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By A. Arokkh. Catawba College.

In contrast rogaine 2 60 ml mastercard, lipid-soluble drugs are usually absorbed transcellularly generic rogaine 2 60 ml overnight delivery, by passive diffusion through the epithelium, down a concentration gradient according to Fick’s Law (Section 1. Drug diffusion rates correlate with their lipid/water diffusion coefficients and are inversely related to their molecular size (Section 1. However, these general observations do not take into account the cyclical changes in the vaginal epithelium, which exert profound effects on vaginal absorption, especially for hydrophilic compounds. The permeability coefficient for the vaginal membrane (P ) is equal to the sum of the permeability coefficientm through the lipid pathway (P ) and the pore pathway (P ):l p P =P +Pm l p For lipophilic drugs, the contribution of the pore pathway to transport is negligible and drug absorption occurs transcellularly, via passive diffusion through the epithelial cells. For example, it has been shown that increasing the chain length (increasing the lipophilicity) of aliphatic alcohols and carboxylic acids results in an increased rate of vaginal absorption. In contrast, for hydrophilic drugs, the pore pathway constitutes the major absorption pathway and this pathway is influenced by the physiological changes in the thickness of the vaginal epithelium and also in the number of intercellular pores and aqueous channels. As described earlier, in rodents, during proestrus and estrus, the epithelium is thick, tightly cohesive and contains a large number of intercellular junctions. However, the metestrous and diestrous phases are characterized by a thinning of the epithelium and a pore- like widening of the intercellular channels. As the vaginal epithelial membrane barrier becomes thin, loose and porous, the permeability is enhanced, particularly to hydrophilic substances. Thus even high molecular 280 weight hydrophilic drugs can be absorbed by the intercellular route during the metestrous and diestrous phases. Several examples of this phenomena are described below: Salicylic acid Vaginal absorption of salicylic acid in different pH buffers has been investigated in rats during proestrus and diestrus. For the unionized, lipophilic form of the drug, the rate of vaginal absorption is rapid and similar for both stages. The unionized, lipophilic form is absorbed via transcellular passive diffusion and thus not affected by the stage of the estrous cycle. However, for the ionized, water-soluble form, a significant difference in the degree of absorption is observed: • proestrus (tight epithelium)=29% absorbed; • diestrus (porous epithelium)=66% absorbed. The hydrophilic form is absorbed mainly through pore-like pathways such as the intercellular channels and thus is highly dependent on the stage of the cycle, with greater absorption occuring when the interceullular channels are wide and porous. The percentage of the dose of phenol red excreted in the urine increased more than an order of magnitude from the proestrous phase (2. Leuprorelin showed similar enhanced absorption during the permeable phase of the estrous cycle (Figure 11. Penicillin In humans high blood levels of penicillin, sufficient to be therapeutic, were demonstrated following insertion of a vaginal suppository near the end of the menstrual cycle and during menopause. In contrast, absorption was shown to be somewhat diminished during estrus and late pregnancy. Vidaribine The permeability coefficients of the hydrophilic antiviral compound vidaribine are 5 to 100 times higher during early diestrus or diestrus than during estrus. These results confirm that the cyclic changes in the reproductive system have profound implications for vaginal drug delivery as: • the vaginal permeability to hydrophilic substances is enhanced during the metestrous and diestrous stages of the estrous cycle, corresponding to the late luteal and early follicular phases of the menstrual cycle; • large fluctuations in absorption occur, depending on the particular stage of the menstrual cycle. Although it is well known that carrier-mediated transport systems exist for di- and tripeptides in the intestine, there is still no evidence for carrier-mediated transport of peptides across the vaginal mucosa, although prostaglandins have been demonstrated to utilize such a mechanism. Although there must be some type of endocytic transport of endogenous peptides into the epithelial cells in order to regulate proliferation, no receptor-mediated or bulk-fluid mechanisms have been reported. Hydrophilic compounds may be absorbed via the paracellular route, moving between the epithelial cells via passive diffusion whereas lipid soluble drugs are usually absorbed transcellularly, at rates which correlate with their lipid/water diffusion coefficients. However, in the vagina these factors must be considered in conjunction with the cyclical changes in the vaginal epithelium. Thus hydrophilic compounds show enhanced absorption during metestrus and diestrus, when the vaginal barrier becomes thin, loose and porous. In addition to physicochemical properties of the drug such as size, pKa, chemical stability etc. Furthermore, peptides and proteins are susceptible to self-association, aggregation or polymerization in the medium due to changes in pH, ionic strength of the medium, or concentration of the substance. It is anticipated that the monomer, oligomer, or aggregated complex may each have a characteristic diffusion and permeation coefficient. Further physicochemical factors associated with the drug which influence vaginal drug delivery include the solubility and stability of the drug in the vaginal fluids. Poorly soluble drugs may demonstrate rate- limiting dissolution in the vaginal fluids. For example, the vaginal absorption of metronidazole is limited not only by the drug permeability across the vaginal epithelium, but also by its dissolution into the small volume of fluid within the vaginal cavity. Such formulations are administered with the aid of an appropriate applicator into the vagina and have different characteristics with respect to ease of administration, drug release profile, sanitary aspects etc. Desirable attributes of all vaginal preparations include: • no adverse reactions, such as tissue irritation; • ease of application; • even distribution of the drug throughout the vagina, rather than being concentrated in one spot; • retention of the drug in the vagina, even when the patient is standing and walking; • absence of an offensive odor; • absence of staining of clothes or skin; • compatibility with other forms of medication and contraception; • minimal interference in sexual activity. Formulation factors which affect vaginal drug delivery which are common to the various types of vaginal dosage forms include: Drug release As discussed above, there is a relatively small volume of fluid within the vaginal cavity. Thus the rate- limiting step for systemic absorption of drugs from intravaginal creams, inserts and tablets is often dissolution within the vaginal fluid, particularly for poorly soluble drugs. Obviously, the type of dosage form affects the rate of dissolution; for example, a drug which is already dissolved in an aqueous vaginal gel will be more rapidly absorbed than a drug which is in solid form within a vaginal tablet preparation. The effective area of contact Although the area of the vaginal cavity is approximately 60 cm , the formulation will influence the size2 of the area over which the drug is deposited. The vehicle should facilitate even distribution of the drug throughout the vagina, rather than concentrating it in one spot. Factors such as the hydrophilicity and viscosity of the vehicle will determine how well it spreads through the vagina. Contact time The formulation will also influence the extent of the contact time the drug has with the absorbing surface of the vaginal epithelium. Typical delivery systems such as foams, gels and tablets are removed in a relatively short period of time by the self- cleansing action of the vaginal tract. New bioadhesive gel delivery systems are being developed to prolong contact time with the absorbing surface and are described below.

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However order rogaine 2 60 ml otc, this is a rather simplistic view and it is important to realize that these considerations are only broad generalizations discount 60 ml rogaine 2 mastercard. Thus although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via other routes and mechanisms. In particular, drugs that are absorbed via active mechanisms are often also absorbed, to a (much) lesser extent, via passive diffusion mechanisms. A brief description of the effect of the physicochemical properties of the drug on the absorption process is given below and is discussed in more detail in the relevant chapters. A measure of the lipid solubility of a drug is given by its oil/water equilibrium partition coefficient. This is determined by adding the drug to a mixture of equal volumes of a lipophilic liquid (often octanol, but other solvents also used) and water and shaking the mixture vigorously to promote partitioning of the drug into each phase. For a given drug: if log P=0, there is equal distribution of the drug in both phases if log P>0, the drug is lipid soluble if log P<0, the drug is water soluble 19 Table 1. Thus in general, the higher the log P, the higher is the affinity for lipid membranes and thus the more rapidly the drug passes through the membrane via passive diffusion. Values of log P that are too high (>6) or too low (<3) may be associated with poor transport characteristics. Drugs with very high log P values have poor aqueous solubility, which is partly the reason for their poor absorption properties, as some degree of aqueous solubility is required for drug absorption (see Section 1. Furthermore, if a drug is too lipophilic, it will remain in the lipidic membrane and never partition out again into the underlying aqueous environment. Very polar compounds (with very low log P values) are not sufficiently lipophilic to be able to pass through lipid membrane barriers. If a drug molecule forms hydrogen bonds with water, desolvation and breaking of the hydrogen bonds is required, prior to partitioning into the apical membrane of the epithelial cell. If the number of hydrogen bonds between the drug and water is > 10, too much energy is required and there will be minimal drug transport across the membrane. The number of hydrogen bonds a drug forms with water can be estimated by inspection of the drug structure (Table 1. The lipid solubility of a drug molecule can be increased by blocking the hydrogen bonding capacity of the drug. This may be achieved by, for example, substitution, esterification or alkylation of existing groups 20 on the molecules and will decrease the drug’s aqueous solubility, favoring partitioning of the drug into the lipid membrane. The development of clindamycin, which differs from lincomycin by the single substitution of a chloride for a hydroxyl group, is such an example. Alternatively, the drug may be covalently bound to a lipid carrier, such as long-chain fatty acids. Altering the structure of the drug carries the concomitant risks of: • compromising the activity of the drug; • increasing the toxicity of the drug; • increasing the molecular weight to such an extent that the molecule will be too large to cross the membrane barrier (see Section 1. An alternative strategy, which overcomes these limitations, is to use the prodrug approach (Figure 1. This involves the chemical transformation of the active drug substance to an inactive derivative (prodrug), which is subsequently converted to the parent compound in vivo by an enzymatic or non-enzymatic process. Thus a prodrug of a drug, because of its increased lipid solubility, may demonstrate enhanced membrane permeability in comparison to the parent drug. Enzymatic or chemical transformation converts the inactive prodrug to the pharmacologically active drug, after absorption has taken place. A further important point, discussed in detail in the next section, is that lipid solubility must be considered in the context of the degree of ionization of the drug. Therefore the pH of the solution will affect the overall partition coefficient of an ionizable substance. For ionizable drugs log P is pH dependent and hence log D, the log distribution coefficient of the drug at different pHs, is usually employed instead of log P, as an estimation and/or prediction of absorptive potential. The pH at which the log D is measured should be reported but values normally correspond to determinations carried out at a physiological pH of 7. Log D is effectively the log partition coefficient of the unionized form of the drug at a given pH. The relationship between the observed overall partition coefficient and the distribution coefficient is given by the equation: where α is the degree of ionization of drug. The interrelationship between the dissociation constant and lipid solubility of a drug, as well as the pH at the absorption site, is known as the pH-partition theory of drug absorption. Accordingly, rapid transcellular passive diffusion of a drug molecule may be due to: • a high proportion of unionized molecules; • a high log P (high lipophilicity); • or a combination of both. The extent of ionization of a drug molecule is given by the Henderson-Hasselbalch Equation (Box 1. In contrast, a very low percentage is unionized in the small intestine, which suggests unfavorable absorption. Strong acids, such as cromoglycate, are ionized throughout the gastrointestinal tract and are poorly absorbed. The reverse is true 22 for weak bases (with pK ′s in the range 5 to 11), which are poorly absorbed, if at all, in the stomach sincea they are largely ionized at low pH, but are well absorbed in the small intestine, where they are unionized. Strong bases, such as mecamylamine, are ionized throughout the gastrointestinal tract and are therefore poorly absorbed. Although the pH-partition hypothesis is useful, it must be viewed as an approximation because it does not adequately account for certain experimental observations. For example, most weak acids are well absorbed from the small intestine, which is contrary to the predictions of the pH-partition hypothesis. These discrepancies arise because the pH-partition hypothesis does not take into account the following: • the large mucosal surface area of the small intestine, which compensates for ionization effects; • the relatively long residence time in the small intestine, which also compensates for ionization effects; • even the ionized form of a drug displays limited absorption; • charged drugs, such as quaternary ammonium compounds, may interact with organic ions of opposite charge, resulting in a neutral species, which is absorbable; • bulk transport of water from the gut lumen to the blood, or vice versa, can drag water-soluble molecules with it, resulting in an increase or decrease in the absorption of water-soluble drugs respectively. A more complex relationship pertains for more complex and organized structures such as lipid bilayers, but again, drug diffusivity is inversely proportional (probably by an exponential relationship) to the molecular volume. This means that drug diffusivity across membranes is sensitive to molecular weight, since molecular volume is determined by a number of factors, including the molecular weight of the molecule. Therefore, in general, large molecules will diffuse at a slower rate than small molecules. However, molecular volume is also determined by: • the overall conformation of the molecule; • the heteroatom content that may be involved in inter- and intramolecular hydrogen bonding. Thus molecules which assume a compact conformation will have a lower molecular volume and thus a higher diffusivity. An important consequence of this property is that even if such molecules have a high molecular weight (i. Molecular size and volume also have important implications for the paracellular route of drug absorption.

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Synthesis of thiol-derivatised gold nanoparticles in a two-phase liquid-liquid system purchase 60 ml rogaine 2 with visa. Synthesis of poly(styrene) monolayers attached to high surface area silica gels through self-assembled monolayers of azo initiators rogaine 2 60 ml free shipping. Surface-confined photopolymerization of pH- responsive acrylamide/acrylate brushes on polymer thin films. Polymer brushes by living anionic surface initi- ated polymerization on flat silicon (SiOx) and gold surfaces: Homopolymers and block copolymers. Homopolymer and block copolymer brushes on gold by living anionic surface-initiated polymerization in a polar solvent. Surface-initiated anionic polymerization of styrene by means of self-assembled monolayers. Synthesis of gold nanoparticles coated with well- defined, high-density polymer brushes by surface-initiated living radical polymeriza- tion. Nanocomposites by surface-initiated living cationic polymerization of 2-oxazolines on functionalized gold nanoparticles. Preparation of poly(N-isopropylacrylamide)- monolayer-protected gold clusters: Synthesis methods, core size, and thickness of monolayer. Preparation of poly(styrene-co-N-isopropylacrylamide) micelles surface-linked with gold nanoparticles and thermo-responsive ultraviolet-visible absorbance. Polymers at interfaces: Using atom transfer radical polymerization in the controlled growth of homopolymers and block copoly- mers from silicon surfaces in the absence of untethered sacrificial initiator. Surface-initiated atom transfer radical polymerization on gold at ambient temperature. Dynamic contact angle measurement of temperature- responsive surface properties for poly(N-isopropylacrylamide) grafted surfaces. Fabrication of thermosensitive polymer nanopat- terns through chemical lithography and atom transfer radical polymerization. A facile route to poly(acrylic acid) brushes using atom transfer radical polymerization. Synthesis of poly(methacrylic acid) brushes via surface-initiated atom transfer radical polymerization of sodium methacrylate and their use as substrates for the mineralization of calcium carbonate. Nanobiotechnology: The promise and reality of new approaches to molecular recognition. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle probes. Glass-coated, analyte-tagged nanoparti- cles: A new tagging system based on detection with surface-enhanced Raman scatter- ing. Angular-ratiometric plasmon-resonance based light scattering for bioaffinity sensing. A comparison of different strategies for the construction of amperometric enzyme biosensors using gold nanoparticle-modified electrodes. Application of impedance spectroscopy for monitoring colloid Au-enhanced antibody immobilization and antibody-antigen reactions. Electrochemical genosensor based on colloidal gold nanoparticles for the detection of Factor V Leiden mutation using disposable pencil graphite electrodes. Electrochemical coding of single-nucleotide poly- morphisms by monobase-modified gold nanoparticles. Reagentless glucose biosensor based on direct electron transfer of glucose oxidase immobilized on colloidal gold modified carbon paste electrode. A strategy for enzyme immobilization on layer-by-layer dendrimer-gold nanoparticle electrocatalytic membrane incorporat- ing redox mediator. A reagentless amperometric immunosensor based on gold nanoparticles/thionine/Nafion-membrane-modified gold electrode for determination of [alpha]-1-fetoprotein. Electrochemical immuno-bioanalysis for carcinoma antigen 125 based on thionine and gold nanoparticles-modified carbon paste interface. Electrochemical biosensors based on colloidal gold-carbon nanotubes composite electrodes. Novel potentiometric immunosensor for hepatitis B surface antigen using a gold nanoparticle-based biomolecular immobilization method. Preparation and application on a kind of immobilization method of anti-diphtheria for potentiometric immunosensor modified colloidal Au and polyvinylbutyral as matrixes. A glucose biosensor based on chitosan-glucose oxidase-gold Gold Nanoparticles and Surfaces 113 nanoparticles biocomposite formed by one-step electrodeposition. Electrochemically deposited chitosan hydrogel for horseradish peroxidase immobilization through gold nanoparticles self-assembly. Amperometric glucose biosensor based on layer-by-layer assembly of multilayer films composed of chitosan, gold nanoparticles and glucose oxi- dase modified Pt electrode. Electrochemical biosensor based on integrated assembly of dehydro- genase enzymes and gold nanoparticles. Colloidal gold nanoparticles: A novel nanoparticle platform for developing multifunctional tumor-targeted drug delivery vectors. Glutathione-mediated delivery and release using monolayer protected nanoparticle carriers. Gold nanoparticles as a versatile platform for opti- mizing physicochemical parameters for targeted drug delivery. Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. Generation of cytotoxic singlet oxygen via phthalocyanine-stabilized gold nanoparticles: A potential delivery vehicle for photody- namic therapy. Nitric oxide, a double edged sword in cancer biology: Searching for therapeutic opportunities. Drug delivery strategy utilizing conjugation via reversible disulfide linkages: Role and site of cellular reducing activities. Materials for fluorescence resonance energy transfer analysis: Beyond traditional donor-acceptor combinations. Tunable reactivation of nanoparticle-inhibited beta-galactosidase by glutathione at intracellular concentrations. Chitosan reduced gold nanoparticles as novel car- riers for transmucosal delivery of insulin.

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