Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid.

OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. RESULTS: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.

Physiologically-Based Pharmacokinetic Modeling of the Drug-Drug Interaction of the UGT Substrate Ertugliflozin Following Co-Administration with the UGT Inhibitor Mefenamic Acid.

The sodium-glucose cotransporter 2 inhibitor ertugliflozin is metabolized by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes UGT1A9 and UGT2B4/2B7. This analysis evaluated the drug-drug interaction (DDI) following co-administration of ertugliflozin with the UGT inhibitor mefenamic acid (MFA) using physiologically-based pharmacokinetic (PBPK) modeling. The ertugliflozin modeling assumptions and parameters were verified using clinical data from single-dose and multiple-dose studies of ertugliflozin in healthy volunteers, and the PBPK fraction metabolized assignments were consistent with human absorption, distribution, metabolism, and excretion results. The model for MFA was developed using clinical data, and in vivo UGT inhibitory constant values were estimated using the results from a clinical DDI study with MFA and dapagliflozin, a UGT1A9 and UGT2B4/2B7 substrate in the same chemical class as ertugliflozin. Using the verified compound files, PBPK modeling predicted an ertugliflozin ratio of area under the plasma concentration-time curves (AUCR ) of 1.51 when co-administered with MFA. ClinicalTrials.gov identifier: NCT00989079.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Celecoxib versus mefenamic acid in the treatment of primary dysmenorrhea.

Background The objective was to compare the effectiveness and tolerability of mefenamic acid and celecoxib in women with primary dysmenorrhea (PD) and to compare the quality of life of study participants pre- and post-treatment. Materials and methods This was a randomized crossover clinical trial conducted among sexually inactive female adults aged 18-25 years with PD. Participants were asked to rate their pain score and answer a validated quality of life questionnaire (EQ-5D-3L) before and after consumption of each medication in two menstrual cycles. The effectiveness of celecoxib and mefenamic acid in treating PD was compared with regard to reduction in pain score and the need for medical leave and rescue therapy. Drug tolerability was determined by comparing the occurrence of side effects of both drugs. Quality of life scores pre- and post-intervention were measured and compared. Results Mefenamic acid had a comparable effect to celecoxib in relieving symptoms of PD. Both drugs were equally tolerable and showed similar impacts on quality of life. Conclusions This study demonstrated that mefenamic acid and celecoxib had similar effectiveness in improving pain score and quality of life in women with PD.

Renal ultrastructural alterations induced by various preparations of mefenamic acid.

Mefenamic acid (MFA) treatment is associated with a number of cellular effects that potentiate the incidence of renal toxicity. The aim of this study is to investigate the potential ultrastructural alterations induced by various preparations of MFA (free MFA, MFA-Tween 80 liposomes, and MFA-DDC liposomes) on the renal tissues. Sprague-Dawley rats were subjected to a daily dose of MFA preparations for 28 days. Renal biopsies from all groups of rats under study were processed for transmission electron microscopic examination. The findings revealed that MFA preparations induced various ultrastructural alterations including mitochondrial injury, nuclear and lysosomal alterations, tubular cells steatosis, apoptotic activity, autophagy, and nucleophagy. These alterations were more clear in rats received free MFA, and MFA-Tween 80 liposomes than those received MFA-DDC liposomes. It is concluded that MFA-DDC liposomes are less potential to induce renal damage than free MFA and MFA-Tween 80 liposomes. Thus, MFA-DDC liposomes may offer an advantage of safe drug delivery.

Effect of alpha-lipoic acid at the combination with mefenamic acid in girls with primary dysmenorrhea: randomized, double-blind, placebo-controlled clinical trial.

Primary dysmenorrhea is a common gynecologic disorder and is one of the main causes for referral to the gynecology clinic. This study aimed to determine the effects of alpha-lipoic acid (ALA) and mefenamic acid and a combination compared with placebo on the girls with primary dysmenorrhea. This double-blind, placebo-controlled clinical trial done on population consisted of female students living in dormitories of Qazvin University of Medical Sciences who had moderate to severe dysmenorrhea using the Visual Analog Scale (VAS) questionnaire. Participants were randomly divided into four groups (n = 100): ALA, mefenamic acid, ALA + mefenamic acid and placebo groups. ALA and mefenamic acid were administrated in 600 mg and 250 mg, respectively. The severity of the pain was measured in the beginning and the end of the study. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL). Our final results suggested that, although mefenamic acid significantly decreased the menstrual pain, ALA supplementation, 600 mg, would be more efficient than mefenamic acid in 250 mg. Also, the combination of ALA and mefenamic acid significantly has been far. Considering the ALA supplementation effect on pain relief in patients with primary dysmenorrhea, this antioxidant can be recommended for the healing of symptoms of these patients.

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis.

BACKGROUND: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties. METHODS: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly. FINDINGS: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly. INTERPRETATION: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

Comparison of Intra-Socket Bupivacaine Administration Versus Oral Mefenamic Acid Capsule for Postoperative Pain Management Following Removal of Impacted Mandibular Third Molars.

PURPOSE: Surgical removal of impacted third molar teeth is one of the most common surgical procedures performed in oral and maxillofacial surgery. Postoperative pain is a common and predictable occurrence after maxillofacial surgery. MATERIALS AND METHODS: This randomized double-blind clinical trial was conducted with a crossover design in which each patient served as his or her own control. Forty-six patients with similar bilateral impacted lower third molars were selected. In each patient, the intervention and control sides of the mandible were randomly determined at the end of surgery. If the removed tooth was in the intervention side, then the patient would receive bupivacaine and a placebo of mefenamic acid. If the impacted tooth was in the control side, then the patient would receive a mefenamic acid capsule and a placebo of bupivacaine. Pain severity was assessed using a visual analog scale. Data were analyzed using paired-sample t test and a P value less than .05 was considered statistically significant. RESULTS: Of 46 participants originally recruited, 43 were included in the present study. The mean postoperative pain score in patients who received bupivacaine was increased to a maximum 4 hours, with marked improvements after this time. The mean intensity of pain after administration of bupivacaine was lower than that of mefenamic acid capsules at different time points. Statistical analysis showed a relevant difference in pain intensity between the 2 study groups. CONCLUSION: The results of the present study showed that local administration of bupivacaine relieves postoperative pain after surgical removal of impacted third molar teeth.

Mefenamic acid-loaded solid SMEDDS: an innovative aspect for dose reduction and improved pharmacodynamic profile.

AIM: The current investigation is focused on solid self-microemulsifying drug-delivery systems (S-SMEDDS) of mefenamic acid (MFA) for improving pharmacodynamic activity. Methodology & results: Solubility assessment in various lipid excipients and optimization of pseudoternary plots were carried out for development of liquid SMEDDS. The optimized liquid SMEDD formulation was spray dried to solid dosage form and observed with enhanced amorphization or molecular dispersion of MFA in S-SMEDDS, as evident from x-ray diffractometry and differential scanning calorimetry studies. Enhanced in vitro dissolution rate of optimized formulation was observed, resulting in multifold enhancement in absorption profile of MFA, as compared with pure drug and marketed product. These studies further substantiate the dose reduction in SMEDDS by gaining equivalent therapeutic profile with marketed product. Enhanced analgesic and anti-inflammatory activity was observed with S-SMEDD formulations in acetic acid-induced writhings and carrageenan-induced paw edema models, respectively. CONCLUSION: The optimized S-SMEDD formulation holds great promise for enhancement of its physiochemical and biological attributes.

Severe enteropathy with villous atrophy in prolonged mefenamic acid users - a currently under-recognized in previously well-recognized complication: Case report and review of literature.

RATIONALE: Mefenamic acid-induced enteropathy may be an under-recognized condition because few reported cases and no review of literature to comprehensively describe all reported cases exist. From inception until February 2017, a systematic literature search identified twenty original reports of cases of mefenamic acid-induced enteropathy. Additional five cases were identified at our hospital. All cases were included in the analyses. PATIENT CONCERNS: Most patients had been regularly taking therapeutic dosages of mefenamic acid for at least three months before symptoms developed. All patients presented with chronic diarrhea with significant weight loss. Approximately one-third of the cases had some degree of anemia and hypoalbuminemia. DIAGNOSES: Endoscopic findings could range from very mild abnormalities, such as mild atrophic mucosa, to marked abnormalities, such as blunted villi with scalloping appearance in the small intestine and inflamed mucosa with a few superficial ulcers in the ileum and colon. Pathological findings included flattened small intestinal villi and mixed inflammatory infiltrates including eosinophils in lamina propria. INTERVENTION: After identifying history of prolong mefenamic acid exposure, all patients were prescribed to stop this medication. Nutritional support and substitutional treatment for mefenamic acid were provided as well. OUTCOMES: All symptoms responded dramatically to drug withdrawal. Some patients could change to use other nonsteroidal anti-inflammatory drugs (NSAIDs) without symptoms reoccurring. LESSONS: Unlike other traditional NSAIDs, mefenamic acid could induce intestinal villous atrophy. An adequate drug history is crucial to identifying the condition. Protracted diarrhea occurring during treatment should be the indication to cease the medicine promptly.

Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity.

Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)-resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.

Central nervous system toxicity of mefenamic acid overdose compared with other NSAIDs: an analysis of cases reported to the United Kingdom National Poisons Information Service.

AIMS: Case reports and small case series suggest increased central nervous system (CNS) toxicity, especially convulsions, after overdose of mefenamic acid, compared with other nonsteroidal anti-inflammatory drugs (NSAIDs), although comparative epidemiological studies have not been conducted. The current study compared rates of CNS toxicity after overdose between mefenamic acid, ibuprofen, diclofenac and naproxen, as reported in telephone enquiries to the UK National Poisons Information Service (NPIS). METHODS: NPIS telephone enquiries related to the four NSAIDs, received between January 2007 and December 2013, were analysed, comparing the frequency of reported CNS toxicity (convulsions, altered conscious level, agitation or aggression, confusion or disorientation) using multivariable logistic regression. RESULTS: Of 22 937 patient-specific telephone enquiries, 10 398 did not involve co-ingestion of other substances (mefenamic acid 461, ibuprofen 8090, diclofenac 1300, naproxen 547). Patients taking mefenamic acid were younger and more commonly female than those using other NSAIDs. Those ingesting mefenamic acid were more likely to experience CNS toxicity than those ingesting the other NSAIDs combined [adjusted odds ratio (OR) 7.77, 95% confidence interval (CI) 5.68, 10.62], especially convulsions (adjusted OR 81.5, 95% CI 27.8, 238.8). Predictors of CNS toxicity included reported dose and age, but not gender. CONCLUSIONS: Mefenamic acid overdose is associated with a much larger and dose-related risk of CNS toxicity, especially convulsions, compared with overdose of other NSAIDs. The benefit-risk profile of mefenamic acid should now be re-evaluated in light of effective and less toxic alternatives.

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid.

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.

ASSESSMENT OF GUAR AND XANTHAN GUM BASED FLOATING DRUG DELIVERY SYSTEM CONTAINING MEFENAMIC ACID.

We aimed to assess guar and xantban gum based floating drug delivery system containing mefenamic acid. Floating tablets of nefenamic acid were formulated with different concentrations of guar and xanthan gum via wet granulation method. The flow properties of granules that is: bulk density, tapped density, flow rate, Carr index, Hausner's ratio, compressibility index and angle of repose as well as physical parameters of the compressed tablets including: hardness, friability, thickness and swelling indices were determined and found to be good. Xanthan gum was superior to guar gum in maintaining drug release, but a combination of polymers was found to be the best for achieving sustained release up to 12 h due to the synergistic effect of both gums. Drug release mechanism was best explained by Korsmeyer-Peppas model. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) studies showed absence of any visible interaction. Stability studies at 40°C (75% RH) showed that the formulation was stable at elevated temperature. It can be concluded that floating tablets can be used as a sustained release matrix due to their superior characteristics.

The effect of mefenamic acid and ginger on pain relief in primary dysmenorrhea: a randomized clinical trial.

PURPOSE: The aim of the study was to compare the effect of mefenamic acid and ginger on pain management in primary dysmenorrhea. METHODS: One hundred and twenty-two female students with moderate to severe primary dysmenorrhea were randomly allocated to the ginger and mefenamic groups in a randomized clinical trial. The mefenamic group received 250 mg capsules every 8 h, and the ginger group received 250 mg capsules (zintoma) every 6 h from the onset of menstruation until pain relief lasted 2 cycles. The intensity of pain was assessed by the visual analog scale. Data were analyzed by descriptive statistics, t test, Chi-square, Fisher exact test and repeated measurement. RESULTS: The pain intensity in the mefenamic and ginger group was 39.01 ± 17.77 and 43.49 ± 19.99, respectively, in the first month, and 33.75 ± 17.71 and 38.19 ± 20.47, respectively, in the second month (p > 0.05). The severity of dysmenorrhea, pain duration, cycle duration and bleeding volume was not significantly different between groups during the study. The menstrual days were more in the ginger group in the first (p = 0.01) and second cycle (p = 0.04). Repeated measurement showed a significant difference in pain intensity within the groups by time, but not between groups. CONCLUSION: Ginger is as effective as mefenamic acid on pain relief in primary dysmenorrhea. Ginger does not have adverse effects and is an alternative treatment for primary dysmenorrhea.

Cryomilling-induced solid dispersion of poor glass forming/poorly water-soluble mefenamic acid with polyvinylpyrrolidone K12.

The effect of mechanical impact on the polymorphic transformation of mefenamic acid (MFA) and the formation of a solid dispersion of mefenamic acid, a poor glass forming/poorly-water soluble compound, with polyvinylpyrrolidone (PVP) K12 was investigated. The implication of solid dispersion formation on solubility enhancement of MFA, prepared by cryomilling, was investigated. Solid state characterization was conducted using powder X-ray diffraction (PXRD) and Fourier-transform infrared (FTIR) spectroscopy combined with crystal structure analysis. Apparent solubility of the mixtures in pH 7.4 buffer was measured. A calculation to compare the powder patterns and FTIR spectra of solid dispersions with the corresponding physical mixtures was conducted. Solid state characterization showed that (1) MFA I transformed to MFA II when pure MFA I was cryogenically milled (CM); and (2) MFA forms a solid dispersion when MFA was cryogenically milled with PVP K12. FTIR spectral analysis showed that hydrogen bonding facilitated by mechanical impact played a major role in forming solid dispersions. The apparent solubility of MFA was significantly improved by making a solid dispersion with PVP K12 via cryomilling. This study highlights the importance of cryomilling with a good hydrogen bond forming excipient as a technique to prepare solid dispersion, especially when a compound shows a poor glass forming ability and therefore, is not easy to form amorphous forms by conventional method.

Nano-proniosomes enhancing the transdermal delivery of mefenamic acid.

Mefenamic acid (MA) is a BCS II class NSAID drug. It is available only in the form of tablets, capsules, and pediatric suspensions. Oral administration of MA is associated with severe gastrointestinal side effects. The aim of this study was to develop a convenient and low-cost transdermal drug delivery system for MA using proniosome as a novel carrier without the addition of penetration enhancers. The formulation factors, such as the presence of cholesterol, types of lecithin, and surfactants were investigated for their influence on the entrapment efficiency, rate of hydration, vesicle size, and zeta potential, in vitro drug release and skin permeation in order to optimize the proniosomal formulations with the minimum dose of the drug. Furthermore, the in vivo anti-inflammatory effect was evaluated on a formalin-induced rat paw edema model. The results showed that the type of surfactants had higher impact on the entrapment efficiency than the type of lecithins, with the highest in Span 80 (82.84%). The release of MA from Span 80 proniosomal gel was significantly affected by the type of lecithin used. The addition of cholesterol significantly increased both the drug release and the skin permeation flux of MA. Zeta potential showed a stable A4 noisomal suspension. DSC revealed the molecular dispersion of MA into the loaded proniosomes. In vivo study of the treatment group with MA proniosome gel showed a significant inhibition of rat paw edema compared with the same gel without the drug (control). The results of this study suggest that proniosomes are promising nano vesicular carriers and safe alternatives to enhance the transdermal delivery of MA.