(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2005/0085440 A1
`
`Birch et al.
`(43) Pub. Date:
`Apr. 21, 2005
`
`US 20050085440A1
`
`(54) FORMULATION
`
`(76)
`
`Inventors: Philip John Birch, Cambridge (GB);
`Ann Gail Hayes, Cambridge (GB);
`Peter James Watts, Nottingham (GB);
`Jonathan David Castile, Nottingham
`(GB)
`
`Correspondence Address:
`NIXON & VANDERHYE, PC
`1100 N GLEBE ROAD
`8TH FLOOR
`
`ARLINGTON, VA 22201-4714 (US)
`
`(21) Appl. NO.:
`
`10/508,336
`
`(22) PCT Filed:
`
`Mar. 19,2002
`
`(86) PCT NO.:
`
`PCT/GB03/01183
`
`(30)
`
`Foreign Application Priority Data
`
`Mar. 19, 2002
`
`(GB) ......................................... 02064483
`
`Oct. 28, 2002
`Oct. 28, 2002
`Oct. 28, 2002
`
`(GB) ......................................... 0225040.5
`(GB) ......................................... 02250413
`(GB) ......................................... 0225042.1
`
`Publication Classification
`
`Int. Cl.7 ...................... A61K 31/485; A61K 31/732
`(51)
`(52) U.S.Cl.
`.............................................. 514/54, 514/282
`
`(57)
`
`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 esteri-
`fication Of less than 50%, (b) chitosan and a polyoxyethyl-
`ene-polyoxypropylene copolymer (poloxamer) or (c) chitO-
`san and hydroxyprOpylmethylcellulose. Such formulations
`can induce rapid and prolonged analgesia When delivered
`intranasally tO a patient. The buprenorphine 0r buprenor-
`phine salt or ester may be delivered t0 the bloodstream tO
`produce Within 30 minutes a therapeutic plasma concentra-
`tion Of buprenorphine, Cther, Of 0.2 ng/ml or greater which
`main
`is maintained for a duration T
`t Of at least 2 hours.
`
`Page 1
`
`BDSI EXHIBIT 1019
`
`Page 1
`
`

`

`Patent Application Publication Apr. 21, 2005 Sheet 1 of 2
`
`US 2005/0085440 A1
`
`FIGURE 1
`
`6.00
`
`0,50
`m ‘
`4.80
`4.40
`
`4,00 ‘
`
`3,1503
`3.20
`
`‘-
`
`”d
`
`2.00-
`
`I,
`'.
`
`ml
`
`0.30 ‘
`0.40
`
`'
`
`(ng/ml) 0.00
`1.20 '
`Plasmabuprenorphineconcentration
`
`
`
`Formulation A: Buprenorphiné
`'._°_ pectin solution (800 pg)
`
`,
`
`,
`
`-- x~i Formulation D: IV buprenorphine
`(400 pg)
`‘
`
`\
`
`0
`
`10
`
`,
`
`60
`
`>
`
`90
`
`120
`
`210
`[80
`150
`Time (minutes)
`
`240
`
`'170
`
`'
`
`300
`
`310
`
`360 ,
`
`FIGURE 2
`
`5,00
`
`50
`E 5.60
`5 5.20
`g
`4.30
`E 4.40
`t=
`4.00
`8
`3.60
`E
`3.20
`:
`.,
`:
`"3°
`‘5
`E‘ m ,
`2.00
`5
`1.50
`E.=
`.3
`1.20
`
`.
`5
`:
`
`V
`
`.
`.
`+FormulatlonBzBuprenorphme-
`"chitosan/HPMC solution (800 pg)
`.
`‘
`.
`~x---FormulationD:Wbuprenorph1ne
`(400%)
`
`,
`
`-
`
`_
`
`0.40 0.00
`
`' 0.30
`
`0
`
`3D
`
`50
`
`1
`
`9°
`
`‘
`
`[20
`
`”0
`
`13°
`
`2 ID
`
`240
`
`170
`
`IUD
`
`330
`
`350
`
`Time (minutes)
`
`N Ef
`
`l!
`
`En
`
`-
`
`Page 2
`
`Page 2
`
`

`

`Patent Application Publication Apr. 21, 2005 Sheet 2 of 2
`
`US 2005/0085440 A1
`
`FIGURE 3
`
`(ng/ml)
`Plasmabuprenorphineconcentration
`
`
`
`—¢— Formulation C: Buprenorphine-
`chitosan/poloxamer 188 solution (800 14g)
`
`--x- - Formulation D. IV buprénorphine (400 tig)
`
`0
`
`30
`
`4
`
`60
`
`90
`
`120
`
`150
`
`ISO
`
`210
`
`240
`
`‘
`
`270
`
`300
`
`330
`
`360
`
`- Time (minutes)
`
`FIGURE 4
`
`6.00
`5.60
`5.20
`4.80
`
`4.40
`4.00
`
`1.50
`3.20
`2.80
`
`1‘“
`2.00
`1.50
`
`1.20
`0.50
`
`‘
`
`.
`E
`
`‘
`
`,
`
`0.40 0.00
`
`'
`
`—~— Formulation A:— Buprenorphine-pectin
`solution'(400 pg model)
`
`,
`
`-- x -- Formulation D: IV buprenorphine
`(400 Hg)
`
`
`
`
`
`
`
`Plasmabuprenorphineconcentration(ng/ml)
`
`0
`
`30
`
`60
`
`90
`
`120
`
`150
`
`180
`
`210
`
`240
`
`270
`
`300
`
`330
`
`360
`
`Time (minutes)
`
`Page 3
`
`Page 3
`
`

`

`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`FORMULATION
`
`FIELD OF THE INVENTION
`
`[0001] The invention relates to pharmaceutical formula-
`tions 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(X,7(X(S)-
`17-(Cyclopropylmethyl)-ot-(1,1-dimethylethyl)-4,5-epoxy-
`18,19-dihydro-3-hydroxy-6-methoxy-ot-methyl-6,14-
`ethenomorphinan-7-methanol) has the formula:
`
`
`
`[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, vomiting, dizziness, mental clouding, dysphoria,
`pruritus, constipation, increased biliary tract pressure, uri-
`nary retention and hypotension. The development of toler-
`ance 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
`
`Page 4
`
`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 admin-
`istration. 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 admin-
`istration to mucosa comprising a pharmacologically active
`compound and a polycationic substance such as DEAE-
`dextran or chitosan. WO 98/47535 discloses a single com-
`ponent liquid pharmaceutical composition for administra-
`tion 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
`
`Improved buprenorphine formulations for nasal
`[0010]
`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:
`
`(1) an aqueous solution suitable for intranasal
`[0011]
`administration, which comprises from 0.1 to 10
`mg/ml of buprenorphine or a physiologically accept-
`able 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) an aqueous solution suitable for intranasal
`[0012]
`administration, which comprises:
`
`(a) from 0.1 to 10 mg/ml of buprenorphine
`[0013]
`or
`a physiologically acceptable salt or ester
`thereof,
`
`[0014]
`
`(b) from 0.1 to 20 mg/ml of a chitosan, and
`
`(c) from 0.1 to 15 mg/ml of hydroxypro-
`[0015]
`pylmethylcellulose (HPMC);
`
`[0016] which solution has a pH of from 3 to 4.8;
`and
`
`(3) an aqueous solution suitable for intranasal
`[0017]
`administration, which comprises:
`
`(a) from 0.1 to 10 mg/ml of buprenorphine
`[0018]
`or
`a physiologically acceptable salt or ester
`thereof,
`
`Page 4
`
`

`

`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`[0019]
`
`(b) from 0.1 to 20 mg/ml of a chitosan, and
`
`(c) from 50 to 200 mg/ml of a polyoxyeth-
`[0020]
`ylene-polyoxypropylene copolymer of the general
`formula
`HO(C2H4O)8(C3H60)b(C2H4O)aH
`wherein a is from 2 to 130 and b is from 15 to 67;
`
`[0033] The invention enables a therapeutic blood plasma
`concentration of buprenorphine, i.e. a buprenorphine con-
`centration that produces pain relief or pain amelioration, to
`be attained within 30 minutes and maintained for up to 24
`hours. The term Cther denotes a therapeutic blood plasma
`maint
`concentration. The term T
`denotes the duration for
`
`[0021] which solution has a pH of from 3 to 4.8.
`
`which Cther is maintained.
`
`[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:
`
`(a) from 1 to 6 mg/ml of buprenorphine or a
`[0023]
`physiologically acceptable salt or ester thereof, cal-
`culated as buprenorphine,
`
`(b) from 10 to 40 mg/ml of a pectin which has
`[0024]
`a degree of esterification from 10 to 35%, and
`
`[0025]
`
`(c) dextrose as a tonicity adjustment agent.
`
`[0026] The invention also provides:
`
`a process for the preparation of solution (1),
`[0027]
`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 com-
`prises 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;
`
`a process for the preparation of solution (2),
`[0028]
`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;
`
`a process for the preparation of solution (3),
`[0029]
`which comprises dissolving buprenorphine or a
`physiologically acceptable salt or ester thereof, a
`chitosan and a polyoxyethylene-polyoxypropylene
`copolymer
`of
`the
`general
`formula
`HO(C2H4O)a(C3H6O)b(C2H4O)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 copoly-
`mer; and adjusting the pH of the solution to a value
`from 3 to 4.8 as desired;
`
`a nasal delivery device loaded with a solution
`[0030]
`of the invention;
`
`use of a solution of the invention for the
`[0031]
`manufacture of a nasal delivery device for use in
`inducing analgesia; and
`
`a method of inducing analgesia in a patient in
`[0032]
`need thereof, which method comprises intranasally
`administering a solution of the invention to the
`patient.
`
`Page 5
`
`[0034] Additionally, therefore, the present invention pro-
`vides 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 Cther
`of 0.2 ng/ml or greater which is maintained for a duration
`mam!
`T _ of at least 2 hours. Also provided are:
`
`use of a pharmaceutical composition which
`[0035]
`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 Cther of 0.2 ng/ml
`maint
`or greater which is maintained for a duration T
`of at least 2 hours;
`
`a pharmaceutical composition suitable for use
`[0036]
`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 buprenor-
`phine or salt or ester thereof is delivered to the
`bloodstream to produce within 30 minutes a thera-
`peutic plasma concentration Cther of 0.2 ng/ml or
`greater which is maintained for a duration Tmint of
`at least 2 hours;
`
`a method of inducing analgesia in a patient in
`[0037]
`need thereof, which method comprises administering
`intranasally to said patient a pharmaceutical compo-
`sition which comprises buprenorphine or a physi-
`ologically 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 Cther of 0.2 ng/ml
`maint
`or greater which is maintained for a duration T
`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 Mg of
`buprenorphine hydrochloride, calculated as buprenorphine.
`Formulation A: buprenorphine hydrochloride-pectin solu-
`tion. Formulation B: buprenorphine hydrochloride-chitosan/
`hydroxypropylmethylcellulose (HPMC) solution. Formula-
`tion C: buprenorphine hydrochloride-chitosan/poloxamer
`188 solution. Also shown for comparison is the pharmaco-
`
`Page 5
`
`

`

`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`kinetic 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 Mg of
`buprenorphine hydrochloride, calculated as buprenorphine.
`
`[0039] FIG. 4 shows a pharmacokinetic profile for a 400
`pg dose of Formulation A. This profile was calculated from
`the data for the 800 pg dose of Formulation A. The phar-
`macokinetic profile for the 400 pg 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 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, tar-
`trate and lactate salts. The hydrochloride salt is preferred.
`
`[0041] The concentration of buprenorphine or buprenor-
`phine 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 buprenor-
`phine 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 pl 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
`pg 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
`4x400 pg,
`i.e. up to 1600 pg, of buprenorphine or the
`buprenorphine salt or ester, calculated as buprenorphine.
`
`[0043] The pectin is a gelling agent. The solution of the
`invention gels 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 conse-
`quently 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%. Apectin
`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 propor-
`tion 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
`
`Page 6
`
`represented as the percentage of the total number of car-
`boxyl 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 concen-
`tration 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 commer-
`cially. 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 con-
`tain a negligible concentration of divalent metal ions or there
`may no detectable divalent metal ions.
`
`[0047] Apectin 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. Ca2+ ions.
`
`[0048] Apectin-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. Aparticularly
`suitable pH is from 3.6 to 3.8. The pH may be adjusted to an
`appropriate value by addition of a physiologically accept-
`able 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 physiologi-
`cally 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 phe-
`nylethyl alcohol or propyl hydroxybenzoate (propylparaben)
`or one of its salts. The phenylethyl alcohol and the propy-
`
`Page 6
`
`

`

`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`lparaben or propylparaben salt are preferably used in com-
`bination. 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. Asolution 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 essen-
`tially of 0.1 to 10 mg/ml of buprenorphine or a physiologi-
`cally 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(C2H4O)8(C3H6O)b(C2H4O)aH wherein a is from 2 to
`130 and b is from 15 to 67, and water.
`
`In each case, the buprenorphine salt may be an acid
`[0054]
`addition salt or a salt with a base. Suitable acid addition salts
`
`are mentioned above. They include the hydrochloride, sul-
`phate, methane sulphonate, stearate, tartrate and lactate salts.
`The hydrochloride salt is preferred.
`
`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 pl spray of a solution
`containing 1 to 4 mg/ml of buprenorphine or a buprenor-
`phine salt or ester, calculated as buprenorphine, thus results
`in a clinical dose of 100 to 400 Mg 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 4x400 pg, i.e. up to 1600 pg,
`of buprenorphine or the buprenorphine salt or ester, calcu-
`lated 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 propor-
`tion of the N—acetyl groups have been removed through
`hydrolysis (deacetylation). Preferably, the chitosan is pro-
`duced 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 physi-
`ologically acceptable salts include salts with a pharmaceu-
`tically acceptable mineral or organic acid such as the nitrate,
`phosphate, lactate, citrate, hydrochloride and acetate salts.
`Preferred salts are chitosan glutmate and chitosan hydro-
`chloride.
`
`[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—(Cl-C6 alkyl) ethers of deacetylated chitin and O-acyl
`esters of deacetylated chitin. Derivatives also include modi-
`fied forms of a deacetylated chitin for example a deacety-
`lated 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 pref-
`erably water-soluble.
`
`[0055] The concentration of buprenorphine or buprenor-
`phine salt or ester in either solution is from 0.1 to 10 mg/ml,
`
`[0062] An aqueous solution of chitosan may be prepared
`by dissolving chitosan base or a derivative of chitosan base
`
`Page 7
`
`Page 7
`
`

`

`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`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 concentra-
`tion 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. Achitosan
`concentration of 5 mg/ml is particularly suitable.
`
`hydroxypropylmethylcellulose
`suitable
`[0064] Any
`(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° 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° 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 copoly-
`mer 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(C2H4O)(C3H50)b(C2H4O)aH
`
`[0067] 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.
`
`[0068] Such copolymers are known as poloxamers. Sev-
`eral different types of poloxamer are available commer-
`cially, 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
`a :a
`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.
`
`[0069] When the solutions contain a poloxamer, the polox-
`amer 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. Apreferred concentration
`is 100 mg/ml.
`
`[0070] Any suitable preservative may be present in the
`solution, in particular a preservative that prevents microbial
`spoilage of the solution. The preservative must be compat-
`ible with the other components of the solution. The preser-
`vative may be any pharmaceutically acceptable preservative,
`for example a quaternary ammonium compound such as
`benzalkonium chloride.
`
`Page 8
`
`[0071] The solution has a pH of from 3 to 4.8. Any pH
`within this range may be employed provided the buprenor-
`phine 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. Aparticularly 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 physi-
`ologically 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.
`
`[0072] Atonicity 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 iso-
`tonic or hypotonic. A sufficient amount of a tonicity adjust-
`ment 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.
`
`[0073] 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.
`
`[0074] The solutions may also contain other ingredients
`such as an antioxidant, chelating agent or other agent
`generally