Europaisches Patentamt
`
`0)
`
`Eumpean Patent Office
`
`Office européen des brevets
`
`63 Publication number:
`
`0 069 600
`
`A2
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@Application number: 823035823
`
`@ Date offiling: 08.07.82
`
`@ lnt.Cl.3: A 61 K 31/485
`A 61 K 9/08
`
`@ Priority: 10.07.81 GB 8121315
`
`@ Applicant: RECKITI' AND COLMAN PRODUCTS
`LIMITED
`
`@ Date of publication of application:
`’
`12.01.83 Bulletin 83/2
`'
`Designated Contracting States:
`BECHDEFRITLILU NLSE
`
`
`
`
`
`PO. Box 26 1-17, Burlington Lane
`London W4 2RWlGB)
`
`® Inventor: Todd, Richard Sydney
`37 Burton Road
`Cottingham North HumbersidelGBl
`
`Representative: Hardisty, David Robert et al,
`BOULT, WADE & TENNANT 27 Furnival street
`London EC4A lPOlGB)
`
`@ Pharmaceutical compositions.
`
`@ A pharmaceutical composition for sublingual adminis-
`tration comprising buprenorphine or a non-toxic salt thereof
`dissolved in 20-30% v/v aqueous ethanol buffered to be-
`tween pH 4.5 to 5.5 with 0.05 to 0.2 molar concentration of a
`buffering agent selected from citric acid/disodium hydrogen
`phosphate, sodium citrate/hydrochloric acid,
`lactic acid/
`disodium hydrogen phosphate,
`lactic acid/sodium lactate,
`sodium citrate/citric acid and sodium acetate/acetic acid, the
`concentration of buprenorphine being between 0.8 and 10
`mg/ml of the composition. Buprenorphine is a potent
`antagonist analgesic with good bioavailability following
`sublingual administration, useful in the relief of moderate to
`N severe pain and also in the treatment of natcotic addiction.
`< The compositions enable higher doses of buprenorphine to
`be administered sublingually.
`
`EP0069600
`
`Page 1 m BDSI EXHIBIT 1038
`
`Page 1
`
`
`
`0)
`
`Eumpean Patent Office
`
`Office européen des brevets
`
`63 Publication number:
`
`0 069 600
`
`A2
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@Application number: 823035823
`
`@ Date offiling: 08.07.82
`
`@ lnt.Cl.3: A 61 K 31/485
`A 61 K 9/08
`
`@ Priority: 10.07.81 GB 8121315
`
`@ Applicant: RECKITI' AND COLMAN PRODUCTS
`LIMITED
`
`@ Date of publication of application:
`’
`12.01.83 Bulletin 83/2
`'
`Designated Contracting States:
`BECHDEFRITLILU NLSE
`
`
`
`
`
`PO. Box 26 1-17, Burlington Lane
`London W4 2RWlGB)
`
`® Inventor: Todd, Richard Sydney
`37 Burton Road
`Cottingham North HumbersidelGBl
`
`Representative: Hardisty, David Robert et al,
`BOULT, WADE & TENNANT 27 Furnival street
`London EC4A lPOlGB)
`
`@ Pharmaceutical compositions.
`
`@ A pharmaceutical composition for sublingual adminis-
`tration comprising buprenorphine or a non-toxic salt thereof
`dissolved in 20-30% v/v aqueous ethanol buffered to be-
`tween pH 4.5 to 5.5 with 0.05 to 0.2 molar concentration of a
`buffering agent selected from citric acid/disodium hydrogen
`phosphate, sodium citrate/hydrochloric acid,
`lactic acid/
`disodium hydrogen phosphate,
`lactic acid/sodium lactate,
`sodium citrate/citric acid and sodium acetate/acetic acid, the
`concentration of buprenorphine being between 0.8 and 10
`mg/ml of the composition. Buprenorphine is a potent
`antagonist analgesic with good bioavailability following
`sublingual administration, useful in the relief of moderate to
`N severe pain and also in the treatment of natcotic addiction.
`< The compositions enable higher doses of buprenorphine to
`be administered sublingually.
`
`EP0069600
`
`Page 1 m BDSI EXHIBIT 1038
`
`Page 1
`
`
`
`0069600
`
`_
`
`1 -
`
`.
`
`Pharmaceutical Compositions
`
`This invention relates to pharmaceutical
`
`compositions and more particularly to compositions
`
`containing buprenorphine.
`
`Buprenorphine (International Non-proprietary Name
`
`for N-cyclopropylmethyl-7a—(l—(S)—hydroxy-l,2,2—trimethyl-
`
`propyl)6,l4-endoethano-6,7,8,l4-tetrahydronororipavine)
`
`has been shown in clinical trials to be a potent
`
`antagonist analgesic lacking the psychotomimetic effects
`
`found with other antagonist analgesics. Buprenorphine
`
`10
`
`effectively relieves moderate to severe pain in doses of
`
`0.15mg or more administered either parenterally or
`
`sublingually.
`
`The optimum therapeutic range for single
`
`doses is 0.3mg — 0.6mg by injection and 0.2 — 0.4mg for
`
`sublingual tablets.
`
`The drug has also been shown to
`
`15
`
`have utility in the treatment of narcotic addiction.
`
`In patients suffering from a chronic condition such as
`
`intractable (cancer) pain or requiring treatment for
`
`narcotic addiction multi-dosing and/or higher dosage
`
`levels are required.
`
`To avoid patient discomfort from
`
`20
`
`too frequent injections the sublingual route is indicated,
`
`since the drug is poorly absorbed orally. With a tablet
`
`presentation there is a physical limit to the number of
`
`tablets which can be retained under the tongue at any one
`
`time and as a result there can be considerable patient
`
`25
`
`variability as to the blood levels of the drug and hence
`
`Page 2
`
`Page 2
`
`
`
`0069600
`
`its biological effects.
`
`We have carried out investigations in an attempt
`
`to produce a liquid composition containing buprenorphine
`which can be administered sublingually. Our studies have
`
`5
`
`shown that the maximum volume of liquid that a patient
`
`can hold sublingually for a reasonable amount of time
`
`without swallowing is lml and that a smaller volume is
`
`preferred say 0.5ml.
`
`We have found it very difficult to prepare stable
`
`10
`
`aqueous solutions of adequate concentration for
`
`sublingual administration. We have discovered in
`
`patients that using solutions buffered at pH's 4,
`
`5 and
`
`6 respectively with citric acid/disodium hydrogen
`
`phosphate buffer that following administration of a
`
`15
`
`400ug/O.5m1 dose of buprenorphine hydrochloride by the
`
`subligual route that the degree of uptake of the drug
`
`was greater at the two higher pH's.
`
`We have now developed stable liquid compositions
`
`containing buprenorphine at a high concentration
`
`20
`
`suitable for sublingual administration.
`
`According to the present invention there is
`
`provided a pharmaceutical composition for sublingual
`
`administration comprising buprenorphine or a non-toxic
`
`salt thereof dissolved in 20-30% v/v aqueous ethanol
`
`25
`
`buffered to between pH 4.5 to 5.5 with 0.05 to 0.2 molar
`
`concentration of a buffering agent selected from citric
`
`acid/disodium hydrogen phosphate, sodium citrate/hydro-
`
`chloric acid, lactic acid/disodium hydrogen phosphate,_
`
`Page 3
`
`Page 3
`
`
`
`0069600
`
`-3-
`
`lactic acid/sodium lactate,sodium citrate/citric acid
`
`and sodium acetate/acetic acid,
`
`the concentration of
`
`buprenorphine being between 0.8 and 10 mg/ml of the
`
`composition.
`
`A preferred salt is the hydrochloride. Preferably
`
`the molar concentration of the buffering agent
`
`is
`
`between 0.1 and 0.15.
`
`The sodium citrate in the sodium citrate/hydro—
`
`chloric acid or sodium citrate/citric acid buffering
`
`agent can be the trisodium or disodium salt according
`
`to the pH required.
`
`By means of the present invention it is possible
`
`to administer doses of between 0.4 to 5.0mg of
`
`buprenorphine in 0.5ml of solution sublingually.
`
`Patients requiring such high doses will normally be in
`
`an institution where self administration will not be the
`
`norm.
`
`The composition will normally be administered
`
`by a doctor or medically trained personnel using for
`
`example a suitable dispenser.
`
`If the dispenser is
`
`calibrated a lesser metered amount can be administered
`
`if a lesser dosage is required particularly in the
`
`treatment of intractable pain where is it desirable to
`
`keep doses low initially to give adequate pain relief
`
`but with the opportunity of increasing the dosage if
`
`and when it becomes necessary.
`
`The composition may also
`
`be presented in a unit dosage form in a form—fill-seal
`
`plastics container with a nominal volume of 0.5 to 1.0ml,
`
`suitably the plastics being polythene or polypropylene.
`
`10
`
`15
`
`20
`
`25
`
`Page 4
`
`Page 4
`
`
`
`_ 4 -
`
`0069600
`
`An example of such a plastics coutainer is Minims
`
`(Registered Trade Mark, Smith & Nephew).
`
`The invention is illustrated by the following
`
`Examples:-
`
`5
`
`Example 1
`
`Preparation of 10mg/ml buprenorphine solution
`
`10ml of a lOmg/ml buprenorphine solution in a pHS _
`
`mixture of a~30% v/v aqueous ethanol:
`
`citric acid/disodium
`
`hydrogen phosphate buffer was prepared as follows:
`
`10
`
`l.
`
`The buffer was prepared by mixing 3.8ml 0.1 M
`
`citric acid (Zlgll of monohydrate) and 3.2m1 0.2 M
`
`disodium hydrogen phosphate (35.6g/l of dihydrate).
`
`2.
`
`3.0ml 95% v/v ethanol was added to the buffer
`
`increasing the pH from ~4.6 to ~5.0.
`
`15
`
`3.
`
`108mg buprenorphine hydrochloride was added with
`
`stirring until dissolved.
`
`Examples 2 to 13
`
`The formulation of Example 1 was varied by employing
`
`differing volumes and molar strengths of the citric acid
`
`20
`
`and disodium hydrogen phosphate solutions, and differing
`
`volumes of the 95% v/v ethanol, and in some cases adding
`
`additional water before dissolving the buprenorphine
`
`hydrochloride.
`
`In the Table, Vol = volume, M = Molarity
`
`and the pH is that of buffer plus ethanol.
`
`PageS
`
`Page 5
`
`
`
`_
`
`5
`
`_
`
`Table
`
`0069600
`
`Ex. Citric acid
`V61. Mol.
`
`Addit. Ethanol Overall
`Phosphate
`Vbl.
`Nbl. water
`Vbl.
`Ethanol
`
`pH
`
`m1
`
`M
`
`ml
`
`M
`
`ml
`
`ml
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`4.2
`
`0.1
`
`2.8
`
`0.2
`
`0.9
`
`4.25
`
`0.1
`
`2.75
`
`0.2
`
`-
`
`3.6
`
`3.4
`
`0.1
`
`0.1
`
`3.4
`
`3.6
`
`0.2
`
`0.2
`
`0.9
`
`-
`
`4.2
`
`0.05
`
`2.8
`
`0.1
`
`0.9
`
`3.7
`
`0.05
`
`3.3
`
`0.1
`
`0.9
`
`2.1
`
`3.0
`
`2.1
`
`3.0
`
`2.1
`
`2.1
`
`10
`
`% v/v
`conc.
`
`20.0
`
`28.5
`
`20.0
`
`28.5
`
`20.0
`
`20.0
`
`4.5
`
`4.5
`
`5.0
`
`5.5
`
`4.5
`
`5.0
`
`5.0
`
`8
`
`9
`
`3.8
`
`0.05
`
`3.2
`
`0.1
`
`3.5
`
`0.05
`
`3.5
`
`0.1
`
`—
`
`-
`
`10
`
`4.1
`
`0.2
`
`2.9
`
`0.4
`
`0.9
`
`11
`
`3.6
`
`0.2
`
`3.4
`
`0.4
`
`0.9
`
`3.0
`
`3.0
`
`2.1
`
`2.1
`
`28.5
`
`28.5
`
`20.0
`
`20.0
`
`15
`
`12
`
`3.75
`
`0.2
`
`3.25
`
`0.4
`
`—
`
`3.0
`
`28.5
`
`13
`
`3.3
`
`0.2
`
`3.7
`
`0.4
`
`, -
`
`3.0
`
`28.5
`
`5.5
`
`4.5
`
`5.0
`
`5.0
`
`5.5
`
`Examples 14—18
`
`The method of Example 1 was varied by employing a
`
`similar volume of differing buffers as follows:
`
`20
`
`Example 14
`
`Sodium citrate/hydrochloric acid: mixed 5.6 ml 0.2M
`
`disodium citrate (42.0gcitric acid monohydrate +400 ml
`
`1 N sodium hydroxide/l) and 1.4 m1 0.2M hydrochloric
`
`acid.
`
`On adding the ethanol
`
`the pH increased from
`
`25
`
`”4.6 to ~5.0.
`
`Example 15
`
`Lactic acid/disodium hydrogen phosphate: mixed
`
`4.0 m1 0.2M lactic acid (20.4g/l of 88% lactic acid) and
`
`Page 6
`
`Page 6
`
`
`
`- 6
`
`—
`
`0069600
`
`3.0 ml 0.2M disodium hydrogen phosphate (35.6g/l of
`
`dihydrate).
`
`On adding the ethanol
`
`the pH increased
`
`from 4.5 to ~5.0.
`
`Example 16
`
`Lactic acid/sodium lactate: mixed 1.3 ml 0.2M
`
`lactic acid (20.4g/l of 88% lactic acid) and 5.7 m1
`
`0.2M sodium lactate (20.4g of 88% lactic acid +200ml
`
`l N sodium hydroxide/l). On adding the ethanol the pH
`
`increased from 4.5 to ~5.0.
`
`10
`
`Example 17
`
`Sodium citrate/citric acid: mixed4.15m1 0.2M
`
`sodium citrate (58.8g/l trisodium citrate dihydtate) and
`
`2.85fl.0.2M citric acid (42.0g/1 citric acid monohydrate).
`
`On adding the ethanol
`
`the pH increased from‘4.6 to ~5.0.
`
`ExamEle 18
`
`Sodium acetate/acetic acid: mixed 3.5 ml 0.2M
`
`sodium acetate (16.4g/l) and 3.5 ml 0.2M acetic acid
`
`(12.0g/l).
`
`0n adding the ethanol
`
`the pH increased from
`
`”4.6 to "5.0.
`
`Page 7
`
`Page 7
`
`
`
`_
`
`7
`
`_
`
`0069600
`
`Claims
`
`1.
`
`A pharmaceutical composition for sublingual
`
`administration comprising buprenorphine or a non—toxic
`
`salt thereof dissolved in 20-30% v/v aqueous ethanol
`
`buffered to between pH 4.5 to 5.5 with 0.05 to 0.2
`
`molar concentration of a buffering agent selected from
`
`citric acid/disodium hydrogen phosphate, sodium citrate/
`
`hydrochloric acid, lactic acid/disodium hydrogen phosphate
`
`lactic acid/sodium lactate, sodium citrate/citric acid
`
`and sodium acetate/acetic acid,
`
`the concentration of
`
`buprenorphine being between 0.8 and 10 mg/ml of the
`
`composition.
`
`2.
`
`A pharmaceutical composition as claimed in claim 1
`
`wherein the buprenorphine salt is the hydrochloride.
`
`3.
`
`A pharmaceutical composition as claimed in claim
`
`1 or claim 2 wherein the molar concentration of the
`
`buffering agent is between 0.1 and 0.15.
`
`4.
`
`A pharmaceutical composition as claimed in claim
`
`2 wherein the buffering agent
`
`is citric acid/disodium
`
`hydrogen phosphate.
`
`DRH/EA654
`
`Page 8
`
`Page 8
`
`
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