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, M. C.

Braude et al. eds. (Raven Press, 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.

This and other objects of the present invention wiil be disclosed in detail, also by means of examples.

Detailed disclosure of the invention Pharmaceuticaily acceptable antioxidants are well known to the person 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. N. Y. USA.

A first group of preferred antioxidants comprises ascorbic acid, its salts and esters, Vitamin E, tocopherol and its salts, sodium metabisulphite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT).

A more preferred group of antioxidants comprises ascorbic acid, sodium metabisulphite, Vitamin E, aipha-iipoic acid.

The most preferred antioxidant is ascorbic acid.

The molar ratio between the antioxidant and buprenorphin is at least 1: 1, 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 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.

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 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

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 quali-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:

TABLE 1 STABILITYPROTOCOLS Batch FRT 10097 0.4 mg Batch FRT 16097 0.2 mg Batch Temgesic T19501 0.2 mg 1. IN GLASS VIALS Temperature 7 days 15 days 30 days 25°C + 60% R. H. X 30°C + 70% R. H. X X 40°C + 75% R. H. X X X XX50°CX

RH = Relative humidity The studies were directed at the determination of the titre of the active ingredient and of the related degradation products.

TABLE 2 shows the results.

TABLE 2 Stability studies in glass vials. Batch 10097 Batch 16097 Temgesic 0.4 mg 0.2 m Batch T19501 0.2 mg days Titre in Total Titre in Total Titre in Total Bupre-degrada-Bupre-degrada-Buprenor-degrada- norphin tion norphin tion phin tion products products products Temperature 25°C + 60% R. H. 0 99.29% 1.19% 99.40% 1.84% 96.10% 2.97% 30 96.82% 7.22% 97.8% 5.62% 90.45% 7.49% +70%Temperature30°C R.H. 0 99.29% 1.19% 99.40% 1.84% 96.10% 2.97% 15 94.65% 8.05% 97.57% 5.71% 91.16% 7.97% 30 94.62% 9.42% 97. 80% 5.62% 88.16% 10.51 % Tem erature 40°C + 75% R. H. 0 99.29% 1.19% 99.40% 1.84% 96.10% 2.97% 7 98.78% 2.31 % 97.78% 3.30% 92.92% 6.10% 15 95.96% 2.82% 94.95% 4.33% 87.42% 8.25% 30 98.28% 3.85% 96.16% 5.43% 86.43% 9.06% Tem erature 50°C 0 99.29% 1.19% 99.40% 1.84% 96.10% 2.97% 7 89.66% 10.47% 93.54% 7.43% 85.59% 11.44% 15 89.42% 9. 97% 95.23% 6.25% 84. 71% 10.56% 30 88.88% 11.31% 96.52% 6.69% 77. 23% 15.15%

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 Example2ExampleExample1 3 INGREDIENT Vitamin CSodium Vitamin E NAME Batch 23038Metabisulphite Batch 25038 Batch 24038 Buprenorphin hydrochloridehydrochloride0.216 mg0.216mg0.216 Equivalentto mgBuprenorphin0.200 0.200 mg 0.200 mg AntioxidantAntioxidant0.151 mg0.163 mg 0.405 mg LactoseLactose29.690 mg29.678 mg29.436 Maize starch9.000 mg9.000mg9.000 Mannitol 18.000mg18.000mgmg PolyvinylpyrrolidonePolyvinylpyrrolidone1.200 mg1.200mg1.200 Anhydrous Citric Acid 0.888 mg0.888 mg 0.888 mg Sodium Citrate mg0.405mg0.405mg0.405 Magnesium Stearate 0.450 mg0.450mg0.450

The batches were tested for stability according to the experimental protocol shown in Table 4 beiow.

TABLE 4 STABILITY PROTOCOLS (In glass vials) Temperature 0.5 Months 1. Month 2.0 Months 3. 0 Months 25°C + 60% R. H. X X X 40°C + 75% R. H. X X X X 50°C X X X80°CX The results are shown in tables 5-7 below.

TABLE 5 Buprenorphin tablets 0.2 mg-Batch 23038 with Vit. C 1/1 Conditions inTotalTitre BuprenorphinDegradation products <0.10%Initial101.00% 60%25°C+ R.H. 1 0.11%100.63% 60%25°C+ R.H. 2 0.57%100.90% 60%R.H.3months99.21%0.48%25°C+ 75%R.H.0.5months102.54%0.35%40°C+ 75%R.H.1month100.15%0.57%40°C+ 75%40°C+ R.H. 2 101.06% 0.73% 75%R.H.3months98.68%0.78%40°C+ 50°C 0.5 102.59% 0.69% 50°C 2 102.23% 0.83% 50°C 3 102.54% 1.12% 80°C 0.5 97.73% 2.44% month93.34%80°C1 3.76% TABLE6 Buprenorphin tablets 0.2 mg-Batch 24038 with Metabis. 1/1 TitreinTotalConditionsTime Buprenorphin Degradation products Initial 100.43% 0.11% 25°C + 60% R.H 1 month 99.60% 0.78% 60%R.H.2months100.91%1.55%25°C+ 60%R.H.3months98.06%2.00%25°C+ 75%R.H.0.5months101.10%1.13%40°C+ 75%R.H1month99.79%3.12%40°C+ 75%R.H.2months99.78%3.05%40°C+ 40°C + 75% R.H. 3 98.41% 3.83% 50°C50°C0.5 101.42% 1.47% months99.06%50°C2 2.77% months99.62%50°C3 2.83% months93.48%4.61%80°C0.5 month90.54%80°C1 11.28% TABLE 7 Buprenorphin tablets 0.2 mg-Batch 25038 with Vit. E 1/1 Conditions Time Titre in Total Buprenorphin Degradation Products Initial 98.83 0.09% 25°C + 60% R.H. 1 month 100.14% 0.64% 25°C + 60% R.H. 2 months 98.86% 1.85% 25C+60% R. H. 1 month 100.14% 0.64% 25°C + 60% R. H. 2 months 98. 86% 1.85% 25°C + 60% R. H. 3 months 98.90% 2.89% 40°C + 75% R. H. 0.5 months 100.20% 1.20% 40°C + 75% R. H. 1 month 98.35% 1.74% 40°C + 75% R. H. 2 months 102.64% 4. 66% 40°C + 75% R. H. 3 months 95.40% 5.81% 50°C 0.5 months 98. 41% 2.64% 50°C 2 months 95.78% 5.35% 50°C 3 months 95.48% 5.34% 80°C 0.5 months 94. 60% 4.18% 80°C 1 month 89.49% 4. 81%

The compositions according to the present invention are more stable than those commercially available and those replicated by Formenti.

It shali 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 ingredient. In a second batch, magnesium ion is eliminated and an altemative lubricant is used. In a third batch, together the alternative lubricant, also a different buffer system is used.

TABLE 8 FORMULATIONS INGREDIENTS Example 4 Example 5 Example 6 Batch 08048 Batch 09048 Batch10048 Buprenorphin 0.216 mg 0.216 mg 0.216 mg Hydrochloride Equivalent to Buprenorphin 0.200 mg 0.200 mg 0.200 mg Vitamin C 0.453 mg 0. 453 mg 0.453 mg LactoseLactose29.388 mg 29.238 mg 29.379 mg Maize starch9.000 mg 9.000mg 9.000 mg MannitolMannitol18.000 mg18.000 mg 18.000 mg Polyvinylpyrrolidone 1.200 mg 1.200mgmg Anhydrous Citric Acid 0.888 mg 0.888 === Sodium Citrate. 2HO 0.405 mg 0.405 mg === Magnesium Stearate 0.450 mg=== === Hydrogenated castor 0.600 mg 0.600 mg oil Glycine/Hydrochloric = = = = = = 0.955 mg acid Hydrochloric Acid ===2ml=== pH3.3 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

Conditions inTotalTitre Buprenorphin Degradation Products Initial 100.93% 0.16% 25°C + 60% R.H. 1 month 99.30% 0.31% 25°C + 60% R.H. 2 months 103.23% 0.47% 60%25°C+ R.H. 3 102,17% 0.47% 75%R.H.0.5months102.98%0.21%40°C+ 75%R.H.1month103,35%0.51%40°C+ 75%40°C+ R.H. 102.52%0.52%months 75%40°C+ R.H. 3 103.80% 0.52% months103.10%0.21%50°C0.5 50°C 2 103.41% 0.54% 50°C 3 100.74% 0.66% 80°C 0.5 97.93% 2.01% 80°C 1 month 92.02% 4.63% TABLE 10 Buprenorphin tablets 0.2 mg-Batch 09048 with Vit. C 3/1 Conditions Time Titre in Total degradation Buprenorphin products Initial 100.81% 0.16% 25°C + 60% R.H. 1 month 101.35% 0.40% Initial 100. 81% 0.16% 60%R.H.1month101.35%0.40%25°C+ ............................................................ ............................................................ ............................................................ ...................... ~. 25°C + 60% R. H. 3 months 104.38% 0.42% 40°C + 75% R. H. 0.5 months 102.73% 0.16% 40°C + 75% R. H. 1 month 101.22% 0.32% 40°C + 75% R. H. 2 months 102. 43% 0. 32% 40°C + 75% R. H. 3 months 103.45% 0.44% 50°C 0. 5 months 101.62% 0.16% 50°C 1 month 100.86% 0.64% 50°C 2 months 101.88% 0.49% 50°C 3 months 103. 38% 0.56% 80°C 0. 5 months 98.58% 1.74% 80°C 1 month 92.72% 4.70% TABLE 11 Buprenorphin tablets 0.2 mg-Batch 10048 with Vit. C 1/1 Glycine/hydrochloride acid and hydrogenated castor oil Total Conditions Time Titre in Degradation Buprenorphin products Initial 101.21% 0.15% 25°C + 60% R.H. 1 month 101.39% 0.49% 25°C + 60% R.H. 2 months 101.22% 0.30% 60%R.H.3months101.36%0.29%25°C+ 75%R.H.0.5months103.27%0.18%40°C+ 75%40°C+ R.H. 1 0.90%100.44% 75%R.H.2months101.72%0.32%40°C+ 40°C + 75% R.H. 3 104.68% 0.29% 50°C 0.5 months 101.96% 0.25% 50°C 1 month 99.20% 0.51% 50°C 2 101.78% 0.41% 50°C 3 months 100.01% 0.54% 80°C 0.5 months 100.00% 1.41% 80°C 1 month 94.62% 5.25%

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. Advantageously, this second embodiment gives a higher stability at more severe conditions.

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: Example 7 Example 8 INGREDIENT Buprenorphin 0.2 mg Buprenorphin 0. 4 mg Buprenorphin 0.216 mg 0.432 mg Hydrochloride Equivalent to Buprenorphin 0.200 mg 0.400 mg Vitamin C 0.453 mg 0.906 mg Lactose 30.588 mg 29.919 mg Maize starch 9.000 mg 9.000 mg Mannitol 18.000 mg 18.000 mg Citc acid hydrochloride 0.888 mg 0.888 mg Sodium Citrate. 2H2O 0.405 mg 0.405 mg Magnesium Stearate 0.450 mg 0.450 mg The tablets comply with the anaiytical requirements.

TABLE 12 Assay References Limits Results Results Buprenorphin Buprenorphin tablets 0, 2 mg tablets 0, 4 mg Appearance Must Complies Complies compl Buprenorphin Must Positive Positive identificationcompiy Average Eur. Ph., 111 60 mg/59.58 mg 59.85 mg tabletweighted. Weight Eur. Ph., III Must Complies Complies uniformity ed. compl Content Eur. Ph., III Must Complies Complies uniformity ed. compl Water Eur. Ph., fit s 5.0% 3.87% 350% ed. Disintegration Eur. Ph., III 5 # 1 minutes 1 minutes Test ed. minutes Dissolution Eur. Ph., III Test ed. --After 2 92.2%93,2%60.0% minutes -After 4 > 80.0% 94.0% 95,4% minutes Degradation 2.0% # 0.1% #0.1% products total Titre 100.62% 105.0%