Cyclodextrins and chitosan derivatives in sublingual delivery of low solubility peptides: A study using cyclosporin A, α-cyclodextrin and quaternary chitosan N-betainate

Systemic drug delivery through intraoral membranes may offer a promising administration route for lipophilic peptide drugs. The aim of the present study was to investigate the effect of α-cyclodextrin (α-CD) and a novel chitosan derivative, chitosan N-betainate (CH), on sublingual absorption of a hydrophobic model peptide cyclosporin A (CsA), and the effect of temperature on the complexation of CsA with α-CD.     

国产复方利福平片与进口药人体相对生物利用度研究

采用随机分组自身前后交叉给药对 18名健康志愿者 ,单剂量口服复方利福平片与进口对照药品 (商品名Rifinah)进行人体相对生物利用度研究。采用HPLC紫外检测法测定给药后受试者血浆中利福平、异烟肼两种有效成分的浓度。结果表明复方利福平片与进口对照药中的利福平平均药动学参数Tmax分别为( 1.2 78± 0 .45 3)和 ( 1.389± 0 .40 4)h ,T1/ 2ke分别为 ( 6 .882± 1.92 0 )和 ( 6 .0 84± 0 .5 6 3)h ,Cmax分别为 ( 19.30 2±5 .830 )和 ( 17.95 1± 5 .6 0 7)mg/L ;两种药中异烟肼的Tmax分别为 ( 0 .6 47± 0 .310 )和 ( 0 .6 89± 0 .5 0 4)h ,T1/ 2ke分别为 ( 3.30 9± 1.46 4)和 ( 3.40 7± 1.2 2 8)h ,Cmax分别为 ( 6 .6 6 7± 2 .45 9)和 ( 6 .876± 2 .5 93)mg/L。两药中利福平的AUC0～ 2 4 分别为 ( 94.5 73± 2 4.478)和 ( 94.36 8± 2 0 .2 46 )h·mg/L。两种药中异烟肼的AUC0～ 12 分别为 ( 15 .2 86±3.85 8)和 ( 16 .738± 4.6 5 9)h·mg/L ,被试制剂中利福平、异烟肼的相对生物利用度分别为 ( 10 0 .3± 12 .3) %、( 92 .4± 10 .5 ) %。对复方利福平片与进口品中两种有效成分利福平和异烟肼分别进行方差分析和双单侧检验 ,无显著性差异 (P <0 .0 5 )。结论 :两者为生物等效制剂。     

消炎痛微囊胶囊剂的制备及其在家兔体内的生物利用度

本文报道了用消炎痛微粉混悬于菜籽油中作囊心物,明胶、阿拉伯胶为囊材,以复凝聚法成囊后制成消炎痛微囊胶囊剂的方法;消炎痛微囊胶囊剂中的微囊粒径约70％为15～30μm,经测定其在家兔体内的药-时曲线下面积与不包囊的微粉胶囊剂相比,有显著性差异(P<0.05),第二个峰时、峰值,均有极显著性差异(P<0.01)。结果表明消炎痛微囊胶囊剂有可能成为剂量小。副作用少、生物利用度高并具有缓释作用的新剂型。     

Bioavailability of diltiazem as a function of the administered dose

Diltiazem undergoes extensive first-pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first-pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter-subject variability was highest at the lowest dose at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11.8 +/- 2.5 per cent after 10 mg to 28.2 per cent after 120 mg; (d) the elimination half-life was dose-related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 +/- 0.3 per cent after 10 mg to 3.0 +/- 0.5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first-pass effect for diltiazem.     

Relative bioavailability of olsalazine from tablets and capsules: a drug targeted for local effect in the colon

The aim of this investigation was to compare two formulations of the prodrug olsalazine (OLZ) with regard to local bioavailability of 5-aminosalicylic acid (5-ASA) in the colon. Since 5-ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N-acetyl-5-aminosalicylic acid (ac-5-ASA). The absorption of OLZ was also studied. A single dose of 1g OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two-period cross-over studies. Blood and urine samples were collected for 72 and 96 h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac-5-ASA (tablet-capsule) compared to that of capsules were -0.31 per cent and 30.8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional +/- 20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were -10.5 per cent and 36.9 per cent while for Ae the values were -20.5 per cent and 23.7 per cent. Within and between subject variability estimates for AUC of ac-5-ASA were 24 per cent and 46 per cent, respectively.     

Bioavailability study of a freeze-dried sodium phenytoin-milk formulation.

The problematic bioavailability of phenytoin's (5,5-diphenylhydantoin) oral formulations serves as a stimulus for examining new formulations and/or administration conditions that may provide more predictable absorption. Attempts to achieve more consistent peroral phenytoin bioavailability from conventional solid dosage forms include changes of binder and crystal size, use of salt form, and inclusion of the drug in cyclodextrins. In addition, various factors which may affect the environment and/or the physiology of the upper gastrointestinal tract can profoundly affect the absorption of phenytoin. Among other approaches, the use of drug-milk freeze-dried formulations has been proposed to overcome problems associated with dissolution-limited bioavailability. The effect has been attributed to the formation of an amorphous precipitate during the drying process which facilitates the re-dissolution of the drug during the regeneration of the milk solution. In this work, we report comparative bioavailability studies utilizing a freeze-dried sodium phenytoin-milk formulation and a capsule formulation administered with either water or milk. In addition, the interaction of the drug with milk components was evaluated in vitro through binding and solubility studies.     

A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy

The pharmacokinetics of midazolam, a water soluble 1,4-benzodiazepine, has been studied in 12 patients (11 male, 1 female; age range 19–57 years) with epilepsy. All patients were taking hepatic enzyme inducing antiepileptic drugs (AEDs) on a regular basis. Midazolam (5 mg) was administered intravenously and 1 week later midazolam was administered intramuscularly, the dose used being dependent on the sedative response to the intravenous dose (10 mg, N = 2; 7 mg, N = 8; 5 mg, N = 2). Serial blood samples were collected at timed intervals for 5–7 h. After intravenous administration initial distribution was rapid with a mean half-life (t¹/2) of 0.06 ± 0.03 h followed by a terminal half-life (t¹/2β or γ) of 1.5 ± 0.3 h. Volume of distribution was 0.62 ± 0.27 1/kg. After intramuscular administration midazolam was rapidly absorbed with peak serum concentrations achieved at 25 ± 23 min. Two patients showed delayed absorption. Mean terminal half-life was 2.8 ± 1.7 h. The absolute bioavailability of intramuscular midazolam was calculated in 11 patients as 87 ± 18%. Sedation was rapid (< 1–2 min) but transient (7–75 min) after intravenous and slower (2–30 min) and for a longer period (20–120 min) after intramuscular administration. Since intravenous administration of AEDs including diazepam is not always feasible in status epilepticus there are obvious advantages in having an effective intramuscular formulation. Our data suggest that midazolam may be such a drug.     

Intestinal solubilization, absorption, pharmacokinetics and bioavailability of chenodeoxycholic acid*

Abstract. Little is known about the physical state, intestinal solubilization, absorption and bioavailability of chenodeoxycholic acid used in the medical treatment of gallstones. Therefore the concentrations of unconjugated chenodeoxycholic acid were measured in the supernatant and precipitate phases of intestinal contents aspirated from stomach, duodenum and jejunum of nine control subjects who took 500 mg chenodeoxycholic acid (4 times 125 mg gelatin-coated capsules) either fasting or together with a standard liquid meal. Chenodeoxycholic acid solubility was markedly influenced by luminal pH but was little affected by endogenous conjugated bile acids when their concentrations were > 1–2 mmol/1.
Systemic bioavailability of 250, 500 and 750 doses of chenodeoxycholic acid was measured in five subjects by comparing areas under 4 h serum concentration-time curves after giving the bile acid first as a bolus intraduodenal aqueous infusion of ³H-labelled chenodeoxycholic acid containing either ¹⁴C-polyethylene glycol or bromsulphthalein as non-absorbable markers, and then as gelatin-coated capsules by mouth.
Absorption was assessed by measuring the ratio of marker: bile acid in intestinal contents aspirated for 2 h from sites 60 and 120 cm distal to the duodenal infusion port and in three subjects quantitative recovery of marker was measured proximal to an occluding intestinal balloon. Absorption of duodenally-infused chenodeoxycholic acid was 96–99% complete and bioavailability was complete with the 250 and 500 mg doses but fell to 81% with the 750 mg dose.     

Improvement of the wettability and dissolution of fenofibrate compacts by plasma treatment

The goal of this study was to investigate the effect of plasma treatment on the wettability and dissolution of fenofibrate compacts. Contact angle measurements and intrinsic dissolution rate studies of untreated and plasma-treated fenofibrate compacts were conducted. The contact angle data clearly show that the wettability of the tablet surface increased with the duration of plasma treatment.Analyses of stability revealed that the surfaces which were plasma-treated for more than 1 min regained some degree of hydrophobicity after storage in air. Since their hydrophobic recovery finally reached the level observed with 1 min plasma-treated fenofibrate compacts it was deduced that permanent incorporation of hydrophilic groups had already attained saturation upon plasma irradiation for 1 min.Dissolution studies revealed the advantages of the hydrophilized surface of plasma-treated fenofibrate compacts. Due to the improved wettability of plasma-treated fenofibrate its intrinsic dissolution rate was vastly increased compared to untreated fenofibrate. This study thus demonstrates the potential of plasma treatment to enhance the wettability and dissolution behavior of poorly water-soluble drugs.     

国产氨酚氢可酮片人体生物等效性研究

目的:评价国产与进口氨酚氢可酮片的生物等效性。方法:采用双周期自身交叉试验设计,24名健康男性志愿者分别单剂量口服国产和进口氨酚氢可酮片1片,分别于给药前及给药后0.25、0.5、1、1.5、2、4、6、8、12、16、24 h采静脉血。采用高效液相色谱-质谱-质谱联用方法分别测定血浆中对乙酰氨基酚和重酒石酸氢可酮的浓度。结果:受试制剂与参比制剂中对乙酰氨基酚的tmax分别为(0.85±0.31)和(0.90±0.33)h,Cmax分别为(8.93±2.91)和(9.59±3.24)mg.L-1,t1/2分别为(3.19±0.71)和(3.20±1.48)h;AUC0-tn分别为(25.97±5.75)和(28.00±5.24)mg.L-1.h,AUC0-∞分别为(26.47±5.72)和(28.47±5.31)mg.L-1.h,受试制剂的相对生物利用度为(93.04±12.06)%。重酒石酸氢可酮的tmax分别为(1.04±0.78)和(0.96±0.751)h;Cmax分别为(22.93±6.45)和(21.49±6.19)μg.L-1;t1/2分别为(5.43±0.99)和(5.65±1.60)h;AUC0-tn分别为(128.59±32.75)和(116.84±29.98)μg.L-1.h;AUC0-∞分别为(135.43±34.05)和(124.74±32.37)μg.L-1.h;受试制剂的相对生物利用度为(112.77±26.54)%。结论:国产与进口氨酚氢可酮片具有生物等效性。