Glimepiride Dispersible Tablets By Solid Dispersion Technology

Diabetes mellitus is a kind of metabolic disease characterized by high blood glucose which is due to defects in insulin secretion or damage caused by the biological effects. With the aging of world population, diabetes has become a common and multiple disease. In developed countries, the number of deaths caused by diabetes complications has ranked the third after that of cardiovascular disease and cancer. The pathogenesis and prevention of diabetes have attracted worldwide concern. Type Ⅱ diabetes is mainly caused by insulin resistance (not sensitive to insulin) and islet β cell dysfunction (The body lack of insulin secretion). The commonly used drugs include sulfonylureas, biguanide hypoglycemic agents, a-glucosidase inhibitors, insulin sensitizers and Glinides insulin secretagogues. Glimepiride, as the third-generation sulfonylurea hypoglycemic agents which is used for the treatment of uncontrolled type Ⅱ diabetes even with moderate diet and exercise is efficient, long-lasting, lower dosage, and fewer hypoglycemia adverse reactions etc. However, the poor solubility and low bioavailability is imperfection. The innovativeness of this article is the preparation of solid dispersion tablets which is administered by oral to improve the rate of dissolution and the bioavailability.The solid dispersion technology is extensively studied to improve the solubility of poorly soluble drugs. The drug and hydrophilic carrier are melted by heating or dissolved in a co-solvent, then cooling or distilling off the solvent to obtain the solid dispersion of the drugs and carrier. In the solid dispersion, the drug is dispersed in the carrier as microcrystalline, molecular or eutectic mixture, which primarily contributes to increase the dissolution rate of poorly soluble drugs and bioavailability, reduce the adverse reactions of drug and improve patient compliance and levels of drug use.Glimepiride was chosen as the model drug in this research. The glimepiride solid dispersion whose carrier is PVP k30was prepared by spray drying to improve the dissolution of glimepiride disintegration tablets. The uniformity of the dispersion of the tablets was improved by inner-adding and external-adding efficient disintegrating agent. Feasibility of prescribing composition and stability of preparation process were confirmed through producing three batches in a larger scale. The quality research was conducted by using similar factor f2, the FDA recommended, comparing vitro dissolution curves between the product and the similar preparations in market named Amaryl in four kinds of dissolution medium:water, pH1.2HCl, pH6.8phosphate buffer, and pH7.8phosphate buffer to evaluate the quality consistency. The study included the preparation process and quality research of glimepiride solid dispersion, as well as the formulation process and quality research of glimepiride dispersion tablets.1. Preparation process and quality research of glimepiride solid dispersion: Glimepiride solid dispersion was prepared by spray drying which chose PVP k30as carrier material, methylene chloride as drug solvent, and ethanol as the solvent of carrier material. The optimal prescription composition and preparation process for glimepiride solid dispersion were determined by respectively Orthogonal test, and then the phase identification among glimepiride, PVP k30and physical mixture was finished by using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction, infrared spectrometry (IR) and use the HPLC method for the determination of related substances and use capillary column gas chromatography to determine the methylene chloride residue in glimepiride solid dispersion. The results showed that PVP k30was the carrier selection, drug and carrier ratio should be1:4, inlet fluid speed at10ml/min, intake air temperature should be controlled at65℃, in which the white or off-white solid prepared through spray drying is glimepiride solid dispersion. The results of integrating SEM, DSC, XRD and IR analysis showed that glimepiride morphological appearance had significant changes in glimepiride solid dispersion, and there was no presence of the crystal, but the amorphous form dispersed in PVP k30carrier material. The-C=O and-NH in glimepiride or-OH in PVP may form a kind of composite with the form of hydrogen bond to preparing an ideal solid dispersion. Three batches of samples were measured by using quartz capillary column (DB-624,30m X0.25mm), hydrogen flame ionization detector, injector temperature250℃, column temperature180℃, choosing nitrogen gas as carrier with flow rate of4.0ml per minute, which showed that residual methylene chloride was less than0.005%, which was far less than what provided by the Chinese Pharmacopoeia2010edition that the methylene chloride residue should not exceed0.06%. The vitro dissolution was measured base on three batches of solid dispersion, which showed that dissolution has been greatly improved, and solubilizing effect of solid dispersion was obvious.2. The preparation process and quality research of glimepiride solid dispersion tablets:According to the prescription pre-design, single factor affecting test results, the prescription and production processes of dispersion tablet were determined by orthogonal test, which chose microcrystalline cellulose and pre-gelatinized starch as diluent, crospovidone and carboxymethyl starch sodium as disintegrants, PVP k30as the bonding agent, water as the moistening agent, and the stearate magnesium as lubricant. Diluent and solid dispersion were mixed by the process of equally incremental which can guarantee uniformity of product with only lmg glimepiride. The process using combined disintegrants technique with PVPP inner-added and CMC-Na external-added highly efficient disintegrant were used to ensure the dispersibility uniformity of the product. Glimepiride tablet was prepared by using optimal prescription and process. After small, pilot, and enlarged scale production, all nine batches of samples met quality requirements, formulation process was stable, and production applicability was favorable.Quality research was conducted based on three batches produced in the pilot scale production. First of all, referring to the United States Pharmacopoeia, Imported Common Tablets Standard and Japan Orange Book, we established dissolution testing methods not using organic solvent—0.02%trihydroxy aminomethane solution but pH7.8phosphate buffer as the dissolution medium, not using small cups but large cups, and the methodology validation were also performed; using f2factor method to compare dissolution curves of original Amaryl tablets with different concentrations in four different medium:water, pH1.2hydrochloric acid, pH6.8phosphate buffer and pH7.8phosphate buffer, which showed that the dissolution curves of self-produced tablets and original research Amaryl tablets were similar. Nine batches of samples were tested and the results are in line with regulations, what’s more, the differences in each one batch and between batches are small.Secondly, HPLC method was established to measure related substances in the dispersion tablets, through the methodology validation, we found it have strong specificity, high sensitivity, well reproducibility, accurate and reliable results. At the same time, HPLC method for the determination of glimepiride content in dispersion tablets was also established, which have good recovery rate, good reproducibility, accurate and reliable results through the methodology validation, and the content uniformity determination method on the basis of determination method was established to check the related substances, content and content uniformity of6batches separately from pilot and commercialized enlarged scale products. The result showed that they were in accordance with the requirements of the Chinese Pharmacopoeia, which confirmed the product preparation process stability and product uniformity.Finally, the three continuous batches production of pilot products were packaged with Aluminum-plastic blister, Aluminum foil bag and carton packaging), which were used for a six-month accelerated testing and36-month long-term stability testing. The results showed that there are no significant changes for their appearance, dispersion uniformity, dissolution, related substances and the content, which were in accordance with the regulations. The existing data showed that the process, packaging materials and other things made the product have the ability of mitigating solid dispersion aging to protect their relative stability within a certain time.Conclusion:The dissolution rate of the products was improved through the solid dispersion technology; content uniformity was ensured through equal increments process; dispersion uniformity was improved by adopting of combined efficient disintegrating agent, inner-added and external-added technology. Small, pilot scale products and nine batches of products in market were in line with regulations. Formulation and preparation process were stable and well reproducible. The quality stability of the product during storage was preliminarily confirmed through six months of accelerated and nine months of long-term trial, which achieved the pre-designed objective of the study.