Category: Novel Drug Delivery

Advances in pharmaceutical research- use of nanotechnology as therapeutic platforms for disease management.

8/15/2017

Dr.Shruti Bhat, an Expert in Pharmaceutical industry, brings to you some highlights from current pharma and clinical research news, views and data.

New nanoparticles deliver bigger drug payload.
Scientists at Brigham and Women's Hospital and the Harvard-MIT Division of Health Sciences and Technology have developed new nanoparticles from a modified polymer that can more efficiently load up on cancer drugs and deliver them more precisely.

These new nanoparticles inhibit the MARK signaling pathway, which helps prevent the spread of cancer cells and makes tumors more susceptible to chemotherapy.

"Current chemotherapy drugs must be administered in high concentration throughout the body in order to destroy tumor cells, translating to high toxicity and discomfort for the patient, mainly due to the effects on normal cells," co-lead author Rania Harfouche said in a release. By modifying the polymer, researchers "allow for lower drug concentrations to be used, and provide opportunity for more potent treatments with lesser side-effects for the patient."

In a study involving mice, the nanoparticles inhibited tumor growth. And the scientists say that this new approach to cancer therapy could have wide applicability.

Scientist creates 'nanocage' drug delivery system.
Washington University's Younan Xia has been attracting considerable attention for his research work on microcapsules that can precisely deliver a drug payload right where it's needed.

Xia has been making microscopic gold 'nanocages,' tiny particles encased in polymer strands that collapse when exposed to heat. "But the really cool part," says Xia, "and the cool part of nanotechnology generally, is that the tiny gold cages have very different properties than bulk gold." In particular, they respond differently to light.

Using a near infrared light, the scientist can trigger a collapse at any point, leaving the tissue unharmed. Adjusting the light can recalibrate the release rate. And by designing the polymers to latch onto specific disease targets, such as a tumor, Xia believes he can concentrate the drug right where it's needed.

Nanoparticles used to deliver targeted ED drugs.
Nanoparticles "smaller than a grain of pollen" have been engineered to carry minute quantities of therapeutics for erectile dysfunction, effectively delivering the drug directly through the skin in animal models. And the team of researchers at Albert Einstein College of Medicine at Yeshiva University says that the same approach could be a better alternative to existing drugs while safely working in men who currently are prohibited from taking the tablet meds.

Scientists used rats bred to suffer from erectile dysfunction to test the nanoparticles. "The response time to the nanoparticles was very short, just a few minutes, which is basically what people want in an erectile dysfunction medication," says Dr. Kelvin Davies. "In both rats and humans, it can take 30 minutes to one hour for oral erectile dysfunction medications to take effect."

The oral drugs are associated with a number of side effects, including blurred vision and upset stomachs. Men who have suffered a heart attack, meanwhile, are prevented from getting the ED drugs at all. But the researchers say that a locally applied topical solution was effective without side effects in rodents. ED drugs have been prominent best-sellers and an improved approach could also prove to be highly profitable.

Nanoparticles boost antibacterial treatments.
The University of Liverpool and IOTA NanoSolutions have developed man-made nanoparticles that could increase the effectiveness of antibacterial treatments. Many current drugs are insoluble and need to be administered at higher doses in order to work. However, this increases the chances that bacteria and other organisms will build up a resistance to the drugs. In time, new formulations of medicines must be developed in order to knock out the mutated organisms.

University of Liverpool researchers found that in some instances, the nanoparticles can be used to make insoluble drugs behave like soluble drugs, increasing their effectiveness at lower doses. Scientists are concentrating on applying the nanoparticle technology to antiparasitic drugs that treat malaria.

"Already our technology has shown the potential to improve a range of current medicines and may lead to treatments that prevent drug resistance," said Professor Steve Rannard, from the Department of Chemistry, who is also co-founder and current Chief Scientific Officer of IOTA NanoSolutions. "If our approach can deliver new antimalarial treatments, it may help to prevent millions of deaths per year and improve the lives of hundreds of millions of current malaria sufferers."

Nanoparticles research aids drug development.
Drugs with the ability to dissolve have much stronger efficacy, however many drugs are insoluble. In order to compensate, drugs often need to be administered in higher doses. This increases the possibility of bacteria and other organisms mutating as the high doses make it easier for them to build resistance to the drugs. This leads to treatments becoming obsolete and the need for new medicines to be developed.

Chemists at the University of Liverpool working with IOTA NanoSolutions have now developed a new technology to produce nanoparticles of insoluble drugs that mimic the behaviour and the effectiveness of dissolved drugs.

Nanoparticles are man-made particles manufactured for use in a number of industries including the cosmetic and pharmaceutical industry; they can make materials stronger, lighter and cleaner.

Recent data has shown that in some cases, low concentrations of insoluble drugs in a nanoparticle form can be more active than previously thought, offering the potential to administer drugs in low dosages without reducing the effectiveness of the treatment. The new technology is allowing the scientists to develop new medicines by converting currently available drugs into a nanoparticle form. Antiparastitic drugs to treat malaria are also being developed in collaboration with the Liverpool School of Tropical Medicine.

Professor Steve Rannard, from the Department of Chemistry who is also co-founder and current Chief Scientific Officer of IOTA NanoSolutions, said: "Already our technology has shown the potential to improve a range of current medicines and may lead to treatments that prevent drug resistance. If our approach can deliver new antimalarial treatments, it may help to prevent millions of deaths per year and improve the lives of hundreds of millions of current malaria sufferers."

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Nanoparticle program delivers anti-cancer therapy.
A research team at Washington University in St. Louis has combined a nanoparticle platform used in imaging growing blood vessels and combined it with the fungal drug fumagillin to create a new weapon to fight the growth of tumors. Fumagillin has long been known as a potent anti-cancer therapy, but its neurotoxic side effects are too harsh for patients. To circumvent the side effects, the scientists adapted nanoparticles designed to dock on a protein carpeted on endothelial cells clustered on the walls of new blood vessels and loaded them with fumagillin. By targeting the therapy directly at the new blood vessels, the therapy can stop angiogenesis, a key target in oncology research.

"It basically becomes a vehicle to dump off a truckload of cargo," Joseph DeSimone of the University of North Carolina tells MIT Technology Review. "It's sort of like a Trojan horse."

There are a number of research programs underway relying on animal studies to determine the effect of new nanoparticle technologies that can interrupt angiogenesis. First-generation nanoparticle therapies rely on passive delivery methods while this second generation round of research is working on new technology aimed at more precise targeting of disease.

Nanomaterials used to fix neuron damage.
Northwestern University researcher Samuel Stupp has presented the results of a study in which he injected nanomaterials into the severed spinal cords of mice, allowing them to walk again after several weeks of therapy. The nanomaterials he used were designed to self-assemble into nanofibers which repaired damaged neurons. The research offers new insights into the near-term research potential of nanotechnology and offers hope for patients with Alzheimer's and Parkinson's who suffer from severe neuron damage.

"Regenerating bone and cartilage are our first targets," Stupp told the Chicago Tribune. "That would be very important to Baby Boomers who value their quality of life. We are also working with regenerating blood vessels to address damage from heart attacks. (Nanotechnology) will first aid in diagnosing illness, but it also will provide therapies to alleviate or cure."

Nanoparticles offer ovarian cancer treatment approach.
Magnetic nanoparticles have been used to ‘drag' cancer cells out of the bodies of mice. Scientists at Georgia Tech coated the nanoparticles with a targeting molecule that caused them to bond to the cancer cells. And the researchers say the approach could be used to treat metastatic ovarian cancer. During metastasis, the cancer cells drift in the abdominal area, offering a target for the nanoparticles. They believe that a patient's abdominal fluid could be drained, cancer cells filtered out, and then infused back into the abdominal cavity.

"It's possible that the particles may not ever have to go into the patient's body," says John McDonald, the chief scientific officer of the Ovarian Cancer Institute at Georgia Tech. "That would be preferable, because then you don't have to worry about any potential toxicity."

References-
Read more: http://www.fiercebiotechresearch.com/story/new-nanoparticles-deliver-bigger-drug-payload/2009-04-28#ixzz0kS4utcYO
http://www.sciencedaily.com/releases/2009/11/091101132539.htm
Read more: http://www.fiercebiotechresearch.com/story/nanoparticles-used-deliver-targeted-ed-drugs/2009-09-22#ixzz0kS5TN3ev
Read more: http://www.fiercebiotechresearch.com/story/nanoparticles-could-boost-antibacterial-treatments/2008-11-10#ixzz0kS5umDfi
Read more: http://www.fiercebiotechresearch.com/story/nanomaterials-used-to-fix-neuron-damage/2007-05-01#ixzz0kS6W39Pt
Read more: http://www.fiercebiotechresearch.com/story/nanoparticles-offer-new-approach-treating-ovarian-cancer/2008-07-22#ixzz0kS6iAbJA

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Pulmonary route for mucosal drug delivery- II

7/5/2017

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Dry powder inhalers-

Dry powder inhalers (DPIs) are breath-actuated devices, by virtue of the fact that the kinetic energy imparted to the drug comes from the patient inhaling. The basic construction of all DPIs consists of mouthpiece and a turbulence chamber for dispersing the drug into the air stream. To reduce the incidence of agglomeration, the active material is normally loosely bound to a longer carrier such as lactose. A metered dose of the drug is introduced into the chamber from its storage area, which can be bulk, capsules or blister form. The patient then inhales and the resulting turbulence possibly assisted by mechanical agitation disperses the powder into the air stream and separates the drug from the carrier. Continued inhalation carries the drug into the airways where deposition occurs. Because of design constraints in order to achieve optimum dispersion, airflow rates through the device have to be relatively high = 60 L/min. Because of high air flows mean and high flow velocities, the inertia of the particles is higher and the resulting deposition in the upper airways in higher.

Future developments-

This area is probably best reviewed by considering the possible developments within each group.

Intrapulmonary and Endotracheal Routes of Administration :

According to current guidelines recommended for the management of cardiac arrest, the American Heart Association has recommended that when intravenous or intraosseous routes cannot be established, endotracheal administration of some resuscitation drugs be used. Medications that can be absorbed through the trachea include lidocaine, epinephrine, atropine, naloxone, and vasopressin (American Heart Association [AHA], 2005). Although the optimal dose of these drugs has yet to be established, two to two and one half times the recommended intravenous dose is used (AHA, 2005).

Recent studies investigated the intrapulmonary route of drug administration. One study suggests that intrapulmonary vancomycin may have efficacy in acute lung injuries, such as meconium aspiration syndrome in neonates (Jeng, Lee, & Soong, 2007). Televancin is also being studied for intrapulmonary use. Because the antibacterial activity is not affected by pulmonary surfactant, further studies of intrapulmonary televancin for use in treating gram-positive respiratory infections are underway (Gotfried et al., 2008).

Nebulisers, by virtue of their design and their need for an external energy source, tend in the main to be bulky and expensive and because of longer treatment period come low on social acceptability scale. Work in this area is likely to be directed towards smaller, most compact, low cost units suitable for home use. Metered dose inhalers represent a field in which developments are currently taking place. Continued interest is being shown in innovations on BAIs and spacer chamber based MDI. Dry powder inhalers will continue to appear in the market place in new and improved forms, the main areas of improvement being in the airflow/dispersion chambers and the drug storage systems, the main objective being ease of use.

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Pulmonary route for mucosal drug delivery- I

7/4/2017

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Choosing the lungs to deliver drugs beyond airways is not new. Nicotine and other anesthetics have been delivered to the blood stream this way for many years. However, the high surface area for absorption, the low level of enzymatic activity, the high physiologic pH together with rapid onset of drug action are key reasons why lung is a good site of delivery for peptides and proteins. It is particularly good for those, which have short half-lives. The key to delivering peptides & proteins to lungs is to target the small airways where the endothelial cells are directly connected with the alveolar endothelium. To deliver drugs deep into the lungs require particles of a precise size and a device, which delivers the drug regardless of a patient’s breathing patterns. Delivering drugs by inhalation requires precision engineering for optimum results.

Inhalation devices- an engineering overview

Today’s inhalation devices have many design criteria, which they must meet. Not only is it important that they deliver the drug in the correct form, to the correct target site they must also offer the patient ease of use, guarantee repeatable performance and low cost and all of which should be coupled to aesthetic appeal and social acceptability.

The large number of devices currently available can be amalgamated into 3 groups broadly, nebulisers, metered dose inhalers (MDIs) and dry powder inhalers (DPIs). For each, the basic operating principles, advantages and drawbacks will be reviewed followed by a consideration of possible enhancements and the future for devices in general.

Nebulisers-

Nebulisers could mostly be described as devices for generating aerosols using an external energy source to achieve atomization. Commercially, there are two basic systems available grouped by the energy source used, air jet nebulisers wherein a stream of high velocity air (dry and clean) is passed over a source of liquid (water) containing the drug. The resulting negative pressure causes the liquid to be drawn into the air stream from the reservoir. The air flow rate, the rate of which liquid is drawn into the stream and to a certain extent the surface tension of the liquid determine the initial droplet size. The stream may then be impacted into a baffle system of plates and filters, which refines the aerosol by removing the large droplets and releasing an aerosol, which is closer to being mono-dispersed at the target size. Typically for air jet nebulisers, this is in the range of 2-4 mm.

Ultrasonic nebulisers are the high frequency vibrations of piezo electric crystals to impart kinetic energy to the liquid; some of this energy in turn is used to create new surface area in the liquid, which will assume the most stable form of spherical droplets, due to its surface tension. These new droplets of liquid retain some of the imparted kinetic energy, which throws them clear of the bulk liquid, forming an aerosol in the nebuliser.

Both types of nebulisers can produce similar size distributions of aerosol, the ultrasonic systems having the advantage that they can nebulise relatively large volumes of liquid, without the associated high airflow requirement and resultant evaporative losses.

Metered dose inhalers (MDI)-

Metered dose inhalers (MDIs) can be viewed as a number of individual interactive components- the valve, the propellant & the inhaler (activator). The propellant systems normally used consist of a cocktail of one or more chloro-fluorocarbon (CFC). These compounds possess properties, which make them difficult to replace easily, such as volatility, low toxicity and low flammability. Because these propellants possess a distinct equilibrium vapor pressure at a given temperature in a closed MDI system that pressure is acting throughout the system and is effectively constant through the life of the pack, as long as liquid propellant remains (excluding preferential evaporation).

The portability, close consistency, accurate targeting, low cost and discrete use of MDIs mean that in terms of total numbers, they are the most frequently prescribed form of inhalation device. Unfortunately there are 2 main disadvantages. The first of these has developed in recent years, in as much as MDI are no longer considered environmentally acceptable (an issue which is beyond the scope of this article) due to the use of chlorofluro carbon propellants. The second disadvantage is a more long-standing problem and is one of misuse, patient in co-ordination and cold cough syndrome. Breath actuated inhalers (BAIs) and inhalers with spacer chamber offer solution to the problems.

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Innovative Strategies and Models for R&D Success.

6/21/2017

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Over the last quarter of the twentieth century, medical research made substantial advances in defining our understanding of diseases, their etiologies, and the biochemical pathways through which they were mediated. Our understanding was further augmented by human genome research. As the pathways of disease were clearly identified, pharmaceutical research largely focused on a “lab to market” approach, which involved identifying/synthesizing molecules that could mediate a disease pathway, characterizing their various attributes, and then commercializing them. In several cases, new molecules had characteristics that were marginally different from others already on the market, and therefore, did not address any unmet clinical need. Commercial success was often determined by the intensity of the sales and marketing effort behind the product, which resulted in an “arms race” (a battle for maximizing share of voice by investing in larger and larger sales teams) and the emergence of “blockbusters.”

The last 10 years have seen a seismic shift in the dynamics of pharmaceutical sales and marketing. The return on investment in sales force expansion is shrinking, causing almost all major pharmaceutical companies to reduce their head counts. Further, it is increasingly evident that the market and regulators are interested in new therapies that address an unmet need rather than yet another product in an existing class of molecules with little or no clinical or economic benefit.

Over the last few years, most of the innovations in pharmaceutical development have been only incremental — for most indications, there are significant therapy options available and it is unlikely that a radically better “wonder drug” will become available soon. Consequently, a disproportionate amount of ongoing research and development (R&D) effort has gone into products already in the market to expand the spectrum of indications where they can be used. A look at the number of drugs approved by the US FDA over the years indicate 35 new drugs approved in 2005 as against only 20 last year.. The decline in approvals is a clear indication of how difficult it will be for pharmaceutical companies to continue to show revenue growth in future.

As they grapple with shrinking pipelines, stricter safety requirements of the regulator, and spiraling costs to bring a product to market, pharmaceutical companies need to ensure that their products genuinely fulfill an unmet market need. Therefore, it is imperative that the R&D effort follow a “market to lab” approach—one that reverses the conventional approach used over the last few decades.

Aligning the organization to the Goals of Clinical Development-
Clinical R&D is a complicated process involving several steps and multiple stakeholders, both internal and external, in a pharmaceutical organization. Over the last 50 years, the journey of a product from laboratory to the market has not only become more arduous and time-consuming, but also more risky. Furthermore, since more and more clinical development plans (CDPs) include global, multi-centric clinical trials, their formulation and execution are broken into several sub-elements, each of which have become the responsibility of different functional silos in a pharmaceutical company. Consequently, clinical R&D at present involves stakeholders from the strategic, marketing, sales, medical, R&D, clinical operations, regulatory affairs, documentation, and health economics teams.

Given that the collective objective of all the teams involved in the CDP is to achieve a desirable Target Product Profile (TPP) and therefore a superior product label, pharmaceutical companies must ensure that all stakeholders are aligned and share a common line of sight to the end objective. This is not always easy, but is a critical challenge that must be overcome. Failure to do so runs the risk of a CDP not being in step with current and future market needs, and oblivious to the competitive scenario in the future.

The essence of “claims-based R&D” lies in taking a backward “market to lab” approach so as to ensure that the CDP is designed to address specific unmet market needs. It also involves the systematic benchmarking of a product’s CDP to current and future competition while continuously evaluating scientific and market threats and opportunities. It involves the integration of multiple inputs to develop the CDP and then prospectively simulate the likely TPP of the product and a SWOT analysis vis-à-vis its inline and pipeline competitors.

The Process of Developing a CDP-
The process of claims-based R&D is iterative since it attempts to temper the desire to develop an “ideal” product with scientific and operational feasibility. With the ever-growing volume of information and data available in the secondary domain, it is now possible to pursue claims-based R&D to a far greater level of granularity than before. It also enables TPP simulation on a near real-time basis as pivotal information becomes available.

Customer Insights-
In an earlier era of pharmaceutical development, unmet market needs were determined almost exclusively from the opinions of physicians and medical key opinion leaders (KOLs). In the modern era, however, there has been a significant shift in the level of influence exerted by different stakeholders (customers) on the patterns of pharmaceutical consumption. These stakeholders (customers) include the patient, the payor, and the regulator.

While pursuing claims-based R&D, it is critical to ensure that the insights and opinions of all the key stakeholders (customers) are accurately captured so that the product(s) developed can genuinely claim to deliver a clinical and/or economic benefit.

These insights are most often captured through primary research and intelligence initiatives, which include engagement with physician groups, patient and caregiver groups, insurance agencies, etc. However, such initiatives can be effectively complemented by research of secondary sources of information such as online patient discussions boards and transcripts of regulatory proceedings.

Scientific Insights-
The volume of scientific research has been growing at an astounding rate. A search on www.pubmed.com (the online index of the National Library of Medicine) reveals that approximately 725,000 articles were published over the last year alone. Journal articles and congress presentations constitute a wealth of information about cutting-edge scientific developments.

A thorough analysis of such publications and academic congresses is critical at the time of developing a CDP and simulating the TPP because:

It serves as an advanced warning system about novel scientific developments that could threaten to make obsolete a particular product.
It could reveal alternate approaches to addressing the unmet clinical need at an early stage, and therefore throw up opportunities for partnerships or ideas for development
It presents the successes and failures of competitive development programs, thereby sparing a lot of unnecessary effort and investment
It is a good source to unveil new information about the epidemiology of a disease and therefore the size of the addressable market opportunity.

Competitor Insights-
Ultimately, pharmaceutical R&D needs to be viewed in the context of competition because of the underlying commercial objectives associated with the process. Consequently, an understanding of the development, licensing, and marketing strategies of the competition constitutes a critical input into the development of the CDP.

It is important to note that competition needs to be viewed not merely in today’s context but also in context of what lies ahead. Therefore, it is recommended that any CDP and its derived TPP be benchmarked to the claims and positioning strategies of competitive products already in the market as well as the likely claims and strategies of pipeline products.

Fortunately, substantial amount of information about clinical trials—completed and ongoing—is available in the public domain through sources such as product labels and clinical trial registries. The main source for clinical trial information is www.clinicaltrials.gov (the official site of the US FDA), which contains several essential details about all registered clinical trials.

Although the information is accessible through sources such as the ones cited above, it is essential to note that deriving insights, simulating competitive claims, etc., is an exercise that requires substantial human expertise.

The Ideal Target Product Profile-
As a first step of an iterative process to design a CDP, it is recommended to build an “ideal TPP.” To do this, one would need to integrate the various insights and inferences described above and evolve a TPP that would address all the unmet needs of the market while also yielding superior marketing claims across all product attributes.

Therefore, an “ideal TPP” would represent best-in-class performance for efficacy, safety (ideally, would result in no adverse effects), tolerability, convenience, drug and food interactions, and perhaps, even cost. In addition, the “ideal TPP” would cover a wider patient population than all competitors.

The Real Target Product Profile (TPP)-
Much as we may aspire for an “ideal TPP,” it is necessary to recognize that in the real world, we cannot get every product attribute we desire. Therefore, we must modify the “ideal TPP” by prioritizing the attributes and claims that the CDP must focus on and compromising on others to arrive at the “real TPP.” This can be done by classifying the product attributes in the “ideal TPP” as either essential or desirable.

The essential features of the TPP would represent a set of product attributes that represent either superiority over competing products or, at the very least, non-inferiority to competing products. Without these features, the product would enjoy no unique selling point when launched.

The desirable features of the TPP would represent additional product attributes that could enhance the product’s marketability. These additional attributes could include some side indications, tolerability improvement, application for specific subpopulations, or even improved product stability. They all represent features that are not absolutely mandatory for commercial success but would certainly amplify the claim of superiority.

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Intranasal administration route for protein & peptide mucosal delivery.

6/6/2017

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Intranasal administration route for protein & peptide mucosal delivery.Picture

Due to its unique physiology and ready accessibility, the nasal cavity is an attractive delivery site for the systemic administration of therapeutics. The nasal membrane or mucosa lines the nasal cavity and is located posterior to the external nares. The surface area of the nasal mucosa is relatively large (180 cm2) and has a rich blood supply (40ml/min/100g). Molecules absorbed across the mucosal membranes are transported directly to the blood stream and therefore avoid clearance due to first pass metabolism. Also, the protease activity in the nasal cavity is greatly diminished relative to the small intestine making enzymatic degradation in the nasal cavity less likely. Relative to chronic parenteral administration, intranasal delivery offers increased patient compliance and in some cases, increased pharmacokinetic control.

Intranasal formulation is a remarkable and easy mode of drug delivery. It is a needle-free, patient-friendly route that does not contribute to biohazardous waste (Wermeling, Miller, & Rudy, N.D.). Pharmacokinetically, the absorption rate is so rapid that it results in a faster onset of action compared with oral and intramuscular administration. In addition, hepatic first-pass metabolism is avoided (Wermeling et al.,). (The metabolism of an administered dose of a drug by the liver before it reaches systemic circulation is referred to as the first-pass metabolism.) For many oral drugs, a clinically significant portion of the drug taken is destroyed during first-pass metabolism, requiring a higher oral dose for a given effect (Wynne, Woo, & Olyaei, 2007).

Intranasal drugs can be delivered in a variety of formulations that include powders, drops, topical gels, and sprays. Consideration must be given to normal physiologic processes when using the intranasal route, as the nose is an important defense system for environmental hazards. Any disruption of its normal physiology may leave the patient vulnerable to a variety of complications (Wermeling et al.). The delivery devices for intranasal medications can be costly, as illustrated by intranasal insulin, and can be a deterrent to patient use. Initially thought to be a desired route compared with subcutaneous insulin, patients found intranasal insulin to be burdensome and costly (R. Talbert, personal communication, February 21, 2008).

Until recently, vitamin B 12 has been available only by intramuscular injection. Calomist (cyanocobalarain) Nasal Spray is now available in a 25-mg/spray form that is used daily in lieu of the monthly injections. This can now be included in the daily routine with less impact of a missed dose.

Medication Adherence

Medication adherence can be problematic with older adults. One of the most basic forms of medication delivery, the pillbox, is continually being updated. An interactive pillbox can be a useful tool in reminding this population about their medication times. Pillboxes are available that can hold as much as a 1-month supply of medications, with separate compartments for as many as four drugs. After programming, the box will beep at the time a medication is due to be taken, indicate the appropriate compartment, and display the number of pills to take. When the compartment lid is lifted, an audio message instructs the patient on the number of pills to take, along with specific information about how that medication should be taken. The data are gathered and can be transmitted via phone lines to the caregiver to confirm the time at which the medication was taken. Even patients thought to be compliant accidentally skip doses of medication, a silent problem improved by these devices. Pillboxes with multiple compartments are particularly helpful for older patients when dealing with multiple pill regimens.

The intranasal administration of small organic compound is a well-established mode of delivery. The majority of these drugs however, are intended for local administration to the nasal mucosa rather than systemic administration.

Factors affecting nasal absorption-

I.  Drug effect-  molecular size, lipophilic balance and ezymatic degradation in nasal cavity.

II. Nasal effect-  membrane permeability (interspecies differences), environmental pH, mucociliary clearance, colds, rhinitis etc.

III.Delivery effect-  formulation (concentration, pH, Osmolality), delivery systems (sprays, drops, gels), deposition, formulation effects in mucociliary clearances, toxic effects on ciliary functions and epithelial membranes.

Pharmacology & Toxicological considerations-

The safety of any delivery technology must be rigorously evaluated before it can be considered as a viable delivery alternative. The assessment should occur individually with both the delivery system and in combination with the active component. This is especially for trans-nasal delivery systems, which will be used systemically. For a nasal product which contains an excipient, that affects nasal permeability, the systemic topical effects of the excipients as well as individual peptide be evaluated. Mucociliary transport rate, patho/histo morphology and ciliary beat frequency tests are the commonly prescribed test for formulations delivered by nasal route.