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Nimodipine (Nimotop), a second generation pharmacological agent, is known as a dihydropyridine calcium channel blocker which is used clinically for prevention and treatment of cerebrovascular dysfunction, ischemic cerebrovascular disease, hypertension, cerebrovascular spasm after subarachnoid hemorrhage, sudden sensorineural hearing loss, migraine, etc. Due to its high lipophilicity, nimodipine is easy to cross blood-brain barrier, and the concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage patients. The characteristics of binding with specific receptors of nervuscentralis make Nimodipine a potential drug for prevention and treatment of ischemic brain damage resulting from cerebrovascular spasm. It leads to dilate blood vessel without interfering peripheral vessel under the appropriate dosage. It also has preferably medicinal effect when increasing dosage properly. However, it is unclear how the pharmacology.However, the precise mechanism of action of nimodipine in humans is unknown. It shows that nimodipine has positive effect on protecting memory and recovering intelligence.
Have been introduced to cerebrovascular drug in clinically for several years, the drug effect of nimodipine is limited because of its low solubility in water and the evident first-pass metabolism. Clinically, the bioavailability and vasodilatability of nimodipine result extremely different due to the difference from preparation and dosageform. By the reason of intrinsic dissolution rate and first pass effect of tablets and capsules, the available bioavailability is only maximum 20%. But it seems that the better way to increase the bioavailability is to improve the first pass effect by employing the solid dispersion technique for making tablet and capsules. Previous reports showed that the traditional preparation of solid dispersion utilizing melting method, solvent method or melting-solvent method was difficult in crush and easiness of change when crushing. In our report, the way of preparation of solid dispersion is using spray drying technique that is based on carrier of water soluble materials, Polyvinylpyrrolidone (PVPk30). The best recipes and preparations were screened after careful analysis of intrinsic dissolution rate from different solid dispersion samples with different ratio of carriers. Preparation of nimodipine solid dispersion based on water soluble materials (PVPk30) is highly loaded, stable and endurable. Spray drying technique is reliable for preparation of nimodipine solid dispersion, and its good reproducibility and the dispersion is fulfilled in demands of all kinds of solid preparation.
Nimodipine tablets and capsules absorbed in gastrointestinal tract entered peritubular capillary or lymphatic vessel, and then blood circulation until metabolized by liver, in that of relatively long time of abortion and distribution the drug effect lost 80% approximately. First pass effect is extremely obvious. Nimodipine injection, however, was absorbed completely after injected directly into blood circulation system, the inconvenience and unacceptability resulted limitation in wide utilization. In order to escape from above reasons, we expected to prepare nimodipine tablets in orally rapid dissolving tablets, a novel preparation of drugs based on modern rapid releasing technique. The tablets we introduced was fast dissolved in mouth without aid of water, convenient, tasty, avoiding from first pass effect, and improving dissolution rate, bioavailability and adaptability of drug.
Commercially available nimodipine tablets is 30 mg per table, the tablets used in our research is 20 mg per tablet, and the hardness is 2 kg cm-2
Because the analogies we used is tablet without aid of water, it needed to keep main effective contents and weight of tablet small for obtaining better disintegration. According to regulation of FDA, the selection of main effective contents is limited. The tablets is made from PVPk30, PVPP, MCC, corrigent and other excipients
The rate of disintegration and dissolution depended on different composition of excipients such as stuffings, disintegrants, Lubricants and adhesives. MMC, a common excipient for oral drugs, is not only used for help of tabletting, but also used for help of improving rapid dissolution in mouth due to good fluidity, disintegration and adhesivity after compression. For the MMC’s poor resistance to swelling, the tablets containing too much MMC became soft and tasted grittiness. Research indicated that the best time of disintegration is the ratio of MMC and Na2CO3 is 3:2, the dissolution is 58% / 0.5 min. Therefore, the best recipe of MMC and Na2CO3 for our tablets is MMC :Na2CO3 = 3:2.
The difference for quality control between common tablet and self-made tablet is disintegration and dissolution. The reported methods for testing disintegration include oral testing by volunteers and modification of pharmacopoeial disintegration testing methods. Determination by volunteers depends on subjective description, taste of no grittiness representing complete disintegration. Moreover, modification of pharmacopoeial disintegration testing methods depends on disintegration without shake, the suspension passing through 10 Å sieve representing complete disintegration.
The disintegration of oral dissolution tablets based on the preparation of modified recipe was dramatically improved to 21.5 s and tasted good, which is fulfilled with the demands. Comparing with dissolution of commercially available tablets 5.4 min, our tablets is 0.47 min, the rate of dissolution is highly increased. Preliminarily, the composition of nimodipine oral dissolution was confirmed. In vitro, the rate of dissolution is extremely faster than marketed tablets before first 15 min, no difference after first 15 min, which indicated intention of rapid release of drug. Preliminary research for self-made nimodipine tablets demonstrated that there was no change in other indexes except for gaining weight in 6 months, which meant it was basically stable in probation.
The testing of dissolution rate was determined from popular phrarmacopeial method accordingly. Requirement for the agreement of behavior in vivo, the method used in common tablets was suitable for self-made tablets.
Nowadays, Nim tablet is widely used in hospitals all over the country in spite of high lipophilicity, low solubility and low oral absorption. The bioavailability and clinical effects of Nim depended on rational recipe and techniques, the development of oral dissolution tablet secured shortage of currently available tablets, and improved the absorbability of Nim after orally ingested. It is very convenient for patients who have difficulty to obtain water and patients who have problem with dysphagia. This research investigated pharmacokinetics and relative bioavailability of Nim in healthy group, and comparatively studied the marketed tablets for reference of the clinical applications of Nim
Nim metabolized to various products in vivo, and the therapeutic level in human blood and other body fluid is relatively low. It is reported that HPLC， GC and RIA could be used for measurement. In our pharmkenetic study, the comparison testing between Nim and marketed tablets was measured for 6 different healthy volunteers using the simple, fast and sensitive mehod is HPLC, and the relative bioavailability from the statistical comparison of calculated parttens was discussed.
The HPLC method reported in this article for measuring the concentration of NiM samples in plasm is convenient and reliable. The signals of impurities, samples and interior labels were fully separated without any interference from endogenous components in plasm, nimodiping was in linear agreement with a range of relative linearity. The relative recovery, precision of intraday and interday, stability, limit of quantitation and detectability were fullfilled with the requirements of determination of biological sample analysis. Nimodipine as an ideal internal label, not metabolites, was fully separated due to its similar chromatographic behaviors in structural, physical and chemical properties.The method in this experiment has high sensitivity, specificity, and accurate characteristics, consistently with requirements of biological sample analysis. In vivo the concentration of nimodipine in healthy volunteers’ plasma was determined by HPLC, and characteristics of pharmacokinetics in hum body were studied. After comparing between ingestion of single dose oral fast dissolving tablets and common tablets, concentration of nimodipine in human plasma was great difference individually.
Single dose oral fast dissolving tablets was significantly different from common tablets in partner of pharmacokinetics, it can be calculated through the value of AUC that the relative bioavailability of self-made oral dissolving tablets was 177.27% than that of common commercially available tablets. Nim oral dissolving tablets increased bioavailability significantly.The time to reach peak value Tmax for oral dissolving tablets was 0.63h faster than common tablets, whereas comparing with common tablets the Cmax of oral dissolving tablets was significantly different (P <0.01), so did the residence time MRT in vivo ( P <0.01). Results indicated that release effect of oral dissolving tablets does not affect the therapeutic effect of drugs in the body.The constant of absorption rate Ka was significantly higher than the commercially availables, which demonstrated that the faster absorption of oral dissolving tablets, the bigger constant of absorption rate was, a consequence of dissolution by saliva and rapid absorption by oral mucosa
People suffering from hypertension, ischemic cerebrovascular disease and dementia etc, the drugs must be used with the aid of water. On the one hand patients, particularly elder people, women and children, often feel inconvenient when using drugs with aid of water; on the other hand, the fast disintegration in mouth (usually 30 seconds or less) can rapidly play a role to greatly enhance the bioavailability. Thus, the technology of oral disintegrating agent has become one of the contemporary prosperous medical technologies with broad prospect.
[ Last edited by xiaoqihu on 2010-3-3 at 15:19 ] |
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