Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid cocrystal in a stable suspension formulation.

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher Cmax of 4.73µ.mL-1 to that of 1.07µ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. Cmax of reference formulation observed was 3.9µmL-1.

Antinociceptive, muscle relaxant and sedative activities of gold nanoparticles generated by methanolic extract of Euphorbia milii.

BACKGROUND: Nanotechnology has potential future for enhancing therapeutic efficacy and reducing the unwanted effects of herbal drugs. The biological research on Euphorbia species has been supported by the use of some plants in traditional medicines. Many species of Euphorbia have been reported as having strong sedative and analgesic effects. In the present research work gold nanoparticles of Euphorbia milii methanolic extract (Au-EM) were synthesized, characterized and tested for antinociceptive, muscle relaxant and sedative activities. METHODS: Au-EM was prepared by stirring 1 mM warm trihydrated tetrachloroaurate solution with E. milii methanolic extract without using any external reducing agents. The gold nanoparticles were characterized by UV-Visible spectroscopy, infrared spectrophotometery, atomic force microscopy and scanning electron microscopy while their stability was evaluated against varying pH and different volumes of sodium chloride (NaCl). The metal sensing capacity of Au-EM was tested towards cobalt, copper, lead, mercury and nickel. Au-EM was evaluated in BALB/c mice at a dose of 10 and 20 mg/kg for antinociceptive, muscle relaxant and sedative activities in comparison with the crude E. milii methanolic extract. RESULTS: Au-EM showed remarkable stability in different NaCl and pH solutions. Au-EM produced significant (P < 0.01) antinociceptive effect at doses of 10 and 20 mg/kg as compared to the crude E. milii methanolic extract. In the rotarod test, Au-EM showed significant muscle relaxant effect at 10 mg/kg (P < 0.05) and 20 mg/kg (P < 0.01) after 30, 60 and 90 min. In an open field test significant sedative effect (P < 0.05) of Au-EM was observed at 10 and 20 mg/kg. Moreover significant detection sensitivity was demonstrated towards all the tested heavy metals. CONCLUSIONS: These results concluded that the gold nanoparticles improved the potency of E. milii methanolic extract and exhibited significant analgesic, muscle relaxant and sedative properties. The significant metals sensing ability and enhanced stability in different NaCl and pH solutions may enable us to explore different formulations of E. milii gold nanoparticles for potentially effective and safe nano-herbal therapy.

Biotransformation of finasteride by Ocimum sanctum L., and tyrosinase inhibitory activity of transformed metabolites: experimental and computational insights.

Transformation of Finasteride (I) by cell suspension cultures of Ocimum sanctum L. was investigated. Fermentation of compound (I) with O. sanctum afforded three oxidized derivatives, 16ß-hydroxyfinasteride (II), 11α-hydroxyfinasteride (III) and 15ß-hydroxyfinasteride (IV). Among these metabolites, compound (II) was a new metabolite. Compound (I) and its derivatives were studied for their tyrosinase inhibition assay. All test compounds exhibited significant activity compared to standard drug kojic acid, with compound IV being the most potent member with an IC50 of 1.87µM. Molecular docking revealed significant molecular interactions behind the potent tyrosinase inhibitory activity of the tested compounds.

Hautriwaic acid as one of the hepatoprotective constituent of Dodonaea viscosa.

It is widely known that hepatitis and its complications such as cirrhosis or hepatocellular carcinoma are one of the major health problems of the world especially since no specific treatment is available. In the present study we investigated the hepatoprotective potential of the methanolic extract of the whole plant of Dodonaea viscosa and its ethyl acetate, aqueous, butanol and n-hexane fractions against carbon tetrachloride (CCl4) induced hepatoxicity in rats. Hepatoprotection was assessed in terms of reduction in serum enzymes (ALT, AST, and ALP) that occur after CCl4 injury, and by histopathology and immunohistochemistry. The methanolic extract reduced the serum enzyme level (ALT, AST, and ALP) down to control levels despite CCl4 treatment. It also reduced the CCl4-induced damaged area to 0% as assessed by histopathology. The CD68+ macrophages were also reduced in number around the central vein area by the methanolic extract. These hepatoprotective effects were better than the positive control silymarin. Similar hepatoprotective activities were found with the ethyl acetate, and aqueous fractions of the methanolic extract. The butanol and n-hexane fractions showed elevated levels of ALT, AST and ALP as compared to the positive control silymarin. Histopathology showed ∼30% damage to the liver cells with the butanol and n-hexane fractions which still showed some protective activity compared to the CCl4 treated control. HPLC fingerprinting suggested that hautriwaic acid present in the methanolic extract and its ethyl acetate, and aqueous fractions may be responsible for this hepatoprotective activity of Dodonaea viscosa which was confirmed by in vivo experiments.

Phlomeoic acid: a new diterpene from Phlomis bracteosa.

A new tricyclic clerodane-type diterpenoid, trivially named phlomeoic acid (1), was isolated from the methanolic extract of Phlomis bracteosa, together with two known compounds, ursolic acid and glutinol, isolated for the first time from this species. Their structures were elucidated by means of spectroscopic and mass spectrometric techniques and comparison with literature data.