U.S. patent application number 13/558463 was filed with the patent office on 2013-07-25 for high bioavailability opioid formulations.
This patent application is currently assigned to CAMURUS AB. The applicant listed for this patent is Ian HARWIGSSON, Markus JOHNSSON, Fredrik TIBERG. Invention is credited to Ian HARWIGSSON, Markus JOHNSSON, Fredrik TIBERG.
Application Number | 20130190341 13/558463 |
Document ID | / |
Family ID | 34982472 |
Filed Date | 2013-07-25 |
United States Patent
Application |
20130190341 |
Kind Code |
A1 |
TIBERG; Fredrik ; et
al. |
July 25, 2013 |
HIGH BIOAVAILABILITY OPIOID FORMULATIONS
Abstract
A high bioavailability opioid depot precursor formulation
comprising: a) a controlled-release matrix; b) at least oxygen
containing organic solvent; c) at least one active agent selected
from buprenorphine and salts thereof. Typically such a precursor
formulation will form a depot composition upon administration to
the body of a subject.
Inventors: |
TIBERG; Fredrik; (Lund,
SE) ; HARWIGSSON; Ian; (Lund, SE) ; JOHNSSON;
Markus; (Lund, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TIBERG; Fredrik
HARWIGSSON; Ian
JOHNSSON; Markus |
Lund
Lund
Lund |
|
SE
SE
SE |
|
|
Assignee: |
CAMURUS AB
Lund
SE
|
Family ID: |
34982472 |
Appl. No.: |
13/558463 |
Filed: |
July 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11798495 |
May 14, 2007 |
8236755 |
|
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13558463 |
|
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11628007 |
Jul 24, 2007 |
8236292 |
|
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PCT/GB2005/002217 |
Jun 6, 2005 |
|
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11798495 |
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Current U.S.
Class: |
514/279 |
Current CPC
Class: |
A61K 9/0002 20130101;
A61Q 11/00 20130101; A61K 47/10 20130101; A61P 31/00 20180101; A61P
25/34 20180101; A61P 27/06 20180101; A61K 8/0295 20130101; A61K
31/5513 20130101; A61P 31/04 20180101; A61Q 19/00 20130101; A61K
9/006 20130101; A61P 27/02 20180101; A61K 9/0043 20130101; A61K
2800/10 20130101; A61K 9/0014 20130101; A61K 8/922 20130101; A61K
9/0024 20130101; A61Q 17/04 20130101; A61K 9/7015 20130101; A61K
8/37 20130101; A61K 47/14 20130101; A61K 31/155 20130101; A61K 8/68
20130101; A61K 47/22 20130101; A61K 9/0063 20130101; A61P 17/02
20180101; A61K 38/31 20130101; A61K 31/416 20130101; A61K 2800/592
20130101; A61K 8/498 20130101; A61K 8/678 20130101; A61K 9/12
20130101; A61Q 3/02 20130101; A61K 8/553 20130101; A61K 31/519
20130101; A61K 31/485 20130101; A61K 31/522 20130101; A61K 8/046
20130101; A61K 8/375 20130101; A61P 17/00 20180101; A61K 38/23
20130101; A61K 38/27 20130101; A61P 31/10 20180101; A61P 1/02
20180101; A61K 9/1274 20130101; A61K 31/198 20130101; A61K 47/24
20130101; A61P 5/00 20180101; A61K 31/4468 20130101; A61K 31/5685
20130101 |
Class at
Publication: |
514/279 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/485 20060101 A61K031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 4, 2004 |
GB |
0412530.8 |
Jan 14, 2005 |
GB |
0500807.3 |
Apr 18, 2005 |
GB |
0507811.8 |
Claims
1. A high bioavailability opioid depot precursor formulation
comprising: a) a controlled-release matrix; b) at least oxygen
containing organic solvent; c) at least one active agent selected
from buprenorphine and salts thereof.
2. The high bioavailability opioid depot precursor formulation of
claim 1 which forms a depot composition upon administration to the
body of a subject.
3. The high bioavailability opioid depot precursor formulation of
claim 1 having a bioavailability, measured as the area under a
curve of plasma concentration against time in a human subject, of
no less than 7 hours*ng/ml per mg of administered
buprenorphine.
4. The high bioavailability opioid depot precursor formulation of
claim 1 wherein the controlled release matrix component a)
comprises a lipid controlled release formulation.
5. The high bioavailability opioid depot precursor formulation of
claim 4 wherein the lipid controlled release formulation comprises:
i) least one neutral diacyl lipid and/or a tocopherol; and ii) at
least one phospholipid;
6. The high bioavailability opioid depot precursor formulation of
claim 5 wherein component i) comprises at least 50% of components
C16 to C18 acyl groups and having zero, one or two
unsaturations.
7. The high bioavailability opioid depot precursor formulation of
claim 5 wherein component ii) comprises at least 50% of components
C16 to C18 acyl groups and having zero, one or two
unsaturations.
8. The high bioavailability opioid depot precursor formulation of
claim 1 wherein component b) comprises NMP.
9. The high bioavailability opioid depot precursor formulation of
claim 1 for a once-weekly administration having a dose in the range
3 to 40 mg buprenorphine (calculated as buprenorphine free
base).
10. The high bioavailability opioid depot precursor formulation of
claim 1 for a once-fortnightly administration having a dose in the
range 6 to 60 mg buprenorphine.
11. The high bioavailability opioid depot precursor formulation of
claim 1 for once-monthly administration having a dose in the range
10 to 80 mg buprenorphine.
12. The high bioavailability opioid depot precursor formulation of
claim 1 wherein the precursor formulation is in ready-to-administer
form.
13. The high bioavailability opioid depot precursor formulation of
claim 12 wherein the precursor formulation is stable to storage in
ready-to-administer form.
14. The high bioavailability opioid depot precursor formulation of
claim 1 containing greater than 30% by weight buprenorphine
(calculated as buprenorphine free base).
15. A depot composition formed by administration to a subject the
depot precursor formulation as claimed in claim 1.
16. The depot composition of claim 15 which provides a Cmax
(maximum concentration) in the blood plasma of said subject after a
single administration of no more than 0.3 ng/ml per mg of
administered buprenorphine.
17. The depot composition of claim 15 which, upon administration to
said subject provides linearity of the AUC dose in comparison with
the administered dose of buprenorphine.
18. The depot composition of claim 15 wherein a half-life plasma
concentration experienced by the subject after Cmax is be greater
than 1 day.
19. The depot composition of claim 15 wherein the steady-state Cmax
concentration in said subject is no more than 20 times the
corresponding Cmin plasma concentration.
20. The depot composition of claim 15 wherein the variation between
Cmin and Cmax at a steady-state of administration of the precursor
formulation as claimed in claim 1 both fall with the range of
between 0.4 ng/mL and 10 ng/mL.
21. A depot composition as claimed in claim 15 which comprises: a)
a controlled-release matrix; b) optionally at least oxygen
containing organic solvent; c) at least one active agent selected
from buprenorphine and salts thereof; d) optionally at least one
aqueous fluid.
22. A method of sustained delivery of an opioid bioactive agent to
a human or non-human animal body, this method comprising
administering a high bioavailability opioid depot precursor
formulation comprising: a) a controlled-release matrix; b) at least
oxygen containing organic solvent; c) at least one active agent
selected from buprenorphine and salts thereof.
23. A method for the formation of a high bioavailability opioid
depot composition comprising exposing a precursor formulation
comprising: a) a controlled-release matrix; b) at least oxygen
containing organic solvent; c) at least one active agent selected
from buprenorphine and salts thereof. to an aqueous fluid in
vivo.
24. A method of treatment or prophylaxis of a human or non-human
animal subject comprising administration of a precursor formulation
of claim 1.
25. A method of claim 24 for the treatment of pain 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
26. A method of transitioning of a subject from daily sublingual
buprenorphine to a sustained buprenorphine formulation comprising
administering to said subject a weekly buprenorphine depot
precursor formulation comprising 0.5 to 3 times his previous daily
buprenorphine dose.
Description
[0001] This application is a CIP of Ser. No. 11/798,495 filed May
14, 2007, now U.S. Pat. No. ______, which in turn is a CIP of
application Ser. No. 11/628,007 filed Nov. 30, 2006, now U.S. Pat.
No. ______, which in turn is the US national phase of international
application PCT/GB2005/002217, filed 6 Jun. 2005, which designated
the U.S. and claims priority of GB 0412530.8, filed 4 Jun. 2004; GB
0500807.3, filed 14 Jan. 2005 and GB 0507811.8, filed 18 Apr. 2005,
the entire contents of each of which are hereby incorporated by
reference.
[0002] The present invention relates to formulation precursors
(pre-formulations) for the in situ generation of controlled release
opioid compositions. In particular, the invention relates to
sustained release compositions and corresponding precursor
formulations, containing at least one opioid bioactive agent, which
provide enhanced bioavailability in vivo in comparison with
existing once-daily formulations.
[0003] Many bioactive agents including pharmaceuticals, nutrients,
vitamins and so forth have a "functional window". That is to say
that there is a range of concentrations over which these agents can
be observed to provide some biological effect. Where the
concentration in the appropriate part of the body (e.g. locally or
as demonstrated by serum concentration) falls below a certain
level, no beneficial effect can be attributed to the agent.
Similarly, there is generally an upper concentration level above
which no further benefit is derived by increasing the
concentration. In some cases increasing the concentration above a
particular level, results in undesirable or even dangerous
effects.
[0004] Some bioactive agents have a long biological half-life
and/or a wide functional window and thus may be administered
occasionally, maintaining a functional biological concentration
over a substantial period of time (e.g. 6 hours to several days).
In other cases the rate of clearance is high and/or the functional
window is narrow and thus to maintain a biological concentration
within this window regular (or even continuous) doses of a small
amount are required. This can be particularly difficult where
non-oral routes of administration (e.g. parenteral administration)
are desirable or necessary. Furthermore, in some circumstances,
such as in the fitting of implants (e.g. joint replacements or oral
implants) the area of desired action may not remain accessible for
repeated administration. Similarly, patient compliance may limit
how regularly and/or how frequently administration can be made. In
such cases a single administration must provide active agent at a
therapeutic level over and extended period, and in some cases over
the whole period during which activity is needed.
[0005] In the case of opioid active agents, the situation can be
complex. Opioids administered for pain relief are given only to the
extent needed because of the risk of dependence but effective pain
management often requires at least a background level of stable
administration. Furthermore, the administrative burden in supplying
opioids is relatively high because of the danger of diversion for
illicit use. The facility to provide a long-acting opioid
administration for use in situations where pain relief for several
days will inevitably be necessary (e.g. post operative pain relief,
relief of cancer pain and/or relief of chronic pain such as chromic
back pain) could therefore improve the experience for the patient
and reduce the burden on the healthcare professionals.
[0006] The situation of administering opioids to people with any
form of opioid dependence is even more complex. Opioids will often
be prescribed to avoid or relieve the symptoms of withdrawal in
those with an opioid dependence, but such subjects may have a
lifestyle that makes daily dosing by a healthcare professional
difficult. Patient compliance may therefore be a problem with such
a regime. Some pharmaceuticals can be supplied to the patient for
self-administration but the risk of diversion to illicit use is
such that opioids are not typically supplied in this way. The dose
required to provide a functional plasma concentration is relatively
high in daily products and this makes the risk of diversion much
higher.
[0007] Various methods have been used and proposed for the
sustained release of biologically active agents. Such methods
include slow-release, orally administered compositions, such as
coated tablets, formulations designed for gradual absorption, such
as transdermal patches, and slow-release implants such as "sticks"
implanted under the skin.
[0008] One method by which the gradual release of a bioactive agent
has been proposed is a so-called "depot" injection. In this method,
a bioactive agent is formulated with carriers providing a gradual
release of active agent over a period of a number of hours or days.
These are often based upon a degrading matrix which gradually
disperses in the body to release the active agent.
[0009] The most common of the established methods of depot
injection relies upon a polymeric depot system. This is typically a
biodegradable polymer such poly (lactic acid) (PLA) and/or poly
(lactic-co-glycolic acid) (PLGA) and may be in the form of a
solution in an organic solvent, a pre-polymer mixed with an
initiator, encapsulated polymer particles or polymer microspheres.
The polymer or polymer particles entrap the active agent and are
gradually degraded releasing the agent by slow diffusion and/or as
the matrix is absorbed. Examples of such systems include those
described in U.S. Pat. No. 4,938,763, U.S. Pat. No. 5,480,656 and
U.S. Pat. No. 6,113,943 and can result in delivery of active agents
over a period of up to several months. These systems do, however,
have a number of limitations including the complexity of
manufacturing and difficulty in sterilising (especially the
microspheres). The local irritation caused by the lactic and/or
glycolic acid which is released at the injection site is also a
noticeable drawback. There is also often quite a complex procedure
to prepare the injection dose from the powder precursor.
[0010] One alternative to the more established, polymer based,
depot systems was proposed in U.S. Pat. No. 5,807,573. This
proposes a lipid based system of a diacylglycerol, a phospholipid
and optionally water, glycerol, ethylene glycol or propylene glycol
to provide an administration system in the reversed micellar
"L.sub.2" phase or a cubic liquid crystalline phase. Since this
depot system is formed from physiologically well tolerated diacyl
glycerols and phospholipids, and does not produce the lactic acid
or glycolic acid degradation products of the polymeric systems,
there is less tendency for this system to produce inflammation at
the injection site. The liquid crystalline phases are, however, of
high viscosity and the L.sub.2 phase may also be too viscous for
ease of application. The authors of U.S. Pat. No. 5,807,573 also do
not provide any in vivo assessment of the release profile of the
formulation and thus it is uncertain whether or not a "burst"
profile is provided.
[0011] The use of non-lamellar phase structures (such as liquid
crystalline phases) in the delivery of bioactive agents is now
relatively well established. Such structures form when an
amphiphilic compound is exposed to a solvent because the amphiphile
has both polar and apolar groups which cluster to form polar and
apolar regions. These regions can effectively solubilise both polar
and apolar compounds. In addition, many of the structures formed by
amphiphiles in polar and/or apolar solvents have a very
considerable area of polar/apolar boundary at which other
amphiphilic compounds can be adsorbed and stabilised. Amphiphiles
can also be formulated to protect active agents, to at least some
extent, from aggressive biological environments, including enzymes,
and thereby provide advantageous control over active agent
stability and release.
[0012] The formation of non-lamellar regions in the
amphiphile/water, amphiphile/oil and amphiphile/oil/water phase
diagrams is a well known phenomenon. Such phases include liquid
crystalline phases such as the cubic P, cubic D, cubic G and
hexagonal phases, which are fluid at the molecular level but show
significant long-range order, and the L.sub.3 phase which comprises
a multiply interconnected bi-continuous network of bilayer sheets
which are non-lamellar but lack the long-range order of the liquid
crystalline phases. Depending upon their curvature of the
amphiphile sheets, these phases may be described as normal (mean
curvature towards the apolar region) or reversed (mean curvature
towards the polar region).
[0013] The non-lamellar liquid crystalline and L.sub.3 phases are
thermodynamically stable systems. That is to say, they are not
simply a meta-stable state that will separate and/or reform into
layers, lamellar phases or the like, but are the stable
thermodynamic form of the lipid/solvent mixture.
[0014] While the effectiveness of known lipid depot formulations is
high, there are certain aspects in which the performance of these
is less than ideal. In particular, cubic liquid crystalline phases
proposed are relatively viscous in nature. This makes application
with a standard syringe difficult and possibly painful to the
patient, and makes sterilisation by filtration impossible because
the composition cannot be passed through the necessary fine-pored
membrane. As a result, the compositions must be prepared under
highly sterile conditions, adding to the complexity of
manufacturing. Where L.sub.2 phases are used, these are generally
of lower viscosity but these may still cause difficulty in
application and allow access to only a small region of the phase
diagram. Specifically, the solvents used in known lipid
formulations have only a limited effect in reducing the viscosity
of the mixture. Water, for example, will induce the formation of a
highly viscous liquid crystalline phase and solvents such as
glycerol and glycols have a high viscosity and do not provide any
greatly advantageous decrease in the viscosity of the composition.
Some glycols, such as ethylene glycol are also toxic and poorly
tolerated in vivo and can in some cases cause irritation when
applied topically.
[0015] Furthermore, the known lipid compositions in the low-solvent
L.sub.2 phase may support only a relatively low level of many
bioactive agents because of their limited solubility in the
components of the mixture in the absence of water. In the presence
of water, however, the formulations adopt a highly viscous cubic
liquid crystalline phase. It would be a clear advantage to provide
a depot system that could be injected at low viscosity and allowed
release of the required concentration of bioactive with a smaller
depot composition volume.
[0016] The known lipid depot compositions also have practical
access to only certain phase structures and compositions because
other mixtures are either too highly viscous for administration
(such as those with high phospholipid concentrations) or run the
risk of separation into two or more separate phases (such as an
L.sub.2 phase in equilibrium with a phase rich in phospholipid). In
particular, phospholipid concentrations above 50% are not reachable
by known methods and from the phase diagram shown in U.S. Pat. No.
5,807,573 it appears that the desired cubic phase is stable at no
higher than 40% phospholipid. As a result, it has not been possible
in practice to provide depot compositions of high phospholipid
concentration or having a hexagonal liquid crystalline phase
structure.
[0017] As indicated above, a class of active agents having
particular utility as depot or slow-release formulations are
opioids. The term "Opioids" as used herein encompasses a class of
naturally occurring, semi-synthetic, and fully synthetic compounds
which show agonistic and/or antagonistic properties for at least
one opioid receptor. Opioids are of very great medical value, being
highly effective analgesics. They are typically used for pain
relief after serious injuries and/or medical procedures and for
this use it can be of value to provide sustained dosing with a
level or gently tapering concentration of active agent to
correspond with a healing and recovery profile over a number of
days or weeks.
[0018] Unfortunately, tolerance to, and physiological dependence
upon, opioids can develop, and can lead to behavioural addiction,
especially where fast-acting opioids are used and/or the drugs are
abused. Furthermore, abuse of opioids is common because of the
euphoric effects which can be caused by their sudden
administration.
[0019] Withdrawal from opioids where dependence has developed can
be unpleasant, especially from fast-acting opioids which are
commonly abused, such as diacetylmorphine (heroin) or fentanyl. One
approach for assisting recovering addicts is thus to transfer them
from fast-acting opioids to slower-acting drugs which can be taken
less frequently without causing the symptoms of withdrawal.
Patients may then be provided with a maintenance level of the
slower-acting opioid or gradually weaned from this by a gently
decreasing dose regime.
[0020] Typical candidates for use as this slower-acting
"opioid-replacement" drug are methadone and buprenorphine, and
studies have shown that these can significantly reduce the chances
of relapse in recovering addicts. One of the advantages of these
opioids over the abused substances is that they generally do not
require administration so frequently in order to avoid withdrawal
symptoms. Methadone, for example, needs to be administered daily,
while the 37-hour half-life of buprenorphine means that a single
dose is effective for 1-2 days, or longer in some patients. Weekly
patches of buprenorphine are also available, although at present
these are for use in pain management rather than in curbing
addiction and have limited bioavailability. Excess drug is
therefore used and waste patches are liable for misuse and
misdirection.
[0021] The two primary dosing methods for these slow-acting opioids
in addiction therapy are "detox", in which a tapering dose is
provided over a period of around 2 weeks, and "maintenance", in
which a level dose is provided over a longer term of, typically, a
few months. In both cases, and with any of the known opioid
preparations, frequent administration is generally required, which
in turn requires on-going patient compliance. Evidently, it would
be a considerable advantage to provide slow-release formulations
which could be administered infrequently, and would provide a
level, or gradually tapering, drug profile, to allow gradual detox
or longer term maintenance without requiring frequent
administration. Furthermore, it would be of benefit both to
healthcare providers and in avoidance of diversion if the dose of
active opioid agent could be lower in a controlled-release
formulation than would be typical as the sum of the doses of daily
formulations provided over the same period. Thus, for example, a
weekly depot composition should advantageously contain less than 7
times the dose of active agent that would be administered daily to
achieve a similar plateau concentration in the blood plasma of the
subject. In addition, the long-acting formulation should show less
time fluctuations and variability of plasma levels over time.
[0022] The present inventors have now established that by providing
a pre-formulation comprising certain opioid active agents,
particularly buprenorphine, can be formulated as highly effective
slow-release formulations having a bioavailability several times
higher than observed for the currently available daily products.
Certain of these precursor formulations (pre-formulations) are easy
to manufacture, may be sterile-filtered, have low viscosity
(allowing easy and less painful administration), allow a high level
of bioactive agent to be incorporated (thus allowing a smaller
amount of composition to be used) and/or provide for effective dose
control by means of control of active agent concentration and/or
injection volume.
[0023] In a first aspect, the present invention thus provides a
high bioavailability opioid depot precursor formulation
comprising:
a) a controlled-release matrix; b) at least one oxygen containing
organic solvent; c) at least one active agent selected from
buprenorphine and its different salt forms.
[0024] Typically such a precursor formulation will form a depot
composition upon administration to the body of a subject.
[0025] The high bioavailability opioid depot precursor formulation
will typically have a bioavailability, measured as the area under a
curve of plasma concentration against time from time of dosing
extrapolated to infinity after a single dose, or between two doses
at steady state, in a human subject, of no less than 7 hours*ng/ml
per mg of administered buprenorphine, preferably no less than 10
hours*ng/ml per mg of administered buprenorphine (measured as free
base). Furthermore, the bioavailability may be independent or
substantially independent of the dose of buprenorphine
administered.
[0026] The high bioavailability opioid depot precursor will
typically have a Cmax (maximum concentration) in human blood plasma
after a single administration of no more than 0.3 ng/ml per mg of
administered buprenorphine. Furthermore, the Cmax may be
proportional or substantially proportional to the dose of
buprenorphine administered.
[0027] The controlled-release matrix comprised in the high
bioavailability opioid depot precursor may be, for example, a lipid
depot composition or a polymeric depot composition, as described
herein.
[0028] In a second aspect, the present invention also provides a
depot composition formed or formable from any of the depot
precursor formulations described herein. Such a depot composition
will preferably exhibit bioavailability and/or Cmax properties
indicated herein. Furthermore, such a depot composition may
comprise:
a) a controlled-release matrix; b) optionally at least one oxygen
containing organic solvent; c) at least one active agent selected
from buprenorphine and salts thereof d) optionally at least one
aqueous fluid.
[0029] Such a depot composition will typically be formed upon
exposure of a precursor formulation of the present invention to an
aqueous fluid in vivo. Exposure to such an aqueous fluid will
generally result in a loss of solvent and/or an addition of water
to the precursor formulation and may result in a phase change such
as from solution to solid (a precipitation) or from a low-viscosity
phase, such as a solution or L.sub.2 phase to a high viscosity
phase such as a liquid crystalline phase.
[0030] In a further aspect of the invention, there is also provided
a method of sustained delivery of an opioid bioactive agent to a
human or non-human animal (preferably mammalian) body, this method
comprising administering (preferably parenterally) a high
bioavailability opioid depot precursor formulation comprising:
a) a controlled-release matrix; b) at least one oxygen containing
organic solvent; c) at least one active agent selected from
buprenorphine and salts thereof.
[0031] Preferably, the precursor formulation (pre-formulation)
administered in such a method is a pre-formulation of the invention
as described herein.
[0032] The method of administration suitable for the above method
of the invention will be a method appropriate for the condition to
be treated or addressed. A parenteral depot will thus be formed by
parenteral (e.g. subcutaneous or intramuscular) administration
while a bioadhesive non-parenteral (e.g. topical) depot composition
may be formed by administration to the surface of skin, mucous
membranes and/or nails, to ophthalmological, nasal, oral or
internal surfaces or to cavities such as nasal, rectal, vaginal or
buccal cavities, the periodontal pocket or cavities formed
following extraction of a natural or implanted structure or prior
to insertion of an implant (e.g a joint, stent, cosmetic implant,
tooth, tooth filling or other implant).
[0033] Since the key medicinal properties of opioids are analgesia
and use in detoxification and/or maintenance from opioid
dependence, the formulations will typically be for systemic
absorption, although topical pain relief can be provided by opioids
and they are additionally of value in cough suppression (especially
codeine and hydrocodone), diarrhoea suppression, anxiety due to
shortness of breath (especially oxymorphone) and antidepression
(especially buprenorphine). For these, appropriate administration
methods, such as bioadhesive pain-relieving gels for topical pain,
or non-absorbed oral compositions for diarrhoea suppression may be
used.
[0034] In a further aspect, the present invention also provides a
method for the formation of a high bioavailability opioid depot
composition comprising exposing a precursor formulation
comprising:
a) a controlled-release matrix; b) at least one oxygen containing
organic solvent; c) at least one active agent selected from
buprenorphine and salts thereof. to an aqueous fluid (particularly
in vivo and/or particularly a body fluid as indicated herein).
Preferably the pre-formulation administered is a pre-formulation of
the present invention as described herein. The exposure to a fluid
"in vivo" may evidently be internally within the body or a body
cavity, or may be at a body surface such as a skin surface,
depending upon the nature of the composition.
[0035] In a still further aspect the present invention provides a
process for the formation of a high bioavailability precursor
formulation suitable for the administration of an opioid bioactive
agent to a (preferably mammalian) subject, said process comprising
forming a mixture of
a) a controlled-release matrix; and b) at least one oxygen
containing organic solvent; and dissolving or dispersing at least
one buprenorphine in the mixture, or in at least one of components
a, or b prior to forming the low viscosity mixture. Preferably the
pre-formulation so-formed is a formulation of the invention as
described herein. The process may additionally comprise
sterilisation, such as by sterile filtration.
[0036] In a still further aspect, the present invention
additionally provides for a method of treatment or prophylaxis of a
human or non-human animal subject comprising administration of a
precursor formulation as described herein. Such a method may be for
the treatment of pain or for the treatment of opioid dependence by
detoxification and/or maintenance as described herein.
[0037] As used herein, the term "low viscosity mixture" is used to
indicate a mixture which may be readily administered to a subject
and in particular readily administered by means of a standard
syringe and needle arrangement. This may be indicated, for example
by the ability to be dispensed from a 1 ml disposable syringe
through a 23 gauge (22 AWG/0.635 mm diameter) needle by manual
pressure. 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. In
other preferred embodiments, a similar functional definition of a
suitable viscosity can be defined as the viscosity of a
pre-formulation that can be sprayed using a compression pump or
pressurized spray device using conventional spray equipment. A
typical range of suitable viscosities would be, for example, 0.1 to
5000 mPas, preferably 1 to 1000 mPas at 20.degree. C. (e.g. 10 to
1000 mPas or 50 to 1000 mPas at 20.degree. C.).
[0038] It has been observed that by the addition of small amounts
of low viscosity solvent, as indicated herein, a very significant
change in viscosity can be provided, particularly for lipid
formulations (as described herein). As indicated in Example 11
below, for example, the addition of only 5% solvent (in the case of
Example 11, ethanol) can reduce viscosity of a lipid mixture by
several orders of magnitude. Addition of 10% solvent will cause a
still greater effect. In order to achieve this non-linear,
synergistic effect, in lowering viscosity it is important that a
solvent of appropriately low viscosity and suitable polarity be
employed. Such solvents include those described herein infra.
[0039] Particularly preferred examples of low viscosity mixtures
are molecular solutions (of both polymer depot precursor
formulations and lipid precursor formulations) and/or isotropic
phases such as L.sub.2 and/or L.sub.3 phases (of lipid precursor
formulations). As describe above, the L.sub.3 is a non-lamellar
phase of interconnected sheets which has some phase structure but
lacks the long-range order of a liquid crystalline phase. Unlike
liquid crystalline phases, which are generally highly viscous,
L.sub.3 phases are of lower viscosity. Obviously, mixtures of
L.sub.3 phase and molecular solution and/or particles of L.sub.3
phase suspended in a bulk molecular solution of one or more
components are also suitable. The L.sub.2 phase is the so-called
"reversed micellar" phase or microemulsion. Most preferred low
viscosity mixtures are molecular solutions, L.sub.3 phases and
mixtures thereof. L.sub.2 phases are less preferred, except in the
case of swollen L.sub.2 phases as described herein.
[0040] The present invention provides a pre-formulation comprising
components a, b and at least one opioid bioactive agent as
indicated herein. In one particularly preferred embodiment, the
controlled release matrix component a) comprises a lipid controlled
release formulation. Such a formulation will preferably
comprise:
i) at least one neutral diacyl lipid and/or a tocopherol; and ii)
at least one phospholipid;
[0041] One of the considerable advantages of the lipid precursor
formulations of the invention is that components i) and ii) may be
formulated in a wide range of proportions. In particular, it is
possible to prepare and use pre-formulations of the present
invention having a much greater proportion of phospholipid to
neutral, diacyl lipid and/or tocopherol than was previously
achievable without risking phase separation and/or unacceptably
high viscosities in the pre-formulation. The weight ratios of
components i):ii) may thus be anything from 5:95 right up to 95:5.
Preferred ratios would generally be from 90:10 to 20:80 and more
preferably from 85:15 to 30:70. A highly suitable range is i):ii)
in the ratio 40:60 to 80:20, especially around 50:50, e.g. 45:55 to
60:40. In one preferred embodiment of the invention, there is a
greater proportion of component ii) than component i). That is, the
weight ratio i):ii) is below 50:50, e.g. 48:52 to 2:98, preferably,
40:60 to 10:90 and more preferably 35:65 to 20:80. In an
alternative and highly valuable embodiment, there may be an equal
or greater amount of component i) in comparison with component ii).
In such an embodiment, there may be, for example, a weight ratio of
50:50 to 80:20 of components i) to ii). A ratio of 50:50 to 70:30
may also be suitable.
[0042] Corresponding to the above, the amount of component i) in
the precursor formulations may be, for example, 18% to 90% by
weight of the total formulation, preferably 18% to 70%, such as 20%
to 60% or 25% to 50% by weight of the total formulation. In one
embodiment, the absolute amount of component i) by weight is no
less than the amount of component ii).
[0043] Similarly, the amount of component ii) in the precursor
formulations may be, for example, 18% to 90% by weight of the total
formulation, preferably 18% to 70%, such as 20% to 60% or 25% to
50% by weight of the total formulation.
[0044] The amount of component b in the pre-formulations of the
invention will be at least sufficient to provide a low viscosity
mixture (e.g. a molecular solution, see above) of components a, b
and the buprenorphine active, and will be easily determined for any
particular combination of components by standard methods. The phase
behaviour of lipid formulations may be analysed by techniques such
as visual observation in combination with polarized light
microscopy, nuclear magnetic resonance, x-ray or neutron
diffraction, and cryo-transmission electron microscopy (cryo-TEM)
to look for solutions, L.sub.2 or L.sub.3 phases, or liquid
crystalline phases. Viscosity may be measured directly by standard
means. As described above, an appropriate practical viscosity is
that which can effectively be syringed and particularly sterile
filtered. This will be assessed easily as indicated herein. The
maximum amount of component b to be included will depend upon the
exact application of the pre-formulation but generally the desired
properties will be provided by any amount forming a low viscosity
mixture (e.g. a molecular solution, see above) and/or a solution
with sufficiently low viscosity. Since the administration of
unnecessarily large amounts of solvent to a subject is generally
undesirable the amount of component b will typically be limited to
no more than ten times (e.g. three times) the minimum amount
required to form a low viscosity mixture, preferably no more than
five times and most preferably no more than twice this amount. The
composition of the present invention may, however, contain a
greater quantity of solvent than would be acceptable in an
immediate dosage composition. This is because the process by which
the active agents are slowly released (e.g. formation of shells of
liquid crystalline phase or the generation of a polymeric
monolithic structure, as described herein) also serve to retard the
passage of solvent from the composition. As a result, the solvent
is released over some time (e.g. minutes or hours) rather than
instantaneously and so can be better tolerated by the body.
[0045] The weight of solvent component b incorporated into the
precursor formulation will depend crucially upon the type of
sustained release formulation a) that is in use. For example, a
polymeric sustained release formulation in solution might require
the solvent to be present at 40 to 70% by weight in order to ensure
a sufficiently low viscosity and full solubilisation. In contrast,
the solvent level typically used for a lipid-based controlled
release formulation would generally be around 0.5 to 50% of the
total weight of the precursor formulation. This proportion is
preferably (especially for injectable depots) 2 to 35% and more
preferably 10 to 30% or 5 to 25% by weight. A highly suitable range
is around 20%, e.g. 5 to 40%, especially, 10 to 30% by weight of
the complete composition. Thus, overall, a solvent level of 1 to
50% of the total precursor formulation weight is appropriate and
suitable ranges for each embodiment will be clear to those with
experience in the art. In one embodiment, a precursor formulation
and corresponding depot & method are provided in which the
administration period is one dose each week and the solvent content
is 10%.+-.5%. In an alternative embodiment, a precursor formulation
and corresponding depot & method are provided in which the
administration period is one dose each month and the solvent
content is 30%.+-.10%.
[0046] Component "i)" as indicated herein is a neutral lipid
component comprising a polar "head" group and also non-polar "tail"
groups. Generally the head and tail portions of the lipid will be
joined by an ester moiety but this attachment may be by means of an
ether, an amide, a carbon-carbon bond or other attachment.
Preferred polar head groups are non-ionic and include polyols such
as glycerol, diglycerol and sugar moieties (such as inositol and
glucosyl based moieties); and esters of polyols, such as acetate or
succinate esters. Preferred polar groups are glycerol and
diglycerol, especially glycerol.
[0047] In one preferred aspect, component i) is a diacyl lipid in
that it has two non-polar "tail" groups. This is generally
preferable to the use of mono-acyl ("lyso") lipids because these
are typically less well tolerated in vivo. The two non-polar groups
may have the same or a differing number of carbon atoms and may
each independently be saturated or unsaturated. Examples of
non-polar groups include C.sub.6-C.sub.32 alkyl and alkenyl groups,
which are typically present as the esters of long chain carboxylic
acids. These are often described by reference to the number of
carbon atoms and the number of unsaturations in the carbon chain.
Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and
Z unsaturations. Examples particularly 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),
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, linoleic,
linolenic, arachidonic, behenic or lignoceric acids, or the
corresponding alcohols. Preferable non-polar chains are palmitic,
stearic, oleic and linoleic acids, particularly oleic acid. In one
preferred embodiment, component i) comprises components with C16 to
C18 alkyl groups, particularly such groups having zero, one or two
unsaturations. In particular, component i) may comprise at least
50% of components having such alkyl groups.
[0048] The diacyl lipid, when used as all or part of component
"i)", may be synthetic or may be derived from a purified and/or
chemically modified natural sources such as vegetable oils.
Mixtures of any number of diacyl lipids may be used as component
i). Most preferably this component will include at least a portion
of diacyl glycerol (DAG), especially glycerol dioleate (GDO). In
one favoured embodiment, component i) consists of DAGs. These may
be a single DAG or a mixture of DAGs. A highly preferred example is
DAG comprising at least 50%, preferably at least 80% and even
comprising substantially 100% GDO.
[0049] An alternative or additional highly preferred class of
compounds for use as all or part of component i) are tocopherols.
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 analogues thereof. Suitable analogues will be
those providing the phase-behaviour, lack of toxicity, and phase
change upon exposure to aqueous fluids, which characterise the
compositions of the present invention. 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 phase-behaviour 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##
[0050] In one embodiment of the invention, component i) consists
essentially of tocopherols, in particular tocopherol as shown
above.
[0051] A preferred combination of constituents for component i) is
a mixture of at least one DAG (e.g. at least one C16 to C18 DAG,
such as GDO) with at least one tocopherol. Such mixtures include
2:98 to 98:2 by weight tocopherol:GDO, e.g. 10:90 to 90:10
tocopherol:GDO and especially 20:80 to 80:20 of these compounds.
Similar mixtures of tocopherol with other DAGs are also
suitable.
[0052] Component "ii)" in lipid embodiments of the present
invention is at least one phospholipid. As with component i), this
component comprises a polar head group and at least one non-polar
tail group. The difference between components i) and ii) 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 component i). In particular C16 to C18 acyl
groups having zero, one or two unsaturations are highly suitable as
moieties forming the non-polar group of the compounds of component
ii). 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.
[0053] Preferred phospholipid polar "head" groups include
phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine
and phosphatidylinositol. Most preferred is phosphatidylcholine
(PC). In a preferred embodiment, component ii) thus consists of at
least 50% PC, preferably at least 70% PC and most preferably at
least 80% PC. Component ii) may consist essentially of PC.
[0054] The phospholipid portion, even more suitably than 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. Such
sources may provide one or more constituents of component ii),
which may comprise any mixture of phospholipids.
[0055] Since the pre-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 i) and ii), as well as
any alternative controlled release matrix are biocompatible. In
this regard, it is preferable to use, for example, diacyl lipids
and 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 suitable in
biocompatibility.
[0056] It is furthermore most preferable that the lipids and
phospholipids of components i) and ii) are naturally occurring
(whether they are derived from a natural source or are of synthetic
origin). Naturally occurring lipids tend to cause lesser amounts of
inflammation and reaction from the body of the subject. Not only is
this more comfortable for the subject but it may increase the
residence time of the resulting depot composition, especially for
parenteral depots, since less immune system activity is recruited
to the administration site. In certain cases it may, however, be
desirable to include a portion of a non-naturally-occurring lipid
in components i) and/or ii). This might be, for example an "ether
lipid" in which the head and tail groups are joined by an ether
bond rather than an ester. Such non-naturally-occurring lipids may
be used, for example, to alter the rate of degradation of the
resulting depot-composition by having a greater or lesser
solubility or vulnerability to breakdown mechanisms present at the
site of active agent release. Although all proportions fall within
the scope of the present invention, generally, at least 50% of each
of components i) and ii) will be naturally occurring lipids. This
will preferably be at least 75% and may be up to substantially
100%.
[0057] Two particularly preferred combinations of components i) and
ii) are GDO with PC and tocopherol with PC, especially in the
region 30-90 wt % GDO/tocopherol, 10-60 wt % PC and 1-30% solvent
(especially ethanol, NMP and/or isopropanol). A composition of
40-80% GDO, 20-60% PC, with 3-20%, preferably 5-10% solvent (e.g.
ethanol, NMP, benzyl alcohol, propylene glycol, benzyl benzoate,
dimethylsulphoxide etc) and 1-40% (e.g. 31 to 40%), preferably
10-35% of at least one opioid active agent is particularly
effective. A ratio of PC/GDO: .about.0.25-1.5, preferably 0.6-1.2
is desirable in many cases.
[0058] In addition to amphiphilic components i) and ii),
lipid-based pre-formulations of the invention may also contain
additional amphiphilic components at relatively low levels. In one
embodiment of the invention, the pre-formulation contains up to 10%
(by weight of components i) and ii)) of a charged amphiphile,
particularly an anionic amphiphile such as a fatty acid. Preferred
fatty acids for this purpose include caproic, caprylic, capric,
lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic,
elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric
acids, or the corresponding alcohols. Preferable fatty acids are
palmitic, stearic, oleic and linoleic acids, particularly oleic
acid.
[0059] Component "b" of the pre-formulations of the invention is an
oxygen containing organic solvent. Since the pre-formulation is to
generate a depot composition following administration (e.g. in
vivo), upon contact with an aqueous fluid, it is desirable that
this solvent be tolerable to the subject and be capable of mixing
with the aqueous fluid, and/or diffusing or dissolving out of the
pre-formulation into the aqueous fluid. Solvents having at least
moderate water solubility are thus preferred.
[0060] In a preferred lipid-based embodiment, the solvent is such
that a relatively small addition to the composition comprising i)
and ii), i.e. below 20% (e.g. 3-20%), or more preferably below 10%
(e.g. 5 to 10%), give a large viscosity reductions of one order of
magnitude or more. As described herein, the addition of 5% or 10%
solvent can give a reduction of several orders of magnitude in
viscosity over the solvent-free composition, even if that
composition is a solution or L.sub.2 phase containing no solvent,
or an unsuitable solvent such as water (subject to the special case
considered below), or glycerol. See Example 11 below for
example.
[0061] Typical solvents suitable for use as component b) include at
least one solvent selected from alcohols, ketones, esters
(including lactones), ethers, amides (including lactams) and
sulphoxides. Examples of suitable alcohols include ethanol,
isopropanol, benzylalcohol and glycerol formal. Monools are
preferred to diols and polyols. Where diols or polyols are used,
this is preferably in combination with an at least equal amount of
monool or other preferred solvent. Examples of ketones include
acetone and propylene carbonate. Suitable ethers include
diethylether, glycofurol, diethylene glycol monoethyl ether,
dimethylisobarbide, and polyethylene glycols. Suitable esters
include ethyl acetate, benzyl benzoate and isopropyl acetate and
dimethyl sulphide is as suitable sulphide solvent. Suitable amides
and sulphoxides include dimethylacetamide (DMA),
n-methylpyrrolidone (NMP), 2-pyrrolidone and dimethylsulphoxide
(DMSO). Less preferred solvents include dimethyl isosorbide,
tetrahydrofurfuryl alcohol, diglyme and ethyl lactate. NMP is a
highly preferred solvent for use in combination with buprenorphine.
In one embodiment, component b) therefore comprises NMP and may
comprise at least 50% or at least 70% NMP.
[0062] Since the pre-formulations are to be administered to a
living subject, it is necessary that the solvent component b) is
sufficiently biocompatible. The degree of this biocompatibility
will depend upon the application method and since component b) may
be any mixture of solvents, a certain amount of a solvent that
would not be acceptable in large quantities may evidently be
present. Overall, however, the solvent or mixture forming component
b) must not provoke unacceptable reactions from the subject upon
administration. Generally such solvents will be hydrocarbons or
preferably oxygen containing hydrocarbons, both optionally with
other substituents such as nitrogen containing groups. It is
preferable that little or none of component b) contains halogen
substituted hydrocarbons since these tend to have lower
biocompatibility. Where a portion of halogenated solvent such as
dichloromethane or chloroform is necessary, this proportion will
generally be minimised. Where the depot composition is to be formed
non-parenterally a greater range of solvents may evidently be used
than where the depot is to be parenteral.
[0063] Component b) as used herein may be a single solvent or a
mixture of suitable solvents but will generally be of low
viscosity. This is important because one of the key aspects of the
present invention is that it provides preformulations that are of
low viscosity and a primary role of a suitable solvent is to reduce
this viscosity.
[0064] This reduction will be a combination of the effect of the
lower viscosity of the solvent and the effect of the molecular
interactions between solvent and controlled release formulation,
such as the polymer or lipid composition. One observation of the
present inventors is that the oxygen-containing solvents of low
viscosity described herein have highly advantageous and unexpected
molecular interactions with the lipid parts of the composition,
thereby providing a non-linear reduction in viscosity with the
addition of a small volume of solvent.
[0065] The viscosity of the "low viscosity" solvent component b)
(single solvent or mixture) should typically be no more than 18
mPas at 20.degree. C. This is preferably no more than 15 mPas, more
preferably no more than 10 mPas and most preferably no more than 7
mPas at 20.degree. C.
[0066] The solvent component b) will generally be at least
partially lost upon in vivo formation of the depot composition, or
diluted by absorption of water from the surrounding air and/or
tissue. It is preferable, therefore, that component b) be at least
to some extent water miscible and/or dispersible and at least
should not repel water to the extent that water absorption is
prevented. In this respect also, oxygen containing solvents with
relatively small numbers of carbon atoms (for example up to 10
carbons, preferably up to 8 carbons) are preferred. Obviously,
where more oxygens are present a solvent will tend to remain
soluble in water with a larger number of carbon atoms. The carbon
to heteroatom (e.g. N, O, preferably oxygen) ratio will thus often
be around 1:1 to 6:1, preferably 2:1 to 4:1. Where a solvent with a
ratio outside one of these preferred ranges is used then this will
preferably be no more than 75%, preferably no more than 50%, in
combination with a preferred solvent (such as ethanol). This may be
used, for example to decrease the rate of evaporation of the
solvent from the pre-formulation in order to control the rate of
liquid crystalline depot formation.
[0067] A further advantage of the present pre-formulations is that
a higher level of bioactive agent may be incorporated into the
system. In particular, by appropriate choice of components
(especially b)), high levels of active agent may be dissolved or
suspended in the pre-formulations.
[0068] The pre-formulations of the present invention typically do
not contain significant amounts of water. Since it is essentially
impossible to remove every trace of water from a lipid composition,
this is to be taken as indicating that only such minimal trace of
water exists as cannot readily be removed. Such an amount will
generally be less than 1% by weight, preferably less than 0.5% by
the weight of the pre-formulation. In one preferred aspect, the
pre-formulations of the invention do not contain glycerol, ethylene
glycol or propylene glycol and contain no more than a trace of
water, as just described.
[0069] There is, however, a certain embodiment of the present
invention in which higher proportions of water may be tolerated.
This is where water is present as a part of the solvent component
in combination with an additional water-miscible component b
(single solvent or mixture). In this embodiment, up to 15 wt %
water may be present providing that at least 3 wt %, preferably at
least 5% and more preferably at least 7 wt % component b is also
present, that component b is water miscible, and that the resulting
preformulation remains non-viscous and thus does not form a liquid
crystalline phase. Generally there will be a greater amount of
component b) by weight than the weight of water included in the
preformulation. Most suitable solvents of use with water in this
aspect of the invention include ethanol, isopropyl alcohol and
NMP.
[0070] The pre-formulations of the present invention contain one or
more buprenorphine bioactive agents (described equivalently as
"bioactive agents" or simply "active agents" herein). Active agents
may be any suitably 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.
[0071] Buprenorphine is an opioid with mixed agonist-antagonist
properties 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.
[0072] Buprenorphine has a unique pharmacological profile with
several potential strengths over other opioid treatments:
[0073] 1. A ceiling on its agonist activity that may reduce its
abuse liability and contribute to a superior safety profile.
[0074] 2. Attenuation of physiological and subjective effects which
likely contributes to the suppression of opioid
self-administration.
[0075] 3. Slow receptor dissociation providing extended
duration.
[0076] Importantly, buprenorphine treatment is associated with a
relatively low-intensity withdrawal syndrome upon discontinuation,
making it particularly promising for detoxification treatments.
[0077] Buprenorphine is currently available 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.
[0078] A depot 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 buprenorphine depot may offer a promising approach for
delivering effective opioid maintenance or detoxification
treatment. Furthermore, a depot formulation 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, depot
buprenorphine should reduce the risks of misuse and drug diversion
of the medication by eliminating or reducing the need for take-home
medication.
[0079] It is a still further advantage of the products of the
present invention that the high bioavailability of the formulations
of the invention means there is no or little increase in exposure
if the drug is intentionally misused e.g. intravenously. Thus while
low bioavailability sublingual formulations may be abused by a more
efficient administration method, the much lower doses necessary in
the slow-release formulations of the invention make this much more
difficult. Moreover, intravenous misuse will not be effective due
to the in situ formation of the depot, which will prevent high
systemic drug concentrations.
[0080] In one key embodiment of the present invention, the
bioavailability of buprenorphine as measured from time zero to time
of last measurement and extrapolated to infinity for a single dose,
or between two consecutive doses at steady state, as the area under
the curve of human plasma concentration against time is no less
than 5 hours*ng/ml per mg of administered buprenorphine, preferably
no less than 7 and more preferably no less than 10 h ng/ml per mg
of administered buprenorphine. This compares with less than 3 hour
ng/ml per mg administered by current sublingual formulations. The
comparative results can be seen in FIGS. 4a and 4b, from which the
areas under the curves are readily estimated. Area-under-curve
values for Formulation A1 against dose buprenorphine for
Formulation A1 (Example 16) are shown graphically in FIG. 6.
[0081] Current sublingual formulations include Subutex.RTM. and
Suboxone.RTM.. Both are sublingual tablets approved by the FDA for
the treatment of opioid addiction. Subutex contains only
buprenorphine hydrochloride as active agent. This formulation was
developed as the initial product. The second medication, Suboxone
also contains naloxone to guard against misuse. Subutex is
typically given during the first few days of treatment, while
Suboxone is used during the maintenance phase of treatment. Both of
these products contain a relatively large dose of buprenorphine
because of their relatively low bioavailability. Thus, there is a
risk of diversion of these products, especially since they are
often prescribed for self-administration. These FDA approved
products are: Subutex (bitter sublingual, no active additives; in 2
mg and 8 mg dosages) and Suboxone (Lemon-lime flavored sublingual,
one part naloxone for every four parts buprenorphine; hexagon
shaped tablet in 2 mg and 8 mg dosages). The existing Suboxone
product is also available in a clinically interchangeable
"sublingual film" formulation. This film product remains a
once-daily dosage product and although it produces a somewhat
higher Cmax than the sublingual tablet, the plasma profile and
bioavailability are very similar to the tablet. The film product is
thus available in the same 8 mg and 2 mg dosages as the sublingual
tablet product.
[0082] The precursor formulations and all corresponding aspects of
the present invention may be formulated with buprenorphine as the
sole active agent. However, in one embodiment, the various
formulations of the invention may be prepared as combination
medicaments. For example, naloxone may be formulated with
buprenorphine (e.g. at between 1:1 and 10:1 buprenorphine:naloxone
by wt). Other opioids may similarly be formulated with the
buprenorphine active agent of the present invention. This will
apply particularly to precursor formulations intended for pain
control such as by analgesia.
[0083] A further key aspect of the present invention is the
comparatively low Cmax (peak plasma concentration) in comparison
with the dose administered and the period over which the drug is
effective. It can be seen, for example, in FIGS. 4a and 4b that
administration of 16 mg of buprenorphine as Subutex gives a Cmax
concentration of 6 ng/mL but is cleared to around 0.5 ng/mL in less
than 24 hours. In comparison, a 15 mg dose administered as a
formulation of the present invention peaks with a Cmax of around
3.5 and remains at around 0.9 ng.mL at 7-days following
administration.
[0084] Thus in a further preferred aspect, the compositions of the
present invention provide a Cmax (maximum concentration) in human
blood plasma after a single administration of no more than 0.3
ng/ml per mg of administered buprenorphine. This will preferably be
no more than 0.22 ng/mL per mg of buprenorphine administered and
more preferably no more than 0.17 ng/mL per mg administered. It can
be seen in comparison that Subutex gives a peak concentration of at
least around 0.4 ng/mL per mg of buprenorphine administered.
[0085] A still further advantage of the compositions of the present
invention is the linearity of the AUC dose experienced by the
subject in comparison with the administered dose of buprenorphine.
This may be seen from FIG. 6 and allows the physician to control
the experienced dose directly by control of the administered dose
in a linear relationship. It can furthermore be seen that Cmax is
additionally observed to vary linearly with administered dose and
again this allows the medical professional to control of the
concentration experienced by the subject (FIG. 5).
[0086] The compositions of the invention provide for an extended
duration of buprenorphine release, e.g., as exemplified in FIG. 4a.
Thus, the half-life plasma concentration experienced by the subject
after Cmax will be greater than 1 day, preferably greater than 2
days and most preferably greater than 3 days.
[0087] Because of the relatively low Cmax and the long half-life of
the buprenorphine depot-precursor formulations of the present
invention, the variation of plasma concentration during a cycle of
administration (once a steady-state has been achieved) will be less
pronounced (and obviously less sudden) than is experienced by a
subject taking a daily administration product. For example, the
steady-state variation between Cmax (the highest plasma
concentration during a cycle of administration) and Cmin (the
lowest plasma concentration over an administration cycle at
steady-state (also termed Ctrough)) may be no more than 20-fold.
Thus the steady-state Cmax concentration may be no more than 20
times the Cmin plasma concentration, preferably no more than 15
times and more preferably no more than 10 times. Most preferably
the Cmax/Cmin ratio will be no more than 6.
[0088] Thus, the variation between Cmin and Cmax at a steady-state
of administration of the products of the present invention may fall
with the range of between 0.4 ng/mL and 10 ng/mL, preferably
falling within the range of 0.5 ng/mL and to 8 ng/mL.
[0089] Because of the very high bioavailability of the
buprenorphine formulated in the preformulations of the present
invention, the transition of a subject currently receiving daily
sublingual buprenorphine to receiving, for example, weekly
formulations according to the present invention will not generally
require that the dose be increased significantly. For example a
subject may transfer from daily sublingual buprenorphine to a
weekly formulation of the present invention and receive 0.5 to 3
times his previous daily dose administered weekly. Preferably the
weekly dose will be 0.5 to 2 times the previous daily maintenance
dose.
[0090] The amount of bioactive agent to be formulated with the
pre-formulations of the present invention will depend upon the
functional dose and the period during which the depot composition
formed upon administration is to provide sustained release.
[0091] Typically, the dose formulated for a particular agent will
be less than half of the equivalent of the normal daily dose
multiplied by the number of days the formulation is to provide
release. Preferably this will be less than one third and more
preferably less than one quarter of the total of the daily doses
administered to that subject. Thus, for example, a subject
receiving a daily sublingual dose of 8 mg buprenorphine might
typically receive around 22.5 mg every seven days as formulated
according to the present invention.
[0092] Since different subjects will have differing tolerance for
opioids, it is important that a suitable dose can be selected by a
medical professional which will provide peak and plateau
concentrations which are acceptable to that subject.
[0093] Doses suitable for a once-weekly administration would
typically be in the range 3 to 40 mg buprenorphine (calculated as
buprenorphine free base), preferably 5 to 30 mg per week.
[0094] Doses suitable for a once-fortnightly administration would
typically be in the range 6 to 60 mg buprenorphine (calculated as
free base), preferably 10 to 50 mg per two weeks (i.e. per
administration).
[0095] Doses suitable for once-monthly administration would
typically be in the range 10 to 100 mg buprenorphine (calculated as
free base), preferably 15 to 80 mg per month (i.e. per
administration).
[0096] Evidently this amount will need to be tailored to take into
account factors such as body weight, gender, and in particular
opioid tolerance and current treatment regime. The precise amount
suitable in any case will readily be determined by one of skill in
the art.
[0097] In a further advantage of the present invention, the
formulations described herein provide a very stable equilibrium
level of buprenorphine once a small number of cycles of regular
administration have been made. This stable level provides for
excellent maintenance dosing and avoidance of withdrawal symptoms.
Furthermore, once a subject is stabilised by, for example, receipt
of weekly buprenorphine depot injections, that subject may then be
moved onto bi-weekly (fortnightly) formulations and in due course
monthly formulations.
[0098] Furthermore, because the blood concentration of
buprenorphine decays with a half-life of 3-4 days, no sudden drop
in plasma concentration is experienced and this may help avoid or
lessen withdrawal symptoms if the subject elects to come off from
opioid maintenance. Thus a treatment regime may involve the
transfer from daily to weekly to fortnightly to monthly
formulations. A transition may then be made to lower doses and in
due course the very slow decay from a stable plateau may allow
withdrawal of opioid treatment with minimal withdrawal
symptoms.
[0099] One key advantage of the various formulations of the present
invention is that they permit the inclusion of buprenorphine at
surprisingly high loadings. This allows for decreased injection
volumes, less pain on injection and at the injection site and thus
better patient compliance. Thus, the overall total buprenorphine
content in the precursor formulations of the present invention will
typically be 2% to 55% by weight of the total formulation. This may
be chosen to be in a suitable range for any particular application
and may thus be, for example in the ranges 5 to 25% or 30 to 50%.
In one particularly preferred embodiment, higher buprenorphine
loadings are used in combination with the use of NMP as at least a
part (e.g. at least 50%) of the solvent component. Thus, precursor
formulations comprising NMP may have a buprenorphine loading of
greater than 30%, for example 31% to 55%, 32% to 55% or 35% to
50%.
[0100] In one embodiment, precursor formulations and corresponding
depots and methods of the present invention which are formulated
with less than 30% buprenorphine may be formulated for dosing no
less frequently than once every 6 weeks (e.g. once weekly, once
fortnightly, once monthly (or once every 4 weeks) or once every 6
weeks). Correspondingly, compositions, formulations, depots and
methods relating to a buprenorphine content of around 30% or more
(e.g. 31% or more) may, in one embodiment, be formulated for
administration and/or administered no more frequently than once
every 4 weeks (e.g. once monthly or once every 4, 6, 8 or 12
weeks).
[0101] In a key embodiment, the pre-formulations of the present
invention will generally be administered parenterally. This
administration will generally not be an intra-vascular method but
will preferably be subcutaneous, intracavitary or intramuscular.
Typically the administration will be by injection, which term is
used herein to indicate any method in which the formulation is
passed through the skin, such as by needle, catheter or needle-free
injector.
[0102] Injection volumes for the precursor formulations of the
present invention will preferably be no more than 5 ml per
administration, more preferably no more than 2 ml and most
preferably no more than 1 ml. The prefilled devices of the
invention will thus typically contain these volumes of
composition.
[0103] One highly valuable aspect of the present invention relates
to the use of lipid controlled release matrices in the formation of
the precursor formulations and depot compositions of the invention.
Such lipid matrices are described herein and in documents cited
herein.
[0104] The lipid-based pre-formulations of the present invention
provide non-lamellar liquid crystalline depot compositions upon
exposure to aqueous fluids, especially in vivo and in contact with
body surfaces. As used herein, the term "non-lamellar" is used to
indicate a normal or reversed liquid crystalline phase (such as a
cubic or hexagonal phase) or the L.sub.3 phase or any combination
thereof. The term liquid crystalline indicates all hexagonal, all
cubic liquid crystalline phases and/or all mixtures thereof.
Hexagonal as used herein indicates "normal" or "reversed" hexagonal
(preferably reversed) and "cubic" indicates any cubic liquid
crystalline phase unless specified otherwise. By use of the lipid
pre-formulations of the present invention it is possible to
generate any phase structure present in the phase-diagram of
components i) and ii) with water. This is because the
pre-formulations can be generated with a wider range of relative
component concentrations than previous lipid depot systems without
risking phase separation or resulting in highly viscous solutions
for injection. In particular, the present invention provides for
the use of phospholipid concentrations above 50% relative to the
total amphiphile content. This allows access to phases only seen at
high phospholipid concentrations, particularly the hexagonal liquid
crystalline phases.
[0105] For many combinations of lipids, only certain non-lamellar
phases exist, or exist in any stable state. It is a surprising
feature of the present invention that compositions as described
herein frequently exhibit non-lamellar phases which are not present
with many other combinations of components. In one particularly
advantageous embodiment, therefore, the present invention relates
to compositions having a combination of components for which an
I.sub.2 and/or L.sub.2 phase region exists when diluted with
aqueous solvent. The presence or absence of such regions can be
tested easily for any particular combination by simple dilution of
the composition with aqueous solvent and study of the resulting
phase structures by the methods described herein.
[0106] In a highly advantageous embodiment, the compositions of the
invention may form an I.sub.2 phase, or a mixed phase including
I.sub.2 phase upon contact with water. The I.sub.2 phase is a
reversed cubic liquid crystalline phase having discontinuous
aqueous regions. This phase is of particular advantage in the
controlled release of active agents and especially in combination
with polar active agents, such as water soluble actives because the
discontinuous polar domains prevent rapid diffusion of the actives.
Depot precursors in the L.sub.2 are highly effective in combination
with an I.sub.2 phase depot formation. This is because the L.sub.2
phase is a so-called "reversed micellar" phase having a continuous
hydrophobic region surrounding discrete polar cores. L.sub.2 thus
has similar advantages with hydrophilic actives. In transient
stages after contact with body fluid the composition can comprise
multiple phases since the formation of an initial surface phase
will retard the passage of solvent into the core of the depot,
especially with substantial sized administrations of internal
depots. Without being bound by theory, it is believed that this
transient formation of a surface phase, especially a liquid
crystalline surface phase, serves to dramatically reduce the
"burst/lag" profile of the present compositions by immediately
restricting the rate of exchange between the composition and the
surroundings. Transient phases may include (generally in order from
the outside towards the centre of the depot): H.sub.II or
L.sub..alpha., I.sub.2, L.sub.2, and liquid (solution). It is
highly preferred that the composition of the invention is capable
forming at least two and more preferably at least three of these
phases simultaneously at transient stages after contact with water
at physiological temperatures. In particular, it is highly
preferred that one of the phases formed, at least transiently, is
the I.sub.2 phase.
[0107] It is important to appreciate that the preformulations of
the present invention are of low viscosity. As a result, these
preformulations must not be in any bulk liquid crystalline phase
since all liquid crystalline phases have a viscosity significantly
higher than could be administered by syringe or spray dispenser.
The preformulations of the present invention will thus be in a
non-liquid crystalline state, such as a solution, L.sub.2 or
L.sub.3 phase, particularly solution or L.sub.2. The L.sub.2 phase
as used herein throughout is preferably a "swollen" L.sub.2 phase
containing greater than 10 wt % of solvent (component b) having a
viscosity reducing effect. This is in contrast to a "concentrated"
or "unswollen" L.sub.2 phase containing no solvent, or a lesser
amount of solvent, or containing a solvent (or mixture) which does
not provide the decrease in viscosity associated with the
oxygen-containing, low viscosity solvents specified herein.
[0108] Upon administration, the pre-formulations of the present
invention undergo a phase structure transition from a low viscosity
mixture to a high viscosity (generally tissue adherent) depot
composition. This takes the form of generation of a non-lamellar
phase from lipid-based controlled release matrices or precipitation
of a polymeric monolith in the case of polymer solution precursor
formulations. Generally, this will be a transition from a molecular
(or polymer) solution, swollen L.sub.2 and/or L.sub.3 phase to one
or more (high viscosity) liquid crystalline phases or solid
polymer. Such phases include normal or reversed hexagonal or cubic
liquid crystalline phases or mixtures thereof. As indicated above,
further phase transitions may also take place following
administration. Obviously, complete phase transition is not
necessary for the functioning of the invention but at least a
surface layer of the administered mixture will form a liquid
crystalline structure. Generally this transition will be rapid for
at least the surface region of the administered formulation (that
part in direct contact with air, body surfaces and/or body fluids).
This will most preferably be over a few seconds or minutes (e.g. up
to 30 minutes, preferably up to 10 minutes, more preferably 5
minutes of less). The remainder of the composition may change phase
to a liquid crystalline phase more slowly by diffusion and/or as
the surface region disperses.
[0109] In one preferred embodiment, the present invention thus
provides a pre-formulation as described herein of which at least a
portion forms a hexagonal liquid crystalline phase upon contact
with an aqueous fluid. The thus-formed hexagonal phase may
gradually disperse, releasing the active agent, or may subsequently
convert to a cubic liquid crystalline phase, which in turn then
gradually disperses. It is believed that the hexagonal phase will
provide a more rapid release of active agent, in particular of
hydrophilic active agent, than the cubic phase structure,
especially the I.sub.2 and L.sub.2 phase. Thus, where the hexagonal
phase forms prior to the cubic phase, this will result in an
initial release of active agent to bring the concentration up to an
effective level rapidly, followed by the gradual release of a
"maintenance dose" as the cubic phase degrades. In this way, the
release profile may be controlled.
[0110] Without being bound by theory, it is believed that upon
exposure (e.g. to body fluids), the pre-formulations of the
invention lose some or all of the organic solvent included therein
(e.g. by diffusion and/or evaporation) and in some cases take in
aqueous fluid from the bodily environment (e.g. moist air close to
the body or the in vivo environment) such that at least a part of
the lipid formulations generate a non-lamellar, particularly liquid
crystalline phase structure. Polymeric precursor solutions lose
solvent to the biological environment and precipitate a solid
polymer. In most cases these non-lamellar structures are highly
viscous and are not easily dissolved or dispersed into the in vivo
environment and are bioadhesive and thus not easily rinsed or
washed away. Furthermore, because the non-lamellar structure has
large polar, apolar and boundary regions, it is highly effective in
solubilising and stabilising many types of active agents and
protecting these from degradation mechanisms. As the depot
composition formed from the pre-formulation gradually degrades over
a period of days, weeks or months, the active agent is gradually
released and/or diffuses out from the composition. Since the
environment within the depot composition is relatively protected,
the pre-formulations of the invention are highly suitable for
active agents with a relatively low biological half-life (see
above).
[0111] It is an unexpected finding of the present inventors that
the pre-formulations result in a depot composition that have very
little "burst" effect in the active agent release profile. This is
unexpected because it might be expected that the low viscosity
mixture (especially if this is a solution) of the pre-composition
would rapidly lose active agent upon exposure to water. In fact,
very high performance is provided in comparison with existing
formulations, as is seen from FIGS. 4a and 4b below. In one
embodiment, the invention thus provides injectable preformulations
and resulting depot compositions wherein the highest plasma
concentration of active after administration is no more than 5
times the average concentration between 24 hours and 5 days of
administration. This ratio is preferably no more than 4 times and
most preferably no more than 3 times the average concentration.
[0112] It is a considerable advantage of the precursor formulations
of the present invention that they may be provided in
storage-stable, ready-to-administer form. That is to say, the
precursor formulations of the present invention may be provided in
a form that requires no further combining of components in order to
generate a formulation that is suitable for injection. Thus the
invention correspondingly provides an administration device
containing at least one precursor formulation as described herein
wherein the formulation is ready for administration and/or
administrable without any further combination or mixing of
components. This contrasts with many controlled-release products,
particularly polymeric controlled-release formulations, which
require various components to be combined before delivery to the
patient. Such an administration device will typically contain a
dose suitable for a single administration where the administration
may be once-weekly, once-fortnightly, once-monthly or once every
two or three months. In all cases, the dose of buprenorphine will
be selected so as to provide over the whole of the dosing period
(at steady state) a Cmax and Cmin that are within the Cmax to Cmin
range experienced following daily sublingual buprenorphine
administration. Suitable administration devices include prefilled
syringes with optional needle stick prevention safety device and/or
auto-injector, pen cartridge systems and similar devices.
[0113] Suitable administration devices of the invention include a
ready-to-use buprenorphine formulation of the present invention in
a cartridge pen combination or prefilled syringe device, optionally
equipped with a needle stick protecting safety device or
auto-injector. The device may have a needle with a gauge higher
than 18 G, preferably above 20 G, more preferably above 22 G (for
example 23G or 25 G). The buprenorphine formulation will generally
be a precursor formulation as described herein in any embodiment.
Such a formulation will generally have a viscosity in the range of
100-500 mPas.
[0114] For ease of self-administration, the device of the present
invention may be or may be used with or incorporated into an
auto-injection device or pen-cartridge device. Such a device may be
disposable or reusable.
[0115] By "storage stable" as used herein is indicated that a
composition maintains at least 90% of the original active agent
content after storage for 36 months at 25.degree. C. and 60%
relative humidity. This is preferably at least 95% and more
preferably at least 98%.
[0116] A ready-to-administer product has obvious advantages for
ease of administration and in particular, if a opioid dependence
product or long term pain relief medication is to be administered
by a healthcare professional at regular intervals to a population
of patients, a significant amount of time may be required in
preparation of the materials prior to injection. In contrast, if
the product is ready to use or even provided in a pre-filled
administration device then the healthcare professional may spend
their time in consultation with patients rather than in mixing
medications.
[0117] The methods of treatment and/or prophylaxis, and
corresponding uses in manufacture, of the present invention will be
for any medical indication for which opioids are indicated. In
particular, chronic conditions such as chronic pain (e.g. in
arthritis, after surgery, in palliative cancer treatment etc.) are
particularly suitable for the use of the present depot formulations
and their precursors. The most suitable indications will, however,
include pain, diarrhoea, depression, opioid dependence, opioid
addiction, and the symptoms of opioid withdrawal. Of these, the
present compositions are most preferably used in methods for the
treatment and/or prophylaxis of opioid dependence, opioid
addiction, and/or the symptoms of opioid withdrawal. Cases where
opioid dependence and/or opioid addiction have resulted from opioid
abuse are particularly suitable for treatment with the present
compositions because they offer advantages in terms of patient
compliance, where the patient's lifestyle may not be compatible
with regular attendance at a clinic or other site of medical
treatment.
[0118] In one aspect, the present invention therefore provides for
a method of detoxification treatment of a (preferably human)
mammalian subject where the subject has or has had an opioid
dependence, addiction, or habit, and/or where the subject is
suffering from or is at risk of suffering from withdrawal symptoms
from opioid administration. Such a detoxification method will
comprise at least one administration of a precursor formulation of
the present invention. Such a formulation may be any such
formulation as described herein and as evident from that
disclosure.
[0119] In a further aspect, the present invention therefore
provides for a method of maintenance treatment of a (preferably
human) mammalian subject where the subject has or has had an opioid
dependence, addiction, or habit, and/or where the subject is
suffering from or is at risk of suffering from withdrawal symptoms
from opioid administration. Such a maintenance treatment method
will comprise at least one and more commonly multiple
administrations of a precursor formulation of the present
invention. Such a formulation may be any such formulation as
described herein and as evident from that disclosure. Such
administrations may be, for example, once weekly, once every two
weeks (fortnightly) or once monthly.
[0120] It is notable that the low ratio of Cmax to Cmin (for
example a ratio of less than 3 as shown in FIG. 3) over 28 days
provided by the products of the present invention demonstrate that
a highly effective once-monthly formulation can be generated
according to the present invention. It is preferable that the ratio
of Cmax to Cmin over 28 days be no more than 10, preferably no more
that 5, more preferably no more than 3 and most preferably no more
than 2.8, measured as plasma buprenorphine concentrations.
[0121] In one key aspect, the precursor formulations of the
invention are given as a subcutaneous injection. Compared with the
sublingual buprenorphine products on the market, the products of
the invention have one or more of the following advantages: 1)
Rapid therapeutic onset (with maximum plasma concentrations
established within 24 hours after injection) followed by steady
long-acting release, 2) Reduced variation in buprenorphine plasma
levels over time (stable plasma levels attained for at least 7
days) resulting in more therapeutic levels and a possible reduction
in morning "cravings", 3) Less frequent dosing resulting in reduced
frequency of clinic visits and need for medical support, 4)
Significantly higher bioavailability and efficacy-over-dose ratio,
meaning less drug substance in circulation and on the street, 5)
Decreased risk of drug diversion, 6) Easier dose adjustment, 7)
"Ready-to-use" dosage formulation, 8) high buprenorphine loading,
9) good systemic tolerability and 10) good local tolerability at
the administration site.
[0122] The Invention will now be further illustrated by reference
to the following non-limiting Examples and the attached Figures, in
which;
[0123] FIG. 1 shows the cumulative release of methylene blue (MB)
from a depot formulation comprising PC/GDO/EtOH (45/45/10 wt %)
when injected into excess water;
[0124] FIG. 2 demonstrates the non-linear decrease of
pre-formulation viscosity upon addition of N-methylpyrolidone (NMP)
and ethanol (EtOH);
[0125] FIG. 3 Shows the pharmacokinetic profile following
administration of different dose volumes of buprenorphine (Example
13) to rats.
[0126] FIG. 4a Shows the plasma concentration in humans (N=26)
following administration of buprenorphine formulated as CAM2038
(Formulation A1) as described in Example 16.
[0127] FIG. 4b Shows the pharmacokinetics of high-dose
buprenorphine following single administration of sublingual tablet
formulations in opioid naive healthy male volunteers under a
naltrexone block (Drug and Alcohol Dependence 72 (2003) 75-83).
[0128] FIG. 5. Shows Cmax versus dose after single injections in
opioid dependent patients (HS-07-307). Hollow diamonds show mean
values and filled diamonds show individual values
[0129] FIG. 6. Shows area under curve (AUC.sub.7days) versus dose
after single injections in opioid dependent patients (HS-07-307).
Hollow diamonds show mean values and filled diamonds show
individual values.
[0130] FIG. 7. shows stability of buprenorphine at long-term
25.degree. C./60% RH and accelerated 40.degree. C./75% RH
conditions in Formulation A1 (also referred to as CAM2038) as
described in Example 16
[0131] FIG. 8a. Shows plasma curves in rats after subcutaneous
injection of different dose volumes of Formulation A1 in Example
16. The minimum dose volume was 0.1 mL/kg (about 0.03 mL per
rat).
[0132] FIG. 8b. Shows plasma curves in rats after subcutaneous
injection of different buprenorphine doses of Formulations A12,
A13, A14 and A1 in Example 16. The dose volume was 0.2 mL/kg.
[0133] FIG. 9 Shows plasma profiles in dogs (N=4) after repeat
dosing of 7.5 mg and 60 mg doses of Formulation A1 (Example 16)
respectively, given in the time interval from Day 28 to Day 56,
following an initial single dose injection followed over one month
(not shown).
[0134] FIG. 10. Shows plasma profiles in rats (N=6) after
subcutaneous injection of Formulation A18 and A3 (Example 16) at
doses of 140 mg/kg and 50 mg/kg, respectively.
[0135] FIG. 11. Shows a schematic illustration of the clinical
study design of the Phase I/II study HS-07-307 in opioid dependent
patients.
[0136] FIG. 12a. Shows plasma concentration versus time in humans
(Pharmacokinetic Set, N=26) following administration of
buprenorphine formulated as CAM2038 (Formulation A1) as described
in Example 16. Groups: A--filled diamonds; B--Open diamonds;
C--filled triangles, D--open triangles.
[0137] FIG. 12b Shows plasma concentration in opiate addicted
patients (Pharmacokinetic Set, N=26) versus time (semi-log scale)
following single dose administration of buprenorphine formulated as
CAM2038 (Formulation A1) as described in Example 16. Groups:
A--filled diamonds; B--Open diamonds; C--filled triangles, D--open
triangles.
[0138] FIG. 13 Shows mean clinical opiate withdrawal score (COWS)
from inclusion and over washout and treatment with a single dose of
CAM2038 (Formulation A1) in HS-07-307. Groups: A--filled diamonds;
B--Open diamonds; C--filled triangles, D--open triangles.
[0139] FIG. 14 Shows mean clinical opiate withdrawal score (COWS)
from inclusion and over washout and treatment with a single dose of
CAM2038 (Formulation A1) in HS-07-307. --Groups: A--filled
diamonds; B--Open diamonds; C--filled triangles, D--open
triangles.
[0140] FIG. 15 Shows Kaplan-Meir plot of time to first intake of
buprenorphine rescue medication after administration of a single
dose of CAM2038 (Formulation A1). --Groups: A--filled diamonds;
B--Open diamonds; C--filled triangles, D--open triangles.
EXAMPLES
Example 1
Availability of Various Liquid Crystalline Phases in the Depot by
Choice of Composition
[0141] Injectable formulations containing different proportions of
phosphatidyl choline ("PC"--Epikuron 200) and glycerol dioleate
(GDO) and with EtOH as solvent were prepared to illustrate that
various liquid crystalline phases can be accessed after
equilibrating the depot precursor formulation with excess
water.
[0142] Appropriate amounts of PC and EtOH were weighed in glass
vials and the mixture was placed on a shaker until the PC
completely dissolved to form a clear liquid solution. GDO was then
added to form an injectable homogenous solution.
[0143] Each formulation was injected in a vial and equilibrated
with excess water. The phase behaviour was evaluated visually and
between crossed polarizes at 25.degree. C. Results are presented in
Table 1.
TABLE-US-00001 TABLE 1 Phase behaviour of PC/GDO formulations.
Phase in Formulation PC (wt %) GDO (wt %) EtOH (wt %) H.sub.2O A
22.5 67.5 10.0 L.sub.2 B 28.8 61.2 10.0 I.sub.2 C 45.0 45.0 10.0
H.sub.II D 63.0 27.0 10.0 H.sub.II/L.sub..alpha. L.sub.2 = reversed
micellar phase I.sub.2 = reversed cubic liquid crystalline phase
H.sub.II = reversed hexagonal liquid crystalline phase
L.sub..alpha. = lamellar phase
Example 2
In Vitro Release of a Water-Soluble Substance
[0144] A water-soluble colorant, methylene blue (MB) was dispersed
in formulation C (see Example 1) to a concentration of 11 mg/g
formulation. When 0.5 g of the formulation was injected in 100 ml
water a stiff reversed hexagonal H.sub.II phase was formed. The
absorbency of MB released to the aqueous phase was followed at 664
nm over a period of 10 days. The release study was performed in an
Erlenmeyer flask at 37.degree. C. and with low magnetic
stirring.
[0145] The release profile of MB (see FIG. 1) from the hexagonal
phase indicates that this (and similar) formulations are promising
depot systems. Furthermore, the formulation seems to give a low
initial burst, and the release profile indicates that the substance
can be released for several weeks; only about 50% of MB is released
after 10 days.
Example 3
Viscosity in PC/GDO (5:5) or PC/GDO (4:6) on Addition of Solvent
(EtOH, PG and NMP)
[0146] A mixture of PC/GDO/EtOH with approximately 25% EtOH was
manufactured according to the method in Example 1. All, or nearly
all, of the EtOH was removed from the mixture with a rotary
evaporator (vacuum, 40.degree. C. for 1 h followed by 50.degree. C.
for 2 h) and the resulting mixture was weighed in glass vial after
which 1, 3, 5, 10 or 20% of a solvent (EtOH, propylene glycol (PG)
or n-methylpyrrolidone (NMP)) was added. The samples were allowed
to equilibrate several days before the viscosity was measured with
a CarriMed CSL 100 rheometer equipped with automatic gap
setting.
[0147] This example clearly illustrates the need for solvent with
certain depot precursors in order to obtain an injectable
formulation (see FIG. 2). The viscosity of solvent-free PC/GDO
mixtures increases with increasing ratio of PC. Systems with low
PC/GDO ratio (more GDO) are injectable with a lower concentration
of solvent.
Example 4
Preparation of Depot Precursor Compositions with Various
Solvents
[0148] Depending on composition of the formulation and the nature
and concentration of active substance certain solvents may be
preferable.
[0149] Depot precursor formulations (PC/GDO/solvent (36/54/10))
were prepared by with various solvents; NMP, PG, PEG400,
glycerol/EtOH (90/10) by the method of Example 1. All depot
precursor compositions were homogeneous one phase solutions with a
viscosity that enabled injection through a syringe (23 G--i.e. 23
gauge needle; 0.6 mm.times.30 mm) After injecting formulation
precursors into excess water a liquid crystalline phase in the form
of a high viscous monolith rapidly formed with NMP and PG
containing precursors. The liquid crystalline phase had a reversed
cubic micellar (I.sub.2) structure. With PEG400, glycerol/EtOH
(90/10) the viscosification/solidification process was much slower
and initially the liquid precursor transformed to a soft somewhat
sticky piece. The difference in appearance probably reflects the
slower dissolution of PEG400 and glycerol towards the excess
aqueous phase as compared to that of EtOH, NMP and PG.
Example 5
Robustness of the Behaviour of the Formulation Against Variations
in the Excipient Quality
[0150] Depot precursor formulations were prepared with several
different GDO qualities (supplied by Danisco, Denmark), Table 2,
using the method of Example 1. The final depot precursors contained
36% wt PC, 54% wt GDO, and 10% wt EtOH. The appearance of the depot
precursors was insensitive to variation in the quality used, and
after contact with excess water a monolith was formed with a
reversed micellar cubic phase behaviour (I.sub.2 structure).
TABLE-US-00002 TABLE 2 Tested qualities of GDO. GDO Monoglyceride
quality (% wt) Diglyceride (% wt) Triglyceride (% wt) A 10.9 87.5
1.6 B 4.8 93.6 1.6 C 1.0 97.3 1.7 D 10.1 80.8 10.1 E 2.9 88.9 8.2 F
0.9 89.0 10.1
Example 6
Degradation of Depot Formulation in the Rat
[0151] Various volumes (1, 2, 6 ml/kg) of the depot precursor (36%
wt PC, 54% wt GDO, and 10% wt EtOH) were injected in the rat and
were removed again after a period of 14 days. It was found that
substantial amounts of the formulations were still present
subcutaneously in the rat after this time, see Table 3.
TABLE-US-00003 TABLE 3 Mean diameter of depot monolith. Dose
(ml/kg) Mean diameter day 3 (mm) Mean diameter day 14 (mm) 1 (n =
3) 15.8 12.5 2 (n = 3) 18.5 15.3 6 (n = 3) 23.3 19.3
Example 7
In Vitro Study of Formation of Depot Monolith after Injection of
Depot Formulation Precursor Between the Bone and Periostium
[0152] A precursor (36% wt PC, 54% wt GDO, and 10% wt EtOH prepared
as described in Example 1) was injected by syringe between the bone
and periostium. The composition was observed to spread to fill
voids and after uptake of aqueous fluids formed a monolith that was
bioadhesive to both the bone and periostium.
Example 8
Compositions Containing PC and Tocopherol
[0153] Depot precursor formulations were prepared with several
different PC/.alpha.-tocopherol compositions using the method of
Example 1 (PC was first dissolved in the appropriate amount of EtOH
and thereafter .alpha.-tocopherol was added to give clear
homogenous solutions).
[0154] Each formulation was injected in a vial and equilibrated
with excess water. The phase behaviour was evaluated visually and
between crossed polarizes at 25.degree. C. Results are presented in
Table 4.
TABLE-US-00004 TABLE 4 Phase behaviour of PC/.alpha.-tocopherol
formulations. .alpha.- tocopherol PC Ethanol Phase in excess
H.sub.2O 2.25 g 2.25 g 0.5 g H.sub.II 2.7 g 1.8 g 0.5 g
H.sub.II/I.sub.2 3.15 g 1.35 g 0.5 g I.sub.2 3.6 g 0.9 g 0.5 g
I.sub.2/L.sub.2
Example 9
In Vitro Release of Water-Soluble Disodium Fluorescein
[0155] A water-soluble colorant, disodium fluorescein (Fluo), was
dissolved in a formulation containing PC/.alpha.-tocopherol/Ethanol
(27/63/10 wt %) to a concentration of 5 mg Fluo/g formulation. When
0.1 g of the formulation was injected in 2 ml of phosphate buffered
saline (PBS) a reversed micellar (I.sub.2) phase was formed. The
absorbency of Fluo released to the aqueous phase was followed at
490 nm over a period of 3 days. The release study was performed in
a 3 mL vial capped with an aluminium fully tear off cap at
37.degree. C. The vial was placed on a shaking table at 150
rpm.
[0156] The release of Fluo from the PC/.alpha.-tocopherol
formulation (see Table 5) indicates that this (and similar)
formulations are promising depot systems. Furthermore, the absence
of a burst effect is noteworthy, and the release indicates that the
substance can be released for several weeks to months; only about
0.4% of Fluo is released after 3 days.
TABLE-US-00005 TABLE 5 In vitro release of disodium fluorescein
from PC/.alpha.-tocopherol composition. % release (37.degree. C.)
Formulation 24 h 72 h PC/.alpha.-tocopherol/EtOH: <0.1* 0.43
27/63/10 wt % *Release below detection limit of the absorbance
assay
Example 10
Fentanyl Formulation
[0157] Formulations were prepared as in Example 1 by mixing the
narcotic analgesic fentanyl with a mixture of GDO, PC, ethanol and
optionally PG in the following proportions.
TABLE-US-00006 TABLE 6 Fentanyl compositions (wt %). Formulation
Fentanyl PC GDO EtOH PG 1 0.05 34 51 10 5 2 0.05 36 54 10 -- 3 0.05
42 43 10 5 4 0.05 45 45 10 -- 5 0.15 34 51 10 5 6 0.15 36 54 10 --
7 0.05 30 45 15 10 8 0.15 30 45 15 10 where EtOH is ethanol, PC is
LIPOID S100 soybean phosphatidylcholine, GDO is glycerol dioleate,
and PG is propylene glycol
[0158] All formulations are low viscosity liquids suitable for
administration by injection or intra oral or nasal liquid jet
application, which generate liquid crystalline phase compositions
upon exposure to aqueous conditions.
Example 11
Further Examples of Viscosity in PC/GDO Mixtures on Addition of
Co-Solvent
[0159] Mixtures of PC/GDO and co-solvent were prepared according to
the methods of Example 1 and Example 3 in the proportions indicated
in the table below. The samples were allowed to equilibrate for
several days before viscosity measurements were performed using a
Physica UDS 200 rheometer at 25.degree. C.
TABLE-US-00007 TABLE 7 Viscosity of PC/GDO mixtures with different
solvents and solvent contents. PC/GDO EtOH/ Glycerol/ H.sub.2O/
Viscosity/ Sample (wt/wt) wt % wt % wt % mPas 1 50/50 3 -- -- 1900
2 50/50 5 -- -- 780 3 50/50 7 -- -- 430 4 50/50 8 -- -- 300 5 50/50
10 -- -- 210 6 50/50 15 -- -- 100 7 45/55 3 -- -- 1350 8 45/55 5 --
-- 540 9 45/55 7 -- -- 320 10 45/55 8 -- -- 250 11 45/55 10 -- --
150 12 45/55 15 -- -- 85 13 40/60 3 -- -- 740 14 40/60 5 -- -- 400
15 40/60 7 -- -- 240 16 40/60 8 -- -- 200 17 40/60 10 -- -- 130 18
40/60 15 -- -- 57 19 40/60 -- 10 -- 8 * 10.sup.6 20 40/60 -- -- 3
2.5 * 10.sup.8 21 40/60 -- -- 5 4 * 10.sup.7
[0160] This example further illustrates the need for a solvent with
viscosity lowering properties in order to obtain injectable
formulations. The mixtures containing glycerol (sample 19) or water
(samples 20 and 21) are too viscous to be injectable at solvent
concentrations equivalent to the samples containing EtOH (compare
with samples 13, 14 and 17).
Example 12
Buprenorphine Depot
[0161] A mixture of GDO, soyPC (SPC; Lipoid 5100, Lipoid, Germany)
and EtOH was manufactured according to the method described in
Example 1. The opioid buprenorphine was added and the formulation
mixed to homogeneity to obtain the following composition:
TABLE-US-00008 TABLE 8 Buprenorphine composition. Buprenorphine GDO
SPC EtOH 5 wt % 45 wt % 45 wt % 5 wt %
[0162] Sterile-filtration was performed by passing the final
precursor formulation through a standard sterile filtration
membrane (Millex GP 0.22 .mu.m).
Example 13
In Vivo Release of Buprenorphine
[0163] Three suitable volumes (0.3 mL/kg, 1.0 mL/kg, and 1.5 mL/kg)
of the composition of Example 12 were injected into 18 male SPF
Sprague-Dawley rats (weighing ca. 300 g). Blood samples were
collected pre-dose, 3 hrs, 6 hrs, 1 day, 2 days, 7 days, 14 days,
21 days and 28 days after dosing. The plasma concentrations were
determined with the aid of a commercial ELISA kit adapted for
analysis of buprenorphine in rat plasma. The results from the three
groups (n=6) are shown in FIG. 3, and demonstrate the ability to
deliver buprenorphine at target human therapeutic levels to rats
for at least 4 weeks. No obvious adverse side effects were
seen.
Example 14
Solubility of Buprenorphine in Depot Precursor Formulations
[0164] Buprenorpine solubility in formulation precursors was
determined by the following protocol; buprenorphine in excess was
added to formulation precursors and samples were equilibrated by
end-over-end mixing at ambient room temperature for four days.
Excess buprenorphine was removed by filtration and the
concentration in precursor formulations was determined with HPLC.
Formulation precursors in the table below differ by the additional
solvent (ethanol (EtOH), benzyl alcohol (BzOH), polyethyleneglycol
400 (PEG400), benzyl benzoate (BzB), and dimethylsulphoxide
(DMSO)).
TABLE-US-00009 TABLE 9 Buprenorphine solubility in various
precursor formulations. Composition of formulation precursor SPC/
GDO/ EtOH/ Additional Buprenorphine Sample wt % wt % wt %
solvent/wt % solubility/wt % 1 47.5 47.5 5 -- 10.4 2 45 45 5 EtOH/5
10.3 3 45 45 5 BzOH/5 9.9 4 45 45 5 PEG400/5 10.8 5 45 45 5 BzB/5
11.2 6 45 45 5 DMSO/5 15.2
Example 15
In Vitro Behaviour of Buprenorphine Depot Precursor
Formulations
[0165] After injection into excess water or excess saline (0.9%
NaCl) a liquid crystalline phase in the form of a high viscous
monolith formed with all formulation precursors described in
Example 14. In general the transformation was somewhat slower with
additional solvent, while buprenorphine appeared not to have a
strong influence on the monolith formation.
Example 16
Ready-to-Administer Lipid Formulations
[0166] The formulations indicated in Table 10 below comprising
buprenorphine, lipids and solvent were generated by adding the
respective component in the required proportions to sterile
injection glass vials followed by capping with sterile rubber
stoppers and aluminium crimp caps. Mixing of the formulations
(sample sizes 5-10 g) was performed by placing the vials on a
roller mixer at ambient room temperature until liquid and
homogenous formulations were obtained. The formulations were
finally sterile filtered through 0.22 .mu.m PVDF membrane filters
using ca 2.5 bar nitrogen pressure.
[0167] The lipids used were Lipoid 5100 (SPC) from Lipoid, Germany,
and Rylo DG19 Pharma (GDO) from Danisco, Denmark.
TABLE-US-00010 TABLE 10 Ready-to-administer lipid buprenorphine
compositions (wt %). Formulation name BUP SPC GDO EtOH NMP A1 5.29
42.36 42.36 10.00 -- A2 7.93 41.04 41.04 10.00 -- A3 5.29 44.10
44.10 6.50 -- A4 7.81 43.60 43.60 5.00 -- A5 7.93 49.25 32.83 10.00
-- A6 7.93 32.83 49.25 10.00 -- A7 7.93 38.54 38.54 15.00 -- A8
7.93 36.04 36.04 20.00 -- A9 5.29 33.88 50.83 10.00 -- A10 5.29
46.59 38.12 10.00 -- A11 5.29 50.83 33.88 10.00 -- A12 0.53 44.74
44.74 10.00 -- A13 1.06 44.47 44.47 10.00 -- A14 2.11 43.94 43.94
10.00 -- A15 15.0 37.5 37.5 -- 10.0 A16 15.0 32.5 32.5 -- 20.0 A17
35.0 17.5 17.5 -- 30.0 A18 35.0 14.0 21.0 -- 30.0 A19 15.0 35.0
35.0 -- 15.0 A20 15.0 30.0 30.0 -- 25.0 A21 30.0 25.0 25.0 -- 20.0
A22 40.0 12.0 18.0 -- 30.0 A23 30.0 16.0 24.0 -- 30.0 A24 25.0 22.0
33.0 -- 30.0 A25 15.0 32.5 32.5 5.0 15.0
Example 17
Ready-to-Administer Polymer Formulations
[0168] The formulations indicated in Table 11 below comprising
buprenorphine, polymer and solvent were generated by adding the
respective component in the required proportions to a sterile
injection glass vial followed by capping with sterile rubber
stopper and aluminium crimp cap. Mixing of the formulations (sample
sizes 5-10 g) was performed by placing the vials on a roller mixer
at ambient room temperature until liquid and homogenous
formulations were obtained. The formulations were finally sterile
filtered through 0.22 .mu.am PVDF membrane filters using ca 2.5 bar
nitrogen pressure.
[0169] The polymer used was PLGA (polymer type 50/50
Poly(DL-lactide-co-glycolide) with inherent viscosity 0.59 dL/g)
from Birmingham Polymers Inc., USA.
TABLE-US-00011 TABLE 11 Ready-to-administer polymer buprenorphine
compositions (wt %). Formulation name BUP PLGA NMP B1 15.0 21.25
63.75 B2 20.0 20.00 60.00 B3 25.0 18.75 56.25 B4 32.5 16.9 50.6 B5
35.0 16.2 48.8 B6 40.0 15.0 45.0
Example 18
Formulations Comprising Water and Buprenorphine Salts
[0170] The formulations indicated in Table 12 below comprising
buprenorphine, lipids and solvent were generated as described in
Example 16 above. For the formulations comprising water, the
additives hydrochloric acid (HCl) and citric acid (CA) were first
dissolved in the aqueous phase followed by addition to the other
components. The respective buprenorphine salt forms (i.e.,
hydrochloride, citrate, benzoate and pamoate salts) are generated
in the formulations after mixing of all components.
[0171] The lipids used were Lipoid 5100 (SPC) from Lipoid, Germany,
and Rylo DG19 Pharma (GDO) from Danisco, Denmark. Benzoic acid and
pamoic (or embonic) acid are abbreviated Bz and PAM,
respectively.
TABLE-US-00012 TABLE 12 Ready-to-administer lipid buprenorphine
compositions comprising water and buprenorphine salts (wt %).
Formulation HCl (aq) name BUP SPC GDO EtOH NMP pH 0.52 WFI CA Bz
PAM C1 2.11 33.95 33.95 15.00 -- 15.00 -- -- -- -- C2 5.29 31.86
31.86 15.00 -- -- 15.00 1.00 -- -- C3 1.06 33.97 33.97 15.00 -- --
15.00 1.00 -- -- C4 2.11 32.95 32.95 15.00 -- -- 15.00 2.00 -- --
C5 2.11 33.75 33.75 15.00 -- -- 15.00 0.40 -- -- C6 2.11 38.75
38.75 10.00 -- -- 10.00 0.40 -- -- C7 5.29 41.10 41.10 10.00 -- --
-- -- 2.60 -- C8 5.29 35.16 35.16 5.00 15.00 -- -- -- -- 4.39 C9
5.29 35.71 35.71 5.00 15.00 -- -- -- -- 3.29 C10 5.29 36.26 36.26
5.00 15.00 -- -- -- -- 2.19 C11 1.06 34.47 34.47 15.00 -- -- 15.00
-- -- -- C12 2.11 33.95 33.95 15.00 -- -- 15.00 -- -- -- C13 1.06
39.47 39.47 10.00 -- -- 10.00 -- -- --
Example 19
Lipid Buprenorphine Formulation Filled into Pre-Filled Syringes
[0172] Formulation A1, hereinafter referred to as CAM2038, was
manufactured according to Example 16 above at a batch size of 100
mL. The formulation was filled into 1 mL (long) pre-filled syringes
(1.0 mL long Gerresheimer glass, staked needle 25 G 16 mm thin
wall, oily siliconized, batch no: 1000102210) and plunger stoppers
(West 2340 4432/50/GRAU B240 Westar.RTM. RS, lot. Nr: 1112020528)
and plunger rods (Gerresheimer Plunger rod 1 mL long 55103, art no:
551030001) were assembled.
Example 20
Absolute Bioavailability
[0173] Formulation A1 (Example 16) was administered subcutaneously
to rats in doses of 5, 10, 20 and 50 mg/kg (N=6 per group) and
blood samples were collected pre-dose, 1 hrs, 6 hrs, 1 day, 2 days,
5 days, 8 days and 14 days after dosing. In a separate group,
Temgesic (aqueous injection solution of buprenorphine hydrochloride
with an equivalent buprenorphine base concentration of 0.30 mg/mL)
was administered intravenously (0.45 mg/kg, N=6) and blood samples
were collected pre-dose, 1 min, 5 min, 10 min, 30 min, 60 min, 3
hrs, 6 hrs and 24 hrs. The plasma concentrations were determined
with the aid of a commercial ELISA kit adapted for analysis of
buprenorphine in rat plasma. The area-under-the-curve (AUC) for the
respective treatment groups was calculated and the absolute
bioavailability was calculated by comparing the AUC for the
subcutaneous Formulation A1 dose groups with the AUC for the
Temgesic intravenous dose group. The results revealed around 100%
absolute bioavailability for all Formulation A1 dose groups.
Example 21
Storage Stability
[0174] Formulation A1 in Example 16 above (Formulation A1,
equivalent to 50 mg buprenorphine base/mL) was manufactured
according to GMP at a scale of 1 kg (ca 1 L) and filled in
injection glass vials of size 2R. The product was subjected to a
stability study according to ICH guidelines at long-term 25.degree.
C./60% RH and accelerated 40.degree. C./75% RH conditions. The
results in terms of buprenorphine content after various storage
times are indicated in FIG. 7. It can be seen that during the
period of the study, no measurable loss of drug content was
observed, neither at long-term nor at accelerated storage
conditions.
Example 22
Dose Control by Concentration and Injection Volume
[0175] Buprenorphine formulations of the invention were
administered subcutaneously to rats at buprenorphine levels of
between 1 and 50 mg/kg. The level was adjusted by means of varying
the administered volume at fixed drug concentration (Formulation
A1; CAM2038BUP-G) and by varying drug concentration for set
administration volume (Formulations A1, A12, A13 and A14). Both
methods provided excellent dose control as shown in FIG. 8 a and
b.
Example 23
Repeat Dose Administration
[0176] In order to achieve a stable plasma concentration, four
doses of Formulation A1 (see Example 16) (CAM2038-G) were
administered to dogs at one dose per week. The resulting plasma
concentrations were monitored. The results in FIG. 9 show that
once-weekly repeated doses of CAM2038-G resulted in steady-state
plasma levels of buprenorphine following the second dose.
Example 24
Controlling PK Profile by Composition
[0177] Formulations A3 and A18 (see Example 16) were administered
subcutaneously to rats in doses of 50 and 140 mg/kg, respectively
(N=6 per group). Blood samples were collected up to 21 days after
dosing. The plasma concentrations were determined as described in
Example 20 and the respective pharmacokinetic profiles are shown in
FIG. 10. As can be seen, whereas Formulation A3 provides a short
time to Cmax (about 24 hrs) and thereafter stable and slowly
declining plasma levels, Formulation A18 provides a longer time to
Cmax (ca 8 days) and thereafter slowly declining plasma levels. It
is also noteworthy that despite the high buprenorphine load of 35
wt % in Formulation A18 and the higher dose administered, the
plasma levels over the first days are lower compared to Formulation
A3.
Example 25
Human Clinical Trial
[0178] A phase I/II clinical trial was performed in opioid addicted
patients with the primary objectives: [0179] To evaluate the
systemic and local tolerability of 4 different doses of CAM2038
(Formulation A1 in Example 16, buprenorphine FluidCrystal.RTM.
Injection depot) when delivered via deep subcutaneous buttock
injection in patients with opioid dependence. [0180] To assess the
pharmacokinetic (PK) profile of buprenorphine in 4 different doses
of CAM2038 (buprenorphine FluidCrystal.RTM. Injection depot) when
delivered via deep subcutaneous buttock injection in patients with
opioid dependence Secondary objectives included:.sub.-- [0181] To
assess the PK profile of the buprenorphine major metabolite
norbuprenorphine in 4 different doses of CAM2038 G (buprenorphine
FluidCrystal.RTM. Injection depot) when delivered via deep
subcutaneous buttock injection in patients with opioid dependence.
[0182] To assess the pharmacodynamic (PD) profile of buprenorphine
in 4 different doses of CAM2038 (buprenorphine FluidCrystal.RTM.
Injection depot) when delivered via deep subcutaneous buttock
injection in patients with opioid dependence.
[0183] This was a single-centre, single-blind, single-dose,
dose-escalation, parallel-group, first time in man trial to
investigate the tolerability, PK, and PD of CAM2038 (Formulation A1
in Example 16, 50 mg buprenorphine/mL) in patients with opioid
dependence. Patients were assigned to 1 of the 4 single-dose
treatment groups, based on their prestudy sublingual maintenance
dose, to receive subcutaneous injections of CAM2038 as described
below and schematically illustrated in FIG. 11.
TABLE-US-00013 Group CAM2038-G dose (mL) Buprenorphine base (mg) A
0.15 7.5 B 0.30 15 C 0.45 22.5 D 0.60 30
[0184] Patients who were eligible for trial participation were
asked to stop all ongoing buprenorphine medication for 48 hours
(washout period). Blood samples for pharmacokinetic analysis were
taken before and during washout and during the treatment phase. If
a patient experienced withdrawal symptoms during the washout
period, codeine was allowed as rescue medication. For inclusion in
each treatment group (A, B, C, or D), the patients were required to
have a dose of maintenance buprenorphine at Screening and for two
weeks prior to screening that was within the pre-determined ranges
shown below (see also FIG. 11).
TABLE-US-00014 Maintenance buprenorphine daily Group dose ranges at
Screening (mg) A 6 to 12 B 8 to 14 C 10 to 16 D 14 to 20
[0185] The trial medication was administered in sequential,
dose-escalating cohorts. Escalation to the next dose level was
determined after evaluation of the safety results in the first 3
patients in each dose cohort. Safety and tolerability were
evaluated by the incidence of treatment-emergent adverse events
(TEAEs) including systemic tolerability and local tolerability at
the injection site and by changes in vital signs measurements from
the time of dosing through Day 35/Early Termination.
[0186] Pharmacodynamics were evaluated by scores on the Subjective
Opiate Withdrawal Scale (SOWS) and the Clinical Opiate Withdrawal
Scale (COWS). Pharmacodynamics were also evaluated by measuring
time from dosing with trial medication until dosing with rescue
medication.
Diagnosis and Main Criteria for Inclusion and Exclusion
[0187] Patients had to meet all of the following inclusion criteria
to be considered for admission into the trial: [0188] Male/female
patient .gtoreq.18 and .gtoreq.65 years of age. [0189] On stable
maintenance treatment with sublingual buprenorphine tablets for
before Screening. [0190] If female and of childbearing potential,
non-lactating and non-pregnant [0191] If female, not of
childbearing potential (defined as postmenopausal for at least 1
year or surgically sterile [bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy]) or practicing 1 medically
acceptable methods of birth control and agrees to continue with the
regimen throughout the trial: [0192] Able to provide written
informed consent to participate in the trial and able to understand
the procedures and trial requirements. [0193] Willing and able to
comply with specified trial requirements.
[0194] Patients presenting with any of the following exclusion
criteria were not included in the trial: [0195] Had received or
required any of the following medications within 5 half-lives (or,
if half-life was unknown, within 48 hours) before dosing with trial
medication: benzodiazepines, tranquillisers, anxiolytics,
anti-tussives, antidepressants, barbiturates, neuroleptics,
sedating antihistamines, clonidine, phenprocoumon, or
strong/moderate cytochrome P450 (CYP 3A4) inhibitors or inducers
(e.g., macrolide antibiotics and grapefruit juice). [0196] Had
received monoamine oxidase inhibitors (MAOIs) in the last 14 days.
[0197] Had a known contraindication or hypersensitivity to codeine
or other opioids. [0198] Had any clinically significant laboratory
test result that, in the opinion of the investigator, could
compromise the patient's welfare, ability to communicate with the
trial staff, or otherwise contraindicate trial participation.
Pharmacokinetics
[0199] Pharmacokinetic blood samples (10 mL) for the analyses of
buprenorphine and norbuprenorphine were collected from all patients
in all treatment groups at: [0200] approximately -36 hours and -12
hours before dosing and between [0201] 8 and 11 AM pre-dose as well
as at [0202] 15, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6,
8, 12, 24, and 48 hours postdose, and at the follow-up visits
(between 8 and 11 AM) on [0203] Days 3, 4, 5, 6, 7, 10, 14, 21, 28,
and 35/Early Termination.
[0204] The following PK parameters were calculated for
buprenorphine and norbuprenorphine: [0205] The maximum plasma
concentration observed (Cmax) [0206] The time to reach the maximum
plasma concentration observed (tmax) [0207] Apparent terminal
elimination rate constant calculated from the regression analysis
(slope) from the log-transformed measured concentrations on the
terminal phase of the time point concentration curve (.lamda.z)
[0208] Apparent terminal half-life calculated as ln(2)/.lamda.z
(t1/2) [0209] The area under the concentration time curve from zero
(0) to the last concentration above the lower limit of
quantification (LLQ; AUC0-last) [0210] The area under the
concentration time curve from zero (0) to infinity (.infin.), as
extrapolated using the formula AUC0-last+[Clast/.lamda.z)]. Clast
is the concentration of the last sample above LLQ
(AUC0-.infin.)
[0211] In addition, partial AUCs were calculated for the following
periods: [0212] from time of dosing to 1 hour (AUC0-1 h) [0213]
from time of dosing to 1 day (AUC0-1 d) [0214] from time of dosing
to 7 days (AUC0-7 d) [0215] from time of dosing to 14 days (AUC0-14
d) [0216] from time of dosing to 28 days (AUC0-28 d)
[0217] Pharmacokinetic samples from patients concurrently taking
buprenorphine other than trial medication were not included in the
PK analysis.
[0218] Plasma profiles for the four groups are shown in FIGS. 12a
and b
[0219] The Cmax and AUC graphs from this study are shown in FIGS. 5
and 6 respectively. The dose comparison with Subutex is shown in
FIG. 4.
The Following PK Results and Conclusions were Drawn from the Study:
[0220] CAM2038 provided dose proportional extended release of
buprenorphine in the dose range studied i.e., 7.5 mg to 30 mg
buprenorphine base with a duration at least 7 days. Both Cmax and
AUC0-7 d demonstrated both linearity and dose proportionality. They
both met the criteria for dose proportionality testing as well as
the 95% CI for the regression line intercept included the origin.
Their linear regression lines indicated linearity with a good fit
to the data (R-squared of 0.62 for Cmax and 0.76 for AUC0-7 d).
[0221] Maximum plasma concentrations were reached approximately 20
hours after dosing in each dose cohort, t.sub.1/2 was approximately
3.5 days, and .lamda.z was similar in each dose cohort
(approximately 0.01 per hour). [0222] Mean plasma buprenorphine
levels for the 7.5 mg, 15 mg, 22.5 mg, and 30 mg doses of CAM2038
(Groups B, C and D, respectively) on Day 7 were 0.3 ng/mL, 0.7
ng/mL, 0.9 ng/mL, 1.1 ng/mL, respectively. [0223] Norbuprenorphine
values were more variable than buprenorphine values as expected
from the additional variability of metabolism between patients.
Maximum plasma concentrations and exposure (Cmax, AUC0-.infin.,
AUC0-last, and AUC0-7 d) of norbuprenorphine increased with
increasing dose of CAM2038- and regression analysis did not reject
dose proportionality for them.
Pharmacodynamic Evaluations:
[0224] Opiate withdrawal scores were completed by subjects at
various stages: [0225] Patients completed the SOWS (subjective
opiate withdrawal scores) and the COWS (clinical opiate withdrawal
scores) at Screening, [0226] pre-dose, after dosing with trial
medication on: [0227] Day 0, once daily on [0228] Days 1 and 2, and
at the follow up visits on [0229] Days 3, 4, 5, 6, 7, 10, 14, 21,
28, and 35/Early Termination.
[0230] Subjective Opiate Withdrawal Scale--The SOWS is a 16-item
rating scale (0=not at all to 4=extremely) used by patients for
measuring the severity of their opiate withdrawal symptoms. Total
score 0 to 64
[0231] Clinical Opiate Withdrawal Scale--The COWS, used to assess a
patient's level of opiate withdrawal, is a written instrument,
administered by the investigator, and rates 11 common opiate
withdrawal signs or symptoms. Total score 0 to 44.
[0232] COWS and SOWS scores for the various groups are shown in
FIGS. 13 and 14.
[0233] Where necessary, patients were offered buprenorphine rescue
medication to alleviate withdrawal symptoms. The dates upon which
that rescue was requested and taken are shown in FIG. 15.
PD Conclusions:
[0234] Median SOWS total scores at Baseline ranged between 6.0 and
7.5 (on a scale from 0 to 64). After dosing with trial medication
on Day O, SOWS total scores fell to a median of 1.0 in all 4 dose
cohorts. Although Baseline values were low, median decreases from
Baseline in SOWS total scores were still observed until Day 7.
[0235] Median COWS total scores at Baseline were also well within
the category for no symptoms and ranged between 2.0 and 2.5. After
dosing with trial medication on Day 0, COWS total scores were
further improved to a median of 0. Median COWS total scores did not
rise above 1.5 up to and including Day 7. [0236] The most frequent
time from dosing with trial medication to first intake of
buprenorphine rescue med. was 10 days, for single dose without
accumulation (multiple dosing).
Overall Conclusions:
[0236] [0237] CAM2038 provided dose proportional extended release
of buprenorphine with a duration at least 7 days. [0238] Mean
plasma buprenorphine levels were above the minimum target of 0.5
ng/mL on Day 7 after the 15 mg, 22.5 mg, and 30 mg single doses of
CAM2038. [0239] Cmax and AUC0-7 d both demonstrated linearity and
dose proportionality meeting the criteria for dose proportionality
testing as the 95% CI for the regression line intercept included
the origin. [0240] Opiate withdrawal symptoms were generally well
controlled for up to 10 days after single dose injection. [0241]
High dose/effect ratio relative sublingual buprenorphine [0242] The
weekly doses of CAM2038 were compatible with the pretrial daily
maintenance doses of sublingual buprenorphine for each treatment
group. [0243] CAM2038 was safe and well tolerated. [0244] No safety
concerns were identified. [0245] The overall results indicate that
CAM2038 is a promising candidate for treatment of opiate
addiction.
[0246] In addition, spontaneous appraisals from patient were
received relating to quality-of-life and absence of withdrawal
symptoms, e.g. morning cravings. Since these were provided by
patients currently receiving daily maintenance doses of the
sublingual buprenorphine product they suggest a subjective
improvement in quality-of-life associated with the weekly depot
products of the invention.
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