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For example : the rate of dissolution of the drug in tablet or a capsule in the gastrointestinal fluids purchase kamagra gold 100 mg with visa erectile dysfunction doctors in toms river nj. Clinical Efficacy of Drugs Medical scientists mainly rely on the measurement of bioavailability of a drug as a positive indicator of therapeutic equivalence kamagra gold 100mg line impotence husband, because clinical efficacy for orally administered drugs depends on the degree of absorption and the presence of the active ingredient in the blood stream kamagra gold 100 mg mastercard erectile dysfunction vacuum pump india. Technical information based on in vivo standards and specifications are generally incorporated in vari- ous official compendia. Hence, in order to record a legitimate assessment of bioavailability, in vivo test is an absolute necessity and the relative data obtained therefrom should form an integral part of the standard specifi- cations in the offcial standard. Hence, a regular feed back of relevant informa- tion on such adverse reactions from the medical practitioners to the appropriate regulatory authorities and the concerned manufacturers would not only help to intensify better safety measures but also widen the scope to improve drug-design by meticulous research scientists all over the world. They are : Example 1 : Aspirin—Increased gastric damage and subsequent bleeding caused by some aspirin fomulations have been specifically attributed to the slowly dissolving aspirin particles in the stomach. However, both effervescent and highly buffered dosage forms (antacid-aspirin-tablet), which help in maintaining the aspirin in solution, have been found to minimise gastro-intestinal toxicity. The physical constants essentially include the melting point, boiling point, refractive index, weight per millilitre, specific optical rotation, light absorption, viscosity, specific surface area, swelling power, infra-red absorption, and the like. However, the most specific and reliable are the chemical tests which may be categorized separately under tests for inorganic substances and organic substances. The former may be carried out by well defined general quantitative inorganic analysis and the latter by specific reactions of one or more of the functional moieties present in a drug molecule. These physical constants will be discussed briefly with typical examples as under : 1. Melting Point It is an important criterion to know the purity of a substance ; however, it has a few limitations. The accuracy and precision of melting point is dependent on a number of factors such as—capillary size, sample size, initial temperature of heating-block and the rate of rise of temperature per unit time (minutes). Keeping in view the different manufacturing processes available for a particular drug the melting point has a definite range usually known as the melting range. Mestranol 146 154 Thus the melting range takes care of the variance in manufacture together with the storage variance over a stipulated period of time. Boiling Point It is also an important parameter that establishes the purity of a substance. Depending on the various routes of synthesis available for a substance a boiling point range is usually given in different official compendia. Refractive Index It is invariably used as a standard for liquids belonging to the category of fixed oils and synthetic chemicals. Weight Per Millilitre Weight per millilitre is prevalent in the Pharmacopoeia of India for the control of liquid substances, whereas Relative Density (20°/20°) or Specific Gravity is mostly employed in the European Pharmacopoeia. Specific Optical Rotation As pharmacological activity is intimately related to molecular configuration, hence determination of specific rotation of pharmaceutical substances offer a vital means of ensuring their optical purity. Morphine Hydrochloride – 112° – 115° Calculated with reference to the dried substance in a 2% w/v soln. Light Absorption The measurement of light absorption both in the visible and ultraviolet range is employed as an authentic means of identification of offcial pharmaceutical substances. Viscosity Viscosity measurements are employed as a method of identifing different grades of liquids. Specific Surface Area The surface area of powders is determined by subsieve-sizer which is designed for measurement of average particle sizes in the range of 0. Swelling Power The swelling power of some pharmaceutical products are well defined. Examples : (i) Isphagula Husk : When 1 g, agitated gently and occasionally for four hours in a 25 ml stoppered measuring cylinder filled upto the 20 ml mark with water and allowed to stand for 1 hour, it occupies a volume of not less than 20 ml and sets to a jelly. Infrared Absorption Measurement and subsequent comparison of the infrared spectrum (between 4000-667 cm–1) of compounds with that of an authentic sample has recently become a versatile method for the identification of drugs having widely varying characteristics. Examples : Infrared spectroscopy is employed to compare samples of chloramphenicol palmitate (biologically active form) recovered from chloramphenicol palmitate mixture vis-a-vis an artificially prepared mixture of authentic sample consisting 10 per cent of the ‘inactive polymorph’. Miscellaneous Characteristics A large number of miscellaneous characteristics are usually included in many official compendia to ascertain the purity, authenticity and identification of drugs—including : sulphated ash, loss on drying, clarity and colour of solution, presence of heavy metals and specific tests. Sulphated Ash Specifically for the synthetic organic compounds, the Pharmacopoeia prescribes values for sulphated ash. The sulphated ash is determined by a double ignition with concentrated sulphuric acid. The method is one of some precision, and provides results which are rather more reproducible than those obtained by simple ignition. Loss on Drying Loss on drying reflects the net weight of a pharmaceutical substance being dried at a specified tempera- ture either at an atmospheric or under reduced pressure for a stipulated duration with a specific quantity of the substance. Clarity and Colour of Solution When a pharmaceutical substance is made to dissolve at a known concentration in a specified solvent it gives rise to a clear solution that may be either clear or possess a definite colouration. Heavy Metals Various tests are prescribed in the offcial compendia to control heavy metal e. Hence, a stringent limit is recommended for the presence of heavy metals in medicinal compounds. Specific Tests In fact, certain known impurities are present in a number of pharmaceutical substances. The presence of such impurities may be carried out by performing prescribed specific tests in various official compendia in order to ascertain their presence within the stipulated limits. Obviously the amount of any single impurity present in an official substance is usually small, and therefore, the normal visible-reaction-response to any test for that impurity is also quite small. Hence, it is necessary and important to design the individual test in such a manner so as to avoid possible errors in the hands of various analysts. It may be achieved by taking into consideration the following three cardinal factors, namely : (a) Specificity of the Tests : A test employed as a limit test should imply some sort of selective reaction with the trace impurity. It has been observed that a less specific test which limits a number of possible impurities rather instantly has a positive edge over the highly specific tests. Exmaple : Contamination of Pb2+ and other heavy metal impurities in Alum is precipitated by thioacetamide as their respective sulphides at pH 3. The sensitivity is governed by a number of variable factors having a common objective to yield reproducible results, for instance : (i) Gravimetric Analysis : The precipitation is guided by the concentration of the solute and of the precipitating reagent, reaction time, reaction temperature and the nature and amount of other substance(s) present in solution. A number of such tests shall be discussed here briefly with specific examples wherever possible and necessary : 1. Limits of Insoluble Matter The limits of insoluble matter present in pharmaceutical substances and stated in various official com- pendia are given below : S. Boric Acid Alcohol insoluble substances Absence of metallic borates and insoluble impurities 2. Chloramine Alcohol-insoluble matter : Sodium chloride impurity : Shake 1 g for 30 mts.
In brief buy 100mg kamagra gold overnight delivery erectile dysfunction information, the monomer was added under stirring to the polymerization medium in which an amount of enzyme was added effective kamagra gold 100mg impotence webmd. In the double-emulsion method 100mg kamagra gold with visa erectile dysfunction doctor in atlanta, enzymes in the aqueous solvent were emulsiﬁed with nonmiscible organic solution of the polymer to form a w/o emulsion. The organic solvent dichloromethane was mainly used and the homogenization step was carried out by using either high-speed homogenizers or sonicators. A homogenization step or intensive stirring is necessary to form a double emulsion of w/o/w. Then, the removal of organic solvent by heating and vacuum evaporation is done by either extracting organic solvent or adding a nonsolvent (i. The ﬁrst process is designated as w/o/w, whereas the second is known as the phase-separation technique. In the spray-drying technique, parti- cle formation is achieved by atomizing the emulsion into a stream of hot air under vigorous solvent evaporation. Enzymes encapsulated into nanoparticles by w/o or w/o/w techniques are susceptible to denaturation, aggregation, oxidation, and cleavage, especially at the aqueous phase–solvent interface. Improved enzymatic activity has been achieved by the addition of stabilizers such as carrier proteins (e. The nanospheres obtained could continuously release the enzyme while preserving the enzymatic activity (74). These results were attributed to a favorable interaction of the enzyme with this speciﬁc copolymer (74,75). Transdermal drug delivery has been approved and has become widely accepted for the systemic administration of drugs. This noninvasive approach avoids the hepatic “ﬁrst-pass” metabolism, maintains a steady drug concentration (extremely important both in the case of drugs with a short half-life and in the case of chronic therapy), allows the use of drugs with a low therapeutic index, and improves patient compliance. For charged and polar molecules or macro- molecules, skin delivery is difﬁcult and has advanced substantially within the last few years. To facilitate the delivery of such entities, a number of strategies were developed. In recent years, specially designed carriers have claimed the ability to cross the skin intact and deliver the loaded drugs into the systemic circulation, being at the same time responsible for the percutaneous absorption of the drug within the skin. Transfersomes are composed of highly ﬂexible membranes obtained by combining into single-structure phospho- lipids (which give structure and stability to the bilayers) and an edge-active compo- nent (to increase the bilayer ﬂexibility) that gives them the capacity to move spon- taneously against water concentration gradient in the skin. It has now been proven that intact Transfersomes, in contrast to liposomes, penetrate the skin without dis- ruption (77). These carriers comprise at least phosphatidylcholine and an edge- active molecule acting as membrane softener. In structural terms, Transfersomes are related to liposomes and many of the techniques for their preparation and characterization are com- mon. For Transfersomes, a properly deﬁned composition is responsible for mem- brane ﬂexibility and consequently for vesicle deformability necessary for through- the-skin passagework. Transfersomes are much more ﬂexible and deformable than liposomes, which are assessed by using membrane penetration assays (78). Among the many drugs that can be incorporated in Transfersomes (79,80), including polypeptides and proteins (81–85), enzymes were also reported to be transferred into the body through the skin after incorporation in these systems. In vitro pen- etrability of deformable vesicles was characterized and was not affected by the incorporation of the studied enzymes (78). Successful enzyme incorporation was obtained by using other membrane-softening agents such as Tween 80, without compromising the vesicles deformability (87). This study on transdermal transport of antioxidant enzymes contributed to an innovative approach in the ﬁeld of the protein transdermal delivery (6). Ethosomes are a special kind of unusually deformable vesicles in which the abundant ethanol makes lipid bilayers very ﬂuid, and thus by inference soft (89). This reportedly improves the delivery of various molecules into deep skin layers (90). No reports on transdermal or dermal region-speciﬁc delivery of enzymes mediated by ethosomes are available to date. Other so-called “elastic vesicles” were found to be responsible for major mor- phological changes in the intercellular lipid bilayer structure in comparison with rigid vesicles (91). No results on the transdermal delivery of enzymes by using these systems were reported. This study is one of the few reporting topical application of enzymes, while using nondeformable liposomes. Although proteins in general and enzymes in particular are relatively new as therapeutic agents, it is envisaged that they will play an important role in the bat- tery of nonconventional formulations of this millennium. Liposomal superoxide dismutases and their use in the treatment of experimental arthritis. Therapeutic efﬁcacy of liposomal rifabutin in a Mycobacterium avium model of infection. Accelerated thrombolysis in a rabbit model of carotid artery thrombosis with liposome-encapsulated and microencapsulated streptok- inase. Protective effect of liposome-entrapped superoxide dismutase and cata- lase on bleomycin-induced lung injury in rats; part I: Antioxidant enzyme activities and lipid peroxidation. Superoxide dismutase entrapped in long- circulating liposomes: Formulation design and therapeutic activity in rat adjuvant arthri- tis. Liposomal formulations of Cu,Zn-superoxide dismutase: Physicochemical characterization and activity assessment in an inﬂammation model. Encapsulation of macromolecules by lipid vesicles under simulated prebiotic conditions. Characterization of bioconjugates of l-asparaginase and Cu,Zn-superoxide dismutase. Proceedings of the Third European Symposium on Con- trolled Drug Delivery; University of Twente, Noodwijk aan Zee, The Netherlands; April 6–8, 1994. Design and characterization of enzymo- somes with surface-exposed superoxide dismutase. Liposomes as carrier systems for proteins: Fac- tors affecting protein encapsulation. The use of French pressed vesicles for efﬁcient incorporation of bioactive macromolecules and as drug carriers in vitro and in vivo. Method for producing solid lipid microspheres having a narrow size distri- bution. Preparation of submicron drug particles in lecithin-stabilized o/w emulsions; part 1: Model studies of the precipitation of cholesteryl acetate. Preparation of solid lipid nanoparticles by a solvent emulsiﬁcation-diffusion technique.
The second part of the curve will be very similar to the first curve but will be higher (have a greater concentration) because some drug remains from the first dose when the second dose is administered buy kamagra gold 100mg line doctor yourself erectile dysfunction. The only difference is that the actual concentrations may be higher at later doses buy 100 mg kamagra gold overnight delivery erectile dysfunction medicine list, because drug has accumulated kamagra gold 100 mg low cost erectile dysfunction 30. Because Ct = C0e at any time (t) after the first dose, it follows that: -Kτ Cmin1 = Cmax1e where Cmin1 is the concentration just before the next dose is given and τ, the dosing interval, is the time from Cmax to Cmin. The plasma drug concentration versus time profile reveals a further increase in the maximum concentration immediately after the third dose, as shown in Figure 4-4. Just as after the first dose: -Kτ Cmin2 = Cmax2e -Kτ -Kτ which, by substitution for Cmax2, equals Cmax1(1 + e )e. Moreover: Cmax3 = Cmin2 + Cmax1 -Kτ -Kτ which, substituting for Cmin2, equals Cmax1(1 + e )e + Cmax1. This simplifies as follows: -Kτ -Kτ Cmax3 = Cmax1[(1 + e )(e ) + 1] -Kτ -2Kτ = Cmax1[e + e + 1] -Kτ 2Kτ = Cmax1[1 + e + e ] As we can see, a pattern emergesafter any number of dosing intervals, the maximum concentration will be: -Kτ -2Kτ -(n-1)Kτ Cmaxn = Cmax1[1 + e + e +. This equation can be simplified by mathematical procedures to a more useful form: where Cmaxn is the concentration just after n number of doses are given. So, if we know Cmax1, the elimination rate, and the dosing interval, we can predict the maximum plasma concentration after any number (n) of doses. It is called the accumulation factor because it relates drug concentration after a single dose to drug concentration after n doses with multiple dosing. This factor is a number greater than 1, which indicates how much higher the concentration will be after n doses compared with the first dose For example, if -1 100 doses of a certain drug are given to a patient, where K = 0. The accumulation factor for two or three doses can also be calculated to predict concentrations before achievement of steady-state. The concept of accumulation factor is discussed in more detail in the section Accumulation Factor later in this lesson. These equations will be used later to predict drug concentrations for given dosage regimens. Clinical Correlate If a drug has a very short half-life (much less than the dosing interval) then the plasma concentrations resulting from each dose will be the same and accumulation of drug will not occur (as shown in Figure 4-5). An example would be a drug such as gentamicin given every 8 hr intravenously to a patient whose excellent renal function results in a drug half-life of 1. With first-order elimination, the amount of drug eliminated per unit of time is proportional to the amount of drug in the body. Accumulation continues until the rate of elimination approaches the rate of administration: rate of drug going in = rate of drug going out As the rate of drug elimination increases and then approaches that of drug administration, the maximum (peak) and minimum (trough) concentrations increase until an equilibrium is reached. After that point, there will be no additional accumulation; the maximum and minimum concentrations will remain constant with each subsequent dose of drug (Figure 4-6). When this equilibrium occurs, the maximum (and minimum) drug concentrations are the same for each additional dose given (assuming the same dose and dosing interval are used). When the maximum (and minimum) drug concentrations for successive doses are the same, the amount of drug eliminated over the dosing interval (rate out) equals the dose administered (rate in) and the condition of "steady state" is reached. Steady state will always be reached after repeated drug administration at the same dosing interval if the drug follows first-order elimination. However, the time required to reach steady state varies from drug to drug, depending on the elimination rate constant. With a higher elimination rate constant (a shorter half-life), steady state is reached sooner than with a lower one (a longer half-life) (Figure 4-7). Steady state is the point at which the amount of drug administered over a dosing interval equals the amount of drug being eliminated over that same period and is totally dependent on the elimination rate constant. Therefore, when the elimination rate is higher, a greater amount of drug is eliminated over a given time interval; it then takes a shorter time for the amount of drug eliminated and the amount of drug administered to become equivalent (and, therefore, achieve steady state). If the half- life of a drug is known, the time to reach steady state can be determined. If repeated doses of drug are given at a fixed interval, then in one half-life the plasma concentrations will reach 50% of those at steady state. By the end of the second half-life, the concentrations will be 75% of steady state, and so on as shown in Table 4-1. For all practical purposes, steady state will be reached after approximately four or five half-lives; the concentrations at steady state may be abbreviated as Css. For a drug such as gentamicin, with a 1- to 4-hour half-life in patients with normal renal function, steady-state concentration is achieved within 10-20 hours. For agents such as digoxin and phenobarbital, however, a week or longer may be needed to reach steady state. With multiple drug doses (Figure 4-8), steady state is reached when the drug from the first dose is almost entirely eliminated from the body. At this point, the amount of drug remaining from the first dose does not contribute significantly to the total amount of drug in the body. After a single dose, approximately four or five half-lives are required for the body to eliminate the amount of drug equivalent to the one dose. However, at steady state, the amount of drug equivalent to one dose is eliminated over one dosing interval. This apparently faster elimination is a result of accumulation of drug in the body. Although the same percentage of drug is eliminated per hour, the greater amount of drug in the body at steady state causes a greater amount to be eliminated over the same time period. The average times to reach steady-state for some commonly used drugs are shown in Table 4-2. These values may vary considerably between individuals and may be altered by disease. However, administration of a loading dose for drugs that take many hours to reach steady state is commonly used to achieve a concentration approximately equal to the eventual actual steady-state concentration. When equivalent doses are given, a drug with a low elimination rate constant and small volume of distribution should achieve higher steady-state plasma concentrations than an otherwise similar agent with a high elimination rate constant and large volume of distribution. Steady-state concentrations are commonly increased in two ways: • Method 1 Increase the drug dose but maintain the same dosing interval (τ), as shown in Figure 4-9, which results in wider fluctuations between the maximum (peak) and minimum (trough) concentrations after each dose. For example, the patient is not receiving maximal benefits because the steady-state concentrations are relatively low or the steady- state levels are high, causing the patient to experience toxic effects. Remember from earlier in this lesson that repeated doses of drug require approximately four or five half-lives to reach steady state. Clinically, this means that each time a dose or dosing interval is changed, four or five half-lives are needed to reach a new steady state. Of course, a drug with a long half-life will require a longer time to achieve the new steady state than a drug with a relatively short half-life. For example, Drug A has a half-life of 6 hours therefore if the dose or dosing interval is changed, steady state will not be reached for 24-30 hours after the change.
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