Background: Amidst levodopa being considered as the “Gold standard” in the treatment of Parkinson’s disease (PD), it still has critical therapeutic issues with its dose regimen and dosage forms leading to severe adverse drug effects, decreased drug efficacy during chronic use, and requires an enforced “drug holiday” in PD patients. Hence, in this study, we designed a novel levodopa and carbidopa water-in-oil-in-water (w/o/w) formulation for bioavailability improvement in the central nervous system (CNS). Methods: The new one-in-one embedment of the w/o/w levodopa and carbidopa emulsion formulation was obtained by a double emulsion technique. The plasma and brain levels following intravenous administration of the emulsions in rats were determined. Results: The incorporation of stearylamine (a cationic surfactant) considerably increased the surface charge density of the emulsion droplets. This formulation exhibited a narrow particle size distribution enabling parenteral administration. The formulation also provided a high drug loading capacity. In in vivo study, this novel formulation significantly increased the bioavailability of levodopa in the CNS (P < 0.001). The strong resistance to desorption (due to higher charge density) and the presence of positive charge on the particles upon dilution may be the main reason for enhanced brain levels of levodopa. Conclusion: Our current formulation F5 may decrease the dose of levodopa, leading to decreased adverse effects and dosing problems, thus appreciably benefit PD patients in the future.

Aim: Aim of this study was to design a solid oral delivery system for a weakly basic drug such as dasatinib (DAS), so as to achieve pH-independent dissolution and improved oral bioavailability. Methods: DAS was solubilised using sodium lauryl sulphate as an aqueous micellar system and such a system containing lactose monohydrate as carrier was spray-dried to obtain a solid mass. Subsequently, the DAS-solid was converted into a tablet using conventional tableting methods. Results: The dissolution study revealed pH-independent dissolution over a wide range of pH conditions. An in vivo bioavailability testing on rats revealed an improved C-max and AUC(0-24). Similarly, viability assay showed a better inhibitory effect of spray-dried dasatinib over the DAS. Conclusions: Micellar solubilisation and spray-drying technology can be approached to resolve poor dissolution and bioavailability of drugs belonging to biopharmaceutical classification system II and III. This technology is amenable to scale-up and has commercial potential.

Purpose: The objective of this study was to evaluate the ability of nano-droplets of Self Nano Emulsifying Drug Delivery System to diffuse into the brain tissue. Methods: The preconcentrate was prepared by dissolving oils, surfactants and cosolvents in 1:1 mixture of methanol and chloroform and flash evaporated at 50°C and was stored at room temperature until their use in subsequent studies. CSEDD with surfactant polysorbate-80 were radiolabel led with radioactive C18 triglyceride. The nanodroplets formed by CSEDD in 5% dextrose were subjected to evaluation in blood and brain. Results: The intravenous pharmacokinetics of carbamazepine in rats of CSEDD formulation generated high initial serum levels (5.25 mcg/ml) at 0.25 h when compared to C-Sol (3.91 mcg/ml) at 0.5 h. It was found that oil to surfactant ratio had an impact on the physical characteristics of the nano-emulsion formed. The brain levels of CBZ from optimized CSEDD were significantly high at all-time points when compared to plain solution. The initial levels of CBZ from CSEDD was 8.023 mcg/ml thereafter the levels were consistently high till 8 h and the initial levels of CBZ from plain solution was 3.62 mcg/ml followed by a gradual decline till 4 h evidently showing that the clearance of CBZ from CSEDD was reduced. The brain targeting index of CSEDD and solution were 3 and 2 respectively. The brain enhancement factor value was found to be 22.29 at 15 min revealing a very rapid penetration of CBZ into brain. Conclusions: This study proposes intravenous CSEDD as a new brain delivery system and highlights two requirements to design adequate delivery systems for long circulating properties of the carrier and appropriate surface characteristics to allow interactions with BBB endothelial cells.

Surfactants are routinely included in tablets during wet or dry granulations or along with directly compressible vehicles to improve wetting, disintegration and dissolution. Besides this micellar solubilization can improve permeability of poorly soluble drugs via gastrointestinal tract membranes thereby enhancing oral bioavailability. Microparticle-entrapped micelles (MEM) technology is a novel method of incorporating surfactants in tablets for improving in vitro and in vivo performance of poorly water-soluble drugs. Valsartan (VAL) was solubilized in cremophor EL micelles at cloud point temperature; lactose was dissolved in micellar dispersion and the dispersion was directly spray-dried to obtain solid product, which was subsequently converted into tablets using suitable excipients. VAL tablets produced by applying MEM technology improved dissolution performance of valsartan tablets. These tablets exhibited superior dissolution rate over controls and marketed tablets in all media employed irrespective of pH conditions and composition.

The current study aimed to evaluate long-chain alkyl esters of p-amino benzoic acid (PABA) as possible new class of permeation enhancers. In this study we have synthesized long-chain alkyl esters of PABA (decyl, dodecyl, and tetradecyl) by a novel and facile method in our laboratory. The PABA derivatives were incorporated into solid lipid nanoparticles and characterized for size, zeta potential and entrapment efficiency. In vitro permeation study was carried out using rat abdominal skin and permeation enhancement was assessed from the permeation parameters (flux, permeability coefficient, and enhancement ratio). Among the formulations tested, Dodecyl PABA containing solid lipid nanoparticles (SLN) has shown a significant enhancement in the permeation of diclofenac compared to control and other PABA derivatives containing solid lipid nanoparticles. The increase in permeation parameters clearly indicates the potential of PABA derivatives as a novel amphiphile that can be explored as a new class of permeation enhancers in topical drug delivery.

The aim of this study is to develop ascorbyl palmitate (ASP) loaded doxorubicin (DOX) pegylated liposomes and to evaluate their targeting potential to tumor. We have prepared conventional (DL), pegylated DOX liposomes with (SDL) and without ascorbyl palmitate (SDL-A). The vesicle size in all the formulations was within the range 105--120 nm and in vitro release studies in serum confirmed the stability of the liposomes. Biodistribution studies carried out in Ehrlich ascites tumor bearing mice indicate higher area under the curve for SDL and SDL-A liposomes compared to DL and plain drug solution. Drug targeting index assessed from tumor-to-serum concentration ratio and therapeutic availability of DOX in tumor tissue was also significantly higher for pegylated liposomes. In conclusion, biodistribution study reveals that the presence of ascorbyl palmitate alters the distribution pattern of liposomes and paves way for better drug targeting.</.

Inflammation is associated with enhanced vascular permeability, production of inflammatory markers and over production of reactive oxygen species (ROS) with depletion of endogenous antioxidants. Several drug targeting approaches to inflammation taking clues from these events have been evolved. Surprisingly, a drug targeting approach utilizing abundant oxidative stress at inflammatory site has not been followed. Antioxidant surface loaded liposomes might preferentially localize at inflammatory sites via redox interaction where at high level of ROS exist. The present study was focused to investigate the role of antioxidant as a targeting ligand on the surface of liposome employing rat granuloma air pouch model of inflammation. We developed conventional and antioxidant loaded diclofenac (DFS) liposomes (co-enzyme Q10 and ascorbyl palmitate) for i.v. administration and characterized for vesicle size, zeta potential and percent entrapment. In vivo drug targeting studies showed an increase in AUC, therapeutic availability of DFS in air pouch fluid (APF) and APF/serum DFS concentration ratios from antioxidant loaded liposomes compared to conventional liposomes and drug solution. The promising results suggest the role of antioxidant as a possible ligand in drug targeting to a site where at abundant ROS exist.

A novel niosome preparation composed of nonionic surfactants, polyglyceryl-3-di-isostearate and polysorbate-80, bilayers stabilized by myristyl alcohol instead of cholesterol was developed. Polyglyceryl-3-diisostearate, myristyl alcohol and polysorbate-80 were in 1:2:1 molar ratio In which 85 % zidovudine (3'-azido-3'-deoxythymidine, azidothymidine, AZT, CAS 30516-87-1) was found to be encapsulated in aqueous core. Pharmacokinetic and tissue distribution studies were conducted on this niosome preparation using rabbits and albino rats, respectively, as animal models. AZT levels in rabbit serum were higher following application of niosomal AZT than with AZT solution. Such levels were maintained for prolonged time. T-1/2 increased, clearance became slow and as a result AUC and AUMC increased and consequently MRT increased following niosomal AZT treatment. Tissue distribution studies on albino rats also confirmed higher concentration and slower decline of serum levels of AZT due to niosomal AZT. In addition niosomal AZT escaped uptake by reticuloendothelial tissues (liver, spleen, and kidney). Invitro release of AZT from niosomes was slow, about 20 % releasing in 18 h. The prolonged AZT levels in rabbit serum following the treatment with niosomal AZT appear to be due to the combined effect of slow invivo release and avoidance of extravascular distribution. Though this preparation seems to maintain AZT levels in serum for a prolonged time, Its therapeutic efficacy cannot be claimed as the present method estimates total AZT In the preparation and not free AZT. Further no specific experiments were conducted to substantiate its therapeutic effect.

Carbamazepine (CBZ) is used in the treatment of generalized tonic clonic and partial seizures. In seizure disorder the focal point of treatment is brain. At present no commercial parenteral formulation of CBZ is available. We developed o/w nanoemulsions of CBZ stabilized by 1-O-alkylglycerol/lecithin for intravenous administration and evaluated the brain targeting potential of these formulations. The nanoemulsions were characterized for globule size, zeta potential (ZP), CBZ content and in vivo tissue distribution in mice. The in vivo data revealed a significant uptake of CBZ in all tissues. Among the nanoemulsions, 1-O-decylglycerol stabilized system showed significantly higher tissue levels and availability of CBZ. Particularly for this system 2.37 times higher brain availability and a brain/serum concentration ratio of 3.0 at 30 min is an important finding. This indicates the brain targeting potential. A systematic formulation development of CBZ nanoemulsions employing 1-O-alkylglycerols might pave way to achieve selective brain delivery of this important antiepileptic drug.

Size of oil globule and emulsifier film covering it are the key factors modifying oral absorption of drugs dissolved/dispersed in oil globules of o/w emulsions. Since oral bioavailability of flutamide (FTM) is poor, nanoemulsions incorporating FTM in oil phase and globules stabilized by a novel lipophilic emulsifier, 1‐O‐alkylglycerol were developed and characterized. All nanoemulsions had a size around 200 nm. They exhibited considerable release retardation in vitro. Flutamide nanoemulsions were evaluated for oral bioavailability in rabbits and in situ intestinal absorption in rats. Serum level data of flutamide obtained in the in situ experiments indicate higher FTM absorption from nanoemulsions than the aqueous FTM suspension. Among the nanoemulsions, 1‐O‐alkylglycerol stabilized systems showed higher absorption. The results of bioavailability studies in rabbits indicate increased absorption and decreased elimination of FTM from nanoemulsions, thus improving the bioavailability. Increased rate of absorption of flutamide in the in situ experiments can be attributed to the permeation enhancement effect of 1‐O‐alkylglycerols. However, size of the oil droplet seems to be the major factor in improving oral bioavailability in rabbits.

In vitro permeation of nabumetone across rat skin from nanoemulsions of soybean oil in 2.5% aqueous glycerol stabilized with a blend of lecithin and 1-O-alkylglycerol (C-10 , C-12 , C-14 , or C-16 chain length) was studied. The mean droplet size of the emulsions was in the range of 214 to 280 nm. 1-O-Alkylglycerol stabilized emulsions showed significant enhancement in permeation of nabumetone. This enhancement is attributed to the interaction of 1-O-alkylglycerol with the skin lipids, fluidizing the lipid matrix and bringing about disordering effect. The extent of interaction appears to depend on chain length of 1-O-alkylglycerol. 1-O-Decylglycerol stabilized emulsion showed highest flux in the first four hours and did not exhibit any lag time. The other emulsions showed increase in lag time with increase in the chain length of 1-O-alkylglycerol. Control nabumetone solution exhibited highest overall flux, but it showed lower flux than nanoemulsions stabilized by 1-O-decylglycerol for the initial four hours and a significantly higher flux thereafter. This appears to be due to slow extraction of skin lipid by the solvent action of control solution and consequent permeabilization of the skin.

Vesicles with biological activity or with a targeting function in addition to carrier properties will have an added advantage. Vesicles prepared with amphiphiles having antioxidant property may have potential applications towards disorders implicated with reactive oxygen species. Ascorbyl palmitate (ASP) was explored as bilayer vesicle forming material. It formed vesicles (Aspasomes) in combination with cholesterol and a negatively charged lipid (dicetyl phosphate). Aspasomes were prepared by film hydration method followed by sonication in which aqueous azidothymidine (AZT) solution was encapsulated in aqueous regions of bilayer. Aspasomes were obtained with all compositions containing 18-72 mol% cholesterol. Differential scanning calorimetric data of aspasome dispersion and anhydrous mixtures of ascorbyl palmitate, cholesterol and dicetyl phosphate confirm the formation of bilayered vesicles with ascorbyl palmitate.Cholesterol content in aspasome did not exhibit any relation with vesicle size, zeta potential or percent entrapment. A substantial change in release rate of azidothymidine from aspasome was noticed on varying the proportion of cholesterol. Release rate and cholesterol content in Aspasomes did not exhibit any relation. A preparation with 45 mol% of cholesterol showed maximum retardation in release rate, than other compositions. The change in capture volume with time (latency) was studied for 8 h and with such a short duration study it was difficult to predict long term stability of these vesicles. But release experiments do indicate stability upto 18 h.Percent reducing activity of aspasome was estimated by measuring the absorbance of a,a-diphenyl-p-picrylhydrazyl (DPPH) at 517 nm after addition of test antioxidant samples. These studies revealed that the antioxidant potency of ascorbyl moiety is retained even after converting ascorbyl palmitate into vesicles (Aspasomes). The antioxidant potency of Aspasomes was assessed by measuring the protection offered by this preparation against quinolinic acid induced lipoperoxidation of whole human blood in vitro, where in the lipoperoxidation was monitored by measuring thiobarbituric acid reactive substances (TBARS) levels. Aspasome rendered much better antioxidant activity than ascorbic acid.Transdermal permeation of aspasomal AZT, ASP-AZT aqueous dispersion and AZT-solution across excised rat skin was investigated in vitro using Franz diffusion cell. Permeation of aspasomal AZT was much higher than the other two preparations. However, ASP-AZT aqueous dispersion has also enhanced permeation of AZT significantly over the AZT-solution, indicating skin permeation enhancing property of ascorbyl palmitate. (C) 2003 Elsevier B.V. All rights reserved.

Monomers of some amphiphiles organize into bilayers to form liposomes and niosomes. Such bilayers are unstable or leaky and hence cholesterol is a common ingredient included to stabilize them. Cholesterol stabilizes bilayers, prevents leakiness, and retards permeation of solutes enclosed in the aqueous core of these vesicles. Other than cholesterol a material with good bilayer-stabilizing properties is yet to be identified. We have substituted cholesterol with fatty alcohols in niosomes containing polyglyceryl-3-di-isostearate (PGDS) and polysorbate-80 (PS-80) to explore their membrane-stabilizing property via permeation studies. Niosomes of polyglyceryl-3-di-isostearate, fatty alcohol/cholesterol, and polysorbate were prepared by ether injection method. Aqueous solution of ketorolac tromethamine (KT) was entrapped in them. The effects of alkyl chain length of fatty alcohols (C(12), C(14), C(16), C(18), and C(16+18)), of acyl chain length of polyoxyethylene sorbitan monoester surfactants, and of the molar ratio of lipid mixture on the release rate of ketorolac from niosomes were assessed by employing modified dissolution-dialysis method. Niosomes with cholesterol or fatty alcohols have exhibited a common release pattern. Niosomes containing fatty alcohol showed a considerably slower release rate of KT than those containing cholesterol. Based on the release rate, fatty alcohols can be ranked as stearyl<myristyl<cetyl<lauryl<cetostearyl. In niosomes containing PGDS, myristyl alcohol (MA), and polysorbate, the fatty acid chain length of polyoxyethylene sorbitan ester-type surfactants has influenced the release rate and encapsulation efficiency. Based on the release rate, polysorbates can be ranked as polysorbate-20 (C(12))<polysorbate-60 (C(18))<polysorbate-80 (C(9=9))<polysorbate-40 (C(16)). In niosome preparation containing polysorbate-20 and dioctyl sodium sulfosuccinate (anionic surfactant), the release rate was slower than niosomes containing polysorbate-20. When MA concentration is kept constant at 50 mole% and the ratio of PGDS and PS-80 was altered, significant changes in entrapment efficiency and the release rate were observed. However, this ratio did not exhibit any relation with encapsulation efficiency or release rate. The release rate and entrapment exhibited an inverse correlation (r(2)=0.8774 at p<0.02 for the data of molar ratios of PGDS:MA:PS80; r(2)=0.975 at p<0.001 for the data of acyl chain length variation of polysorbates). It can be concluded that stable niosomes of polyglyceryl-3-di-isostearate could be prepared with fatty alcohols and polysorbates instead of cholesterol and that the release of solutes from these niosomes can be optimized by altering membrane constituents and their concentrations.

1-O-alkylglycerols (ALKG) have exhibited several biological activities and a prominent effect on blood-brain barrier permeability. They have markedly improved brain uptake of cancerostatic agents. Since ALKG are amphiphilic, we explored their tendency to assemble into bilayer vesicles, which can be applied as carriers for drugs. Vesicles (Algosomes) were formed by film hydration method using ALKG (tetra-, penta-, hexa-, hepta-, octa- or nona-decylglycerols) in combination with cholesterol (CHOL) and dicetyl phosphate (DCP) (1-O-alkylglycerol:CHOL:DCP in 45:45:10 molar ratio). On microscopic examination, the algosomes were found to be conspicuously spherical and the dispersion was a mixture of multi-lamellar and small-unilamellar vesicles. Phase transition temperatures of 1-O-hexadecylglycerol (HXDG) and CHOL mixtures were tested by differential scanning calorimetry (DSC). The changes in phase transition temperatures indicate the vesicle forming tendency of ALKG in presence of CHOL. Alkyl chain length dependent variations in vesicle size, zeta-potential (ZP) and capture volume (CV) could not be observed. Vesicles of 1-O-tetradecylglycerol (TTDG) showed improvement in CV with increase in CHOL content from 15 to 55 mol%. However the vesicle size decreased. On challenging algosomes with hypertonic salt solution [potassium iodide (KI) in water], vesicle size decreased and thus algosomes were found to be osmotically sensitive. Algosome dispersions on addition of higher concentrations of KI (40–100 mM) brought about increases in vesicle size and at concentrations 60 mM and above showed aggregation. All vesicular dispersions were stable for only a few days.

Several insoluble drugs when prepared as solid dispersions showed improved solubility and dissolution. Techniques of melting and melt-solvent methods were used to prepare solid dispersions to enhance the solubility of poorly soluble sulphamethoxazole. Solid dispersions of various compositions were prepared using mannitol as carrier. An improvement in the solubility and dissolution rates of sulphamethoxazole from solid dispersions was observed. Solid dispersions of sulphamethoxazole mannitol in the proportion of 1:2 prepared by melting and melt solvent method were developed into tablet dosage forms by both wet granulation and direct compression methods. The solid dispersion tablets were evaluated and compared with some of the sulphamethoxazole-trimethoprime conventional tablets available commercially (only sulphamethoxazole was estimated). Solid dispersion tablets of melt solvent method prepared by direct compressable method have shown highest dissolution rate.

Rifampicin, an antitubercular agent, is a known metabolic inducer. Previous studies have suggested that rifampicin may interfere with the pharmacokinetics of oral zidovudine when the two drugs are co-administered. Circadian variations in the pharmacokinetics of rifampicin have been reported. We report here a circadian influence on the pharmacokinetics of zidovudine in the presence of rifampicin when administered orally in rabbits. Either zidovudine or zidovudine with rifampicin was administered orally at 10.00 or 22.00 h to 12 healthy rabbits in a randomized cross-over study. Serum zidovudine was estimated by HPLC. A significant (p <0.05) lowering of Cmax, (1/2), AUC(0-6h) and MRT was observed following zidovudine and rifampicin co-administration compared to zidovudine alone at 10.00 h. Accordingly clearance increased to a significant extent. However, such an interaction effect was masked following administration at 22.00 h. The time-dependent influence of rifampicin on the pharmacokinetics of zidovudine may be due to time-dependent changes in absorption and elimination of rifampicin, thus modifying its induction effect on the levels of UDP glucuronyl transferase and cytochrome P-450 content in liver which are responsible for metabolism of zidovudine.

Sumatriptan is a 5HT1D agonist used in the treatment of migraine. Nonsteroidal anti‐inflammatory drugs, β‐blockers, and calcium channel‐blocking antagonists are used in the prophylaxis of migraine. Hence, there is a need to investigate the interaction of these prophylactic drugs with sumatriptan. The interaction of sumatriptan with propranolol, flunarizine, pizotifen, and butorphanol were reported earlier. Naproxen is shown to be effective in prophylactic treatment of migraine. In this study, the authors have investigated the circadian rhythm effect of naproxen on the pharmacokinetics of sumatriptan at 1000 and 2200 hours. Twelve healthy volunteers were treated with 100 mg sumatriptan succinate either alone or along with 500 mg naproxen orally at either 1000 or 2200 hours in a randomized Latin square design with a washout period of 10 days. Serum samples were collected at predetermined time intervals and analyzed for unchanged sumatriptan by high‐performance liquid chromatography. The pharmacokinetic parameters were calculated by using model‐independent methods. Naproxen had no statistically significant (p > 0.05) effect on any pharmacokinetic parameters of sumatriptan both at 1000 and 2200 hours treatment. The results of this study suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking naproxen prophylactic therapy.

The pharmacokinetics of pentoxifylline (CAS-6493-05-6) was studied in healthy subjects by orally administering a 400 mg sustained release tablet (Trental(R)) at two different times (10:00 or 22:00 h) of the day in a crossover design. Pentoxifylline concentrations in serum samples were estimated by using high performance liquid chromatography. The mean values of C-max (326.38 +/- 39.77 vs 266.35 +/- 36.0 ng/ml, p < 0.01, n = 8), AUC(0-t) (2424 +/- 382 vs 2141 +/- 300 ng/ml/h, p < 0.05, n = 8) were significantly higher and V-ss/f (16537 +/- 2869 vs 20136 +/- 5006 ml/kg), v(d)/f (11807 +/- 2704 vs 15801 +/- 5960 ml/kg) were significantly (p < 0.05, n = 8) lower following morning (10:00 h) administration than in the night (22:00 h). These variations should be considered while designing sustained release dosage forms.

Clotrimazole (CLTZ) solid dispersions of various compositions were prepared by melting or melt-solvent methods using mannitol as carrier. Cream base of O/W type was prepared by emulsification method and the solid dispersion were incorporated in cream base by trituration. The in vitro antifungal activity of CLTZ solid dispersion creams were estimated using the test organism Candida albicans. The interaction of sulphamethoxazole (SMZ) with CLTZ in the form of solid dispersion creams were also estimated for their antifungal activity. improved antifungal activity was found with CLTZ solid dispersions. However, there was no significant improvement in the activity in presence of SMZ.