Applying drugs to brain via scalp (transdermal)

Many medications are intended only for the brain, but are taken orally. Hence <10% finds its intended target, while the remaining >90% is at best wasted, and at worst causes unwanted side-effects.

Valproate is a classic example; it is medicated as an antiepileptic, but only a small fraction crosses the brain blood barrier to make it into the brain. Because of this, a large dose is required, and unwanted side-effects are common.

However, certain (small molecule?) drugs (e.g. Ibuprofen) can be applied transdermally.

For a drug intended for brain tissue that allows transdermal application, is there any sense in applying on the (preferably shaved) scalp?

Is this a known mechanism of administration? If so, does it have a name?

Is there any way of correctly scaling the dosage? For example, if experiment shows that 50% of substance X taken transdermally reaches the bloodstream, if it is administered to the scalp is there any way of figuring out how much ends up in the brain and how much ends up in the rest of the body? Since this is a tricky and obscure question, may I also ask this: how to go about finding an answer to this? Where else can I ask?

The short answer is no, it will take forever for a drug to pass through skull bones.

The usual reason to apply drugs on skin is if you want them to act right there, on the skin. Acne creams fit here. You need less drugs, you get where it is needed sooner, and you have fewer off-target effects, when compared to taking them by mouth. The brain is not "right there", so this scenario does not apply.

The second reason is convenience. Some drugs cannot by taken by mouth, because they would be degraded by the stomach or guts. In most cases, the drug has to be given through painful, expensive injections. But if such a drug does pass through skin (usually when it is a fat-loving small molecule), you may get away with applying it on skin. Testosterone is one such drug. However, it usually doesn't matter whether the skin you are applying on is close of far from the target organ. The drug will be taken from the skin by blood, get to the heart through veins, and then spread to the whole body, eventually reaching the target. There is no reason to shave your head, since it will go through the same detour before reaching the desired destination.

Biomedical applications of microemulsion through dermal and transdermal route

Microemulsions are thermodynamically stable, transparent, colloidal drug carrier system extensively used by the scientists for effective drug delivery across the skin. It is a spontaneous isotropic mixture of lipophilic and hydrophilic substances stabilized by suitable surfactant and co-surfactant. The easy fabrication, long-term stability, enhanced solubilization, biocompatibility, skin-friendly appearance and affinity for both the hydrophilic and lipophilic drug substances make it superior for skin drug delivery over the other carrier systems. The topical administration of most of the active compounds is impaired by limited skin permeability due to the presence of skin barriers. In this sequence, the microemulsion represents a cost-effective and convenient drug carrier system which successfully delivers the drug to and across the skin. In the present review work, we compiled various attempts made in last 20 years, utilizing the microemulsion for dermal and transdermal delivery of various drugs. The review emphasizes the potency of microemulsion for topical and transdermal drug delivery and its effect on drug permeability.

The blood–brain barrier is formed by special tight junctions between endothelial cells lining brain blood vessels. Blood vessels of all tissues contain this monolayer of endothelial cells, however only brain endothelial cells have tight junctions preventing passive diffusion of most substances into the brain tissue. [1] The structure of these tight junctions was first determined in the 1960s by Tom Reese, Morris Kranovsky and Milton Brightman. Furthermore, astrocytic "end feet", the terminal regions of the astrocytic processes, surround the outside of brain capillary endothelial cells". [1] The astrocytes are glial cells restricted to the brain and spinal cord and help maintain blood-brain barrier properties in brain endothelial cells. [1]

The main function of the blood–brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in the blood stream. It accomplishes this because of its structure, as is usual in the body that structure defines its function. The tight junctions between the endothelial cells prevent large molecules as well as many ions from passing between the junction spaces. This forces molecules to go through the endothelial cells in order to enter the brain tissue, meaning that they must pass through the cell membranes of the endothelial cells. [2] Because of this, the only molecules that are easily able to transverse the blood–brain barrier are ones that are very lipid-soluble. These are not the only molecules that can transverse the blood–brain barrier glucose, oxygen and carbon dioxide are not lipid-soluble but are actively transported across the barrier, to support normal cellular function of the brain. [3] The fact that molecules have to fully transverse the endothelial cells makes them a perfect barricade to unspecified particles from entering the brain, working to protect the brain at all costs. Also, because most molecules are transported across the barrier, it does a very effective job of maintaining homeostasis for the most vital organ of the human body. [1]

Because of the difficulty for drugs to pass through the blood–brain barrier, a study was conducted to determine the factors that influence a compound’s ability to transverse the blood–brain barrier. In this study, they examined several different factors to investigate diffusion across the blood–brain barrier. They used lipophilicity, Gibbs Adsorption Isotherm, a Co CMC Plot, and the surface area of the drug to water and air. They began by looking at compounds whose blood–brain permeability was known and labeled them either CNS+ or CNS- for compounds that easily transverse the barrier and those that did not. [4] They then set out to analyze the above factors to determine what is necessary to transverse the blood–brain barrier. What they found was a little surprising lipophilicity is not the leading characteristic for a drug to pass through the barrier. This is surprising because one would think that the most effective way to make a drug move through a lipophilic barrier is to increase its lipophilicity, it turns out that it is a complex function of all of these characteristics that makes a drug able to pass through the blood–brain barrier. The study found that barrier permittivity is "based on the measurement of the surface activity and as such takes into account the molecular properties of both hydrophobic and charged residues of the molecule of interest." [4] They found that there is not a simple answer to what compounds transverse the blood–brain barrier and what does not. Rather, it is based on the complex analysis of the surface activity of the molecule as well as relative size.

Other problems persist besides just simply getting through the blood–brain barrier. The first of these is that a lot of times, even if a compound transverses the barrier, it does not do it in a way that the drug is in a therapeutically relevant concentration. [5] This can have many causes, the most simple being that the way the drug was produced only allows a small amount to pass through the barrier. Another cause of this would be the binding to other proteins in the body rendering the drug ineffective to either be therapeutically active or able to pass through the barrier with the adhered protein. [6] Another problem that must be accounted for is the presence of enzymes in the brain tissue that could render the drug inactive. The drug may be able to pass through the membrane fine, but will be deconstructed once it is inside the brain tissue rendering it useless. All of these are problems that must be addressed and accounted for in trying to deliver effective drug solutions to the brain tissue. [5]

Exosomes to deliver treatments across the blood–brain barrier Edit

A group from the University of Oxford led by Prof. Matthew Wood claims that exosomes can cross the blood–brain barrier and deliver siRNAs, antisense oligonucleotides, chemotherapeutic agents and proteins specifically to neurons after inject them systemically (in blood). Because these exosomes are able to cross the blood–brain barrier, this protocol could solve the issue of poor delivery of medications to the central nervous system and cure Alzheimer's, Parkinson's Disease and brain cancer, among other diseases. The laboratory has been recently awarded a major new €30 million project leading experts from 14 academic institutions, two biotechnology companies and seven pharmaceutical companies to translate the concept to the clinic. [7] [8] [9] [10]

Pro-drugs Edit

This is the process of disguising medically active molecules with lipophilic molecules that allow it to better sneak through the blood–brain barrier. Drugs can be disguised using more lipophilic elements or structures. This form of the drug will be inactive because of the lipophilic molecules but then would be activated, by either enzyme degradation or some other mechanism for removal of the lipophilic disguise to release the drug into its active form. There are still some major drawbacks to these pro-drugs. The first of which is that the pro-drug may be able to pass through the barrier and then also re-pass through the barrier without ever releasing the drug in its active form. The second is the sheer size of these types of molecules makes it still difficult to pass through the blood–brain barrier. [11]

Peptide masking Edit

Similar to the idea of pro-drugs, another way of masking the drugs chemical composition is by masking a peptide’s characteristics by combining with other molecular groups that are more likely to pass through the blood–brain barrier. An example of this is using a cholesteryl molecule instead of cholesterol that serves to conceal the water soluble characteristics of the drug. This type of masking as well as aiding in traversing the blood–brain barrier. It also can work to mask the drug peptide from peptide-degrading enzymes in the brain [7] Also a "targetor" molecule could be attached to the drug that helps it pass through the barrier and then once inside the brain, is degraded in such a way that the drug cannot pass back through the brain. Once the drug cannot pass back through the barrier the drug can be concentrated and made effective for therapeutic use. [7] However drawbacks to this exist as well. Once the drug is in the brain there is a point where it needs to be degraded to prevent overdose to the brain tissue. Also if the drug cannot pass back through the blood–brain barrier, it compounds the issues of dosage and intense monitoring would be required. For this to be effective there must be a mechanism for the removal of the active form of the drug from the brain tissue. [7]

Receptor-mediated permabilitizers Edit

These are drug compounds that increase the permeability of the blood–brain barrier. [12] By decreasing the restrictiveness of the barrier, it is much easier to get a molecule to pass through it. These drugs increase the permeability of the blood–brain barrier temporarily by increasing the osmotic pressure in the blood which loosens the tight junctions between the endothelial cells. By loosening the tight junctions normal injection of drugs through an [IV] can take place and be effective to enter the brain. [8] This must be done in a very controlled environment because of the risk associated with these drugs. Firstly, the brain can be flooded with molecules that are floating through the blood stream that are usually blocked by the barrier. Secondly, when the tight junctions loosen, the homeostasis of the brain can also be thrown off which can result in seizures and the compromised function of the brain. [8]

Nanoparticles Edit

The most promising drug delivery system is using nanoparticle delivery systems, these are systems where the drug is bound to a nanoparticle capable of traversing the blood–brain barrier. The most promising compound for the nanoparticles is Human Serum Albumin (HSA). The main benefits of this is that particles made of HSA are well tolerated without serious side effects as well as the albumin functional groups can be utilized for surface modification that allows for specific cell uptake. [5] These nanoparticles have been shown to transverse the blood–brain barrier carrying host drugs. To enhance the effectiveness of nanoparticles, scientists are attempting to coat the nanoparticles to make them more effective to cross the blood–brain barrier. Studies have shown that "the overcoating of the [nanoparticles] with polysorbate 80 yielded doxorubicin concentrations in the brain of up to 6 μg/g after i.v. injection of 5 mg/kg" as compared to no detectable increase in an injection of the drug alone or the uncoated nanoparticle. [13] This is very new science and technology so the real effectiveness of this process has not been fully understood. However young the research is, the results are promising pointing to nanotechnology as the way forward in treating a variety of brain diseases.

Loaded microbubble-enhanced focused ultrasound Edit

Microbubbles are small "bubbles" of mono-lipids that are able to pass through the blood–brain barrier. They form a lipophilic bubble that can easily move through the barrier. [14] One barrier to this however is that these microbubbles are rather large, which prevents their diffusion into the brain. This is counteracted by a focused ultrasound. The ultrasound increases the permeability of the blood–brain barrier by causing interference in the tight junctions in localized areas. This combined with the microbubbles allows for a very specific area of diffusion for the microbubbles, because they can only diffuse where the ultrasound is disrupting the barrier. [10] The hypothesis and usefulness of these is the possibility of loading a microbubble with an active drug to diffuse through the barrier and target a specific area. [10] There are several important factors in making this a viable solution for drug delivery. The first is that the loaded microbubble must not be substantially greater than the unloaded bubble. This ensures that the diffusion will be similar and the ultrasound disruption will be enough to induce diffusion. A second factor that must be determined is the stability of the loaded micro-bubble. This means is the drug fully retained in the bubble or is there leakage. Lastly, it must be determined how the drug is to be released from the microbubble once it passes through the blood–brain barrier. Studies have shown the effectiveness of this method for getting drugs to specific sites in the brain in animal models. [10]

Applications of Polymers in Drug Delivery

Applications of Polymers in Drug Delivery, Second Edition, provides a comprehensive resource for anyone looking to understand how polymeric materials can be applied to current, new, and emerging drug delivery applications.

Polymers play a crucial role in modulating drug delivery and have been fundamental in the successful development of many novel drug delivery systems. This book describes the development of polymeric systems, ranging from conventional dosage forms to the most recent smart systems. Regulatory and intellectual property aspects as well as the clinical applicability of polymeric drug delivery systems are also discussed. The chapters are organized by specific delivery route, offering methodical and detailed coverage throughout. This second edition has been thoroughly revised to include the latest developments in the field.

This is an essential book for researchers, scientists, and advanced students, in polymer science, drug delivery, pharmacology/pharmaceuticals, materials science, tissue engineering, nanomedicine, chemistry, and biology. In industry, this book supports scientists, R&D, and other professionals, working on polymers for drug delivery applications.

Applications of Polymers in Drug Delivery, Second Edition, provides a comprehensive resource for anyone looking to understand how polymeric materials can be applied to current, new, and emerging drug delivery applications.

Polymers play a crucial role in modulating drug delivery and have been fundamental in the successful development of many novel drug delivery systems. This book describes the development of polymeric systems, ranging from conventional dosage forms to the most recent smart systems. Regulatory and intellectual property aspects as well as the clinical applicability of polymeric drug delivery systems are also discussed. The chapters are organized by specific delivery route, offering methodical and detailed coverage throughout. This second edition has been thoroughly revised to include the latest developments in the field.

This is an essential book for researchers, scientists, and advanced students, in polymer science, drug delivery, pharmacology/pharmaceuticals, materials science, tissue engineering, nanomedicine, chemistry, and biology. In industry, this book supports scientists, R&D, and other professionals, working on polymers for drug delivery applications.

Toxicological hazards of nanoparticles

General concepts

To use the potential of Nanotechnology in Nanomedicine, full attention is needed to safety and toxicological issues. For pharmaceuticals specific drug delivery formulations may be used to increase the so called therapeutic ratio or index being the margin between the dose needed for clinical efficacy and the dose inducing adverse side effects (toxicity). However, also for these specific formulations a toxicological evaluation is needed. This is particularly true for the applications of nanoparticles for drug delivery. In these applications particles are brought intentionally into the human body and environment, and some of these new applications are envisaged an important improvement of health care ( Buxton et al 2003 European Technology Platform on Nanomedicine 2005 Ferrari 2005 ). Opinions started to divert when toxicologists claimed that new science, methods and protocols are needed ( Borm 2002 Nel et al 2006 ). However, the need for this is now underlined by several expert reports ( Oberdörster, Maynard et al 2005 SCENIHR 2006 ) and more importantly by the following concepts:

Nanomaterials are developed for their unique (surface) properties in comparison to bulk materials. Since surface is the contact layer with the body tissue, and a crucial determinant of particle response, these unique properties need to be investigated from a toxicological standpoint. When nanoparticles are used for their unique reactive characteristics it may be expected that these same characteristics also have an impact on the toxicity of such particles. Although current tests and procedures in drug and device evaluation may be appropriate to detect many risks associated with the use of these nanoparticles, it cannot be assumed that these assays will detect all potential risks. So, additional assays may be needed. ( SCENIHR 2006 ) This may differ depending on the type of particles used, ie, biological versus non-biological origin.

Nanoparticles are attributed qualitatively different physico-chemical characteristics from micron-sized particles, which may result in changed body distribution, passage of the blood brain barrier, and triggering of blood coagulation pathways. In view of these characteristics specific emphasis should be on investigations in (pharmaco)kinetics and distribution studies of nanoparticles. What is currently lacking is a basic understanding of the biological behavior of nanoparticles in terms of distribution in vivo both at the organ and cellular level.

Effects of combustion derived nanoparticles in environmentally exposed populations mainly occur in diseased individuals. Typical pre-clinical screening is almost always done in healthy animals and volunteers and risks of particles may therefore be detected at a very late stage.

It may be argued that some if not all of these specific effects will be detected during routine testing and post marketing evaluation after clinical use. All would depend on the types of assays used in the preclinical evaluation, which should be considered in the light of the use of the final products. In addition, one cannot rely on the toxicological profile of the bulk material when that material is used in a nanoformulation. What is clear is that the safety evaluation and the risk benefit analysis need to be performed on a case by case basis.

The use of nanoparticles as drug carrier may reduce the toxicity of the incorporated drug. In general the toxicity of the whole formulation is investigated while results of the nanoparticles itself are not described. So, discrimination between drug and nanoparticle toxicity cannot be made. So, there should be a specific emphasis on the toxicity of the 𠇎mpty” non-drug loaded particles. This is especially important when slowly or non degradable particles are used for drug delivery which may show persistence and accumulation on the site of the drug delivery, eventually resulting in chronic inflammatory reactions.

Evidence for nanoparticle toxicity

The largest database on the toxicity of nanoparticles has originated from inhalation toxicology including the PM10 literature (particulate matter with a size below 10 mm), where the ‘NP hypothesis’ has proved to be a powerful drive for research ( Donaldson et al 2002 , 2004 Oberdörster, Oberdörster et al 2005 Borm et al 2006 ). An overview of particle terminology in relation to ambient effects is given in Table 3 . Therefore it relevant to discuss this evidence in the expectation that it will shed light on the toxicity of engineered NPs. The idea that combustion-derived NPs are an important component that drives the adverse effects of environmental particulate air pollution or PM10 comes from several sources:

Table 3

Various denominations of particles in inhalation toxicology and drug delivery in relation to their source (ambient, bulk, engineered)

Particle typeDescription
PM10, PM2.5Particle mass fraction in ambient air with a mean diameter of 10 or 2.5 μm respectively. Basis of current standards for ambient particles in Europe and USA
Coarse particlesThe mass fraction of PM10, which is bigger than 2.5 μm
Ultrafine particles (PM0.1)The fraction of PM10 with a size cut-off at 0.1 μm. Contains primary particles and agglomerates smaller than 100 nm
PSPPoorly soluble particles with low specific toxicity. Maybe be fine or ultrafine. Terminology used in relation to bulk synthetic particles. Examples TiO2, carbon blacks, Amorphous silica, Iron oxides (Fe2O3), Zinc oxides (ZnO)
CDNPCombustion derived nanoparticles, such as diesel exhaust particles (DEP)
DEPDiesel exhaust particles

Much of the mass of PM10 is considered to be non-toxic and so there has arisen the idea that there is a component(s) of PM10 that actually drives the pro-inflammatory effects and combustion-derived NP seems a likely candidate.

Nanoparticles are the dominant particle type by number suggesting that they may be important and their small size means that they have a large surface area per unit mass. Particle toxicology suggests that, for toxic particles generally, more particle surface equals to more toxicity.

Substantial toxicological data and limited data from epidemiological sources support the contention that NPs in PM10 are important drivers of adverse effects.

The adverse health effects of particulate matter (PM) are measurable as exacerbations of respiratory disease and deaths as well as hospitalizations and deaths from respiratory and cardiovascular disease ( Dockery et al 1993 Brooke et al 2004 Pope et al 2004 ). Inflammation is the common factor that binds together these adverse effects and the ability of NPs to cause inflammation can be seen as an important property. It is not clear what effects of NPs have pulmonary inflammation as a prerequisite and what effects could potentially be driven by exposures below those causing inflammation. There is also the potential for pulmonary inflammation to result in changes in membrane permeability that in turn may impact the potential for particles to distribute beyond the lung. Some NPs may have the extra potential of affecting cardiovascular disease directly. Vascular function was impaired after inhalation of diesel exhaust particles ( Mills et al 2005 ). However, data to date are limited and not all studies of nanoparticles have shown significant translocation from lung to the blood. In some studies translocation has been rather minimal ( Kreyling et al 2002 Takenaka et al 2006 ). Understanding clearance kinetics of inhaled ambient air nanoparticles will also be important in understanding their potential for adverse effects.

The current paradigm in particle toxicology is that ultrafine ambient air particles have the potential of affecting cardiovascular disease both indirectly via pulmonary inflammation and directly through particle distribution. Although important, this property of redistribution has yet to be demonstrated for NPs present in real PM10. It should be noted that there are several mechanisms whereby NPs could lead to inflammatory effects, as is the case for larger particles. These mechanisms are either based on the large surface area of particle core or on soluble components released by the NPs. In addition various chemicals including those of biological origin like endotoxin may be adsorbed onto the NP and released ( Carty et al 2003 Kreyling et al 2004 Schins et al 2004 ). Several toxicological studies support the contention that NPs in PM10 could drive inflammatory effects. There are a number of components of PM10 that contribute to the mass but have little toxicity – these include salts such as sulfates, chlorides and ammonium salts and nitrates, but also wind-blown or crustal dust. In fact within PM10 there are only few components that toxicologists would identify as likely mediators of adverse effects – ie, particle surfaces, organics, metals and endotoxin (in some PM10 samples). In fact, a large surface area, organics and metals are all characteristic of combustion�rived particles and so these have attracted considerable toxicological attention ( Donaldson et al 2005 ). However, it is difficult to untangle, in a combustion particle sample, the relative roles of surface, organics and metals, although this has been most attempted in vitro. The aggregation of multiple chemical species including biological compounds like endotoxin limits the extrapolation of the results on the toxicological effects of such particles.

Toxicological effects of nanoparticles

As already mentioned above, NPs exert some very special properties that are very relevant in the further design of toxicity testing of engineered nanomaterials. An overview of most striking effects of (nano) particles that have been observed over the last decades is given in Table 4 along with the particle type that have been tested in this response. Several effects are just quantitatively different from fine particles. In this case nanoparticles may cause the same effects as ‘traditional’ particles (eg, inflammation, lung cancer) but they may be more potent because of their greater surface area.

Table 4

Toxicity of engineered and combustion (nano) particles as illustrated by their most unique adverse effects in vivo and in vitro

Description of finding, in vivoParticle types
NPs cause pulmonary inflammation in the ratAll PSP
Later studies show that inflammation is mediated by surface area doseSWCNT, MWCNT
NPs cause more lung tumors than fine particles in rat chronic studies. Effect is surface area mediatedPSP only
NPs cause progression of plague formation (ApoE -/- mice)SWCNT, PM2.5
NPs affect immune response to common allergensPolystyrene, CB, DEP
NsP can have access to systemic circulation upon inhalation and instillationSpecific NP, dependent on surface coating
Description of finding, in vitro
NPs cause oxidative stress in vivo and in vitro, by inflammatory action and generation of surface radicalsPSP, NP general, CNT
NPs inhibit macrophage phagocytosis, mobility and killingCB, TiO2
NPs cause platelet aggregationPM, SWCNT, fullerenes, latex-COOH surface
NPs exposure adversely affects cardiac function and vascular homeostasisPM, SWCNT
NPs interfere with Ca-transport and cause increased binding of pro-inflammatory transcription factor NF-kBCB (< 100 nm), ROFA, PM2.5
NPs can affect mitochondrial functionAmbient NP,
NPs can translocate to the brain from the noseMnO2, Au, carbon
NPs do affect rolling in hepatic tissueCB

However, nanoparticles could also cause new types of effects not previously seen with larger particles (eg, mitochondrial damage, uptake through olfactory epithelium, platelet aggregation, cardiovascular effects). These effects depicted in Table 4 clearly need a new way of handling their toxicology. In addition, epidemiological evidence suggests that these effects occur predominantly in subjects that have an impaired health. This finding should be considered in developing toxicological testing models.

Effects on blood and cardiovascular system

As we discussed earlier, ligand coated engineered nanoparticles are being explored and used as agents for molecular imaging or drug delivery tools. This has led to a considerable understanding of particle properties that can affect penetration in tissue without affecting tissue function. Cationic NPs, including gold and polystyrene have been shown to cause hemolysis and blood clotting, while usually anionic particles are quite non-toxic. This conceptual understanding maybe used to prevent potential effects of unintended NP exposure. Similarly, drug loaded nanoparticles have been used to prolong half-life or reduce side-effects and have shown which particle properties need to be modified to allow delivery, while being biocompatible ( Gupta and Gupta 2005 ).

On the other hand, one is trying to find explanations for the increased risk of patients with cardiovascular diseases upon exposure to PM and/or traffic. Several toxicological studies have demonstrated that combustion and model NPs can gain access to the blood following inhalation or instillation and can enhance experimental thrombosis but it is not clear whether this was an effect of pulmonary inflammation or particles translocated to the blood ( Nemmar et al 2002 , 2003 Mills et al 2005 ). High exposures to DEP by inhalation caused altered heart rate in hypertensive rats ( Campen et al 2003 ) interpreted as a direct effect of DEP on the pacemaker activity of the heart. Inflammation in distal sites has long been associated with destabilization of atheromatous plaques and both instillation and inhalation of PM cause morphological evidence of atheromatous plaque increase and destabilization in rabbits ( Suwa et al 2002 ) and mice ( Chen and Nadziejko 2005 ). Ultrafine carbon black instilled into the blood has been reported to induce platelet accumulation in the hepatic microvasculature of healthy mice in association with prothrombotic changes on the endothelial surface of the hepatic microvessels ( Khandoga et al 2004 ). Recent studies with carbon derived nanomaterials showed that platelet aggregation was induced by both single and multi-wall carbon nanotubes, but not by the C60-fullerenes that are used as building blocks for these CNT ( Radomski et al 2005 ). These data show that not all nanomaterials act similar in this test, and that surface area is not the only factor playing a role here. The data also corroborate the earlier concept developed in medicine that mainly cationic species have an effect on blood clotting. Interestingly, this is the first study that allows bridging of data, since also a real life PM10 sample (SRM1648) was included in the test-series. Actually the PM sample showed a lower effect compared to the carbon nanotubes ( Radomski et al 2005 ).

Uptake and effects of nanoparticles in the brain

Nanoparticles can get access to the brain by two different mechanisms, ie, (1) transsynaptic transport after inhalation through the olfactory epithelium, and (2) uptake through the blood-brain barrier. The first pathway has been studied primarily with model particles such as carbon, Au and MnO2 in experimental inhalation models in rats ( Oberdörster et al 2004 Oberdörster, Oberdörster et al 2005 ). The second pathway has been the result of extensive research and particle surface manipulation in drug delivery ( Kreuter 2001 Koziara et al 2006 Tiwari and Amiji 2006 ). The latter studies suggest that the physiological barrier may limit the distribution of some proteins and viral particles after transvascular delivery to the brain, suggesting that the healthy BBB contains defense mechanisms protecting it from blood borne nanoparticle exposure. When nanoparticles with different surface characteristics were evaluated, neutral nanoparticles and low concentrations of anionic nanoparticles were found to have no effect on BBB integrity, whereas high concentrations of anionic nanoparticles and cationic nanoparticles were toxic for the BBB. Nanoparticles have been shown to induce the production of reactive oxygen species and oxidative stress ( Nel et al 2006 ) and this has been confirmed in the brain after inhalation of MnO2 nanoparticles ( Elder et al 2006 ). Oxidative stress has been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Evidence for the involvement of ambient air nanoparticles in these effects is presented by studies in biopsies from city dwellers. Alzheimer’s like pathology was demonstrated in brain sections by increased markers of inflammation and AB42-accumulation in frontal cortex and hippocampus in association with the presence of nanoparticles ( Calderon-Garciduenas et al 2004 ). Also inhalation exposure of BALB/c mice to particulate matter showed activation of pro-inflammatory cytokines in the brain ( Campbell et al 2005 ). Whether this is due to the fraction of combustion nanoparticles remains to be investigated.


The major conclusions of our literature review on the safety of topically applied ethanol are summarized in the Appendix.

The facts that ethanol is widely used in topical applications and that its adverse effects were seldom reported should not be dismissed. But a confounding factor in any study is the widespread use of alcoholic beverages. However, the prevalent consumption of alcoholic beverages in our society cannot be used as an excuse to completely negate any adverse effect of ethanol in cosmetic or other topical preparations, especially in occupational settings with high exposure to the ethanol containing products. As was pointed out in some of the studies reviewed in this article, the possibility exists that on the point of impact, very high concentrations of ethanol and acetaldehyde may cause chronic toxic effects. The effects may be more pronounced in ALDH-deficient humans, but this association demands further research.

Due to the conflicting evidence in many cases, the precautionary toxicological principle should be currently favoured in the evaluation of ethanol for topical uses. Until unambiguous evidence about the safety of ethanol in topical preparations exists, the necessity of its use should be critically evaluated. In certain product groups (e.g. mouthwashes), ethanol can be easily substituted for other compounds. In other product groups - especially hand disinfectants in hospital hygiene -, the advantages for the patients may outweigh the potential risks for the users. However, in this case, the formulations should be critically evaluated if ethanol cannot be at least partially substituted with e.g. other alcohols with a more favourable toxicological profile.

Assessment of cosmetic safety was introduced into European cosmetics law by Council Directive 93/35/EEC (amending for the sixth time Directive 76/768/EEC on the approximation of the laws relating to cosmetic products) [8]. This Directive is an important instrument in the protection of consumer health in terms of the use of cosmetic products. A re-examination and actualization of the safety assessment is necessary if scientific evidence concerning the ingredient employed in cosmetics changes [189]. With respect to the past years' scientific findings about the carcinogenic properties of ethanol, and the recent re-evaluation of this agent by the International Agency for Research on Cancer (IARC), it seems necessary to re-evaluate and actualize the safety assessment of topical products that contain this alcohol.

Finally, an advancement in testing strategies for genotoxicity and mutagenicity appears to be necessary [190], with a refocus on testing the final formulation rather than the isolated constituents [191]. The effect of ethanol as penetration enhancer for other constituents of the formulations must especially be considered in such a safety evaluation of cosmetics.

Chemotherapy: Scalp cooling physically protects hair follicles

Ground-breaking research from the University of Huddersfield, announced ahead of World Cancer Day 2021, demonstrates that scalp cooling physically protects hair follicles from chemotherapy drugs. It is the world's first piece of biological evidence that explains how scalp cooling actually works and the mechanism behind its protection of the hair follicle.

The study, entitled 'Cooling-mediated protection from chemotherapy drug-induced cytotoxicity in human keratinocytes by inhibition of cellular drug uptake', has been published in the peer-reviewed journal PLOS ONE.

The data was part of an innovative hair follicle research project carried out by the dedicated Scalp Cooling Research Centre based at the University of Huddersfield. It involved the cultivation of cells isolated from human hair follicles in the lab.

The £1 million Scalp Cooling Research Centre was established at the University in 2019 with the backing of Huddersfield firm Paxman -- global leaders in scalp cooling technology.

The team of experts in biology and design technology have been working together with the aim of Paxman becoming the only hair loss-preventing scalp cooling provider firmly based on biological research. It also brings the family-run business one step closer to achieving in its vision of 'zero hair loss' for cancer patients undergoing chemotherapy treatment.

Chemotherapy works by targeting all rapidly dividing cells in the body. Hair is the second fastest dividing cell, and this is the reason why many chemotherapy drugs cause alopecia. The hair follicles in the growth phase are attacked, resulting in hair loss approximately two weeks after the commencement of chemotherapy treatment.

Co-director of the centre and lead author of the journal article is Dr Nik Georgopoulos, a cancer expert at the University's Department of Biological Sciences who has collaborated with Paxman since 2011.

"Scalp cooling is currently the only treatment to combat 'chemotherapy-induced alopecia', yet little is known about its cytoprotective effect on human hair follicles," said Dr Georgopoulos.

Before now, he explained, the most common and obvious presumption to describe how scalp cooling worked was that as the scalp is cooled, the veins become constricted thereby reducing the amount of blood flow, meaning less of the chemotherapy drug enters the hair follicle.

"However, this is a really exciting discovery because our research now shows it is not as simple as that. We were able to measure how much chemotherapy drug goes into the cultured cells from hair follicles and what we have found is that cooling actually dramatically reduces the amount of chemotherapy drug being absorbed by the rapidly-diving cells of the hair follicle," he added.

This means there is now evidence for the first time, which demonstrates cooling has a direct effect on reducing the amount of drug that goes in and is not an indirect effect as thought before with the restricted blood flow.

"Our results provide evidence that attenuation of cellular drug uptake represents at least one of the mechanisms underpinning the ability of cooling to rescue human keratinocytes from chemotherapy drug-cytotoxicity, thus supporting the clinical efficacy of scalp cooling," he added.

In addition to providing evidence of how the treatment works, the Centre has also been working on developing innovative scalp cooling-related treatments and individual 3D-printed cooling caps. This has involved a collaboration of researchers from across two of the University's schools of study, the School of Applied Sciences and the School of Art, Design and Architecture.

"This latest project builds upon our previous research," continued Dr Georgopoulos.

"We had already demonstrated that if you cool at just 3 or 4 degrees lower, this can be the difference between the cells surviving or dying. We have now shown that a few degrees in temperature can also mean a more dramatic reduction in chemotherapy drug uptake by cells.

"The more evidence we can provide, the more data the designers have to facilitate the design of a better a cap. A better fit could mean more of a reduction in temperature, so more effective cooling means more survival of the follicles, leading to a better outcome."

The percentage of hair loss can be further reduced when scalp cooling is combined with the application of a topical agent. One of the Centre's tasks has been to develop the best way to deliver this agent to hair follicles on the scalp.

Richard Paxman, CEO of Paxman, added: "This latest research brings us one step closer to achieving our vision of 'zero hair loss' for cancer patients undergoing chemotherapy treatment. This is fabulous news and is a ground-breaking step in the field of scalp cooling research."

New Rasagiline Formulation May Allow Application to Skin

A new formulation of rasagiline, approved for Parkinson’s disease, may allow the therapy to be given by applying it to the skin.

Rasagiline works by blocking the activity of proteins that normally degrade dopamine in the brain, thus increasing brain levels of the neurotransmitter. An oral formulation of the medication is marketed as Azilect by Teva Pharmaceuticals.

Because the medication is metabolized fairly quickly within the body, patients usually need to take Rasagiline multiple times every day to get a therapeutic effect. Additionally, delivering Rasagiline orally can result in inconsistent amounts of the medication getting into the brain over time, since it needs to pass through the digestive tract first. Furthermore, oral medications may be difficult to take for people who have swallowing difficulties.

In light of these challenges, in the new study, an international team of researchers set out to create a formulation of rasagiline that can be delivered via the transdermal route — that is, applied to the skin and then absorbed into the body.

To develop this formulation, the researchers created microemulsions. Essentially, these are tiny droplets composed of water, oils, and other molecules that help the medication to be transported through the skin.

“Although no commercial ME [microemulsion]-based product for transdermal delivery is available, ME have tremendous potential for enhancing dermal and transdermal drug delivery,” the researchers wrote.

The researchers dubbed their formulation RSM-MEG, short for rasagiline maleate microemulsion-based gel.

After optimizing and characterizing the microemulsion-based formulation, the team tested its safety and effectiveness in laboratory models.

In rabbits, application of RSM-MEG to the skin did not cause any signs of irritation or inflammation after two days.

“This indicated safety of gel for skin application,” the researchers wrote.

In experiments using rat skin, the team demonstrated that RSM-MEG could deliver rasagiline through the skin more effectively than another gel formulation that didn’t use microemulsions (hydrogel), and could effectively deliver the medication into the bloodstream.

Finally, the team tested their formulation in a rat model of Parkinson’s induced by the pesticide rotenone. Treatment with RSM-MEG substantially improved motor function in this rat model, and RSM-MEG showed similar efficacy to orally administered rasagiline.

“These results demonstrate the potential of RSM-MEG for transdermal application as an antiparkinson’s therapy,” the researchers concluded.

The team is now planning further studies using pig and/or human skin to further validate these findings from rat models.

Drug Delivery in Central Nervous System Diseases - Technologies, Markets & Companies

The delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance.

Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug delivery to the CNS. Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the BBB endothelium. Receptor-mediated transcytosis can transport peptides and proteins across the BBB. Methods are available to assess the BBB permeability of drugs at the discovery stage to avoid the development of drugs that fail to reach their target site of action in the CNS.

Various strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain include osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier systems. Other strategies for drug delivery to the brain involve bypassing the BBB. Various pharmacological agents have been used to open the BBB and direct invasive methods can introduce therapeutic agents into the brain substance. It is important to consider not only the net delivery of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Various routes of administration as well as conjugations of drugs, e.g., with liposomes and nanoparticles, are considered. Some routes of direct administration to the brain are non-invasive such as transnasal route whereas others involve entry into the CNS by devices and needles such as in case of intrathecal and intracerebroventricular delivery. Systemic therapy by oral and parenteral routes is considered along with the sustained and controlled release to optimize the CNS action of drugs. Among the three main approaches to drug delivery to the CNS - systemic administration, injection into CSF pathways, and direct injection into the brain - the greatest developments is anticipated to occur in the area of targeted delivery by systemic administration.

Many of the new developments in the treatment of neurological disorders will be biological therapies and these will require innovative methods for delivery. Cell, gene and antisense therapies are not only innovative treatments for CNS disorders but also involve sophisticated delivery methods. RNA interference (RNAi) as a form of antisense therapy is also described.

The role of drug delivery is depicted in the background of various therapies for neurological diseases including drugs in development and the role of special delivery preparations. Pain is included as it is considered to be a neurological disorder. A special chapter is devoted to drug delivery for brain tumors. Cell and gene therapies will play an important role in the treatment of neurological disorders in the future.

The method of delivery of a drug to the CNS has an impact on the drug's commercial potential. The market for CNS drug delivery technologies is directly linked to the CNS drug market. Values are calculated for the total CNS market and the share of drug delivery technologies. Starting with the market values for the year 2020, projections are made to the years 2025 and 2030. The market values are tabulated according to therapeutic areas, technologies and geographical areas. Unmet needs for further development in CNS drug delivery technologies are identified according to the important methods of delivery of therapeutic substances to the CNS. Finally suggestions are made for strategies to expand CNS delivery markets. Besides the development of new products, these include the application of innovative methods of delivery to older drugs to improve their action and extend their patent life.

Profiles of 77 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 101 collaborations. These include pharmaceutical companies that develop CNS drugs and biotechnology companies that provide technologies for drug delivery. A number of cell and gene therapy companies with products in development for CNS disorders are included. References contains over 420 publications that are cited in the report. The report is supplemented with 52 tables and 17 figures.

The report contains information on the following:

  • Basics of drug delivery to the CNS
  • Blood-brain barrier
  • Methods of drug delivery to the CNS
  • Delivery of cell, gene and antisense therapies to the CNS
  • Drug delivery in the treatment of CNS disorders
  • Drug delivery for brain tumors
  • Markets for drug delivery in CNS disorders
  • Companies

0. Executive Summary

1. Basics of Drug Delivery to the Central Nervous System

  • Introduction
  • Historical evolution of drug delivery for CNS disorders
  • Neuroanatomical and neurophysiological basis of drug delivery
  • The cerebrospinal fluid
  • The lymphatic drainage system of the brain
  • The extracellular space in the brain
  • Neurotransmitters
  • Extracellular vesicles as drug delivery vehicles
  • Neuropharmacology relevant to drug delivery
  • Introduction to neuropharmacology
  • Pharmacokinetics
  • Absorption and distribution of drugs
  • Drug metabolism and elimination
  • Pharmacodynamics
  • Receptors
  • Sites of drug action in the CNS
  • Receptors coupled to guanine nucleotide binding proteins
  • Acetylcholine receptor channels
  • Dopamine receptors
  • GABA receptor channels
  • Glutamate receptor channels
  • Non-competitive NMDA antagonists
  • Serotonin receptors
  • G-protein coupled receptors
  • In vivo study of drug action in the CNS in human patients
  • Electroencephalography
  • Brain imaging
  • Chronopharmacology as applied to the CNS
  • Role of drug delivery in personalized therapy of CNS disorders

2. Blood Brain Barrier

  • Introduction
  • Features of the blood-brain barrier relevant to CNS drug delivery
  • The neurovascular unit
  • Functions of the BBB
  • BBB as an anatomical as well as physiological barrier
  • BBB as a biochemical barrier
  • Glucose transporters at the BBB
  • Role of shear stress on development of BBB
  • Genomics of BBB
  • Proteomics of BBB
  • Other neural barriers
  • Blood-cerebrospinal fluid barrier
  • Blood nerve barrier
  • Blood-retinal barrier
  • Blood-labyrinth barrier
  • Passage of substances across the blood-brain barrier
  • Transporters localized in the BBB
  • Adenosine carrier
  • Amino acid transporters
  • Efflux transport systems
  • Glucose transporter
  • Ionic transporter
  • BBB-specific enzymes
  • Receptor-mediated transcytosis
  • Lysophosphatidic acid-mediated increase in BBB permeability
  • Folate transport system
  • Transferrin receptor
  • Molecular biology of the BBB
  • Transport of peptides and proteins across the BBB
  • Passage of leptin across the BBB
  • Passage of cytokines across the BBB
  • Passage of hormones across the BBB
  • Passage of enzymes across the BBB
  • Passage of omega-3 fatty acids across the BBB
  • Drugs that cross the BBB by binding to plasma proteins
  • Current concepts of the permeability of the BBB
  • BBB permeability in relation to disease
  • BBB permeability in relation to drug delivery
  • Factors that increase the permeability of the BBB
  • BBB disruption as an adverse effect of pharmaceuticals
  • BBB disruption as adverse effect of vaccines for CNS disorders
  • CNS disorders and BBB
  • Autoimmune disorders
  • Brain tumors
  • Primary brain tumors
  • Cerebral metastases
  • Central nervous system injuries
  • Cerebrovascular disease
  • Cerebral ischemia
  • Intracerebral hemorrhage
  • Epilepsy
  • Infections
  • Inflammation
  • Mitochondrial encephalopathies
  • Multiple sclerosis
  • Neurodegenerative disorders
  • BBB in Alzheimer disease
  • BBB in Parkinson disease
  • BBB in amyotrophic lateral sclerosis
  • West Nile virus infection
  • Testing permeability of the BBB
  • In vitro models of BBB
  • In vivo study of BBB
  • Brain imaging
  • In silico prediction of BBB
  • Relevance of the BBB penetration to pharmacological action
  • BBB penetration and CNS drug screening
  • BBB models for testing drug delivery
  • In vivo brain distribution of P-glycoprotein
  • Transthyretin monomer as a marker of blood-CSF barrier disruption
  • Evaluation of BBB permeability by brain imaging
  • Biomarkers of disruption of blood-brain barrier
  • Future directions for research on the BBB
  • Use of neural stem cells to construct the blood brain barrier
  • Strategies to cross the BBB

3. Methods of Drug Delivery to the CNS

  • Introduction
  • Routes of drug delivery to the brain
  • Drug delivery to the brain via the nasal route
  • Devices for nasal administration of drugs for CNS
  • Role of nanobiotechnology in nasal drug drug delivery
  • Nasal mucosal patch to facilitate drug delivery across the BBB
  • Passage of viruses to the brain via the nasal route
  • Potential and limitations of nasal drug delivery to the brain
  • Drugs that can be delivered to the brain via the nasal route
  • Erythropoietin
  • Esketamine
  • Hypocretin
  • IFN beta-1b
  • Levetiracetam
  • Lysosomal enzymes
  • Midazolam
  • Neurotrophic factors
  • Thyrotropin-releasing hormone
  • Neuroprotective drugs for stroke
  • Transdermal drug delivery for neurological disorders
  • Drug delivery to the brain via inner ear
  • Drug delivery for disorders of the spinal cord
  • Intrathecal drug delivery
  • Anatomical & physiological aspects of intrathecal drug delivery
  • Advantages of intrathecal drug delivery
  • Drugs that can be delivered by intrathecal route
  • Pharmacokinetics of intrathecal drug delivery
  • Retrograde delivery to the brain via the epidural venous system
  • Devices for drug delivery to the CNS
  • Catheters for drug delivery to the CNS
  • Reservoirs and pumps for drug delivery to the CNS
  • Invasive neurosurgical approaches
  • Intraarterial drug delivery to the brain
  • Direct injection into the CNS substance or CNS lesions
  • Targeted delivery of biologicals to the spinal cord by microinjection
  • Intraventricular injection of drugs
  • Strategies for drug delivery to the CNS across the BBB
  • Increasing the permeability (opening) of the BBB
  • Osmotic opening of the BBB
  • Chemical opening of the BBB
  • Cerebral vasodilatation to open the BBB
  • Modulation of vascular permeability by laser irradiation
  • Neurostimulation for opening BBB
  • Ultrasound-induced focal disruption of BBB
  • Ultrasound-induced delivery across BBB without focal disruption
  • Use of nitric oxide donors to open the BBB
  • Manipulation of the sphingosine 1-phosphate receptor system
  • Pharmacological strategies to facilitate transport across the BBB
  • 2B-Trans™ technology
  • ABC afflux transporters and penetration of the BBB
  • Adenosine agonist-mediated drug delivery across the BBB
  • Carrier-mediated drug delivery across the BBB
  • Fusion of receptor-binding peptide from apoE with therapeutic protein
  • G-Technology®
  • Glycosylation Independent Lysosomal Targeting
  • Inhibition of P-glycoprotein to enhance drug delivery across the BBB
  • LipoBridge technology
  • Modification of the drug to enhance its lipid solubility
  • Monoclonal antibody fusion proteins
  • Neuroimmunophilins
  • Peptide-mediated transport across the BBB
  • Prodrug bioconversion strategies and their CNS selectivity
  • Transport of small molecules across the BBB
  • Transport across the BBB by short chain oligoglycerolipids
  • Transvascular delivery across the BBB
  • Trojan horse approach
  • Role of the transferrin-receptor system in CNS drug delivery
  • Use of receptor-mediated transocytosis to cross the BBB
  • Cell-based drug delivery to the CNS
  • Activated T lymphocytes
  • Microglial cells
  • Neural stem cells
  • Drug delivery to the CNS by using novel formulations
  • Crystalline formulations
  • Liposomes
  • Monoclonal antibodies
  • Microspheres
  • Microbeads
  • Brain-targeted chemical delivery systems
  • Nanotechnology-based drug delivery to CNS
  • Nanoparticles for drug delivery across the BBB
  • Nanovesicles for transport across BBB
  • Nanoparticle-based reservatrol delivery to the brain
  • Penetration of BBB by nanoparticles coated with polysorbate 80
  • Targeting nicotinic acetylcholine receptor
  • Transcytosis of transferrin-containing nanoparticles across the BBB
  • V-SMART® drug delivery platform
  • Nanotechnology-based devices and implants for CNS
  • Biochip implants for drug delivery to the CNS
  • Controlled-release microchip
  • Nanoscaffold for delivering antiinflammatory molecules to the brain
  • Retinal implant chip
  • Convection-enhanced delivery to the CNS
  • Systemic administration of drugs for CNS effects
  • Sustained and controlled release drug delivery to the CNS
  • Fast dissolving oral selegiline
  • Choice of the route of systemic delivery for effect on the CNS disorders
  • Methods of delivery of biopharmaceuticals to the CNS
  • Delivery of biopharmaceuticals across the BBB
  • Methods of delivery of peptides for CNS disorders
  • Alteration of properties of the BBB for delivery of peptides
  • Challenges for delivery of peptides across the BBB
  • CNS delivery of peptides via conjugation to biological carriers
  • Delivery of conopeptides to the brain
  • Direct delivery of neuropeptides into the brain
  • Molecular manipulations of peptides to facilitate transport into CNS
  • Transport to spinal cord motor neurons after peripheral injection
  • Transnasal administration of neuropeptides
  • Delivery of neurotrophic factors to the nervous system
  • Systemic administration of NTFs
  • Delivery systems to facilitate crossing of the BBB by NTFs
  • Direct application of NTFs to the CNS
  • Intracerebroventricular injection
  • Intrathecal administration
  • Implants for delivery of neurotrophic factors
  • Use of neurotrophic factor mimics
  • Use of microspheres for delivery of neurotrophic factors
  • Use of nanobiotechnology for delivery of neurotrophic factors
  • Use of microorganisms for therapeutic entry into the brain
  • Bacteriophages as CNS therapeutics
  • Intracellular drug delivery in the brain
  • Local factors in the brain affecting drug action
  • Methods for testing drug delivery to the CNS
  • Animal models for testing drug delivery
  • Conducting preclinical studies of CNS drug delivery
  • Screening for drug-P-gp interaction at BBB
  • Translating from preclinical to clinical application

4. Delivery of Cell, Gene and Antisense Therapies to the CNS

  • Introduction
  • Cell therapy of neurological disorders
  • Methods for delivering cell therapies in CNS disorders
  • Cerebrospinal fluid-stem cell interactions for therapy of CNS disorders
  • Engineered stem cells for drug delivery to the brain
  • Encapsulated cells
  • Intrathecal delivery of stem cells
  • Intraparenchymal delivery of stem cells to the spinal cord
  • Intravascular administration
  • Neural stem cells as therapeutic delivery vehicles
  • Gene therapy techniques for the nervous system
  • Introduction
  • Methods of gene transfer to the nervous system
  • AAV vector mediated gene therapy for neurogenetic disorders
  • Ideal vector for gene therapy of neurological disorders
  • Promoters of gene transfer
  • Routes of delivery of genes to the nervous system
  • Direct injection into CNS
  • Introduction of the genes into cerebral circulation
  • Introduction of genes into cerebrospinal fluid
  • Intravenous administration of vectors
  • Delivery of gene therapy to the peripheral nervous system
  • Cell-mediated gene therapy of neurological disorders
  • Neuronal cells
  • Neural stem cells and progenitor cells
  • Astrocytes
  • Cerebral endothelial cells
  • Implantation of genetically modified encapsulated cells into the brain
  • Genetically modified bone marrow cells
  • Nanoparticles as nonviral vectors for CNS gene therapy
  • Applications of gene therapy for neurological disorders
  • Companies involved in cell/gene therapy of neurological disorders
  • Antisense therapy of CNS disorders
  • Delivery of antisense oligonucleotides to the CNS
  • Delivery of oligonucleotides cross the BBB
  • Cellular delivery systems for oligonucleotides
  • High-flow microinfusion into the brain parenchyma
  • Systemic administration of peptide nucleic acids
  • Introduction of antisense compounds into the CSF Pathways
  • Intrathecal administration of antisense compounds
  • Intracerebroventricular administration of antisense oligonucleotides
  • Nanoparticle-based delivery of antisense therapy to the CNS
  • Methods of delivery of ribozymes
  • Delivery aspects of RNAi therapy of CNS disorders
  • Delivery of siRNA to the CNS
  • Future drug delivery strategies applicable to the CNS

5. Drug Delivery for Treatment of Neurological Disorders

  • Introduction
  • Targeted drug delivery for neurological disorders
  • Parkinson's disease
  • Drug delivery systems for Parkinson's disease
  • Methods of delivery of levodopa in PD
  • Duodenal levodopa infusion
  • Inhaled levodopa
  • Sublingual apomorphine
  • Transdermal drug delivery for PD
  • Transdermal dopamine agonists for PD
  • Transdermal administration of other drugs for PD
  • Intracerebral administration of GDNF
  • Cell therapy for PD
  • Human dopaminergic neurons for PD
  • Graft survival-enhancing drugs
  • Xenografting porcine fetal neurons
  • Encapsulated cells for PD
  • Stem cells for PD
  • Engineered stem cells for drug delivery to the brain in PD
  • Human retinal pigment epithelium cells for PD
  • Delivery of cells for PD
  • Gene therapy for Parkinson disease
  • Rationale
  • Techniques of gene therapy for PD
  • Prospects of gene therapy for PD
  • Companies developing gene therapy for PD
  • RNAi therapy of Parkinson's disease
  • Alzheimer disease
  • Drug delivery for Alzheimer disease
  • Blood-brain partitioning of an AMPA receptor modulator
  • Clearing amyloid through the BBB
  • Delivery of the passive antibody directly to the brain
  • Delivery of thyrotropin-releasing hormone analogs by molecular packaging
  • Exosome-based drug delivery in AD
  • Nanoparticle-based drug delivery for Alzheimer’s disease
  • Perispinal etanercept
  • Slow release implant of an AChE inhibitor
  • Intranasal insulin in Alzheimer disease
  • Transdermal drug delivery in Alzheimer's disease
  • Trojan-horse approach to prevent build-up of Aβ aggregates
  • Cell and gene therapy for Alzheimer disease
  • NGF gene therapy
  • Neprilysin gene therapy
  • RNAi therapy of Alzheimer's disease
  • Huntington's disease
  • Treatment of HD
  • Gene therapy of HD
  • Encapsulated genetically engineered cellular implants
  • Viral vector mediated administration of neurotrophic factors
  • RNAi therapeutics for the treatment of HD
  • Amyotrophic lateral sclerosis
  • Treatment of ALS
  • Drug delivery in ALS
  • Delivery of stem cell therapy for ALS
  • Gene and antisense therapy of ALS
  • Neurotrophic factor gene therapies of ALS
  • Antisense therapy of ALS
  • RNAi therapy of amyotrophic lateral sclerosis
  • Cerebrovascular disease
  • Treatment of stroke
  • Drug delivery in stroke
  • Intraarterial administration of thrombolytic agents in stroke
  • Drug delivery for prevention of restenosis of carotid arteries
  • In-stent restenosis
  • Targeted local anti-restenotic drug delivery
  • Catheter-based drug delivery for restenosis
  • Stents for prevention of restenosis
  • Drug-eluting stents
  • Antisense approach to prevent restenosis
  • Drug-eluting stents for the treatment of intracranial atherosclerosis
  • Tissues transplants for stroke
  • Transplant of encapsulated tissue secreting neurotrophic factors
  • Methods for delivery of neurotrophic factors in stroke
  • Cell therapy for stroke
  • Stem cell transplant into the brain
  • Immortalized cell grafts for stroke
  • Intravenous infusion of marrow stromal cells
  • Intravenous infusion of umbilical cord blood stem cells
  • Future of cell therapy for stroke
  • Gene therapy of cerebrovascular diseases
  • Gene transfer to cerebral blood vessels
  • NOS gene therapy for restenosis
  • Gene therapy for cerebral ischemia
  • Gene therapy of strokes with a genetic component
  • Drug delivery to intracranial aneurysms
  • Drug delivery for vasospasm following subarachnoid hemorrhage
  • Intrathecal tissue plasminogen activator
  • Gene therapy for vasospasm
  • Drug delivery in multiple sclerosis
  • An electronic device for self injection of interferon beta-1a
  • Oral therapies for MS
  • Drug delivery for MS across the BBB
  • Delivery of methylprednisolone across the BBB
  • Monoclonal antibodies for MS and the BBB
  • Antisense and RNAi approaches to MS
  • Cell therapy for multiple sclerosis
  • Hematopoietic stem cell transplantation for multiple sclerosis
  • Embryonic stem cells and neural precursor cells for MS
  • Gene therapy for multiple sclerosis
  • Drug delivery in epilepsy
  • Routes of administration of antiepileptic drugs
  • Controlled-release preparations of carbamazepine
  • Intravenous carbamazepine
  • Various routes of administration of benzodiazepines
  • Methods of delivery of novel antiepileptic therapies
  • Use of neuronal membrane transporter
  • Delivery of the antiepileptic conopeptides to the brain
  • Nasal administration of AEDs
  • Intracerebral administration of AEDs
  • The role of drug delivery in status epilepticus
  • Cell therapy of epilepsy
  • Gene therapy for epilepsy
  • Gene therapy for neuroprotection in epilepsy
  • Concluding remarks on drug delivery in epilepsy
  • Drug delivery for pain
  • Intranasal delivery of analgesics
  • Intranasal administration of morphine
  • Intranasal morphine derivatives
  • Intranasal fentanyl
  • Intranasal buprenorphine
  • Intranasal ketamine
  • Intranasal ketorolac
  • Delivery of analgesics by inhalation
  • Delivery of analgesics to peripheral nerves
  • Spinal delivery of analgesics
  • Epidural dexamethasone
  • Epidural morphine
  • Relief of pain by intrathecal ziconotide
  • Intrathecal neostigmine
  • Intrathecal prostaglandin antagonists
  • Intrathecal fadolmidine
  • Intrathecal siRNA for relief of neuropathic pain
  • Concluding remarks on intrathecal delivery of analgesic agents
  • Intracerebroventricular drug delivery for pain
  • Delivery of analgesics to the CNS across the BBB
  • Drug delivery for migraine
  • Management of migraine
  • Novel drug delivery methods for migraine
  • Nasal formulations for migraine
  • Sublingual spray for migraine
  • Needle-free drug delivery for migraine
  • Drug delivery for traumatic brain injury
  • Cell therapy of traumatic brain injury
  • Gene therapy for traumatic brain injury
  • Drug delivery for spinal cord injury
  • Administration of neurotrotrophic factors for spinal cord injury
  • Cell therapy for spinal cord injury
  • Transplantation of glial cells for SCI
  • Fetal neural grafts for SCI
  • Embryonic stem cells for SCI
  • Schwann cell transplants for SCI
  • Olfactory glial cells for SCI
  • Marrow stromal cells for SCI
  • Intravenous injection of stem cells for spinal cord repair
  • Combinatorial approach for regeneration in SCI
  • Cell therapy of syringomyelia
  • Gene therapy of spinal cord injury
  • Drug delivery in CNS infections
  • Drug delivery in neuroAIDS
  • Drug delivery for miscellaneous neurological disorders
  • Drug delivery for CNS involvement in Hunter syndrome
  • Trojan horse therapeutics to treat mucopolysaccharidosis types I & II
  • Antisense therapy for spinal muscular atrophy
  • Antisense gene splicing for SMA
  • Intrathecal antisense delivery
  • Genetically modified stem cells for metachromatic leukodystrophy
  • Relief of spasticity by intrathecal baclofen
  • Drug delivery for retinal disorders
  • Age-related macular degeneration
  • Squalamine
  • Combretastatin A4P for myopic macular degeneration
  • Gene therapy for AMD
  • Anti-VEGF approach to AMD
  • Delivery of pegaptanib for treatment of AMD
  • Stem cell therapy for retinitis pigmentosa
  • Proliferative retinopathies
  • Retinoblastoma
  • Drug delivery for inner ear disorders
  • Delivery of stem cells for hearing loss
  • Auditory hair cell replacement by gene therapy
  • Future prospects of drug delivery to the inner ear
  • Drug delivery in psychiatric disorders
  • Delivery of antidepressants
  • Transdermal delivery of antidepressants
  • Nasal delivery of antidepressants
  • Delivery methods and formulations of antipsychotics
  • Long-acting injectable antipsychotics
  • Transdermal haloperidol
  • Transdermal risperidone for treatment of schizophrenia
  • Transdermal blonanserin for treatment of schizophrenia
  • Transnasal oxytocin for schizophrenia
  • Transdermal lithium for bipolar disorder

6. Drug delivery for brain tumors

  • Introduction
  • Methods for evaluation of anticancer drug penetration into brain tumor
  • Innovative methods of drug delivery for glioblastoma
  • Delivery of anticancer drugs across the blood-brain barrier
  • Anticancer agents with increased penetration of BBB
  • BBB disruption
  • Nanoparticle-based targeted delivery of chemotherapy across the BBB
  • Tyrosine kinase inhibitor increases topotecan penetration into CNS
  • Bypassing the BBB by alternative methods of drug delivery
  • Intranasal perillyl alcohol
  • Intraarterial chemotherapy
  • Enhancing tumor permeability to chemotherapy
  • PDE5 inhibitors for increasing BTB permeability
  • Local delivery of therapeutic agents into the brain
  • Biodegradable microspheres containing 5-FU
  • Carmustine biodegradable polymer implants
  • Fibrin glue implants containing anticancer drugs
  • Interstitial delivery of dexamethasone for reduction of peritumor edema
  • Magnetically controlled microspheres
  • Convection-enhanced delivery
  • CED for receptor-directed cytotoxin therapy
  • CED of topotecan
  • CED of a modified diphtheria toxin conjugated to transferrin
  • CED of nanoliposomal CPT-11
  • CED for delivery 131I-chTNT-1/B MAb
  • Anticancer drug formulations for targeted delivery to brain tumors
  • Intravenous delivery of anticancer agents bearing transferrin
  • Liposomes for drug delivery to brain tumors
  • MAbs targeted to brain tumors
  • Targeted delivery of drug-peptide conjugates to glioblastoma
  • Multiple targeted drugs for brain tumors
  • Nanoparticles for targeted drug delivery in glioblastoma
  • Targeted antiangiogenic/apoptotic/cytotoxic therapies
  • Targeted drug delivery to gliomas using cholera toxin subunit B
  • Introduction of the chemotherapeutic agent into the CSF pathways
  • Intraventricular chemotherapy for meningeal cancer
  • Intrathecal chemotherapy
  • Photodynamic therapy for chemosensitization of brain tumors
  • Nanoparticles for photodynamic therapy of brain tumors
  • Innovative delivery of radiotherapy to brain tumors
  • GliaSite Radiation Therapy System
  • Boron neutron capture therapy for brain tumors
  • Cell therapy for malignant brain tumors
  • Chimeric antigen receptor T cells
  • Mesenchymal stem cells to deliver treatment for gliomas
  • Intra-cavity stem cell therapy for medulloblastoma
  • Gene therapy for glioblastoma
  • Antiangiogenic gene therapy
  • Anticancer drug delivery by genetically engineered MSCs
  • Intracerebroventricular delivery of gene therapy for gliomas by NSCs
  • Intravenous gene delivery with nanoparticles into brain tumors
  • Ligand-directed delivery of dsRNA molecules targeted to EGFR
  • MSC-based gene delivery
  • Neural stem cells for drug/gene delivery to brain tumors
  • Peptides targeted to glial tumor cells
  • RNAi gene therapy of brain cancer
  • Single-chain antibody-targeted adenoviral vectors
  • Targeting normal brain cells with an AAV vector encoding interferon-
  • Poliovirus-based vaccine for glioblastoma
  • Treatment of medulloblastoma by suppressing genes in Shh pathway
  • Virus-mediated oncolytic therapy of brain cancer
  • HIV-mediated Oncolysis
  • Autophagy by conditionally replicating adenoviruses
  • Reovirus-mediated Oncolysis
  • Measles virus-mediated oncolysis
  • Oncolytic virus targeted to brain tumor stem cells
  • Oncolysis with vesicular stomatitis virus
  • Future of viral-mediated oncolysis
  • Vaccination for glioblastoma

7. Markets for Drug Delivery in CNS Disorders

  • Introduction
  • Methods of calculation of CNS drug delivery markets
  • Markets for CNS drug delivery technologies
  • Drug delivery share in selected CNS markets
  • CNS share of drug delivery technologies
  • Geographical distribution of CNS drug delivery markets
  • Impact of improved drug delivery on CNS drug markets
  • Neurodegenerative disorders
  • Alzheimer disease
  • Parkinson disease
  • Huntington disease
  • Amyotrophic lateral sclerosis
  • Epilepsy
  • Migraine and other headaches
  • Stroke
  • Central nervous system trauma
  • Multiple sclerosis
  • Brain tumors
  • Limitations of the current drug delivery technologies for CNS
  • Unmet needs in CNS drug delivery technologies
  • Regulatory considerations for drugs that cross the BBB
  • Public-private collaboration for transfer of research to the clinic
  • Future strategies for expanding CNS drug delivery markets
  • Education of neurologists
  • Demonstration of the advantages of the newer methods of delivery
  • Rescue of old products by novel drug delivery methods
  • Facilitation of the approval process of new drugs

8. Companies

9. References

Table 1-1: Landmarks in the development of drug delivery to the CNS
Table 2-1: Proteins expressed at the neurovascular unit
Table 2-2: Transporters that control penetration of molecules across the BBB
Table 2-3: Enzymes that control the penetration of molecules across the BBB
Table 2-4: Factors that increase the permeability of the BBB
Table 2-5: Diseases with associated disturbances of BBB
Table 3-1: Various methods of drug delivery to the central nervous system
Table 3-2: Drugs available for intrathecal administration
Table 3-3: Investigational drugs administered by intrathecal route
Table 3-4: Strategies for drug delivery to the CNS across the BBB
Table 3-5: Specific inhibitors of P-glycoprotein in clinical development
Table 3-6: Molecules attached to Trojan horses injected intravenously for CNS effect
Table 3-7: Examples of controlled and sustained release drug delivery for CNS disorders
Table 3-8: Novel methods of delivery of drugs for CNS disorders
Table 3-9: Indications for the clinical applications of NTFs in neurologic disorders
Table 3-10: Methods for delivery of neurotrophic factors to the CNS
Table 4-1: Methods for delivering cell therapies in CNS disorders
Table 4-2: Classification of methods of gene therapy
Table 4-3: Methods of gene transfer as applied to neurologic disorders
Table 4-4: Potential indications for gene therapy of neurologic disorders
Table 4-5: Companies developing cell/gene therapies for CNS disorders
Table 4-6: Methods of antisense delivery as applied to the CNS
Table 5-1: Strategies for the treatment of Parkinson's disease
Table 5-2: Drug delivery systems for Parkinson's disease
Table 5-3: Types of cell used for investigative treatment of Parkinson's disease
Table 5-4: Status of cell therapies in development for Parkinson's disease
Table 5-5: Gene therapy techniques applicable to Parkinson disease
Table 5-6: Companies developing gene therapy for Parkinson's disease
Table 5-7: Classification of pharmacotherapy for Alzheimer disease
Table 5-8: Novel drug delivery methods for Alzheimer disease therapies
Table 5-9: Classification of neuroprotective agents for amyotrophic lateral sclerosis
Table 5-10: Methods of delivery of therapies in development for ALS
Table 5-11: Classification of treatments for stroke
Table 5-12: Treatments of stroke involving innovative drug delivery methods
Table 5-13: Drug delivery for prevention of carotid artery restenosis after angioplasty
Table 5-14: Gene transfer in animal models of carotid artery restenosis
Table 5-15: Neuroprotective gene transfer strategies in models of cerebral ischemia
Table 5-16: Gene Therapy for reducing cerebral infarction in animal stroke models
Table 5-17: Pharmacological agents for treatment of cerebral vasospasm
Table 5-18: Gene therapy strategies for vasospasm
Table 5-19: A classification of drug delivery methods used in management of pain
Table 5-20: Spinal administration of drugs for pain
Table 5-21: Investigational drugs for pain administered by intrathecal route
Table 5-22: Current management of migraine
Table 5-23: Novel drug delivery methods for migraine
Table 6-1: Innovative methods of drug delivery for glioblastoma
Table 6-2: Strategies for gene therapy of malignant brain tumors
Table 7-1: Share of drug delivery technologies in selected CNS markets: 2020-2030
Table 7-2: CNS market share of drug delivery technologies 2020-2030
Table 7-3: Value of CNS drug delivery in the major world markets from 2020-2030
Table 7-4: Limitations of the current drug delivery technologies for CNS
Table 8-1: Collaborations of companies in CNS drug delivery

Figure 1-1: Interaction of neurotransmitters with receptors
Figure 2-1: The neurovascular unit
Figure 2-2: Various forms of passage of substances across the blood brain barrier
Figure 2-3: Disruptive vs non-disruptive changes in BBB as response to disease
Figure 2-4: Role of BBB models for drug delivery in preclinical CNS drug development
Figure 3-1: Routes of drug delivery to the brain
Figure 3-2: Extracellular mechanism for drug transportation to the brain following intranasal administration
Figure 3-3: Penetration of CSF into spinal cord
Figure 3-4: Disposition of opioids after intrathecal administration
Figure 3-5: Use of receptor-mediated transcytosis to cross the BBB
Figure 3-6: Nanotechnology-based strategies for delivery of BDNF to the CNS
Figure 5-1: Oral versus transdermal administration of a drug in Parkinson's disease
Figure 5-2: Effect of tyrosine hydroxylase gene delivery on dopamine levels
Figure 5-3: Trojan horse approach for delivery of AGT-181 to the brain
Figure 6-1: A concept of targeted drug delivery to glioblastoma across the BBB
Figure 6-2: Mechanism of antitumor effects of poliovirus-based vaccine for glioblastoma
Figure 7-1: Unmet needs in the CNS drug delivery technologies

Applying drugs to brain via scalp (transdermal) - Biology

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