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
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960003627 gemfibrozil Drugs 0.000 title claims abstract description 32
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 238000009472 formulation Methods 0.000 title claims abstract description 11
- 239000008180 pharmaceutical surfactant Substances 0.000 claims abstract description 13
- 239000004094 surface-active agent Substances 0.000 claims description 15
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 8
- -1 alkali metal salt Chemical class 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229950008882 polysorbate Drugs 0.000 claims 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 2
- 239000002156 adsorbate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- 229940117013 triethanolamine oleate Drugs 0.000 description 2
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000034423 Delivery Diseases 0.000 description 1
- ZMJBYMUCKBYSCP-UHFFFAOYSA-N Hydroxycitric acid Chemical compound OC(=O)C(O)C(O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 1
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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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