Prevacid
Formulation study for lansoprazole fast-disintegrating tablet. II. Effect of triethyl citrate on the quality of the products.

Shimizu T, Kameoka N, Iki H, Tabata T, Hamaguchi N, Igari Y.

Pharmaceutical Development Laboratories, Pharmaceutical Production Division, Takeda Chemical Industries, Ltd. Ossaka, Japan. Shimizu_Toshihiro takeda.co.jp

The purpose of this study was to develop enteric-coated microgranules for the lansoprazole fast-disintegrating tablet (LFDT), which is a rapidly disintegrating tablet containing enteric-coated microgranules. In our previous study, it was clarified that sufficient flexibility of the enteric layer was achieved by the optimized combined ratio of methacrylic acid copolymer dispersion to ethyl acrylate-methyl methacrylate copolymer dispersion and adding the optimized concentration of triethyl citrate to reduce the damage during the compression process. However, since triethyl citrate has an unpleasant bitter taste and is especially incompatible with lansoprazole, it adversely affects the taste and stability of lansoprazole in the enteric-coated microgranules. The enteric layer containing macrogol 6000 was proven useful to improve the unpleasant bitter taste and stability of lansoprazole, because macrogol 6000 does not have an unpleasant bitter taste and is more compatible than triethyl citerate. By covering the inner (first enteric layer) and outer side (third enteric layer) of the enteric layer containing triethyl citrate (second enteric layer) with the enteric layer containing macrogol 6000, we resolved the stability problem of lansoprazole and the unpleasant bitter taste. Finally, we developed enteric-coated microgranules comprising seven layers: 1) core, 2) active compound layer, 3) intermediate layer, 4) first enteric layer, 5) second enteric layer, 6) third enteric layer, and 7) over coating layer. The enteric-coated microgranules have the multiple functions of reducing the damage to the enteric layer during the compression process, improving the stability of lansoprazole, and masking the unpleasant bitter taste.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12951443&dopt=Abstract lansoprazole Prevacid



Prevacid
Quality of life and cost-effectiveness of combined therapy for reflux esophagitis.

Si JM, Wang LJ, Chen SJ, Zhao L, Dai N.

Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China. sijm 163.net

OBJECTIVE: To evaluate clinical, Quality of Life (QoL) and medical cost outcomes in patients with symptomatic reflux esophagitis (RE) receiving different "triple combination therapy". METHODS: A multicenter medical effectiveness trial conducted in 10 hospitals of 5 regions in Zhejiang Province. 248 patient-volunteers were assigned to 8 weeks of "triple combination therapy" with Lansoprazole plus Cisapride and Sucralfate or Ranitidine plus Cisapride and Sucralfate. Main outcomes assessment included symptoms scale scores, RE severity, QoL at baseline and 8 weeks. Medical cost data were collected with cost analysis questionnaire. RESULTS: (1) More Lansoprazole group patients noted RE symptoms resolution than Ranitidine group (92.3% vs 78.4%, P<0.01). There was no striking difference between two groups in RE healing rate (90.8% vs 82.9%, P>0.05). (2) RE significantly impaired QoL of patients (P<0.001). Compared with Ranitidine group, QoL in Lansoprazole group had significant improvement (rate of "good" QoL 64.5% vs 45.6%, P<0.01). (3) There was close correlation between symptomic effectiveness and QoL rating scale in both the Lansoprazole and Ranitidine group (P<0.01, r=0.235 and 0.353 respectively). There were no statistical difference of medical cost between the two groups (P>0.05). CONCLUSION: RE significantly impaired QoL of patients. "Triple combination therapies" can significantly improve RE symptoms and QoL. Lansoprazole combination therapy was more cost-effective than Ranitidine combination group.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12958722&dopt=Abstract lansoprazole Prevacid



Prevacid
Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects.

Flouvat B, Delhotal-Landes B, Cournot A, Dellatolas F.

Toxicology and Pharmacokinetics Laboratory, AMBROISE PARE Hospital, 92100 Boulogne-Billancourt, France.

Plasma concentrations of lansoprazole and of its sulphone, sulphide and 5-hydroxylated metabolites were determined after oral administration of a single 30 mg dose and after 7 days of treatment with a daily 30 mg dose in 12 elderly subjects (mean age 83 years). Results after a single dose were compared with those from a historical control group of 18 young subjects (mean age 23 years). Mean values of AUC after single dose were 2668 ng ml(-1) h in the young subjects and 5216 ng ml(-1) h in the elderly (P < 0.05). Mean t 1/2z values in young and elderly subjects were 1.4 h and 2.9 h, respectively (P < 0.001). Plasma concentrations of the metabolites were similar in both groups. However, the hydroxylated metabolite of the sulphone was detected only in elderly subjects. Steady state plasma concentrations of lansoprazole were reached after 3 days of dosing with lansoprazole. The accumulation ratio was 1.31 in the elderly subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959297&dopt=Abstract lansoprazole Prevacid



Prevacid
Stereoselective metabolism of lansoprazole by human liver cytochrome P450 enzymes.

Kim KA, Kim MJ, Park JY, Shon JH, Yoon YR, Lee SS, Liu KH, Chun JH, Hyun MH, Shin JG.

Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine Clinical Pharmacology Center, Busan Paik Hospital Busan, Korea.

The stereoselective metabolism of lansoprazole enantiomers was evaluated by incubation of human liver microsomes and cDNA-expressed cytochrome p450 (p450) enzymes to understand and predict their stereoselective disposition in humans in vivo. The intrinsic clearances (Clint) of the formation of both hydroxy and sulfone metabolites from S-lansoprazole were 4.9- and 2.4-fold higher than those from the R-form, respectively. The sums of formation Clint of both metabolites were 13.5 and 57.3 microl/min/mg protein for R- and S-lansoprazole, respectively, suggesting that S-lansoprazole would be cleared more rapidly than the R-form. The p450 isoform selective inhibition study in liver microsomes, and the incubation study of cDNA-expressed enzymes, demonstrated that the stereoselective sulfoxidation is mediated by CYP3A4 and that the hydroxylation is mediated by CYP2C9 and CYP3A4 as well as by CYP2C19. Total Clint values of hydroxy and sulfone metabolite formation catalyzed by all these p450 enzymes were consistently higher for S-lansoprazole than for the R-form. The CYP3A4 produced the greatest difference of Clint between S- and R-enantiomers, mainly due to a difference of sulfoxidation metabolism (Clint 76.5 versus 10.8 microl/min/nmol of p450, respectively), whereas CYP2C19-catalyzed hydroxylation resulted in a minor difference of Clint between S- and R-enantiomers (179.6 versus 143.3 microl/min/nmol of p450, respectively). However, the affinity of CYP2C19 on hydroxylation was 5.7-fold higher for S-enantiomer than for the R-form (Km 2.3 versus 13.1 microM), suggesting that the role of CYP2C19 on stereoselective hydroxylation would be more prominent at concentrations around the usual therapeutic level. These findings suggest that both CYP2C19 and CYP3A4 are major enzymes contributing to the stereoselective disposition of lansoprazole, but stereoselective hydroxylation of lansoprazole enantiomers is mainly influenced by CYP2C19, especially at the usual therapeutic doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12975331&dopt=Abstract lansoprazole Prevacid



Prevacid
Relaxant effect of omeprazole and lansoprazole in guinea pig gallbladder muscle strips in vitro.

Aydin C, Sarac B, Koyuncu A, Yildirim S, Sen M, Sarioglu Y.

Department of General Surgery, Cumhuriyet University School of Medicine, Sivas, Turkey.

BACKGROUND: The aim of this study was to investigate the role of omeprazole and lansoprazole, H(+)-K(+) ATPase inhibitors, in gallbladder smooth muscle contractility in vitro. METHODS: Gallbladder muscle strips obtained from guinea pigs were mounted in an organ bath. The responses of both precontracted strips and strips under basal tension to omeprazole and lansoprazole were determined. RESULTS: Spontaneous contractile activity was blocked following omeprazole and lansoprazole administration. The agents also caused concentration-dependent relaxation in carbachol- and KCl-precontracted gallbladder muscle strips. Pretreatment with atropine (1 microM), N(W)-nitro L-arginine methyl ester (L-NAME; 30 microM), indomethacin (10 microM), ammonium chloride (7.5 mM), sodium acetate (7.5 mM), tetraethylammonium chloride (0.5 mM), glibenclamide (1 micro M), 4-aminopyridine (0.1 mM), or clotrimazole did not inhibit this relaxation. Gallbladder strips were placed in high-concentrtion potassium (80 mM), calcium-free solution. The contraction produced with the addition of Ca(2+) (2.5 mM) was completely relaxed by omeprazole, lansoprazole, and nifedipine separately. CONCLUSIONS: These results demonstrate that omeprazole and lansoprazole have potent inhibitory effects on spontaneous contractions and cause dose-dependent relaxation in precontracted gallbladder smooth muscle strips of guinea pig in vitro. This effect could be due to blockade of the calcium channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14505131&dopt=Abstract lansoprazole Prevacid