in triacyl lipids and these may be used
either in their extracted form or in partially or fully purified
forms. Animal or preferably vegetable oils are highly suitable
sources of triacyl lipids (especially triacyl glycerols) and may
include olive oil, corn oil, sunflower oil, rapeseed (canola) oil,
palm oil, soybean oil, sesame oil, castor oil and mixtures thereof.
Sesame oil, soybean oil, castor oil and mixtures thereof are
preferred.
[0041] In one embodiment, the lipid matrix component a) contains up
to 50% of lipids that are not triacyl lipids. Such lipids may be
any appropriate component including mono-, and di-glycerides,
phospholipids (diacyl and/or "lyso" monoacyl), cholesterol,
tocopherol etc. One preferred embodiment provides for the
non-triacyl lipid to comprise: [0042] i) at least one neutral
diacyl lipid [0043] ii) at least one tocopherol; and/or [0044] iii)
at least one phospholipid;
[0045] Lipids that are not triacyl lipids will evidently comprise
that part of component a) which is not accounted for by triacyl
lipids, thus, the amount on non-triacyl lipids may be, for example
0 to 49%, such as 1 to 40% or 3 to 30%. In one embodiment less than
10% of component a) (e.g. 0.5 to 10%) is a non-triacyl lipid, such
as i) to iii) above or mixtures thereof.
[0046] Component i) above may be any neutral diacyl lipid and will
typically comprise a non-ionic polar "head" group as described
above, linked (e.g. by and ester, ether, C--C bond or amide) to two
non-polar "tail" groups such as the acyl groups described herein.
Preferred polar head groups and non-polar tail groups described
herein above apply to the diacyl lipid component (and equally to
any mono-acyl lipid that may be present).
[0047] Component ii) above is "tocopherols", which are a class of
compounds which may be used as part of component a) in any
compatible aspect or embodiment herein. As used herein, the term "a
tocopherol" is used to indicate the non-ionic lipid tocopherol,
often known as vitamin E, and/or any suitable salts and/or
structural analogues thereof. Suitable analogues will be those
providing the physical properties, lack of toxicity, and structure
which is equivalent or highly similar to tocopherol itself. Such
analogues will generally not form liquid crystalline phase
structures as a pure compound in water. The most preferred of the
tocopherols is tocopherol itself, having the structure below.
Evidently, particularly where this is purified from a natural
source, there may be a small proportion of non-tocopherol
"contaminant" but this will not be sufficient to alter the
advantageous physical properties or lack of toxicity. Typically, a
tocopherol will contain no more than 10% of non-tocopherol-analogue
compounds, preferably no more than 5% and most preferably no more
than 2% by weight.
##STR00001##
[0048] Component iii) above is at least one phospholipid. As with
triacyl and diacyl lipids, this component comprises a polar head
group non-polar tail group(s). The key feature of the phospholipid
lies principally in the polar group. The non-polar portions may
thus suitably be derived from the fatty acids or corresponding
alcohols considered above for triacyl lipids (e.g. independently
chosen from C16 to C22 acyl groups with zero to two unsaturations).
It will typically be the case that the phospholipid will contain
two non-polar groups, although one or more constituents of this
component may have one non-polar moiety. Where more than one
non-polar group is present these may be the same or different.
[0049] Preferred phospholipid polar "head" groups include
phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine
and phosphatidylinositol. Preferred phospholipids are
phosphatidylcholine (PC), phosphatidylethanolamine (PE). Most
preferred is phosphatidylcholine (PC).
[0050] The phospholipid portion, as well as the triacyl lipid and
any diacyl lipid portion, may be derived from a natural source.
Suitable sources of phospholipids include egg, heart (e.g. bovine),
brain, liver (e.g. bovine) and plant sources including soybean,
castor bean and sesame seed. Such sources may provide one or more
constituents of component iii), which may comprise any mixture of
phospholipids.
[0051] If one or more phospholipids are present in the injectable
formulation of the invention then it is preferred that the ratio of
triacyl lipid(s):phospholipid(s) (w/w) in the lipid
controlled-release matrix a) is in the range of 50:50 to 100:0,
preferably 80:20 to 100:0, especially 90:10 to 100:0, such as 93:7
to 100:0, 95:5 to 100:0 or 97:3 to 100:0.
[0052] Taken as a whole, the combined amount of phospholipid(s)
present in the injectable formulation may be less than 8 wt % of
the formulation, 6 wt % or less, 4 wt % or less, or 2 wt % or less.
In particular, the amount of phospholipid in the formulation may be
less than 5% by weight, such as less than 4.5% by weight (e.g. 0%
to 4.4%), or less than 4.2% by weight of the total formulation
(e.g. of the total of components a) to c)).
[0053] In a further embodiment, the amount of triacyl lipid in
component a) of the formulation may be at least 90% by weight. This
may be at least 95% (e.g. 96 to 100%) or at least 95.5%. Preferred
triacyl lipids include those described herein, including
triacylglycerols and triacyldiglycerols. In a corresponding
embodiment, the amount of phospholipid in component a) may be less
than 5% by weight, such as less than 4.5% by weight (e.g. 0 to 4.4%
by weight), or less than 4.2% by weight of component a). Evidently,
components b) and c) will generally not contain any phospholipid
components.
[0054] Since the formulations of the invention are to be
administered to a subject for the controlled release of an active
agent, it is preferable that the components a and b, including
components i) to iii) if present, are biocompatible. In this
regard, it is preferable to use, for example, diacyl phospholipids
rather than mono-acyl (lyso) compounds. A notable exception to this
is tocopherol, as described above. Although having only one alkyl
chain, this is not a "lyso" lipid in the convention sense. The
nature of tocopherol as a well tolerated essential vitamin
evidently makes it highly biocompatible.
[0055] In one embodiment, the formulations of the present invention
comprise only a single extract or component as component a). That
is to say, component a) may be a single naturally occurring mixture
or a single mixture separated from a single natural product. Thus,
component a) may consist of or consist essentially of a single
vegetable oil. Suitable examples include castor oil or sesame oil.
In such an embodiment, the compositions are comparatively simple to
prepare and validate for tasks such as quality control and
regulatory approval. This potentially makes them simpler and/or
more economical to manufacture than comparable compositions
containing mixtures of lipid components.
[0056] Component b) of the various aspects of the present invention
is at least one oxygen-containing organic solvent. Organic solvents
comprise at least one carbon and generally at least one
carbon-hydrogen bond and in the case of component b) will contain
at least one oxygen in their structure. Such solvents may also
contain at least one other "heteroatom" such as nitrogen, sulphur
or a halide (chloride, fluoride, bromide, iodide). It is preferred
that component b) consists of at least 80% by weight solvents not
containing any halogen, more preferably at least 95%. Conversely,
it is preferred that component b) comprises at least 50% solvents
having at least one nitrogen and/or sulphur atom in their
structure. Preferred component b) will comprise at least 75% and
preferably at least 90% of such solvents.
[0057] Preferred solvents will typically be around 45 to 500 g/mol
in molar mass, more typically around 50 to 200 g/mol. Preferred
solvents include alcohols, amides, including lactams, and
sulphoxides. Thus, in one embodiment, component b) may comprise,
consist essentially of, or consist of amides, sulphoxides or
mixtures thereof.
[0058] Two highly preferred solvents which may be included
(individually or as a mixture) in component b) are
N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO). In one
preferred embodiment applicable to any aspect or compatible
embodiment of the invention, component b) will comprise at least
50% of NMP and/or DMSO. Preferably component b) will comprise at
least 70% of NMP, DMSO or mixtures thereof, more preferably at
least 80% and most preferably at least 90%. In one embodiment
component b) consists of NMP, DMSO or mixtures thereof or consists
essentially of such components.
[0059] As used herein, as with common use, the term "substantially"
is used to indicate that an aspect or component is, in substance,
defined by the indicated limitation but allows for insubstantial
variation not having any material effect upon the nature or
behaviour. Such variation might be by, for example 10% or
preferably 5% from the indicated amount, state or behaviour.
Similarly, a component that "consists essentially of" some stated
component will, in essence, consist of that component but may
contain small, trivial or unavoidable other components such as
deliberate additives (e.g. flavourings, preservatives, tracers etc)
or components that are not easily or economically separable (such
as lipids with a distribution of chain lengths etc) including
contaminants and/or impurities which do not change the essential
behaviour of the stated component. A component "consisting
essentially" of a stated compound or mixture may include such
compound(s) in any amount that controls the essential behaviour but
typically at greater than 90% (e.g. 90% to 100%), more preferably
greater than 95% and most preferably greater than 98%. Terms
"about" and "around" carry meanings equivalent to "substantially"
or "essentially".
[0060] Component b) may be present at any amount that provides a
formulation suitable for injection (e.g. subcutaneous injection).
Such a formulation will have the sterility, biocompatibility etc.
required of an injectable formulation but will additionally have a
viscosity suitable for injection. Such viscosities are discussed
herein and the solvent may be chosen and used at a level to provide
any such viscosities. The solvent will also be required in order to
help dissolve the active agent and provide suitable controlled
release. Such properties may be optimised from the Examples and
discussion herein.
[0061] Typically, the formulations of the present invention in all
aspects will comprise component b) present at 10 to 60%, especially
15 to 50% by weight of the precursor formulation. This will
preferably be 20 to 45%, most preferably 25 to 40% by weight.
[0062] Component c) of the formulations and compositions of all
aspects and embodiments of the present invention is at least one
active agent selected from buprenorphine and salts thereof,
calculated as buprenorphine free base. This may be any suitably
active and biotolerable form of any buprenorphine compound having
an effect (e.g. agonism and/or antagonism) at one or more opioid
receptors. Buprenorphine free base is the most preferred
buprenorphine active agent and where weight percentages are
specified herein, these are in terms of the equivalent amount of
buprenorphine free base unless otherwise specified. Suitable salts,
including mixtures thereof, may be used and these salts may be any
biocompatible salt. Suitable salts include acetate, citrate,
pamoate or halide (e.g. chloride or bromide) salts, or any of the
many biocompatible salts which are known in the art. The structure
of buprenorphine free base is shown below:
##STR00002##
[0063] Buprenorphine is an opioid with mixed agonist-antagonist
properties (also known as a partial agonist) that has been used in
the treatment of opioid dependence in a number of countries. It is
approved by the Food and Drug Administration (FDA) for the
treatment of opioid dependence in the United States and clinical
studies have shown buprenorphine to be effective in reducing
opioid-positive urines and retaining patients in outpatient
maintenance treatment of opioid dependence, as well as in the
detoxification of opioid abusers.
[0064] Buprenorphine has a unique pharmacological profile with
several potential strengths over other opioid treatments:
[0065] 1. A ceiling on its agonist activity that may reduce its
abuse liability and contribute to a superior safety profile.
[0066] 2. Attenuation of physiological and subjective effects which
likely contributes to the suppression of opioid
self-administration.
[0067] 3. Slow receptor dissociation providing extended
duration.
[0068] Importantly, buprenorphine treatment is associated with a
relatively low-intensity withdrawal syndrome upon discontinuation,
making it particularly promising for detoxification treatments.
[0069] Buprenorphine is currently available commercially in
sublingual dosing forms, which require dosing every 1-2 days either
at a clinic, or with "take-home" medication. Because of the
potential for abuse of opioids, however, "take-home" of any opioid
poses potential logistic and legislative problems. This is made
more problematic by the low bioavailability of existing sublingual
formulations meaning that the dose being "taken home" is
potentially quite a significant one.
[0070] A controlled-release formulation of the present invention
offers several advantages in use for treating opioid dependence,
including fast onset and relatively stable levels of buprenorphine
over time, thereby suppressing withdrawal symptoms and blocking the
effects of exogenously-administered opioids for several weeks. The
slow decay and elimination of the depot buprenorphine could also
provide a gradual opioid detoxification with minimal withdrawal
syndrome. Hence, a controlled-release buprenorphine injection may
offer a promising approach for delivering effective opioid
maintenance or detoxification treatment. Furthermore, a
controlled-release formulation administrable at intervals of at
least 1 month should minimize the burdens of patient compliance as
it would require a less frequent dosing regimen, thereby also
reducing the frequency of clinic visits and the amount of clinical
support needed. Finally, a periodic buprenorphine injection in
controlled-release form should reduce the risks of misuse and drug
diversion of the medication by eliminating or reducing the need for
take-home medication.
[0071] The amount of buprenorphine required in the treatment of any
particular subject will depend greatly upon the indication and upon
the tolerance of the specific subject, as well as the frequency of
administration and the rate of release following administration. In
general, pain treatment will require lower doses than opioid
dependence related therapies.
[0072] Buprenorphine will be present in the formulations of the
present invention at 16% by weight or more as discussed herein.
[0073] The injectable liquid formulations in any aspects and
embodiments of the present invention will generally have a dose of
buprenorphine in the range 20 to 240 mg buprenorphine (calculated
as free base) per month of release duration. The term "release
duration" as used herein will be the period (typically the average
or recommended period) between injections for a fully compliant
subject. Suitable periods are discussed herein below. The
buprenorphine content will thus depend upon the frequency of
administration and may be, for example, 20 to 200 mg per month,
preferably 20 to 1140 mg per month of buprenorphine (based upon
equivalent amount of free base).
[0074] The total dose of buprenorphine or buprenorphine salt
present will, as discussed above, depend upon the rate of release
and frequency of administration. Typically, formulations in any
aspect or embodiment of the present invention will have a dose in
the range 20 to 800 mg, such as 50 to 600 mg buprenorphine per dose
(calculated as free base) particularly 60 to 300 mg, more
preferably 90 to 200 mg.
[0075] In all aspects and embodiments of the present invention,
administration takes place on a periodic basis. Such administration
will be less frequent than the dosing every 1-2 days used with
current sublingual products. Generally the administration will be
no more frequently than once every 28 days. An administration about
once every 1 to 4 months may be desirable, such as every 28 to 136
or 28 to 96 days. This may be at periods of around 1 month, around
2 months or around 3 months. Thus, administration may be once every
28 to 32 days, once every 56 to 62 days, or once every 82 to 95
days. Such periods may be the recommended periods for
administration and may be the periods between administration
(generally the average periods) for a fully compliant subject.
[0076] The formulations in all aspects and embodiments of the
invention are "injectable". Such formulations thus have the
properties of sterility and biocompatibility required of a
formulation for injection. Administration by injection is used
herein to indicate any method in which the formulation is passed
through the skin or other body surface, such as by needle, catheter
or needle-less injector. Subcutaneous, intracavitary, intravitreal
or intramuscular injection by any suitable method will thus be
appropriate with subcutaneous or intramuscular, particularly
subcutaneous injection being preferred.
[0077] Furthermore, such formulations must be capable of injection,
preferably manually using convention equipment such as a disposable
syringe and hypodermic needle of conventional gauge (e.g. 18 to 28
gauge). This requires that the formulations be of low viscosity. In
all aspects of the present invention, the formulations are
preferably low viscosity mixtures. Herein, the term "low viscosity
mixture" is used to indicate a mixture which may be readily
administered to a subject. This may be indicated, for example, by
the ability to be dispensed from a 1 ml disposable syringe through
a 22 gauge needle by manual pressure, preferably within a period of
less than 1 minute. In a particularly preferred embodiment, the low
viscosity mixture should be a mixture capable of passing through a
standard sterile filtration membrane such as a 0.22 .mu.m syringe
filter. A typical range of suitable viscosities would be, for
example, 20 to 600 mPas at 20.degree. C., preferably 50 to 400 mPas
at 20.degree. C., most preferably 80 to 300 mPas at 20.degree.
C.
[0078] In addition to being a simple and highly effective
controlled-release formulation, the formulations of the present
invention are advantageous in that they may be provided in a form
that does not require mixing or lengthy preparation before
administration. Thus, in one embodiment, the formulations of the
invention may be in ready-to-administer form. Such a form may be in
a sealed vial or similar vessel, or in a pre-filled administration
device, such as a pre-filled syringe or cartridge. Generally such a
device will contain a single dose and optionally the means to vary
the administered dose according to the needs of the subject (such
as volume markings). Such pre-filled devices evidently form a
further aspect of the invention.
[0079] The injectable formulations of the invention can be provided
in ready-to-administer for because, in one embodiment, they can be
stable to storage in such ready-to-administer form. Stability to
storage will typically mean that a formulation of the invention
will lose less than 20%, preferably less than 10%, more preferably
less than 5% of its buprenorphine content after storage for at
least 1 month, preferably at least 6 months, more preferably at
least 12 months. Such storage will preferably be at 2-8.degree. C.,
more preferably at 25.degree. C.
[0080] When administered to a subject, the formulations of the
present invention will preferably form the controlled-release
compositions of the invention. This is typically upon contact with
body fluid. Such subjects will be animal subjects, typically
mammalian and most preferably human subjects.
[0081] It has been surprisingly established that in spite of the
simplicity of the formulations of the present invention and the
lack of essential need for a change of phase upon administration,
the controlled-release compositions of the invention release
buprenorphine in a very controlled fashion, providing that at least
16% of buprenorphine is present. Illustration of this is provided
in FIG. 1 below.
[0082] Following administration to a subject of an injectable
liquid formulation (as described in any appropriate embodiment
herein) once monthly for at least 6 months, the average (mean) Cmin
and Cmax (preferably in a population of at least 10 subjects) at a
steady-state both fall with the range of between 0.3 ng/mL to 12
ng/mL, preferably 0.4 ng/mL and 5 ng/mL. This allows for the
therapeutic window of buprenorphine to be maintained very
effectively and gives a significantly improved experience for the
subject.
[0083] The formulations of the invention will lose solvent
component b) upon administration and my take up at least a little
water. Such compositions after injection may thus comprise: [0084]
a) a lipid controlled-release matrix comprising at least 50%
triacyl lipids; [0085] b) optionally at least oxygen containing
organic solvent; [0086] c) at least 16% by weight of at least one
active agent selected from buprenorphine and salts thereof,
calculated as buprenorphine free base; [0087] d) optionally at
least one aqueous fluid.
[0088] Evidently, all of components a) to c) will correspond to any
of those described herein for any aspect or embodiment of the
invention. Aqueous component d), where present, will typically be
an aqueous body fluid.
[0089] All of the injectable formulations described herein may be
used in therapy. Such therapy will be for any condition for which
buprenorphine is indicated, particularly over an extended period.
Such indications include pain, particularly chronic pain including
post-operative pain, cancer pain, and pain due to degenerative
diseases such as arthritis. Most importantly, such indications will
include treatment or maintenance in opioid dependence or
withdrawal. Therapy for opioid dependence typically includes
several phases of treatment including "induction", "stabilisation"
and "maintenance". Formulations of the present invention may be
used in any such phase, and/or in gradual dose reduction if
desirable. Due to the long duration of the controlled-release
effect, the formulations and compositions of the invention are very
suitable for the maintenance phase. Thus, a subject who is
receiving frequent injections (e.g. daily injections) or sublingual
buprenorphine for opioid dependence may transition onto
formulations of the present invention for stabilisation and/or
maintenance phases of treatment.
[0090] In addition to use in opioid dependence, buprenorphine
formulations of the present invention may be used in therapy
relating to dependence on other substances including cocaine.
[0091] In view of the above, the present invention further provides
methods of treatment of a human or animal subject (such as one
described herein) comprising administering any of the formulations
described herein. Such a method will typically be for the treatment
of any conditions for which buprenorphine is indicated. These
include all the conditions and therapies discussed herein in any
aspect or embodiment of the invention.
[0092] The present invention will now be illustrated further by
reference to the following non-limiting examples, and the attached
figures.
BRIEF SUMMARY OF THE FIGURES
[0093] FIG. 1. Shows dose normalized plasma buprenorphine (BUP)
concentrations after subcutaneous administration of Formulations A1
and C1 (from Examples 1 and 3 respectively) to rats. The data
points represent the mean value and error bars standard deviation
(N=6).
EXAMPLES
Example 1
Composition Comprising Buprenorphine Base, Sesame Oil and N-Methyl
Pyrrolidone (NMP)
[0094] The composition according to Table 1 was prepared by
weighing 2.03 g buprenorphine base, 1.80 g NMP and 2.17 g of Sesame
oil in a 10 mL injection glass vial. The vial was closed with
Flurotec.RTM.-coated rubber stopper and aluminum crimp cap followed
by end-over-end rotation mixing at ambient room temperature until a
liquid, transparent and homogenous formulation was obtained. The
formulation was finally subjected to filtration through a sterile
0.22 .mu.m Millex.RTM.-GV membrane (Millipore) under nitrogen
pressure.
TABLE-US-00001 TABLE 1 Composition of buprenorphine, triglyceride
and solvent (wt %) Formulation Buprenorphine Sesame oil NMP A1 33.8
36.2 30.0 NMP = N-methyl pyrrolidone
Example 2
Compositions Comprising Buprenorphine Base, Triglycerides and
Solvents
[0095] The compositions according to Table 2 are prepared by
weighing the required amounts of buprenorphine base, triglyceride
and solvent in 4 mL injection glass vials. The vials are closed
with Flurotec.RTM.-coated rubber stoppers and aluminum crimp caps
followed by end-over-end rotation mixing at ambient room
temperature.
TABLE-US-00002 TABLE 2 Composition of buprenorphine, triglyceride
and solvent (wt %) Sesame Castor Formulation Buprenorphine oil oil
MCT NMP DMSO B1 33.8 -- 36.2 -- -- 30.0 B2 25.4 -- 44.6 -- -- 30.0
B3 16.9 -- 63.1 -- -- 20.0 B4 40.0 -- 20.0 -- -- 40.0 B5 25.4 44.6
-- -- 30.0 -- B6 16.9 63.1 -- -- 20.0 -- B7 40.0 20.0 -- -- 40.0 --
B8 33.8 -- -- 36.2 30.0 -- B9 25.4 -- -- 44.6 30.0 -- B10 16.9 --
-- 63.1 20.0 -- B11 40.0 -- -- 20.0 40.0 -- DMSO = Dimethyl
sulphoxide NMP = N-methyl pyrrolidone MCT = Medium Chain
Triglycerides (e.g. Labrafac Lipophile WL 1349, Gattefosse,
France)
Example 3
Composition Comprising Low Drug Load Buprenorphine Base,
Triglyceride and Solvent
[0096] The composition according to Table 3 was prepared by
weighing 0.0424 g buprenorphine base, 0.400 g Ethanol and 3.558 g
of Castor oil in a 10 mL injection glass vial. The vial was closed
with Flurotec.RTM.-coated rubber stopper and aluminum crimp cap
followed by end-over-end rotation mixing at ambient room
temperature until a liquid, transparent and homogenous formulation
was obtained. The formulation was finally subjected to filtration
through a sterile 0.22 .mu.m Millex-GP membrane (Millipore) under
nitrogen pressure.
TABLE-US-00003 TABLE 3 Composition of buprenorphine, triglyceride
and solvent (wt %) Formulation Buprenorphine Castor oil EtOH C1
1.06 88.94 10.00 EtOH = Ethanol
Example 4
Pharmacokinetics of Formulations Comprising Buprenorphine Base,
Triglycerides and Solvents in Rat
[0097] Formulations A1 (see Example 1) and C1 (see Example 3) were
administered subcutaneously to rats in doses of 30 and 2 mg/kg,
respectively (N=6 per group). Blood samples were collected up to 14
days after dosing. The plasma concentrations were determined as
described below and the respective dose normalized pharmacokinetic
profiles are shown in FIG. 1. As can be seen, Formulation A1
provides a rapid onset of buprenorphine release and stable
buprenorphine plasma levels thereafter. In contrast, the plasma
buprenorphine levels decline more rapidly after the initial peak
for the low buprenorphine loading Formulation C1. In summary,
Formulation A1 is seen to provide stable plasma levels over the
entire study period whereas the buprenorphine levels for
Formulation C1 decline about one order of magnitude during the same
period.
[0098] Protocol
[0099] Formulations A1 and C1 were administered subcutaneously to
rats (male MPF Sprague-Dawley rats) in doses of 30 and 2 mg/kg,
respectively, and blood samples were collected pre-dose, and at 1
hour, 6 hours, 1 day, 2 days, 5 days, 8 days, 14 days after dosing.
A blood volume of 0.25 mL was collected into EDTA-treated test
tubes (Capiject.RTM.3T-MQK, Terumo Medical Corporation) by
sub-lingual bleeding. The blood samples were placed on ice
immediately after collection and centrifuged (approximately
1500.times.g, at 5.degree. C. for 10 min) within 30 to 60 minutes.
The plasma was transferred into 0.5 mL propylene test tubes
(Eppendorf Safe lock tubes, Fisher Scientific) and stored below
-70.degree. C. until bioanalysis. The plasma concentrations were
determined with the aid of a commercial ELISA kit adapted for
analysis of buprenorphine in rat plasma.
* * * * *