Study On The Immediate-release Oral Formulations Of Flupirtine Maleate

Research backgroundFlupirtine maleate is a non-opioid analgesic acting on the central nervous system. It was first synthesized in1980s in Germany and was marketed by Degussa Pharma. It is a nonopioid, non-NSAID analgesic, and is devoid of common adverse effects seen with NSAIDs and opioids. It is a type of selective neuronal potassium channel opener (SNEPCO), acting as pain relieving, muscle relaxation and neuroprotective effects. It does not produce tolerance and dependence. In clinical, flupirtine maleate shows the analgesic and muscle tone normalizing efficacy upon treatment of acute and chronic pain associated with muscle tenseness, tension headache, tumor pain, dysmenorrhoea, and pain after traumatologic/orthopaedic operations and injuries. Although it is not yet approved by United States Food and Drug Administration (US FDA), it is still used in many countries including India. Recently, US FDA granted permission to carry out phase II clinical trial with flupirtine for the treatment of fibromyalgia.Flupirtine maleate is almost completely absorbed from the gastrointestinal tract. The bioavailability was70%. The peak concentration was obtained at1.6h-2h, maximum conentration was0.8～2.0mg·L-1Flupirtine maleate is available in50and100mg oral capsules and75and150mg rectal suppositories. The usual adult dosage is one100mg capsule or one150mg suppository3to4times daily, to a maximum of6doses daily.It is considerably important to solve the pain of patients as soon as possible. In the course of study, the developments of immediate release formulation become the focus of experiments. The formulations of dry suspension, orally disintegrating tablet and solid dispersion technology improve the dissolution rate of drugs, so that drugs play a batter pharmacological. At the same time, it is necessary to study its pharmacokinetics and pharmacodynamic in rats.Main contents1. To prepare flupirtine maleate solid dispersion and evaluated its pharmacokinetic parameters and bioavailability after intragastric administration in rats in comparison with crude drug. Plasma concentrations were determined by the HPLC fluorescence method. The pharmacodynamics were evaluated by the hot-plate and acetic acid-induced writhing tests in mice2. To prepare and optimize the formulation of flupritine maleate orally disintegrating tablets.3. To prepare the flupirtine maleate dry suspension and investigate the quality of the newly designed suspension.Methods1. Determination of Equilibrium Solubility and Apparent Oil-water Partition CoefficientChromatographic Conditions:The mobile phase of flupirtine maleate was disodium hydrogen phosphate solution(5mmol·L-1):acetonitrile=55:45(pH6.7). Fluorescence-detected excitation wavelength was323nm. Emission wavelength was370nm. Chromatographic column was Hypersil ODS (4.0mm×125mm,5μm). Column temperature was room temperature. The drawing of standard curve, precision test, recovery test and stability test were conducted, as well as the equilibrium solubility and apparent oil-water partition coefficient was determinated under the above conditions.HPLC fluorescence method was established to determine the equilibrium solubility of flupirtine maleate in Water, pHl HC1, pH2.0,3.0,4.0,5.0,6.8,8.0phosphate buffer, methanol, ethyl acetate. Apparent oil-water partition coefficient for the n-octanol mixed with water was determined by shaking flask method.2. Study on the preparation and quality control of solid dispersionThe solid dispersion of flupirtine maleate was prepared using Macrogol6000(PEG6000), polyvinylpyrrolidone (PVP) as carriers by melting or solvent methods with ratio of drug to carriers1:1,1:2,1:4and1:6. The status of flupirtine maleate in carrier was determined by X-ray diffracttion and differential scanning calorimetry. The dissolution of the dispersion was determined with paddle method.3. Studies on pharmacokinetics of solid dispersionAt the first, the establishment of a high selectivity, high sensitivity determination of flupirtine maleate and flupirtine maleate solid dispersion concentration in rats plasma by high performance liquid chromatography fluorescence method, and the method precision, recovery and stability the determination.A healthy SPF Wistar rats (weight200-220g) as the experimental animals were randomly divided into two groups, one single oral administration of flupirtine maleate suspension, given the other group was given mixed flupirtine maleate solid dispersion suspension, both given the same dose of flupirtine maleate (17mg·kg-1), oral administration at different time points after the HPLC fluorescence method for the determination of flupirtine maleate concentration in plasma samples.Studies with Drug And Statistics2.0(DAS2.0) pharmacokinetic compartment model analysis software and its solid dispersion pharmacokinetic parameters: maximum plasma concentration (Cmax), area under the curve (AUC), time to peak (Tmax) and the clearance rate (CL), this analysis of flupirtine maleate and flupirtine maleate solid dispersion in rats in vivo pharmacokinetic differences.4. Studies on pharmacodynamics of solid dispersionThe healthy SPF Kunming mice were regarded as the research object. The analgesic effect was investigated by the hot-plate and acetic acid-induced writhing tests in mice. After adaptive feeding week, the experimental groups were randomly divided into8groups, n=10. The experimental groups consisted of negative control group, positive control group, bulk drug high(36mg·kg-1), medium(16mg·kg-1), low(4mg·kg-1) dose group, solid dispersion high(36mg·kg-1), medium(16mg·kg-1) and low(4mg·kg-1) dose group.5. Preparation and quality control of the orally disintegrating tabletsThe preparation of tablets were formulated by the wet granulation compression method and the prescription was optimized with an orthogonal design according to disintegrating time in vitro and dissolution. Filter paper test was designed to evaluate disintegration time of tablets. The results were compared with in vivo disintegration times in the mouth and common method. The suitable flavoring agent was chosen to adjust the taste of tablets. L-HPC and PVPP were selected as disintegrants. The in vitro release of flupirtine maleate orally disintegrating tablets was determined by small glass. The HPLC fluorescence method was used to determine the content of main component in tablets. 6. Preparation and quality control of dry suspensionThe dry suspension was prepared by the method of powder direct mixing. The mint flavor, sugar powder and silica were selected as aromatic agent, flavoring agent and flow agent. To investigate the suspending effect of the following hydrophilic polymer:HPMC and CMC-Na. The optimum formulation was investigated with the sedimentation and redispersibility as the content index. The HPLC fluorescence method was used to determine the content of main component in formulations. The viscosity was determined by the NDJ-4type rotary viscometer.7. The comparison of dissolution behaviour and investigation of stabilityIn vitro testing of capsule, dry suspension, orally disintegrating tablets and solid dispersion were conducted. Solid dispersion technology greatly improve the dissolution rate of flupirtine maleate. The illumination affectd the quality of drugs on the basic of stability experiments, and therefore should be avoided in storage.Results1. At room temperature, the solubility of flupirtine maleate in was and in basic buffer solution had lower values. Apparent n-octanol-water partition coefficient of flupirtine maleate was41.69(1gP=1.62). Flupirtine maleate under the established detection methods can be separated well and has no obvious impurity peaks. Flupirtine maleate in the0.66-6.6μg·mL-1has a good linear. Low, medium, high concentration solution precision and intraday precision were1.37%,1.02%,1.21%and1.63%,0.82%,1.45%. Low, medium, high concentration of recoveries were99.75%,99.35%,99.74%. Stability results were good. Above-mentioned contents illustrate that the method has good accuracy and reproducibility.2. The dissolution of flupirtine maleate solid dispersion with PEG6000as carrier was similar to solid dispersion with PVP as carrier. The dissolution of flupirtine maleate solid dispersion (1:4) solid dispersion was the highest. Drug in solid dispersion partly existed as molecule and partly as fine crystal. The main pharmacokinetics parameters of flupirtine maleate solid dispersions and flupirtine maleate crude drugs were compared. Tmax was1.583±0.204and1.083±0.204. Cmax was10.161±0.867and13.602±0.875. AUC0→∞was86.468±10.685and94.332±12.604. The results showed that the solid dispersion could shorten the Tmax in vivo, which answered to in vitro release test. Pharmacodynamic study showed that flupirtine maleate solid dispersion produced quicker and better effect than crude drug at the same dose.3. The taste of tablets were desirable. The tablets were disintegrated within34.1±4.8s in mouth, filter paper test31.3±4.2s and common method8.5±2.4s. The results are similar between in vivo disintegration times in the mouth and filter paper test. The cumulative dissolution percentage was higher than60%within30min.4. The sedimentation ratio of flupirtine maleate dry suspension was1within3h with good redispersibility and liquidity.Conclusions1. The dissolution in vitro and dissolution rate were increased by solid dispersion technique. The flupritine maleate in solid dispersion improves the absorption rate and blood concentration. The analgesic effect was investigated by the hot-plate and acetic acid-induced writhing tests in mice.2. The formulation technology of flupritine maleate orally disintegrating tablets was reasonable. The design could closely estimate the disintegration time of orally disintegrating tablets.3. The flupirtine maleate dry suspension comformed the quality standard. A rotary viscometer was used to determinate the viscosity of suspension. Its hydrodynamics behavior is similar to shear thinning liquid.