Modern Day Delivery Drug Systems Biology Essay

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Drug delivery today is at the leading edge of pharmaceutical science and product development. Historically, the field of drug delivery basically based on inventing new forms of drugs with the compatibility of diseases. Nowadays, drug delivery is being used as a method of system through which new improved medicines can be made by immense research and study.

The current state of drug delivery activities are to reduce toxicity, increase the absorption of an insoluble or improve the drug release profile. Drug delivery is being considered earlier in the drug development timeline with the engineering of drug delivery systems to meet the current therapeutic needs. In the development process while studying on productivity and quality there is a very big potential to improve results and invent completely new effective products.

The development of more sophisticated drug delivery systems to meet product and patient needs demands sophistication of the analytical services requires since ages. Method development of potency and purity methods has been complicated by polymers, nanotechnology, and drug infused medical devices used in implantable time-release drug delivery systems. The drug evolution profile of these systems requires experience and expertise, as well as newer drug release instrumentation such as flow-through dissolution.

It is also observed that a significant increase in analytical development involving extractable and conclude profiles of polymeric materials used in medicated implants, as well as in device parts for dry powder inhalers and the complex coatings of transdermal devices. These complex drug delivery

matrices, require both state-of-the-art instrumentation and in-house technical expertise accustomed to working in complex products.

Increased sophistication in drug delivery systems translates into a greater portion of the drug development process being devoted to drug product formulation.

The Researchers are trying to over come such problems to deal drug delivery issues specially in nanomedicine side. For instance when there are only certain possibilities to deliver drug dosages or therapy due to the limitation that only very few amount get onto the effected area of the body. Those medications should be on their positive effect once taken and digested to deliver treatment quickly rather than adverse effects. To most the injectable form of drugs should be cheap in price and more effective if taken orally. However, this improvement can not be changed in contrast if more targeted drugs be developed for the particular effected organs such as liver, heart, lungs etc. In females like breast cancer diseases can be handled with new developed therapies in nanomedicine where less chances are seen to effect other parts of the body.

On the other side the use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body. 

Role of drugs into the delivery?

There are many methods of drug delivery where medications are given to the patients. Nowadays it is very advanced era of time but the basic methods are still same out of some new ones. Tables or syrups can be taken by mouth and it is more easily without pain. Through injection is also very common with rapid effect but care must be taken because it's effect is very fast directly to the organs of the body. The other methods including the skin, rectum, eyes, lungs, muscle or under the tongue are also very common depends on the nature of patient and disease. If for example for asthamatic patients, inhalation is the best for drug delivery because it directly hits the area in very low time.

Inorganic nanomaterials (INMs) and nanoparticles (NPs) are important in our lives because of their use as drugs, imaging agents, and antiseptics. Among the most promising INMs being developed are metal, silica, dendrimers, organic-inorganic hybrids, and bioinorganic hybrids. Gold NPs are important in imaging, as drug carriers, and for thermotherapy of biological targets. Gold NPs, nanoshells, nanorods, and nanowires have the extensive potential to be an integral part of our imaging toolbox and useful in the fight against cancer. Metal NP contrast agents enhance magnetic resonance imaging and ultrasound results in biomedical applications of in vivo imaging. Hollow and porous INMs have been exploited for drug and gene delivery, diagnostic imaging, and photothermal therapy. Silver NPs show improved antimicrobial activity. Silica NPs have been used in drug delivery and gene therapy. Biomolecular inorganic nanohybrids and nanostructured biomaterials have been exploited for targeted imaging and therapy, drug and gene delivery, and regenerative medicine. Dendrimers find use as drug or gene carriers, contrast agents, and sensors for different metal ions.

Drug delivery and nanomedicine

1. Current (macro & microscale) methods of drug delivery • transdermalsystems • microneedles • implantable systems • tissue reaction to implantable systems

Typical drug dosages •currently, typical dose of drug is tens to hundreds of micrograms -300 μgepinephrine to treat anaphylactic shock (severe allergic reaction, rapid constriction of airways) -keeps airway open. -antibiotics such as penicillin ~ 1 g/day for adults -current drug formulations often contain carriers, binders, coatings, flavouringagents.

Why drug delivery? •Improve therapy -Improve efficacy, prolong duration, improve bioavailability, improve targeting, mimic biopattern •Increase patient compliance -Decrease dose frequency, allow self‐ administration •Add competitive advantage (e.g. post drug patent)

Methods • Oral • Parenteral(IV, etc) • Inhalation • Ocular • Transdermal • Needleless • Implants • Liposomes

David Beebe, U. Wisconsin

Parenteral Parenteral other than GI tract (i.e. intravenous, subcutaneous, intramuscular, transdermal, etc.) • Intravenous -Immediate action -Size/location (>7 μm trapped in lung, <0.1 μm accumulate in bone marrow, 0.17 μm taken up by liver/spleen) • Intramuscular / Subcutaneous -Sustained action -Injected into skeletal muscle / subcutaneous tissue

TransdermalDelivery • Skin receives 1/3 of blood • Accessible • Barriers -Permeation -Irritation • Advantages -Avoids "first pass"metabolism and GI degradation •"First pass"effect metabolic breakdown in the liver -Ideal for continuous delivery -Improved patient compliance

Microfabricated drug delivery systems

There are different effective methods are useful for delivery of drugs in the human body. While the most common three methods are given as under.

Bio capsules and micro particles.

Oral delivery methods like solids or suspension in a micro coated form.

2. Implant able micro systems.

Micro electronic systems directly attached with the body

3.Mirco needle for transdermal delivery.

Very small needles to inject into the body with almost negligible pain.

Bio-capsulesand microparticles

The small contains of these drugs are coated in very small capsules to release them in a very controlled way.

There effects in the circulation in the blood also can be monitored by connecting with electronic equipments.

Diabetes (Insulin drugs)

It monitors and regulates the amount of insulin into the blood and tissue. Normally it controls through brain because brain decides the amount of insulin to the body requires. Once this disease initiated, the insulin un- controls the level of glucose in the blood. While it is too difficult to check this amount in every part of time. This could be possible in nanomedicine specific drug delivery system through specific methods.

Shape-specific polymeric nanomedicine

In nanomedicine, the size of medicine in nanoparticles are the key factor to be considered first. Shapes can be different in multiple applications.

It is shown by studies that the size of drug is important especially during circulation with the blood. However the importance of particle shape has only recently started in nanomedice. For instance, cylindricall drug within 20 to 50 nm, is very effective while circulation of blood for seven days through injection as compare to spherical type. The other nanoparticle shpe is disc. It is also very effective in targeted drug delivery in molecular level.

New developed computer programs are now made for easy understanding of shape and size for particular area of drug delivery when the focused area is human cell. Nanomedicine has the potential to initiate the performance of nanoparticles on the diagnosis of disease by means of chemotherapy or imaging technology.

Nanomedicine is very fast growing new technology that changes the entire infrastructure of system for diagnosis and treatment of diseases. The development of targeted nanoparticles capable of delivering therapeutic

and diagnostic agents to specific biological targets are the examples of achievements . In a nanoparticle-based platform, therapeutic drugs or imaging agents are encapsulated in polymeric carriers, providing multiple advantages over conventional small molecular formulas, such as cell targeting, reduction of clearance and systemic toxicity, the ability to deliver large payloads of hydrophobic drugs and the potential for incorporating multiple payloads in a single carrier for multiple applications.

Over the past few decades, various nanoplatforms, including liposomes, polymeric micelles, quantum dots, dandrimers, polymers, are introduced with their biological and chemical integration. The nanoparticulate being used nowadays are mostly spherical of shape, and extensive work has been dedicated to studying their biological behaviors in vitro and in vivo.

Similar to size, shape is a fundamental property of micro/nanoparticles that is critically important for their intended biological functions. Unlike size, the biological effects of particle shape are less well understood. Recent data have shown that particle shape may have a profound effect on their biological properties. For example, cylindrically shaped filomicelles can effectively evade non-specific uptake by the reticuloendothelial system, allowing the flow of drug through injection across seven days period. Theoretical modeling work has shown that non-spherical particles can significantly increase particle adhesion to cellular receptors under flow conditions compared with spherical particles.

It is sowed that disk-shaped nanoparticles (0.1 _ 1 _ 3 mm) increased (.20

times increase in immunospecificity index) particle targeting to intercellular adhesion molecule 1-expressed pulmonary endothelium over spherical particles of similar size. Other non-spherical nanoparticles (e.g. carbon nanotubes, wormshaped iron oxide nanoparticles ) have also demonstrated

considerably increased accumulation and retention in tumor tissues in vivo. These data, as well as a wide array of naturally occurring shape-specific nanoparticulates are beginning to highlight the importance of controlling particle shape for nanomedicine applications.

Despite these early studies, there still is a lack of systematic and fundamental understanding of how shape affects the in vivo behavior of nanoscale constructs. One contributing factor is that conventional fabrication methods are limited in their ability to control the shape and size of nanoparticles simultaneously. This limitation hinders direct investigation

of the effects of shape independent of size or other factors. There is also a lack of integration between computational modeling and experimental

validation, an important requirement for understanding the effects of shape at nanoscale in the biological systems.

Fabrication of shape-specific nanoparticles

Both bottom-up chemistry and top-down engineering methods have the capability to produce polymeric nanostructures. Most polymeric nanoparticles currently used for biomedical applications are produced using bottom-up methods. These methods can produce nanoparticles with a spherical shape and a wide variety of sizes driven by favorable thermodynamics leading to the self-assembly of the nanoparticles.

Although non-spherical shapes are possible using diblock co-polymers, size and shape are difficult to control independently using bottom-up methods.

Several bottom-up techniques have been developed to fabricate non-spherical particles. As shown in Table 1, a self-assembly method to produce polyethylene- glycol (PEG)-based filomicelles loaded with the antineoplastic agent paclitaxel. Park et al synthesized magnetic iron oxide worm-shaped clusters in the presence of higher molecular weight dextran. Although all show exciting results with interesting science, most of these methods still lack precise and uniform control over shape and size independently. Currently, the bottom-up methods will be limited in the production of non-spherical nanoparticles, with systematic change of one dimension at a time to test shape-specific hypotheses in biology.

In contrast, polymers can be precisely patterned and used as resistors for microelectronic applications, with good control over their final shape using electron, ion or photon beam lithographic techniques. The costliness of these techniques has led to the development of low-cost top-down techniques, such as nanoimprint lithography, soft lithography and others.

Table 1 summarizes some of the processes used to produce non-spherical polymeric particles, including particle replication in non-wetting templates elastic stretching of spherical particles, step-flash imprint lithography (S-FIL) and template-induced printing (TIP). These techniques have obtained promising results in manufacturing nonspherical platforms for nanomedicine applications.

Size and shape comparison of various naturally occurring nanoparticulate objects

Biological functions of shape-specific particulates

An in vitro study on the cellular localization of spherical particles by

endothelial cells was performed by Muro et al.25 Remarkable reduction of internalization was observed for discs relative to spheres despite the two particles sharing the same endocytic pathway. Champion and Mitragotri reported the importance of shape on phagocytosis, which is a pathway for cellular internalization of micron scale particles. Local shape at the contact point between particle and cell was the dominant parameter that initiated phagocytosis. For example, worm-shaped polystyrene particles reduced phagocytosis compared with the spherical ones of the same volume. A similar observation was also reported for filomicelles, and increase of the aspect-ratio of filomicelles leads to reduced phagocytosis by human macrophage cells. The decreased clearance by phagocytosis could contribute

to the elongated lifetime of long filomiceles in blood circulation.

In vivo, nanoparticles are exposed to complex biological and physiological environments that cannot be easily simulated experimentally. Computational models that simulate biological conditions can greatly facilitate the testing and verification of shape-specific hypotheses for biological systems.

For intravascular delivery, the efficacy of targeted delivery of nanoparticles is impacted by several fundamental processes margination to the periphery of blood vessels, adhesion to endothelial cells via cell/particle interactions

and cellular internalization. Margination and adhesion of particles under vascular flow conditions are within the scope of intravascular dynamics modeling while cellular level modeling can be used to study the

adhesion forces between particles and targeted cells.

Conclusion

Recent discoveries of the unique shape effects on biological functions at

nanoscale have multiple shape-specific particulate platforms for

nomedicine applications. Various techniques for the fabrication of non-spherical particles have been established. Many of these techniques, such as PRINT, stretching spherical particles, S-FIL and TIP, hold great promise because of their ability to simultaneously and independently control shape, size and chemical compositions of fabricated polymeric nanoparticles. Computational models of the effects of particle shape on intravascular dynamics and cellular uptake have been developed. Both modeling

data and experimental results indicate that for particulate platforms, shape can have a profound impact on pharmacokinetics and pharmacodynamics.

Future advances in the implementation of shape-specific nanomedicine would include the capability to scale-up without sacrificing the precise control over size and shape.

The development of efficient methods for imprinted nanoparticles is also important for techniques. Also necessary is a well-controlled, systematic

study of the effects of shape on particle behavior under biologically relevant conditions. Computational models also need to be integrated to elucidate the effects of shape on the degradation profile, intra- and extracellular trafficking of particles. Only with the mechanistic understanding on how shape would affect fundamental processes during in vivo targeting applications, can a rational design incorporating shape into a given nanoparticulate platform be possible.

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