`(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 (GB) ....................................... .. 0225040.5
`Oct. 28, 2002 (GB) ....................................... .. 02250413
`Oct. 28, 2002 (GB) ....................................... .. 0225042.1
`
`Publication Classi?cation
`
`(51) Int. Cl? .................... .. A61K 31/485; A61K 31/732
`(52) Us. 01. ............................................ .. 514/54; 514/282
`
`ABSTRACT
`(57)
`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
`?cation 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 or buprenor
`phine salt or ester may be delivered to the bloodstream to
`produce Within 30 minutes a therapeutic plasma concentra
`tion of buprenorphine, Cther, of 0.2 ng/ml or greater Which
`is maintained for a duration T
`of at least 2 hours.
`rnaint
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`Patent Application Publication Apr. 21, 2005 Sheet 1 of 2
`
`US 2005/0085440 A1
`
`FIGURE 1
`
`
`
`Plasma buprenorphine concentration (ng/ml)
`
`
`
`
`
`6.00
`
`5160 ‘
`
`is
`
`I
`
`_
`
`14°
`
`-‘
`
`1.60‘
`
`1.20-
`
`020
`
`S.
`
`Formulation A: Buprenorphinc<
`pectin solution (800 pg)
`
`__
`
`v
`
`.
`
`(400 Pg)
`
`'
`
`r
`
`‘
`
`Formulation D: IV buprenorphine
`
`"
`
`i
`
`i
`
`.
`
`-
`
`‘
`
`'
`
`0.40-
`
`}
`
`-
`
`0.00
`
`-
`
`'
`
`.
`
`.
`
`.
`
`150
`
`.
`
`no
`
`.
`
`210
`
`'
`
`.
`
`240
`
`.
`
`.
`
`?
`
`-170
`
`'
`
`300
`
`3:0
`
`:60’
`
`0
`
`1o
`
`,
`
`so
`
`>
`
`90
`
`120
`
`Time (minutes)
`
`FIGURE 2
`
`5400
`
`5.50 <
`
`5.20 -
`
`4.30 -
`
`4.40 ' _
`
`4.00 '
`
`3.60 -
`1.10 -i
`
`no‘ '
`
`14°-
`
`100 '
`
`1.50- *
`
`1.20‘
`
`I.
`
`v
`
`+ Formulation B: Buprenorphine
`' 'chitosan/HPMC solution (800 ng)
`
`' ~K---Formulation Dzlvbupreriorphine
`
`(400 Hg)
`
`'
`
`-
`
`.
`
`l 030
`
`0.40 '
`
`0.00
`
`0
`
`v
`
`3D
`
`-
`
`50
`
`.
`
`90
`
`l
`
`.
`
`[20
`
`.
`
`l
`
`.
`
`lit)
`130
`210
`Time (minutes)
`
`.
`
`240
`
`.
`
`170
`
`.
`
`JD!)
`
`.
`
`330
`
`350
`
`
`
`Plasma buprenorphine concentration (ng/ml)
`
`
`
`
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`Patent Application Publication Apr. 21, 2005 Sheet 2 0f 2
`
`US 2005/0085440 A1
`
`FIGURE 3
`
`
`
`
`
`
`
`Plasma buprenorphine concentration (ng/ml) Plasma buprenorphine concentration (ng/ml)
`
`
`
`
`
`
`
`
`
`5.00
`
`5.601 _
`
`5.20 ‘
`
`4.80 '
`
`4.40 '
`
`4.00 ‘
`
`3.60 - E
`
`3.10 '
`
`2.80 '
`
`2.40 "
`
`L
`
`1.00 ‘
`
`L60 ‘
`
`1.10 '
`
`0.80 ‘
`
`0.00 ‘
`
`6.00
`
`5.20
`
`4.80
`
`4.40
`
`4.00
`
`1.50
`
`_
`
`2. S0
`
`2. 40
`
`2.00
`
`l . 50
`
`1.20 ‘
`
`0.50
`
`0.40
`
`0.00
`
`-,=— Formulation C: Buprenorphine
`chitosan/poloxamer 188 solution (800 pg)
`
`- Formulation
`
`IV bupronorphine (400 pig)
`
`60
`
`I20
`
`I50
`
`I80
`
`2l0
`
`Z40 ’
`
`270
`
`J00
`
`J30
`
`- Time (minutes)
`
`FIGURE 4
`
`—~— Formulation Az- Buprenorphine-pectin
`solution'(400 pg model)
`
`-- x -- Formulation D: IV buprenorphine
`(400 Hg)
`
`30
`
`90
`
`I20
`
`150
`180
`210
`Time (minutes)
`
`240
`
`270
`
`300
`
`130
`
`360
`
`in
`
`'n
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`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) de?nes drugs With
`morphine-like properties. Opioids can be sub-classi?ed on
`the basis of their receptor speci?city. 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 ef?cacy
`mu agonists.
`[0004] Buprenorphine (CAS RN 52485-79-7; [5a,7ot(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 ef?cacy
`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
`
`?rst 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 esteri?cation
`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 pro?le 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 accept
`able salt or ester thereof and from 5 to 40 mg/ml of
`a pectin having a degree of esteri?cation 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 hydroxypro
`pylmethylcellulose (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,
`
`TEVA EXHIBIT 1004
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`
`
`
`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`[0019] (b) from 0.1 to 20 mg/ml of a chitosan, and
`[0020] (c) from 50 to 200 mg/ml of a polyoXyeth
`ylene-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;
`
`[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 1 to 6 mg/ml of buprenorphine or a
`physiologically acceptable salt or ester thereof, cal
`culated as buprenorphine,
`
`[0024] (b) from 10 to 40 mg/ml of a pectin Which has
`a degree of esteri?cation 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 esteri?cation
`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;
`
`[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(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;
`
`[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, ie 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
`concentration. The term T
`denotes the duration for
`rnaint
`Which Cther is maintained.
`[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
`T _‘ of at least 2 hours. Also provided are:
`
`main
`
`[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 Cther of 0.2 ng/ml
`or greater Which is maintained for a duration T
`rnaint
`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 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 Trnaint 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 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
`or greater Which is maintained for a duration T
`rnaint
`of at least 2 hours.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`[0038] FIGS. 1 to 3 shoW the pharmacokinetic pro?les 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 pg 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
`
`TEVA EXHIBIT 1004
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`
`
`US 2005/0085440 A1
`
`Apr. 21, 2005
`
`kinetic pro?le 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 pg of
`buprenorphine hydrochloride, calculated as buprenorphine.
`
`[0039] FIG. 4 shoWs a pharmacokinetic pro?le for a 400
`pg dose of Formulation A. This pro?le Was calculated from
`the data for the 800 pg dose of Formulation A. The phar
`macokinetic pro?le for the 400 pg dose of Formulation D is
`also shoWn for comparison.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0040] A ?rst 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 esteri?cation, in
`particular a degree of esteri?cation 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 esteri?cation 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 esteri?cation
`The term DE is
`Well understood by those skilled in the art and may be
`
`represented as the percentage of the total number of car
`boXyl groups that are esteri?ed, ie if four out of ?ve acid
`groups is esteri?ed this represents a degree of esteri?cation
`of 80%, or as the methoXyl content of the pectin. DE as used
`herein refers to the total percentage of carboXyl groups that
`are esteri?ed. Pectins can be categorised into those having a
`loW degree of esteri?cation (loW methoXylation) or a high
`degree of esteri?cation (high methoXylation). A“loW DE” or
`“LM” pectin has a degree of esteri?cation beloW 50%
`Whereas a “high DE” or “HM” pectin has a degree of
`esteri?cation 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
`esteri?cation 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 ?uid as described in WO
`98/47535. The degree of esteri?cation of the pectin used in
`the invention is preferably less than 35%. The degree of
`esteri?cation 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 esteri?cation 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
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`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
`?nal solution through a sterilising ?lter. 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)a(C3H6O)b(C2H4O)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, sul
`phate, methane sulphonate, stearate, tartrate and lactate salts.
`The hydrochloride salt is preferred.
`
`[0055] The concentration of buprenorphine or buprenor
`phine 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 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 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, 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—(C1-C6 alkyl) ethers of deacetylated chitin and O-acyl
`esters of deacetylated chitin. Derivatives also include modi
`?ed 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.
`[0062] An aqueous solution of chitosan may be prepared
`by dissolving chitosan base or a derivative of chitosan base
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`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.
`[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° C. as measured by a cone and plate viscometer (e.g.
`Brook?eld), 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
`
`[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
`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.
`
`[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