(71) Applicant (for all designated States except US): FARMA-
`
`(21) International Application Number:
`
`PCT/EP99/O7595
`
`(22) International Filing Date:
`
`11 October 1999 (11.10.99)
`
`(30) Priority Data:
`MI98A002222
`
`16 October 1998 (16.10.98)
`
`
`27 April 2000 (27.04.00)
`(43) International Publication Date:
`
`
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`
`
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`
`
`
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`
`
`SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
`
`IT
`US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
`
`
`LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
`
`
`AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
`
`
`BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`
`
`MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
`
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`
`Published
`
`With international search report.
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(51) International Patent Classification 7 :
`WO 00/23079
`(11) International Publication Number:
`A61K 31/485, 9/00
`
`
`
`CEUTICI FORMENTI S.P.A. [IT/IT]; Via Correggio, 45,
`I—20149 Milano (IT).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): VALENTI, Mauro [IT/IT];
`Via di Vittorio, 2, 1—21040 Origgio (IT).
`
`
`
`
`
`(74) Agent: MINOJA, Fabrizio; Bianchetti Bracco Minoja Srl, Via
`Rossini, 8, I—20122 Milano (IT).
`
`
`(54) Title: ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING BUPRENORPHIN
`
`(57) Abstract
`
` An oral pharmaceutical composition containing buprenorphin or a pharmaceutically acceptable salt thereof as the active ingredient,
`
`
`characterised in that it contains a pharmaceutically acceptable antioxidant.
`
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`
`Zimbabwe
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Albania
`ES
`LS
`Lesotho
`SI
`Armenia
`FI
`LT
`Lithuania
`SK
`Austria
`FR
`LU
`SN
`Luxembourg
`Australia
`GA
`LV
`Latvia
`SZ
`GB
`MC
`Monaco
`TD
`Azerbaijan
`GE
`MD
`TG
`Bosnia and Herzegovina
`Republic of Moldova
`Barbados
`GH
`MG
`TJ
`Madagascar
`MK
`GN
`TM
`Belgium
`The former Yugoslav
`Burkina Faso
`GR
`TR
`Republic of Macedonia
`HU
`Mali
`TT
`Bulgaria
`Benin
`IE
`UA
`Mongolia
`IL
`Brazil
`UG
`Mauritania
`Belarus
`IS
`Malawi
`IT
`Canada
`Mexico
`JP
`Central African Republic
`Niger
`KE
`Netherlands
`Congo
`Switzerland
`KG
`Norway
`KP
`Céte d’Ivoire
`New Zealand
`Cameroon
`Poland
`China
`Portugal
`Cuba
`Romania
`Russian Federation
`Czech Republic
`Sudan
`Germany
`Denmark
`Sweden
`Estonia
`Singapore
`
`KR
`KZ
`LC
`LI
`
`LR
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING BUPRENOR-
`
`PHIN
`
`The present
`
`invention relates to oral pharmaceutical compositions,
`
`in
`
`particular to compositions containing buprenorphin as active ingredient. These
`
`compositions are particularly stable with respect to the commercially available
`
`products.
`
`Background of the invention.
`
`_
`
`Buprenorphin,
`
`namely
`
`21 —cyclopropyl-7a—(2—hydroxy-3,3-dimethyl-
`
`2butyl-)-6,14-endo-ethano-6,7,8,18—tetrahydroripavine,
`
`is a morphine alkaloid
`
`with analgesic properties.
`
`Its preparation is disclosed in US 3433791, for a
`
`review see J.W.Lewis in Advan. Biochem. Psychopharmacol. Vol. 8, MC.
`
`Braude et al. eds. (RaveniPress, New York, 1974).
`This
`analgesic
`is marketed under
`the
`trade marks TEMGESIC,
`
`BUPRENEX, LEPETAN.
`
`Sublingual
`
`tablets containing buprenorphin as active ingredient,
`
`for
`
`example TEMGESIC 0.2 and 0.4 mg, show the presence of products from the
`
`degradation of the active ingredient.
`
`Disclosure of the invention
`
`It has now been found that the addition of pharmaceutically acceptable
`
`antioxidants gives oral pharmaceutical compositions, containing buprenorphin
`
`or a pharmaceutically acceptable salt
`
`thereof as active ingredient, a
`
`particularly good stability, decreasing the formation of
`
`the degradation
`
`products.
`
`Advantageously, the oral pharmaceutical compositions according to the
`
`present invention are more stable than the presently available dosage forms
`
`of the state of the art, hence they have a longer shell-life.
`
`Therefore, it is an object of the present invention an oral pharmaceutical
`
`composition containing buprenorphin or a pharmaceutically acceptable salt
`
`thereof as active ingredient characterised in that it contains a pharmaceutically
`
`acceptable antioxidant in addition to conventional vehicles and eccipients.
`
`10
`
`15
`
`20
`
`25
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`2
`
`This and other objects of the present invention will be disclosed in detail,
`
`also by means of examples.
`
`Detailed disclosure of the invention
`
`Pharmaceutically acceptable antioxidants are well known to the person
`
`5
`
`skilled in the art and are described in the technical literature forming the general
`
`common knowledge. A source of information,
`
`for example, can be found in
`
`"Remington’s Pharmaceutical Sciences Handbook", Mack Pub. NY. USA.
`
`A first group of preferred antioxidants comprises ascorbic acid,
`
`its salts
`
`and esters, Vitamin E, tocopherol and its salts, sodium metabisulphite, butylated
`
`1O
`
`hydroxyanisole (BHA), butylated hydroxytoluene (BHT).
`
`A more preferred group of antioxidants comprises ascorbic acid, sodium
`
`metabisulphite, Vitamin E, alpha-lipoic acid.
`
`The most preferred antioxidant is ascorbic acid.
`
`The molar ratio between the antioxidant and buprenorphin is at least 1:1,
`
`15
`
`more preferably 3:1.
`
`The commercial
`
`formulations contain magnesium ions due to the
`
`presence of magnesium stearate, a well-known lubricant.
`
`It has surprisingly been found that significantly better results are achieved
`
`if the presence of magnesium ion is avoided in the formulation of the present
`
`20
`
`invention. Therefore, a further object of the present
`
`invention is an oral
`
`formulation containing buprenorphin or a pharmaceutically acceptable salt
`
`thereof as active ingredient characterised in
`
`that
`
`it
`
`further contains a
`
`pharmaceutically acceptable antioxidant and in that the magnesium ion is
`
`absent.
`
`25
`
`in a first embodiment of this further aspect of the invention, magnesium
`
`stearate is substituted by another lubricant. Hydrogenated castor oil
`
`is a
`
`preferred example.
`
`It has further surprisingly been found that significant results are also
`
`achieved if the presence of magnesium ion is avoided and the buffer system is
`
`30
`
`changed in the formulation of the present invention. Therefore, a further object
`
`of the present invention is an oral formulation containing buprenorphin or a
`
`pharmaceutically acceptable salt thereof as active ingredient characterised in
`
`

`

`W0 (JO/23079
`
`PCT/EP99/07595
`
`3
`
`that it further contains a pharmaceutically acceptable antioxidant,
`
`in that the
`
`magnesium ion is absent and in that the buffer system differs from that of the
`
`commercial formulations.
`
`In a preferred embodiment of
`
`this
`
`further aspect of
`
`the invention,
`
`glycine/hydrochloric acid is the buffer system.
`
`The formulations obtained according to this further aspects of the present
`
`invention, are fully satisfactory in view of the stability of the active ingredient,
`
`but have a poor external aspect, so that the consumers could not accept
`them.
`
`While searching to improve the stability of the oral
`
`formulation, by
`
`reducing the amount of degradation products, and maintaining a good
`
`external aspect
`
`it has surprisingly been found that
`
`the elimination of
`
`polyvinylpyrrolidone, even keeping magnesium stearate as lubricant, and
`
`without changing the buffer system,
`
`gives very good results. Therefore, a
`
`further aspect of the present invention is an oral pharmaceutical composition
`
`containing buprenorphin or a pharmaceutically acceptable salt thereof as
`
`active ingredient characterised in that it further contains a pharmaceutically
`
`acceptable antioxidant and in that it does not contain polyvinylpyrrolidone.
`
`The present invention applies to oral dosage forms. Oral dosage forms
`
`are conventionally known in the art, and no particular disclosure is herein
`
`needed,
`
`since they can be prepared by resorting to general common
`
`knowledge as provided by textbooks, manuals and other technical literature,
`
`which are normally available.
`
`Examples of oral dosage forms are pills, capsules,
`
`tablets, powders,
`
`solutions, suspensions and the like.
`
`in a preferred embodiment of this
`
`invention, oral compositions are in the form of sublingual tablets.
`
`Commercial batches of TEMGESIC having the same quail-quantitative
`
`composition were replicated (hereinafter referred to as "FRT") and tested for
`
`stability together with a batch of TEMGESIC as available on the market.
`
`Stability protocols were designed as outlined in Table 1 below:
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`4 T
`
`ABLE 1
`
`STABILITY PROTOCOLS
`
`Batch FRT 10097
`
`Batch FRT 16097
`
`0.4 mg
`
`0.2 mg
`
`Batch Temgesic T19501
`
`0.2 mg
`
`1.
`
`IN GLASS VIALS
`
`Temperatu re
`
`50°C
`
`
`25° C +60%R
`
`0°C + 70%R
`
`40° C + 75%R
`
`RH = Relative humidity
`
`‘
`
`The studies were directed at the determination of the titre of the active
`
`10
`
`ingredient and of the related degradation products.
`
`TABLE 2 shows the results.
`
`

`

`PCT/EP99/O7595
`
`,—
`
`0 T
`
`ABLE 2
`
`Stability studies in giass viais.
`
`WO 00/23079
`
`
`
`Batch 10097
`0.4 m .
`
`Batch 16097
`0.2 m-
`
`Temgesic
`Batch T19501 0.2 m-
`
`
`
`96.82%
`
`7.22%
`
`97.8%
`
`5.62%
`
`
`Tern nerature 30°C + 70% R.H.
`
`90.45%
`
`7.49%
`
`96.10%
`
`
`
`2.97%
`
`91.16%
`
`7.97%
`
`
`88.16%
`
`
`
`10.51%
`
`WWWWMM
`
`
`
`
`
`
`
`a 99.29%
`
`
`
`
`
`
`
`
`94.65%
`
`
`94.62%
`
`_
`
`v
`
`98.78%
`
`m 99.29%
`
`
`
`
`
`
`
`
`Titre in
`Total
`Titre in
`Total
`Titre in
`Total
`
`
`
`Bupre-
`degrada- Bupre-
`degrada- Buprenor- degrada-
`
`
`
`
`
`
`norphin
`tion
`norphin
`tion
`phin
`tion
`
`
`
`
`
`
`. rod ucts
`. roducts
`,, . dut 7
`
`
`
`
`
`
`
`Tern oerature 25°C + 60% R.H.
`__...,H
`
`
`a 99.29%
`1.19%
`99.40%
`1.84%
`96.10%
`2.97%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`erature C + 75% hHm
`
`
`99.40%
`
`1.84%
`
`97.57%
`
`5.71%
`
`97.80%
`
`5.62%
`
`97.78%
`
`1.19%
`
`8.05%
`
`9.42%
`
`2.31%
`
`1.19%
`
`
`
`
`
`Tem oerature 50°C
`99.40%
`
`v‘uu.
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`6
`
`Three batches of buprenorphin tablets were prepared according to the
`
`present
`
`invention,
`
`each batch containing a different pharmaceutically
`
`acceptable antioxidant. The compositions of the batches are shown in Table
`
`3 below.
`
`The molar ratio antioxidant/buprenorphin is 1/1.
`
`TABLE 3
`
`FORMULATIONS
`
`lNGREDlENT
`NAME
`
`Buprenorphin
`hydrochloride
`
`Equivalent to
`BUorenorohin
`
`Antioxidant
`
`Lactose
`
`Maize starch
`
`Mannitol
`
`
`
`Polvvinvl- rrolidone
`
`Anh drous Citric Acid
`
`Sodium Citrate 2H70
`
`
`
`.
`
`
`
`9.000 m 9.000 mo
`
`18.000 m i
`
`18.000 m
`
`1.200 mo1.200 m
`
`0.888 m.
`
`0.405
`
`mo
`
`0.888 mu
`
`0.405 m
`
`ExamleZ
`Exam'le 1
`Sodium
`Vitamin C
`Batch 23038 Metabisulphite
`Batch 24038 .
`
`
`
`0.216
`
`mg
`
`:
`0.200 m.
`
`0.151
`
`m-
`
`29.690 mo
`
`0. 216 mg
`
`0.200 mu
`
`0.163 m
`
`29.678 mo
`
`Exam-le 3
`Vitamin E
`Batch 25038
`
`0.216
`
`mg
`
`0.200
`
`m-
`
`0.405
`
`m-
`
`29.436 m-
`
`9.000 m
`
`18.000 m-
`
`1.200
`
`m-
`
`0.888
`
`m-
`
`.
`
`0.405 m
`
`
`
`Maonesium Stearate
`
`0.450 m.
`
`0.450 mo
`
`0.450
`
`m-
`
`

`

`W0 (JO/23079
`
`PCT/EP99/07595
`
`7
`
`The batches were tested for stability according to the experimental
`
`protocol shown in Table 4 below.
`
`TABLE 4
`
`STABILITY PROTOCOLS
`
`(In glass vials)
`
`
`“mm
`
`
`
`_--——-:
`
`
`
`
`°
`'
`x --
`
`
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`8
`
`The results are shown in tables 5-7 below.
`
`TABLE 5
`
`Buprenorphin tablets 0.2 mg - Batch 23038 with Vit. C 1/1
`
`Conditions
`
`Time
`
`
`Titre in
`Total
`
`
`
`
`
`Degradatmn
`Buprenorphin
`
`0 roducts _
`7m .
`
`
`
`
`
`
`
`I
`_— mooo
`
`0.11%
`I
`' 25°C + 60% RH.
`1 month
`100.63%
`
`
`
`
`
`25°C + 60% RH.
`2 months
`100.90%
`
`
`
`
`
`
`
`
`102.54%
` 0.5 months
`
`97.73%
`
` 1 month
`93.34%
`
`

`

`wo 00/23079
`
`PCT/EP99/07595
`
`9 T
`
`ABLE 6
`
`Buprenorphin tablets 0.2 mg - Batch 24038 with Metabis. 1l1
`
`Conditions
`
`Titre in
`
`Total ’
`
`Buprenorphin
`
`Degradation
`
`
`
`
`
`25°C + 60% RH
`
`25°C + 60% RH.
`
`99.60%
`
`100.91%
`
`25°C + 60% RH.
`
`98.06%
`
`40°C + 75% RH.
`
`0.5 months
`
`101.10%
`
`40°C+75% R.H
`
`¥
`
`1 month
`
`99.79%
`
`2 months
`
`99.78% ’
`
`3 months
`
`98.41%
`
`0.5 months
`
`101.42%
`
`2 months
`
`99.06%
`
`3 months
`
`99.62%
`
`0.5 months
`
`93.48%
`
`1 month
`
`90.54%
`
`

`

`W0 00/23079
`
`PCT/EP99/07595
`
`10
`
`TABLE 7
`
`Buprenorphin tablets 0.2 mg - Batch 25038 with Vit. E 1/1
`
`
`
` Total
`Conditions
`
`
`Degradation
`
`Buprenorphin
`
`Titre in
`
`25°C + 60% RH.
`
`1 month
`
`
`
`
`
`
`
`
`25°C + 60% RH.
`2 months
`
` 3 months
`
`25°C + 60% RH.
`
`
`
`
`40°C + 75%
`0.5 months
`
`
`
`1 month
`98.35%
`
` 2 months
`102.64% «
` 40°C + 75%
`
`
`
`
`2 months
`95.78%
`
`
`3 months
` 0.5 months
`
`
`94.60%
` 1 month
`
`100.20%
`
`3 months
`
`95.40%
`
`0.5 months
`
`98.41%
`
`40°C + 75% RH.
`
`40°C + 75% RH.
`
`50°C
`
`95.48%
`
`89.49%
`
`

`

`wo 00/23079
`
`PCT/EP99/07595
`
`1 1
`
`The compositions according to the present invention are more stable than
`
`those commercially available and those replicated by Formenti.
`
`It shall be noted that ascorbic acid gives very good results. The total
`
`amount of degradation products is by far lower than the one found in
`
`commercial products, even in the worst conditions of experimental protocol.
`
`Sodium metabisulphite and Vitamin E give the same results.
`
`Another embodiment of the present invention is disclosed in the following.
`
`Three batches were prepared according to the experimental design of Table 8
`
`below. Ascorbic acid is used in a molar ratio of 3/1 with respect to the active
`
`1O
`
`ingredient. In a second batch, magnesium ion is eliminated and an alternative
`
`lubricant is used.
`
`In a third batch, together the alternative lubricant, also a
`
`different buffer system is used.
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`12
`
`TABLE 8
`
`FORMULATIONS
`
`
`
`INGREDIENTS
`
`Example 4
`
`Example 5
`
`Example 6
`
`Batch 08048
`
`Batch 09048
`
`
`
`
`
`
`Batch10048
`
`
` Buprenorphin
`
`
`Hydrochloride
`
`
`
`
`
`
`Buprenorphin
`9
`9
`
`
`
`
`Equivalent to
`
`Vitamin C
`
`Lactose
`
`Maize starch
`
`Mannitoi
`
`Polyvinyipyrroiidone
`
`Anhydrous Citric Acid
`
`
`
`
`
`
`_
`18.000 mg
`
`i
`1.200
`m(D
`
`
`
`
`
`
`0.888 m —
`
`
`
`
`Sodium Citrate. 2HZO
` Magnesium Stearate
`
`
` Hydrogenated castor
`oil
`
`
` Glycine/Hydrochloric
`acid
`
`Hydrochloric Acid to
`o H 3.3
`
`
`
`
`
`
`
`0453
`
`mg
`
`0.453
`
`m
`
`0.453
`
`m
`
`29.388 mg
`
`29.238 m.
`
`29.379 m
`
`9.000
`
`m
`
`o
`
`9.000
`
`mo
`
`4‘ 18.000 m-
`
`18.000 mo
`
`1.200
`
`I
`
`m
`
`1.200 m
`
`9.000
`
`mg
`
`0.888
`
`mg
`
`0.405
`
`mg
`
`0.450
`
`mg
`
`
`
`
`
`
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`1 3
`
`Stability protocols are the same as the former tests.
`
`The results are shown in tables 9-11 below.
`
`TABLE 9
`
`Buprenorphin tablets 0.2 mg - Batch 23038 with Vit. C 1/1
`
`Titre in
`
`Total
`
`Buprenorphin
`
`Degradation.
`
`Products
`
`0.16%
`
`
`
`25°C + 60% RH.
`
`25°C + 60% RH.
`
`99.30%
`
`103.23%
`
`25°C + 60% RH.
`
`. 102,17%
`
`40°C +75% .
`
`40°C+75% .
`
`.
`
`.
`
`0.5 months
`
`102.98%
`
`1 month
`
`103,35%
`
`40°C + 75% .
`
`.
`
`2 months
`
`102.52%
`
`2 months
`
`103.41%
`
`3 months
`
`100.74%
`
`1 month
`
`92.02%
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`14
`
`TABLE 10
`
`Buprenorphin tablets 0.2 mg - Batch 09048 with Vit. C 3/1
`
`Conditions
`
`Titre in
`
`Total
`
`Buprenorphin
`
`degradation
`
`100.81%
`
`0.16% '
`
`25°C+60% RH.
`
`2 months
`
`101.89%
`
`25°C +60% R.H.
`
`3 months
`
`104.38%
`
`.
`
`
`
`
`102.73%
`0.5 months
`40°C + 75% R.H.
`101.22%
`8
`1 month
`;
`40°C+75% RH.
`...........................................................................................................................................................................t-
`40°C+75% R.H.
`2 months
`102.43% r
`
`1
`
`40°C+75% R.H.
`
`3 months
`
`103.45%
`
`0.5 months
`
`101.62%
`
`1 month
`
`100.86%
`
`2 months
`
`101.88%
`
`3 months
`
`103.38%
`
`0.5 months
`
`98.58%
`
`1 month
`
`92.72%
`
`

`

`wo 00/23079
`
`PCT/EP99/07595
`
`15
`
`TABLE 11
`
`Buprenorphin tablets 0.2 mg - Batch 10048 with Vit. C 1/1
`
`Glycine/hydrochloride acid and hydrogenated castor oil
`
`Conditions
`
`Time
`
`
`Titre in
`Total
`‘
`
`
`
`
`Buprenorphin
`Degradation »
`
`V
`
`
`
`
`
`
`
`
`
`25°C + 60% RH.
`101.39%
`
`
`25°C + 60% RH.
`101.22%
`
`
`25°C + 60% RH.
`
`
` 40°C + 75% RH.
`0.5 months
`103.27%
`.............................mm............---.-...-. um...-.............................................. ....................................-m-..mm... ..-.......................................mu.
`
`
`40°C + 75% RH.
`1 month
`100.44%
`
`
`101.72%
`2 months
`40°C + 75% RH.
`.......m...............n...-.............---......-... "mum"...................................mu... .....................................--m-u....... ..........-......................muu«mu.
`
`
` 3 months
`40°C + 75% RH.
`104.68%
` 0.5 months
`
`
`101.96%
`
` 2 months
`
`
`101.78%
`
` 0.5 months
`
`
`100.00%
`.......................M............................... ..«..............-.-m.m...................-~---u- mu............................................... mu...m..........................«u-mm
` 1 month
`
`101.36%
`
`1 month
`
`99.20%
`
`3 months
`
`100.01%
`
`94.62%
`
`

`

`wo 00/23079
`
`PCT/EP99/07595
`
`1 6
`
`The compositions according to this embodiment of the present invention
`
`have the same stability of those of the first embodiment at r.t., but the amount
`
`of degradation
`
`products
`
`is decreased. Advantageousiy,
`
`this
`
`second
`
`embodiment gives a higher stability at more severe conditions.
`
`5
`
`It shall be noted that the elimination of magnesium ions still
`
`improves
`
`stability. Changing buffer system also confirms the trend to good results.
`
`Another embodiment of the present invention comprises the elimination of
`
`polyvinylpyrrolidone from the formulation.
`
`Buprenorphin sublingual tablets were prepared according to the following
`composition:
`
`10
`
`. Buprenorphin 0.2 mg Buprenorphin 0 4 mg
`
`
`
`Example 7
`
`
`
`
`
`
`
`
`
`INGREDIENT
`
`Buprenorphin
`Hydrochloride
`
`Equivalent to
`Buprenorphin
`
`Vitamin C
`
`Lactose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.216
`
`mg
`
`
`
`
`0.200
`mg
`
`
`0.453
`
`30.588
`
`mg
`
`mg
`
`Example 8
`
`0.432
`
`mg
`
`0.400
`
`0 906
`.
`
`29.919
`
`mg
`
`mg
`
`mg
`
`
`
`
`
`
`
`
`
`
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`17
`
`The tablets comply with the analytical requirements.
`
`TABLE 12
`
`Buprenorphin Buprenorphin 3
`tablets 0,2 m -
`tablets 0,4 m- 3
`
`
`
`
`
`
`References
`Limits
`Results
`Results
`3
`
`Appearance - Must
`
`
`identification
` Average
`
`
`
`
`
`
`
`
`
`Test
`minutes
`Dissolution
`Eur. Ph., Ill
`
`Test
`
`
`ed.
` - After 2
`minutes
`
`
`- After 4
`minutes
`
`5 2.0%
`
`total
`
`s 0.1%
`
`s 0.1%
`
`’
`
`
`
`
`
`95.o .
`10.o%_
`
`100.62%
`
`100.62% f
`
`'
`
`,
`
`:j
`
`
`1
`
`
`coml
`
`Must
`coml
`
`60 mg/
`tablet
`
`Must
`comol
`
`Must
`
`coml
`
`Eur. Ph.,
`
`Eur. Ph., lll
`ed.
`
`Eur. Ph., lll
`
`Complies ‘
`
`Positive
`
`Positive
`
`59.58 mg
`
`59.85 mg
`
`Complies
`
`Complies
`
`1
`
`!
`
`Buprenorphin
`
`
`
`Content
`
`uniformi
`
`
`
`Disintegration
`
`
`
`
` Degradation
`
` products
`
`
`
`
`

`

`WO 00/23079
`
`PCT/EP99/07595
`
`18
`
`CLAIMS
`
`1. An oral pharmaceutical
`
`composition containing buprenorphin or a
`
`pharmaceutically acceptable salt thereof as active ingredient characterised in
`
`that it further contains a pharmaceutically acceptable antioxidant.
`
`2. An oral pharmaceutical composition according to claim 1, wherein said
`
`antioxidant is selected from the group consisting of: ascorbic acid, its salts and
`
`esters, Vitamin E, tocopherol and its salts, sodium metabisulphite, butylated
`
`hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-Iipoic acid.
`
`3. An oral pharmaceutical composition according to claim 2, wherein said
`
`antioxidant is selected from the group consisting of: ascorbic acid, its salts and
`
`esters, Vitamin E, sodium metabisulphite.
`
`4. An oral pharmaceutical composition according to claim 3, wherein said
`
`antioxidant is ascorbic acid, its salts and esters.
`5. An oral pharmaceutical composition
`according to claim 1, wherein the
`
`molar ratio between said antioxidant and buprenorphin is at least 1:1, more
`
`preferably 3:1.
`
`6. An oral pharmaceutical composition according to any one of claims 1-5,
`
`wherein the magnesium ion is absent.
`
`7. An oral pharmaceutical composition
`
`according to claim 6, wherein
`
`1O
`
`15
`
`20
`
`hydrogenated castor oil is the lubricant.
`
`8. An oral pharmaceutical composition according to any one of claims 1-7,
`
`wherein glycine/hydrochloric acid is the buffer system.
`
`9. An oral pharmaceutical composition according to any one of claims 1-8,
`
`wherein polyvinylpyrrolidone is absent.
`
`25
`
`10. An oral pharmaceutical composition according to any one of claims 1-9 in
`
`the form of a sublingual tablet.
`
`

`

`
`INTERNATIONAL SEARCH REPORT
`Inal Application No
` inter
`
`
`PCT/EP 99/07595
`
`A. CLASSIFICATION OF S BJECT MATTER
`
`IPC 7
`A61K31 485
`A61K9/00
`
`
`
`According to International Patent Classification (IPC) or to both national classification and ”’0
`B. FIELDS SEARCHED
`
`
`
`
`
`
`
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 7
`A61K
`
`
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`
`
`Electronic data base consulted during the international search (name oi data base and, where practical. search terms used)
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation or document, with indication, where appropriate. of the relevant passages
`
`Relevant to claim No.
`
`
`
`
`
`
`
`
`Category °
`
`X
`
`A
`
`
`
`
`
`
`
`
`18 September 1997 (1997-09-18)
`claims 8,9,12,13
`
`EP 0 180 303 A (AMERICAN HOME PRODUCTS)
`7 May 1986 (1986—05—07)
`claims
`tables
`
`
`
`INO9733566A(ALZA)
`
`
`
`
`
`Patent family members are listed in annex.
`D Further documents are listed in the continuation of box 0.
`
`
`H
`‘
`‘
`g
`° Special categories of cited documents :
`"T" later document published alter the International filing date
`or priority date and not in conflict with the application but
`"A" document detining the general state of the art which is not
`cited to understand the principle or theory underlying the
`considered to be of particular relevance
`invention
`
`"X" document of particular relevance the claimed invention
`"E" earlier document but published on or alter the International
`cannot be considered novel or cannot be considered to
`"th date
`_
`‘
`.
`involve an inventive step when the document is taken alone
`"L" document which may throw doubts on priority claim(s) or
`"Y" document of particular relevance; the claimed invention
`which is cited to establish the publication date of another
`cannot be considered to involve an inventive step when the
`“tam" or other spectal reason (as specmed)
`.
`‘
`document is combined With one or more other such docu—
`“0" document referring to an oral disclosure, use. exhibition or
`ments. such combination being obvious to a person skilled
`other means
`I” the 3'1-
`filing date but
`"P" document published prior to the international
`iater than the priority date claimed
`"&" document member of the same patent family
`
` Date oi the actual completion of the international search
`Date ol mailing or the international search report
` 27/01/2000
`
`21 January 2000
`Authorized officer
`Name and mailing address oi the ISA
`
`European Patent Office, PB. 5818 Patentiaan 2
`
`NL — 2280 HV Fiijswijk
`
`Tel. (+31—70) 340—2040, Tx‘ 31 651 epo nl.
`
`
`Fax: (4-31—70) 340-3016
`Scarponi,
`U
`
`
`Form PCT/ISNZ‘lO (second sheet) (July 1992)
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`Information on patent family members
`
`
`
`Patent document
`cited in search report
`
`NO 9733566
`
`Publication
`data
`
`
`
`
`
`Intern
`' nal Applicatlon No
`
`
`
`Patent family
`member((5)
`
`
`PCT/EP 99/07595
`Publication
`date
`
`2059297
`01-10- 1997
`0914097
`
`12-05-1999
`5866164
`02-02-1999
`
`
`
`
` EP 180303
`A
`07-05-1986
`41602
`15-04-1989
`572689
`12-05-1988
`4713685
`10-04-1986
`1251402
`21-03-1989
`438785
`29-03-1986
`2165149
`09-04-1986
`19990
`23-03-1990
`39359
`29-09-1986
`58139
`14-07-1993
`76393
`30-06-1988
`1896970
`23-01-1995
`6021060
`23-03-1994
`61085314
`30-04-1986
`8900905
`13-04-1989
`213573
`28-07-1988
`20498
`21-01-1987
`71489
`02-03-1990
`4605671
`12-08-1986
`
`
`
`
`
`
`
`Form PCT/ISAI210 (patent lamfly annex) (July 1992)
`
`