Novel Aceclofenac-l-Cystine and Aceclofenac-Urea Cocrystals with Enhanced Oral Bioavailability.

AIM: Present research work focuses on the improvement of biopharmaceutical properties of aceclofenac (ACF) by the cocrystal approach. BACKGROUND: ACF is one of the frequently used Nonsteroidal Anti-Inflammatory Drugs (NSAID). ACF is a BCS Class - II drug (low solubility and high permeability) with poor solubility and low oral bioavailability. Hence, the improvement in solubility and bioavailability of ACF is very crucial for successful product development. Nowadays, pharmaceutical cocrystals are considered a novel solid form of drugs. These cocrystals may have different physicochemical as well as biopharmaceutical properties as compared to the parent drug. In a previous study, the cocrystal of ACF (ACF-l-CYS NG and ACF-UREA NG) was successfully prepared and characterized. These cocrystals have shown superior solubility and dissolution rate than pure ACF in HCl buffer (pH 1.2). The synthesized cocrystals were also found non-hygroscopic and stable for 6 months under standard test settings. However, pharmacokinetic evaluation of these cocrystals has not been explored yet. OBJECTIVE: The specific objective of this research work was the measurement of bioavailability and other pharmacokinetic parameters of ACF cocrystals prepared by the mechanochemical grinding method. METHODS: Cocrystals of ACF with l-cystine and urea were prepared by neat grinding (NG) method and in-vivo oral bioavailability of prepared cocrystals was measured in Wistar rats. The plasma drug concentration was measured by high-performance liquid chromatography (HPLC), and the pharmacokinetic data was analyzed by "PK solver" software. RESULTS: Percent relative bioavailability of ACF-l-CYS NG and ACF-UREA NG cocrystals in Wistar rats was found to be 242.05 ± 65.27and 178.93 ± 45.21 respectively, which were significantly higher (ANOVA, P < 0.05) than that of pure ACF. CONCLUSION: The present study indicates that the enhanced aqueous solubility of the prepared cocrystals leads to enhanced oral bioavailability of ACF. Thus, the cocrystals may be an alternative crystalline form of the drug that can enhance the solubility, dissolution rate, and oral bioavailability of many poorly soluble drugs.

Novel Aceclofenac Cocrystals with l-Cystine: Virtual Coformer Screening, Mechanochemical Synthesis, and Physicochemical Investigations.

AIM: Current work focuses on the improvement of the solubility and dissolution of ACF by the cocrystal approach. BACKGROUND: Aceclofenac (ACF) is one of the commonly used Nonsteroidal Anti-Inflammatory Drug (NSAID) representing a variety of therapeutic applications including management of pain, inflammation, rheumatoid arthritis, and osteoarthritis, etc. But very low solubility and dissolution rate of ACF compromise its therapeutic utility. Now a day's cocrystallization technique has emerged as a novel technique for modulation of the said problems. OBJECTIVE: The Specific objectives of this research work were mechanochemical synthesis, characterization, and performance evaluation of aceclofenac cocrystal. METHODS: ACF was screened with various pharmaceutically acceptable coformers (Selected from GRAS and EAFUS list) using MOPAC software and physical screening method to find out novel cocrystals of ACF with enhanced solubility and dissolution rate. Novel cocrystals (multi-component crystalline solid) of ACF with l-cystine were prepared by a neat grinding method and by liquid assisted grinding method. The synthesized cocrystals (ACF-l-CYS NG and ACF-l-CYS LAG) were characterized carefully by Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and Powder XRay Diffraction (PXRD) to verify the formation of the cocrystals. Pharmaceutically significant properties such as powder dissolution rate, solubility, and stability of the prepared cocrystals were evaluated. RESULTS: Compared to pure ACF, the prepared cocrystals showed superior solubility and dissolution rate. The prepared cocrystals were found to be stable and non-hygroscopic under study conditions. CONCLUSION: The cocrystallization technique was successfully utilized to increase the solubility and dissolution rate of aceclofenac.

Solvent-free Methods for Co-crystal Synthesis: A Review.

BACKGROUND: Pharmaceutical co-crystals are the homogeneous crystalline substances composed of two or more substances bound together in the same crystal lattice via noncovalent interactions like hydrogenbonding, electrostatic interaction and Vander Waals interactions. Currently, co-crystals provide excellent opportunities to the formulation scientists in developing new pharmaceutical products by improving the pharmaceutically significant properties like solubility, dissolution rate, bioavailability, stability, and some other derived properties. Due to their ability to improve pharmacokinetic performance and their important intellectual property status, co-crystals are likely to have a very significant role in future drug development. Thus, formulation scientists have their focus on the development aspects of a co-crystallization process that include a rational selection of co-former, the discovery of novel synthetic procedures and new characterization techniques, and large scale production of these novel materials. OBJECTIVE: The objective of this article is to present an extensive review of solvent-free methods for co-crystal synthesis, mainly focusing on the principle mechanisms, advantages, and drawbacks of each method. CONCLUSION: From the review of the topic, it is clear that the solvent-free methods can offer numerous advantages over solvent-based methods in the design and the production of co-crystals of pharmaceutical use and these methodologies can also pave the path to advancing the field of co-crystal synthesis. Some of the advantages accompanied with solvent-free methods are the use of no or very less amount of solvent(s), exceptional purity and quality of produced co-crystal, large scale production and the short reaction times in few cases.

Carbon nanotubes as a novel drug delivery system for anticancer therapy: a review

Carbon nanotubes (CNTs) were discovered in 1991 and shown to have certain unique physicochemical properties, attracting considerable interest in their application in various fields including drug delivery. The unique properties of CNTs such as ease of cellular uptake, high drug loading, thermal ablation, among others, render them useful for cancer therapy. Cancer is one of the most challenging diseases of modern times because its therapy involves distinguishing normal healthy cells from affected cells. Here, CNTs play a major role because phenomena such as EPR, allow CNTs to distinguish normal cells from affected ones, the Holy Grail in cancer therapy. Considerable work has been done on CNTs as drug delivery systems over the last two decades. However, concerns over certain issues such as biocompatibility and toxicity have been raised and warrant extensive research in this field.

Os nanotubos de carbono foram descobertos em 1991 e suas propriedades físico-químicas únicas demonstradas, despertando interesse em sua aplicação em vários campos, incluindo a entrega liberação de fármacos. As propriedades únicas dos nanotubos de carbono, tais como a facilidade de captação pela célula, carga alta de fármaco, ablação térmica, entre outras, tornaram-nos úteis para terapia de câncer, uma das doenças mais difíceis dos tempos modernos, pois sua terapia envolve a distinção entre as células normais saudáveis e as afetadas pela doença. Os nanotubos de carbono têm um papel importante nessa área porque fenômenos como EPR permitem que estes possam distinguir as células normais das afetadas, que é o Santo Graal na terapia do câncer. Trabalho considerável tem sido feito ao longo das duas últimas década com nanotubos de carbono, como sistemas de liberação de fármacos. No entanto, preocupações sobre algumas questões, como biocompatibilidade e toxicidade, surgiram ao longo do tempo, demandando extensas pesquisa nesse campo.

Formulation and In-vitro Evaluation of pH-Sensitive Oil Entrapped Polymeric Blend Amoxicillin Beads for the Eradication of Helicobacter pylori.

Oral pH sensitive drug delivery systems are of utmost importance as these systems deliver the drug at specific part of the gastrointestine (GI) as per the pH of GI, resulting in improved patient therapeutic efficacy and compliance. The pH range of fluids in various segments of the GI tract may provide environmental stimuli for drug release. The aim of this study was to design buoyant beads containing amoxicillin (Am) and to evaluate its potential for the eradication of Helicobacter pylori (H. pylori). The gel bead of gellan, wherein the oil was entrapped, was blended with hydroxypropyl methyl cellulose or Carbopol 934. Buoyant beads of gellan were prepared through ionotropic gellation technique to achieve the controlled and pH-sensitive drug release in stomach. The effects of processing variables such as particle size, buoyancy, percent encapsulation efficiency and in-vitro antimicrobial activity were evaluated. The scanning electron micrograph indicated that prepared beads were spherical in shape and all the beads showed satisfactory floating efficiency in the phthalate buffer solution. The diameter of the gel beads was increased through raising the gellan gum and calcium carbonate concentration. The formulation exhibited sustained release profile and was best fitted in the Peppas model with n < 0.45. Subsequent coating of microbeads exhibited zero-order sustained pattern of the drug release up to 8 h. In-vitro growth inhibition study showed complete eradication of the isolated H. pylori strain .These results provide evidence that the optimized formulation bearing antibiotics like amoxicillin should be useful in H. pylori treatment.

Evaluation of pH triggers in situ porous controlled release micro balloon delivery of amoxicillin for eradication of Helicobacter pylori.

Helicobacter pylori reside in the gastric mucus layer and at the mucus-epithelial cell interface wherein access of antimicrobial drug to the infection site is restricted both from the stomach and from the gastric blood supply. The aim of the present study was to develop pectin or gellan gum blended sodium alginate microspheres in order to eradicate gastric Helicobacter pylori. The percentage drug release and mucoadhesion were decrease on increasing the calcium chloride in the formulation dispersion. Curing time significantly effected encapsulation efficiency and was not affected % drug content, % buoyancy, and particle size and drug release. The efficacy of the optimized formulation was evidenced by absence of amplified bacterial gene in treated stomach tissue of Mongolian gerbils as observed using in polymerase chain reaction. The results demonstrate that the developed formulation of Am has potential to eradicate Helicobacter pylori by targeted and prolonged retention at gastric mucosa.

Protective effect of Amaranthus spinosus against D-galactosamine/lipopolysaccharide-induced hepatic failure.

The current study is an effort to identify the hepatoprotective activity of the 50% ethanol extract of the whole plant of Amaranthus spinosus Linn. (Amaranthaceae) against d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced liver injury in rats. d-GalN/LPS (300 mg/kg body weight/30 µg/kg body weight)-induced hepatic damage was manifested by a significant (p <0.05) increase in the activities of marker enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase) and bilirubin level in serum while phospholipids significantly decreased. All other parameters, i.e. cholesterol, triglycerides and free fatty acids were increased significantly in both serum and liver compared to the control group. Pretreatment of rats with A. spinosus extract (400 mg/kg) significantly (p <0.05) reversed these altered parameters to normal compared to the intoxicated group. The biochemical observations were supplemented by histopathological examination of liver sections. There were no significant changes in the activities of marker enzymes, bilirubin level and lipids in the rats treated with A. spinosus extract alone. Results of this study revealed that A. spinosus extract could afford a significant protection against d-GalN/LPS-induced hepatocellular injury.

Hepatoprotective and antioxidant activity of Amaranthus spinosus against CCl4 induced toxicity.

AIM: 50% ethanolic extract (ASE) of Amaranthus spinosus (whole plant) was evaluated for in vitro antioxidant and hepatoprotective activity. METHODS: The total phenolics and reducing capacity of ASE was determined using standard curve of gallic acid (0-1.0mg/ml) and butylated hydroxy anisole. In vitro antioxidant activity was determined by DPPH, superoxide, hydroxyl radicals, hydrogen peroxide and nitric oxide scavenging methods. The hepatoprotective activity of ASE was evaluated at 6, 7, 8, 9 and 10 microg/ml concentration against CCl(4) (1%) induced toxicity in freshly isolated rat hepatocytes and HepG2 cells. RESULTS: ASE was found to contain 336+/-14.3mg/g total polyphenolics expressed as gallic acid equivalent while the reducing capacity was 2.26 times of BHA. ASE showed significant antioxidant activity in DPPH assay (IC(50) 29 microg/ml), scavenges superoxide (IC(50) approximately 66-70 microg/ml), hydrogen peroxide (IC(50) approximately 120-125 microg/ml), hydroxyl radicals (IC(50) approximately 140-145 microg/ml) and nitric oxide (IC(50) approximately 135-140 microg/ml). ASE (6, 7, 8, 9 and 10 microg/ml) was able to normalise the levels of biochemical parameters in isolated rat hepatocytes intoxicated with CCl(4). A dose dependent increase in percentage viability was observed in CCl(4) intoxicated HepG2 cells. CONCLUSIONS: ASE possesses significant hepatoprotective activity which might be due to antioxidant defence factors and phenolics might be the main constituents responsible for activity.

Antinociceptive activity of Amaranthus spinosus in experimental animals.

AIM OF THE STUDY: 50% ethanol extract (ASE) of Amaranthus spinosus (whole plant) has been evaluated for antinociceptive and antiinflammatory activities. MATERIALS AND METHODS: Analgesic and antiinflammatory activities were studied by measuring nociception by formalin, acetic acid, hot plate, tail immersion method while inflammation was induced by carrageenan. RESULTS: ASE had significant dose dependent percentage protection against acetic acid (0.6% of 10 ml) induced pain and the effects were also compared to aspirin, morphine and naloxone while formalin induced pain (0.05 ml of 2.5%) was significantly blocked only at higher dose (400mg/kg) in first phase. ASE significantly blocked pain emanating from inflammation at all the doses in second phase. The reaction time in hot plate was increased significantly and dose dependently where as pretreatment with naloxone rigorously reduced the analgesic potentials of ASE. Further in tail immersion test the same dose dependent and significant activity was observed. Aspirin had no effect on thermal induced pain i.e. hot plate and tail immersion tests but showed an effect on writhing test. CONCLUSIONS: Our investigation show that Amaranthus spinosus possess significant and dose dependant antiinflammatory activity, it has also central and peripheral analgesic activity.

Hepatoprotective activity of Amaranthus spinosus in experimental animals.

The hepatoprotective and antioxidant activity of 50% ethanolic extract of whole plant of Amaranthus spinosus (ASE) was evaluated against carbon tetrachloride (CCl4) induced hepatic damage in rats. The ASE at dose of 100, 200 and 400 mg/kg were administered orally once daily for fourteen days. The substantially elevated serum enzymatic levels of serum glutamate oxaloacetate transaminase (AST), serum glutamate pyruvate transaminase (ALT), serum alkaline phosphatase (SALP) and total bilirubin were restored towards normalization significantly by the ASE in a dose dependent manner. Higher dose exhibited significant hepatoprotective activity against carbon tetrachloride induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. Meanwhile, in vivo antioxidant activities as malondialdehyde (MDA), hydroperoxides, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were also screened which were also found significantly positive in a dose dependent manner. The results of this study strongly indicate that whole plants of A. spinosus have potent hepatoprotective activity against carbon tetrachloride induced hepatic damage in experimental animals. This study suggests that possible mechanism of this activity may be due to the presence of flavonoids and phenolics compound in the ASE which may be responsible to hepatoprotective activity.

Synthesis of disulfide esters of dialkylaminocarbothioic acid as potent, non-detergent spermicidal agents.

S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31) were prepared and evaluated for the spermicidal activity and antifungal activity. Dialkyldithiocarbamates (1-5) were reacted with epichlorohydrin to give 1-dialkylaminocarbothioic acid S-[(2,3-epithio)propyl]ester (7-11), these on further reaction with a secondary amine gave S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31). Some of these compounds (16, 19-21, 23, 30, 31) were found to be very potent spermicidal agents with marginal antifungal activity. Two compounds (20, 21) were 25 times more active than nonoxynol-9 (N-9), the spermicide currently in the market.

Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats.

Bacopa monniera (BM) is well known for its neuropharmacological effects. Our previous studies indicated the adaptogenic effect of standardized extract of BM in various stress models. In the present study, effect of BM was evaluated on acute stress (AS) and chronic unpredictable stress (CUS) induced changes in plasma corticosterone and monoamines-noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in cortex and hippocampus regions of brain in rats. Panax root powder (Panax quinquefolium) was taken as standard. Subjecting animals to AS (immobilization for 150 min once only) and CUS (different stressors for 7 days) resulted in significant elevation in plasma corticosterone levels, which was significantly countered by treatment with BM at a dose of 40 and 80 mg/kg p.o. similar to the effects of Panax quinquefolium (PQ) at 100 mg/kg p.o. AS exposure significantly increased the levels of 5-HT and decreased NA content in both the brain regions while DA content was significantly increased in cortex and decreased in hippocampus regions. In CUS regimen, levels of NA, DA and 5-HT were significantly depleted in cortex and hippocampus regions of brain. Treatment with BM (40 and 80 mg/kg) attenuated the stress induced changes in levels of 5-HT and DA in cortex and hippocampus regions but was ineffective in normalizing the NA levels in AS model, whereas PQ treatment significantly reverted back the effects of stress. In CUS model, pretreatment with BM and PQ significantly elevated the levels of NA, DA and 5-HT levels in cortex and levels of NA and 5-HT in hippocampus regions. Hence, our study indicates that the adaptogenic activity of BM might be due to the normalization of stress induced alteration in plasma corticosterone and levels of monoamines like NA, 5-HT and DA in cortex and hippocampus regions of the brain, which are more vulnerable to stressful conditions analogous to the effects of PQ.

Adaptogenic effect of Bacopa monniera (Brahmi).

As stress is linked to many diseases, research on an effective antistress agent (adaptogen) from plants has gained importance. We report the investigations on the adaptogenic property of a standardized extract of Bacopa monniera against acute (AS) and chronic stress (CS) models in rats. Panax root powder (Panax quinquefolium) was taken as a standard. Male SD rats, weighing 180-200 g, exposed to immobilization stress for 150 min once only for AS and for seven consecutive days in CS, were fed with B. monniera or Panax root powder daily for 3 days in AS and for 7 days in CS, 45 min prior to each exposure of stress. Rats were sacrificed immediately after stress, the blood was collected, and the plasma was separated out for biochemical estimation. Adrenals, spleen, and thymus were dissected for organ weight and stomach for ulcer score. AS exposure significantly increased the ulcer index, adrenal gland weight, plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) but significantly decreased the spleen weight. Pretreatment with B. monniera at 40 mg/kg po significantly reduced the AS-induced increase in the ulcer index, adrenal gland weight, plasma glucose, AST, and CK. A dose of 80 mg/kg po significantly reversed the AS-induced changes in adrenal gland weight, spleen weight, plasma glucose, ALT, and AST. Panax root powder, 100 mg/kg po, significantly reversed the AS-induced changes in spleen weight, plasma ALT, AST, and CK. CS exposure resulted in a significant increase in the ulcer index, adrenal gland weight, plasma AST, and CK with a significant decrease in the thymus and spleen weight, plasma triglyceride, and cholesterol. Pretreatment with low dose of B. monniera extract at 40 mg/kg significantly reversed changes in ulcer index and plasma AST only, whereas the pretreatment with higher dose significantly reversed CS-induced changes in ulcer index, adrenal gland weight, CK, and AST. Panax root powder significantly reversed CS-induced increase in ulcer index, adrenal gland weight, CK, and AST. On the basis of our result, it is concluded that the standardized extract of B. monniera possesses a potent adaptogenic activity.

Substituted acrylophenones and related mannich bases as possible spermicides and inhibitors of HIV envelope glycoprotein-CD4 interaction.

Several appropriately substituted 4-(dialkylamino-alkyl)-substituted-styryl-alkyl ketones or acetophenones were prepared and subjected to the Mannich reaction to yield compounds that would incorporate both alpha,beta-unsaturated keto groups and a substituted aminomethyl function with or without another olefinic moiety at position 4. The spermicidal activity of the prepared compounds was evaluated. Several compounds 2d, 4a and 4e were found to possess spermicidal activity at 0.005% concentration, while compounds 2a, 2c, 2f, 3a and 4b were active at 0.01% concentration. Compounds 2a, 2c, 3a, 4a and 4e also inhibited the interaction between recombinant HIV Env and CD4. Out of these, compound 2c was found to be most active.

A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba: anticholinesterase and cognitive enhancing activities.

Bacopa monniera and Ginkgo biloba are well-known cognitive enhancers in Indian and Chinese traditional medicine systems. Standardized extracts of B. monniera and G. biloba were used to evaluate the antidementic and anticholinesterase activities in adult male Swiss mice. Antidementic activity was tested against scopolamine (3 mg/kg ip)-induced deficits in passive avoidance test. Three different extracts of B. monniera (30 mg/kg) and extract of G. biloba (15, 30 and 60 mg/kg) were administered postoperatively, daily for 7 days and 60 min after the last dose, i.e., on Day 7, first trial was conducted. In passive avoidance test, increased transfer latency time (TLT) and no transfer response (NTR) were taken as criteria for learning. TLT and NTR were significantly increased and decreased in second trial, 24 h after the first trial in control group and scopolamine-dementia group, respectively. The B. monniera- and G. biloba-treated groups produced significant increase in TLT and NTR on second trial (40-80%) after scopolamine treatment, thus, attenuating its antidementic effect. Both the extracts showed a dose (10-1000 microg)-dependent inhibitory effect on acetylcholinesterase (AChE) activity (in vitro), performed spectrophotometrically. IC(50) of G. biloba was 268.33 microg, whereas none of the extracts of B. monniera showed more than 50% inhibition. At a dose concentration of 30 and 60 mg/kg, extracts of G. biloba showed a cognitive enhancing property and, at the same time, a significant decrease in AChE-specific activity in both per se and scopolamine-dementia groups. These extracts possess a significant anticholinesterase and antidementic properties, which may be useful in the treatment of dementia.