MXPA01003856A - Oral pharmaceutical compositions containing buprenorphin - Google Patents
Oral pharmaceutical compositions containing buprenorphinInfo
- Publication number
- MXPA01003856A MXPA01003856A MXPA/A/2001/003856A MXPA01003856A MXPA01003856A MX PA01003856 A MXPA01003856 A MX PA01003856A MX PA01003856 A MXPA01003856 A MX PA01003856A MX PA01003856 A MXPA01003856 A MX PA01003856A
- Authority
- MX
- Mexico
- Prior art keywords
- oral pharmaceutical
- pharmaceutical composition
- composition according
- further characterized
- antioxidant
- Prior art date
Links
- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 17
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 18
- 230000003078 antioxidant Effects 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000011780 sodium chloride Substances 0.000 claims abstract description 13
- 229960001736 buprenorphine Drugs 0.000 claims description 21
- 235000006708 antioxidants Nutrition 0.000 claims description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 5
- 230000001105 regulatory Effects 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L 7681-57-4 Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 229940095259 Butylated Hydroxytoluene Drugs 0.000 claims description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- 229940046009 Vitamin E Drugs 0.000 claims description 4
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- 235000019165 vitamin E Nutrition 0.000 claims description 4
- 239000011709 vitamin E Substances 0.000 claims description 4
- 150000003712 vitamin E derivatives Chemical class 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 3
- 239000006190 sub-lingual tablet Substances 0.000 claims description 3
- AGBQKNBQESQNJD-SSDOTTSWSA-N Lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 2
- 235000019136 lipoic acid Nutrition 0.000 claims description 2
- 229960002663 thioctic acid Drugs 0.000 claims description 2
- RMRJXGBAOAMLHD-CTAPUXPBSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-CTAPUXPBSA-N 0.000 claims 2
- 229940098466 Sublingual Tablet Drugs 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N Buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 19
- 239000003826 tablet Substances 0.000 description 10
- 239000007857 degradation product Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000000111 anti-oxidant Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 230000000202 analgesic Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- -1 2-hydroxy-3,3-dimethyl-2-butyl Chemical group 0.000 description 1
- 229940087828 Buprenex Drugs 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- UAIXRPCCYXNJMQ-CYVYHKOSSA-N Finibron Chemical compound Cl.C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)C(C)(O)C(C)(C)C)OC)CN2CC1CC1 UAIXRPCCYXNJMQ-CYVYHKOSSA-N 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 229960001295 Tocopherol Drugs 0.000 description 1
- 229940088594 Vitamin Drugs 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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.
Description
ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING BUPRENORPHINE
FIELD OF THE INVENTION
The present invention tes to oral pharmaceutical compositions, in particular to compositions containing buprenorphine as an active ingredient. These compositions are particularly stable with respect to commercially available products.
BACKGROUND OF THE INVENTION
Buprenorphine, ie 21-cyclopropyl-7a- (2-hydroxy-3,3-dimethyl-2-butyl) -6,14-endo-ethane-6,7,8,18-tetrahydrohpavin, is an alkaloid of morphine with analgesic properties. Its preparation is described in E.U.A. 3433791, for 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 sold in the market under the trademarks TEMGESIC, BUPRENEX, LEPETAN. Sublingual tablets containing buprenorphine as an active ingredient, for example TEMGESIC 0.2 and 0.4 mg, show the presence of degradation products of the active ingredient.
BRIEF DESCRIPTION OF THE INVENTION
It has now been found that the addition of pharmaceutically acceptable antioxidants gives the oral pharmaceutical compositions, containing buprenorphine or a pharmaceutically acceptable salt thereof as the active ingredient, particularly good stability, reducing the formation of degradation products. Advantageously, the oral pharmaceutical compositions according to the present invention are more stable than the currently available dosage forms of the most advanced technique, although they have a longer shelf life. Therefore, an objective of the present invention is an oral pharmaceutical composition containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient characterized in that it contains a pharmaceutically acceptable antioxidant in addition to conventional carriers and excipients. This and other objects of the present invention will be described in detail, also by means of examples.
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutically acceptable antioxidants are well known to those skilled in the art and are described in the technical literature
forming the common general knowledge. A source of information, for example, can be found in "Remington's Pharmaceutical Sciences Handbook," Mack Pub. N.Y. E.U.A. A first group of preferred antioxidants comprises ascorbic acid, its salts and esters, vitamin E, tocopherol and its salts, sodium metabisulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT). A more preferred group of antioxidants comprises ascorbic acid, sodium metabisulfite, vitamin E, alpha-lipoic acid. The most preferred antioxidant is ascorbic acid. The molar ratio between the antioxidant and buprenorphine is at least 1: 1, more preferably 3: 1. Commercial formulations contain magnesium ions due to the presence of magnesium stearate, a well-known lubricant. Surprisingly it has been found that significantly better results are achieved if the presence of magnesium ions is avoided in the formulations of the present invention. Thus, a further objective of the invention is an oral formulation containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient characterized in that it also contains a pharmaceutically acceptable antioxidant and that magnesium is absent. In a first embodiment of this additional aspect of the invention, the magnesium stearate is replaced by another lubricant. A preferred example is hydrogenated castor oil.
It has also surprisingly been found that significant results are also achieved if the presence of magnesium is avoided and the pH regulating system is changed in the formulations of the present invention. Therefore, a further objective of the present invention is an oral formulation containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient characterized in that it also contains a pharmaceutically acceptable antioxidant., because the magnesium ion is absent and because the pH regulating system differs from that found in commercial formulations. In a preferred embodiment of this additional aspect of the invention, the pH regulating system is glycine / hydrochloric acid. The formulations obtained in accordance with these additional aspects of the present invention are completely satisfactory in view of the stability of the active ingredient, but have a poor external appearance, so that consumers may not accept them. Although it has been sought to improve the stability of the oral formulation, by reducing the amount of degradation products, and maintaining a good external appearance, it has surprisingly been found that the elimination of polyvinylpyrrolidone, while maintaining magnesium stearate as a lubricant, and without changing The pH regulator system gives very good results. Therefore, a further aspect of the present invention is an oral pharmaceutical composition containing buprenorphine or a pharmaceutically acceptable salt thereof as the active ingredient, characterized
because it also contains a pharmaceutically acceptable antioxidant and because it does not contain polyvinylpyrrolidone. The present invention is applied to oral dosage forms. Oral dosage forms are conventionally known in the art, and no particular description is needed here, since they can be prepared by resorting to common general knowledge such as that provided by textbooks, manuals and other technical literature, which is normally available . Examples of oral dosage forms are pills, capsules, tablets, powders, solutions, suspensions and the like. In a preferred embodiment of this invention, the oral compositions are in the form of sublingual tablets. Commercial batches of TEMGESIC that have the same quantitative quality composition doubled (hereafter referred to as "FRT") and were tested for stability together with the TEMGESIC batch available on the market. The stability protocols were designed as described in table 1 below:
TABLE 1 Stability protocols
Lot FRT 10097 0.4 mg Lot FRT 16097 0.2 mg Lot Temgesic T19501 0.2 mg.
1. IN GLASS VIALS
HR = relative humidity The studies were digested to determine the title of the active ingredient and the related degradation products. Table 2 shows the results.
TABLE 2 Stability studies in glass vials
Three batches of buprenorphine 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 of antioxidant / buprenorphine is 1/1.
^ • ^^? TTIIL I II? JMT ~ 'TABLE 3 Formulations
The lots were evaluated for stability according to the experimental protocol shown in Table 4 below.
* - "-« * - "* -« - • ** TABLE 4 Stability protocols (in glass vials)
The results are shown in Tables 5-7 below.
TABLE 5 Buprenorphine Tablets 0.2 mq - lot 23038 with Vit. C 1/1
TABLE 6 Tablets of buprenorphine 0.2 mq - lot 24038 with Metabis. 1/1
TABLE 7 Buprenorphine Tablets 0.2 mq - lot 25038 with Vit. E 1/1
The compositions according to the present invention are more stable than those commercially available and those duplicated by Formenti. It should be noted that ascorbic acid gives very good results. The total amount of degradation products is much lower than that found in commercial products, even under the worst experimental protocol conditions. Sodium metabisulfite and vitamin
And they give the same results. Another embodiment of the present invention is described below. Three batches were prepared according to the experimental design of table 8 below. The ascorbic acid was used in a molar ratio of 3/1 with respect to the active ingredient. In a second batch, the magnesium ion was removed and an alternative lubricant was used. In a third batch, together with the alternative lubricant, a different pH regulation system was also used.
TABLE 8 Formulations
The stability protocols are the same as in the formal tests. The results are shown in tables 9-11 below.
fc. ^ - a ^. ^. ^ ..- -t - «f t f jüt TABLE 9 Tablets of buprenorphine 0.2 mq - lot 23038 with Vit. C 1/1 ^ m ^ TABLE 10 Buprenorphine tablets 0.2 mq - lot 09048 with Vit. C 3/1
TABLE 11 Buprenorphine Tablets 0.2 mq - Lot 10048 with Vit. C 1/1 glycine / hydrochloric acid and hydrogenated castor oil
The compositions according to this embodiment of the present invention have the same stability as those of the first embodiment at room temperature, but the amount of degradation product is less. Advantageously, this second embodiment gives greater stability under more severe conditions.
It should be noted that the elimination of magnesium is still improving stability. The change of the pH regulating system also confirms the tendency to good results. Another embodiment of the present invention comprises the removal of polyvinylpyrrolidone from the formulation. Sublingual buprenorphine tablets were prepared according to the following composition:
The tablets met the analytical requirements
TABLE 12
^^ ¡É ^^^ L,
Claims (9)
1. An oral pharmaceutical composition containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient characterized in that it contains a pharmaceutically acceptable antioxidant in a molar ratio between said antioxidant and buprenorphine in the range of 1: 1 to 3: 1.
2. An oral pharmaceutical composition according to claim 1, further characterized in that said antioxidant is selected from the group consisting of: ascorbic acid, its salts and esters, vitamin E, iocoferol and its salts, sodium metabiisulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-lipoic acid.
3. An oral pharmaceutical composition according to claim 2, further characterized in that said antioxidant is selected from the group consisting of: ascorbic acid, its salts and esters, vitamin E, sodium metabisulfite.
4. An oral pharmaceutical composition according to claim 3, further characterized in that said antioxidant is ascorbic acid, its salts and esters.
5. - An oral pharmaceutical composition according to any of claims 1-4, further characterized in that the magnesium ion is absent.
6. An oral pharmaceutical composition according to claim 5, further characterized in that the lubricant is hydrogenated castor oil.
7. An oral pharmaceutical composition according to any of claims 1-6, further characterized in that the pH regulating system is glycine / hydrochloric acid.
8. An oral pharmaceutical composition according to any of claims 1-7, further characterized in that the povvinylpyrrolidone is absent.
9. An oral pharmaceutical composition according to any of claims 1-8, further characterized in that it is in the form of a sublingual tablet.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MIMI98A002222 | 1998-10-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01003856A true MXPA01003856A (en) | 2002-07-25 |
Family
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