Bioequivalence of metformin hydrochloride sustained-release tablets under fed condition in healthy subjects / 中国药科大学学报

@#To evaluate bioequivalence and safety of two kinds of metformin hydrochloride sustained-release tablets (test preparation vs reference preparation) under the condition of fed and single administration.A single center, randomized, open, single-dose, two-period, two-sequence, and double-crossover design was used.32 healthy subjects took 0.5 g of test preparation or reference preparation under fed and single-dose administration.4 mL of venous blood was collected from before administration (0 h) to 1, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 15, 24, 36 and 48 h after administration.The concentration of metformin in plasma samples was detected, and then the pharmacokinetic parameters were calculated by WinNonlin 7.0 software.When the 90% confidence intervals of cmax, AUC0-t and AUC0-∞ geometric mean ratio of test preparation and reference preparation were within 80.00%-125.00% equivalent intervals respectively, the bioequivalence of the two preparations was proved.One subject fell off due to adverse events.The main pharmacokinetic parameters of test preparation and reference preparation as follows: cmax were (0.68 ± 0.14) and (0.65 ± 0.11) mg/L, AUC0-t were (7.33 ± 1.65) and (7.00 ± 1.89) h·mg/L, AUC0-∞ were (7.39 ± 1.67) and (7.06 ± 1.91) h·mg/L, respectively.The 90% confidence intervals of the geometric mean ratio of the two main pharmacokinetic parameters were 101.45%-109.14%, 100.08%-112.32% and 100.24%-112.28%, respectively, which fell within the bioequivalence interval of 80.00%-125.00%.There were no serious adverse events and unexpected adverse events during the trial.The results show that test preparation and reference preparation are bioequivalent under fed and single-dose administration, safe and well tolerated in healthy subjects.

Pharmacokinetic effects of metformin hydrochloride, food and alcohol on Ramulus Mori (Sangzhi) alkaloids / 药学学报

Ramulus Mori (Sangzhi) alkaloids (SZ-A) are a group of polyhydroxy alkaloids extracted and isolated from the traditional Chinese medicine mulberry twig, which is mainly used for the treatment of type 2 diabetes mellitus (T2DM). In addition to acting as a glycosidase inhibitor in the small intestine after oral administration, SZ-A can also be absorbed into blood and widely distributed to target organs related to diabetes, exerting multiple pharmacological effects. It is important to elucidate the possible pharmacokinetic influences of SZ-A for its clinical rational applications, such as drug interactions, the effects of food and alcohol on the absorption of SZ-A. However, studies in this area are limited. Therefore, the pharmacokinetic interactions between orally administrated SZ-A (50 mg·kg-1) and metformin hydrochloride (Met, 200 mg·kg-1) in Sprague-Dawley (SD) rats were examined. Then, the effect of food (standard feed) on the pharmacokinetics of SZ-A was investigated using fasting administration of SZ-A (50 mg·kg-1) in rats as a control. Finally, we investigated the pharmacokinetic characteristics of SZ-A (50 mg·kg-1) in different concentrations alcohol solutions using aqueous solution of SZ-A administered to rats as a control to evaluate the effect of alcohol on the bioabsorption of SZ-A. The results showed no significant pharmacokinetic interactions between SZ-A and Met after combination treatment. The standard feed had little effect on the pharmacokinetic profile of SZ-A. Alcohol retarded the absorption of SZ-A, resulting in a significant decrease in the Cmax of SZ-A. The decrease was greater at higher alcohol concentrations; however, no significant difference was observed in the AUC0-t. These results support the clinical rational applications of SZ-A. All animal protocols were approved by the Ethics Committee of Kangtai Medical Laboratory Service Hebei Co., Ltd. (Hebei, China) (No. MDL2022-01-17-1).

Effects of metformin hydrochloride tablets on clinical efficacy and number of dominant follicles in polycystic ovary syndrome / 药学实践杂志

Objective To explore the effect of metformin hydrochloride tablets on the clinical efficacy, number of dominant follicles and ovarian volume of polycystic ovary syndrome. Methods 150 patients diagnosed with polycystic ovary syndrome who were diagnosed and treated in our hospital from January 2019 to March 2021 were selected .The patients were divided into observation group and control group by random number table. The control group was treated with letrozole + gonadotropin, and the observation group was treated with letrozole + gonadotropin + hydrochloric acid + Metformin tablets. The clinical efficacy, endometrial thickness, number of high-quality follicles, sex hormone levels, blood lipid levels, and adverse reactions were compared between the two groups. Results ① The effective rate of treatment in the observation group was 90.67%, which was significantly higher than that in the control group, 78.67% (P<0.05). ② After treatment, the endometrial thickness of the observation group was lower than that of the control group, and the number of high-quality follicles was more than that of the control group(P<0.05). ③ After treatment, the levels of Luteinizing Hormone-LH, Follicle Stimulating Hormone-FSH and Testosterone (T) in the observation group were lower than those in the control group (P<0.05). ④ After treatment, the total cholesterol (TC) and triglyceride (TG) in the observation group were lower than those in the control group (P<0.05). ⑤ The incidence of adverse reactions in the observation group was 8.00%, which was significantly lower than 20.00% in the control group (P<0.05). Conclusion Letrozole + gonadotropin + metformin hydrochloride tablets could significantly improve the sex hormone and blood lipid levels in patients with polycystic ovary syndrome, relieve the symptoms of the patients, and improve their uterine condition, which had a good clinical effect.

Bioequivalence of metformin hydrochloride sustained-release tablets in healthy subjects / 中国临床药理学与治疗学

AIM: To study the bioequivalence of two metformin hydrochloride sustained-release tablets in Chinese healthy subjects. METHODS: A randomized, open-label, two-period, crossover study design was adopted in the study. In fasting test 36 and in fed test 23 healthy subjects were given a single oral dose of metformin hydrochloride sustained-release tablet (0.5 g). The concentration of metformin in plasma was measured by HPLC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin 7.0 program, and statistical analysis were performed by using SAS9.4 statistics software. RESULTS: In the fasting test, the pharmacokinetic parameters of metformin of the test (T) and reference(R) preparation were as follow: C

Formulation and stability studies of metformin hydrochloride in a controlled porosity osmotic pump system

This study was designed to formulate, for the first time, metformin hydrochloride (MH, 850 mg/tablet) as a controlledporosity osmotic pump (CPOP) system to achieve zero-order release pattern. MH core tablet was coated with celluloseacetate membrane containing PEG 400. The effect of different percentages and molecular weights of polyethyleneoxide (PEO, 900K and 4M) in tablet core was studied. The United States Pharmacopeia (USP) apparatus II andphosphate buffer pH 6.8 were used for the release studies; meanwhile, a promising formula was tested in biorelevantmedia. The stability of some selected formulations was carried out for 6 months, at bench and accelerated conditions.Evaluation included: MH content, Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM),drug release, and kinetics. Results revealed that increasing PEO percentage within the core decreased MH release.SEM verified formation of pores in the membrane that accounts for MH release. Almost all stored tablets werestable for all studied parameters. MH endothermic peak maintained its position and energy of enthalpy on storageas confirmed by DSC. MH release rate from a promising formula, following zero-order release model, increased by28% in biorelevant media compared to phosphate buffer. Subsequently, in vitro release in biorelevant media could beemployed as a tool to anticipate in vivo tone of CPOP formulations

Determination of the Stability Constants Comlexes of Metformin Hydrochloride With Cu(II), Cd(II) and Zn(II)

In the present work, binary complexes of Copper(II), Cadmium(II) and Zinc(II) with metformin hydrochloridehave been studied potentiometrically. Stability constants of binary complex systems have been estimated by themethod proposed by Irving-Rossotti at 25ºC and 0.11M ionic strength (NaClO4) in aqueous solution. Theconditional formation constants of the complexes formed between ligand and metal were calculated according topH function. The maximum values of the conditional formation constants were found to be in accordance with themixed metal-ligand complex formation constants in a given pH region. In addition to these, the molar fractionswere calculated using the formation constants of the mixed metal-ligand complexes. As a result of theexperimental study, the values of stability constants of metal-ligand complexes at 25ºCare as noted below:logK1=8.45; logK2=8.30 for Zn(II)-Metformin hydrochloride; logK1=8.78 ; logK2=8.00 for Cu(II)-Metforminhydrochloride: logK1=8.18; logK2=7.36 for Cd(II) – Metformin hydrochloride.

Comparative In Vitro Dissolution Study On Metformin Market Products Using Different Dissolution Apparatuses

Objective: This study was proposed to evaluate and compare the in vitro dissolution profiles of six Metformin Hydrochloride (MH) market products. Methods: Different dissolution apparatuses (USP apparatus II, IV and beaker method) were used to evaluate the dissolution profiles (in phosphate buffer, pH 6.8) of two immediate release (IR) generic products of Metformin Hydrochloride (MH): Cidophage® 1000 mg (G1, Egyptian market) and Metformin arrow® 1000 mg (G2, French market) with respect to the reference products named Glucophage® 850 mg (R1, Egyptian market and R2, French market). In addition to a generic controlled-release (CR) product; Cidophage Retard® 850 mg (G3) versus the reference product; Glucophage XR® 1000 mg (R3) (both from Egyptian market). Dissolution efficiency (D. E.) and the similarity factor (f2) were calculated. Weight uniformity, hardness, tablet dimensions and MH content were measured. Results: Results of the three apparatuses showed that MH IR products studied (reference and generics) did not meet the 75% USP 30 specifications for MH dissolved at 30 min. For MH CR products, Glucophage XR® did not fulfill the USP release criteria, while Cidophage Retard® did. USP apparatus IV revealed the highest sensitivity and discriminative capability. Conclusion: Generally, MH IR generics (G1 and G2) might be interchangeable with the innovator product (Glucophage®). However, Cidophage Retard® might not be interchangeable with Glucophage XR®.

A Rapid Validated Uni-Dimensional Double Development Hptlc-Densitometry Method For Simultaneous Estimation Of Metformin Hydrochloride, Gliclazide And Pioglitazone Hydrochloride

Objective: To develop and validate a uni-dimensional double development high-performance thin layer chromatography (UDDD-HPTLC) for estimation of anti-diabetic medicine compromising of metformin (MET) gliclazide (GLZ) and pioglitazone hydrochloride (PIO). Methods: The chromatographic separation of these drugs was carried out on precoated TLC plates silica gel 60F254by two mobile phases consisting of Ammonium Sulphate: Methanol: Acetonitrile: Water (4:3:2:1) for MET and PIO and Toluene: Ethyl Acetate: Formic Acid (6:4:0.5) for GLZ respectively for ideal separation and good resolution. The densitometric detection and quantification were carried out at 237 nm for MET and 200 nm for GLZ and PIO. The validation parameters were strictly followed as per the ICH guidelines. Results: The linearity range was obtained at 3000-8000ng/spot, 360-960 ng/spot, 90-240 ng/spot for MET, GLZ and PIO with r2value>0.999. The other parameters such as precision, reproducibility, robustness were efficiently obtained within the limits. The proposed method was successfully applied for simultaneous determination of MET, GLZ and PIO in the commercial formulation. Conclusion: In simultaneous estimation, the different polarity of drugs makes it more cumbersome to develop and validate any chromatographic method. In the present study, a uni-dimensional double development high-performance thin layer chromatography (UDDD-HPTLC) for estimation of these drugs have been developed and validated to resolve the estimation problem. It is an effortless and speedy method which was developed and validated using ICH guidelines. The developed and validated method using ICH guidelines is effortless and speedy technique.

Enantiometric Separation Of Sitagliptin In A Fixed Dose Combination Formula Of Sitagliptin And Metformin By A Chiral Liquid Chromatographic Method

Objective: Sitagliptin phosphate and metformin hydrochloride tablet is an FDA approved combination product for the treatment of diabetes mellitus type 2. There are no reported evidence for estimation of undesired (S)-sitagliptin in a combination product. The objective of this study was to develop a high sensitive liquid chromatography method for the determination of (S)-enantiomer of sitagliptin phosphate in a fixed dose combination formula of metformin and sitagliptin. Methods: The proposed novel high-performance liquid chromatography (HPLC) method uses programmed gradient elution of a mixture of ethanol-diethylamine(DEA) 100:0.1 (v/v) as mobile phase-A and a mixture of methanol-water 60:40 (v/v) as mobile phase-B. The chromatographic conditions were designed to nullify the metformin interference and in which sitagliptin enantiomers elute first and followed by metformin. A satisfactory resolution (≥2.5) between (S)-sitagliptin and active form (R)-sitagliptin was achieved with gradient elution on Chiralpak IA column (5μm, 4 × 250 mm) at a flow rate of 0.5 ml/min and the detector wavelength set at 265 nm. The injection volume set as 10 µl. The developed method has been validated as per the International Conference on Harmonisation (ICH) guidelines. Results: The proposed HPLC method for determination of (S)-sitagliptin, showed good linearity in the concentration range of 0.5 µg/ml to 13.6 µg/ml and capable to quantify accurately up to the lowest level (LOQ) of 0.017%. The validated method was successfully applied to quantify the (S)-sitagliptin for different marketed formulations of sitagliptin with metformin and sitagliptin alone, and the corresponding recovery values were found to be in the range of 95.1% to 98.4%. Conclusion: The proposed validated HPLC method was found to be suitable for the quantitative determination of (S)-sitagliptin in the formulations of sitagliptin with metformin and sitagliptin alone.

Effects of Alcohol on Release Characteristics of Metformin Hydrochloride Extended-Release Tablets in Vitro and in Vivo / 中国药学杂志

OBJECTIVE: To investigate the effects of alcohol on release characteristics of metformin hydrochloride extended-release tablets in vitro and in vivo. METHODS: The release behaviors and swelling of self-made metformin hydrochloride extended-release tablets and commercial products Glucophage XR in different release media including water, 5% alcohol, 20% alcohol and 40% alcohol were investigated and similar factor method was used to evaluate the similarity of release. Based on results in vitro, water and the alcoholic medium with significant differences were selected for Beagle dogs experiments to investigate further the effects of alcohol on release characteristics of metformin hydrochloride extended-release tablets in vivo. RESULTS: Along with the increase of the alcohol concentration in the release media, both formation rate of the gel layer became slower and the penetration of the solvents became less in the swelling process, only dissolving a small amount of drug, so the release of self-made tablets and Glucophage XR gradually decreased in vitro. Both release in 40% alcohol produced a significant difference compared with that in water (f2<50), but the release of self-made tablets was greatly similar to Glucophage XR in the same media.In vivo studies of Beagle dogs revealed that an initial low release of both preparations was observed in 40% alcohol which was consistent with the vitro, while a certain increase was observed later, but the overall release was not statistically different from that of the water supply group. Moreover,the main pharmacokinetic parameters of the self-made tablets and Glucophage XR between the water-supply group and the 40% alcohol-supply group had no statistical difference. CONCLUSION: Alcohol has the same effects on the release characteristics of self-made metformin hydrochloride extended-release tablets and Glucophage XR in vitro and in vivo. High concentration of alcohol has a significant effect on the release characteristics in vitro, but it has no significant effect on the overall release in vivo.

Clinical efficacy of anti-helicobacter pylori in treatment of type 2 diabetes mellitus with helicobacter pylori infection / 中国综合临床

Objective To explore the clinical efficacy of anti-helicobacter pylori (HP) treatment on patients with type 2 diabetes mellitus and HP infection.Methods A total of 112 type 2 Diabetes patients were diagnosed with HP infection in Combine Traditional Chinese and Western Medicine Hospital of Taizhou from April 2012 to June 2016.These patients were divided into control and treatment group based on the preprandial blood glucose averages from lower to higher hierarchy.Thus,there were 56 patients in each of the two groups.The control group was given Motilium and Talcid for gastric symptoms in addition to anti-diabetes treatment,while the treatment was administered the same treatments as well as the quadruple anti-HP therapy (omeprazole,amoxicillin,clarithromycin and colloidal-bismuth-subcitrate,with Talcid stopped while colloidal-bismuth-subcitrate was administered).The anti-HP lasted for 14 days.The two groups were compared the gastric symptoms,the blood glucose levels,and the HbA1c one month after treatment.Half a year and one year post treatment,the two groups were compared the gastric mucus signs under gastroscopy.Results The improvement rates after treatment with the treatment group in abdominal pain,bloating,regurgitation,belching and diarrhea/constipation were 88.5％ (23/26),83.3％ (25/30),74.1％ (20/27),83.9％ (26/31),82.6％ (19/23),respectively,and with the control group being 29.2％(7/24),32.1％(9/28),28％(7/25),30.3％(10/33),18.2％ (4/22),respectively.The differences between the two groups were significant (x2=8.06,6.62,3.92,7.65,6.66,P＜0.05 or P＜0.01).The control group did not show significant changes in preprandial glucose levels,the glucose levels two hours post meals and the HbA1c(P＞0.05) while the treatment group showed statistically significant changes(P＜0.05 or P＜0.01).The differences in the three indicators after treatment between the two groups were significant (t =4.07,7.85,4.16,P＜ 0.05).The Gastric mucus signs under gastroscopy showed improvements in both groups after treatment.The improvement rates with the treatment group were 86.2％(25/29),86.7％ (13/15),77.8％ (14/18),72.7％ (8/11) respectively,with the control group being 36％ (9/16),27.3％ (3/11),13.3％ (2/15),14.3％ (1/7),respectively.The differences between the two groups were significant (x2 =6.71,4.12,4.38,3.85,P ＜ 0.05 or P＜ 0.01).The effectiveness rate,which was based on combined improvements in gastric symptoms,glucose levels and gastric mucus signs,was 76.8％ with the treatment group and 32.1％ with the control group.The difference was statistically significant (x2 =6.78,P＜0.01).Conclusion Anti-HP treatment can relieve the gastric symptoms,stabilize the glucose levels,and help to reverse the changed gastric mucus.All these can reduce the complications of the diabetes and improve the prognosis of the patients.

Efficacy and safety of psychological intervention combined with Metformin Hydrochloride Enteric-Coated Capsules in the treatment of type 2 diabetes mellitus / 中国生化药物杂志

Objective To investigate the effectiveness and safety of psychological intervention combined with Metformin Hydrochloride Enteric-Coated Capsules in the treatment of type 2 diabetes mellitus. Methods A total of 80 patients with type 2 diabetes mellitus were selected from May 2015 to October 2016 in our hospital. The subjects were randomly divided into control group and experimental group, with 40 patients in each group. The control group was given repaglinide treatment, given metformin treatment of Metformin Hydrochloride Enteric-Coated Capsules on the basis of the experimental group, psychological intervention on the mental status of patients and patients, strengthen communication and exchanges, increase confidence in the treatment and the treatment compliance of patients. Results After the corresponding treatment, the patients in the experimental group and the control group had no serious adverse reactions, and the safety was better. The probability of hypoglycemia in the experimental group (15%) was significantly higher than that in the control group (5%), with statistical difference (P<0.05). Before treatment, the fasting blood glucose levels of the experimental group and the control group were (9.21±2.31) and (9.38±2.28) nmol / L, and there was no significant difference between the two groups, and there was no statistical significance The fasting blood glucose level (7.31±1.02), nmol / L in the experimental group was significantly lower than that in the control group (7.90±0.82) nmol / L. The effect of diabetes treatment in the experimental group was significantly better than that in the control group, with statistical difference (P<0.05). Conclusion Psychological intervention combined with Metformin Hydrochloride Enteric-Coated Capsules in the treatment of type 2 diabetes mellitus has high efficacy and low incidence of adverse reactions. It has clinical significance.

Influencing Factors in Fluidized Bed Granulation Process of Metformin Hydrochloride / 中国药师

Objective:To study the effects of process parameters of fluidized bed granulation on the physical properties of metform-in hydrochloride granule. Methods:The physical properties of metformin hydrochloride were used as the evaluation indices. Single fac-tor experiment was conducted to investigate the influences of equipment factors ( including the nozzle height and the nozzle orifice) and the process parameters ( including binder dosage, inlet air temperature, inlet air flow rate, spray rate and atomization pressure) on the physical prperties. Results: The influences of equipment factors on the physical properties of the granule were not significant. The binder dosage, inlet air temperature, inlet air flow rate, spray rate and atomization pressure showed significant influences on the physi-cal properties of metformin hydrochloride granule. Conclusion:The parameters of fluidized bed granulation process ( binder dosage, in-let air temperature, inlet air flow rate, spray rate and atomization pressure) have significant effects on the physical properties of met-formin hydrochloride granule, which should be controlled according to the requirements of granule properties.

Analytical method development and validation for simultaneous estimation of Teneligliptin hydrobromide hydrate and Metformin hydrochloride from it’s pharmaceutical dosage form by three different UV spectrophotometric methods.

Three new UV spectrophotometric methods namely simultaneous equation, absorbance ratio and first derivative (zero crossing) spectroscopic methods were developed and validated for simultaneous estimation of teneligliptin hydrobromide hydrate and metformin hydrochloride in tablet formulation which were simple, sensitive, precise and accurate. In simultaneous equation method, absorbance was measured at 237 and 246 nm for both the drugs. Teneligliptin hydrobromide hydrate and metformin hydrochloride was estimated using 237 and 247.5 nm in absorbance ratio method. First derivative (zero crossing) method was based on the transformation of UV spectra in to first derivative spectra followed by measurement of first derivative signal at 237 and 246 nm for teneligliptin hydrobromide hydrate and metformin hydrochloride, respectively using 2 nm as wavelength interval (Δλ) and 1 as scaling factor. Developed methods were validated according to ICH guidelines including parameters viz., specificity, linearity and range, precision, accuracy, limit of detection and quantification. All the three methods showed linear response in the concentration range of 1-20 µg/ml for both the drugs. Results of method validation parameters follows ICH guideline acceptable limits. Based on the assay results obtained, methods were compared using one-way ANOVA followed by Bonferroni multiple comparison tests (95% confidence level) using computer based fitting program (Prism, Graphpad version 5, Graphpad Software Inc). Outcome of the statistical analysis proved that there was no considerable dissimilarity between all the developed methods. Methods were found to be simple, fast, highly sensitive, cost effective and hence can be useful for simultaneous estimation of teneligliptin hydrobromide hydrate and metformin hydrochloride in commercial tablet formulation for routine quality control analysis.

The application effect of insulin aspart alone or in combination with metformin to treat diabetes / 中国基层医药

Objective To study the application effect of insulin aspart alone or in combination with metformin to treat diabetes.Methods 80 patients with diabetes from February 2014 to February 2015 were studied.They were randomly divided into observation group and control group,40 cases in each group.The observation group was given insulin aspart therapy combined with metformin hydrochloride tablets.The control group was treated with insulin aspart.The blood glucose levels,insulin dosage were recorded,the incidence of hypoglycemia was analyzed in the two groups.Results After treatment,the blood glucose levels in the two groups were lower than before treatment,the decrease of the observation group was more significant than the control group,the difference was statistically significant (P 0.05), the highest blood glucose value of the observation group was lower than the control group [(7.3 ±1.1)mmol/L vs (8.5 ±1.8)mmol/L)],there was statistically significant difference (t =3.597 8,P =0.000 2).The average blood glucose level of the observation group was also shorter than the control group,there was statistically significant differ-ence (t =10.880 3,P =0.000 2).After treatment,NIHSS scores of the two groups were decreased,NIHSS score reduce the magnitude of the observation after treatment was significantly higher than the control group (4.33 ± 0.82)vs.(5.24 ±1.25),there was significant difference(t =3.849 8,P =0.000 2).The effect of improving lipid levels observed were significantly better than the control group,the difference was statistically significant (P <0.05). Conclusion Combination of insulin aspart and metformin hydrochloride tablets in the treatment of patients with dia-betes to control blood sugar levels is better than the effect of single treatment with insulin aspart,insulin aspart therapy combined with metformin hydrochloride tablets in patients with diabetes can reduce postprandial 2h,fasting glucose, reduce the incidence of hypoglycemia,it should be popularized and used in the clinical.

In vitro Study of Interactions of Sildenafil Citrate with Bovine Serum Albumin in Presence of Bisoprolol Fumarate and Metformin Hydrochloride by Fluorescence Spectrophotometry.

Aims: This paper describes the In vitro study of protein binding by sildenafil citrate (SC) in presence of bisoprololfumarate (BF) and metformin hydrochloride (MH). Study Design: Study was designed to assess In vitro of quenching of bovine serum albumin (BSA) by sildenafil citrate (SC) in presence of bisoprolol fumarate (BF) and metformin hydrochloride (MH) by fluorescence spectrophotometry. Place and Duration of Study: Drug Analysis and Research Laboratory, Centre for Advanced Research in Sciences, University of Dhaka, Dhaka-1000, Bangladesh between December 2013 and March 2014. Methodology: In the present work, the In vitro study of quenching of BSA by SC in presence of BFand MH have been studied by fluorescence emission spectroscopy under different conditions. At first, the BSA solution (20 μM) was prepared in phosphate buffer (pH =7.4) in eight test tubes and different amounts of sildenafil citrate was added to each BSA solution to obtain the final concentrations as 0, 20, 40, 80, 120, 160,240 and 320 × 10-6 molL-1, respectively. Then the fluorescence emission spectra of BSA-SC system were recorded for eight test tubes at two excitation wavelengths of BSA (λExmax= 280 nm and λExmax=293 nm) at 298 K and 308 K. Similarly, the fluorescence emission spectra of BSA-(SC+BF), BSA-(SC+MH) and BSA-(SC+BF+MH) systems were recorded at 280 nm and293 nm at 298 K and 308 K. Quenching constants were determined using the Stern-Volmer equation to provide a measure of the strength of quenching of BSA by SC in presence of BF and MH in all the systems. Results: The quenching of BSA by SC was increased in presence of BF and MH but remained close in presence of both BF and MH. Quenching constants were larger for the BSA-(SC+BF) system and ranked in the order as BSA-(SC+BF)>BSA-(SC+MH)>BSA-(SC+BF+MH)≈ BSA-SC at 280 nm at two different temperatures, respectively. But quenching at the excitation wavelength of 293 nm was ranked in order as BSA-(SC+BF) >BSA-(SC+MH) >BSA-(SC+BF+MH)>BSA-SC at 298 K and 308 K, respectively. Conclusion: It was found that BSA quenched by SC in presence of BF and MH, which indicated that the effectiveness of SC might be predominately influenced by these drugs.

Preparation of Metformin Hydrochloride Extended Release Matrix Tablets by Direct Compression Method and Its In vitro Evaluation.

Aims: Metformin Hydrochloride, a biguanide, is an orally active antihyperglycemic agent, used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). It has relatively short plasma half life, low absolute bioavailability. Extended release formulation of Metformin Hydrochloride by direct compression method has significant challenges due to its poor inherent compressibility and high dose. The aim of this study was to develop extended release tablets of Metformin Hydrochloride by direct compression method and In vitro evaluation. Study Design: Nine different formulations were made by varying drug-polymer ratio and were subjected to different physical property tests of the powder blend as well as prepared tablets, followed by dissolution test. Place and Duration of Study: Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh, between January 2013 and July 2013. Methodology: Nine formulations of Metformin Hydrochloride matrix tablets - F-1, F-2, F- 3, F-4, F-5, F-6, F-7, F-8 and F-9 - were prepared by direct compression method using release retarding materials, Methocel K100 MCR Premium (derivative of hydroxypropyl methylcellulose - HPMC) and Xanthan gum. The drug and polymer ratio were 1:0.41, 1:0.45, 1:0.49, 1:0.59, 1:0.63, 1:0.67, 1:0.77, 1:0.81 & 1:0.85 respectively. The micromeritic behavior of the powder blends were evaluated for bulk density, angle of repose, compressibility index along with post compressional attributes of the tablets such as thickness, hardness, friability, weight variation and content of Metformin Hydrochloride in the tablets. The in-vitro drug release study was carried out in 1000 mL phosphate buffer medium (pH 6.8) at 37±0.5°C at 100 rpm for 10 hours using USP Apparatus Type-II (paddle) method. Results: FT-IR study showed drug-excipient compatibility and DSC analysis showed no solid state interaction between components. The physical properties of the powder blend and the tablets were within the acceptable limits. Maximum and minimum drug release were found in formulation F-1 and F-9 respectively which indicate that release rate is inversely proportional to the concentration of Methocel K100 MCR Premium and Xanthan gum in combination. Dissolution study also showed that, formulations F-7, F-8 & F-9 do not comply with drug release specification of USP and among the rest six formulations F- 3, F-4 & F-5 comply better with drug release specification of USP. After fitting the data to Korsmeyer-Peppas equation we found that diffusion along with erosion could be the mechanism of drug release.Considering the micromeritic behaviour of the powder blend, physical attributes of the compressed tablets, and dissolution, formulation F-4 seemed most suitable. Conclusion: Extended release Metformin Hydrochloride tablets can be produced to overcome frequent dosing related problems. However, Further study on formulation optimization and scale up, stability and bioequivalence is needed to confirm the appropriateness of these formulated extended release tablets.

RP-HPLC and HPTLC Methods for Simultaneous Estimation of Metformin Hydrochloride and Vildagliptin from Bulk and Marketed Formulation: Development and Validation.

The reversed-phase high performance liquid chromatography (RP-HPLC) and high performance thin layer chromatography (HPTLC) methods for simultaneous estimation of Metfomin Hydrochloride (MET) and Vildagliptin (VLD) in bulk and their marketed combined dosage form were developed. For RP-HPLC, separation was carried out using HiQsil C18HS (4.6mmø×250mm) analytical column and detection was carried out using variable wavelength detector. The mobile phase was composed of phosphate buffer (pH adjusted to 6 using 3M KOH): methanol: acetonitrile in the ratio of 50:30:20 v/v/v. Flow rate was kept at 0.8ml/min. The drugs- MET and VLD were retained at 3.7 minutes and 4.8 minutes respectively. The HPTLC method was developed using Camag HPTLC system. Silica Gel 60GF254 precoated TLC plates were used as stationary phase. The mobile phase was ammonium acetate in methanol (1% w/v): Toluene; (10:0.5). The detection of spots was carried out densitometrically at 214 nm in absorbance mode. The Rf values for MET and VLD were found to be 0.44 and 0.55 respectively. Performance characteristics of both of these RP-HPLC and HPTLC methods for simultaneous estimation of MET and VLD in bulk and their marketed combined dosage form were statistically validated as per the recommendations of ICH guidelines of analytical method validation. The RP-HPLC method was found to be linear across concentration range of 10-60μg/mL for MET and VLD respectively. For RP-HPLC the LOD values for MET and VLD were 1.09μg/ml and 1.70μg/ml respectively and LOQ values for MET and VLD were 3.32μg/ml and 5.15μg/ml respectively. The HPTLC method was found to be linear with across the range 1000-5000ng/spot and 500-2000ng/spot for MET and VLD respectively. For HPTLC the LOD values for MET and VLD were 17.22ng/spot and 34.60ng/spot respectively and LOQ values for MET and VLD were 52.20ng/spot and 104.85ng/spot respectively. Both of these RP-HPLC and HPTLC methods were found to be simple, specific, linear, accurate, precise and robust, hence any of these methods can be conveniently adopted for routine analysis of the formulations containing MET and VLD, for their simultaneous estimation.

Drug layering process of model drugs with different dose and solubility / 中国药学杂志

OBJECTIVE: To study drug layering process of model drugs with different dose and solubility.

Metformin hydrochloride antagonizes glucotoxicity in osteoblasts by restraining the expression of PPARγ / 中国药学杂志

OBJECTIVE: To investigate the protective effects of metformin hydrochloride (MF) on osteoblasts which were exposed to constant high glucose condition, and the relationship between MF and the expression of peroxisome proliferator-activated receptor (PPAR)γ. METHODS: Mouse cranium osteoblasts were cultured in vitro and divided into 5.5 mmol · L-1 normal glucose +0 μmol · L-1 MF group, 25 mmol · L-1 high glucose with different concentration of MF (0, 25, 50, 100 μmol · L-1 MF, respectively) and intervened for 1,2 and 3 w, then the mRNA expression levels of PPARγ and bone morphogenetic protein (BMP)-2 were detected by RT-PCR, and the protein expression levels of PPARγ was examined by Western blot. RESULTS (1)The mRNA expression levels of PPARγ was marked higher in high glucose group compared to the control group with the same intervene time (all P < 0.05); when the intervention time prolonged to 3w, the protein expression of PPARγ increased significantly (P < 0.05); the mRNA expression levels of BMP-2 in the high glucose group was lower than in the control group (all P < 0.05). (2)At the same intervening time, the expression of PPARγ mRNA decreased while BMP-2 mRNA increased (all P < 0.05) with the increasing concentration of MF (from 0 μmol · L-1 to 100 μmol · L-1); when the intervention time prolonged from 1w to 3w, the mRNA expression levels of PPARγ increased in all the high glucose groups while the mRNA expression levels of BMP-2 decreased (all P < 0.05). (3)When interviewed for 3w, the protein expression of PPARγ decreased gradually with the increasing concentration of MF in high glucose condition (P < 0.05). CONCLUSION: Pathological concentration of glucose could lead to poorly differentiated of osteoblasts, which might association with the enhanced mRNA and protein expression levels of PPARγ; MF can protect osteoblasts by restraining the expression of PPARγ.