MBA 560 Healthcare Management

Questions: Q1. Fusion method is an example of techniques that used to prepare solid dispersion systems. In this method, cooling rate can affect the properties of the solid dispersion system. Mention one example illustrates how this factor affects the formed system. Q2. Describe how solid dispersion enhances dissolution rate of low aqueous soluble drugs (mechanisms)? Q3. In solvent evaporation method, the remaining solvent is removed by different methods. What are these methods? Q4. Ritonavir capsules (Norvir®) is an example of solid dispersion system that was withdrawn from the market. Explain the reason for this action? Q5. One stability issue that affects shelf life of solid dispersion systems is crystallization of amorphous drug. The researchers found that some carrier system (e.g. polymers) may help in retarding crystallization of amorphous drug during storage. Mention one example of these carriers? Q6. The in vivo effects of permeation enhancers may not be as great as their in vitro effects on isolated membrane, explain the reason. Q7. What are the reasons behind low membrane permeability of some compounds? Q8. In case of proteins or peptides that are degraded or metabolized at the absorption site, how could a formulator improve their bioavailability? Q9. Describe the mechanisms of absorption enhancement of drugs through gastrointestinal membrane induced by absorption promoters. Q10. Sodium caprate is one of the absorption promotors, discuss its mechanism of absorption enhancement. Answers: 1. The step of cooling is very much important in pursuing the method of fusion to form solid dispersions. In preparation of nifedipine–PEG 6000 solid dispersion, at first, physical mixtures of the drugs were melted at 80-85 degree centigrade temperature. After that, it was rapidly cooled by using mixture of sodium chloride and ice. Then the solids were stored for 24 hours before sieving and pulverization. 2. Lower water solubility is one of the major hindrances in the way of developing new drugs. However, the solubility can be enhanced by several methods like solubilization, reducing the particle size of the drug, salt formation. Solid dispersion technique is quite effective in increasing the dissolution rate of the water soluble drugs. Commonly, process of particle size reducing is used to enhance the solubility. Poorly water soluble drug when taken with solid dispersion/ solution, the drug particles are disintegrated. As a result the size of the drug particles are reduced to a very size that is the size almost become < 1 micron. This size reduction helps in increasing the dissolution rate and ultimately the absorption rate increases. In this way, solid dispersion enhances the dissolution rate. 3. Different researchers had used different techniques to remove solvent. Ethanolic solvent can be evaporated by steam bath technique and residual solvent can be removed by application of low pressure. In addition, ethanolic solution can be removed by drying from a solution of griseofulvin and PEG 6000 can be removed by applying 115 degree centigrade temperature in an oil bath until ethanol bubbles appear. After that, viscous mass is kept to be in a solid condition by keeping it in a flow of cold air. Along with this, spray drying, lyophilization, vacuum-drying, sugarbeads spray by the help of fluidized bed-coating system. This techniques can be used to remove solvents from in solvent evaporation method. 4. It is reported that, in the solid dispersion, the drug particles stay in an unchanged condition if it is mixed with the carrier. However, if it is dissolved in the carrier, the state of the particle will be changed. In addition, if heat is applied to dissolve the drug particle into the carrier, it will be crystalized and may come out from the carrier. This crystallization of the drug negatively affect the dissolution of the capsule. Along with this, the capsule produced a solution which was thermodynamically stable. As a result the main purpose that is the enhancement of the dissolution rate was hampered. That was the reason behind the withdrawal of the Ritonavir capsule from the market. 5. The conversion of the drug into a crystalize form is the crucial step of drug stability with solid dispersion that is prepared by the solvent method. In this case, Polyvinylpyrrolidone, commonly known as PVP is very much useful carrier in retardation of crystallization process to amorphous drugs. PVP is not converted into the crystalize form. In a study it was seen that, there was no crystallization in the furosemide-PVP dispersion method in the temperature range of 6-45 degree centigrade in relative humidity of 45% (for 1 year). So it was assumed that PVP is responsible for retardation of crystallization in the solid dispersion method. 6. The permeation enhancers was less effective in the in vivo condition than that of the in vitro condition. In an in vitro study, a researcher could easily control the environment of the research and even the micro environment of the research could also be controlled. The actual concentration of the drug was also remain same in case of in vitro condition. However in case of the in vivo condition that is the actual target side inside the body, the condition cannot be controlled. The original concentration of the delivered drug could be also diluted by the fluids present in that region. This one of the reasons of less functioning of drugs in a in vivo condition. Moreover it was seen that, the permeation enhancer could be more effective in the excised membrane than that of the intact membrane that was in the in vivo condition. 7. There were several molecules that have lower membrane permeability due various reasons. One of the major reason is the size of the molecules. The larger molecule weight of the orally administered drugs is the most common issue due to their larger molecular weight and alongbwith this, they have a lot of hydrogen bonding groups that is also responsible for the poor membrane permeation. Along with this, the hydrophilic nature of the compounds, strong ionization capacity are the barrier for the membrane permeation. In case of paracellular absorption, the membrane permeation is restricted as the molecular size is higher than that of the effective pore size. 8. The permeation of the peptides or proteins can be enhanced by using a formulator. In this context, formulation technology such as transient permeability enhancer (TPE) system can be used. This formulation may include protease inhibitor, bile salt, EDTA, bile acids and those are responsible for the enhancing permeation through the membrane. 9. The enhancement of the absorption in the gastrointestinal membrane by using absorption promoters is completed by targeting specific channels present on the gastrointestinal membrane. In this scenario, mainly zonula occludens is first identified and then a peptide fragment helped to enhance the absorption mechanism of intestinal membrane. Along with this, modulation of the tight junctions that are present in that region are also responsible for the increment of the absorption through the gastrointestinal membrane. However, the enhancement using tight junction modulation had not have enough evidence in in vivo condition. 10. Sodium caprate is one of the important absorption promoter and it has been used to enhance the oral absorption of drugs. It is thought that, sodium caprate enhanced the exposure time of the gastrointestinal membrane to the absorption promoter. As a result, the promoter can affect the permeation for long time. Along with this, enhancer also increase the surface area of the membrane. By this mechanism, sodium caprate enhances the absorption.

MBA 560 Healthcare Management

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