The Effect of Particle Size on Bioavailability in Cyclosporine Preparations Based on Submicron Dispersions

Vrána, Aleš; Andrýsek, Tomáš

doi:10.5507/bp.2001.007

Cited by 10 publications

(7 citation statements)

References 7 publications

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“…Early findings were later on in contrast with facts that also crude types of nascent dispersions allow to obtain the same bioavailability of cyclosporine A in blood as with very fine microemulsion 3,4,5 . As the first, physical aspect of novel highly available formulation was investigated gel formation upon contact with aqueous milieu 6,7 , which was associate with phase transition, when liquid crystalline phase is rising.…”

Section: Introductionmentioning

confidence: 56%

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Excipients and Their Role in Absorption: Influencing Bioavailability of Cyclosporine by Triglycerides and Polyglycerol Esters

Andrýsek¹

2006

BIOMED PAP

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Aims:The goal of the experiment was to verify bioavailability of immunosuppressive drug cyclosporine after oral administration, to determine, in particular, effect of triglycerides and polyglycerol esters on bioavailability of this lipophilic, poorly soluble drug.Methods: 1) Absorption of cyclosporine A from soya oil and polyglycerol-3-oleate was tested after intra-duodenal application to rats. This method enable to administer dispersion directly to the site of absorption and avoid problems with potential precipitation of active substances in the stomach. Samples were pre-dispersed in water and diluted on concentration 1mg/ml prior administration. In defined time intervals a blood sample was taken in a volume of 0.5 ml from the cannuled carotid. Blood was sampled in time 5, 15, 30, 45, 60, 90, 120, 180 and 240 minutes after application. For the comparison, Equoral ® oral solution diluted and pre-dispersed in the same manner was used. 2) 100 mg of cyclosporin in form of 1% dispersion in water was administered orally to dogs under fasting condition. The blood level of cyclosporine was evaluated from samples taken in time 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12 and 24 hours following application. Formulations containing different ratio of polyglycerol esters / olive oil were compared.Results: The experiments conducted indicate that cyclosporine is 19× more available from polyglycerol-3-oleate than from soya oil. When applying cyclosporine in polyglycerol-3-oleate the average maximum blood level is 10x higher then in application of cyclosporine in oil. If polyglycerols are fully substituted with plant oils in the formula observed, its pharmacokinetic parameters decrease to 1/10 of the initial values.Conclusions: The right selection of a type of excipient accompanying cyclosporine affects significantly cyclosporine availability and thus its efficiency.

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Section: Introductionmentioning

confidence: 56%

“…In defined time intervals a blood sample was taken in a volume of 0.5 ml from the cannuled carotid. Blood was sampled in time 5, 15, 30, 45, 60, 90, 120, 180 and 240 minutes after application. For the comparison, Equoral ® oral solution diluted and pre-dispersed in the same manner was used.…”

mentioning

confidence: 99%

Excipients and Their Role in Absorption: Influencing Bioavailability of Cyclosporine by Triglycerides and Polyglycerol Esters

Andrýsek¹

2006

BIOMED PAP

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“…In pharmaceutical products, the particle size of drugs and components may affect the processing and bioavailability. [1][2][3][4] A number of compounds in pharmaceutical field have low aqueous solubility and fall in class II and IV of the biopharmaceutical classification system. Particle size reduction, leading to increase in surface area, is a very promising technique to increase dissolution rate and, in turn, the bioavailability of poorly water-soluble and steroidal compounds.…”

Section: Introductionmentioning

confidence: 99%

Dissolution enhancement of Tibolone by micronization technique

Bansal¹,

Pankaj²,

Padhee³

et al. 2012

Arch Pharma Pract

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Objectives:Tibolone is an estrogen-like compound used for the treatment of the symptoms associated with the menopausal transition and also for the treatment of osteoporosis. The aim of this study was to evaluate impact of micronization on the dissolution profile so as to improve the release rate of Tibolone drug from tablet dosage form. Materials and Methods: Tibolone oral tablet 2.5 mg is formulated using micronized and unmicronized drug in a preoptimized formula and was evaluated for drug content, dissolution, hardness, thickness, and disintegration time. Particle size reduction of Tibolone drug was achieved by Air Jet Milling and evaluated by using Malvern mastersizer instrument. Results: Micronization of Tibolone enhanced its dissolution rate to a significant extent when compared with unmicronized material. The dissolution profile of formulation with micronized Tibolone was similar to that of European market product (Livial tablet 2.5 mg). Conclusion: Micronization technique has a significant impact on the dissolution of Tibolone. The experimental findings suggest that micronization can be used for the preparation of rapidly dissolving formulations of Tibolone, and could potentially lead to improvement in the in-vivo bioavailability of Tibolone oral tablets.

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“…The currently used CsA formulation, Neoral ® has greater and more balanced gastrointestinal absorption and improved bioavailability than the older formulations. Neoral ® is a microemulsion pre-concentrate of particle size <100 nm 20,21 compared with Sandimmun ® , similar C 0 levels, but higher C max as well as AUC were achieved during the steady state in patients who received Neoral ® . Pharmacokinetic data in patients with RA and psoriasis, as well as patients with solid organ transplantations, showed better bioavailability for Neoral ® than Sandimmun ® .…”

Section: Introductionmentioning

confidence: 99%

“…The original oil-based preparation of CsA showed wide inter-and intra-patient variability. Absorption is significantly affected by solubilisation of CsA in bile and a number of other factors, e.g diet, gastrointestinal transit time, concurrent medications and others [16][17][18][19][20][21] . The currently used CsA formulation, Neoral ® has greater and more balanced gastrointestinal absorption and improved bioavailability than the older formulations.…”

Section: Introductionmentioning

confidence: 99%

Single-Dose and Steady State Pharmacokinetics of Csa and Two Main Primary Metabolites, Am1 and Am4n in Patients With Rheumatic/Autoimmune Diseases

Suchý¹,

Dostálek²,

Perinova³

et al. 2011

BIOMED PAP

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Background. Cyclosporine A (CsA) is an immunomodulatory agent used in standard immunosuppressive regimens in solid organ transplantations as well as in the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus and psoriasis. Its immunosuppressive activity is primarily due to parent drug. However, following oral administration, absorption is incomplete and varies between individuals. Further, there is a dearth of pharmacokinetic data for CsA in autoimmune patients compared to transplant recipients.Aim. The goal of this study was to investigate the single-dose and steady state pharmacokinetics of CsA and two main primary metabolites, AM1 and AM4N, in patients with rheumatic/autoimmune diseases.Methods. Thirty-eight subjects, average age (years± SD) 46.8 (±11.6) years with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis and undifferentiated SpA were included in an observational open study. The single dose pharmacokinetics (area under the concentration-time curve of CsA and its metabolites (AUC) and other PK parameters) were determined over a 24 h period following oral administration of 1.3 mg/kg oral CsA. Two CsA formulations-Neoral and the Czech generic substitute Consupren ® , were used. Pharmacokinetic analysis was performed on all 38 patients after administration of a single dose of CsA (1.34 mg/ kg/day). In 12 patients only, a second series of blood samples was taken to calculate monitored PK parameters under steady state conditions.Results. Pharmacokinetic assessment showed AUC 0-24 3009.66 ± 1449.78 ng/ml.h and C max 827.84 ± 425.84 after administration of a single dose of CSA, AUC 0-24 3698.50 ± 2147 ng/ml.h and C max 741 ± 493 ng/ml after repeated dose. The proportion of the AM1 metabolite (AUC 0-24 ) after a single dose of CsA corresponded to 40% of the parent compound and to approximately 35% of the parent compound in steady state conditions. The proportion of AM4N metabolite was low in both conditions and represented only 3 and 4.5% after a single dose and at steady state, respectively.Conclusion. The pharmacokinetic data (AUC CsA, C max ) for the whole 24 h interval were similar to the published findings, mainly under steady state conditions. The AM1 (AUC 0-24 ) after a single dose of CsA and in steady state conditions represented about 40% of the parent drug. The ratio of AM4N metabolite was low in both conditions.

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The Effect of Particle Size on Bioavailability in Cyclosporine Preparations Based on Submicron Dispersions

Cited by 10 publications

References 7 publications

Excipients and Their Role in Absorption: Influencing Bioavailability of Cyclosporine by Triglycerides and Polyglycerol Esters

Excipients and Their Role in Absorption: Influencing Bioavailability of Cyclosporine by Triglycerides and Polyglycerol Esters

Dissolution enhancement of Tibolone by micronization technique

Single-Dose and Steady State Pharmacokinetics of Csa and Two Main Primary Metabolites, Am1 and Am4n in Patients With Rheumatic/Autoimmune Diseases

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