You have finished your education and have accepted a full-time position at the R

Question

You have finished your education and have accepted a full-time position at the Rogers Research Institute (RRI), commencing June 1, 2018. It will be your responsibility to develop polymeric materials that can be commercialized by RRI’s affiliate FutureWay , which markets superior specialty materials for the medical sector. Long-term employment at RRI depends on your securing funding for your research. The successful grant application will require presentation of background information, which will require searching primary and trade journals for first-hand, up-to-date information on your topic, and a description of one new experiment that the PI would like to perform. Come up with a procedure using polymers to help with the drug delivery time in pharmaceuticals.

Explanation / Answer

Drug Release

Drug-release behavior is an important factor for polymer nanoparticle application, directly related to drug stability and therapeutic results, as well as formulation development.3,5 The drug-release rates from polymer nanoparticles depend on (1) desorption of the surface-bound/adsorbed drug; (2) diffusion from the polymer nanoparticles; (3) polymer nanoparticle erosion; and a combined erosion/diffusion process. Thus, diffusion and biodegradation govern the process of drug release. In most cases, rapid drug release from polymer nanoparticles, called “ burst release”, can be observed initially. It is reported that the release profiles of the drugs from polymer nanoparticles depend upon the nature of the delivery system. In the case of a polymer nanoparticle matrix, the drug is uniformly distributed/dissolved in the matrix and the release occurs by diffusion or erosion of the matrix. If the diffusion of the drug is faster than matrix degradation, the mechanism of drug releaseoccurs mainly by diffusion. Rapid initial release or burst release is attributed to the fraction of the drug which is adsorbed or weakly bound to the large surface area of the polymer nanoparticles rather than to the drug incorporated in polymer nanoparticles.

Drug Release and Biodegradation

Drug release refers to the process by which the drug loaded in or on the NMs is released in the body through diffusion or dissolution of the NMs matrix releasing the drug in solution. Biodegradation refers to the process by which the drug delivery system is broken down inside the body.

Both drug release and biodegradation are important to consider when developing an NMs drug delivery system. Ordinarily, effectiveness of drugs is dependent not only on its active components but also on its solubility and diffusion. When the drug is delivered using an NMs delivery system, effectiveness is affected by parameters such as the particle size, release process which is in turn affected by the biodegradation of the particle matrix. The smaller the particles, the larger the surface area-to-volume ratio; therefore, most of the drug associated with small particles would be at or near the particle surface which leads to faster drug release. In contrast, larger particles have large cores, which allow more drugs to be encapsulated per particle and give slower release. Thus, control of particle size provides a means of tuning drug release rates.

5.7.1 Factors Affecting Drug Release

In general, the drug release rate depends on: (1) drug solubility, (2) desorption of the surface-bound or adsorbed drug, (3) drug diffusion out of the NM matrix into the body, (4) NM matrix erosion or degradation, and (5) the combination of erosion and diffusion processes.118 The method of drug incorporation into the NM delivery system also affects the release profile.

Drug release when loaded by covalent attachment on the particle system is affected almost solely by drug–NM diffusion. This system has a relatively small burst effect and sustained release characteristics.119 When the drug is encapsulated inside a NM, the release is controlled by diffusion of the drug from the NM interior.

The polymer coating acts as a drug release barrier; hence, the drug solubility and diffusion in or across the polymer membrane becomes a determining factor in drug release. The release rate can also be affected by ionic interactions between the drug and secondary ingredients. In the event that polymer-encapsulated drug interacts with auxiliary ingredients, a less water-soluble complex may form causing a slower drug release that almost has no burst release effect.62 On the other hand, addition of auxiliary ingredients, e.g. ethylene oxide–propylene oxide block copolymer (PEO-PPO), to chitosan (CS) reduces the interaction of the drug with the matrix material via competitive electrostatic interaction of PEO-PPO with CS, and an increase in drug releasecould be achieved.61

In an encapsulated drug where the drug is uniformly distributed inside the NM matrix, drug release occurs by diffusion and/or erosion of the matrix. When the diffusion of the drug is faster than matrix erosion, diffusion largely controls the mechanism of release. The rapid, initial release, or “burst,” is mainly attributed to weakly bound or adsorbed drug to the relatively large surface of NMs.120

There are several in vitro methods that can be used to study the release of drugs loaded in an NM. These include: (1) side-by-side diffusion in cells with artificial or biological membranes, (2) diffusion through a dialysis bag, (3) reverse dialysis bag diffusion, (4) agitation followed by ultracentrifugation or centrifugation, (5) ultrafiltration, or (6) pH change. In general, drug release study is carried out by controlled shaking to allow the drug to ooze out of the NM into a release media followed by centrifugation to separate the NM from the drug in solution. However, the difficulties in the separation of NMs from the release media favor the use of the dialysis technique. Exception to these is the use of IOMNPs where loading with drugs is performed at high pH and drug is released at low physiological pH. After the drug release, the IOMNPs can easily be separated from the media with the use of magnets (SuperMag, Ocean NanoTech) and the concentration of drug in the release media can be established depending upon the properties of the drug (unpublished paper, Ocean Nanotech).

Only a few studies have been published on drug release,118,121especially on the release mechanisms. The mechanisms on in vitro drug release were generated by studying the model drugs tetracaine, etomidate, and prednisolone.66,122 However, lipid NMs exhibited burst release when incorporating tetracaine and etomidate. A prolonged drug release was obtained first with prednisolone that demonstrated the suitability of the solid lipid NMs for prolonged drug release. Drug release can be controlled as a function of the lipid matrix, surfactant concentration, and production parameters such as temperature122 achieving as long as 5–7 weeks. The formulation can be modulated for prolonged release without any burst or with different percentages of burst followed by prolonged release.67 The burst can be used to deliver an initial dose when desired.

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