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N. Marcus, M.B.A., M.B.B.S., M.H.S.
Clinical Director, Campbell University School of Osteopathic Medicine
Physicochemistry of Skin Permeation There are three basic steps in the process of percutaneous absorption women's gynecological health issues effective aygestin 5 mg, and the first two of these are governed by the physicochemical properties of the permeating molecule womens health kettlebell order 5mg aygestin overnight delivery. Initially the permeant has to escape from the vehicle and penetrate into the stratum corneum (step 1) women's health diet plan aygestin 5 mg online. Diffusion across the stratum corneum (step 2) is related to binding characteristics and women's health clinic edmonton hours order aygestin 5mg free shipping, to a lesser extent, molecular size of the diffusing molecule. On the other hand, clearance from the epidermis/dermis (step 3) is governed mainly by physiological factors, such as blood flow. The most important factor in step 1 is the ability to partition from the application vehicle into the intercellular lipid lamellae of the stratum corneum. The partition coefficient (K) of a drug between the skin and vehicle can be written as Csc =Cv, where Cv is the concentration of drug in the vehicle. The amount absorbed (Q) may be expressed in terms of the area of application and the exposure time (T). Equation 3 is based on steady-state conditions and assumes that there is no appreciable accumulation of the drug on the distal side of the barrier, or depletion of the drug on the application side. These include the fact that the amount of a drug absorbed will depend on the area of application, the concentration applied, the duration of application, and the permeability coefficient, which, as shown above, is defined by the physicochemical properties of the solute and the vehicle. Permeability Coefficients and Diffusivity To understand more fully the role of the structure of the drug and the nature of the applied vehicle on the amount of drug absorbed through the skin, the steady-state flux Js of the drug across the stratum corneum barrier may be deconvoluted into its fundamental components of 480 Walters and Brain drug diffusivity (D), the path length for diffusion (h), and the concentrations of drug immediately below the outside Csc(o) and the inside Csc(i) of the stratum corneum. In theory, drug transport could go via a polar pathway, with a permeability coefficient kp;polar0 as well as through the intercellular lipid pathway, with a permeability coefficient kp;lipid0, although the existence and possible magnitude of a polar pathway remains controversial. The observation that the maximum flux is related to Ssc suggests that a drug substantially more polar or lipophilic than stratum corneum will have a lower maximal flux than a drug with a polarity in the vicinity of octanol. However, it should be noted that the above analysis is confined to data generated for a limited number of compounds, which had similar hydrogen-bonding (H-bonding) capacity and molecular size. Figure 2 Skin flux, absorption or pharmacodynamic activity as a function of permeant lipophilicity. It is likely that, for most lipophilic drugs, an epidermal reservoir will exist after application because there is a substantial lag time as the drug diffuses through the skin (equation 1) and/or the epidermis and dermis do not act as efficient sinks. Historical evidence of reservoir formation is illustrated by the work of Vickers (1963) in which steroid-induced vasoconstriction was observed on occlusion of a previously treated area of skin two weeks following a single topical application of the drug. Furthermore, the permeability coefficients for a series of phenols, alcohols, and steroids were found to be inversely related to the number of H-bonding groups present (Roberts, 1976). It has been shown that, after allowing for molecular size and partitioning into the stratum corneum, the permeability coefficient is related to the number of H-bonding groups in the permeant. The complexity and selectivity of the processes, which may be determinants of permeation, is well illustrated by the demonstration of significantly differential permeation of isomeric drugs. The mechanisms and significance of this selectivity have been reviewed (Heard and Brain, 1995). Vehicle (Formulation) Thermodynamic Effects the flux of a drug through the skin is dependent not only on the physicochemical nature of the permeant but also on the nature of the formulation and the vehicle composition. A formulation may alter the properties of the skin, and hence enhance or retard the permeation of a drug by increasing or decreasing its diffusivity and/or solubility within the stratum corneum. In the theoretical analysis above, most emphasis was placed on the description of drug absorption from dilute aqueous solution. The historical data, shown in Figure 3, illustrate that, whereas the permeability coefficient of alcohols increased with chain length from an aqueous vehicle, the permeability coefficient decreased with chain length when applied in lipophilic vehicles (olive oil and isopropyl palmitate). Similarly, the permeability coefficients for a number of phenolic compounds were reported to increase with lipophilicity for aqueous solutions but decrease with increasing lipophilicity for ethanol and arachis (peanut) oil formulations (Roberts, 1991). Figure 3 Effect of application vehicle on alcohol [expressed in terms of number of carbons present] permeability coefficients through human skin. Topical and Transdermal Delivery 483 Maximal flux was traditionally derived from saturated solutions. However, it is now known that an even higher flux can be achieved using supersaturated solutions (Davis and Hadgraft, 1993).
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Sueding A sueder is sometimes referred to a s a sander since the machine consists of one or more rolls covered with sand paper a s the abrasive womens health weekly generic aygestin 5mg fast delivery. The hand will depend on the fiber composition women's health center queens hospital aygestin 5mg amex, the filament count in the yarn and the intensity with which the fabric is worked pregnancy symptoms at 3 weeks order aygestin 5mg visa. Filament fabrics can be made to feel like a spun fabric and generally speaking women's health center in grand rapids mi aygestin 5mg generic, all fabrics will have a softer hand. Multi-Cylinder Sueders There are two basic categories of sueders, multi-cylinder and single cylinder machines. The multi-cylinder machine usually h a s five rotating cylinders, each independently driven and they can be rotated clockwise or counter clockwise. Some are abrasive covered rolls either free standing or as tubes mounted around the 232 periphery of a rotating cylinder shaft. Others are fluted cylindrical rolls with the high portions of the flutes covered with abrasive. Ahead a n d behind each cylinder are adjustable idle rolls which control the pressure of the fabric to a greater or lesser degree against the abrasive cylinder. Entry and exit drive rolls transport and control the fabric tension a s it progresses through the machine. Single Cylinder Sueder the single-cylinder sueder has one abrasive covered metallic roll and one rubber covered pressure roll. The pressure roll presses the fabric against the abrasive cylinder and is micrometer adjustable. The abrasion of the fibers on the surface of the fabric takes place in the nip between the pressure roll a n d the abrasive cylinder. Abrasive Covered Rolls the quality of the nap will depend on the fabric construction and selection of abrasive grit. Fabric construction will determine the abrasive grit size, the wrong grit may over sand the fabric and either weaken woven fabrics or perforate knit fabrics. Since the abrasive material deteriorates with use, it must be changed on a regular basis to guarantee a uniform suede throughout a production run. Advantages and Disadvantages Both machine designs perform very well and produce very acceptable products. Knot holes or over-sanded selvages may occur on the single cylinder machine because the fabric is compressed against the abrasive cylinder. A single roll sueder is more effective on fabrics with terry loops on the face t h a t must be broken. Also difficult styles that require shaving the face to develop a surface effect are more effectively and more efficiently sanded on a single cylinder machine. Some fabrics tend t o develop a directional pile when sanded on a single cylinder machine. The multi-roll machine may be operated with the cylinders rotating in opposing directions eliminating this effect. Napping Nappers also change the aesthetics of fabrics by developing a pile on the surface of the fabric. The depth of pile developed on a napper can be much greater than can be obtained by sueding, assuming the fabric construction is correct. For example fleeces, velours, high-pile fur-like effects, flannels and bed blanket finishes are produced by napping. It is important t h a t the yarns acted on by the napper are not the ones responsible for the strength and integrity of the fabric. Fabric to be napped should have a napping lubricant or softener applied prior to napping t o allow the fibers in the yarn t o slide more freely during the napping operation. Nappers Wire nappers, known as planetary nappers, a r e the most commonly used machines in the industry. The basic design of a wire napper is 24 to 36 small, pile wire clad rolls (worker rolls) mounted on the periphery of a large main cylinder. The large napper cylinder rotates in the same direction a s the flow of the fabric at a constant speed while the worker rolls rotate on their own axis in a direction opposite to the rotation of the main cylinder. Cleaning rolls or brushes below the main cylinder remove lint and entangled pile to keep the wires at high efficiency. The speed of the worker rolls, the type of wire, the angled direction of the wire all influence the degree of nap.
Concentration gradient: the greater the difference between the concentrations on the two sides of the membrane women's health clinic okc cheap aygestin 5mg overnight delivery, the faster the rate of diffusion menstruation krampfe purchase aygestin 5mg otc. Size of molecule: Smaller molecules tend to travel further before colliding with other molecules women's health center greenville nc generic 5 mg aygestin with mastercard, so diffusion rates are faster for smaller molecules pregnancy xx massage aygestin 5 mg amex. Viscosity of the medium: the viscosity is a measure of the "thickness" of the solvent. Membrane permeability: Since we are talking about movement of solutes into and out of the cell, the permeability of the membrane to the solute will affect how fast solutes diffuse across the cell membrane. For example, ions and other charged molecules that are hydrophilic do not readily cross the membrane due to the hydrophobic core of the bilayer. Conversely, oxygen and carbon dioxide, both nonpolar molecules, can readily diffuse through the membrane. Surface area: the greater the surface area of the membrane, the faster the rate of diffusion across the membrane. Areas in our bodies, where diffusion is especially important, typically employ structural modifications that increase the available surface area. For example, in the lungs, the hundreds of millions of small alveoli have a total surface area of nearly 70 square meters for gas exchange! Distance: Diffusion is quite rapid over short distances but gets slower the further it goes. The time it takes for something to diffuse is proportional to the square of the distance. Therefore, if it takes 1 second to diffuse 1 cm, it would take 100 seconds to diffuse 10 cm, and 10,000 seconds to diffuse 100 cm. In the body, diffusion is quite sufficient to cross the thin cell membrane, but to travel long distances by diffusion would be very slow. This is why we have other mechanisms like the blood circulation for moving substances long distances. Molecules that are large, or that have an electrical charge, generally are prevented from moving through the membrane. Recall that embedded in the cell 102 membrane are several types of proteins that pass completely through the membrane, the integral membrane proteins. There are a number of specialized integral proteins what assist in the diffusion of solutes across the membrane. These channel proteins resemble fluid filled tubes through which the solutes can move down their concentration gradients across the membrane. These channels are often responsible for assisting ions such as Na+, K+, Ca2+ and Cl-cross the membranes. Even though they are open tubes, they are often very specific for the ions that pass through them. Also, as we shall learn later, the regulation of the movement of the various ions across the membranes is crucial for many important cellular functions. These channels, therefore, are often gated (they have doors or gates that can be opened or closed). Depending on the channel, these gates may respond to voltage difference across the membrane (voltage-gated channels), specific signal molecules (ligand-gated channels), or even stretching or compressing the membrane (mechanically-gated channels). The second type of facilitated diffusion utilizes carrier proteins in the membrane. Unlike the channel proteins, these carriers do not open to both sides of the membrane simultaneously. This binding causes the carrier to change shape, which moves the solute to the other side of the membrane (think of a revolving door). Like the channel proteins, these carriers can be very specific for the solute they transport, since the solute must bind to a receptor site that is designed to fit the specific solute. Another interesting characteristic of these carriers is that they have a maximum rate of transport and can thus become saturated if the solute concentration is high enough. As mentioned above, one of the characteristics of carrier proteins is that they can become saturated.
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There have been modifications to the original test women's health clinic on wright street aygestin 5 mg with amex, but they all involve instilling a drop of the formulation into the conjunctival sac of one eye of an albino rabbit womens health personal trainer aygestin 5mg lowest price, the other eye acting as a control menstrual 3 weeks generic 5mg aygestin with visa. The condition of both eyes is then evaluated after stipulated time periods and scored relative to the control eye menopause symptoms treatment order aygestin 5 mg without prescription. A high score indicates that the formulation is likely to be an irritant and would not be recommended for progression. More recently, there has been much effort to replace animal tests with in vitro test models, such as isolated tissues and cell cultures (Hutak and Jacaruso, 1996). These have some advantages in that they are less costly than in vivo tests, use relatively simple methodology, and can be used to identify primary changes at the cellular level. The disadvantages are that they do not mimic the eye response, cannot be used to evaluate insoluble materials. It is conceivable that in vitro methods could be used for primary screening tests, while more standard in vivo methods are used to verify the result. Contact lenses are manufactured from a range of materials and may be broadly classified as rigid, soft, and scleral lenses, based on differences in the purpose and material used. The potential for interaction between the drug or excipients and a contact lens depends largely on the material of the lens. It is most likely that highly water-soluble and charged materials will interact with a soft, hydrophilic contact lens. There are several consequences of this happening, including a reduction in available drug, potential alterations to aesthetics of the contact lens (especially if the drug is colored), and possible deformation of the lens polymer affecting patient vision. The uptake and release of ophthalmic drugs into contact lenses can be evaluated with in vitro models designed to simulate the human eye. This involves soaking the contact lens in buffered saline containing drug product and continuously diluting the system with buffered saline to simulate tear turnover in the eye. The lens is removed for cleaning at the end of a day according to routine wear, and left to soak overnight. This can be continued over several days and the soaking solutions analyzed for drug at intervals to determine the buildup of drug in the lens. This test involves subjecting a range of contact lenses to incubation in a series of dilutions of drug product. If the uptake of drug into the lens appears to be problematic, the use of the drug product with contact lens wearers may be contraindicated, or, alternatively, a specific cleaning/soaking program may be recommended. Wherever possible, wearers of such lenses should remove them before administration and allow time for the medication to be removed by the tears. Finally, compatibility tests can be carried out to demonstrate that the drug product is compatible with other commercially available eye products, which may be coadministered. Each mixture is examined for signs of chemical and physical compatibility over a short period of time. These in vitro results should be validated by the successful use of the drug product with concomitant therapy in clinical studies. Quite often, it is discovered that some formulations cannot withstand a stressful sterile process such as autoclaving. Chemical degradation or changes to the formulation properties of multiphase systems, such as suspensions and gels, can occur. In all cases, the compendial sterility test requirements described in the various pharmacopoeias must be complied with. There are certain expectations and requirements for "acceptable" sterile products from the regulatory agencies, particularly in Europe (Matthews, 1999) and also the United States. The guidance emphasizes that heat lability of a packaging material should not itself be considered adequate justification for not utilizing terminal sterilization, for otherwise heat-stable products. Alternative packaging material should be thoroughly investigated before making any decision to use a nonterminal sterilization process. However, it could be that the drug candidate, or one or more of the formulation excipients, is not stable to heat. According to the decision trees, where it is not possible to carry out terminal sterilization by heating because of formulation instability, a decision should be made to utilize an alternative method of terminal sterilization, filtration, and/or aseptic processing.