U.S. patent application number 12/588528 was filed with the patent office on 2010-02-18 for buprenorphine formulations for intranasal delivery.
This patent application is currently assigned to VERNALIS (R&D) LIMITED. Invention is credited to Phillip John Brich, Jonathan David Castile, Ann Gail Hayes, Peter James Watts.
Application Number | 20100041624 12/588528 |
Document ID | / |
Family ID | 28457822 |
Filed Date | 2010-02-18 |
United States Patent
Application |
20100041624 |
Kind Code |
A1 |
Brich; Phillip John ; et
al. |
February 18, 2010 |
Buprenorphine formulations for intranasal delivery
Abstract
Aqueous formulations suitable for intranasal administration
comprise buprenorphine or a physiologically acceptable salt or
ester thereof and (a) a pectin having a degree of esterification of
less than 50%, (b) chitosan and a polyoxyethylene-poly-oxypropylene
copolymer (poloxamer) or (c) chitosan and
hydroxypropylmethylcellulose. Such formulations can induce rapid
and prolonged analgesia when delivered intranasally to a patient.
The buprenorphine or buprenorphine salt or ester may be delivered
to the bloodstream to produce within 30 minutes a therapeutic
plasma concentration of buprenorphine, C.sub.ther, of 0.2 ng/ml or
greater which is maintained for a duration T.sub.maint of at least
2 hours.
Inventors: |
Brich; Phillip John;
(Cambridge, GB) ; Hayes; Ann Gail; (Cambridge,
GB) ; Watts; Peter James; (Nottingham, GB) ;
Castile; Jonathan David; (Nottingham, GB) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
VERNALIS (R&D) LIMITED
Winnersh
GB
ARCHIMEDES DEVELOPMENT LIMITED
Nottingham
GB
|
Family ID: |
28457822 |
Appl. No.: |
12/588528 |
Filed: |
October 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10508336 |
Dec 1, 2004 |
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PCT/GB03/01183 |
Mar 19, 2002 |
|
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12588528 |
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Current U.S.
Class: |
514/55 ;
514/279 |
Current CPC
Class: |
A61K 31/405 20130101;
A61K 47/36 20130101; A61P 15/00 20180101; A61P 29/00 20180101; A61P
5/24 20180101; A61K 31/195 20130101; A61P 43/00 20180101; A61P
25/04 20180101; A61K 47/34 20130101; A61P 25/02 20180101; A61P
27/16 20180101; A61K 31/485 20130101; A61K 31/54 20130101; A61K
9/0043 20130101; A61K 31/407 20130101; A61K 31/5415 20130101; A61K
31/196 20130101; A61K 47/38 20130101 |
Class at
Publication: |
514/55 ;
514/279 |
International
Class: |
A61K 31/722 20060101
A61K031/722; A61K 31/4355 20060101 A61K031/4355 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 19, 2002 |
GB |
0206448.3 |
Oct 28, 2002 |
GB |
0225040.5 |
Oct 28, 2002 |
GB |
0225041.3 |
Oct 28, 2002 |
GB |
0225042.1 |
Claims
1. An aqueous solution suitable for intranasal administration,
which comprises from 0.1 to 10 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof and from 5 to 40
mg/ml of a pectin having a degree of esterification of less than
50%; which solution has a pH of from 3 to 4.2, is substantially
free from divalent metal ions and gels on the nasal mucosa.
2. A solution according to claim 1, wherein the buprenorphine or
buprenorphine salt or ester is present in an amount of from 0.5 to
8 mg/ml.
3. A solution according to claim 2, wherein the buprenorphine or
buprenorphine salt or ester is present in an amount of from 1 to 6
mg/ml calculated as buprenorphine.
4. A solution according to claim 1, which comprises buprenorphine
hydrochloride.
5. A solution according to claim 1, wherein the pectin is present
in an amount of from 10 to 30 mg/ml.
6. A solution according to claim 1, wherein the pectin has a degree
of esterification of from 10 to 35%.
7. A solution according to claim 1, wherein the pH is from 3.5 to
4.0.
8. A solution according to claim 1, wherein the pH has been
adjusted by means of hydrochloric acid.
9. A solution according to claim 1, which comprises a
preservative.
10. A solution according to claim 9, which comprises phenylethyl
alcohol and propyl hydroxybenzoate as preservatives.
11. A solution according to claim 1, which has an osmolality of
from 0.35 to 0.5 osmol/kg.
12. A solution according to claim 1, which contains dextrose as a
tonicity adjustment agent.
13. An aqueous solution suitable for intranasal administration,
which has a pH of from 3.5 to 4.0, which is substantially free from
divalent metal ions and which comprises: (a) from 1 to 6 mg/ml of
buprenorphine or a physiologically acceptable salt or ester
thereof, calculated as buprenorphine, (b) from 10 to 40 mg/ml of a
pectin which has a degree of esterification from 10 to 35%, and (c)
dextrose as a tonicity adjustment agent.
14. A process for the preparation of an aqueous solution as defined
in claim 1, which process comprises dissolving buprenorphine or a
physiologically acceptable salt or ester thereof in water; mixing
the resulting solution with a solution in water of a pectin having
a degree of esterification of less than 50% such that the mixed
solution comprises from 0.1 to 10 mg/ml of buprenorphine or said
salt or ester thereof and from 5 to 40 mg/ml of the pectin; and
adjusting the pH of the solution to a value from 3 to 4.2 if
desired.
15. A process according to claim 14, wherein the resulting solution
is introduced into a nasal delivery device.
16. An aqueous solution suitable for intranasal administration,
which comprises: (a) from 0.1 to 10 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof, (b) from 0.1 to
20 mg/ml of a chitosan, and (c) from 0.1 to 15 mg/ml of
hydroxypropylmethylcellulose; which solution has a pH of from 3 to
4.8.
17-18. (canceled)
19. An aqueous solution suitable for intranasal administration,
which comprises: (a) from 0.1 to 10 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof, (b) from 0.1 to
20 mg/ml of a chitosan, and (c) from 50 to 200 mg/ml of a
polyoxyethylene-polyoxypropylene copolymer of the general formula
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
wherein a is from 2 to 130 and b is from 15 to 67; which solution
has a pH of from 3 to 4.8.
20-37. (canceled)
38. A nasal delivery device loaded with a solution as claimed in
claim 1.
39. A device according to claim 38, which is a spray device.
40. (canceled)
41. A method of inducing analgesia in a patient in need thereof,
which method comprises intranasally administering an aqueous
solution as defined in claim 1.
42-47. (canceled)
48. A pharmaceutical composition suitable for use as an analgesic
which comprises buprenorphine or a physiologically acceptable salt
or ester thereof and a delivery agent whereby, on introduction into
the nasal cavity of a patient to be treated, the buprenorphine or
salt or ester thereof is delivered to the bloodstream to produce
within 30 minutes a therapeutic plasma concentration C.sub.ther of
0.2 ng/ml or greater which is maintained for a duration T.sub.maint
of at least 2 hours.
49. A method of inducing analgesia in a patient in need thereof,
which method comprises administering intranasally to said patient a
pharmaceutical composition which comprises buprenorphine or a
physiologically acceptable salt or ester thereof and a delivery
agent whereby, on introduction into the nasal cavity of said
patient to be treated, the buprenorphine or salt or ester thereof
is delivered to the bloodstream to produce within 30 minutes a
therapeutic plasma concentration C.sub.ther of 0.2 ng/ml or greater
which is maintained for a duration T.sub.maint of at least 2
hours.
50. A method according to claim 49, wherein a unit dosage of 0.1 to
0.6 mg of buprenorphine or buprenorphine salt or ester, calculated
as buprenorphine, is administered intranasally.
51. A method according to claim 49 wherein T.sub.maint is up to 6
hours.
52. A method according to claim 51 wherein C.sub.ther is 0.5 to 5
ng/ml.
53. A method according to claim 52 wherein T.sub.maint is up to 12
hours.
54. A method according to claim 49 wherein the time to reach the
peak plasma concentration T.sub.max is 10 to 30 minutes.
55. A method according to claim 54 where T.sub.max is 15 to 25
minutes.
56. A method according to claim 54 wherein the peak plasma
concentration C.sub.max is 1 to 5 ng/ml.
57. A method according to claim 49 wherein C.sub.ther is 0.4 ng/ml
or more and is attained within a time of 2 to 15 minutes.
Description
FIELD OF THE INVENTION
[0001] The invention relates to pharmaceutical formulations of
buprenorphine and physiologically acceptable salts and esters
thereof.
BACKGROUND OF THE INVENTION
[0002] The term opioid (or opiate) defines drugs with morphine-like
properties. Opioids can be sub-classified on the basis of their
receptor specificity. Mu-agonist opioids provide intense analgesia.
These opioids can be long-acting (e.g. methadone) or short-acting
(e.g. remifentanil).
[0003] Mixed agonist/antagonist opioids (e.g. butorphanol and
buprenorphine) are partial agonists (the former at mu and kappa
receptors and the latter at the mu receptor) and can produce good
quality analgesia. They produce less respiratory depression and
constipation than high efficacy mu agonists.
[0004] Buprenorphine (CAS RN 52485-79-7;
[5.alpha.,7.alpha.(S)-17-(Cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)--
4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorp-
hinan-7-methanol) has the formula:
##STR00001##
[0005] The hydrochloride is also active (CAS RN 53152-21-9).
[0006] Buprenorphine is a highly lipophilic derivative of thebaine.
It is a partial mu agonist and mediates analgesia at the mu opioid
receptor. Buprenorphine produces a similar maximum analgesic effect
to full mu agonists such as morphine in animal models of pain and,
although it may have a ceiling effect in certain pain types in man,
it has been shown to produce good quality analgesia of similar
efficacy to morphine in most clinical situations including severe
pain. An unusual property of buprenorphine observed in in vitro
studies is its very slow rate of dissociation from its
receptor.
[0007] As a class, opioids are associated with a number of
undesirable side-effects, including respiratory depression, nausea,
vomitting, dizziness, mental clouding, dysphoria, pruritus,
constipation, increased biliary tract pressure, urinary retention
and hypotension. The development of tolerance and the risk of
chemical dependence and abuse are further problems. Buprenorphine,
however, is unusual in exhibiting a low maximum effect for
respiratory depression and also a bell-shaped dose response curve
where the effect first increases with larger doses, reaches a
ceiling and then diminishes as the dosage is further increased,
which makes it a safer drug than morphine, where respiratory
depression will ultimately lead to death. Buprenorphine has also
been shown to have a lower incidence of other side-effects like
constipation in man, and it has a lower abuse potential than full
mu agonists.
[0008] Buprenorphine has previously been administered via the
intravenous, intramuscular and sublingual routes to human subjects.
There are limited reports of nasal administration. Eriksen et al,
J. Pharm. Pharmacol. 41, 803-805, 1989 report administration to
human volunteers of a nasal spray. The spray consisted of 2 mg/ml
of buprenorphine hydrochloride dissolved in 5% dextrose and the pH
of the solution was adjusted to pH 5.
[0009] WO 90/09870 describes a composition for administration to
mucosa comprising a pharmacologically active compound and a
polycationic substance such as DEAE-dextran or chitosan. WO
98/47535 discloses a single component liquid pharmaceutical
composition for administration to a mucosal surface. The
composition comprises a therapeutic agent, a pectin with a low
degree of esterification and an aqueous carrier that gels or can be
adapted to gel at the site of application. Neither WO 90/09780 nor
WO 98/47535 mentions buprenorphine.
SUMMARY OF THE INVENTION
[0010] Improved buprenorphine formulations for nasal administration
have now been devised. Rapid uptake of the buprenorphine across the
nasal mucosa into the plasma can be achieved, which results in fast
onset of analgesia. Further, the residence time of the
buprenorphine in the nasal cavity can be increased, which results
in prolonged analgesia. An improved profile of absorption of
buprenorphine into the systemic circulation can thus be achieved by
use of the formulation. Accordingly, the present invention
provides: [0011] (1) an aqueous solution suitable for intranasal
administration, which comprises from 0.1 to 10 mg/ml of
buprenorphine or a physiologically acceptable salt or ester thereof
and from 5 to 40 mg/ml of a pectin having a degree of
esterification of less than 50%; which solution has a pH of from 3
to 4.2, is substantially free from divalent metal ions and gels on
the nasal mucosa; [0012] (2) an aqueous solution suitable for
intranasal administration, which comprises: [0013] (a) from 0.1 to
10 mg/ml of buprenorphine or a physiologically acceptable salt or
ester thereof, [0014] (b) from 0.1 to 20 mg/ml of a chitosan, and
[0015] (c) from 0.1 to 15 mg/ml of hydroxypropylmethylcellulose
(HPMC); [0016] which solution has a pH of from 3 to 4.8; and [0017]
(3) an aqueous solution suitable for intranasal administration,
which comprises: [0018] (a) from 0.1 to 10 mg/ml of buprenorphine
or a physiologically acceptable salt or ester thereof, [0019] (b)
from 0.1 to 20 mg/ml of a chitosan, and [0020] (c) from 50 to 200
mg/ml of a polyoxyethylene-polyoxypropylene copolymer of the
general formula
HO(C.sub.2H.sub.4O).sub.1(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
wherein a is from 2 to 130 and b is from 15 to 67; [0021] which
solution has a pH of from 3 to 4.8.
[0022] A preferred solution of the invention has a pH of from 3.5
to 4.0, is substantially free from divalent metal ions and
comprises: [0023] (a) from i to 6 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof, calculated as
buprenorphine, [0024] (b) from 10 to 40 mg/ml of a pectin which has
a degree of esterification from 10 to 35%, and [0025] (c) dextrose
as a tonicity adjustment agent.
[0026] The invention also provides: [0027] a process for the
preparation of solution (1), which comprises dissolving
buprenorphine or a physiologically acceptable salt or ester thereof
in water; mixing the resulting solution with a solution in water of
a pectin having a degree of esterification of less than 50% such
that the mixed solution comprises from 0.1 to 10 mg/ml of
buprenorphine or said salt or ester thereof and from 5 to 40 mg/ml
of the pectin; and adjusting the pH of the solution to a value from
3 to 4.2 if desired; [0028] a process for the preparation of
solution (2), which comprises dissolving buprenorphine or a
physiologically acceptable salt or ester thereof, a chitosan and
HPMC in water to provide a solution comprising from 0.1 to 10 mg/ml
of buprenorphine or said salt or ester thereof, from 0.1 to 20
mg/ml of chitosan and from 0.1 to 15 mg/ml of HPMC; and adjusting
the pH of the solution to a value from 3 to 4.8 as desired; [0029]
a process for the preparation of solution (3), which comprises
dissolving buprenorphine or a physiologically acceptable salt or
ester thereof, a chitosan and a polyoxyethylene-polyoxypropylene
copolymer of the general formula
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
wherein a is from 2 to 130 and b is from 15 to 67, in water to
provide a solution comprising from 0.1 to 10 mg/ml of buprenorphine
or said salt or ester thereof, from 0.1 to 20 mg/ml of a chitosan
and from 50 to 200 mg/ml of the polyoxyethylene-polyoxypropylene
copolymer; and adjusting the pH of the solution to a value from 3
to 4.8 as desired; [0030] a nasal delivery device loaded with a
solution of the invention; [0031] use of a solution of the
invention for the manufacture of a nasal delivery device for use in
inducing analgesia; and [0032] a method of inducing analgesia in a
patient in need thereof, which method comprises intranasally
administering a solution of the invention to the patient.
[0033] The invention enables a therapeutic blood plasma
concentration of buprenorphine, i.e. a buprenorphine concentration
that produces pain relief or pain amelioration, to be attained
within 30 minutes and maintained for up to 24 hours. The term
C.sub.ther denotes a therapeutic blood plasma concentration. The
term T.sub.maint denotes the duration for which C.sub.ther is
maintained.
[0034] Additionally, therefore, the present invention provides use
of buprenorphine or a physiologically acceptable salt or ester
thereof and a delivery agent for the manufacture of a medicament
for administration intranasally for the treatment of pain whereby,
on introduction into the nasal cavity of a patient to be treated,
the buprenorphine or salt or ester thereof is delivered to the
bloodstream to produce within 30 minutes a therapeutic plasma
concentration C.sub.ther of 0.2 ng/ml or greater which is
maintained for a duration T.sub.maint of at least 2 hours. Also
provided are: [0035] use of a pharmaceutical composition which
comprises buprenorphine or a physiologically acceptable salt or
ester thereof and a delivery agent for the manufacture of a nasal
delivery device for use in inducing analgesia whereby, on
introduction into the nasal cavity of a patient to be treated, the
buprenorphine or salt or ester thereof is delivered to the
bloodstream to produce within 30 minutes a therapeutic plasma
concentration C.sub.ther of 0.2 ng/ml or greater which is
maintained for a duration T.sub.maint of at least 2 hours; [0036] a
pharmaceutical composition suitable for use as an analgesic which
comprises buprenorphine or a physiologically acceptable salt or
ester thereof and a delivery agent whereby, on introduction into
the nasal cavity of a patient to be treated, the buprenorphine or
salt or ester thereof is delivered to the bloodstream to produce
within 30 minutes a therapeutic plasma concentration C.sub.ther of
0.2 ng/ml or greater which is maintained for a duration T.sub.maint
of at least 2 hours;
[0037] a method of inducing analgesia in a patient in need thereof,
which method comprises administering intranasally to said patient a
pharmaceutical composition which comprises buprenorphine or a
physiologically acceptable salt or ester thereof and a delivery
agent whereby, on introduction into the nasal cavity of said
patient to be treated, the buprenorphine or salt or ester thereof
is delivered to the bloodstream to produce within 30 minutes a
therapeutic plasma concentration C.sub.ther of 0.2 ng/ml or greater
which is maintained for a duration T.sub.maint of at least 2
hours.
BRIEF DESCRIPTION OF DRAWINGS
[0038] FIGS. 1 to 3 show the pharmacokinetic profiles that were
obtained when buprenorphine formulations according to the invention
(Formulations A to C) were administered intranasally to healthy
volunteers at a dose of 800 .mu.g of buprenorphine hydrochloride,
calculated as buprenorphine. Formulation A: buprenorphine
hydrochloride-pectin solution. Formulation B: buprenorphine
hydrochloride-chitosan/hydroxypropylmethylcellulose (HPMC)
solution. Formulation C: buprenorphine
hydrochloride-chitosan/poloxamer 188 solution. Also shown for
comparison is the pharmacokinetic profile that was obtained when a
commercial solution of buprenorphine hydrochloride (Temgesic--trade
mark; Formulation D) was administered intravenously to healthy
volunteers in the same study at a dose of 400 .mu.g of
buprenorphine hydrochloride, calculated as buprenorphine.
[0039] FIG. 4 shows a pharmacokinetic profile for a 400 .mu.g dose
of Formulation A. This profile was calculated from the data for the
800 .mu.g dose of Formulation A. The pharmacokinetic profile for
the 400 .mu.g dose of Formulation D is also shown for
comparison.
DETAILED DESCRIPTION OF THE INVENTION
[0040] A first pharmaceutical solution of the invention consists
essentially of 0.1 to 10 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof, from 5 to 40
mg/ml of a pectin having a low degree of esterification, in
particular a degree of esterification of less than 50%, and water.
The buprenorphine salt may be an acid addition salt or a salt with
a base. Suitable acid addition salts include the hydrochloride,
sulphate, methane sulphonate, stearate, tartrate and lactate salts.
The hydrochloride salt is preferred.
[0041] The concentration of buprenorphine or buprenorphine salt or
ester is from 0.1 to 10 mg/ml, for example from 0.5 to 8 mg/ml.
Preferred concentrations are 1 to 6 mg/ml, for example 1 to 4 mg/ml
calculated as buprenorphine. Suitable solutions can contain
buprenorphine or a buprenorphine salt or ester in an amount of 1
mg/ml or 4 mg/ml, calculated as buprenorphine.
[0042] The solution is typically delivered as a nasal spray. A 100
.mu.l spray of a solution containing 1 to 4 mg/ml of buprenorphine
or a buprenorphine salt or ester, calculated as buprenorphine thus
results in a clinical dose of 100 to 400 .mu.g of the buprenorphine
or buprenorphine salt or ester, calculated as buprenorphine. Two
such sprays may be given per nostril per administration time to
deliver a dose of up to 4.times.400 .mu.g, i.e. up to 1600 .mu.g,
of buprenorphine or the buprenorphine salt or ester, calculated as
buprenorphine.
[0043] The pectin is a gelling agent. The solution of the invention
gals on the mucosal surfaces of the nasal cavity after delivery
without the need for an extraneous source of divalent metal ions.
The buprenorphine or buprenorphine salt or ester that is formulated
with the pectin is thus retained for longer on the surfaces of the
nasal epithelium. The resulting sustained release of the
buprenorphine or buprenorphine salt or ester into the bloodstream
enables prolonged analgesia to be achieved. Improved delivery of
buprenorphine or a buprenorphine salt or ester can consequently be
obtained. Rapid uptake of the buprenorphine or buprenorphine salt
or ester also results, which leads to fast onset of analgesia.
[0044] The solutions of the invention contain a pectin having a
degree of esterification of less than 50%. A pectin is a
polysaccharide substance present in the cell walls of all plant
tissues. Commercially pectins are generally obtained from the
dilute acid extract of the inner portion of the rind of citrus
fruits or from apple pomace. A pectin consists of partially
methoxylated polygalacturonic acids. The proportion of galacturonic
acid moieties in the methyl ester form represents the degree of
esterification (DE). The term DE is well understood by those
skilled in the art and may be represented as the percentage of the
total number of carboxyl groups that are esterified, i.e. if four
out of five acid groups is esterified this represents a degree of
esterification of 80%, or as the methoxyl content of the pectin. DE
as used herein refers to the total percentage of carboxyl groups
that are esterified. Pectins can be categorised into those having a
low degree of esterification (low methoxylation) or a high degree
of esterification (high methoxylation). A "low DE" or "LM" pectin
has a degree of esterification below 50% whereas a "high DE" or
"HM" pectin has a degree of esterification of 50% or above. The
gelling properties of aqueous pectin solutions can be controlled by
the concentration of pectin, the type of pectin, especially the
degree of esterification of the galacturonic acid units, and the
presence of added salts.
[0045] Low DE pectins are used in the present invention. The
primary mechanism by which such pectins gel in aqueous solution is
through exposure to metal ions, such as those found in the nasal
mucosal fluid as described in WO 98/47535. The degree of
esterification of the pectin used in the invention is preferably
less than 35%. The degree of esterification may thus be from 10 to
35%, for example from 15 to 25%. Low DE pectins may be purchased
commercially. An example of a low DE pectin is SLENDID (trade mark)
100, supplied by CP Kelco (Lille Skenved) which has a degree of
esterification of around 15 to 25%.
[0046] A pectin-containing solution of the invention must not gel
on storage. It should not gel prior to application to the nasal
cavity. It must therefore be substantially free of agents which
would cause the solution to gel. In particular, a solution of the
invention must be substantially free of divalent metal ions and
especially calcium ions. The content of divalent metal ions in the
solution must therefore be minimised. A solution of the invention
may therefore contain a negligible concentration of divalent metal
ions or there may no detectable divalent metal ions.
[0047] A pectin is present in the solutions of the invention at a
concentration of from 5 to 40 mg/ml, for example from 5 to 30
mg/ml. More preferably, the pectin concentration is from 10 to 30
mg/ml or from 10 to 25 mg/ml. The pectin and the pectin
concentration are selected such that the solution gels on delivery
to the nasal mucosa. The solution gels on the nasal mucosa in the
absence of an extraneous source of divalent metal ions, e.g.
Ca.sup.2+ ions.
[0048] A pectin-containing solution of the invention has a pH of
from 3 to 4.2. Any pH within this range may be employed provided
the buprenorphine or buprenorphine salt or esteremains dissolved in
the solution. The pH may be from 3.2 to 4.0, for example from 3.5
to 4.0. A particularly suitable pH is from 3.6 to 3.8. The pH may
be adjusted to an appropriate value by addition of a
physiologically acceptable acid and/or physiologically acceptable
buffer. The pH may thus be adjusted solely by means of a
physiologically acceptable mineral acid or solely by means of a
physiologically acceptable organic acid. The use of hydrochloric
acid is preferred.
[0049] Any suitable preservative may be present in the solution, in
particular a preservative that prevents microbial spoilage of the
solution. The preservative may be any pharmaceutically acceptable
preservative, for example phenylethyl alcohol or propyl
hydroxybenzoate (propylparaben) or one of its salts. The
phenylethyl alcohol and the propylparaben or propylparaben salt are
preferably used in combination. The preservative must be compatible
with the other components of the solution and, in particular, must
not cause gelling of the solution.
[0050] Solutions may include a tonicity adjustment agent such as a
sugar, for example dextrose, or a polyhydric alcohol for example
mannitol. A solution may be hypertonic, substantially isotonic or
hypotonic. A substantially isotonic solution can have an osmolality
of from 0.28 to 0.32 osmol/kg. An exactly isotonic solution is 0.29
osmol/kg. The osmolality of the solution may be from 0.1 to 0.8
osmol/kg such as from 0.2 to 0.6 osmol/kg or preferably from 0.3 to
0.5 osmo/kg. A sufficient amount of a tonicity adjustment agent
such as dextrose or mannitol may therefore be present to achieve
such osmolalities. Preferably a solution contains 50 mg/ml dextrose
or mannitol.
[0051] A pectin-containing solution of the invention is prepared by
dissolving buprenorphine or a physiologically acceptable salt or
ester thereof in water, typically Water for Injections, and the
resulting solution is mixed with a solution of a suitable pectin in
water, again typically Water for Injections. The amount of the
buprenorphine or salt or ester thereof and of the pectin are
selected so that from 0.1 to 10 mg/ml of buprenorphine or the
buprenorphine salt or ester and from 5 to 40 mg/ml of pectin are
dissolved in the mixed solution. A preservative or combination of
preservatives may be dissolved in the solution. The pH of the mixed
solution can be adjusted to a value within the range from 3 to 4.2
as required. Preferably, the pH is adjusted with hydrochloric acid
if pH adjustment is required.
[0052] Other components can be provided in solution at any
convenient stage. For example, dextrose or mannitol may be
dissolved in the water in which the buprenorphine or buprenorphine
salt or ester is being dissolved. A sterile solution can be
obtained either by using sterile starting materials and operating
under sterile conditions and/or by using standard sterilising
techniques such as passing the final solution through a sterilising
filter. A pyrogen-free solution can thus be provided. The solution
can then be introduced into a nasal delivery device, typically a
sterile such device. If required, prior to sealing the device, the
solution may be overlaid with an inert gas such as nitrogen to
protect it from oxidation.
[0053] A second solution of the invention consists essentially of
0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable
salt or ester thereof, from 0.1 to 20 mg/ml of a chitosan, from 0.1
to 15 mg/ml of HPMC, and water. A third solution of the invention
consists essentially of 0.1 to 10 mg/ml of buprenorphine or a
physiologically acceptable salt or ester thereof, from 0.1 to 20
mg/ml of chitosan, from 50 to 200 mg/ml of a
polyoxyethylene-polyoxypropylene copolymer of the general formula
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
wherein a is from 2 to 130 and b is from 15 to 67, and water.
[0054] In each case, the buprenorphine salt may be an acid addition
salt or a salt with a base. Suitable acid addition salts are
mentioned above. They include the hydrochloride, sulphate, methane
sulphonate, stearate, tartrate and lactate salts. The hydrochloride
salt is preferred.
[0055] The concentration of buprenorphine or buprenorphine salt or
ester in either solution is from 0.1 to 10 mg/ml, for example from
0.5 to 8 mg/ml. Preferred concentrations are 1 to 6 mg/ml, for
example 1 to 4 mg/ml. Suitable solutions can contain the
buprenorphine or buprenorphine salt or ester at a concentration of
1 mg/ml or 4 mg/ml, calculated as buprenorphine. Each solution is
typically delivered as a nasal spray. A 100 .mu.l spray of a
solution containing 1 to 4 mg/ml of buprenorphine or a
buprenorphine salt or ester, calculated as buprenorphine, thus
results in a clinical dose of 100 to 400 .mu.g of the buprenorphine
or buprenorphine salt or ester, calculated as buprenorphine. Two
such sprays may be given per nostril per administration time to
deliver a dose of up to 4.times.400 .mu.g, i.e. up to 1600 .mu.g,
of buprenorphine or the buprenorphine salt or ester, calculated as
buprenorphine.
[0056] A chitosan is present in both solutions. Chitosans are
cationic polymers that have mucoadhesive properties. The
mucoadhesion is thought to result from an interaction between the
positively charged chitosan molecule and the negatively charged
sialic acid groups on mucin (Soane et al, Int. J. Pharm 178, 55-65,
1999).
[0057] By the term "chitosan" we include all derivatives of chitin,
or poly-N-acetyl-D-glucosamine, including all polyglucosamines and
oligomers of glucosamine materials of different molecular weights,
in which the greater proportion of the N-acetyl groups have been
removed through hydrolysis (deacetylation). Preferably, the
chitosan is produced from chitin by deacetylation to a degree of
greater than 40%, preferably between 50 and 98%, more preferably
between 70% and 90%.
[0058] The chitosan typically has a molecular weight of 4,000 Da or
more, preferably from 10,000 to 1,000,000 Da, more preferably from
15,000 to 750,000 Da and most preferably from 50,000 to 500,000
Da.
[0059] The chitosan may thus be a deacetylated chitin. It may be a
physiologically acceptable salt. Suitable physiologically
acceptable salts include salts with a pharmaceutically acceptable
mineral or organic acid such as the nitrate, phosphate, lactate,
citrate, hydrochloride and acetate salts. Preferred salts are
chitosan glutmate and chitosan hydrochloride.
[0060] The chitosan may be a derivative of a deacetylated chitin.
Suitable derivatives include, but are not limited to, ester, ether
or other derivatives formed by bonding of acyl and/or alkyl groups
with the hydroxy groups, but not the amino groups, of a
deacetylated chitin. Examples are O--(C.sub.1-C.sub.6 alkyl) ethers
of deacetylated chitin and O-acyl esters of deacetylated chitin.
Derivatives also include modified forms of a deacetylated chitin
for example a deacetylated chitin conjugated to polyethylene
glycol.
[0061] Low and medium viscosity chitosans suitable for use in the
present invention may be obtained from various sources, including
FMC Biopolymer, Drammen, Norway; Seigagaku America Inc., MD, USA;
Meron (India) Pvt, Ltd., India; Vanson Ltd, VA, USA; and AMS
Biotechnology Ltd., UK. Suitable derivatives include those that are
disclosed in Roberts, Chitin Chemistry, MacMillan Press Ltd.,
London (1992). Particularly preferred chitosan compounds that may
be mentioned include "Protosan" (trade mark) available from FMC
Biopolymer, Drammen, Norway. The chitosan is preferably
water-soluble.
[0062] An aqueous solution of chitosan may be prepared by
dissolving chitosan base or a derivative of chitosan base in a
pharmaceutically acceptable mineral or organic acid such as
hydrochloric, lactic, citric or glutamic acid or by dissolving a
chitosan salt in water.
[0063] The chitosan is present in solution at a concentration of
from 0.1 to 20 mg/ml, for example from 0.5 to 20 mg/ml. Preferably
the solution contains from 1 to 15 mg/ml, more preferably from 2 to
10 mg/ml, of chitosan. A chitosan concentration of 5 mg/ml is
particularly suitable.
[0064] Any suitable hydroxypropylmethylcellulose (HPMC) may be
employed. Several grades of HPMC are available. For example, Dow
Chemical Company produces a range of HPMC polymers under the trade
mark Methocel. The grade and concentration of HPMC is chosen such
that the solution of the invention preferably has a viscosity, at
25.degree. C. as measured by a cone and plate viscometer (e.g.
Brookfield), in the range from 1 to 200 cps, more preferably from 3
to 150 cps and most preferably from 5 to 100 cps.
[0065] Producing a solution having a particular viscosity is within
the capability of one skilled in the at and can be achieved, for
example, by using a high concentration of a low viscosity HPMC or a
low concentration of a high viscosity HPMC. The HPMC used in the
solution of the invention is preferably one having an apparent
viscosity (measured as a 2% solution in water at 20.degree. C.) in
the range from 3000 to 6000 cps. The concentration of the HPMC
having a viscosity of from 3000 to 6000 cps is in the range from
0.1 to 15 mg/ml, preferably from 0.5 to 10 mg/ml and preferably
from 1 to 5 mg/ml.
[0066] The polyoxyethylene-polyoxypropylene copolymer typically has
a molecular weight of from 2,500 to 18,000 for example from 7,000
to 15,000. The copolymer is a block copolymer of the general
formula
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H6O).sub.b(C.sub.2H.sub.4O).sub.aH
wherein a is from 2 to 130 and b is from 15 to 67. The value for a
may be from 40 to 100 such as from 60 to 90 or from 70 to 95. The
value for b may be from 20 to 40 such as from 25 to 35.
[0067] Such copolymers are known as poloxamers. Several different
types of poloxamer are available commercially, from suppliers such
as BASF, and vary with respect to molecular weight and the
proportions of ethylene oxide "a" units and propylene oxide "b"
units. A commercially available poloxamer suitable for use in the
present invention is poloxamer 188 which structurally contains 80
"a" units and 27 "b" units and has a molecular weight of 7680-9510
(Handbook of Pharmaceutical Excipients, editor A. H. Kippe, third
edition, Pharmaceutical Press, London, UK, 2000). Preferably the
poloxamer is poloxamer 188.
[0068] When the solutions contain a poloxamer, the poloxamer is
present at a concentration in the range of from 50 to 200 mg/ml,
preferably from 65 to 160 mg/ml and more preferably from 80 to 120
mg/ml. A preferred concentration is 100 mg/ml.
[0069] Any suitable preservative may be present in the solution, in
particular a preservative that prevents microbial spoilage of the
solution. The preservative must be compatible with the other
components of the solution. The preservative may be any
pharmaceutically acceptable preservative, for example a quaternary
ammonium compound such as benzalkonium chloride.
[0070] The solution has a pH of from 3 to 4.8. Any pH within this
range may be employed provided the buprenorphine or buprenorphine
salt or ester remains dissolved in the solution. The pH may be from
3.2 to 4.2, for example from 3.2 to 4.0 or 3,5 to 4.0. A
particularly suitable pH is from 3.6 to 3.8. The pH may be adjusted
to an appropriate value by addition of a physiologically acceptable
acid and/or physiologically acceptable buffer. The pH may thus be
adjusted solely by means of a physiologically acceptable mineral
acid or solely by means of a physiologically acceptable organic
acid. The use of hydrochloric acid is preferred.
[0071] A tonicity adjustment agent may be included in the solution.
The tonicity adjustment agent may be a sugar, for example dextrose,
or a polyhdryic alcohol, for example mannitol. A solution may be
hypertonic, substantially isotonic or hypotonic. A sufficient
amount of a tonicity adjustment agent such as dextrose or mannitol
may therefore be present to achieve a desired osmolality.
Preferably a solution contains 50 mg/ml dextrose or mannitol.
[0072] The osmolality of a solution containing chitosan and HPMC or
a poloxamer may be from 0.1 to 0.8 osmol/kg such as from 0.2 to 0.6
osmol/kg or preferably from 0.32 to 0.4 osmol/kg.
[0073] The solutions may also contain other ingredients such as an
antioxidant, chelating agent or other agent generally used in
pharmaceutical liquid preparations. The solution can be a sterile
solution.
[0074] The solution containing chitosan and HPMC is prepared by
dissolving buprenorphine or a physiologically acceptable salt or
ester thereof, a chitosan and HPMC in water, typically Water for
Injections. The amount of the buprenorphine or salt or ester
thereof is selected so that from 0.1 to 10 mg/ml of buprenorphine
or the buprenorphine salt or ester is dissolved in the solution.
The required concentrations of the chitosan and of HPMC are
provided too. A preservative can be dissolved in the solution. The
pH of the solution can be adjusted to a value within the range from
3 to 4.8 as required. Preferably the pH is adjusted by means of
hydrochloric acid.
[0075] A solution containing chitosan and a
polyoxyethylene-polyoxypropylene copolymer is prepared by
dissolving buprenorphine or a physiologically acceptable salt or
ester thereof, a chitosan and the polyoxyethylene-polyoxypropylene
copolymer in water, typically Water for Injections. The amount of
the buprenorphine or salt or ester thereof is selected so that from
0.1 to 10 mg/ml of buprenorphine or the buprenorphine-salt or ester
is dissolved in the solution. The required concentrations of the
chitosan and of the polyoxyethylene-polyoxypropylene copolymer are
provided too. A preservative can be dissolved in the solution. The
pH of the solution can be adjusted to a value within the range from
3 to 4.8 as required. Preferably, the pH is adjusted by means of
hydrochloric acid.
[0076] Other components can be provided in the solutions at any
convenient stage. For example, dextrose or mannitol may be
dissolved in the water in which the buprenorphine or buprenorphine
salt or ester is being dissolved. A sterile solution can be
obtained either by using sterile starting materials and operating
under sterile conditions and/or by using standard sterilising
techniques such as passing the final solution through a sterilising
filter. A pyrogen-free solution can thus be provided. The solution
can then be introduced into a nasal delivery device, typically a
sterile such device. If required, prior to sealing the device, the
solution may be added with an inert gas such as nitrogen to protect
it from oxidation.
[0077] Each of the three solutions of the invention is administered
intranasally to a patient in order to induce analgesia. Rapid onset
of analgesia and prolonged analgesia can thus be obtained. An
effective amount of buprenorphine or a salt or ester thereof is
delivered to a patient. A unit dose can be delivered to one
nostril. Alternatively, half of a dose or two doses can be
delivered to each nostril each administration time. The dose will
depend upon a number of factors including the age and sex of the
patient, the nature and extent of the pain to be treated and the
period of treatment. A suitable dose of buprenorphine or a
buprenorphine salt or ester is from 0.02 to 1.2 mg, such as from 50
to 600 .mu.g or from 100 to 400 .mu.g, calculated as
buprenorphine.
[0078] Multiple doses of a solution according to the invention may
be employed. For example, the rapid onset analgesia produced by the
solution of the invention may permit self-titration of analgesic by
the patient. The analgesic effect of an initial dose can be quickly
and reliably gauged by the patient and, if insufficient, can be
immediately supplemented by further dose(s) (often alternating
between each nostril) until the required level of analgesia is
attained. Multiple dosing may also be used in order to extend pain
relief. For example, from 2 to 4 doses per day may be
indicated.
[0079] The solutions of the invention may be used to treat an
existing pain condition or to prevent a pain condition from
occurring. An existing pain may be alleviated. Solutions of the
invention can be used to treat or manage chronic or acute pain, for
example the management of post-operative pain (e.g. abdominal
surgery, back surgery, caesarean section, hip replacement or knee
replacement).
[0080] Other medical uses include: pre-operative intranasal
administration of the solution of the invention; therapy or
prophylaxis adjunctive to anesthesia; post-operative analgesia; the
management of trauma pain; the management of cancer pain; the
management of endometriosis; the management of inflammatory pain;
the management of arthritis pain (including pain associated with
rheumatoid arthritis and osteoarthritis); the management of back
pain; the management of myocardial pain (for example ischaemic or
infarction pain); the management of dental pain; the management of
neuropathic pain (e.g. diabetic neuropathy, post-herpetic neuralgia
or trigeminal neuralgia); the management of colic (e.g. renal colic
or gallstones), headache, migraine, fibromyalgia or dysmenorrhoea;
the management of breakthrough pain associated with malignant and
non-malignant disease; and the management of acute procedural pain
(e.g. bone marrow aspiration or lumber puncture).
[0081] The solutions according to the invention may be administered
to the nasal cavity in forms including drops or sprays. The
preferred method of administration is using a spray device. Spray
devices can be single (unit) dose or multiple dose systems, for
example comprising a bottle, pump and actuator. Suitable spray
devices are available from various commercial sources including
Pfeiffer, Valois, Bespak and Becton-Dickinson.
[0082] As already mentioned, rapid onset of analgesia and prolonged
analgesia can be achieved by means of the invention. The analgesic
delivery profile that can be attained may avoid the relatively high
C.sub.max values associated with intravenous administration and so
lead to an improved therapeutic index. The peak plasma
concentration of an analgesic that is attained after administration
is defined as C.sub.max. The invention can permit reduction or
elimination of some or all of the side effects associated with the
analgesic.
[0083] C.sub.max is typically from 1 to 5 ng/ml, for example from 1
to 4 ng/ml or from 1.5 to 3 ng/ml. C.sub.max may be from 1 to 2
ng/ml, especially for lower doses of buprenorphine. The time at
which C.sub.max is reached (T.sub.max) is typically 10 to 40
minutes after administration, for example 10 to 30 minutes or 15 to
25 minutes such as 15 to 20 minutes.
[0084] In preferred embodiments, the delivery agent is adapted to
deliver the analgesic component such that C.sub.max=C.sub.opt. The
term C.sub.opt is used in relation to analgesic drugs which exhibit
a dose-response curve to analgesia which is displaced to the left
with respect to the dose-response curve for side-effects. The term
defines a therapeutic plasma concentration or range thereof which
produces acceptable pain relief or pain amelioration but which does
not produce side-effects or produces side effects which are less
than those associated with higher plasma concentrations.
[0085] Preferably, the solutions of the invention enable the
buprenorphine or salt or ester thereof to be delivered such that a
C.sub.ther of 0.2 ng/ml or more, for example 0.4 ng/ml or more, is
attained within 30 minutes (for example within 0.5 to 20 minutes,
such as 2 to 15 minutes or 5 to 10 minutes) after introduction into
the nasal cavity. The term C.sub.ther defines a therapeutic plasma
concentration or range thereof. Thus, the term is used herein to
define a blood plasma concentration (or range of plasma
concentrations) of the buprenorphine or salt or ester thereof that
produces pain relief or pain amelioration. C.sub.ther may be from
0.4 to 5 ng/ml, for example 0.4 to 1 ng/ml or 0.5 to 4 ng/ml or 0.8
to 2 ng/ml.
[0086] The T.sub.maint is typically at least 2 hours. The term
T.sub.maint defines the duration of maintenance of C.sub.ther after
administration of the analgesic. For example, the T.sub.maint can
be from up to 24 hours, up to 12 hours or up to 6 hours such as
from 2 to 4 hours or 2 to 3 hours. By means of the invention,
therefore, a C.sub.ther of at 0.4 ng/ml may be attained within 2 to
15 minutes and maintained for a time period T.sub.maint of from 2
to 4 hours.
[0087] A further aspect of the invention relates to the
pharmacokinetic profile that may be attained. By use of the
solutions of the invention, not only can fast onset of analgesia be
achieved but also prolonged analgesia can result. More generally,
therefore, buprenorphine or a buprenorphine salt or ester can be
combined with a delivery agent in an intranasal formulation such
that, on introduction into the nasal cavity of a patient to be
treated, the buprenorphine or salt or ester thereof is delivered to
the bloodstream to produce within 30 minutes a therapeutic plasma
concentration C.sub.ther of 0.2 ng/ml or greater which is
maintained for a duration T.sub.maint of at least 2 hours.
[0088] The buprenorphine is therefore provided in a formulation
suitable for nasal administration in combination with a delivery
agent. The formulation is typically a liquid formulation,
especially as an aqueous solution. Alternatively, the formulation
may be in the form of a powder or microspheres. The buprenorphine
salt may be an acid addition salt or a salt with a base. Suitable
acid addition salts include the hydrochloride, sulphate, methane
sulphonate, stearate, tartrate and lactate salts. The hydrochloride
salt is preferred:
[0089] When the formulation is a liquid formulation, the
concentration of buprenorphine or buprenorphine salt or ester is
from 0.1 to 10 mg/ml, for example from 0.5 to 8 mg/ml. Preferred
concentrations are 1 to 6 mg/ml, for example 1 to 4 mg/ml
calculated as buprenorphine. Suitable formulations can contain
buprenorphine or a buprenorphine salt or ester in an amount of 1
mg/ml or 4 mg/ml, calculated as buprenorphine.
[0090] The delivery agent is selected so that rapid onset and
prolonged analgesia is obtained. The delivery agent acts to deliver
the buprenorphine or buprenorphine salt or ester to the
bloodstream. Thus, the delivery agent acts as an analgesic
absorption modifier and any of a wide variety of delivery agents
may be used providing that this functional requirement is met.
[0091] The delivery agent may comprise an absorption promoting
agent. Such agents promote uptake of the analgesic component into
the bloodstream. They may act via a variety of different
mechanisms. Particularly preferred are mucosal adhesives. Such
adhesives maintain an intimate association between the bulk
analgesic composition and the nasal mucosa, so enhancing absorption
and extending the T.sub.maint of the analgesic component. They can
also be used to lower the analgesic C.sub.max, which may be
important in applications where the minimization or elimination of
side-effects is desired.
[0092] Suitable absorption promoting agents include cationic
polymers (particularly chitosans), surface active agents, fatty
acids, chelating agents, mucolytic agents, cyclodextrins,
diethylaminoethyl-dextran (DEAE-dextran; a polycationic derivative
of dextran) or combinations thereof. Particularly preferred are
pectins as described above having a degree of esterification of
less than 50%, especially from 10 to 35%, and chitosans also as
described above.
[0093] Other cationic polymers besides chitosans suitable for use
as absorption promoting agents include polycationic carbohydrates.
The polycationic substances preferably have a molecular weight of
at least 10,000. They may be in liquid formulations at
concentrations of 0.01 to 50% w/v, preferably 0.1 to 50% w/v and
more preferably 0.2 to 30% w/v.
[0094] Examples of suitable polycationic polymers are
polyaminoacids (e.g. polylysine), polyquatemary compounds,
protamine, polyamine, DEAE-imine, polyvinylpyridine,
polythiodiethyl-aminomethylethylene, polyhistidine,
DEAE-methacrylate, DEAE-acrylamide, poly-p-aminostyrene,
polyoxethane, co-polymethacrylates (e.g. copolymers of HPMA,
N-(2-hydroxypropyl)-methacrylamide), GAFQUAT (see for example U.S.
Pat. No. 3,910,862) and polyamidoamines.
[0095] Suitable surface active agents for use according to the
present invention are bile salts (for example sodium deoxycholate
and cholylsarcosine,.a synthetic N-acyl conjugate of cholic acid
with sarcosine [N-methylglycine]). Also suitable for use in the
invention are bile salt derivatives (for example sodium tauro
dihydrofusidate). Any of a wide range of non-ionic surfactants
(e.g. polyoxyethylene-9 lauryl ether), phospholipids and
lysophosphatidyl compounds (e.g. lysolecithin,
lysophosphatidyl-ethanolamine, lysophosphatidylcholine,
lysophbsphatidylglycerol, lysophosphatidylserine and
lysophosphatidic acid) may also be used. Water-soluble
phospholipids may also be employed (e.g. short chain
phosphatidylglycerol and phosphatidylcholines). The concentration
of surface active agents used according to the invention varies
according to the physico-chemical properties of the surface active
agent selected, but typical concentrations are in the range 0.02 to
10% w/v.
[0096] Particularly preferred surface active agents for use as
absorption promoting materials are phospholipids and
lysophosphatides (hydrolysis products of phospholipids), both of
which form micellar structures.
[0097] When microspheres are used as the delivery agent, they are
preferably prepared from a biocompatible material that will gel in
contact with the mucosal surface. Substantially uniform solid
microspheres are preferred. Starch microspheres (crosslinked if
necessary) are preferred.
[0098] Microspheres may also be prepared from starch derivatives,
modified starches (such as amylodextrin), gelatin, albumin,
collagen, dextran and dextran derivatives, polyvinyl alcohol,
polylactide-co-glycolide, hyaluronic acid and derivatives thereof
(such as benzyl and ethyl esters), gellan gum and derivatives
thereof (such as benzyl and ethyl esters) and pectin and
derivatives thereof (such as benzyl and ethyl esters). The term
"derivative" covers inter alia esters and ethers of the parent
compound, which can be functionalised (for example to incorporate
ionic groups).
[0099] Any of a wide variety of commercially available starch
derivatives may be used, including hydroxyethyl starch,
hydroxypropyl starch, carboxymethyl starch, cationic starch,
acetylated starch, phosphorylated starch, succinate derivatives of
starch and grafted starches.
[0100] Suitable dextran derivatives include,
diethylaminoethyl-dextran (DEAE-dextran), dextran sulphate, dextran
methyl-benzylamide sulphonates, dextran methyl-benzylamide
carboxylates, carboxymethyl dextran, diphosphonate dextran, dextran
hydrazide, palmitoyldextran and dextran phosphate.
[0101] The preparation of microspheres for use according to the
invention may be carried out by known processes, including emulsion
and phase separation methods (see for example Davis et al., (Eds),
"Microspheres and Drug Therapy", Elsevier Biomedical Press, 1984,
which parts relating to microsphere preparation are incorporated
herein by reference). For example, albumin microspheres may be made
using the water-in-oil emulsification method where a dispersion of
albumin in oil is produced by homogenization or stirring, with the
addition if necessary of small amounts of an appropriate surface
active agent.
[0102] The size of the microspheres is largely determined by the
speed of stirring or the homogenization conditions. Agitation can
be provided by a simple laboratory stirrer or by more sophisticated
devices (such as microfluidizers or homogenisers). Emulsification
techniques may also be used to produce starch microspheres (as
described in GB 1518121 and EP 223303) and for the preparation of
gelatin microspheres.
[0103] Proteinaceous microspheres may be prepared by coacervation
methods. Such methods include simple or complex coacervation as
well as phase separation techniques (using solvents or electrolyte
solutions). Such methods are well known to those skilled in the art
and details may be found in standard textbooks (for example
Florence and Attwood, Physicochemical Principles of Pharmacy 2nd
Ed., MacMillan Press, 1988, Chapter 8).
[0104] The microspheres may advantageously have controlled-release
properties, which may be conferred by modifications of the
microspheres (for example by controlling the degree of
cross-linking or by the incorporation of excipients that alter the
diffusional properties of the analgesic component). Alternatively,
controlled release properties may be incorporated by exploiting
ion-exchange chemistry (for example DEAE-dextran and chitosan are
positively charged and can be used for an ion-exchange interaction
with metabolites that are negatively charged).
[0105] The maximum amount of analgesic component that can be
carried by the microspheres is termed the loading capacity. It is
determined by the physico-chemical properties of the analgesic
component and in particular its size and affinity for the matrix of
the microspheres. High loading capacities can be achieved when the
analgesic is incorporated into the microspheres during microsphere
manufacture.
[0106] Microcapsules (which may be bioadhesive and which may also
exhibit controlled release properties) may also be employed as an
absorption promoting agent in the compositions of the invention.
These microcapsules can be produced by a variety of methods. The
surface of the capsule may be inherently adhesive or can be
modified by standard coating methods known to those skilled in the
art. Suitable coating materials include bioadhesive polymers such
as polycarbophil, carbopol, DEAE-dextran, alginate,
microcrystalline cellulose, dextran, polycarbophils and
chitosan).
[0107] Oil-in-water formulations can provide for the effective
nasal delivery of analgesics that are poorly soluble in water. In
such applications nasal irritation may also be reduced.
[0108] The oil phase of the emulsions of the invention may comprise
a hydroxylated oil, particularly a hydroxylated vegetable oil. As
used herein the term "hydroxylated oil" is intended to cover any
oil that contains hydroxylated fatty acids. Preferred hydroxylated
oils are hydroxylated vegetable oils, and a preferred hydroxylated
vegetable oil for use in the present composition is castor oil.
[0109] As used herein, the term "castor oil" is intended to include
ricinus oil, oil of Palma Christie, tangantargon oil and Neoloid
(as described in Merck Index, 12th Edition, p. 311), as well as the
oil from Ricinus Zanzibarinus. The latter has a high content of
glycerides of ricinoleic acid. Thus, castor oil comprises
glycerides of ricinoleic acid (a hydroxy fatty acid).
[0110] When castor oil is used in the present invention, it may
conveniently be obtained by cold pressing of the seeds of Ricinus
Communis L. (family Euphorbiaceae).
[0111] The oil phase in the emulsions of the invention may
constitute 1 to 50% v/v of the emulsion. A preferred concentration
of oil in the emulsion is from 10 to 40% v/v. Particularly
preferred are concentrations of 20 to 30% v/v.
[0112] The emulsion compositions of the invention can be prepared
using conventional methods such as by homogenisation of a mixture
of the oil and analgesic component with an aqueous phase
(optionally together with a stabilizing agent). Any suitable device
may be used, including a microfluidizer or ultrasonic device,
though microfluidizers are preferred for large scale
production.
[0113] Suitable stabilizers for use in the emulsions of the
invention include block copolymers containing a polyoxyethylene
block (i.e. a block made up of repeating ethylene oxide moieties).
An example of a suitable stabilizer of this type is Poloxamer.TM..
Other suitable stabilizers include phospholipid emulsifiers (for
example soy and egg lecithins). Particularly preferred is the egg
lecithin Lipoid B80.TM. (from Lipoid.TM.), which contains both
phosphatidylcholine and phosphatidyl ethanoline. Other suitable
phospholipids include phospholipid-polyethylene glycol (PEG)
conjugates (see for example Litzinger et al., Biochem Biophys Acta,
1190 (1994) 99-107).
[0114] Any suitable concentration of stabilizer/emulsifier may be
used, and it typically falls within the range 0.1 to 10% w/v in the
aqueous phase of the emulsion. Particularly preferred are
concentrations of 1 to 5% w/v.
[0115] The stability of the emulsion can be enhanced by the
addition of one or more co-emulsifier(s). Suitable
pharmaceutically-acceptable co-emulsifiers include fatty acids,
bile acids and salts thereof. Preferred fatty acids have greater
than 8 carbon atoms, and particularly preferred is oleic acid. Of
the suitable bile acids, preferred is deoxycholic acid. Suitable
salts pf the foregoing include the alkali metal (e.g. Na and K)
salts. Co-emulsifiers can be added at a concentration of 1% w/v or
less on the aqueous phase.
[0116] Buffering agents may also be used in the composition. For
example, a buffer may used to maintain a pH that is compatible with
nasal fluid, to preserve emulsion stability and/or to ensure that
the analgesic component does not partition from the emulsion oil
phase into the aqueous phase.
[0117] It will be clear to the person skilled in the art that
additional components can also be added to the emulsion including
thickening and gelling agents (such as cellulose polymers,
particularly sodium carboxymethyl cellulose, alginates, gellans,
pectins, acrylic polymers, agar-agar, gum tragacanth, gum xanthan,
hydroxyethyl cellulose, chitosan, as well as block copolymers of
polyoxyethylene-polyoxypropylene). Preservative agents such as
methyl parabenzoates, benzylalcohol and chlorobutanol may also be
added.
[0118] The delivery agent may comprise a liposome. Liposomes are
microscopic vesicles composed of an aqueous compartment surrounded
by a phospholipid bilayer that acts as a permeable entrapment
barrier. Many different classes of liposomes are known (see
Gregoriadis (ed.) in Liposome Technology, 2nd edition, vol I-III,
CRC Press, Boca Ranto, Fla., 1993). Some liposomes can provide
controlled sustained release of the encapsulated drug. In such
systems, the rate of drug release is determined by the liposome's
physicochemical properties. Liposomes can be tailored for a
specific application by modification of size, composition, and
surface charge to provide the desired rate of drug delivery (see
Meisner D, et al: In Proceedings, 15th International Symposium on
Controlled Release of Bioactive Materials. 15:262-263, 1988; Mezei
M: In Drug Permeation Enhancement, Theory and Application. Hsieh DS
(ed.): Marcel Dekker Inc., New York, 1993, pp 171-198; and Meisner
D, et al: J Microencapsulation 6:379-387, 1989). Thus,
liposome-encapsulation can act as an effective and safe delivery
agent in the compositions of the invention.
[0119] The sustained release property of the liposomal product can
be regulated by the nature of the lipid membrane and by the
inclusion of other excipients in the composition of the liposomal
products. Current liposome technology permits a reasonable
prediction on the rate of drug release based on the composition of
the liposome formulation. The rate of drug release is primarily
dependent on the nature of the phospholipids, e.g. hydrogenated
(--H) or unhydrogenated (-G), or the phospholipid/cholesterol ratio
(the higher this ratio, the faster the rate of release), the
hydrophilic/lipophilic properties of the active ingredients and by
the method of liposome manufacturing.
[0120] Materials and procedures for forming liposomes are well
known to those skilled in the art and include ethanol or ether
injection methods. Typically, the lipid is dissolved in a solvent
and the solvent evaporated (often under reduced pressure) to
produce a thin film. The film is then hydrated with agitation. The
analgesic component is incorporated at the lipid film forming stage
(if lipophilic) or at the hydration phase as part of the aqueous
hydrating phase (if hydrophilic). Depending on the hydration
conditions selected and the physicochemical properties of the
lipid(s) used, the liposomes can be multilamellar lipid vesicles
(MLV), unilamellar lipid vesicles (including small unilamellar
vesicles (SUV) and large unilamellar vesicles (LUV)) and as
multivesicular liposomes.
[0121] Lipid components typically comprise phospholipids and
cholesterol while excipients may comprise tocopherol, antioxidants,
viscosity inducing agents and/or preservatives. Phospholipids are
particularly useful, such as those selected from the group
consisting of phosphatidylcholines, lysophosphatidylcholines,
phosphatidylserines, phosphatidylethanolamines, and
phosphatidylinositols. Such phospholipids may be modified using,
for example, cholesterols, stearylamines, stearic acid, and
tocopherols.
[0122] The compositions of the invention may further comprise other
suitable excipients, including for example inert diluents,
disintegrating agents, binding agents, lubricating agents,
sweetening agents, flavouring agents, colouring agents and
preservatives. Suitable inert diluents include sodium and calcium
carbonate, sodium and calcium phosphate, and lactose, while corn
starch and alginic acid are suitable disintegrating agents. Binding
agents may include starch and gelatin, while the lubricating agent,
if present, will generally be magnesium stearate, stearic acid or
talc.
[0123] Excipients such as humectants, isotoning agents,
antioxidants, buffers and/or preservatives are preferably used.
Formulation and dosage would depend on whether the analgesic is to
be used in the form of drops or as a spray (aerosol).
Alternatively, suspensions, ointments and gels can be applied to
the nasal cavity. However, it is known that nasal mucous membranes
are also capable of tolerating slightly hypertonic solutions.
Should a suspension or gel be desired instead of a solution,
appropriate oily or gel vehicles may be used or one or more
polymeric materials may be included, which desirably should be
capable of conferring bioadhesive characteristics to the
vehicle.
[0124] Many other suitable pharmaceutically acceptable nasal
carriers will be apparent to those skilled in the art. The choice
of suitable carriers will depend on the exact nature of the
particular nasal dosage form desired, for example whether the drug
is to be formulated into a nasal solution (for use as drops or as a
spray), a nasal suspension, a nasal ointment or a nasal gel. In
another embodiment, nasal dosage forms are solutions, suspensions
and gels, which contain a major amount of water (preferably
purified water) in addition to the active ingredient. Minor amounts
of other ingredients such as pH adjusters (e.g. a base such as
NaOH), emulsifiers or dispersing agents, buffering agents,
preservatives, wetting agents and jelling agents (e.g.,
methylcellulose) may also be present.
[0125] The nasal compositions of the invention may be isotonic,
hypertonic or hypotonic. If desired, sustained release nasal
compositions, e.g. sustained release gels, can be readily prepared,
preferably by employing the desired drug in one of its relatively
insoluble forms, such as the free base or an insoluble salt.
[0126] The composition of the present invention may be adjusted, if
necessary, to approximately the same osmotic pressure as that of
the body fluids (i.e. isotonic). Hypertonic solutions can irritate
the delicate nasal membranes, while isotonic compositions do not.
Isotonicity can be achieved by adding glycerol or an ionic compound
to the composition (for example, sodium chloride). The compositions
may take the form of a kit of parts, which kit may comprise the
intranasal composition together with instructions for use and/or
unit dosage containers and/or an intranasal delivery device.
[0127] The compositions of the invention enable the buprenorphine
or salt or ester thereof to be delivered such that a C.sub.ther of
0.2 ng/ml or more, for example 0.4 ng/ml or more, is attained
within 30 minutes (for example within 0.5 to 20 minutes, such as 2
to 15 minutes or 5 to 10 minutes) after introduction into the nasal
cavity. The term C.sub.ther defines a therapeutic plasma
concentration or range thereof. Thus, the term is used herein to
define a blood plasma concentration (or range of plasma
concentrations) of the buprenorphine or salt or ester thereof that
produces pain relief or pain amelioration. C.sub.ther may be from
0.4 to 5 ng/ml, for example 0.4 to 1 ng/ml or 0.5 to 4 ng/ml or 0.8
to 2 ng/ml.
[0128] The T.sub.maint is typically at least 2 hours. The term
T.sub.maint defines the duration of maintenance of C.sub.ther after
administration of the analgesic. For example, the T.sub.maint can
be from up to 24 hours, up to 12 hours or up to 6 hours such as
from 2 to 4 hours or 2 to 3 hours. By means of the invention,
therefore, a C.sub.ther of at 0.4 ng/ml may be attained within 2 to
15 minutes and maintained for a time period T.sub.maint of from 2
to 4 hours.
[0129] As already mentioned, rapid onset of analgesia and prolonged
analgesia can be achieved. The analgesic delivery profile that can
be attained may avoid the relatively high C.sub.max values
associated with intravenous administration and so lead to an
improved therapeutic index. The peak plasma concentration of an
analgesic that is attained after administration is defined as
C.sub.max. The invention can permit reduction or elimination of
some or all of the side effects associated with the analgesic.
[0130] C.sub.max is typically from 1 to 5 ng/ml, for example from 1
to 4 ng/ml from 1.5 to 3 ng/ml. C.sub.max may be from 1 to 2 ng/ml,
especially for lower doses of buprenorphine. The time at which
C.sub.max is reached (T.sub.max) is typically 10 to 40 minutes
after administration, for example 10 to 30 minutes or 15 to 25
minutes such as 15 to 20 minutes.
[0131] In preferred embodiments, the delivery agent is adapted to
deliver the analgesic component such that C.sub.max=C.sub.opt. The
term C.sub.opt is used in relation to analgesic drugs which exhibit
a dose-response curve to analgesia which is displaced to the left
with respect to the dose-response curve for side-effects. The term
defines a therapeutic plasma concentration or range thereof which
produces acceptable pain relief or pain amelioration but which does
not produce side-effects or produces side effects which are less
than those associated with higher plasma concentrations.
[0132] The compositions of the invention are administered
intranasally to a patient in order to induce analgesia. An
effective amount of buprenorphine or a salt or ester thereof is
delivered to a patient. As previously mentioned, a unit dose can be
delivered to one nostril. Alternatively, half of a dose or two
doses can be delivered to each nostril each administration time.
The dose will depend upon a number of factors including the age and
sex of the patient, the nature and extent of the pain to be treated
and the period of treatment. A suitable dose of buprenorphine or a
buprenorphine salt or ester is from 0.02 to 1.2 mg, such as from 50
to 600 .mu.g or from 100 to 400 .mu.g, calculated as
buprenorphine.
[0133] Multiple doses of a composition according to the invention
may be employed. For example, the rapid onset analgesia produced by
the solution of the invention may permit self-titration of
analgesic by the patient. The analgesic effect of an initial dose
can be quickly and reliably gauged by the patient and, if
insufficient, can be immediately supplemented by further dose(s)
(often alternating between each nostril) until the required level
of analgesia is attained. Multiple dosing may also be used in order
to extend pain relief. For example, from 2 to 4 doses per day may
be indicated.
[0134] The compositions of the invention may be used to treat an
existing pain condition or to prevent a pain condition from
occurring. An existing pain may be alleviated. Compositions can be
used to treat or manage chronic or acute pain, for example the
management of post-operative pain (e.g. abdominal surgery, back
surgery, caesarean section, hip replacement or knee replacement).
Other medical uses have been described above.
[0135] When in the form of a solution, compositions according to
the invention may be administered to the nasal cavity in forms
including drops or sprays. The preferred method of administration
is using a spray device. Spray devices can be single (unit) dose or
multiple dose systems, for example comprising a bottle, pump and
actuator. Suitable spray devices are available from various
commercial sources including Pfeiffer, Valois, Bespak and
Becton-Dickinson.
[0136] When in the form of powder or microspheres, a nasal
insufflator device may be employed. Such devices are already in use
for commercial powder systems intended for nasal application. The
insufflator may be used to produce a fine, dispersed plume of the
dry powder or microspheres. The insufflator is preferably provided
with means for administering a predetermined dose of the analgesic
composition. Powder or microspheres may be contained in a bottle or
container adapted to be used with the insufflator. Alternatively,
powders or microspheres may be provided in capsules (e.g. gelatin
capsules) or other single dose devices adapted for nasal
administration, in which embodiments the insufflator may comprise
means for breaking open the capsule. (or other single dose
device).
[0137] The following Examples illustrate the invention.
Example 1
Nasal Solution Containing Buprenorphine (4 mg/ml) and Pectin
[0138] 5 g of pectin (SLENDID (trade mark) 100, CP Kelco, Denmark)
was dissolved by stirring into approximately 180 ml of water for
injection (WFI) (Baxter, UK). 1075 mg of buprenorphine
hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose
(Roquette) were dissolved into the pectin solution. 1.25 ml of
phenylethyl alcohol (R. C. Treat, UK) and 50 mg of propyl
hydroxybenzoate (Nipa, UK) were dissolved into the
pectin/buprenorphine solution. The solution was adjusted to 250 ml
using WFI. 1M hydrochloric acid (BDH, UK) was added to adjust the
pH to 3.6.
[0139] The final product was a slightly turbid solution 4.3 mg/ml
buprenorphine hydrochloride (corresponding to 4 mg/ml
buprenorphine), 20 mg/ml pectin, 50 mg/ml dextrose, 5 .mu.l/ml
phenylethyl alcohol and 0.2 mg/ml propyl hydroxybenzoate. The pH of
the solution was 3.6, as mentioned above. The osmolality of the
solution was 0.46 osmol/kg.
[0140] Single dose nasal spray devices (Pfeiffer, Germany) were
filled with the solution. Each device was filled with 123 .mu.l of
liquid. Actuation of the device delivered a dose of 100 .mu.l of
liquid containing 400 .mu.g of buprenorphine and 2 mg of
pectin.
Example 2
Nasal Solution Containing Buprenorphine (2 mg/ml) and Pectin
[0141] 5 g of pectin is dissolved by stirring into approximately
180 ml of WFI. 538 mg of buprenorphine hydrochloride and 12.5 g of
dextrose are dissolved into the pectin solution. 1.25 ml of
phenylethyl alcohol and 50 mg of propyl hydroxybenzoate are
dissolved into the pectin/buprenorphine solution. The solution is
adjusted to 250 ml using WFI.
[0142] The final product is a slightly turbid solution containing
2.16 mg/ml buprenorphine hydrochloride (corresponding to 2 mg/ml
buprenorphine), 20 mg/ml pectin, 50 mg/ml dextrose, 5 .mu.l/ml
phenylethyl alcohol and 0.2 mg/ml propyl hydroxybenzoate.
[0143] 123 .mu.l of the above solution is filled into a Valois
Monospray single dose nasal spray device (Pfeiffer, Germany).
Actuation of the device will deliver a dose of 100 .mu.l of liquid
containing 200 .mu.g of buprenorphine and 2 mg of pectin.
Example 3
Nasal Solution Containing Buprenorphine (4 mg/ml), Chitosan and
HPMC
[0144] 0.75 g of HPMC (Methocel (trade mark) E4M, Colorcon, UK) was
dispersed into approximately 125 ml of pre-heated (70-80.degree.
C.) water for injection. (WFI) (Baxter, UK). The HPMC dispersion
was stirred in an ice bath until a clear solution had formed. 1.25
g of chitosan glutamate (Protosan (trade mark) UPG213, Pronova,
Norway) was dissolved in the HPMC solution. 75 mg of 50% w/w
benzalkonium chloride solution (Albright and Wilson, UK) was
dispersed in 10 ml of WFI and transferred with an additional 40 ml
of WFI to a 250 ml volumetric flask. 1075 mg of buprenorphine
hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose
(Roquette, UK) were transferred into the volumetric flask. The
chitosan/HPMC solution and an additional 40 ml of WFI were added to
the flask. The solution was adjusted to pH 3.4 using 1M
hydrochloric acid solution (BDH, UK) and the flask contents
adjusted to 250 ml using WFI.
[0145] The final product was a clear colourless solution containing
a 4.3 mg/ml buprenophine hydrochloride (corresponding to 4 mg/ml
buprenorphine), 5 mg/ml chitosan glutamate, 3 mg/ml HPMC, 50 mg/ml
dextrose and 0.15 mg/ml benzalkonium chloride. The osmolality of
the final solution was 0.34 osmol/kg and the viscosity, as measured
using a Brookfield CP70 cone and plate viscometer was 84.7 cps at
2.5 rpm and 25.degree. C.
[0146] Single dose nasal spray devices (Pfeiffer, Germany) were
filled with the solution. Each device was filled with 123 .mu.l of
liquid. Actuation of the device delivered a dose of 100 .mu.l of
liquid containing 400 .mu.g of buprenorphine, 0.5 mg of chitosan
and 0.3 mg of HPMC. Hence, a dose of 400 .mu.g buprenorphine is
provided by a single spray into one nostril. A dose of 800 .mu.g is
provided by a single spray into each nostril.
Example 4
Nasal Solution Containing Buprenorphine (1 mg/ml), Chitosan and
HPMC
[0147] A solution containing HPMC, chitosan glutamate and
benzalkonium chloride is prepared according to Example 3. 269 mg of
buprenorphine hydrochloride and 12.5 g of mannitol (Sigma, UK) are
transferred into the volumetric flask. The chitosan/HPMC solution
and an additional 40 ml of WFI are added to the flask. The pH of
the solution is adjusted to pH 3.6 using 1M hydrochloric acid
solution and the flask contents adjusted to 250 ml using WFI.
[0148] The final product is a clear colourless solution containing
1.08 mg/ml buprenorphine hydrochloride (corresponding to 1 mg/ml
buprenorphine), 5 mg/ml chitosan glutamate, 3 mg/ml HPMC, 50 mg/ml
mannitol and 0.15 mg/ml benzalkonium chloride.
[0149] 123 .mu.l of the above solution is filled into a single dose
nasal spray device (Pfeiffer, Germany). Actuation of the device
will deliver a dose of 100 .mu.l of liquid containing 100 .mu.g of
buprenorphine, 0.5 mg of chitosan and 0.3 mg of HPMC.
[0150] 5 ml of the solution is filled into a 10 ml glass bottle. A
Valois VP7, 100 .mu.l pump and actuator (Valois, France) are
attached to the bottle. When primed, the pump will dispense 100
.mu.l of solution containing 100 .mu.g of buprenorphine.
Example 5
Nasal Solution Containing Buprenorphine (4 mg/ml), Chitosan and
Poloxamer
[0151] 25 g of poloxamer 188 (Lutrol (trade mark) F-68, BASF,
Germany) was dissolved by stirring into 100 ml of water for
injection (WFI) (Baxter, UK) at a temperature of 2 to 8.degree. C.
1.25 g of chitosan glutamate (Protasan (trade mark) UPG213?
Pronova, Norway) was dissolved in the poloxamer solution. 75 mg of
50% w/w benzalkonium chloride solution (Albright and Wilson, UK)
was dispersed in 10 ml of WFI and transferred with an additional 40
ml of WFI to a 250 ml volumetric flask. 1075 mg of buprenorphine
hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose
(Roquette, UK) were transferred into the volumetric flask. The
chitosan/poloxamer solution and an additional 40 ml of WFI were
added to the flask. The solution was adjusted to pH 3.4 using 1M
hydrochloric acid solution (BDH, UK) and the flask contents
adjusted to 250 ml using WFI.
[0152] The final product was a clear colourless solution containing
4.3 mg/ml buprenorphine hydrochloride (corresponding to 4 mg/ml
buprenorphine), 5 mg/ml chitosan glutamate, 100 mg/ml poloxamer
188, 50 mg/ml dextrose and 0.15 mg/ml benzalkonium chloride. The
osmolality of the final solution was 0.60 Osmol/kg.
[0153] Single dose nasal spray devices (Pfeiffer, Germany) were
filled with the solution. Each device was filled with 123 .mu.l of
liquid. Actuation of the device delivered a dose of 100 .mu.l of
liquid containing 400 .mu.g of buprenorphine, 0.5 mg of chitosan
and 10 mg of poloxamer 188.
Example 6
Nasal Solution Containing Buprenorphine (1 mg/ml), Chitosan and
Poloxamer
[0154] A solution containing chitosan glutamate, poloxamer 188 and
benzalkonium chloride is prepared according to Example 5. 269 mg of
buprenorphine hydrochloride and 12.5 g mannitol (Sigma, UK) are
transferred into the volumetric flask. The chitosan/poloxamer
solution and an additional 40 ml of WFI are added to the flask. The
pH of the solution is adjusted to pH 3.6 using 1M hydrochloric acid
and the flask contents adjusted to 250 .mu.l using WFI.
[0155] The final product is a clear colourless solution containing
1.08 mg/ml buprenorphine hydrochloride (corresponding to 1 mg/ml
buprenorphine), 5 mg/ml chitosan glutamate, 100 mg/ml poloxamer
188, 50 mg/ml mannitol and 0.15 mg/ml benzalkonium chloride.
[0156] 123 .mu.l of the above solution is filled into a single dose
nasal spray device (Pfeiffer, Germany). Actuation of the device
will deliver a dose of 100 .mu.l of liquid containing 100 .mu.g of
buprenorphine, 0.5 mg of chitosan and 10 mg of poloxamer 188.
[0157] 4 ml of the solution is filled into a 5 ml glass bottle. A
Pfeiffer 100 .mu.l nasal spray pump and actuator are attached to
the bottle. When primed, the pump will dispense 100 .mu.l of
solution containing 100 .mu.g of buprenorphine.
Example 7
Effects of Varying Parameters of Buprenorphine-Pectin Solutions
General Methods
[0158] The appearance, pH (Mettler MP230 pH meter) and osmolality
(Osmomat 030 cryoscopic osmometer) of the solutions were
determined.
[0159] The viscosity of the solution was measured using a
Brookfield Cone and Plate Rheometer. Results given are the mean of
determinations at three rotation speeds appropriate to the
viscosity of the solution.
[0160] The spray characteristics from a Pfeiffer multi-dose nasal
spray device (standard nozzle, 0.1 ml pump, Cat. No. 62897) were
evaluated by measurement of plume angle using image analysis.
Results given are the mean of four determinations (two at one
orientation and two at a 90.degree. rotation to the first
orientation)
[0161] The buprenorphine content of formulations was determined by
hplc.
[0162] Gels were prepared by controlled mixing of 20 ml of
formulation with 5 ml of a standard calcium chloride solution (9.44
mg/ml CaCl.sub.2.2H.sub.20) before standing for 1 hour at room
temperature. A visual assessment of the structure, uniformity,
clarity and evidence of syneresis of each gel was conducted and, in
addition, the gel structure was examined with a Stable Microsystems
Texture Analyser. Results (from single determinations) are
expressed in terms of force (maximum penetration force) and area
(total work of gel penetration).
Effect of Pectin Concentration on Appearance Solution/Gel
Properties and Spray Characteristics
1. Methods
[0163] Buprenorphine hydrochloride (107.5 mg) and anhydrous
dextrose (1.25 g) were stirred in 18-20 ml water in a 25 ml
volumetric flask together with an appropriate quantity of pectin
and the mixture stirred overnight or until a solution formed. The
mixture was then made up to 25 ml with water to give a solution
containing 4 mg/ml buprenorphine, 50 mg/ml dextrose and 1, 5, 10,
20, 30, 40 or 80 mg/ml pectin and the pH, appearance, osmolality,
viscosity were determined. In addition, spray characteristics from
a Pfeiffer multi-dose nasal spray device (standard nozzle, 0.1 ml
pump, Cat. No. 62897) were evaluated by measurement of plume angle
using image analysis. Gels were prepared by controlled mixing of 20
ml of formulation with 5 ml of a standard calcium chloride solution
(9.44 mg/ml CaCl.sub.2.2H.sub.20) before standing for 1 hour at
room temperature. A visual assessment of the structure, uniformity,
clarity and evidence of syneresis of each gel was conducted and, in
addition, the gel structure was examined with a Stable Microsystems
Texture Analyser.
[0164] An in vitro method was employed to simulate the gelling that
may occur when the pectin formulation comes into contact with the
nasal mucosal surface. This involved adding 2 ml of each
formulation to an equal volume of simulated nasal electrolyte
solution (SNES) (comprised 8.77 g/l sodium chloride, 2.98 g/l
potassium chloride and 0.59 g/l calcium chloride dihydrate) and
agitating gently. The mixtures were left to stand for 1 hour at
room temperature before visual assessment.
2. Results
[0165] As pectin concentration increased, solutions became
increasingly turbid, osmolality and viscosity increased and plume
angle decreased (Table 1). An excellent relationship was obtained
between concentration and plume angle up to 30 mg/ml pectin. The pH
was not significantly affected by pectin concentration.
[0166] Upon addition of calcium ions pectin formed visually
satisfactory gels in the concentration range 5-20 mg/ml (Table 2).
Correspondingly greater integrity of gel structure was noted over
this range. At higher pectin concentrations texture analysis
results were inconclusive because homogeneity of the gel is
difficult to control and increasing syneresis was observed.
[0167] At a lower calcium ion concentration (SNES) pectin produced
mobile gels at 10-20 mg/ml and strong, inhomogeneous gels at higher
concentrations.
TABLE-US-00001 TABLE 1 Appearance, pH, osmolality, viscosity and
spray characteristics (plume angle) of buprenorphine solutions
containing 4.3 mg/ml buprenorphine hydrochloride (BPN.HCl), 50
mg/ml dextrose and different concentrations of pectin (Slendid
100). Pectin Conc. Osmolality Viscosity Plume Batch No. (mg/ml) pH
(osmol/kg) (cps) angle (.degree.) Appearance 105 1 4.4 0.32 1.4 56
Clear, colourless solution 106 5 4.2 0.33 2.1 53 Very slightly
turbid, colourless solution 107 10 4.1 0.34 3.7 42 Slightly turbid,
colourless solution 108 20 4.0 0.37 9.0 29 Slightly turbid, pale
yellow solution 153 30 3.9 0.40 16.8 21 Turbid, pale yellow
solution 109 40 4.0 0.43 33.9 20 Turbid, pale yellow solution 110
80 4.0 0.55 N/M* 16 Very turbid, pale yellow solution *N/M = not
measurable
TABLE-US-00002 TABLE 2 Gelling properties of buprenorphine
solutions containing 4.3 mg/ml BPN.cndot.HCl, 50 mg/ml dextrose and
different concentrations of pectin (Slendid 100) when mixed with a
standard calcium chloride solution. Texture Pectin analysis Batch
Conc. Force Area No. (mg/ml) (g) (g s) Visual assessment 105 1 --
-- Clear, slightly viscous, colourless solution. Did not gel. 106 5
116 1420 Slightly opalescent, strong, uniform gel with minimum
syneresis. 107 10 220 3858 Semi-transparent, strong, uniform gel
with minimum syneresis. 108 20 279 4872 Semi-transparent, pale
yellow, strong, uniform gel with minimum syneresis. 153 30 190 4259
Semi-transparent, pale yellow, strong, uniform gel with some
syneresis. 109 40 234 2691 Semi-transparent, pale yellow, very
strong, non-uniform gel with some syneresis. 110 80 303 5356
Semi-transparent, yellow, extremely strong, non-uniform gel with
significant syneresis.
TABLE-US-00003 TABLE 2a Gelling properties of buprenorphine
solutions containing 4.3 mg/ml BPN.cndot.HCl, 50 mg/ml dextrose and
different concentrations of pectin (Slendid 100) when mixed with
SNES. Pectin Conc. Batch No. (mg/ml) Visual assessment 161 1 Clear,
slightly viscous, colourless solution. Did not gel. 162 5 Clear,
viscous, colourless solution. Did not gel. 163 10 Clear,
colourless, weak diffuse gel. 164 20 Pale yellow, semi-transparent
weak diffuse gel. 165 30 Semi-transparent pale yellow, strong gel
with some syneresis. 166 40 Semi-transparent pale yellow, strong
gel with some syneresis. 167 80 Opaque pale yellow, very strong gel
with significant syneresis.
Effect of pH on Solubility and Gelling Properties of Buprenorphine
Hydrochloride
1. Methods
[0168] Stock solutions containing pectin (Slendid 100) (20 mg/ml)
and dextrose (50 mg/ml) were prepared at various pH in the range pH
3.0 to 6.0 (pH adjustments were made with 0.1M HCl or 0.1M
meglumine). An excess of buprenorphine hydrochloride was then
stirred overnight at 18.degree. C. in 5 or 25 ml of each solution.
Saturated solutions were recovered by passing each mixture through
a 0.2 .mu.m polycarbonate membrane filter. The concentration of
buprenorphine hydrochloride in the filtrate was determined by
hplc.
[0169] In preliminary experiments addition of excess buprenorphine
hydrochloride was found to reduce the pH of the (unbuffered)
solutions. In order to produce solutions at the higher end of the
desired pH range, a minimal excess of buprenorphine hydrochloride
was added to solutions (5 ml) containing pectin (Slendid 100) (20
mg/ml) and dextrose (50 mg/ml) adjusted to various pH values in the
range pH 4.5 to 6.0 with 0.1M HCl or 0.1M meglumine. The quantity
of excess buprenorphine hydrochloride added was based on
preliminary findings and on reported solubility data for
buprenorphine hydrochloride (Cassidy et al, J. Controlled Release
25, 21-29, 1993). Following overnight stirring at 18.degree. C.,
mixtures were examined to confirm that undissolved drug remained
before saturated solutions were recovered by passing each mixture
through a 0.2 .mu.m polycarbonate membrane filter.
[0170] For selected formulations gels were prepared by controlled
mixing of 20 ml of formulation with 5 ml of a standard calcium
chloride solution (9.44 mg/ml CaCl.sub.2.2H.sub.20) before standing
for 1 hour at room temperature. A visual assessment of the
structure, uniformity, clarity and evidence of syneresis of each
gel was conducted and, in addition, the gel structure was examined
with a Stable Microsystems Texture Analyser.
2. Results
[0171] Buprenorphine was sparingly soluble (greater than 10 ng/ml)
in aqueous solutions containing 20 mg/ml pectin+50 mg/ml dextrose
at pH below 4.4 (Table 3). In general, solubility fell as pH
increased above 4.5 (Table 3a). Solutions were slightly soluble
(less than 10 ng/ml) at pH 4.5-6.0.
[0172] Gelling properties were largely unaffected by pH (and
therefore by buprenorphine concentration) (Table 4).
TABLE-US-00004 TABLE 3 Solubility of BPN.cndot.HCl at pH 3.2-4.0 in
solutions containing 20 mg/ml pectin (Slendid 100) and 50 mg/ml
dextrose. Buprenorphine Batch No. Final pH detected* (mg/ml) 043
3.2 12.3 085 3.6 14.2 086 3.8 13.5 087 3.9 15.8 048 4.0 14.3
*Expressed as buprenorphine free base
TABLE-US-00005 TABLE 3a Solubility of BPN.cndot.HCl at pH 4.4-5.3
in solutions containing 20 mg/ml pectin (Slendid 100) and 50 mg/ml
dextrose. Buprenorphine Batch No. Final pH detected* (mg/ml) 202
4.4 11.6 203 4.5 9.0 204 4.7 7.3 205 4.7 6.0 206 4.8 3.5 207 5.1
2.7 209 5.2 1.4 208 5.3 1.3 *Expressed as buprenorphine free
base
TABLE-US-00006 TABLE 4 Effect of pH on the gelling properties of
BPN.cndot.HCl in solution containing 20 mg/ml pectin (Slendid 100)
and 50 mg/ml dextrose when mixed with a standard calcium chloride
solution. Texture analysis* pH Area Batch No. (actual) Force (g) (g
s) Visual assessment 043 3.0 (3.2) 328 4439 Semi-transparent,
uniform gel with minimum syneresis. 086 3.5 (3.8) 309 4018
Semi-transparent, uniform gel with minimum syneresis. 048 4.0 (3.9)
371 4056 Semi-transparent, uniform gel with minimum syneresis. 089
5.5 (5.1) 168 1620 Semi-transparent, uniform gel with some
syneresis. *Reduced volumes (14 ml of formulation and 3.5 ml of
CaCl.sub.2.cndot.2H.sub.20) were used due to higher than expected
loss of volume during filtration.
Effect of Osmolality (Dextrose or Mannitol Concentration) on
Viscosity, Spray Characteristics and Gelling Properties of
Buprenorphine Hydrochloride
1. Methods
[0173] Buprenorphine hydrochloride (107.5 mg) and pectin (Slendid
100) (500 mg) were stirred in 18-20 ml water in a 25 ml volumetric
flask together with an appropriate quantity of anhydrous dextrose
or mannitol and the mixture stirred overnight or until a solution
formed. The mixture was then made up to 25 ml with water to give a
solution containing 4 mg/ml buprenorphine, 20 mg/ml pectin and 15,
50, 87, 122, 157 or 192 mg/ml dextrose (or 15, 50, 87, 122 mg/ml
mannitol) and the pH, appearance, osmolality, viscosity were
determined. In addition, spray characteristics from a Pfeiffer
multi-dose nasal spray device (standard nozzle, 0.1 ml pump, Cat.
No. 62897) were evaluated by measurement of plume angle using image
analysis. Gels were prepared by controlled mixing of 20 ml of
formulation with 5 ml of a standard calcium chloride solution (9.44
mg/ml CaCl.sub.2.2H.sub.20) before standing for 1 hour at room
temperature. A visual assessment of the structure, uniformity,
clarity and evidence of syneresis of each gel was conducted and, in
addition, the gel structure was examined with a Stable Microsystems
Texture Analyser.
2. Results
[0174] As dextrose concentration increased from 15 to 50 mg/ml
spray characteristics from a nasal spray device were affected as
indicated by a decrease in plume angle associated with an increase
in viscosity: a narrow plume was consistently obtained above 50
mg/ml dextrose (Table 5). As mannitol concentration increased there
was a slight increase in viscosity and a slight decrease in plume
angle (Table 6).
[0175] Gel structure may have been slightly weakened as dextrose
concentration increased. This was indicated by a visual assessment
but texture analysis results were inconclusive (Table 7).
[0176] Gel structure was affected at higher mannitol concentration.
Visual assessment and texture analysis indicated that less uniform
and weaker gels were produced (Table 8).
TABLE-US-00007 TABLE 5 Osmolality, viscosity and spray
characteristics of 4.3 mg/ml BPN.cndot.HCl/ 20 mg/ml pectin
(Slendid 100) solution containing varying concentrations of
dextrose. Dextrose concentration Osmolality Plume Batch No. (mg/ml)
(osmol/kg) Viscosity (cps) angle (.degree.) 114 15 0.15 8.0 43 115
50 0.37 9.2 30 116 87 0.62 10.3 22 117 122 0.88 11.5 19 118 157
1.18 13.0 23 119 192 1.5 14.5 17
TABLE-US-00008 TABLE 6 Osmolality, viscosity and spray
characteristics of 4.3 mg/ml BPN.cndot.HCl/ 20 mg/ml pectin
(Slendid 100) solution containing varying concentrations of
mannitol. Mannitol conc. Osmolality Viscosity Plume angle Batch No.
(mg/ml) (osmol/kg) (cps) (.degree.) 120 15 0.16 8.4 33 121 50 0.37
9.2 22 122 87 0.61 10.3 22 123 122 0.85 11.3 21 124 157* -- -- --
125 192* -- -- -- *Did not dissolve
TABLE-US-00009 TABLE 7 Gelling properties of 4.3 mg/ml
BPN.cndot.HCl/20 mg/ml pectin (Slendid 100) solution containing
varying concentrations of dextrose. Osmolality Texture analysis
Batch No. (osmol/kg) Force (g) Area (g s) Visual assessment 114
0.15 574 10338 Very strong, uniform, semi- transparent pale yellow
gel with minimum syneresis. 115 0.37 359 6589 Very strong; uniform,
semi- transparent pale yellow gel with minimum syneresis. 116 0.62
280 5520 Strong, uniform, semi-transparent pale yellow gel with
minimum syneresis. 117 0.88 336 5019 Strong, uniform,
semi-transparent pale yellow gel with minimum syneresis. 118 1.18
467 7066 Strong, uniform, semi-transparent pale yellow gel with
minimum syneresis. 119 1.5 249 3435 Strong, uniform,
semi-transparent pale yellow gel with some syneresis.
TABLE-US-00010 TABLE 8 Gelling properties of 4.3 mg/ml
BPN.cndot.HCl/20 mg/ml pectin (Slendid 100) solution containing
varying concentrations of mannitol when mixed with a standard
calcium chloride solution. Texture analysis Osmolality Force Area
Batch No. (osmol/kg) (g) (g s) Visual assessment 120 0.16 477 9006
Strong, uniform, semi- transparent pale yellow gel with some
syneresis. 121 0.37 497 8991 Strong, uniform, semi- transparent
pale yellow gel with some syneresis. 122 0.61 358 7160 Weak,
non-uniform, semi- transparent pale yellow gel with some syneresis
123 0.85 221 3881 Weak, non-uniform, semi- transparent pale yellow
gel with some syneresis
Effect of Dextrose and Mannitol Concentration on Buprenorphine
Solubility
1. Methods
[0177] Solutions containing pectin (Slendid 100) (20 mg/ml) were
prepared at pH 3, 4, 5 and 6 (pH adjustments were made with 0.1M
HCl or 0.1M meglumine). Into 5 ml of each solution was dissolved 0,
62.5, 125, 187.5 or 200 mg anhydrous dextrose or mannitol to give
approximate dextrose/mannitol concentrations of 0, 12.5, 25, 37.5
or 50 mg/ml respectively. An excess of buprenorphine hydrochloride
was then added and the mixture stirred overnight at 18.degree. C.
Saturated buprenorphine hydrochloride solutions were produced by
passing each mixture through a 0.2 .mu.m polycarbonate membrane
filter. The concentration of buprenorphine hydrochloride in the
filtrate was determined by hplc.
2. Results
[0178] Buprenorphine solubility in aqueous solution containing 20
mg/ml pectin was not affected significantly by dextrose (Table 9)
or mannitol (Table 10) concentration across the measured pH
range.
TABLE-US-00011 TABLE 9 Effect of dextrose concentration on the
solubility of BPN.cndot.HCl in solution containing 20 mg/ml pectin
(Slendid 100). Dextrose Buprenorphine concentration pH detected*
Batch No. (mg/ml) (actual) (mg/ml) 036 0 3 (3.1) 13.7 040 12.5 3
(2.9) 13.1 041 25 3 (2.7) 13.9 042 37.5 3 (3.0) 13.9 043 50 3 (3.2)
12.3 037 0 4 (3.9) 16.4 045 12.5 4 (3.8) 16.0 046 25 4 (3.9) 15.6
047 37.5 4 (4.0) 15.6 048 50 4 (4.0) 14.3 038 0 5 (4.9) 4.4 050
12.5 5 (5.0) 5.7 051 25 5 (5.0) 4.4 052 37.5 5 (5.1) 4.4 053 50 5
(5.2) 4.6 039 0 6 (5.9) 1.8 055 12.5 6 (5.7) 1.6 056 25 6 (5.8) 1.7
057 37.5 6 (5.7) 1.7 058 50 6 (5.6) 1.8 *Expressed as buprenorphine
free base
TABLE-US-00012 TABLE 10 Effect of mannitol concentration on the
solubility of BPN.cndot.HCl in solution containing 20 mg/ml pectin
(Slendid 100). Mannitol Buprenorphine concentration pH detected*
Batch No. (mg/ml) (actual) (mg/ml) 036 0 3 (3.2) 13.7 060 12.5 3
(3.1) 13 061 25 3 (3.1) 12.3 062 37.5 3 (3.0) 12.4 063 50 3 (3.2)
13.9 037 0 4 (3.9) 16.4 065 12.5 4 (4.0) 16.4 066 25 4 (4.0) 15.8
067 37.5 4 (4.0) 15.7 068 50 4 (4.0) 15.5 038 0 5 (4.9) 4.4 070
12.5 5 (5.1) 4.9 071 25 5 (5.2) 3.9 072 37.5 5 (5.1) 4.6 073 50 5
(5.2) 4.3 039 0 6 (5.9) 1.8 075 12.5 6 (5.9) 2.0 076 25 6 (5.6) 1.9
077 37.5 6 (5.6) 2.4 078 50 6 (5.3) 1.8 *Expressed as buprenorphine
free base
Negative Control Experiment: Effect of Mixing HM (High Methoxy)
Pectin (20 mg/ml Genu (trade mark) Pectin [Citrus] Type USP-H)
Solution with Calcium
[0179] The pectins suitable for retaining drugs at mucosal surfaces
have a low degree of esterification (also called "low methoxy" or
"LM" pectins) and, in aqueous solution, will gel in the presence of
ions found in mucosal fluid, especially divalent ions, in
particular calcium. As a negative control, a solution of "high
methoxy" pectin was prepared and mixed with a solution containing
calcium ions.
1. Methods
[0180] Buprenorphine hydrochloride (107.5 mg), anhydrous dextrose
(1.25 g) and pectin (Genu pectin [citrus] type USP-H; CP Kelco,
Lille Skenved, Denmark) (500 mg) were stirred in 18-20 ml water in
a 25 ml volumetric flask overnight or until a solution formed. The
mixture was then made up to 25 ml with water to give a solution
containing 4 mg/ml buprenorphine, 20 mg/ml pectin and 50 mg/ml
dextrose and the pH and osmolality were determined. A 20 ml aliquot
of the formulation was mixed (under controlled conditions) with 5
ml of a standard calcium chloride solution (9.44 mg/ml
CaCl.sub.2.2H.sub.20) before standing for 1 hour at room
temperature. The structure, uniformity and clarity of the product
were then evaluated.
2. Results
[0181] The solution had a pH of 3.3 and an osmolality of 0.35
osmol/kg. An opaque, pale yellow solution was formed when the
solution was mixed with 9.44 mg/ml CaCl.sub.2.2H.sub.20. The
solution did not gel even when left for 1 hour at room
temperature.
Example 8
Clinical Study
[0182] Unit doses of the intranasal buprenorphine formulations of
Examples 1, 3 and 5 (Formulations A to C) and one intravenous
commercial buprenorphine formulation (Temgesic-trade mark;
Formulation D) were administered to healthy human volunteers. The
unit doses administered to the volunteers were as follows: [0183]
800 .mu.g buprenorphine hydrochloride, calculated as buprenorphine,
of Formulations A, B or C administered intranasally; and [0184] a
single slow intravenous injection of 400 .mu.g buprenorphine
hydrochloride, calculated as buprenorphine, of Formulation D.
[0185] The dosing was performed on twelve healthy volunteers using
a randomised, complete crossover design. Each dose was separated
by, at least, seven days. The volunteers were required to fast
overnight prior to dosing. Subjects were admitted to a clinic the
evening before each dose of administration and remained in the
clinic until blood sample collection for each study day. Blood
samples were collected at regular intervals up to 24 hours after
each dose administration. The volunteers were discharged from the
clinic after completion of all 24 hour study procedures. There was
a wash out period of, at least seven days, between each dose.
[0186] The pharmacokinetics of each dosage regimen were evaluated.
The results are shown in FIGS. 1 to 3. All three intranasal
solutions showed similar pharmacokinetic profiles. The C.sub.ther
was reached within 5 to 10 minutes for each formulation and the
C.sub.max was reached in 20 minutes or less. The data indicated
that the initial plasma peak was blunted for the intranasal
formulations compared to intravenous administration. That appeared
most pronounced for Formulation A. All three intranasal solutions
gave high bioavailability (Table 11)
TABLE-US-00013 TABLE 11 Comparison of key pharmacokinetic
parameters derived from the clinical study data on intranasal
buprenorphine with published data on the sublingual tablet and with
a dextrose formulation of buprenorphine. Clinical study data (prior
art) (prior art) Intranasal Buprenorphine sublingual intranasal 0.8
mg 0.8 mg Buprenorphine Buprenorphine PK 0.8 mg Chitosan/ Chitosan/
0.4 mg 0.8 mg 0.3 mg dextrose Parameter Pectin HPMC Poloxamer
tablet tablet solution C.sub.max (ng/ml) 3.7 4.4 3.8 0.5 1.04 1.8
T.sub.max (min) 20 18 20 210 192 31 Bioavailability 80% 81% 72% 56%
48%
[0187] A pharmacokinetic profile was computed for a 400 .mu.g
intranasal dose of Formulation A, calculated as buprenorphine, from
the data for the 800 .mu.g dose of Formulation A. This profile is
shown in FIG. 4. FIG. 4 also shows the pharmacokinetic profile for
the 400 .mu.g dose of Formulation A that was administered
intravenously.
* * * * *