National Pharmacy Technician Association. Norwegian Pharmacy Association. North Carolina Association of Pharmacists. North Carolina Board of Pharmacy. Ohio Pharmacists Association. Ohio Society of Health-System Pharmacists. Ohio State Board of Pharmacy. Oklahoma Society of Health-System Pharmacists. Oklahoma State Board of Pharmacy. Ontario Pharmacists' Association.
Oregon Board of Pharmacy. Oregon State Pharmacy Association. Pan American Health Organization. Pediatric Pharmacy Advocacy Group. Pennsylvania Pharmacists Association. Pharmaceutical Research and Manufacturers of America Foundation. Pharmaceutical Society of Australia. Pharmaceutical Society of Korea. Pharmacists Society of the State of NY. Pharmacy Benefit Management Institute, Inc. Pharmacy Guild of Australia. Pharmacy Technician Certification Board. Pinoy Pharmacy. Regulatory Affairs Professionals Society. Royal Microscopial Society.
Royal Pharmaceutical Society of Great Britain. Society for Biomolecular Sciences. Society of Hospital Pharmacists of Australia. South Carolina Pharmacy Association. Southeastern Society of Health-System Pharmacists. Tennessee Pharmacists Association. Texas State Board of Pharmacy. The Pharmaceutical Association of Mauritius. Turkish Pharmacists Association.
University College of Pharmaceutical Sciences. Utah Pharmaceutical Association. Pharmaceutical Chemistry is the study of drug design to optimize pharmacokinetics and pharmacodynamics, and synthesis of new drug molecules Medicinal Chemistry The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it.
Drug design frequently but not necessarily relies on computer modeling techniques. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. The development of strong correlations between drug concentrations and their pharmacologic responses has enabled clinicians to apply pharmacokinetic principles to actual patient situations. Use of glorious statistical software even based on artificial neural networking are made the task of preformulation and optimization process easier.
With the increasing number of novel and specialized compounds being developed, a "one size fits all" approach to drug formulation and delivery is no longer optimal, necessitating the consideration of formulations unique to each drug. There are more than sustained or controlled release drugs have been approved all over the world.
Size reduction is a fundamental unit operation having important applications in pharmacy. Drugs in the nanometer size range enhance performance in a variety of dosage forms. Pharmaceutical nanotechnology is most innovative and highly specialized field, which will revolutionize the pharmaceutical industry in near future. Pharmaceutical nanotechnology presents revolutionary opportunities to fight against many diseases. It helps in detecting the antigen associated with diseases such as cancer, diabetes mellitus, neurodegenerative diseases, as well as detecting the microorganisms and viruses associated with infections.
It is expected that in next 10 years market will be flooded with nanotechnology devised medicine. These factors can enhance properties such as reactivity, strength, electrical characteristics, and in vivo behavior. As the particle size decreases, a greater proportion of atoms are found at the surface compared to inside. An NP has a much greater surface area per unit mass compared with larger particles, leading to greater reactivity. In tandem with surface area effects, quantum effects can begin to dominate the properties of matter as size is reduced to the nanoscale.
These can affect the optical, electrical, and magnetic behavior of materials. Their in vivo behavior can be from increased absorption to high toxicity of nanomaterials. Key players in the market include Amgen, Inc. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue.
The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult and the reduced ability to adjust the dosages.
Pharmaceutical Nanoemulsions and Their Potential Topical and Transdermal Applications
A biomaterial is any substance that has been engineered to interact with biological systems for a medical purpose - either a therapeutic treat, augment, repair or replace a tissue function of the body or a diagnostic one. Such functions may be benign, like being used for a heart valve, or may be bioactive with a more interactive functionality such as hydroxy-apatite coated hip implants.
A biomaterial may also be an autograft, allograft or xenograft used as a transplant material. Vaccine is a material that induces an immunologically mediated resistance to a disease but not necessarily an infection. Vaccines are generally composed of killed or attenuated organisms or subunits of organisms or DNA encoding antigenic proteins of pathogens. Sub-unit vaccines though exceptionally selective and specific in reacting with antibodies often fail to show such reactions in circumstances such as shifts in epitopic identification center of antibody and are poorly immunogenic.
Delivery of antigens from oil-based adjuvants such as Freunds adjuvant lead to a reduction in the number of doses of vaccine to be administered but due to toxicity concerns like inductions of granulomas at the injection site, such adjuvants are not widely used. FDA approved adjuvants for human uses are aluminium hydroxide and aluminium phosphate in the form of alum. Other reasons driving the development of vaccines as controlled drug delivery systems are as follows:. Immunization failure with conventional immunization regimen involving prime doses and booster doses, as patients neglect the latter.
Allow for the incorporation of doses of antigens so that booster doses are no longer necessary as antigens are released slowly in a controlled manner. Control the spatial and temporal presentation of antigens to the immune system there by promoting their targeting straight to the immune cells. These routes are of interest for local delivery, as in asthma, but also for rapid delivery of drugs to the system circulation and direct delivery to the central nervous system. Devices that account for specific anatomical and physiological features of the intranasal and pulmonary routes will be featured.
Such devices are used as part of one or more medical treatments. Many in the industry have long felt overly burdened by what they consider to be an unnecessarily complex approval process. Critics claim it impedes innovation and delays the availability of better health care. Biologics are used to prevent, treat, diagnose, or cure a variety of diseases including cancer, chronic kidney disease, autoimmune disorders, and infectious diseases. Under U. It may not have any clinically meaningful differences in terms of safety and effectiveness from the reference product.
Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. Validation is one of the important steps in achieving and maintaining the quality of the final product.
If each step of production process is validated we can assure that the final product is of the best quality. Validation of the individual steps of the processes is called the process validation. Different dosage forms have different validation protocols. It gives a higher degree of assurance. Packaging is one of the largest industry sectors in the world, worth several billions. The global healthcare industry has seen a shift in paradigm and is now skewed toward effective and meaningful packaging.
A clinical trial involves research participants. It follows a pre-defined plan or protocol to evaluate the effects of a medical or behavioral intervention on health outcomes. Pharmacogenetics is the science that supports understanding the part that a person's hereditary make-up plays in how well a prescription functions, and additionally what symptoms are probably going to happen, enhancing our capacity to distinguish the hereditary reasons for illnesses and look for new medication targets.
The importance of intellectual property law is well established at all levels-statutory, administrative and judicial. The Agreement provides norms and standards in respect of following areas of intellectual properties are Patents, Trademarks, copyrights, Geographical indications, Industrial designs. Physical pharmacy gives the premise to understanding the synthetic and physical wonders that oversee the in vivo and in vitro activities of pharmaceutical items.
Clinical pharmacy is a health science discipline in which pharmacists provide patient care that optimizes medication therapy and promotes health, and disease prevention. The statements were developed by the profession to bring uniformity to the practice of hospital pharmacy. Pharmacovigilance is the science and exercises identifying with the discovery, evaluation, comprehension and counteractive action of unfavorable impacts or some other pharmaceutical related issue. Advance instruction, understanding and clinical preparing in Pharmacovigilance and its successful accessibility to people in general.
It is related with antagonistic impacts of Pharmaceutical items including numerous other logical perspectives, for example, the reactions of medications, the nature of solutions, prescription mistake in utilization of medications, absence of viability of medications, and fake medications. The standards ensure that newly registered pharmacists are competent to practice safely and effectively. Huber et al. Consistent with the above results, they found that gene expression after exposure to plasmid alone or plasmid plus microbubbles was minimal.
Although ultrasonication of the vessel with plasmid increased the gene expression, insonation with plasmid and albumin microbubbles increased gene expression even more. In an ex vivo model, Teupe et al. Ultrasound alone, or microbubbles alone produced a minimal gene expression, whereas the combination of 2. In a slight twist of the conventional reports above, Du et al. These were injected into the femoral artery of pigs and subjected to diagnostic Doppler imaging. Gene expression was subsequently found 6 days later in all experiments. Unfortunately there were no control experiments in which genes were delivered without ultrasound.
Apparently solid echogenic microspheres can deliver genes, but at this point the transfection efficiency cannot be compared with microbubble delivery systems. There is considerable interest in genetic targeting of tumors as an anticancer therapy, and several studies have examined the feasibility of such a therapy. For example, Manome et al. Application of 1 MHz transcutaneous insonation increased the reporter activity 3-fold over the non-insonated control. Higher power densities increased reporter activity, as did increasing insonation time up to 30 seconds.
Using a cationic lipid-cholesterol transfection complex, Anwer et al. Insonation significantly increased the gene expression, and the transfected tissue was limited to the tumor vasculature. The expression of IL was sufficient to inhibit tumor growth compared with the control conditions. Although the authors did not expressly introduce microbubbles, or mention their possible existence, it is possible that the synthesis of the DNA-lipid-cholesterol complex created some liposomes, some of which could contain gas and become acoustically active during insonation. McCreery describes a similar procedure for plasmid gene delivery to human adenocarcinoma grown in nude mice, with similar results [ 62 ].
Insonation at 0. In a related procedure, Bao reports the use of a lithotripter to deliver a luciferase reporter to B16 melanoma grown in mice [ 78 ]. A lithotripter generates a shock wave containing a spectrum of acoustic frequencies and can produce cavitation phenomena.
Various regimens of shock waves were subsequently applied, and the luciferase expression evaluated. The results showed that shock waves with direct injection enhanced expression roughly fold relative to direct injection alone, and that application of air produced a further 7-fold increase in expression.
More information on in vitro gene delivery by lithotripter shock waves is reviewed elsewhere [ 49 ]. Other applications aim at promoting neovascularization for tissue repair. Thus there are several articles written on US-enhanced gene delivery to skeletal muscles. In some in vivo experiments in rats, the triceps brachii or gastrocnemius was exposed to diagnostic ultrasound.
A mixture of plasmid encoding for luciferase and commercial microbubble contrast agents was injected into the muscle IM , followed immediately by insonation. The results showed that insonation in the presence of microbubbles and plasmid resulted in higher luciferase activity than injection of plasmid alone, plasmid plus microbubbles without insonation , or plasmid lipofection.
Virtually no luciferase activity was observed in other muscle or other organs. In similar experiments, Christiansen et al. Only the rat hind limb skeletal muscle was insonated. Transfection was fold greater with the IA than with the IV route, and was thus similar to intramuscular injection of plasmid.
No transfection was observed if the plasmid was administered without microbubbles. These results indicated that insonation of plasmid-microbubbles at a remote site away from the injections site produced sufficient extravascular deposition and DNA incorporation leading to genetic expression. Other groups have also used luciferase and microbubbles to transfect rodent skeletal muscle [ 80 , 81 ]. Schratzberger et al. A plasmid reporter gene was injected IM and insonation was immediately applied.
Consistent with the above findings, the plasmid reporter gene showed very little expression when DNA but not ultrasound was applied. They concluded that gene expression increased as the duty cycle the fraction of time that US is activated in a pulse sequence or the power density increases, consistent with the hypothesis that cavitation is involved in the gene delivery. Apparently no microbubbles were used in these experiments. Gene transfection on a fetal mice in utero was done using a plasmid encoding a fluorescent marker [ 56 ].
In this procedure, an incision was made on a pregnant mouse and the uterus externalized. Then plasmid mixed with microbubbles was delivered to specific locations by micropipette, the ultrasound applied, the uterus replaced, and the fetus developed for another 24 to 48 hours. However, application of 1 MHz ultrasound to plasmid and microbubbles produced about a fold enhancement in gene expression.
Micrographs showed some disruption to the fetal skin under conditions of ultrasound with microbubbles. As of this writing, we could find no examples of in vivo enhancement of gene delivery using ultrasound. However, there are some publications of in vitro delivery to neural tissue in culture [ 63 , 83 ], and reports of employing ultrasound to breach the blood-brain barrier [ 35 , 43 , 84 — 87 ]. Because lung tissue contains gas, it reflects and scatters ultrasound; thus transcutaneous ultrasound cannot be used to deliver therapeutics to the lungs. An alternative use of ultrasound in gene delivery is to create an aerosol using an ultrasonic nebulizer.
Cationic-DNA complexes have been delivered to mice, rats and Guinea pigs, and their lung epithelial cells transfected [ 88 , 89 ]. Since most of the recent progress in gene delivery involves microbubble cavitation, the most pressing need is a better understanding of cavitation physics and US-microbubble interactions. Of course this will aid in not just gene delivery, but in all aspects of drug delivery.
Another need is to develop better protection for the genetic material so that it is not degraded by fluid shear forces or enzymes before it can be delivered to the cells. In addition, the loading of genetic material needs to be optimized such that the genes are delivered only to the target tissues and not to tissues downstream from the insonated site. We will differentiate proteins from other macromolecules by their size and characteristic polypeptide backbone. In this review, we will consider proteins as having a molecular weight of over Daltons.
Smaller polypeptides can be treated as low molecular weight drugs. Compared to low molecular weight drugs, the proteins have very different transport and solubility characteristics in tissues, and thus their delivery is usually much more complex. Specifically, proteins do not diffuse easily through solids and most gels. A simple bilayer lipid membrane is sufficient to preclude the transport of a protein.
Two systems with large surface area, the skin and the GI tract, are problematic. The skin is designed to be impermeable to protein transport, and the GI tract hydrolyses proteins into smaller peptides and amino acids for absorption. The high surface area of the lungs makes the pulmonary system attractive for protein delivery. However, lung tissue blocks ultrasound as previously mentioned. These limitations relegate most protein delivery to injection with some applications employing inhalation.
Regulatory hormones are the center of focus for controlled protein delivery; specifically insulin delivery for diabetes therapy comprises the vast majority of protein delivery research, with some research effort in growth-related hormones and birth control hormones. With respect to US-assisted protein delivery, nearly all research is focused on insulin delivery, and the great majority of that research is on transdermal delivery.
Ultrasonic delivery is ideal because a small transducer can be placed on the skin surface for a painless, non-invasive delivery route. There is a tremendous amount of literature on the use of ultrasound to enhance the permeability of skin for transdermal drug delivery, including several excellent reviews to which the reader is referred [ 90 — 97 ].
Sometimes chemical enhancers were used to further increase the permeability [ — ]. However, no significant transport of protein could be achieved until 10 years ago when Mitrogotri et al. Skin permeability increased with decreasing frequency, and with increasing time of exposure and intensity beyond a threshold , thus identifying collapse cavitation as a causative mechanism [ — , , , ]. The current theory is that cavitation events open reversible channels in the lipids layers of the stratum corneum and provide less tortuous paths of transport for proteins such as insulin [ 90 , — , ].
Tezel and Mitrogotri have formulated a model of the shock wave and microject cavitation events and their impact upon skin permeability [ 24 , ]. Although their model can be fit to their data, there are many assumptions and parameters in the model, and more direct evidence is needed to conclusively reveal the mechanisms of US-enhanced transdermal protein delivery. The future of US-enhanced transdermal protein delivery is brimming with potential, but it has not yet appeared in the clinic.
Because large pores and channels are opened through the natural skin barriers, many hormones and proteins could be candidates for transdermal delivery [ , , — ]. Kwok et al. In the absence of insonation, the alkyl chains appeared to form an organized and less permeable barrier to proteins; upon insonation, the surface organization was apparently disrupted and protein within the depot matrix escaped.
In their research very little insulin was released until 1. Upon termination of insonation the low permeability of the lipid-like surface layer was restored. Such a device is envisioned as a subcutaneous depot with an external transducer positioned over the depot that can be activated either automatically or on demand as insulin is required. The transport of tissue plasminogen activator tPA and other lytic proteins such as urokinase into clots is beneficial in increasing the rate of fibrinolysis of clots [ , ].
In most studies, the protein is delivered to the clot via intravenous catheter, and the ultrasound is applied transdermally. Francis et al. They speculated that enhanced transport could be due to fluid motion from shock waves, microstreaming, or penetration of the clot by micro-jets. Later studies showed that pulsed low frequency ultrasound 27 kHz is more effective than higher frequencies in enhancing fibrinolysis by tPA, again supporting a non-thermal cavitation-related transport into the clots [ ].
The same group also showed that water permeability through a fibrin gel was increased by ultrasound in the absence of any lytic enzymes [ ]. This increase was reduced when the fibrin gels were degassed, and thus these authors attributed the increase to cavitational activity. Other authors have shown that high intensity focused US produced echo-dense material in the clot, most probably by creating cavitation bubbles [ ]. Although US by itself is beneficial in enhancing thrombolysis, the addition of microbubbles appears to enhance thrombolysis even more [ — ]. As early as , it was shown that application of US with albumin-based contrast agent significantly increased fibrinolysis by urokinase of thrombus in vitro [ — ].
In vivo studies using tPA and other enzymes came to the same conclusions [ , ]. Still another advance in this technology is to attach receptors for the thrombus material to the microbubbles, thus attaching the bubble to the thrombus surface during the ultrasonic exposure. We envision that bubbles cavitating on the thrombus surface will produce micro-jets that can mechanically disrupt the clot. There are several reports of protein delivery to the lungs via inhalation of ultrasonically aerosolized protein solutions.
Because nebulization requires rather severe cavitation, it has been found beneficial to protect the proteins by the addition of certain surfactant stabilizers [ , ]. These additives appear to complex with the proteins and protect them from degradative shear stresses and perhaps from free radical attack. It is possible that the surfactants may form micelles or liposomes that sequester the proteins and protect them from cavitation stresses. A short list of ultrasonically nebulized protein delivery includes interferon [ ], platelet-activating factor [ ], lactate dehydrogenase [ ], superoxide dismutase [ ], alpha1 protease inhibitor [ , ], urokinase plasminogen activator [ ], and aviscumine [ ].
As mentioned at the beginning of this section, protein delivery is currently fairly limited by very slow diffusion of proteins through skin and polymeric depots, and by the proteinolysis that occurs in the upper GI tract. We foresee a need for technology in which a polymeric depot can be implanted, perhaps in subcutaneous, intraperitoneal, or intramuscular locations.
Then timed drug release could by activated by transdermal ultrasound. Polymers in a depot can be degraded by ultrasound [ 27 , ], but this is a fairly slow process, and the same physicochemical mechanisms that degrade the polymers may degrade the proteins in the depot.
What is needed is technology that will open and close the depot to protein transport. The technology of Kwok et al is a good start in this direction, but the depot needs to completely shut off protein delivery when not insonated. It would also be advantageous if the depot were activated by stable cavitation or some other low intensity phenomenon related to ultrasound.
Collapse cavitation may be capable of opening depots, but repeated ultrasonic exposure over long periods may start to have adverse effects on the healthy tissue in the region of the depot. Finally it would be beneficial if the depot were eventually degradable so that it did not need to be surgically removed when it was emptied.
A refillable depot would also be useful. In the last two decades, ultrasound has been investigated as a delivery mechanism for a variety of therapeutic agents to diseased cells throughout the body. Section 2. The use of ultrasound as a drug release and potentiation mechanism in traditional chemotherapy has been studied extensively. In this section, we will discuss ultrasonic chemotherapy delivery in free, micellar and liposomal forms.
A synergistic effect between the pharmacological activity of chemotherapeutic drugs and ultrasound has been reported for a variety of agents. Loverock et al. Exposure to ultrasound alone did not affect cell viability. Flow cytometry revealed an increase in Dox concentration inside the cells, but the authors did not attribute the increased uptake to any particular mechanism.
Tachibana et al. Ultrasonication for seconds in the presence of Ara-C, reduced the number of observed colonies fold when compared to cells incubated with the same concentration of the drug. This increase in cell death was not caused by hyperthermia, since the temperature increase was less than 0.
They concluded that low intensity ultrasound altered the cell membrane, which resulted in the increase of Ara-C cell uptake. In another study, Tachibana et al. They claimed that sonoporation caused the cytoplasm of HL60 cells to extrude through pores formed in their cell membrane. The same effect was not observed when cells were exposed to ultrasound alone, thus implicating a synergism between the drug and US. Saito et al. The increase in permeability appeared to be reversible and the cells regained their membrane integrity after several minutes.
Rapoport et al. They found that the amount of Dox that intercalated the DNA increased after one hour of insonation. In another related study, Munshi et al. Yu et al. They concluded that the synergism reported was not due to the decrease of the multidrug resistance mdr1 gene level by insonation. Thus multidrug resistance gene expression is not inhibited by ultrasound. The group did not report whether any changes in drug accumulation occurred.
Some investigators attribute this synergism between drug activity and ultrasound to an increase in the local temperature of the sonicated area hyperthermia [ — ]. Saad and Hahn exposed Chinese hamster cells to US average intensities range between 0. The study showed that at lower intensities 0.
To summarize, ultrasound has been used in combination with chemotherapeutic agents for increased efficacy. Insonation appears to enhance the transport of drugs into cells and tissues. Considering the physics of cavitation processes, we opine that ultrasound produces transient micropores in the cell membrane, which would increase the passive accumulation of the drugs in the cells and tissues. Although the cytotoxic effect of chemotherapeutic agents has been shown to increase with insonation, this effect has not been shown to be independent of any increase in drug uptake.
Most studies attribute ultrasonic enhanced killing of cancer cells in the presence of drugs to a phenomena called chemopotentiation. The use of the term chemopotentiation is rather misleading, since it suggests that ultrasound alters the structure of the drug and renders the chemical more potent. Most data reported in literature support the hypothesis that ultrasound permeabilizes the membrane so that more chemotherapeutic drug molecules are able to diffuse into the cells.
In some cases, the permeabilization appears truly synergistic in that both drug and ultrasound are required simultaneously to render the cell membrane more permeable. In general, though, at sufficiently high intensities the ultrasound permeabilizes the membrane, most probably through shear stresses in the membrane from microstreaming or shock waves.
A major problem associated with whole body chemotherapy is not totally alleviated by US; the drug is still delivered systemically thus causing systemic side effects. For this reason, research in recent years has focused on developing molecular vehicles that can sequester the drug inside a package and then release it using ultrasound stimulus at the tumor site.
Two types of drug delivery molecules have been developed for this purpose: polymeric micelles and liposomes. Polymeric micelles have been used to improve site-specific drug delivery in cancer therapy. Although several groups have investigated the use of polymeric carriers to deliver chemotherapeutic as well as other drugs, the only group that has reported the use of polymeric micelles in conjunction with ultrasound is Rapoport, Pitt and colleagues at the University of Utah and Brigham Young University.
At sufficiently high aqueous concentrations they form micelles [ — ]. These micelles have several advantages as drug deliver vehicles. They are stable in blood and other biological fluids. These micelles are large enough to escape renal excretion while being small enough to extravasate at the tumor site. Antineoplastic agents can be easily sequestered inside the core of these polymeric micelles by the simple act of mixing [ , ], this avoiding the complexities involved with covalently boding the drug to the polymeric carrier [ ].
Several studies have reported the effect of Pluronic surfactants in overcoming multidrug resistance MDR [ — ]. Furthermore the PEO chains on the micelle exterior prevent its recognition by cells of the reticulo endothelial system. The feasibility of using ultrasound with Pluronic micelles to deliver anti-cancer agents in vitro was first reported by Munshi et al.
They reported that a combination of 70 kHz ultrasound and Pluronic Pencapsulated Dox substantially increased the cytotoxicity of the drug. The enhanced toxicity upon insonation was attributed to the release of the agent from micelles under the action of ultrasound [ , ].
Using fluorescent microscopy and flow cytometry, thy also reported that insonation enhanced the intracellular uptake of Pluronic micelles and its internalization into the nucleus of HL60 cells [ — ]. The main challenge facing the use of micelles to deliver chemotherapy drugs is that the concentration of the polymer must remain above the critical micellar concentration CMC to guarantee that the micellar structures remain intact and do not dissolve and prematurely release the drug before reaching the target site. Pruitt et al. The network-micellar structure is eventually degraded after a few days the half life is approximately 17 hours [ ].
Nelson et al. When unencapsulated Dox was administered, the same dose was lethal to the rats within two weeks of injection. Gao et al. The study showed that insonation at 1 MHz was able to enhance the accumulation of these labeled micelles at the tumor site in ovarian cancer-bearing nu-nu mice. Using the same in vivo mouse model, Rapoport et al. The mechanisms of this acoustically activated micellar drug delivery system are still being investigated, and there is a strong correlation with insonation frequency and power density that suggests a strong role of stable and transient cavitation.
Unlike micelles, liposomes can sequester both hydrophilic and hydrophobic drugs in their aqueous interior and lipid bilayer membrane respectively. Liposomes are also larger than the previously discussed polymeric micelles; the average diameters of liposomes range between and nm compared to 5—30 nm for micelles. Herman et al. Zvi et al. The studies mentioned above rely on the increased accumulation of liposomes at the tumor site due to increased extravasation passive targeting.
Recently, there have been reports in literature where ultrasound is used as an active targeting mechanism to release drugs from liposomes. Ning et al. Several others reports have shown that other drugs can be released from liposomes using ultrasonic hyperthermia [ 2 , — ]. Rediske et al. This synergistic killing effect was most pronounced at lower frequencies and decreased as the frequency of insonation increased [ , ].
The effect was more pronounced in E. They found that this enhanced killing synergistic effect is prevalent with certain antibiotics the aminoglycosides , but does not exist when others are used. They hypothesized that stable cavitation or sonoporation might be involved in increasing the transport of antibiotics into the bacteria either by reducing the mass transfer boundary layer around the cells, or by altering the cell membrane, thus allowing the antibiotics to diffuse through newly formed membrane pores.
In vivo experiments in a rabbit model of an implant infection confirmed the increased toxicity of gentamicin against E. Pulsed US applied for 48 hours with gentamicin was effective in eliminating E. Vancomycin combined with US was somewhat effective against S. The role of ultrasound in small chemical delivery involves permeabilization of the cell membrane such that these molecules can enter more easily. Currently there is very little known about the details of how US permeabilizes the cell membrane. Are small transient holes formed for microsecond timescales, allowing diffusive entry?
Or are larger more permanent holes or disorganized regions formed? Is a different treatment needed for molecules of different sizes? Neither is much known about how US may regulate gene expression and protein production. Does US cause a stress response similar to heat shock that may enhance or interfere with the action of drugs?
Is this response similar for all cells and does it differ for various ultrasonic frequencies and intensities? These and other questions about cell physiology need to be addressed. Finally, liposomes used in drug delivery are thermodynamically stable, but are cleared by the reticulo-endothelial system RES. Alternatively, micelles may not be cleared by the RES, but they are thermodynamically unstable when diluted in blood.
Neither system is ideal, and thus there is a need to make the liposomes more stealthy and the micelles more stable. Obviously the field of ultrasonic-enhanced drug delivery has expanded tremendously during the past decade, and we expect that this trend will continue as our understanding and technology increases. Furthermore, the use of microbubbles to assist drug delivery has exploded in the past 5 years, and we expect that much of the technological growth in the next decade will be in the clever use of microbubbles and ultrasonic pulse sequences.
The published literature regarding US and microbubble in gene delivery is solid, makes important contributions, and is definitely worth studying. This review has cited many innovations, and more are sure to come. We posit that US-enhanced gene delivery will experience the greatest growth and provide the greatest medical contribution because ultrasound and microbubbles allow genes to be delivered through non-viral technologies to specific locations.
Such genetic therapy can make monumental contributions to the treatment of heart disease, vascular disease, cancer, autoimmune diseases, and much more. As microbubble collapse is controlled and fine-tuned, we speculate that it can be applied to deliver genetic therapy to the brain to treat neurological diseases. The area of protein delivery has been limited in the past to insulin delivery technology, and will probably remain so, with some small expansion into delivery of a few other small regulatory hormones.
Despite 10 years of solid research on transdermal delivery of proteins, there are still limitations in the rate at which a protein can pass through the skin without inflicting permanent damage. Transport can be increased by increasing the surface area, but a larger treatment area and heavy transducers may lead to difficulty with patient compliance. We foresee some growth in this area, but not wide clinical application until the size of the transducer is reduced such that it can be easily attached and carried at work or at home.
Technological developments for small chemical delivery will follow those of gene delivery. For cancer chemotherapy or antibiotic therapy, delivery to specific tissues will be targeted by decorating the carriers or microbubbles with antibodies or other site-specific adhesive molecules. The basis of future technological advancement requires a better understanding of the behaviour of microbubbles in ultrasonic fields. This will require more modeling and experimental understanding of the physics of microbubble oscillation and collapse as a function of microbubble size, internal gas composition, membrane or wall thickness and mechanical properties modulus, shear strength, viscosity, etc.
What are the optimal bubble sizes and ultrasonic frequencies for drug delivery? The goal of such research should be to develop the acoustic parameters and perhaps the pulse sequences that can excite a bubble to cavitate without imposing mechanical or thermal damage to tissues. Some modeling effort has commenced [ 17 , ], but much more is needed. Even better would be a multi-frequency transducer that can perform three functions, perhaps all at different frequencies: target imaging, bubble destruction, and cell membrane permeabilization. As mentioned in conjunction with transdermal drug delivery, small-sized low-frequency transducers need to be developed so that patients can wear them for continuous insulin delivery.
Although some intra-luminal transducers are available in a catheter format, these are currently designed for imaging; catheter-based transducers also need to be developed for drug delivery. Finally, we must not forget the issue of biological response to these new applications of US in drug delivery. Is the frequency for optimum drug release from a carrier also the optimum frequency for permeabilizing a cell membrane without destroying the cell?
It is very probable that frequencies that optimize membrane permeability are different that frequencies that optimize drug release. Thus the response of cells and their membranes to US must be studied so that in our efforts to optimize drug release we do not produce collateral damage to the target or adjacent tissues.
In our opinion the best current technologies are those that employ gas bubbles that have the therapeutic agent in or on the bubble, such as DNA decorating the exterior of a surfactant-stabilized microbubble, or a thick-shelled microbubble [ 12 , 42 ] that can carry the drug inside, either in an oil or aqueous phase. In these systems the drug and cavitation agent are intimately mixed and drug is therefore released at the location where tissues are stressed by cavitation. Micelles and liposomes without gas are less useful because the cavitation is not necessarily produced at the same time or place as is the drug.
Application of free drug or free DNA is least efficient because it is not sequestered, and thus can interact with non-targeted tissue or be cleared or degraded before it can reach therapeutic concentrations. Gas liposomes or microbubbles constructed from native proteins such as albumin or having poly ethylene oxide chains on the surface may have an advantage in that they will not be recognized and cleared as fast from the circulatory system [ , ].
Another current and innovative technology in which we anticipate more growth is the attachment of targeting molecules to microbubbles or drug carriers. Because the targeting molecules may be different for each application such as unique of individualized antibodies , it may be advantageous to attach a generic binder to the microbubbles. Then the specific antibodies could be attached to a complementary binder. The target-specific antibodies could then be mixed with the generic microbubbles to create custom drug delivery systems with the drug attached to the bubbles.
Although biotin and streptavidin have been suggested for such a system [ ], these proteins may elicit an antigenic response. Thus other systems should be investigated such as a self-assembled biological system or a chemical system such as maleimide-thiol bond formation. Without a crystal ball, one cannot predict what specific technology will be in place 10 years from now. However, we can predict that ultrasonic-activated drug delivery will play an ever-increasing role in targeted drug therapies.
Thus, the presence of microbubbles enormously enhances ultrasonic delivery of genetic material, proteins and smaller chemical agents. Numerous reports show that the most efficient delivery of genetic material occurs in the presence of cavitating microbubbles. Attaching the DNA directly to the microbubbles, or to gas-containing liposomes, enhances gene uptake even further.
Ultrasonic-enhanced gene delivery has been studied in various tissues, including cardiac, vascular, skeletal muscle, tumour and even fetal tissue. Ultrasonic-assisted delivery of proteins has found most application in transdermal transport of insulin. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; and makes cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has on cells and drug-carrying vesicles.
The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Expert Opin Drug Deliv. Author manuscript; available in PMC Feb 6. PMID: William G. Pitt , Dr.
Husseini , Dr. Ghaleb A. Bryant J. Corresponding Author: Dr. Pitt, Clyde Bldg. Copyright notice. The publisher's final edited version of this article is available at Expert Opin Drug Deliv. See other articles in PMC that cite the published article.
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Abstract Ultrasound US has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Keywords: ultrasound, targeted drug delivery, liposomes, microbubbles, micelles, chemopotentiation, hyperthermia, cavitation, DNA, protein, chemotherapy. Mechanisms of Ultrasonic-Enhanced Drug Delivery Ultrasound US has been employed to enhance the delivery and activity of drugs for the past two decades.
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