text:
J Crit Rev, Vol 2, Issue 3, 9-10 Review Article
Sardar Bhagwan Singh Post Graduate Institute of Biomedical Sciences and Research, Balawala, Dehradun, Uttarakhand, India, 248161
Email: email@example.com
Received: 20 Feb 2015 Revised and Accepted: 14 Aug 2015
The colon is a site where both local and systemic delivery of drugs can take place. Local delivery could, for instance, allow topical treatment of inflammatory bowel disease. Treatment could be made more efficient if it was possible for drugs to be targeted like a shot to the colon. Systemic side effects could also be reduced. Colon specific systems might also allow oral administration of peptide and protein drugs, which are normally inactivated in the upper portions of the gastrointestinal tract. Primary approaches for CDDS (Colon Specific Drug Delivery), which includes prodrugs, pH and time dependent systems and microbial triggered drug delivery system achieved limited success and accepting limitations. Newly developed CDDS, which includes pressure controlled colonic delivery capsules (PCDCS), CODESTM and osmotic controlled drug delivery are unparalleled in terms of achieving in vivo site specificity and feasibility of fabrication operation. This review also focuses on evaluations of CDDS in general.
Keywords: Colon specific drug delivery, Prodrugs, CODESTM, PCDCS.
Targeted drug delivery to the colon is extremely desirable for local treatment of inflammatory bowel diseases such as ulcerative colitis, Crohn's disease etc., amoebiasis, colonic cancer, as well as for the systemic delivery of protein and peptide drugs [1]. The colon specific drug delivery system (CDDS) should be capable of protecting the drug enroute to colon (i.e. Drug release and absorption should not take place in the abdomen and the small intestine and bioactive agent should not be degraded) [2]. and to allow drug release only in the colon. The colon is believed to be a suitable site for absorption of peptides and proteinous drugs for following reasons: (i) Less diversity and strength of digestive enzymes. (ii) The proteolytic activity of colon mucosa is comparatively very less than that of small intestine, thus CDDS protects peptide drugs from hydrolysis and enzymatic degradation in the duodenum and jejunum. The release of drug molecules in the ileum or colon leads to greater systemic bioavailability. (iii) The colon has a long residence time (up to 5 d) [3]. and is extremely responsive towards absorption enhancers [4]. Oral route is the most convenient and preferred route [5]. but other routes for CDDS may also be employed. Rectal administration offers the shortest route for targeting drugs to the colon. However, arriving at the proximal portion of the colon via rectal administration is difficult. Rectal administration can also be uncomfortable for the patient and the compliance may be less than optimal [6]. Drug preparations for intrarectal administration is supplied as the solution, foam and suppositories. The intrarectal route is used both as a means of systemic dosing and for the delivery of topically active drug to the large intestine [7]. Corticosteroids such as hydrocortisone and Prednisolone are administered via the rectum for the treatment of ulcerative colitis. Although these drugs are ingested from the large bowel, it is broadly conceived that their efficacy is due mainly to topical application. The absorption of drug reaching the colon will depend on formulation factors, the extent of retrograde spreading and the retention time. Foam and suppositories have been registered to retain mainly in the rectum and sigmoid colon. Enema solutions have a great spreading capacity. Because of the high water absorption capability of the colon, the colonic contents are considerably viscous and their blending is not efficient. Hence availability of most drugs to the absorptive membrane is low. The human colon has over 400 distinct species of bacteria as resident flora (a population of up to 1010 bacteria per gram of colonic contents). The reactions carried out by these gut flora are like azoreduction, enzymatic cleavage etc. These metabolic processes may be responsible for the metabolism of many drugs and may likewise be applied to the colon-targeted delivery of peptide based macromolecules like insulin by oral administration.
The important bacterias present in the colon such as Bacteroides, Bifidobacterium, Eubacterium, Peptococcus, Lactobacillus, Clostridium secrete a wide range of reductive and hydrolytic enzymes such as β-glucuronidase, β-xylosidase, β-galactosidase, α-arabinosidase, nitroreductase, azoreductase, deaminase and urea hydroxylase. These enzymes are responsible for degradation of di, tri and polysaccharides [8, 9].
Need of colon targeted drug delivery [10].
- Targeted drug delivery to the colon would ensure direct treatment of the disease site with lower dosing and fewer systemic side effects.
- Situation-specific or targeted drug delivery system would allow oral administration of peptide and protein drugs, colon-specific formulation could also be applied to extend the drug delivery.
- The colon is a site where both local or systemic drug delivery could be achieved, topical treatment of inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Such inflammatory conditions are normally treated with glucocorticoids and sulphasalazine (targeted).
- Other serious disease of the colon like Colorectal cancer, might be capable of being treated more effectively if drugs were targeted to the colon.
- Formulations for colonic delivery are also suitable for delivery of drugs which are polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract, highly affected by hepatic metabolism. It is also suitable for therapeutic proteins and peptides.
Advantages of CDDS
Chronic Colitis e. g. ulcerative colitis and crohn's disease are currently treated with glucocorticoids and other anti-inflammatory agents. Administration of glucocorticoids e. g. Dexamethasone and methyl prednisolone by the oral and i. v. routes produces systemic side effects including adenosuppression, immunosuppression, Cushinoid symptoms and bone resorption. So the selective delivery of drug for colon could lower the required dose and thus reduce the systemic side effects [11]. The system delivers the advantage of more effective therapy at a reduced dosage along with reduced undesirable side effects associated with high dosages [12].
Standards for selection of drug for CDDS
Drug candidate
Drugs which shows poor absorption from the stomach or bowel, including peptides are most suitable for CDDS. The drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis, diarrhea and colon cancer are ideal prospects for colonic delivery [13].
Drug carrier
The selection of the carrier for the particular drug candidate depends on the physiochemical nature of the drug as well as the disease for which the system is to be used. The factors such as chemical nature, stability and partition coefficient of the drug and the type of absorption enhancer chosen influences the carrier choice. Moreover, the choice of drug carrier depends on the working groups of the drug molecules [14]. For example, aniline or Nitro groups on a drug may be used to connect it to another benzene group through an azo bond. The carriers, which contain additives like polymers (may be used as matrices and hydro gels or coating agents) may influence the release properties as well as efficacy of the dosage form [15].
The approaches employed for site specific drug delivery to Colon (CDDS)
Approaches used for site-specific drug delivery are:
[A]-Primary approaches for CDDS [13].
a) pH sensitive polymer coated drug delivery to colon
b) Delayed (Time controlled release system) release drug delivery to colon
c) Microbially triggered drug delivery to the colon
(i) Prodrug approach for drug delivery to the colon
(ii) Azo-polymeric approach for drug delivery to the colon
(iii) Polysaccharide based approach for drug delivery to the colon
[B]-Newly developed approaches for CDDS [11].
- Pressure controlled drug delivery system (PCDCS)
- CODESTM (A Novel colon targeted delivery system)
- Osmotic controlled drug delivery to colon (OROS-CT)
- Pulsatile drug delivery system
- Hydrogels
- Microspheres
- Nanoparticles
- Self-microemulsifying drug delivery system
- Multiparticulate beads
- Liposomes in CDDS
- Bioadhessive systems
[A] Primary approaches for CDDS
pH sensitive polymer coated drug delivery to colon
In the stomach, pH ranges between 1 and 2 during fasting but increases after consuming food [16]. The pH is arround 6.5 in the proximal small intestine and of about 7.5 in the distal small intestine [14]. From the ileum to the colon, pH declines significantly. It is about 6.4 in the caecum. However, pH values as low as 5.7 have been measured in the ascending colon in healthy volunteers [12]. The pH in the transverse colon is found to be 6.6 as well as in the descending colon is 7.0. Role of pH-dependent polymers are based on these differences in pH levels. The polymers described as pH-dependent on colon specific drug delivery are insoluble at low pH levels, but become increasingly soluble as the pH goes up. Although a pH-dependent polymer can protect a formulation in the stomach and proximal small intestine, it may goes to dissolve even in the lower small intestine and the situation-specificity of formulations can be measureable [15]. The decline in pH from the remainder of the small bowel to the colon can also result in problems such as longer lag times at the ileo-cecal junction or rapid transportation system through the ascending colon can also result in poor site-specificity of enteric-coated single-unit formulations [14].
Delayed (Time controlled release system) release drug delivery to the colon
Time controlled release system (TCRS) such as prolonged or delayed release dosage forms are also very bright. Yet due to the potentially large variation of gastric emptying time of dosageforms in man [16]., the colonic arrival time of dosage forms can not accurately predicted, resulting in poor clinical availability [17]. Disadvantages of this system are-(i) Gastric emptying time varies markedly between subjects or in a manner depending on the character and quantity of food intake. (ii) Gastrointestinal movement, especially peristalsis or contraction in the stomach would results in a change in gastrointestinal transit time of the drug [13]. (iii) Accelerated transit through different areas of the colon has been noticed in patients with the inflammatory bowel disesases (IBD), [18]. the carcinoid syndrome and diarrhea and the ulcerative colitis [19]. Therefore time dependent systems are not ideal to deliver drugs to colon, especifically for the treatment of colonic diseases. Appropriate integration of pH sensitive and time release functions into a single dosage form may improve the site specificity of drug delivery to the colon [17]. The time-release function (or timer function) should operate more efficiently in the small intestine as compared to the stomach. In the small intestine drug carrier will be given up to the target position and drug release will start at a predetermined time period after gastric emptying. On the other hand, in the stomach, the drug release should be inhibited by a pH sensing function (acid resistant) in the dosage form, which would cut down variation in gastric residence time [13].
Enteric-coated time-release press coated (ETP) tablets
ETP tablets are composed of three components, a drug containing core tablet (rapid release function), the press coated swellable hydrophobic polymer layer (Hydroxy propyl cellulose layer (HPC), time release function) and an enteric coating layer (acid resistance function) [20]. Tablet does not relese the drug in the stomach due to the acid resistance of the outer enteric coating layer. After gastric emptying, the enteric coating layer dissolves rapidly and the intestinal fluid begins to slowly gnaw at the press coated polymer (HPC) layer. When the erosion front reaches the core tablet, rapid drug release occurs since the erosion process takes a long time on that point. The duration of lag phase can be controlled either by the weight or adjustment of the polymer (HPC) layer [21].
Microbially triggered drug delivery to the colon
The microflora of the colon is in the range of 1011-1012 CFU/ml [18]. It is mainly consisting of anaerobic bacterias, such asBacteroides, Bifidobacteria, Eubacteria, Clostridia, Enterococci, Enterobacteria and Ruminococcus etc. This vast microflora fulfills its energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e. g. di, tri and polysaccharides etc [20]. For this fermentation, the microflora produces a huge number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase deaminase, and urea dehydroxylase [16]. Because of the compartment of the biodegradable enzymes present in the colon, the usage of biodegradable polymers for colon-specific drug delivery seems to be a more site-specific approach as compared to other approaches [15]. These polymer shields the drug from the environments of the stomach and small intestine and are able to rescue the drug to the colon. On turning over the colon, they undergo assimilation by micro-organism or degradation by enzymes or breakdown of the polymer backbone leading to a subsequent reduction in their molecular weight and thereby loss of mechanical force. They are then unable to halt the drug entity any longer [21].
Prodrug approach for drug delivery to colon
Prodrug is pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in-vivo to release the active components. For colonic delivery the prodrugs are designed to undergo minimal absorption and hydrolysis in the tracts of upper GIT and undergo enzymatic hydrolysis in the colon, thereby freeing the active drug moiety from the drug carrier. Metabolism of azo compounds by intestinal bacteria is one of the most extensively studied bacterial metabolic processes [22]. A number of other linkages susceptible to bacterial hydrolysis especially in the colon have been organized where the drug is attached to hydrophobic moieties like amino acids, glucoronic acids, glucose, galactose, cellulose etc. Limitations of prodrug approach is that it is not very versatile approach as its expression depends upon the functional group available on the drug moiety for chemical linkage. Furthermore, prodrugs are new chemical entities and require a great deal of evaluation before being employed as bearers [23].
Azo-polymeric prodrugs
Newer approaches are aimed at use of polymers as drug carriers for drug delivery to the colon. Both synthetic as well as naturally occurring polymers are employed for this function. Subsynthetic polymers have been utilized to form polymeric prodrug with a linkage between the polymer and drug moiety [23, 24]. These have been evaluated for CDDS. Various azo polymers have also been evaluated as coating materials over drug cores. They have been set up to be similarly susceptible to cleavage by the azoreducatase in the large intestine. Coating of peptide capsules with polymers cross linked with azoaromatic group has been found to protect drugs from digestion in the stomach and small intestine. In the colon the azo bonds are broken by azoreductase and the drug is going to be released [25].
Glycoside conjugates
Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon targeted drug delivery system. Drug glycosides are hydrophilic and thus poorly absorbed from the small bowel. In one case such a glycoside reaches the colon, it can be cleared by bacterial glycosidases, releasing the free drug to be assimilated by the colonic mucosa. The major glycosidases identified in human expressions are: 1) D-galactosidase, 2) D-glucosidase, 3) L-arabinofuranosidase, 4) D-xylopyranosidase Due to the bulky and hydrophilic nature of these glycosides, they do not get through the biological membrane upon ingestion [26].
Glucuronide conjugates
Glucuronide and sulphate conjugation is the major mechanisms for the inactivation and preparation for clearance of a variety of drugs. Bacteria of the lower GIT, however, secrete glucuronidase and can deglucuronidate a variety of drugs in the bowel. Since the deglucuronidation process results in the passing of active drug and enables its re-absorption, Glucuronide prodrugs would be required to be superior for colon targeted drug delivery [27, 28].
Cyclodextrin conjugates
Cyclodextrins (CyDs) are cyclic oligosaccharides consisted of six to eight glucose units through 1, 4 glucosidic bonds and have been utilized to improve certain properties of drugs such as solubility, stability and bioavailability. The interior of these particles are relatively lipophilic and the exterior is relatively hydrophilic. They tend to form inclusion complexes with various drug molecules. Nevertheless, they are fermented by colonic micro flora into small saccharides and thus absorbed in the colonic area [28, 29]. Because of their bio adaptability and multi functional characteristics, kids are capable of alleviating the undesirable attributes of drug particles in various routes of administration through the formation of inclusion complexes. In an oral drug delivery system, the hydrophilic and unusable CyDs can serve as potent drug carriers in the immediate release and delayed release formulations respectively, while hydrophobic kids can check the release rate of water-soluble drugs. Since, kids are able to continue the use of pharmaceutical additives, the combination of molecular encapsulation with other carrier materials will become effective and a valuable creation in the improvement of drug formulation. Moreover, the most desirable attribute for the drug carrier is its ability to deliver a drug to a targeted site. Conjugates of a drug with kids can be a versatile means of constructing a novel division of colon targeting prodrugs. The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyDs-5-ASA conjugate was much more depressed than that after the oral administration of 5-ASA alone. The lowest concentration was attributable to the enactment of the conjugate through the abdomen and small intestine without significant degradation or absorption, followed by the debasement of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone [30].
Polysaccharide based delivery systems
The role of naturally occurring polysaccharides is attracting tons of care for drug targeting to the colon. These polymers are inexpensive and are available in a verity of a structure with varied properties [31]. They can be modified chemically and biochemically, and are highly stable. They are safe, nontoxic, hydrophilic, gel forming and biodegradable. These include naturally occurring polysaccharides from plants (guar gum, inulin), animals (chitosan, chondrotin sulphate), algal (alginates) or microbial (dextran). These are broken down by the colonic microflora to simple mono saccharides [32]. So these fall into the category of "generally regarded as safe" (GRAS).
Table 1: Showing Polysaccrides studied for colon specific drug delivery with their dosages forms along with their results summary.
Polysaccharides already
API used
dosage forms
Types of model used
(In vitro/In vivo)
Functionalization of the system
5-(6) carboxy
fluorescein (CF)
Chitosan capsules
In vitro
Little release of CF in upper GIT conditions and
100% drug release in 33% cecal contents within 4
h of dissolution [33].
Amidated pectin
Matrix tablets
In vitro
These matrices were not suitable for drug delivery to colon [34].
Matrix tablet
In vitro
Drug release increases in presence of rat cecal content.
Also it was observed that as crosslinking increased,
drug release decreased [35].
[B] Newly developed approaches for CDDS
Pressure-controlled drug-delivery systems
As a result of peristalsis, higher pressures are taken on in the colon than in the small intestine. Takaya et al. (1995) have developed pressure controlled colon delivery capsules prepared using an ethyl cellulose, which is insoluble in water. In such systems drug release occurs following the disintegration of a water-insoluble polymer capsule as a outcome of force per unit area in the lumen of the colon. The thickness of the ethyl cellulose membrane is the most important factor for disintegration of the formulation [36]. The system also appeared to depend on capsule size and compactness. Because of reabsorption of water from the colon, the viscosity of luminal content is higher in the colon than in the small intestine. It has therefore been concluded that drug dissolution in the colon could present a problem in relation to colon-specific oral drug delivery systems. Lag times of three to five hours in relation to drug absorption were noted when pressure-controlled capsules were administered to human [37].
Newly developed colon targeted delivery system (CODESTM)
It is an unique CDDS technology which was contrived to avoid the constitutional problems associated with pH or time dependent schemes. CODESTM is combined approach of pH dependent and microbially triggered CDDS. It has been produced by using an unique mechanism involving lactulose, which works as a trigger for site specific drug release in the colon. The system comprises of a normal tablet core containing lactulose, which is coated over with Eudragit E (the acid soluble material) and further coated with Eudragit L(the enteric coating polymer). The intension behind the technology is that CODES™ remains intact in the stomach due to the enteric protection, but the enteric and barrier coating will dissolve in the small intestine, where the pH is above 6. Because Eudragit® E starts to dissolve at pH-5, the inner Eudragit® E coating is only slightly permeable and swellable in small intestine. Upon entry into the colon, the polysaccharide inside the core tablet will dissolve and diffuse through the coating. The bacteria will enzymatically degrade the polysaccharide into organic acid. This lowers the pH surrounding the system sufficient to effect thedissolution of the acid-soluble coating and subsequent drug release [38].
Osmotically controlled drug delivery (ORDS-CT)
The delivery system OROS-CT from Alza Corporation is much more useful in targeting the drug molecules to the colonic region for their local therapeutic response as well as systemic effect [22]. The above system can be either a single osmotic unit or can be comprising of a maximum 5-6 push-pull units, each having the diameter of 4 mm and encapsulated in a hard gelatin capsule. Each bilayer pull push unit contains a drug layer and an osmotic push layer, both of them are surrounded with a semi permeable membrane. An opening is drilled on the membrane next to the drug layer. Immediately after the OROS-CT is swallowed, the gelatin capsule having the pull push units gets dissolved. Each pull push unit is prevented from uptaking of water in the acidic aqueous environment/medium of the stomach due to the presence of drug-impermeable enteric coating, hence no drug release had been observed. As the unit travels into the small intestine, the coating gets dissolved in the higher pH environment (pH>7), water starts entering into the unit, which leads to swelling of the osmotic push compartment and concomitantly develops a valuable gel in the drug compartment. Swelling of the osmotic push compartment helps in forcing the drug gel segment out of the orifice at a rate significantly controlled by the pace of water entered through the semi permeable membrane. In order to treat ulcerative colitis, each pull push unit is designed with a 3-4 hour post gastric delay for preventing the delivery of drugs in the small intestine. Drug release begins when the unit arrives at the colon. OROS-CT units can sustain a constant discharge rate for up to 24 h in the colon. Evaluation of colon specific dissolution system. Several in vitro/in vivo evaluation techniques has been developed and offered to test the operation and stability of CDDS [39].
Pulsatile drug delivery system
Pulsincap® system
Single-unit systems are mostly developed in a capsule form. The interim time is kept in line by a plug, which gets pushed away by swelling or erosion and the drug is expelled as a "Pulse" from the insoluble capsule shell. One such system comprises of a drug reservoir entrapped inside a water insoluble capsule. The drug molecules were sealed by a swellable hydrogel plug present in the capsule body. As soon as the capsule comes in contact with the dissolution fluid, it starts swelling and after a certain lag time, the plug pushes itself outside the capsule and resulting in the release of the drug. Polymers used for the hydrogel plug are different viscosity grades of hydroxyl propyl methyl cellulose (HPMC), poly methyl methacrylate, polyvinyl acetate and poly ethylene oxide. The length of the plug and its level of introduction into the capsule controls the lag time [28, 40].
The port® system
The Port® System comprises of a gelatin capsule coated with a semipermeable membrane (e. g., Cellulose acetate) containing an insoluble plug (e. g., lipidic) along with an osmotically active agents with the drug formulation. By coming in contact with the aqueous medium, water diffuses through the semi permeable membrane, thus resulting in an increased inner pressure which helps in ejecting the plug after a certain lag time. The interim time is controlled by coating thickness [28]. This system avoids the second time dosing [40]. The coming of the pulsatile drug delivery system is based on the principle of delaying of drug release until the system transmits from mouth to colon. The transit time of the small intestine is about 3-4 h so lag-time of 5 h is usually believed, which is comparatively invariant.
The presence of pH-sensitive monomers and also cross-linking agents in the hydrogel structure produce colon specificity to the expression. As these hydrogel travels through the GIT, their swelling capacity increases as the pH increases, being highest around pH 7.4. The drug entrapped in the hydrogel is put out by the progressive degradation of hydrogen network via the cleavage of the cross-ties. They can be obtained by cross-linking polymerization of N-substituted (meth) acryl amides, N-tert-butylacrylamide and acrylic acid with 4,4'-di (methacryloylamino) azobenzene, 4,4'-di (N-methacryloyl-6-aminohexanoylamino) or 3,3',5,5'-tetrabromo-4,4, 4',4'-tetrakis (methacryloylamino) azobenzene as the cross linking agents. The hydrogels were also prepared by polymer–polymer reaction using the same polymeric precursor with the corresponding copolymer containing side chains terminating in NH2 groups. The degradation rate of hydrogel was associated with the equilibrium degree of swelling and being inversely proportional to the cross linking density [40, 41].
Cross-linked guar gum microspheres containing methotrexate were developed and characterized for their local release in the colon for efficient treatment of colorectal cancer. In this method gluteraldehyde was used as a cross-linking agent and guar gum microspheres were developed by emulsification method. From the results of in vitro and in vivo studies, the methotrexate loaded cross-linked guar gum microspheres delivered most of the loaded drugs (79%) to the colon, where as the normal drug suspensions could able to deliver only 23% of their total dose to the target tissue. Colon specific microspheres of 5-fluorouracil were developed and valued for the treatment of colon cancer. In this method core microspheres of alginate were prepared by modified emulsification method in liquid paraffin by using calcium chloride as a cross-linking agent. The core microspheres were coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the gastric as well as small intestine area. The outcomes indicated that this method had great potential in the delivery of 5-fluorouracil to the colon region [26].
Nanoparticles are expected to become drug carriers for achieving oral peptide delivery. Because of polymeric nanoparticles have the advantages of protecting the protein and peptide drugs from a chemical and enzymatic degradation in the GIT, so increasing their stability and absorption across the intestinal epithelium as well as holding the drug release. A routine of techniques such as polymerization, nanoprecipitation, inverse microemulsion can be utilized to prepare polymeric nanoparticles, however, most of these methods require the usage of organic solvents, heat and vigorous agitation which may be harmful to the peptide and protein drugs. More recently the ionic gelation technique has been used as the most favorable [40].
Self-microemulsifying drug delivery system
Zhang L et al. Has prepared, characterize, and evaluate a fleet-modified self-microemulsifying drug delivery system (FSMEDDS) with the intension for improveing the solubility of curcumin as well as its delivery to the colon, mediated through endocytosis of FSMEDDS by foliate receptors on colon cancer cells. Ternary phase diagrams were generated in order to get the most effective self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. And so, three lipophilic foliate derivatives (foliate-polyethylene glycol-distearoylphosphatidylethanolamine, flat-polyethylene glycol-cholesterol hemisuccinate, and foliate-polyethylene glycol-cholesterol) used as a surfactant were incorporated to curcumin-loaded SMEDDS formulations. The optimization of the formulations of FSMEDDS were carried out through an in situ colon perfusion method, applied on rats. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The results obtained from the in vitro release study indicated that, the formulation of curcumin could reach the colon efficiently and release the drug succesfully. Cellular uptake studies analyzed by fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind to the folate receptors on the surface of positive folate receptor cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled colon-targeted capsules are a possible carrier for colon delivery of curcumin [42].
Multiparticulate beads
In the ionotropic gelation method, polysaccharides (alginate, gallant and pectin) are dissolved in water or in weak acidic medium (chitosan). These solutions are then added drop wise under constant stirring to the solutions containing other counter ions. Due to the complexation between oppositely charged species, polysaccharides undergo ionic gelation and precipitate to form spherical particles. The beads are removed by filtration, rinsed with distilled water and dried. The counter ions used for ionotropic gelation can be divided into two major categories:Low molecular weight counter ions e.g.CaCl2,BaCl2,MgCl2,CuCl2,ZnCl2,CoCl2,pyrophosphate,tripolyphosphate,tetrapolyphosphate,octapolyphosphate,hexametaphosphate and[Fe(CN)6].-4/[Fe(CN)6].; High molecular weight ions e.g.octyl sulphate,lauryl sulphate,hexadecyl sulphate,cetylstearyl sulphate [43].
Liposomes in CDDS
Liposomes are the bilayered closed vesicular structures comprises of hydrated phospholipids. Liposomes have the capacity to entrap compounds of different solubilities due to their alternating hydrophilic and hydrophobic structure. How ever the extensive modification or tailoring of basic liposomal structure of hydrated phospholipid bilayer is associated with the physicochemical makeup of the vesicle. This versatility of liposomes are very much useful in various applications such as in radiology, cosmetology and Vaccinology. Liposomes with a size range from 25 millimeter to several micrometers are usually propagated in an aqueous medium. Several nomenclatures are there for defining liposome subtypes depending upon their method of vesicle preparation or on structural parameters. Liposomes are also can be distinguished according to their size and number of lamellae such as large unilamellar vesicles (LUV), Small unilamellar vesicles (SUV), and large multilamellar vesicles or multivesicular vesicles. SUVs with low particle sizes within nm range are of interest as liposomal nanocarriers for drug and antigen delivery [44].
Bioadhesive systems
Some drugs requires high local concentration in the large intestine through oral administration for their optimal therapeutic effects. Bioadhesion is a procedure by which a dosage form remains in contact with a special organ for an augmented period of fourth dimension. This longer residence time of the drug results an increased local concentration. In case of poorly absorbable drugs it helps in improveing absorption characteristics. This strategy is much more useful in formulating CDDS. Several polymers like polycarbophils, polyurethanes and polyethylene oxide-polypropylene oxide copolymers have been investigated as materials for Bioadhesive systems. However, Bioadhesion has been believed to be showing a better performance and increasing the mean residence time of colonic drug delivery systems [45].
Table 2: List of marketed preparations available against colonic ailments
Brand name
Dosage form
Manufacturing company
100 mg and 50 mg Injection
Colon cancer
Fresenius Kabi, India
20 mg/ml Injection
Colon cancer
Pfizer ltd.
2 mg/ml Injection
Colon cancer
Bristol-Myers Squibb Company
25 mg/ml injection
Colon cancer
Genentech ltd
500 mg tablets
Colon cancer
Genentech ltd
500 mg tablets
Crohns disease
Pfizer Limited
500 mg tablets
Ulcerative Colitis
Pfizer Limited
250 mg Capsules
500 mg tablets
Crohns disease
UCB ltd
250 mg tablets
Crohns disease
Ferring Pharmaceuticals
250 mg tablets
Crohns disease
Dr Falk Pharma UK Ltd
Evaluation parameters of CDDS
For in vitro evaluation, not any standardized evaluation technique is available for evaluation of CDDS because an ideal in vitro model should posses the in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity, and other components of food. Generally, these conditions are influenced by the diet, physical stress, and these factors make it difficult to design a slandered in-vitro model. In vitro models used for CDDS are:
a) In vitro dissolution test
Dissolution of controlled-release formulations used for colonspecific drug delivery are usually complex, and the dissolution methods described in the USP cannot fully mimic in vivo conditions such as those relating to pH, bacterial environment and mixing forces.[46]. Dissolution tests relating to CDDS may be carried out using the conventional basket method. Parallel dissolution studies in different buffers may be undertaken to characterize the behavior of formulations at different pH levels. Dissolution tests of a colonspecific formulation in various media simulating pH conditions and times likely to be encountered at various locations in the gastrointestinal tract have been studied.[47]. The media chosen were, for example, pH 1.2 to simulate gastric fluid, pH 6.8 to simulate the jejunal region of the small intestine, and pH 7.2 to simulatethe ileum segment. Enteric-coated capsules for CDDS have been investigated in a gradient dissolution study in three buffers. The capsules were tested for two hours at pH 1.2, then one hour at pH 6.8, and finally at pH 7.4 [48].
b) In vitro enzymatic tests
Incubate carrier drug system in fermenter containing suitable medium for bacteria (strectococcus faccium and B. Ovatus).The amount of drug released at different time intervals are determined.Drug release study is done in buffer medium containing enzymes (ezypectinase, dextranase), or at or guinea pig or rabbit cecal contents.The amount of drug released in a particular time is determined, which is directly proportional to the rate of degradation of polymer carrier.
c) In vivo evaluation
A number of animals such as dogs, guinea pigs, rats, and pigs are used to evaluate the delivery of drug to colon because they resemble the anatomic and physiological conditions as well as the microflora of human GIT. While choosing a model for testing a CDDS, relative model for the colonic diseases should also be considered. Guinea pigs are commonly used for experimental IBD model. The distribution of azoreductase and glucouronidase activity in the GIT of rat and rabbit is fairly comparable to that in the human.[49]. For rapid evaluation of CDDS, a novel model has been proposed. In this model, the human fetal bowel is transplanted into a subcutaneous tullel on the back of thymic nude mice, which bascularizes within four weeks, matures, and becomes capable of developing of mucosal immune system from the host.
i) Drug Delivery Index (DDI) and Clinical Evaluation of Colon-Specific Drug Delivery Systems
DDI is a calculated pharmacokinetic parameter, following single or multiple dose of oral colonic prodrugs. DDI is the relative ratio of RCE (Relative colonic tissue exposure to the drug) to RSC (Relative amount of drug in blood i.e. that is relative systemic exposal to the drug). High drug DDI value indicates better colon drug delivery. Absorption of drugs from the colon is monitored by colonoscopy and intubation. Currently, gamma scintigraphy and high frequency capsules are the most preferred techniques employed to evaluate colon drug delivery systems.
ii) γ–Scintigraphy
With growing complexity in the design of novel drug delivery systems (including colon-specific delivery systems) and associated fabrication process, it is critical to understand the in vivo performance of those delivery systems and demonstrate that the system functions in vivo in accordance with the proposed rationale. In most cases, conventional pharmacokinetic evaluation may not generate sufficient information to elucidate the intended rationale of system design.
γ-Scintigraphy is an imaging modality, which enables the in vivo performance of drug delivery systems to be visualized under normal physiological conditions in a non-invasive manner. Since first employed to investigate the functionality of tablets and capsules in vivo more than two decades ago [50, 51]. γ-scintigraphy has become an established technique and extensively used to monitor the performance of novel drug delivery systems within human GI tract. The underlying principles of γ-scintigraphy and its applications in pharmaceutical research and development are available in the literature [52-54]. Through γ-scintigraphy imaging, the following information regarding the performance of a colon-specific delivery system within human GI tract can be obtained: the location as a function of time, the time and location of both initial and complete system disintegration, the extent of dispersion, the colon arrival time, stomach residence and small intestine transit times.
Limitations and challenges in colon targeted drug delivery
- The resident micro flora affects the colonic efficiency by metabolic degradation of the drug. Relative tightness of the tight junctions in the colon as well as ower surface area can restrict the drug transport across the mucosa and into the systemic circulation.
- As a site for the drug delivery, the colon offers a near neutral pH, a long transit time, reduced digestive enzymatic activity and increased responsiveness to the absorption enhancers; however, targeting of drugs to the colon is really complicated. Due to its position in the distal portion of the nutrient canal, the colon is difficult to access
- In summation, the stability of drug must be considered into consideration while designing the delivery organization. The drug may potentially bind in a nonspecific way to dietary residues, mucus and intestinal secretions or fecal matter [55].
Opportunities in colon targeted drug delivery
- Drugs targeting to the colonic area is not only associated with the treatment of colonic ailments locally, but also delivering drugs such as proteins and peptides for their systemic effects which are degraded and/or poorly taken up in the stomach and small bowel.
- This is likewise a suitable site for the treating diseases associated with circadian rhythms such as angina, asthma and arthritis. The urgent demand for legal transfer of drugs to the colon that reported to be occupied in the colon, such as steroids, which would increase efficiency and shortens the effective dosage.
- The colonic disorders like inflammatory bowel disease, Crohn's disease, irritable bowel syndrome (IBS) as well as colon cancers etc, it is much more needful to achieve a high absorption of the active agent by colon-specific rescue.
- The evolution of a dosage form that improves the oral absorption of peptide and protein drugs whose bioavailability is very depressed (due to instability in the GI tract) [41].
Now a days colon is becoming the best target site for drug delivery in the GI tract. CDDS is providing much more therapeutic advantages for both systemic as well as local theraphy. For colon targeted drug delivery four primary approaches were proposed for CDDS like prodrugs, pH, time dependent systems and microbially triggered drug delivery system. Of these first three approaches are not ideal for CDDS. New approaches developed for CDDS are more specific. Colon specificity is more probable to be achieved with systems by using materials from natural sources and degraded by colonic bacterial enzymes. It was also concluded that more than one testing method is essential to determine the drug release and justify system objective for conducting in vitro evaluation of a colon-specific drug delivery system. Depending upon the sophistication of colon-specific drug delivery systems and the uncertainty of current dissolution methods in establishing possible in vitro/in vivo correlation, challenges are there for pharmaceutical scientists to train and validate a dissolution method that incorporates the physiological features of the colon and even can be used routinely in an industrial setting for the evaluation of CDDS.
The authors have declared no conflict of interest
- Adkin DA, Davis SS, Sparrow RA, Wilding IR. Colonic transit of different sized tablets in healthy subjects. J Controlled Release 1993;23:147-56.
- Ahrabi SF, Madseh G, Dyrstad K, Sande SA, Graffner C. Development of pectin matrix tablets for colonic delivery of model drug ropivacanie. Eur J Pharm Sci 2000;10:43-52.
- Ahmed S. Effect of simulated gastrointestinal condition on drug release from pectin/ethyl cellulose as film coating for drug delivery to the colon. Drug Dev Ind Pharm2005;31:465-70.
- Aiedeh K, Taha MO. Synthesis of chitosan succinate and chitosan phthalate and their evaluation as suggested matrices in orally administered colon specific drug delivery system. Arch Pharmacol Res 1999;332:103-7.
- Akala EO, Elekwachi O, Chase V, Johnson H, Marjorie L, Scott K. Organic redox initiated polymerization process for the fabrication of hydrogel for colon specific drug delivery. Drug Dev Ind Pharm 2003;29:375-86.
- Ashord M, Fell JT, Attwood D, Sharma H, Woodhead P. An evaluation of pectin as a carrier for drug targeting to the colon. J Controlled Release 1993a;26:213-20.
- Asford M, Fell JT, Attwood D, Sharma H, Woodhead PJ. Studies on pectin formulations for colonic drug delivery. J Controlled Release 1994;30:225-32.
- Sinha VR, Rachna K. Coating polymers for colon specific drug delivery: A comparative in vitro evaluation. Acta Pharm 2003;53:41-7.
- Cavalcanti OA, Mooter GV, Soares IC, Kinget R. Polysaccharides as excipients for colon-specific coatings, permeability and swelling properties of casted films. Drug Dev Ind Pharm 2002;28:157-64.
- Mehta TJ. Need of colon specific drug delivery system: review on primary and novel approaches. Int J Res Dev 2011;3:134-53.
- Hita V, Singh R, Jain SK. Colonic targeting of metronidazole using azo aromatic polymers, development and characterization. Drug Delivery 1997;4:19-22.
- Basit A, Bloor J. Prespectives on colonic drug delivery. Business briefing: Pharmtech; 2003. p. 185-90.
- Bussemer T, Bodmeier IRO. Pulsatile drug-delivery systems. Crit Rev Ther Drug Carrier Syst 2003;18:433-58.
- Chan RP, Pope DJ, Gilbett AP, Sneta PJ, Baron JH, Bennardjones JF. Studies of two novel sulphasalazine analogs I. P. salazide and balsalazide. Dig Dis Sci 1983;28:609-716.
- Chavan MS, Sant VP, Nagarsenker MS. Azo-containing urethane analogues for colonic drug delivery: synthesis, characterization and in vitro evaluation. J Pharm Pharmacol 2001;53:895-900.
- Jung YJ, Lee JS, Kim HH, Kim YK, Han SK. Synthesis and evaluation of 5-aminosalicylicylglycine as a potential colon specific prodrug of 5-aminosalicylic acid. Arch Pharmacol Res 1998;21:174-8.
- Vandelli MA, Leo E, Forni F, Bernabei MT. In vitro evaluation of a potential colonic delivery system that releases drug after a controllable lag-time. Eur J Pharm Biopharm 1996;43:148-51.
- Cole E, Scott R, Connor A, Wilding I, Petereit HU, Schminke C, et al. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int J Pharm 2002;231:83-95.
- Cummings JH, Englyst HN. Fermentation in the human large intestine and available substrates. Am J Clin Nutr 1987;45:1243-55.
- Cui N, Friend DR, Fedora RN. A budesonide prodrug accelerates of colitis in rats. Gut 1994;35:1439-46.
- Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut 1986;27:886-92.
- Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988;29:1035-41.
- Tozaki H, Komoike J, Tada C, Maruyama T, Terabe A, Suzuki T, et al. Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon. J Pharm Sci 1997;86:1016-21.
- Friend DR, Chang GW. A colon-specific drug delivery system based on drug glycosides and glycosidase of colonic bacteria. J Med Chem 1984;27:261-6.
- Friend DR, Chang GW. Drug glycosides: potential prodrugs for colon specific drug delivery. J Med Chem 1985;28:51-7.
- Choudhury PK, Panigrahi TK, Murthy PN, Tripathy NK, Behera S, Panigrahi R. Novel approaches and developments in colon specific drug delivery systems-a review. Web Center Pharm Sci 2012;3:1-20.
- Philip AK, Philip B. Colon targeted drug delivery system: a review on primary and novel approaches. Oman Med J 2010;25:70-8.
- Singh KI. Colon specific drug delivery system: review on novel approaches. IntJ Pharm Sci Res 2012;3:637-47.
- Kishore G. Development and evaluation of colon targeted tablets of praziquantel and its β-cyclodextrin complex to treat schistosomiasis. J Pharm Sci Technol 2010;2:269-75.
- Zou MJ, Cheng G, Okamoto H, Hao XH, An F, Cui FD, et al. Colon-specific drug delivery systems based on Cyclodextrin prodrugs: In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates. World J Gastroenterol 2005;11:7457.
- Friend DR, Phillip S, Tozer TN. Colon specific drug delivery from a glucosidic prodrug in the guinea pig efficacy study. J Controlled Release 1991;15:47-54.
- Fukui E, Miyamura N, Kobayashi M. An in vitro investigation of the suitability of presscoated tablets with hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydrophobicn additives in the outer shell for colon targeting. J Controlled Release 2001;70:97-107.
- Tozaki H, Komoike J, Tada C, Maruyama T, Terabe A, Suzuki T, et al. Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon. J Pharm Sci 1997;86:1016-21.
- Wakerly Z, Fell J, Attwood D, Parkins D. Studies on amidated pectins as potential carriers in colonic drug delivery. J Pharm Pharmacol 1997;49:622-5.
- Rubinstin A, Nakar D, Sintov A. Chondroitin sulphate: a potential biodegradable carrier for colon-specific drug delivery. Int J Pharm 1992;84:141-50.
- Fukui E, Miyamura N, Verma K, Kobayashi M. Preparation of enteric coated time released press coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting. Int J Pharm 2000;204:7-15.
- Gazzaniga A, Iamartino P, Maffino G, Sangalli ME. Oral delayed release system for colonic specific drug delivery. Int J Pharm 1994;108:77-83.
- Hata T, Shimazaki Y, Kagayama A, Tamura S, Ueda S. Development of a novel drug delivery system, time-controlled explosion system (TES). Part 5 Animal pharmacodynamic and human bioavailability studies. Int J Pharm 1994;110:1-7.
- Hay DJ, Sharma H, Irving MH. Spread of steroid containing foam after intrarectal administration. Br Med J 1979;1:1751-3.
- Kothawade PD. Conventional and novel approaches for colon specific drug delivery: a review. J Sci Technol 2011;2:33-56.
- Nanoparticle for colon specific drug delivery system. 3rd International conference on Nanotech and Expo, Las Vegas, USA; 2013.
- Patel PB, Dhake AS. Multiparticulate approach: an emerging trend in colon specific drug delivery for Chronotherapy. J Pharm Sci 2011;1:59-63.
- Onuigbo EB, Okore VC, Ngene AA, Esimone CO, Attama AA. Preliminary studies of a stearylamine-based cationic liposome. J Pharm Res 2011;10:25-9.
- Onuigbo EB, Okore VC, Esimone CO, Ngene A, Attama AA. Preliminary evaluation of the immunoenhancement potential of newcastle disease vaccine formulated as a cationic liposome. Avian Pathol 2012; 41:355-60.
- Goyal S, Vashist H, Gupta A, Jindal S, Goyal A. Development of alginate gel beads-entrapped liposome for colon specific drug delivery of prednisolone. Pharm Sin 2011;2:31-8.
- Saffron M, Field JB, Pena J, Jones RH, Ohuda Y. Oral insulin in diabetic dogs. J Endocrinol 1991;131:267-78.
- Wakerly Z, Fell J, Attwood D, Parkins D. Studies on amidated pectins as potential carriers in colonic drug delivery. J Pharm Pharmacol 1997;49:622-5.
- Ahrabi SF, Madseh G, Dyrstad K, Sande SA, Graffner C. Development of pectin matrix tablets for colonic delivery of model drug ropivacanie. Eur J Pharm Sci 2000;10:43-52.
- Rubinstin A, Nakar D, Sintov A. Chondroitin sulphate: a potential biodegradable carrier for colon-specific drug delivery. Int J Pharm 1992;84:141-50.
- Alpsten M, Ekenved G, Soelvell L. A profile scanning method of studying the release properties of different types of tablets in man. Acta Pharm Suec 1976;13:107–22.
- Casey DL, Beihn RM, Digenis GA, Shambu MB. Method for minitoring hard gelatin capsule disintegrationtimes in human using external scintigraphy. J Pharm Sci 1976;65:1412–3.
- Digenis GA, Sandefer E. Gamma scintigraphy and neutron activation techniques in the in vivo assessment of orally administered dosage forms. Crit Rev Ther Drug Carrier Syst 1991;7:309–45.
- Wilding IR, Coupe AJ, Davis SS. The role of γ-scintigraphy in oral drug delivery. Adv Drug Delivery Rev 1991;7:87–117.
- Newman SP, Wilding IR. Imaging techniques for assessing drug delivery in man. Pharm Sci Tech Today 1999;2:269–88.
- Patel A. Novel approaches for colon targeted drug delivery system. J Pharm Cosmetol 2011;1:85-97.
About this article
- There are currently no refbacks.


text:
How Much I Appreciate You Quotes
quotes romantic love quotes romantic love quotes romantic love quotes
You To Know How Much I Love And Appreciate You. You're The Best
if you want someone to like you then be
How much do you really value yourself?
Mother quotes and sayings related to Birthday Poems Deceased Mother
quotes about dysfunctional family members | family tree | 1
Photo illustration by h.koppdelaney via Flickr
Love Quotes on Pinterest | Life quotes, Quotes and Quotes For Girls
Different Events for Employee Appreciation Day : The Employee
love you so much babe your my everything more romances quotes you
How to Increase Your Self-Esteem with Self-Care | Building Self-Esteem
Copy and Paste the code below in your Orkut Scrap Profile Or Website
You dont know what youve got till its gone.
Do you get inspiration/hope out of quotes? And do you have a favorite
Quotes, Feelings Unloved Quotes, Notable Quotable, Inspiration Quotes
We Appreciate You Quotes. QuotesGram
to you may our lord bless you with a joyous and restful day god bless
NEW Foundation Routine +TOP KNOT Hair Tutorial
Oh Sister! | Melrose Fulgencio Weblog
ways. Sometimes, I forget to tell them how much I really do appreciate

subset: commoncrawl


text:
"Mom, have you been meditating lately?" Really a sweet reminder, especially if I have enough awareness to take the cue and head to my spot.
Then what? Somehow, if I manage to sit down and gaze first at the inspiring pictures on my shrine, I am brought into a different place that reminds me over and over how beautiful and simple the practice of meditation can be.
Even when I discover I have been lost in the wilderness of my own thinking, a place that can at once be very exciting and yet on a deeper level quite lonely, isolating and separate, mindfulness and awareness are always present, available and accessible as soon as I turn my mind inwards.
Now that thick fog of self interest begins to dissipate and lift.
And I feel my true self begin to shine. Sometimes this process resembles the action of a rubber band being stretched between two fingers. The stretching out represents the true self breaking free through the practice of meditation and the rebounding represents the old habits of being lost in my head.
Just the other day I recognized that for the past few months I have been watching my mind tighten it's grip on really wanting to have something, and then watching it tighten even more when I began to fear that I would not in fact be able to have what I so desired. Say for example, when you meet someone who makes you feel so amazingly whole and good, the tendency is to believe firstly that it is this other person who gives you these good feelings and secondly that to feel this way, you have to be with this person as much as possible. It is understandable that a deep desire is ignited and much thinking and distraction are devoted to creating time to see this person.
Then say, suddenly, this person goes away, without saying goodbye or giving any explanation, they are just gone. Poof!. What do you do with your desire? Does it remain? Or does it change into anger at the person for leaving without an explanation or goodbye? Perhaps it just dwindles away?
Whatever the course, I know that thoughts, desires and frustrations are always on the move, always changing in large part due to the circumstances that they are bound to.
I find this type of pattern repeats itself over and over again. And for me, the only true antidote is to bring myself back to the cushion or chair or hammock and to examine my mind and the process. This is the other side of the equation, the formula that helps me to break the rubber band cycle.
There is always an invitation to come and sit and examine my mind. Painful as it may be to steal myself away from the fantasy, the practice of mindfulness, which is the beautiful result of the mind's ability and capacity to examine itself, opens up the possibility for freedom from the habitual torment of thinking too much. Applying a light awareness to breathing in and breathing out, or gazing upon picture that evokes peacefulness, each can lead to the space between thoughts and breaths, the space where our life flows. At these moments I have to ask myself, where is that desire now? Where is the frustration? I find them to be logged into the files of the past moments, hours, days and years. But they are not here, not now.
So sweet to be finally home.


text:
There are several uses of vinegar , and the few of them are listed hereunder.
1. Add little vinegar to kill the odor of lemon pickle.
2. The non-stick pans and utensils could be cleaned by vinegar.
Wikimedia Commons by Brücke-Osteuropa
4. The mutton and chicken could be cleaned by vinegar to kill all bad odors.
5. The stains on furniture could be cleaned by rubbing the paste of little vinegar added to cigarette ash.
6. Put some vinegar in washing machine after washing the clothes to clean the machine.
7. The bad smells of thermos flasks and water bottles could be removed by putting a cup of vinegar in the bottle and washing it after 2 hours.
8. The gum gets dried in bottles if kept unused for long time. To get it back to its normal form, add 2-3 drops pf vinegar to stop the gum from drying.
9. To remove the rust from knives and scissors, it is better to apply some vinegar on these tools and put them in warm water for 2-3 hours.
10. The leather or foam of detergent or soap will not spill over, if few drops of vinegar are added to it.
11. After dusting the carpet, wipe it with a cloth soaked in vinegar to make the carpet shining.
12. Take half a cup of curd and add few drops of vinegar to it. Apply the mixture on feet and let it remain for 10-15 minutes. Then wash the feet with warm water. This will clean the feet and make the skin soft and silky.
13. Washing the hands with vinegar removes several types of stains.
14. Rub the cotton swab dipped in vinegar on lips, to remove the blackish color of the lips and to make them pink.
15. Wash the hair with a water containing vinegar to make them silky and shining.


text:
There are items in your cart.
You have no items in your shopping cart.
If you don't know ENTOMBED A.D., the deadly sonic force fronted by former Nihilist/Entombed vocalist L-G Petrov, well, then you're either no metalhead, slept under a rock since the late 80's or have already gone the way of all flesh with crawling swarms of maggots deliciously peeling every single bit of meat from your sorry bones. L-G was part of such classics as "Left Hand Path" or "Wolverine Blues" and apart from that classic guitar sound pivotal in forging the cult status of Entombed. Compared to "Back To The Front" in 2014, "Dead Dawn" sounds way more aggressive, focused and apart from striking artwork by Watain's Erik Danielsson impresses with the classy death metallic opening riff of "Midas In Reverse", the powerful groove of the title track or "Silent Assassin", the beyond cool Randy-Rhoads-tribute-riff and morbid twist of "The Winner Has Lost", the full-frontal-Autopsy-like assault of "Black Survival" as well as the sickened ballad "Hubris Fall", which reminds of Entombed's ingenious Roky Erickson cover, "Night Of The Vampire". Great songs, a great sound and the right attitude make "Dead Dawn" a damn great album and L-G's sums it up perfectly on the driving "Total Death": "It's only rock'n'roll – DESTRUCTION!"
|Entombed A.D.
|Dead Dawn
|Century Media
|Generic musical style
|Death Metal / Grind
|Detailed musical style
|Swedish Death Metal
|Catalog #
|Release Date
|26 Feb 2016
Please save your coupon now, you will not receive it by email!


text:
"American BeheMouth" is now available in paperback.
Download the free Kindle app for your PC or other device. Then, purchase the Kindle edition.
What is contained in "American BeheMouth"?
1) "American BeheMouth" chronicles the raising and catching of a 27-pound largemouth bass, providing a scientific formula that can be duplicated. This raises many ethical questions about world records in American sports.
2) "American BeheMouth" shows the epic journey of one man who immerses himself in fisheries science to answer age-old freshwater mysteries while delving into universal existential questions.
3) " American BeheMouth" shows conflicting values of Americans struggling to do it all while trying to stay balanced. How do we innovate and achieve great things without becoming despicable cheats or taking questionable short cuts in life?
4) The entire novella is a metaphor for the American economic system and American consumerism. The BeheMouth is the giant bigmouth bass swallowing trout whole, but figuratively, the BeheMouth represents America, becoming lazy and fat, waiting for another handout.


text:
Nirlep Cookware Customer Care Number, Nirlep Appliances Phone No. | Nirlep Kitchen Appliances Induction Cooktop Service Center, Complaints | Nirlep Appliances Private Ltd Dealers Head Office Contact Address
Nirlep Appliances Private Limited is manufacturer of kitchen Appliances. Company have Special Technology for non-stick cookware in India. Nirlep has Network of distributors and retailers.
Nirlep Appliances Products
- Nonstick Cookware
- Enamel Cookware
- Pressure Cooker
- Hard Anodised Cookware
- Induction Cooktop
- Gas Lighter
- Kitchen Gas Top
- Nonstick Snackmaker
- Cookware Gift Set
- Induction Compatible Cookware
Nirlep Appliances Head Office Contact Details
Nirlep Appliances Private Limired, B-5, MIDC, Station Road, Aurangabad, Maharashtra, India
Phone Number – 0240-2376121/ 0240-2376085
Fax No. – 0240-2376214
Email Id – firstname.lastname@example.com
Nirlep Appliances Dealers Contact Address
Line Number- 8, Shop Number- 13, Near Fish market, Bistupur, Jamshedpur, Jharkhand
Mobile Number – 9934071651 / 9431317575
153-B, Shop Number- G3, Ground Floor, Dongre Building, Opp. Ruia College, Matunga East Mumbai, Maharastra
Contact Number – 022-24141430
808, Indu Arcade, Defence Colony, Near IDBI ATM, Sainikpuri, Secunderabad, Andhra Pradesh.
Phone No. – 040-42627514


text:
Radically New Solas-Certified Throwable Device
Whether faced with a man-overboard situation or worst-case scenario—a sinking—professional mariners understand the importance of reliable safety gear. Life Cell Marine Safety manufactures the radically new Life Cell Crewman. It's an innovative container that holds user-supplied survival and signaling gear, and is a SOLAS-certified Throwable Buoyancy Device rated to support four people in the water.
In the best of conditions, it can take minutes to get a rescue boat in the water in a man-overboard situation. And while a personnel recovery device is quick to deploy, it's no match for a vessel doing even just 3 knots, which can travel 100 yards in only 60 seconds. A thrown, highly visible Life Cell can contain a full SOLAS kit, including rocket flares, flare gun, smoke, air horn, EPIRB, VHF or other safety gear best-suited for the boat's working conditions. The device remains fully buoyant open or closed, and a series of clips and retaining devices hold equipment in place.
In the case of a sinking, the Life Cell floats off its included mounting brackets. Eight integrated handles and lanyards keep people together.
The Life Cell Crewman is manufactured from durable impact, fire, fuel and UV-resistant material with stainless steel hardware. It's 27.5" H x 22.8" W x 8.7" D. It comes with a two-year warranty and starts at $469.
The products and services herein described in this press release are not endorsed by The Maritime Executive.


text:
Many people see me, they see a woman (nearly wrote girl there...!) who stands out from the crowd. And by stands out, I do not mean the likes of Cara Delevigne or Robbie Williams (though both are wicked human beings, let's be fair!) I stand out because I have a skin disorder. And believe me I wish and pray to god I didn't have it sometimes. It's scary sometimes, leaving the comforts of the family home in the mornings to make the long trip to work. I open myself up to stares, taunts and it scares me, knowing that today could be the day some unwitting person sends me on a further downward spiral, alienating myself from such an unforgiving environment that is The World, it's not only Hong Kong or Mainland China, I'm talking the World. I don't know how some days I manage to block the shit out, but some days, I'm filled with such anger and sadness that it builds up and escalates into something more.
Like many people with Ichthyosis, our lives consist of struggling to get society to accept us, to understand that beauty is skin deep but there is so much more to our lives than just an appearance in which skin sheds, we look permanently sun burnt and as a result, we have to work extra hard to get people OUTSIDE our close circle to understand that we have dreams and aspirations too. We are not thick people just because we look different. I know this well because aside from Ichthyosis, I have a few friends in Hong Kong who face the wrath of society, just trying to get by on life while dealing with physical disabilities. If anything, society, especially where I live, society could learn a thing or two from the people they so happily shun away since they are probably the nicest people on the planet who are just screaming for people to take them in their arms and work on that little thing called Inclusion.
Am I scared of what the future holds for me? Both in society and in life? Yes, I'm terrified and sometimes I turn to Facebook which isn't the wisest idea at times, but it helps me try to decipher what I have or I could have.
Occasionally I write on Facebook about people who have hurt me that day and I receive a ribbon of support from people telling me to keep me chin up and to keep fighting through because they know I am capable of doing so. I have a lovely friend who has unfortunately left for Down Under...(I like kangaroos and koalas!). But she reads my posts a few times and offers sage advice but something she pointed out made me think she truly understood. When people post negative comments, it's customary to get a barrage of support. But in essence, she said this, I hope you don't mind Kaye!
"Easy to make supportive comments, but basically it sucks and you are one of the most amazing people I know ... Don't know if I could do what you do. Lots of love & hugs ... And a few tears. Ga yauh!!! "
It's easy for people to say things like "chin up" and "don't let people get to you" but the fact of the matter is, that it does and people often don't realise, and I am equally guilty as sin. But what people who offend don't realise, they make their comments without realising that the other person is already scarily fragile and that comment, may sometimes be the final straw and the other person just crumbles. And unfortunately, people who give love and support can't really offer anything but words because especially in my case, chances are, my lot would go up to the offending person and basically scare them shitless. Let me give you a little anecdote from a night down at the pub a while back.
I have known people in Sai Kung, where I live since the day my parents brought me home to Sai Kung, so basically I have a massive extended family whom I love very much. But I was sitting outside with a family friend called Peter King who has known me since I was 3 and having a lively chat about work and how it's hard for expats and those who don't speak Chinese to get good solid work if you're not with the 'banker wanker' lot. But there was another bloke sitting there as well listening to the conversation. But as we were talking, he seemed to be a nice person but as soon as Peter got up to do something, he turned around to me and said, 'please don't take this the wrong way but you look really burnt and not very pretty'. His words stubbed me to the core and the anger building up inside of me was horrible, like a bubbling cauldron and I knew I had to leave before I did something I regretted. I quickly found Pete and made my excuses and explained what they guy said before leaving for home which is about a 10 minute walk away in the first village leaving the town. I texted another friend for Pete's digits as I wanted to make sure all was okay and that he didn't beat the guy up though by the look on his face when I left I couldn't be sure. When I explained why I needed his number, it all came spilling out and effectively I was so sure I'd have to deal with the ignorant soul myself, it never occurred to me to ask for help around me, as someone else quoted later, "Mui wanted to solve her own battles". It didn't occur to me that I didn't have to leave as abruptly as I did because I had an army of Liverpudlians and friends to rally around me and that's what's so good about Sai kung. Whether you have been here for a day, a month or a lifetime, we look after each other and no one, thick or clever has to fight battles on their own.
I challenge you and every person who makes snarky remarks and damages the confidence of the people around them to take a very good look at themselves and to think , "what if I was in their shoes, how would I feel?!" Go on.


text:
That Universal Soldier: Day of Reckoning emerged late last year as something of a critical darling should have surprised exactly no one. Its aesthetic influences, which range from David Lynch to Gaspar Noé, all but guaranteed the film's elevation from the slums of B-movie obscurity to some kind of vulgar-auteurist master class, where a surrealist action niche nobody asked for could suddenly be filled. The idea of a Lost Highway for a post-UFC world is an appealing proposition, at least in cinephilic circles where high-art and exploitation flicks freely intermingle. And the cognitive dissonance generated by seeing Lynchian surrealism applied to what's still essentially a Jean-Claude Van Damme action vehicle, replete with elaborate martial arts bouts and their attendant swaths of blood, makes for a pretty compelling viewing experience, particularly if the stylistic friction remains unexpected going in. There's an element of "seeing it to believe it" built into the presentation: Expectations based on the history of a mostly direct-to-video franchise, an aging action-hero cast, and a patently absurd premise so conspicuously contradict the art-house sensibility of the film itself that you can hardly blame the first wave of audiences for feeling wowed by the shock.
But when this initial sense of surprise dissipates, one is left to contend with the film on its own terms, and Day of Reckoning simply doesn't have the substance to justify its own formal grandiosity. It's worth remembering that the aesthetic tendencies of somebody like Lynch, however striking or fascinating they are in practice, aren't in and of themselves sources of depth or substance; his style is a consequence of the emotional logic of his films, not the other way around, which is to say that his idiosyncrasies of form are warranted by the material. Day of Reckoning appropriates those qualities for the simple reason that they look cool; their presence adds a palpably Lynchian atmosphere that gives only the illusion of substance. It obscures or altogether elides important narrative information to the same end: Obscurity and elision are the tools of art-house filmmaking, and adopting them lends the work de facto art-house credibility. Unabashedly exploitative fight scenes are thus bestowed the prestige of a high-art sensibility. The effect is a bit like when a cool indie band slathers a pop song in a thick layer of noise and distortion; something perceived as frivolous or facile is newly coded in one gesture as palatable to a more serious audience.
This, it probably goes without saying, warrants a great deal of skepticism. And there's still something to be said for the film's supremely well-executed action sequences, of which it contains a hefty number. Though John Hyams is a somewhat dubious appropriator of difficult conventions, he excels at clean and simple fight choreography, as many of these skirmishes prove; he treats a good movie fight in the same way the director of a musical might treat a movie dance, training his camera on the elegance of his players' physicality and grace. The two major fight sequences—the first and best in a sports store, the second in an armory—are well shot and unfussy in a way that none of the film's more laboriously "moody" or contemplative sequences are, which suggests that a better film might have been made, ironically, had Hyams's vision been scaled back. Day of Reckoning, simply put, is a solid B movie bogged down by its own art-house aspirations. And while that problem, almost in and of itself, makes it a more interesting failure than the bulk of its contemporaries, it's nevertheless a source of justifiable frustration, as the film's capacity to enthrall as a largely traditional action film seems somehow intruded on by half-baked surrealist trimmings, flirtations with a more serious cinema whose substance lay beyond the reach of this material.
Universal Soldier: Day of Reckoning serves as a good case study for the best and worst qualities of high-definition digital photography, both of which this practically flawless 1080p transfer brings into relief. On the one hand, the image's immense detail and sharpness is often gasp-worthy, which is particularly evident during close-ups (check the sweat on Dolph Lundgren's neck during the nightclub raid for proof); one the other, however, the image is clear and high-gloss to the point of transparency, which makes it feel rather sterile and cold. In a technical sense, then, the movie looks superb, but I for one sorely miss the texture of 35mm. In any case, Sony's Blu-ray does a top-notch job of preserving the original look of the film, er, video, and fidelity is paramount. Likewise, the DTS-HD Master Audio delivers precisely the depth and richness a film with this many hard-hitting foley sounds needs.
Misleading feature-listing alert: The back cover of Sony's Blu-ray indicates the inclusion of "3 making-of featurettes," but it's really just one hour-long EPK doc divided via on-screen title cards into three segments. The production of Universal Soldier, given its strange history as a franchise and the apparent idiosyncrasies of this new iteration, is well-worth exploring in detail, but, to that end, a talky commentary track from John Hyams and co-star Lundgren provides more substantial context and on-set anecdotes than anything in the stand-alone featurette. Hyams and Lundgren wax nostalgic about old-school movie fights and the giddy violence of exploitation cinema, and Lundgren, after a little prodding, talks at length about his experience working on Rocky IV, which is a treat.
Essentially Lost Highway for a post-UFC world, Universal Soldier: Days of Reckoning is an intriguing but ultimately rather empty experience.


text:
I am embarrassed to come on here after so much time has gone by. I cannot believe it was November when I last posted. Where or where does the time go? We've had the joy of Christmas are into a new year and soon it will be Easter when we celebrate our Risen Lord.
Here in Alberta we have had a good winter, fairly mild weather, only of bit of bitter cold. Of course we aren't out of the woods yet, we could still get a big blast of cold and snow but at least it won't be around very long.
I love music, have always wished I could play an instrument so I really like this card with the piano keys and musical notes.
Black and white is one of my favourite colour combinations.
No stamps, piano keys are off the internet
Ink: there is no ink
Paper: black and white card stock, Stampin Up designer paper
Accessories: white flowers, black flower brads, black musical note brads, shimmery ribbon, dimensionals
Blessings to all,


text:
On this week's delayed edition, Phil and Jamie let out all of their bottled up frustration and angry towards X-Men Origins: Wolverine. Everything from its inevitable box-office plummet next weekend to the (many) inconsistencies (and Jamie hates on Halle Berry somewhere in between) are discussed.
And since they don't want to spend an entire hour bitching and moaning about the film (even though this podcast series is called Movie Moan), the trailers for G.I. Joe and Transformers: Revenge of the Fallen are talked up and Phil gives his prediction of what will be the next 80s toyline turned into a $200+ million summer blockbuster franchise.
All that, and a deep philosophical chat about James Bond Junior and the (presumably many) bastard offspring of 007 and Captain Kirk on this week's Movie Moan!


text:
Who do you hate? The player that makes your favorite look silly and then for good measure slams the ball in the back of the net. After that fleeting moment of hate, you start to realize deep down you love what that dude can do and start to smile.https://www.youtube.com/watch?v=UNiGSf2Sy30#t=43
adidas is talking to the inner spirit of players and fans around the globe with their new cleat teaser 'There Will Be Haters' featuring Luis Suarez, Gareth Bale, James Rodriguez, and Karim Benzema.
The look of haters will stretch across all 4 adidas silos, adizero F50, Predator Instinct, Nitrocharge and 11Pro. The new looks will make their on field debuts on January 23 with the cleats landing in stores on February 2.
But once again we ask, who do you hate? Talk about your villain #1 in the comment section.
Check it out and let us know what you think. Available soon at World Soccer Shop!


text:
He's Growin' Up!
So my little boy is now a big 03. I can't believe it. He is growing up so fast. We had a baseball birthday of course. It ended up being in two places because of the weather. We started out at Conchas Park (by Lexington Apts) grilling hot dogs, eating chips and the kids playing on the play equipment. We were there because we wanted to play a game of baseball...
Parker's been talking about doing that since my birthday...but the weather had other ideas. As we were finishing eating when the wind started to blow something fierce and it started to sprinkle. The kids didn't seem to notice, but the adults did. (I've never seen Grandpa Bob run so fast!) So we packed everything up and went to the house, and the kids headed straight for the backyard while the adults took cover inside. We sang and had baseball cake and ice cream and opened presents. When the weather was nice enough, we played a mini baseball game outside. Everything didn't go as planned, but Parker didn't notice. He had a blast with his cousins, aunts, uncle and grandparents.
p.s. I'm sorry there's no pics...I accidentally deleted them from my camera...I hear my bro-in-law knows how to rescue them. I hope so!
2 comments:
- Becky, Brad and Eli said...
I'm sad we couldn't be there. Thanks for putting mine and Brad's song on your playlist (I'm sure you did it for us:).
- Thursday, May 08, 2008 2:18:00 PM
- shelbell said...
Happy Birthday Parker!! I seriously can't believe your handsome little guy is 3 already. Sounds like a fun party!
- Sunday, May 11, 2008 3:13:00 PM
Subscribe to: Post Comments (Atom)


text:
People run a firm from dwelling for numerous one of a kind explanations: to make dollars, show probable, or be recognized for exclusive skills -- to name a few of. No concern you have a terrific reason! No doubt you want to prosper! Suitable in this article are some useful strategies from other men and women who have absent down this highway in adv
Make Your Residence Firm Get the work carried out With These Strategies
Every man or woman needs they ended up becoming their extremely own supervisor. Uncover as significantly as you can to arrive at a amazing degree of accomplishment. You truly really should be correctly on your way to functioning a productive little tiny company proper right after wanting at this brief post.Research for assets organization choices t


text:
The MD-1000 is a single frequency modulator. Sold as a companion product to the MX-GS200, the MD-1000 receives its configuration and transport stream via a high speed USB 2.0 connection and outputs a modulated RF signal consisting of one MPTS. This modulator is both frequency agile (48 MHz - 900 MHz) and modulation agile.
The MD-1000 supports the following transmission standards:
Copyright © 2017 - All Rights Reserved - West Pond Technologies, LLC
Template by OS Templates


text:
In the name of my father, I have them! If it took the murder of Lorna Bell, I have all the evidence I need that the Collinses are Satan's servants! The mark on her forehead matches the unholy glyph on the ring of Quentin Collins, renowned practitioner of the Black Arts. With the aide of Gerard Stiles, I shall have my justice and the House of Trask shall be avenged!
L. Trask


text:
- ipbr21054Asked on February 04, 2017 at 04:51 AM
This is the form 62115565434352
When i click inject CSS and "before i touch / edit ANYTHING" your form automatically decides to change my form to a transparent background.
This happens every time now.
Please take a look why ?
- BorisAnswered on February 04, 2017 at 08:44 AM
It looks like there was some corruption with your form's background, so what I would recommend you do to resolve it is to simply reset / refresh the form background color.
You can do this easily by changing your form's background to any other setting, and then simply change it back to color #0099ff:
Please let us know should you need any further assistance after that. Thank you.
- ipbr21054Answered on February 04, 2017 at 02:18 PM
Is that using version 4 as at present i am using version 3.
If you are to use version 4 for your help / advice i would need to know how to switch to version 4 so i can follow you.
- JotForm SupportKevin_GAnswered on February 04, 2017 at 10:47 PM
In the v3 builder you could do this by opening the designer wizard, here's an image as reference:
If you want to go to the v4 builder then you only need to open your account settings, there you will find the option to switch the builder version:
Hope this helps.


text:
transport chiefs are set to launch their biggest consultation about the future of public transport in Leeds.
Representatives from leading transport bodies across the city and region will attend a summit to help shape a future transport strategy for Leeds.
The meeting will be the first in a series of discussions to be held across the city.
Key themes for the summit will include the latest position on future transport projects and an update on current work being undertaken around the city such as new park and ride sites, better cycle and walking routes and railway network improvements.
People are being asked to send in their thoughts and ideas about transport in Leeds to firstname.lastname@example.com. The event will be opened by Councillor Judith Blake, leader of Leeds City Council. Coun Blake said: "This summit will, we hope, be the spark for a new, inclusive discussion that will give people in communities all across Leeds the chance to be part of planning for the future of public transport in their city.
"We know that public transport and how people get from A to B has become an increasingly pivotal issue for Leeds and in particular for our ability to continue to grow and capitalise on our economic success.
"We also know that the people of Leeds deserve better and what we have now is an opportunity to gather the full of range of talent and ideas from the people living, working and travelling in the city.
"It is imperative that we now work together as a city and region to ensure that the £173.5m that has been secured for transport in Leeds is put to the best possible use in improving journeys for local commuters."
The Yorkshire Evening Post recently featured a series of special reports examining the city's transport network after the scrapping of Leeds's long-delayed £250m New Generation Transport (NGT) trolleybus scheme.


text:
Over the last several years, I have looked forward to the spring not only for the warmer and more pleasant weather, but also the arrival of the fishing vessels of the herring fleet along the Halifax waterfront. The waterfront in winter is usually quite sparse, with few if any interesting vessels berthed in the downtown area that I walk along on my way to work, and even during the summer one is not guaranteed of an interesting sailboat or yacht to break the tedium. The herring fleet over the last few years has guaranteed at least a handful, if not more, of brightly coloured ships big enough to provide varied photographic opportunities - especially useful after a winter in which I felt I was suffering from some photographic withdrawal. In my case, because they are usually static and alongside when I pass by, I have tended to abstract and detail shots, rather than the more documentary shots that I would typically take of boats and ships.
|An image from this year: Morning Star's hull is strengthened with these ribs near the stern. I like the angles and reflections.
When I am passing by in the morning, it is often calm (or relatively so) in the shelter of the jetties, which makes good conditions for reflections on the surface of the water. In the case above, the red bottom paint shows through the white and blue reflections from the waterline and hull. I probably had to apply a gradient filter in post production of this image to balance, somewhat, the hull against the darker reflection. It also looks as though I may have used my thirds grid to help in composition.
I have also tended toward some minimalism at times, perhaps attempting my own take on Barnett Newman's "Voice of Fire" in the National Gallery in Ottawa. You know the one.
|I could call this "Herring of Fire" perhaps. Maybe "Red Herring"?
I don't think anyone will be offering me millions of dollars for mine, though. If the National Gallery needs to use up their budget before government fiscal year end, though, please feel free to contact me - I could negotiate my price upwards to the necessary amount.
Looking back year over year, the same subjects appear in my photos, but there is always something different even when looking at other images of Morning Star:
|Morning Star from last year, this time showing some rust, and her load markings, both of which are missing from the first image above.
|A different angle on Morning Star again, this time with ripples distorting the reflection of her waterline. The red stands out better in the sun.
|Sometimes the ship isn't as up to date on its maintenance and cleaning, and we get to add some green to the mix. Plus, roman numerals! Classy!
It is fairly easy to pick out the images that were taken on sunny days (like 3 of the 5 images above), but often the more subdued lighting of an overcast morning works just as well.
|I don't always aim for the waterline - sometimes there are nice ropes and chains to add to the mix.
|Occasionally I allow other floating objects to intrude on the image, in this case some tire bumpers.
|Sometimes buoys and bumpers add to the colour mix.
|In this case, drips from the ship's bilge pump disturb the waterline reflection.
I once took a series of photography night courses from a local instructor who likes to direct his lead-in lines to the various corners of his images. Occasionally (OK, maybe frequently) this crops up in my images as well, now.
|Look, ma! Corners! Three of them!
Sometimes, it is interesting to see what different compositions you can get from the same area on the same boat. In this case, I demonstrate with three different angles on the prow of one particular red boat. I can't decide which I like the best.
|Here I went for symmetry.
|In this one I went for considerable negative space to the bottom of the image. And to heck with symmetry!
|Here, I went for a corner..actually, three corners! Two aren't so obvious. I must have been careful with this one to get everything to line up! I also love the effect with the hourglass formed by the load line numbers as they reflect on the water.
My use of vignetting in post production of my images is perhaps most noticeable in the three images above. While software correcting for lens distortion removes vignetting, I often add it back into the image because I like it for some reason. Perhaps it draws the eye back to the centre of the image, when I choose to centre my subject.
|Same area on a ship, but different colours this time.
I will finish off this post with an image of one of the few wooden ships left in the fleet. I think the planking adds to the image by providing more texture, especially in this case where the ship has been chipped and repainted so many time.
I have applied similar treatments to other ships and yachts on the waterfront, but I will save those for another post.


text:
Does having (paraphrasing)"Allow PC to Download from Anywhere" turned ON allow updates to arrive faster? My wife's PC had this setting turned on, and received the big update really early in the release cycle.
Still I have not received any update. WHAT is going on ??
EDIT: I have the Enterprise edition.
So how is the booting and restart performance on the new build? I'm still on 10240 RTM and still on the fence on upgrading since I heard i will have to redo all my settings all over again. What's irking me about my current W10 is the time it takes to restart so If the new build has significant faster time to restart then I might upgrade
i ha dto use the MCT to update went smooth (about 35ish mins)i lost a Memory Utility to monitor and clear unreleased Memory (aka ram claimed in use that isnt being used.) (windows 10 Pro now sittin on 10586.3 )
The latest should be about 30% faster as far as boot time according to the report I saw where I had to note that 7 was actually the one to see the desktop come up faster but 10 sees all the processes finish loading sooner while the desktop takes a longer to arrive. The shutdown speed for 7 blows 10 off however as 10 seems to drag on exit! Now here's a look at two VM's on being the 10586 Insider Preview where you see the version number, OS build, and product iD while the public release shows only the product ID tag.
I renamed each VM with a specified PC name to indicate which build or release was being seen. The 10586 Pro x64 on the left with the Threshold 2 download by way of MC tool on the right.
I just downloaded the update using the link someone had posted in here earlier today. It does seem like its a bit smoother and faster then it was. If you had not had the upgrade for 30 days you won't get the update through windows.
Well it's not an update but an upgrade that takes place into the newer build. If you signed up for the Get Insider builds logging in with a new MS account of course you would set the updates to automatic and the speed setting to Fast not Slow and simply wait a matter of hours once you get past the initial Windows Defender, Culmilative security, IE Flash player, and one or two other preliminary updated to then see the Th2_10 edition option come up and start downloading automatically.
One report stated about this being 30% faster then 7 while the 7 desktop loads up faster then 10's! Yet the processes finish loading up faster on 10 so by the time the desktop arrives you are almost ready while you are still waiting for things to finish up on 7. The improvements besides a couple of new items just added in will mostly be under the hood anyways.


text:
The BME seminars will start this Friday 5th October with Professor Wafa SKALLI for a conference.
This conférence is entitled "Spine Biomechanics, from a basic research to clinical routine".
The conference will take place at Arts & Métiers ParisTech, 151 boulevard de l'Hôpital, 75013 Paris, Amphi Fournel, from 13h30 to 15h00.
Thank you for being punctual.


text:
Please enter a maximum of 5 recipients. Use ; to separate more than one email address.
Norway introduced an inflation target as part of its
monetary policy framework in 2001. The operational target of
monetary policy in Norway is an annual consumer price inflation
of close to 2.5% over time. Norges Bank operates a flexible
inflation targeting regime where weight is also given to the
variability of output and employment. The Regulation on
Monetary Policy is now being considered by the Ministry of
Finance, which is natural after 15 years' experience of
inflation targeting. Overall, our experience shows that the
monetary policy framework has served the Norwegian economy
Inflation has been predominantly low and stable since
inflation targeting was introduced in 2001. Average annual
consumer price inflation has been close to, but somewhat below,
2.5%. At the same time, employment has consistently been more
stable since 2001 than earlier.
The inflation target has anchored inflation expectations.
With a flexible inflation targeting regime, the scope for the
use of judgement has also allowed monetary policy to respond to
shocks and dampen associated effects on output and
Norway has been exposed mainly to external shocks over the
past 16 years with large shifts in its terms of trade and
strong effects from fluctuations in the world economy. Global
interest rates have been very low and labour immigration to
Norway has been high. In response to these developments,
monetary policy has had to make trade-offs between stabilising
output and employment and stabilising inflation around the
Providing for flexibility in inflation targeting has proved
essential for making the appropriate trade-offs in response to
these shocks. The time horizon for achieving the target must be
sufficiently long. The exchange rate has also played an
important role as a shock absorber, particularly during the
financial crisis and in periods of falling oil prices. At the
same time, the interest rate level abroad places limitations on
the room for manoeuvre in monetary policy in a small open
economy like Norway.
The global interest rate level will likely remain low for
several years ahead. This has raised the question of how far
monetary policy should go in addressing financial stability.
For Norges Bank, the consideration of restraining the build-up
of financial imbalances has long been an element of a robust
monetary policy. The aim is to mitigate the risk of
particularly adverse economic outcomes further ahead.
The build-up of financial balances increases the risk of a
deep downturn. Monetary policy can reduce vulnerabilities by
leaning against the wind, i.e. by keeping the interest rate
higher than necessary to meet the inflation target in the short
run. But this policy could also involve costs in terms of
somewhat weaker economic developments in the short run than
would otherwise be the case.
The aim of leaning against the wind is to achieve a
sustainable path for inflation, output and employment. This is
in line with our central bank mandate. Flexible inflation
targeting with a sufficiently long horizon should take account
of financial stability where possible and necessary.
At the same time, it should be stressed that financial
regulation and supervision are the first line of defence
against shocks to the financial system. The main task of
monetary policy is to provide the economy with a nominal
anchor. When inflation is firmly anchored, monetary policy can
also contribute to real economic stability.
The material on this site is for financial institutions, professional investors and their professional advisers. It is for information only. Please read our terms and conditions and privacy policy before using the site. All material subject to strictly enforced copyright laws. © 2018 Euromoney Institutional Investor PLC. For help please see our FAQ.
Get unlimited access to IFLR.com for 7 days*, including the latest regulatory developments in the global financial sector, updated daily.
Read IFLR's global coverage whenever and wherever you want for 7 days with IFLR mobile app for iPad and iPhone
"The format of the Review has changed over the years; the high quality of its substantive content has not."
Lee C Buchheit, Cleary Gottlieb


text:
Scattered hedgehogs on grey background
$7.00 per Fat Quarter or $28.00 per metre
Multicoloured hedgehogs on grey cotton.
100% cotton. 44 inches / 110 cm wide.
Ordering Fabric:
Fabric can be ordered as a Fat Quarter or by a custom meterage.
A Fat Quarter is approximately 50 cm by 55 cm.
To order a custom meterage, select 'Custom Meterage' and then enter the number of centimetres in the quantity box. For example, to order 1/2 metre, enter 50. To order 2 3/4 metres, enter 275.
Note: There is a minimum order of 25 centimetres for the custom meterage.