Mark Corson

By L. Vak. California State University, Dominguez Hills. 2018.

The prodrug form can protect the parent compound from hydrolysis or enzymatic attack buy 50mg revia with amex. A series of ester prodrugs of propranolol were synthesized by incorporating substituents (straight alkyl buy cheap revia 50 mg online, branched alkyl order revia 50 mg amex, acyloxyalkyl and cycloalkyl) into the β-hydroxyl function of propranolol (Figure 6. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma level at 0–0. Prodrug strategies are also being developed to protect enzymatically labile peptide and protein drugs, as well as nucleosides and nucleotides, from premature degradation. Orally administered dexamethasone and a prodrug, dexamethasone-D-glucoside, demonstrated no significant differences in the anti-inflammatory effect, but few side-effects were observed for the prodrug. Similarly, oral budesonide-D- glucuronide was shown to have enhanced anti-inflammatory activity than free budesonide, but did not result in adrenal suppression, whereas free budesonide treatment did. Prodrugs can be used to exploit natural transport mechanisms (see below, Section 6. Their most important physicochemical features include: • They are generally hydrophilic molecules with numerous hydrogen bond forming groups. Several mechanisms of the polymer/mucus interaction have been suggested, including the electronic, adsorption, wetting, diffusion, and fracture theories. Considerable work has been carried out on the mucoadhesive polymer, polycarbophil, a poly(acrylic acid) lightly cross-linked with divinyl glycol, in order to promote absorption in the gastrointestinal tract and also at other mucosal sites. Carbopol (carboxypolymethylene) is a further mucoadhesive poly(acrylate), comprising a totally synthetic co-polymer of acrylic acid and allyl sucrose. Both these mucoadhesive polymers have been shown to increase the oral absorption of poorly absorbed drugs, including insulin, the peptide drug buserelin and the model peptide drug 9-desglycinamide, 8-arginine vasopressin. In the latter case, the absorption across rat intestinal tissue was increased by 330% by polycarbophil. A new mucoadhesive delivery system has been developed for the oral delivery of the peptide desmopressin acetate. The system is based on an oil-in-water mucoadhesive (Carbopol) submicron emulsion, and preliminary reports are encouraging. Both 157 polymers have been shown to be potent inhibitors of the intestinal proteolytic enzyme trypsin. Trypsin inhibition was found to be time-dependent upon addition of Ca2+ and both polycarbophil and carbomer showed a strong Ca2+ binding ability. The amount of Ca2+ depleted out of the trypsin structure and the reduction of enzyme activity were comparable. In particular, lipidization strategies have been investigated for the oral absorption of therapeutic peptides and proteins, which are generally hydrophilic compounds. One such strategy involves the conjugation of a fatty acid to a peptide or protein drug. This strategy has also been applied to thyrotropin-releasing hormone, tetragastrin, calcitonin, and insulin. These transporters may be of use in facilitating oral drug absorption, as such transporters may take up drugs possessing a similar structure to endogenous nutrients. In Caco-2 cells, the active transport of this drug by the amino acid transporter was seven times higher than transport by passive diffusion. Its absorption may be further increased by upregulating the amino acid transporter, as has been observed in the 20–70% stimulation of carrier-mediated amino acid transport by treatment of 0. Utilizing the+ same transporter, the bioavailability of acyclovir, an antiviral drug, can be increased 3-fold by administering its L-valyl ester prodrug, valaciclovir (Figure 6. The H /oligopeptide transporter is also responsible for+ the oral absorption of several beta lactam antibiotics (e. Utilizing monosaccharide transporters, p-nitrophenyl-D-gluco- pyranoside and p-nitrophenyl-D-mannopyranoside-insulin have been shown to afford a hypoglycemic effect after intra-intestinal administration in rats. Penetration enhancers are widely used in drug delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral drug absorption is the non-specific nature of their effects. These include increased membrane fluidity, chelation of the calcium ions that serve to maintain the dimension of the intercellular space, solubilization of the mucosal membrane, enhancement in water flux, and reduction of the viscosity of the mucus layer adhering to the epithelial cells. A discussion of various types of pentration enhancers and their mechanism (s) of action is given in Chapter 8 (Section 8. This force compresses the flexible drug reservoir, discharging the drug through the orifice. Drug Enhancer Results Insulin Sodium glycocholate Absorption only in presence of enhancer (F 0. An important consideration here is that osmotic-controlled devices require only an osmotic pressure to be effective, thus such devices operate essentially independently of the drug formulation and also the surrounding environment. Hence, for oral delivery, changes in pH or ionic strength in the gastrointestinal tract will not affect the drug release rate. Thus, far less variability in drug release is achieved with this system, in comparison to traditional coating strategies. Relatively constant plamsa drug concentrations were achieved within 6 h and maintained for at least 24 hours (Figure 6. A two-fold improvement in cholesterol lowering efficacy was realized by using osmotic pump technology for the oral delivery of simvastatin. The colon can also be used as an absorption site for the delivery of drugs to the systemic circulation. Although absorption from the colon is generally considerably lower than from the small intestine, systemic drug delivery via the colon is associated with a number of advantages, including: • prolonged residence time, thus the drug is allowed prolonged contact with the absorbing surface; • relatively low enzyme secretion and low brush border enzyme activity, which makes it a particularly attractive site for the absorption of enzymatically labile drugs such as therapeutic peptides and proteins; • drugs absorbed from the proximal colon are delivered directly into the systemic circulation, avoiding hepatic first-pass effect. Some approaches, such as the use of sustained release formulations, enteric-coated dosage forms and osmotic pumps, were not 162 originally designed for colon-specific drug delivery. However, it is possible to increase the proportion of the drug delivered to the colon by modifying the original formulations.

If the alternative pro- uled process for all products when devi- cedure of emptying the retort is fol- ations from such specifications may af- lowed 50mg revia fast delivery, the subsequent handing methods fect the scheduled process revia 50mg with mastercard. All meas- used for the containers in the retort at urements and recordings of critical fac- the time of the temperature drop shall tors should be made at intervals not to be entered on the production records purchase revia 50mg without prescription. Each retort shall thermal processing requirements may be equipped with at least one mercury- be used before restarting the retort in-glass thermometer whose divisions reel. Alternatively, container entry to are easily readable to 1 °F and whose the retort shall be stopped and an au- thorized emergency agitating process temperature range does not exceed 17 may be used before container entry to °F per inch of graduated scale. When emer- mometers shall be tested for accuracy gency procedures are used, no con- against a known accurate standard tainers may enter the retort and the thermometer upon installation and at process and procedures used shall be least once a year thereafter, or more noted on the production records. Records of thermometer ac- specified in the scheduled process shall curacy checks which specify date, be measured and recorded on the proc- standard used, method used, and person essing record at intervals of sufficient performing the test should be main- frequency to ensure that the factors tained. Each thermometer should have are within the limits specified in the a tag, seal, or other means of identity scheduled process. The minimum that includes the date on which it was headspace of containers, if specified in last tested for accuracy. A thermom- the scheduled process, shall be meas- eter that has a divided mercury column ured and recorded at intervals of suffi- or that cannot be adjusted to the cient frequency to ensure that the standard shall be repaired or replaced headspace is as specified in the sched- before further use of the retort. The headspace of solder- mometers shall be installed where they tipped, lapseam (vent hole) cans may can be accurately and easily read. The headspace of double seamed be installed either within the retort cans may also be measured by net shell or in external wells attached to weight determinations for homogenous the retort. External wells or pipes shall liquids, taking into account the spe- be connected to the retort through at cific can end profile and other factors least a 3⁄4-inch-diameter opening, and which affect the headspace, if proof of equipped with a 1⁄16-inch or larger the accuracy of such measurements is bleeder opening so located as to pro- maintained and the procedure and re- vide a full flow of steam past the sultant headspace is in accordance length of the thermometer bulb. When the bleeder for external wells shall emit product consistency is specified in the steam continuously during the entire scheduled process, the consistency of processing period. I (4–1–10 Edition) shall be the reference instrument for additional bleeders shall be located not indicating the processing temperature. Each Bleeders may be installed at positions retort shall have an accurate tempera- other than those specified above, as ture-recording device. Graduations on long as there is evidence in the form of the temperature-recording devices heat distribution data that they ac- shall not exceed 2 °F within a range of complish adequate removal of air and 10 °F of the processing temperature. Each chart shall have a working scale In retorts having top steam inlet and of not more than 55 °F per inch within bottom venting, a bleeder shall be in- a range of 20 °F of the processing tem- stalled in the bottom of the retort to perature. All bleeders shall be adjusted to agree as nearly as pos- be arranged in a way that enables the sible with, but to be in no event higher operator to observe that they are func- than, the known accurate mercury-in- tioning properly. A means of preventing unauthor- The air in each retort shall be removed ized changes in adjustment shall be before processing is started. A lock, or a notice from man- tribution data or documentary proof agement posted at or near the record- from the manufacturer or from a com- ing device that provides a warning that petent processing authority, dem- only authorized persons are permitted onstrating that adequate venting is to make adjustments, is a satisfactory achieved, shall be kept on file. At the means for preventing unauthorized time steam is turned on, the drain changes. The recorder may be com- should be opened for a time sufficient bined with the steam controller and to remove steam condensate from the may be a recording-controlling instru- retort and provision should be made for ment. The temperature-recorder bulb containing drainage of condensate dur- shall be installed either within the re- ing the retort operation. Each temperature-recorder bulb speed of the retort shall be specified in well shall have a 1⁄16-inch or larger the schedules process. The speed shall bleeder opening emitting steam con- be adjusted, as necessary, to ensure tinuously during the processing period. The rotational speed should have adequate filter systems to as well as the process time shall be re- ensure a supply of clean, dry air. Each retort should Alternatively, a recording tachometer be equipped with a pressure gage, may be used to provide a continuous which should be graduated in divisions record of the speed. A lock, or a be equipped with an automatic steam notice from management posted at or controller to maintain the retort tem- near the speed-adjustment device that perature. This may be a recording-con- provides a warning that only author- trolling instrument when combined ized persons are permitted to make ad- with a recording thermometer. A justments, is a satisfactory means of steam controller activated by the preventing unauthorized changes. Critical factors able if it is mechanically maintained specified in the schedules process shall so that it operates satisfactorily. Bleeders, except those for essing record at intervals of sufficient thermometer wells, shall be one-eighth frequency to ensure that the factors inch or larger and shall be wide open are within the limits specified in the during the entire process, including the scheduled process. Graduations on seam (vent hole) cans may be measured the temperature-recording devices by net weight determinations. When shall not exceed 2 °F within a range of the product consistency is specified in 10 °F of the processing temperature. The temperature chart shall and recorded at intervals of sufficient be adjusted to agree as nearly as pos- frequency to ensure that the consist- sible with, but to be in no event higher ency is as specified in the scheduled than, the known accurate mercury-in- process. Minimum closing machine glass thermometer during the process vacuum in vacuum-packed products, time. A means of preventing unauthor- maximum fill-in or drained weight, ized changes in adjustment shall be minimum net weight, and percent sol- provided. A lock, or a notice from man- ids shall be as specified in the sched- agement posted at or near the record- uled process for all products for which ing device that provides a warning that deviations from such specifications only authorized persons are permitted may affect the scheduled process. All to make adjustment, is a satisfactory measurements and recordings of crit- means for preventing unauthorized ical factors should be made at intervals changes. The temperature-recorder bulb agitating retorts—(1) Indicating mercury- shall be installed either within the re- in-glass thermometer. Each retort shall tort shell or in a well attached to the be equipped with at least one mercury- shell. Air-operated temperature con- in-glass thermometer whose divisions trollers should have adequate filter are easily readable to 1 °F and whose systems to ensure a supply of clean dry temperature range does not exceed 17 air.

The increased hydrophobicity of the complex may enhance interaction with cell membranes and facilitate cell uptake discount 50mg revia free shipping. However purchase revia 50 mg fast delivery, these polymers cannot be used for in vivo application due to their poor transfection efficiency and high cytotoxicity 50 mg revia sale. The effect of colloidal and surface characteristics of plasmid/ dendrimer complexes on gene transfer has been examined. These complexes were monodisperse, with a mean hydrodynamic diameter of about 200 nm. The particle size, surface charge and gene transfer efficiency of plasmid/dendrimer complexes prepared with the 5th generation of dendrimers has been shown to be influenced by dendrimer concentration in the complexes. The colloidal and surface properties of plasmid/chitosan complexes have been shown to depend on the molecular weight of chitosan, the ratio of plasmid to chitosan and the preparation medium. Smaller nanoparticles have been observed with low molecular weight chitosan (2 kDa) as compared to high molecular weight chitosan (540 kDa). Interestingly, the transfection efficiency of the complexes was not affected by the presence of serum proteins, even though the presence of serum is known to adversely affect the transfection efficiency. The blood capillary walls are comprised of four layers, namely plasma-endothelial interface, endothelium, basal lamina, and adventia. Macromolecules can cross the endothelial barrier: • through the cytoplasm of endothelial cells themselves; • across the endothelial cell membrane vesicles; • through inter-endothelial cell junctions; • through endothelial cell fenestrae. Based on the morphology and continuity of the endothelial layer, capillary endothelium can be divided into three categories: continuous, fenestrated, and discontinuous endothelium (see Section 5. The continuous capillaries are found in skeletal, cardiac, and smooth muscles, as well as in lung, skin, subcutaneous and mucous membranes. The endothelial layer of brain microvasculature is the tightest endothelium, with no fenestrations. Capillaries with fenestrated endothelia and a continuous basement membrane are generally found in the kidney, small intestine and salivary glands. Most of these capillaries have diaphragmed fenestrae, which are circular openings of 40–60 nm in diameter. The discontinuous capillaries, also known as sinusoidal capillaries, are common in the liver, spleen, and bone marrow. These capillaries show large interendothelial junctions (fenestrations up to 150 nm). Highly phagocytic Kupffer cells line the sinusoids of the liver, and those of the bone marrow by flattened, phagocytic reticuloendothelial cells. In the spleen, the endothelial cells contain a large number of pinocytic vesicles (up to 100 nm in diameter). Due to their large molecular weight (> 1,000 kDa) and hydrodynamic diameter in aqueous suspension of 100 nm, plasmids extravasate poorly via continuous capillaries because of tight junctions between the cells. However, plasmids can easily extravasate to sinusoidal capillaries of liver and spleen. Formulating plasmids into unimeric particles of 20–40 nm in diameter may enhance extravasation of plasmids across continuous and fenestrated capillaries. The (patho)physiology and microanatomy of tumors is significantly different from normal tissues (see Section 5. A tumor contains vessels recruited from the pre-existing network and vessels resulting from angiogenic response induced by cancer cells. There is a considerable variation in the cellular composition, basement membranes and in the size of the interendothelial cell fenestrations. Tumor interstitium is characterized by large interstitial volume and high diffusion rate. Sven Frøkjaer, Lona Christrup and Povl Krogsgaard-Larsen; Munksgaard, Copenhagen, 1998, pp. Tumor accumulation of plasmid could result from the enhanced permeability of the tumor vasculature, combined with their reduced clearance from the tumor due to the absence of the lymphatic system. Pharmacokinetic analysis of in vivo disposition profiles of radiolabeled plasmid provides useful information on the overall distribution characteristics of systemically administered plasmids, with one critical limitation. The plasma half-life of plasmid is less than 10 min, and hence tissue distribution and pharmacokinetic parameters of plasmid calculated on the basis of total radioactivity are not valid at longer time points. Thus, polymerase chain reaction and Southern-blot analysis are required to establish the time at which the radiolabel is no longer an index of plasmid distribution. The deposition of plasmids after systemic administration is restricted to the intravascular space due to its low microvascular permeability in most organs with continuous capillary bed. Some organs with fenestrated capillaries, such as liver, spleen, and bone marrow, provide some opportunities for extravasation of plasmids. Intravenously injected plasmids initially perfuse the pulmonary vascular beds, maximizing the 347 Figure 14. Reproduced with permission from: Biodistribution and gene expression of plasmid/lipid complexes after systemic administeration, Mahato R. Southern-blot analysis of blood showed the rapid degradation of plasmid, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. By Southern-blot analysis, there was no detectable plasmid in the brain, large intestine, small intestine, or gonads at the 1-hr timepoint. Southern blot analysis also demonstrated that plasmid remained in the liver, spleen, lung, marrow, and muscle, although at diminished levels, up to 24 hr postinjection. The plasma membrane is the next obstacle to be overcome in delivering genes into a cell.

However order revia 50mg online, one should recall that a hydrophilic drug also tends to have higher clearance than a lipophilic drug cheap revia 50mg line, which has higher membrane permeability (Section 8 generic revia 50mg overnight delivery. Of course, the choice of salt form for ionized compounds would affect the extent of solubilization. It should be noted that the water solubility factor has already been taken into account by the distribution coeffcient, because water solubility correlates well with log D6. Moreover, one should not forget that from a very simplistic viewpoint, the word “hydrophilic” suggests that the compound would “love to be in water. A way of improving water solubility in a peptide drug is to introduce a water solubilization moiety. Phospholipids are a major component of cell membranes by forming a lipid bilayer within the membrane. Generally speaking, phospholipids have an amphipathic character where the “head” of the molecule is a hydrophilic phos- phate group, while the “tail” is lipophilic. Much like a phospholipid, the structure of amprenavir can be considered as the lipophilic “tail” and the phosphate group as the hydrophilic “head. Consequently, fosamprenavir is a slow-release version of amprenavir that reduces the “pill burden” of the standard regimen of amprenavir. It is noteworthy that plasma protein binding for fosampre- navir is still theoretically 90% because conversion to the parent drug, amprenavir, is needed before reaching the bloodstream. The depicted spacer demonstrated an improvement in water solubility from less than 0. Different spacers would produce different prodrugs with different water solubility and conversion time values. This means that the water solubility and conversion time of the prodrug can be controlled by the structural features of the spacer. In the exemplifed cleaner strategy that does not require a spacer, water solubility was 13 mg/mL with a conversion half-life of less than 1 min. Thus, we have shown that prodrugs of drugs with little water solubility could exhibit much improved water solubility profles and modifable conversion time. Lipinski’s rule attempts to associate the drug’s susceptibility to metabolic reactions with its ability to form hydrogen bonds. A hydrogen atom attached to a relatively electronegative atom is a hydrogen bond donor. An electronegative atom is a hydrogen bond acceptor, regard- less of whether it is bonded to a hydrogen atom or not. Drugs with a high hydrogen-bond potential have a higher risk of undergoing acid–base reactions or reactions that are catalyzed by enzymes. These reactions often change the chemical structure of the drug, thereby deactivating the drug and increase the hydrophilicity of the drug thus facilitating clearance of the drug from the body. In contrast to Lipinski’s oversimplifed rule on hydrogen bond acceptors and donors, several structural characteristics, that is, chemical functional groups have been strongly correlated with oral bioavailability. Certain functional groups are more susceptible to transformations in the gut wall, liver, or conjugated in several ways. For a functional group, the signifcance in reducing bioavailability is related to the metabolic reactivity of the function. Structural functions that can undergo metabolic reactions have been parameterized into quantitative structure–activity relationship equations to predict oral bioavailability [13]. One should note that functionally reactive groups and hydrogen bond potential contribute to hydrophilicity. Readily oxidized entities, thiols and dihydropyridines, have the most pronounced effect on oral bioavailability. The reactions are rapid and produce hydrophilic metabo- lites that are readily cleared from the body. Peptide drugs containing thiol containing amino acid cysteine are often promptly deactivated. The formation of a glucuronide metabolite is an example of a sugar-conjugated phenol group. Functional groups that are known to easily undergo hydrolysis include esters, lactones, β-lactams, and alkyl carbamates. Metabolic carbon oxidative processes play a signifcant role in reducing bioavail- ability, where para-hydroxylation of an activated aromatic ring has the largest effect, followed by aryl methyl and allylic groups contributing to a lesser extent. Reduc- tion of ketones may contribute to the same extent as aromatic para-hydroxylation on decreasing bioavailability. As examples, amino acids serine and threonine each possesses an alcoholic hydroxy group. However, certain compounds, such as lidocaine and ketamine, may undergo rapid dealkylation. The reactivity of aromatic and heterocyclic amines, hydrazines, hydrazones, and amidines to metabolic acetylation and oxidation seems to be proportional to their pKa values. In other words, their signifcance in metabolic deactivation is related to their pKa values. Issues with metabolic transformations and conjugations can be addressed by further improving on the structure of the peptide drug. To further greatly reduce the risk of glucuronidation at the P2 position, the P2 phenol moiety was replaced by a 3-amino-2-chlorobenzoate moiety. It was also found that a slight bulk increase by a ′ P2 2,6-dimethylbenzyl moiety could improve stability against glucuronidation.