CA2044507A1 - Gemfibrozil formulations - Google Patents
Gemfibrozil formulationsInfo
- Publication number
- CA2044507A1 CA2044507A1 CA 2044507 CA2044507A CA2044507A1 CA 2044507 A1 CA2044507 A1 CA 2044507A1 CA 2044507 CA2044507 CA 2044507 CA 2044507 A CA2044507 A CA 2044507A CA 2044507 A1 CA2044507 A1 CA 2044507A1
- Authority
- CA
- Canada
- Prior art keywords
- gemfibrozil
- pharmaceutically acceptable
- surfactant
- ing
- acceptable surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Improved oral formulations are prepared by admix-ing gemfibrozil with from 1 to 4%, by weight, of a pharmaceutically acceptable surfactant having an HLB
value of from about 10 to about 50.
Improved oral formulations are prepared by admix-ing gemfibrozil with from 1 to 4%, by weight, of a pharmaceutically acceptable surfactant having an HLB
value of from about 10 to about 50.
Description
2 ~ 7 G7.Y~I9ROZIL FOR~ TION~
The present invention relates to improved for~ula-tions of gemfikrozil.
Bac~around Gemfibrozll, or 5~(2,5-dimethylphenoxy)-2,2-di-methylpentanoic ac~d, is a widely used antihyperlipo-proteinemic agent. Physically the chemical is a crys-talline material which melts in the range of 61- to 63-c (hexane) and exhibits a boiling point of 158-1590.O2C. The suDstance is nonhygroscopic and gener-ally compatible with common pharmaceutical excipientsbut has ve~y pcor solubility in water. This is partic-ularly true in a highly acidic medium (such as is encountered in the stomach) since its apparent pKa is 4.7.
The typical daily dose is high, generally about 1200 mg, probably because of the poor water solubility.
This dosage generally ig administered using for example two capsules of 300 mg or a single compressed tablet of 600 mg, administration in each case being b.i.d.
The present invention pertains to improvements in gemfibrozil formulations which improve the compound's dissolution profile and thus increase the drug's blood levels upon oral administration.
:- .
2 ~
U.S. Patent No. 4,716,033 discloses a medicament adsorbate such as magnesium aluminum silicate having a medicament, including inter alia gemfibrozil, and sur-factant adsor~ed thereon.
U.S. Patent No. 4,753,800 discloses a medicament adsorbate having a medicament, including inter alia gemfibrozil, dispersed in an edible wax adsorbed thereon.
U.S. Patent No. 4,814,354 discloses pharmaceutical compositions of an anion exchange resin lipid regula-tor, such as cholestyramine or cholestipol, and gemfi-brozil.
U.S. Patent No. 4,778,676 discloses a chewable confection delivery system of coated cholestyramine and lS a confectionery matrix U.S. Patent No. 4,816,264 discloses an oral deliv-ery syste~ having a core portion of drug and a cellu-losic gelling polymer and a semipermeable membrane around the core.
U.S. ~atent No. 4,865,850 discloses a method of expelling fat from the gastrointestinal tract by admin-istering non-biodegradable collagen particles having fat receptors, including inter alia gemfibrozil, on their surface.
EP-A 295,637 A2 discloses pharmaceutical co~posi-tions in which a lipid regulating component, including inter alia gemfibrozil, is combined with inhibitor of acylCoA:cholesterol acyltransferase.
2 0 ~ 7 E2-~ 261, 693 ~l discloses a lipid regulating com-pcnent, including inter alia gemfibrozil, which has been pretreated to render it stable until such time as it reaches the proximal section of the intestines.
PCT WO 88/05296 discloses pharmaceutical composi-ticns in ~hich a lipid regulating component, including inter alia gemfibrozil, is combined with inhibitor of 3-hydro~f-3-methylgluta~yl coenzyme A reductase.
Commercially available gemfibrozil capsules con-tain a small amount of sodium lauryl sulfate, typically less than 0.2~. Compressed tablets of gemfibrozil which are comme~~ially available contain somewhat more but again less than 1%; e.~., 0.7%.
Detailed Descri~tion lS The present invention is based on the discovery when gemfibrozil is admixed with from 1 to 4~, by weight of gemfibrozil, of a pharmaceutically acceptable surfactant having a hydrophilic-lipophylic balance value ("HLB") of from about 10 to about 50, significant improvements in the rate of dissolution in both acid and alkaline media are observed.
Suitable pharmaceutically acceptable surfactants~
having an HLB value of from about 10 to about 50 include polysorbates, pluronics, alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate, salts of fatty acids such as sodium oleate and triethanolamine oleate, and the like. The following .
2 ~ 0 7 list exemplifies trpical surfactants and their HLB
values:
Surf ctant HLB
Pluronic F68 29.0 Sodium oleate 18.0 ~een 20 16.7 ~een 40 15.6 ~een 80 15.0 ~een 60 14.8 ~een 21 13.3 Triethanolamine oleate 12.0 ~een 85 11.0 ~een 65 10.5 ~een 81 10.0 A preferred ratio utilizes from 1% to about 2~
of the surfactant. In addition, the pharmaceutically acceptable sur~actant preferably has an HLB value of from about 15 to about 40.
Generally the indicated amount of surfactant is dissolved with the amount of water ultimately required for granulation of the gemfibrozil. The gemfibrozil, together with any other excipients to be granulated such as silicon dioxide, hydroxypropyl cellulose starch, and the like is then granulated in this aqueous solution. After granulation and drying, any other dry ingredients, as for example microcrystalline starch, lubricants such as calcium stearate, additional sili-con dioxide, and the like, are added and blended and the mixture then compressed into tablets.
2 ~ 0 ~
The following is a t~pical formulation:
Gemfibrezil ........................... 600.00 Silicon Dioxide......................... 12.00 Hydro~ypro~yl cPllulose ................ 16.00 Preselatinized starch 1551............. 141.00 The foregoing components, including the active ingredient and the granulation additives, are milled through a ~0 screen and blended with 141.00 g of pregelatinized starch 1551. This mixture then is gran-ulated with a solution of the selected surfactant (indicated below) in 100 mL of purified water USP. The granulation is dried, combined with an additional 10.00 g of silicon dioxide, remilled through a Fitzmill No.
2A RH screen and t~en blended with 64.80 g of granular microcrystalline cellulose and 10.00 g of calcium stearate.
Aliquots of 860 mq are punched on 0.745" x 0.360"
elliptical punches at a hardness of 12 to 16 kp and about 0.300" gauge.
Tablets prepared in the foregoing manner were tested to evaluate their rate of dissolution in various~
media: O.lN hydrochloric acid, 0.05M phosphate buffer at two pH values (5.5 and 7.4), and 0.2 phosphate buffer at pH 7.4. the results are as follows:
2 ~ 0 7 (1) o.l~ Hydrochloric Acid Polysorbate 80 Time Amount of Surfactant ~minutes) 0.0% O.S% 1.0% 2.0 % Dissolved 0.3 0.9 1.4 1.7 0.5 1.0 1.8 2.2 0.8 1.3 2.2 2.5 1.2 1.5 2.3 2.6 1.5 1.7 2.4 2.7 1.7 1.9 2.5 2.7 1.9 2.0 2.5 2.7 Sodium Lauryl Sulfate Time Amount of Surfactant (minutes) 0.0% 0.5% 1.0% 2.0 % Dissolved 0.3 1.0 0.8 1.5 - 10 0.5 1.1 1.1 1.9 0.8 1.6 1.7 2.2 1.2 2.0 2.0 2.2 1.5 2.1 2.2 2.3 1.7 2.2 2.3 2.3 1.9 2.4 2.3 2.3 (2) 0.05M Phosphate Buffer (pH 5.5) Polysorbate 80 TimeAmount of Sur~actant (minutes) o.o% 0.5% 1.0% 2.0 % Dissolved 0.13 0.6 3.9 8.0 0.7 0.7 6.5 10.5 1.9 3.6 9.4 11.7 3.2 5.310.6 11.9 4.4 6.811.2 12.1 5.5 . 8.011.3 12.1 6.4 8.911.5 12.1 :
.
:
:
.
2 ~ 1~ Li~ 0 7 Sodium Lauryl Sulfate Time A~ount of Surfactant 5(minutes) 0.0~ 0.5% 1.0~ 2.0 ~ Dissolved 0.1 1.8 1.4 5.4 0.7 2.1 2.8 7.6 1.9 3.4 5.1 9.7 3.2 4.6 7.0 10.6 4.4 5.8 8.3 11.0 5.5 6.8 9.3 11.2 6.4 7.7 9.9 11.3 (3) 0.05~ Phosphate Buffer (pH 7.4 Polysor~ate 80 Time A~ount of Surfactant (minutes) 0.0~ 0.5% 1.0% 2.0 % Dissolved 12.223.9 57.5 82.3 23.844.0 78.9 95.0 43.369.0 94.6 99.5 58.583.7 98.4 100.0 69.192.5 99.4 100.0 77.097.7 100.0 100.0 82.9100.6100.0 100.0 Sodium Lauryl Sulfate Time~ount of Surfactant (minutes) o.o~ 0.5% 1.0~ 2.0 % Dissolved 12.2 22.127.8 68.2 23.8 42.451.9 86.5 43.3 69.080.1 100.0 5~.s 83.592.6 100.0 69.1 91.197.4 100.0 77.0 95.1100.0 100.0 82.9 97.2100.0 100.0 (4) 0.2M Phosphate Buffer (pH 7.4) Polysorbate 80 20 Time~ount of Surfactant (minutes) 0.0~ 0.5% 1.0% 2.0%
~ Dissolved 17.921.6 62.1 87.7 33.042.0 84.8 96.2 56.868.7 97.3 100.0 73.184.4 99.6 100.0 83.792.9 100.0 100.0 90.897.6 100.0 100.0 95.4100.0 100.0 100.0 Sodium Lauryl Sulfate Time Amount of Surfactant (minutes) 0.0% 0.5% 1.0% 2.0%
% Dissolved 17.930.5 46.3 82.0 33.056.4 74.4 91.5 56.885.0 94.5 100.0 73.195.0 98.7 100.0 83.798.4 99.7 100.0 90.899.7 100.0 100.0 95.4100.0 100.0 100.0 As can be seen from the above, the ~ncorporation of the surfactant significantly increases the rate of dissolution in otherwise identical formulations over a wide range of pH values.
, , , : . ,
The present invention relates to improved for~ula-tions of gemfikrozil.
Bac~around Gemfibrozll, or 5~(2,5-dimethylphenoxy)-2,2-di-methylpentanoic ac~d, is a widely used antihyperlipo-proteinemic agent. Physically the chemical is a crys-talline material which melts in the range of 61- to 63-c (hexane) and exhibits a boiling point of 158-1590.O2C. The suDstance is nonhygroscopic and gener-ally compatible with common pharmaceutical excipientsbut has ve~y pcor solubility in water. This is partic-ularly true in a highly acidic medium (such as is encountered in the stomach) since its apparent pKa is 4.7.
The typical daily dose is high, generally about 1200 mg, probably because of the poor water solubility.
This dosage generally ig administered using for example two capsules of 300 mg or a single compressed tablet of 600 mg, administration in each case being b.i.d.
The present invention pertains to improvements in gemfibrozil formulations which improve the compound's dissolution profile and thus increase the drug's blood levels upon oral administration.
:- .
2 ~
U.S. Patent No. 4,716,033 discloses a medicament adsorbate such as magnesium aluminum silicate having a medicament, including inter alia gemfibrozil, and sur-factant adsor~ed thereon.
U.S. Patent No. 4,753,800 discloses a medicament adsorbate having a medicament, including inter alia gemfibrozil, dispersed in an edible wax adsorbed thereon.
U.S. Patent No. 4,814,354 discloses pharmaceutical compositions of an anion exchange resin lipid regula-tor, such as cholestyramine or cholestipol, and gemfi-brozil.
U.S. Patent No. 4,778,676 discloses a chewable confection delivery system of coated cholestyramine and lS a confectionery matrix U.S. Patent No. 4,816,264 discloses an oral deliv-ery syste~ having a core portion of drug and a cellu-losic gelling polymer and a semipermeable membrane around the core.
U.S. ~atent No. 4,865,850 discloses a method of expelling fat from the gastrointestinal tract by admin-istering non-biodegradable collagen particles having fat receptors, including inter alia gemfibrozil, on their surface.
EP-A 295,637 A2 discloses pharmaceutical co~posi-tions in which a lipid regulating component, including inter alia gemfibrozil, is combined with inhibitor of acylCoA:cholesterol acyltransferase.
2 0 ~ 7 E2-~ 261, 693 ~l discloses a lipid regulating com-pcnent, including inter alia gemfibrozil, which has been pretreated to render it stable until such time as it reaches the proximal section of the intestines.
PCT WO 88/05296 discloses pharmaceutical composi-ticns in ~hich a lipid regulating component, including inter alia gemfibrozil, is combined with inhibitor of 3-hydro~f-3-methylgluta~yl coenzyme A reductase.
Commercially available gemfibrozil capsules con-tain a small amount of sodium lauryl sulfate, typically less than 0.2~. Compressed tablets of gemfibrozil which are comme~~ially available contain somewhat more but again less than 1%; e.~., 0.7%.
Detailed Descri~tion lS The present invention is based on the discovery when gemfibrozil is admixed with from 1 to 4~, by weight of gemfibrozil, of a pharmaceutically acceptable surfactant having a hydrophilic-lipophylic balance value ("HLB") of from about 10 to about 50, significant improvements in the rate of dissolution in both acid and alkaline media are observed.
Suitable pharmaceutically acceptable surfactants~
having an HLB value of from about 10 to about 50 include polysorbates, pluronics, alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate, salts of fatty acids such as sodium oleate and triethanolamine oleate, and the like. The following .
2 ~ 0 7 list exemplifies trpical surfactants and their HLB
values:
Surf ctant HLB
Pluronic F68 29.0 Sodium oleate 18.0 ~een 20 16.7 ~een 40 15.6 ~een 80 15.0 ~een 60 14.8 ~een 21 13.3 Triethanolamine oleate 12.0 ~een 85 11.0 ~een 65 10.5 ~een 81 10.0 A preferred ratio utilizes from 1% to about 2~
of the surfactant. In addition, the pharmaceutically acceptable sur~actant preferably has an HLB value of from about 15 to about 40.
Generally the indicated amount of surfactant is dissolved with the amount of water ultimately required for granulation of the gemfibrozil. The gemfibrozil, together with any other excipients to be granulated such as silicon dioxide, hydroxypropyl cellulose starch, and the like is then granulated in this aqueous solution. After granulation and drying, any other dry ingredients, as for example microcrystalline starch, lubricants such as calcium stearate, additional sili-con dioxide, and the like, are added and blended and the mixture then compressed into tablets.
2 ~ 0 ~
The following is a t~pical formulation:
Gemfibrezil ........................... 600.00 Silicon Dioxide......................... 12.00 Hydro~ypro~yl cPllulose ................ 16.00 Preselatinized starch 1551............. 141.00 The foregoing components, including the active ingredient and the granulation additives, are milled through a ~0 screen and blended with 141.00 g of pregelatinized starch 1551. This mixture then is gran-ulated with a solution of the selected surfactant (indicated below) in 100 mL of purified water USP. The granulation is dried, combined with an additional 10.00 g of silicon dioxide, remilled through a Fitzmill No.
2A RH screen and t~en blended with 64.80 g of granular microcrystalline cellulose and 10.00 g of calcium stearate.
Aliquots of 860 mq are punched on 0.745" x 0.360"
elliptical punches at a hardness of 12 to 16 kp and about 0.300" gauge.
Tablets prepared in the foregoing manner were tested to evaluate their rate of dissolution in various~
media: O.lN hydrochloric acid, 0.05M phosphate buffer at two pH values (5.5 and 7.4), and 0.2 phosphate buffer at pH 7.4. the results are as follows:
2 ~ 0 7 (1) o.l~ Hydrochloric Acid Polysorbate 80 Time Amount of Surfactant ~minutes) 0.0% O.S% 1.0% 2.0 % Dissolved 0.3 0.9 1.4 1.7 0.5 1.0 1.8 2.2 0.8 1.3 2.2 2.5 1.2 1.5 2.3 2.6 1.5 1.7 2.4 2.7 1.7 1.9 2.5 2.7 1.9 2.0 2.5 2.7 Sodium Lauryl Sulfate Time Amount of Surfactant (minutes) 0.0% 0.5% 1.0% 2.0 % Dissolved 0.3 1.0 0.8 1.5 - 10 0.5 1.1 1.1 1.9 0.8 1.6 1.7 2.2 1.2 2.0 2.0 2.2 1.5 2.1 2.2 2.3 1.7 2.2 2.3 2.3 1.9 2.4 2.3 2.3 (2) 0.05M Phosphate Buffer (pH 5.5) Polysorbate 80 TimeAmount of Sur~actant (minutes) o.o% 0.5% 1.0% 2.0 % Dissolved 0.13 0.6 3.9 8.0 0.7 0.7 6.5 10.5 1.9 3.6 9.4 11.7 3.2 5.310.6 11.9 4.4 6.811.2 12.1 5.5 . 8.011.3 12.1 6.4 8.911.5 12.1 :
.
:
:
.
2 ~ 1~ Li~ 0 7 Sodium Lauryl Sulfate Time A~ount of Surfactant 5(minutes) 0.0~ 0.5% 1.0~ 2.0 ~ Dissolved 0.1 1.8 1.4 5.4 0.7 2.1 2.8 7.6 1.9 3.4 5.1 9.7 3.2 4.6 7.0 10.6 4.4 5.8 8.3 11.0 5.5 6.8 9.3 11.2 6.4 7.7 9.9 11.3 (3) 0.05~ Phosphate Buffer (pH 7.4 Polysor~ate 80 Time A~ount of Surfactant (minutes) 0.0~ 0.5% 1.0% 2.0 % Dissolved 12.223.9 57.5 82.3 23.844.0 78.9 95.0 43.369.0 94.6 99.5 58.583.7 98.4 100.0 69.192.5 99.4 100.0 77.097.7 100.0 100.0 82.9100.6100.0 100.0 Sodium Lauryl Sulfate Time~ount of Surfactant (minutes) o.o~ 0.5% 1.0~ 2.0 % Dissolved 12.2 22.127.8 68.2 23.8 42.451.9 86.5 43.3 69.080.1 100.0 5~.s 83.592.6 100.0 69.1 91.197.4 100.0 77.0 95.1100.0 100.0 82.9 97.2100.0 100.0 (4) 0.2M Phosphate Buffer (pH 7.4) Polysorbate 80 20 Time~ount of Surfactant (minutes) 0.0~ 0.5% 1.0% 2.0%
~ Dissolved 17.921.6 62.1 87.7 33.042.0 84.8 96.2 56.868.7 97.3 100.0 73.184.4 99.6 100.0 83.792.9 100.0 100.0 90.897.6 100.0 100.0 95.4100.0 100.0 100.0 Sodium Lauryl Sulfate Time Amount of Surfactant (minutes) 0.0% 0.5% 1.0% 2.0%
% Dissolved 17.930.5 46.3 82.0 33.056.4 74.4 91.5 56.885.0 94.5 100.0 73.195.0 98.7 100.0 83.798.4 99.7 100.0 90.899.7 100.0 100.0 95.4100.0 100.0 100.0 As can be seen from the above, the ~ncorporation of the surfactant significantly increases the rate of dissolution in otherwise identical formulations over a wide range of pH values.
, , , : . ,
Claims (12)
1. An improved oral formulation of gemfibrozil compris-ing gemfibrozil admixed with from 1 to 4%, by weight of gemfibrozil, of a pharmaceutically acceptable surfac-tant having an HLB value of from about 10 to about 50.
2. An improved oral formulation of gemfibrozil accord-ing to claim 1 wherein the amount of surfactant is from 1% to about 2%.
3. An improved oral formulation of gemfibrozil accord-ing to claim 1 wherein the pharmaceutically acceptable surfactant has an HLB value of from about 15 to about 40.
4. An improved oral formulation of gemfibrozil accord-ing to claim 1 wherein the pharmaceutically acceptable surfactant is a polysorbate.
5. An improved oral formulation of gemfibrozil accord-ing to claim 1 wherein the pharmaceutically acceptable surfactant is an alkali metal salt of a fatty alcohol sulfate.
6. An improved oral formulation of gemfibrozil accord-ing to claim 5 wherein the pharmaceutically acceptable surfactant is sodium lauryl sulfate.
7. A gemfibrozil tablet wherein the gemfibrozil is admixed with from 1 to 4%, by weight of the gemfib-rozil, of a pharmaceutically acceptable surfactant hav-ing an HLB value of from about 10 to about 50.
8. A gemfibrozil tablet according to claim 7 wherein the amount of surfactant is from 1% to about 2%.
9. A gemfibrozil tablet according to claim 7 wherein the pharmaceutically acceptable surfactant has an HLB
value of from about 15 to about 40.
value of from about 15 to about 40.
10. A gemfibrozil tablet according to claim 7 wherein the pharmaceutically acceptable surfactant is a polysorbate.
11. A gemfibrozil tablet according to claim 7 wherein the pharmaceutically acceptable surfactant is an alkali metal salt of a fatty alcohol sulfate.
12, A gemfibrozil tablet according to claim 11 wherein the pharmaceutically acceptable surfactant is sodium lauryl sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2044507 CA2044507A1 (en) | 1990-06-15 | 1991-06-13 | Gemfibrozil formulations |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2044507 CA2044507A1 (en) | 1990-06-15 | 1991-06-13 | Gemfibrozil formulations |
| US539,158 | 1995-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2044507A1 true CA2044507A1 (en) | 1991-12-16 |
Family
ID=4147809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2044507 Abandoned CA2044507A1 (en) | 1990-06-15 | 1991-06-13 | Gemfibrozil formulations |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2044507A1 (en) |
-
1991
- 1991-06-13 CA CA 2044507 patent/CA2044507A1/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |