Nasal delivery technology impotence-

I like to think I have a nose for news. And, some might say, too much of a penchant for puns and alliteration. Impotence drug profits won't be going up big pharma's nose. The tiny New Jersey-based biotech company Palatin Technologies says it's giving up on its experimental nasal spray for erectile dysfunction. A few years ago I did a story on potential next-generation sexual dysfuction drugs for men and women.

Nasal delivery technology impotence

Nasal delivery technology impotence

Nasal delivery technology impotence

Nasal delivery technology impotence

Fair Trading Minister Virginia Judge said in February she had asked dissatisfied customers to come forward with complaints of unconscionable contracts and undeliverable guarantees. But Dr Vaisman had another analogy: "Why are people sniffing cocaine, why they don't swallow cocaine? Overall it's still a multi-billion dollar-a-year segment with two strong leaders. Kanye West buys poo emoji cushion for his infamously minimal home while shopping in NY Meghan King Edmonds' husband Jim files for divorce License this article. Monday, Oct 28th 5-Day Forecast. I tell patients if I can't give you a full and lasting erection, if I can't give controlled ejaculation, if I can't bring women to orgasm, I will refund techno,ogy money. Viagra works Nasal delivery technology impotence blocking an enzyme in the body and allowing more blood to flow to the penis. Art and craft.

Kat von d model. Related Securities

An air-filled compartment is compressed until a pin ruptures a membrane Nasal delivery technology impotence release the pressure to emit the plume of powder. However, the clinical relevance of these results from healthy volunteers for rhinosinusitis patients with blocked sinus openings remains to be determined. Illum L. J Appl Physiol. They have also announced plans to develop a powder-based influenza vaccine www. Ejaculatory technoloyg is one of the most common male sexual disorders, yet it is still frequently misdiagnosed or overlooked as a result of numerous patient and physician barriers. Undoubtedly, as Nasal delivery technology impotence quality and capabilities increase, CFD simulations will play an increasingly important role and allow for realistic simulation of nasal physiology and drug delivery. A handheld battery-driven atomizer intended for nasal drug delivery has been introduced ViaNase by Kurve Technology Inc. Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, absorption and biologic response. Interestingly, an area of increased trigeminal chemosensitivity is found in the anterior part of the nose, mediating touch, pressure, temperature, and pain [ 39 ]. Finally, it does not address aspects and challenges related to the nasal anatomy and physiology that are highly relevant for the device performance in the Lave strapon setting dwlivery body position, need for coordination, and impact of airflow techonlogy breathing patterns at delivery. The device has been used in studies in rabbits, but no data from human deposition or clinical studies have been published Nasal delivery technology impotence 84 ]. The man behind AMI, Dr Jack Vaisman, the Sydney entrepreneur often dismissed as a shonky operator, told The Sunday Telegraph that he had "successfully treated'' more thanAustralian men for impotence and premature ejaculation. The particle size and plume geometry can vary within certain limits and depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied [ 3 ]. Techniques of intranasal steroid use.

Patients seeking treatment for erectile dysfunction were not warned they would have to try injections into their penis before they could qualify for a refund, a court has heard.

  • Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis.
  • Do you want help for Premature Ejaculation and Erectile Dysfunction?
  • Nasal Technology has come to the forefront in recent years and has been used for more than just allergies and nasal congestion as was its original use.

I like to think I have a nose for news. And, some might say, too much of a penchant for puns and alliteration. Impotence drug profits won't be going up big pharma's nose. The tiny New Jersey-based biotech company Palatin Technologies says it's giving up on its experimental nasal spray for erectile dysfunction. A few years ago I did a story on potential next-generation sexual dysfuction drugs for men and women.

Turns out, though, the drug apparently raised something else I mean, I thought I was paying for commercial-free radio--commercials and email spam for prescription and over-the-counter, "homeopathic" ED remedies that it's a topic of relatively high interest.

Overall it's still a multi-billion dollar-a-year segment with two strong leaders. LLY sold nearly a billion-and-a-half dollars worth of Cialis last year, but sales went down sequentially from the fourth quarter to the first quarter.

Cialis is the one that lasts in the body for about a day-and-a-half and Lilly recently won approval of a one-a-day formulation of the drug. Levitra sales, especially because they're split at least three ways, are relatively immaterial although Bayer recently announced it's still trying to goose revenue with the launch of a new ad campaign oddly named, "Restore the Man. Pharma cnbc.

Sign up for free newsletters and get more CNBC delivered to your inbox. Get this delivered to your inbox, and more info about our products and services. Privacy Policy. All Rights Reserved. Data also provided by. Markets Pre-Markets U. Mike Huckman MikeHuckman.

Source: palatin. Mike Huckman. Related Securities Symbol. News Tips Got a confidential news tip? We want to hear from you. Get In Touch. CNBC Newsletters.

Sometimes, the anteriorly deposited surplus is wiped off, as has been observed in gamma-deposition studies [ ]. The results from the study described above comparing deposition and clearance after delivery from the same spray pump actuated in different manners show that the initial site of deposition has a profound impact on the clearance rates [ 3 , 13 , 14 ]. One approach to avoiding lung deposition is the Bi-Directional TM technology employed in OptiNose devices; this technology ensuring operation of the nebulizer only on generation of a pressure sufficient to close the palate, avoiding the problems associated with suction pumps and special breathing instructions. Previous sinus surgery had no impact on the efficacy. Nasal Technology has come to the forefront in recent years and has been used for more than just allergies and nasal congestion as was its original use. The mechanical properties of different modes of aerosol generation are already well described in depth in a previous publication [ 3 ]. Characterization and in vitro evaluation of freeze-dried microparticles composed of granisetron-cyclodextrin complex and carboxymethylcellulose for intranasal delivery.

Nasal delivery technology impotence

Nasal delivery technology impotence

Nasal delivery technology impotence

Nasal delivery technology impotence. Introduction

Sensory, motor, and parasympathetic nerves are involved in a number of nasal reflexes with relevance to nasal drug delivery [ 4 ]. Consequently, deposition studies in nasal casts and CFD simulation of airflow and deposition are of value, but their predictive value for the clinical setting are all too often overestimated. For most purposes, a broad distribution of the drug on the mucosal surfaces appears desirable for drugs intended for local action or systemic absorption and for vaccines [ 3 ].

However, in chronic sinusitis and nasal polyposis, targeted delivery to the middle and superior meatuses where the sinus openings are, and where the polyps originate, appears desirable [ 42 , 43 ]. However, recent animal data suggest that some degree of transport can also occur along the branches of the first and second divisions of the trigeminal nerve innervating most of the mucosa at and beyond the nasal valve [ 44 ].

This suggests that, in contrast to the prevailing opinion, a combination of targeted delivery to the olfactory region and a broad distribution to the mucosa innervated by the trigeminal nerve may be optimal for N2B delivery.

Targeted delivery will be discussed in more detail below. The details and principles of the mechanics of particle generation for the different types of nasal aerosols have been described in detail by Vidgren and Kublik [ 3 ] in their comprehensive review from and will only be briefly described here, with focus instead on technological features directly impacting particle deposition and on new and emerging technologies and devices.

Liquid formulations currently completely dominate the nasal drug market, but nasal powder formulations and devices do exist, and more are in development. Overview of the main types of liquid and powder delivery devices, their key characteristics, and examples of some key marketed nasal products and emerging devices and drug—device combination products in clinical development.

The liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered. Liquid formulations are considered convenient particularly for topical indications where humidification counteracts the dryness and crusting often accompanying chronic nasal diseases [ 3 ]. In traditional spray pump systems, preservatives are typically required to maintain microbiological stability in liquid formulations. Studies in tissue cultures and animals have suggested that preservatives, like benzalkonium chloride in particular, could cause irritation and reduced ciliary movement.

However, more recent human studies based on long-term and extensive clinical use have concluded that the use of benzalkonium chloride is safe and well tolerated for chronic use [ 45 ].

For some liquid formulations, in particular peptides and proteins, limited stability of dissolved drug may represent a challenge [ 46 ]. Drops and vapor delivery are probably the oldest forms of nasal delivery. Dripping breast milk has been used to treat nasal congestion in infants, vapors of menthol or similar substances were used to wake people that have fainted, and both drops and vapors still exist on the market e.

Drops were originally administered by sucking liquid into a glass dropper, inserting the dropper into the nostril with an extended neck before squeezing the rubber top to emit the drops. An advantage is that preservatives are not required. In addition, due to inadequate clinical efficacy of spray pumps in patients with nasal polyps, a nasal drop formulation of fluticasone in single-dose pipettes was introduced in the EU for the treatment of nasal polyps.

The rationale for this form of delivery is to improve drug deposition to the middle meatus where the polyps emerge [ 47 , 48 ]. Compliance is often poor as patients with rhinosinusitis often experience increased headache and discomfort in head-down positions. A simple way for a physician or trained assistant to deposit drug in the nose is to insert the tip of a fine catheter or micropipette to the desired area under visual control and squirt the liquid into the desired location.

This is often used in animal studies where the animals are anesthetized or sedated, but can also be done in humans even without local anesthetics if care is taken to minimize contact with the sensitive mucosal membranes [ 50 ].

This method is, however, not suitable for self-administration. Harris et al. Despite a rather cumbersome procedure with considerable risk of variability in the dosing, desmopressin is still marketed in some countries with this rhinyle catheter alongside a nasal spray and a tablet for treatment of primary nocturnal enuresis, Von Willebrand disease, and diabetes insipidus.

Squeeze bottles are mainly used to deliver some over-the-counter OTC products like topical decongestants. By squeezing a partly air-filled plastic bottle, the drug is atomized when delivered from a jet outlet. The dose and particle size vary with the force applied, and when the pressure is released, nasal secretion and microorganisms may be sucked into the bottle. Squeeze bottles are not recommended for children [ 3 ]. The particle size and plume geometry can vary within certain limits and depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied [ 3 ].

Traditional spray pumps replace the emitted liquid with air, and preservatives are therefore required to prevent contamination.

However, driven by the studies suggesting possible negative effects of preservatives, pump manufacturers have developed different spray systems that avoid the need for preservatives.

These systems use a collapsible bag, a movable piston, or a compressed gas to compensate for the emitted liquid volume [ 3 ] www. The solutions with a collapsible bag and a movable piston compensating for the emitted liquid volume offer the additional advantage that they can be emitted upside down, without the risk of sucking air into the dip tube and compromising the subsequent spray.

This may be useful for some products where the patients are bedridden and where a head-down application is recommended. Another method used for avoiding preservatives is that the air that replaces the emitted liquid is filtered through an aseptic air filter.

In addition, some systems have a ball valve at the tip to prevent contamination of the liquid inside the applicator tip www. These preservative-free pump systems become more complex and expensive, and since human studies suggest that preservatives are safe and well tolerated, the need for preservative-free systems seems lower than previously anticipated [ 45 ].

More recently, pumps have been designed with side-actuation and introduced for delivery of fluticasone furoate for the indication of seasonal and perennial allergic rhinitis [ 52 ]. The pump was designed with a shorter tip to avoid contact with the sensitive mucosal surfaces. New designs to reduce the need for priming and re-priming, and pumps incorporating pressure point features to improve the dose reproducibility and dose counters and lock-out mechanisms for enhanced dose control and safety are available www.

Metered-dose spray pumps require priming and some degree of overfill to maintain dose conformity for the labeled number of doses. They are well suited for drugs to be administered daily over a prolonged duration, but due to the priming procedure and limited control of dosing, they are less suited for drugs with a narrow therapeutic window.

For expensive drugs and vaccines intended for single administration or sporadic use and where tight control of the dose and formulation is of particular importance, single-dose or duo-dose spray devices are preferred www. A nosepiece with a spray tip is fitted to a standard syringe.

The liquid drug to be delivered is first drawn into the syringe and then the spray tip is fitted onto the syringe. This device has been used in academic studies to deliver, for example, a topical steroid in patients with chronic rhinosinusitis and in a vaccine study [ 53 , 54 ]. A similar device for two doses was marketed by a Swiss company for delivery of another influenza vaccine a decade ago. The device technology is now owned by a Dutch vaccine company Crucell N.

Leiden, the Netherlands; www. The single- and duo-dose devices mentioned above consist of a vial, a piston, and a swirl chamber. The spray is formed when the liquid is forced out through the swirl chamber. These devices are held between the second and the third fingers with the thumb on the actuator.

A pressure point mechanism incorporated in some devices secures reproducibility of the actuation force and emitted plume characteristics [ 58 ].

Currently, marketed nasal migraine drugs like Imitrex www. With sterile filling, the use of preservatives is not required, but overfill is required resulting in a waste fraction similar to the metered-dose, multi-dose sprays.

Most drugs intended for local nasal action are delivered by spray pumps, but some have also been delivered as nasal aerosols produced by pMDIs. Following the ban on ozone-depleting chlorofluorocarbon CFC propellants, the number of pMDI products for both pulmonary and nasal delivery diminished rapidly, and they were removed from the US market in [ 60 ].

The particles emitted from the traditional pMDIs had a particle velocity much higher than a spray pump 5, vs. The pressure created by the force actuating a spray pump drives the liquid through the swirl chamber at the tip of the applicator and out through the circular nozzle orifice [ 64 ]. Importantly, a hollow spray cone is formed with particles mainly at the periphery. The key parameters influencing the properties of the plume and subsequently the deposition pattern of the particles are the swirl effect, nozzle orifice dimensions, the spray cone angle, and the break-up length.

Inthavong et al. Another study reported a spray cone diameter of 2. With most of the particles in the periphery of the plume, it becomes quite evident that the majority of the particles will impinge in the non-ciliated mucosal walls of the vestibule anterior to the valve. Particles actually penetrating the valve will do so primarily through the lower and wider part of the triangle, a delivery pattern that is accentuated if delivery is performed during sniffing. Nebulizers use compressed gasses air, oxygen, and nitrogen or ultrasonic or mechanical power to break up medical solutions and suspensions into small aerosol droplets that can be directly inhaled into the mouth or nose.

The smaller particles and slow speed of the nebulized aerosol are advocated to increase penetration to the target sites in the middle and superior meatuses and the paranasal sinuses [ 42 ]. In light of this problem of lung delivery, it is unsurprising that nasal inhalation of nebulized antibiotics intended for topical action in patients with chronic rhinosinusitis resulted in coughing and increased need for inhaled medications following nasal inhalation [ 67 ].

A new nebulizer intended for delivery to the nose and sinuses in patients with chronic rhinosinusitis utilizing a pulsating aerosol generated via a perforated vibrating membrane has recently been introduced VibrENT PARI Pharma GmbH. The pulsation in combination with small particles is assumed to offer better penetration to the sinuses, and instruction on specific breathing technique during delivery is advocated to minimize inhalation [ 68 ]. Delivery of an aerosol with small particles with a mass median aerodynamic diameter MMAD of 3.

Nasal aerosol delivery was also performed when the subjects were instructed to maintain the soft palate closed while a flow resistor was connected to the left nostril. Correction for background radiation and decay was performed, but correction for tissue attenuation was not performed, which is likely to change the relative distribution and potentially increase the fraction actually deposited in the lungs [ 68 — 71 ].

Nevertheless, the results suggest that the use of a pulsating aerosol in combination with the breathing technique and an exit resistor may enhance deposition in the sinuses in healthy volunteers. However, the clinical relevance of these results from healthy volunteers for rhinosinusitis patients with blocked sinus openings remains to be determined.

The new system consists of two integrated components: the nebulizer compressor administering a constant airflow rate transporting the aerosol into one nostril via a nozzle and a pump simultaneously aspirating from a second nozzle in the other nostril at the same airflow rate while the subject is instructed to avoid nasal breathing [ 72 ].

With much longer delivery time, a substantial fraction of the dose delivered beyond the nasal valve will be cleared to the gastrointestinal GI tract. Furthermore, aerosol distribution deposition in the vertical plane showed a similar profile for both nebulizers with a distinct maximum close to the floor of the nose 0.

Lung deposition and relatively low nasal delivery fractions are issues with nasal nebulizers. Although lung deposition appears to be reduced with simultaneous aspiration from the contralateral nostril and with specific breathing instructions, this complex mechanism for use, coupled with the need for careful patient compliance with breathing, may be challenging, especially in children or other special populations [ 66 , 68 , 72 ].

The study design, comparing not only two different nebulization techniques but also very different breathing techniques, makes interpretation of the results comparing the nasal nebulizers in terms of deposition efficacy and clinical significance very difficult. This pattern of deposition suggests the nebulizer is not effectively delivering to the prime target sites for chronic rhinosinusitis and nasal polyposis i.

To date, no clinical data has been published with the new nebulizer systems [ 68 , 72 ]. One approach to avoiding lung deposition is the Bi-Directional TM technology employed in OptiNose devices; this technology ensuring operation of the nebulizer only on generation of a pressure sufficient to close the palate, avoiding the problems associated with suction pumps and special breathing instructions.

However, clinical data using this approach with a nebulizer has also not been published. A handheld battery-driven atomizer intended for nasal drug delivery has been introduced ViaNase by Kurve Technology Inc.

This device atomizes liquids by producing a vortical flow on the droplets as they exit the device www. The induced vortical flow characteristics can be altered in circular velocity and direction to achieve different droplet trajectories [ 42 , 73 ].

As discussed above, it is not clear that vortex flow is desirable for penetration past the nasal valve; however, it has been suggested that this technology is capable of targeting the sinuses, and some gamma-deposition images suggesting delivery to the sinuses have been published. However, no information related to impact of prior surgery or numerical quantification of nasal or sinus deposition verifying the claimed improved deposition to the upper parts of the nose has been published [ 42 , 73 ].

In these studies, delivery of insulin was performed over a 2-min period by nasal inhalation. However, when insulin is delivered with this device, lung deposition is likely to occur, and some concerns related to airway irritation and reduction in pulmonary function have been raised in relation to long-term exposure to inhaled insulin when Exubera was marketed for a short period as a treatment for diabetes [ 71 , 76 ].

This example highlights the issue of unintended lung delivery, one important potential clinical problem associated with using nebulizers and atomizers producing respirable particles for nasal drug delivery. A nasal atomizer driven by highly pressurized nitrogen gas is under development by Impel Inc. The device is intended to enable drug delivery to the upper parts of the nose in order to achieve N2B delivery [ 77 ]. To date, only animal data has been presented, making it difficult to evaluate its potential in human use, as nasal deposition and the assessment of nasal deposition in animal models vary significantly from humans.

As previously noted, however, pMDIs are associated with a number of limitations. Powder medication formulations can offer advantages, including greater stability than liquid formulations and potential that preservatives may not be required.

Powders tend to stick to the moist surface of the nasal mucosa before being dissolved and cleared. The use of bioadhesive excipients or agents that slow ciliary action may decrease clearance rates and improve absorption [ 46 , 78 ]. A number of factors like moisture sensitivity, solubility, particle size, particle shape, and flow characteristics will impact deposition and absorption [ 3 ].

Powder sprayers with a compressible compartment to provide a pressure that when released creates a plume of powder particles fairly similar to that of a liquid spray;. Breath-actuated inhalers where the subject uses his own breath to inhale the powder into the nostril from a blister or capsule; and. Nasal insufflators describe devices consisting of a mouthpiece and a nosepiece that are fluidly connected.

Delivery occurs when the subject exhales into the mouthpiece to close the velum, and the airflow carries the powder particles into the nose through the device nosepiece similar to the rhinyle catheter described above. It is marketed for allergic rhinitis and nasal polyps in some markets as an alternative to the liquid spray, but it does not seem to offer any particular advantage [ 80 ].

However, nasal symptom scores were significantly more reduced in the liquid spray compared to the powder [ 80 ]. If corrected for tissue attenuation in the lungs, it is likely that the fraction would be substantially higher [ 69 , 79 ].

Aptar group www. The blister is pierced before use and the device nosepiece placed into one nostril. The subject closes the other nostril with the finger and inhales the powder into the nose.

Apparently, further development has been discontinued. Nippon Shinyaku Co. The capsule is pierced, and when the subject inhales from the nosepiece, the powder is deagglomerated and delivered into the nose with the airflow. SBNL Pharma www.

The zolmitriptan absorption was rapid, and the relative bioavailability was higher than the marketed tablet and nasal spray www. The company has their own capsule-based, single-dose powder devices Fit-lizer [ 82 ].

When inserted into a chamber, the top and bottom of the capsule is cut off by sharp blades. A plastic chamber is compressed by hand, compressed air passes through a one-way valve and the capsule during actuation, and the powder is emitted.

In vitro testing shows high-dose reproducibly and minimal residuals, but no data on particle size distribution or in vivo deposition and clearance patterns appear to be available. They have also announced plans to develop a powder-based influenza vaccine www. Bespak www.

An air-filled compartment is compressed until a pin ruptures a membrane to release the pressure to emit the plume of powder. Delivery of powder formulations of a model antibody human IgG has been tested in a nasal cast model based on human MRI images. The company report in their website that they have entered into a collaboration to develop an undisclosed nasal powder product with this device www. The device has been used in studies in rabbits, but no data from human deposition or clinical studies have been published [ 84 ].

BD www. A device based on this technology is being tested with powder vaccines [ 85 ]. Trimel www. There are two versions of this device that looks like a small drinking straw. One version is intended for pulmonary drug delivery where subjects inhale through the small tubular device and one for nasal drug delivery where subjects blow into one end of the tube while the other end is inserted into the vestibule of the nostril. The device can in principle be viewed as a powder version of the rhinyle catheter for liquid delivery.

This tubular device includes a middle section with corrugations. The corrugations allow flexion of the device and create turbulence that deagglomerates the powder. One end of the small tubular device is inserted between the lips and the other into the nasal vestibule. The subject then exhales through the device to expel the powder from the tube and into the nostril. As when using the rhinyle catheter, exhalation into the device causes the soft palate to automatically elevate to separate the oral cavity and the nasal passages, preventing lung inhalation during delivery.

OptiNose www. This novel concept exploits natural functional aspects of the upper airways to offer a delivery method that may overcome many of the inherent limitations of traditional nasal devices.

The user slides a sealing nosepiece into one nostril until it forms a seal with the flexible soft tissue of the nostril opening, at which point, it mechanically expands the narrow slit-shaped part of the nasal triangular valve.

The user then exhales through an attached mouthpiece. When exhaling into the mouthpiece against the resistance of the device, the soft palate or velum is automatically elevated by the positive oropharyngeal pressure, isolating the nasal cavity from the rest of the respiratory system.

Owing to the sealing nosepiece, the dynamic pressure that is transferred from the mouth through the device to the nose further expands the slit-like nasal passages. By optimizing design parameters, such as the nosepiece shape, the flow rate, the particle size profile, and release angle, it is possible to optimize delivery to target sites beyond the nasal valve, avoid lung deposition, and to assure that particles are deeply deposited without exiting the contralateral nostril.

Device variants using this mechanism of nasal drug delivery have been tested in gamma-deposition studies where assessments of the regional deposition and clearance patterns in human subjects were studied in detail [ 13 , 14 , 69 ].

In contrast, the summed initial deposition to the lower anterior and posterior regions for spray was three times higher compared to Opt-Powder Opt-Powder Results generally suggest that superior deep nasal deposition with clinically important potential can be achieved in the clinic, and two drug—device combinations are currently in Phase 3 development: sumatriptan powder for acute migraine and fluticasone propionate for chronic rhinosinusitis with nasal polyposis [ 87 — 90 ] www.

Midazolam—sedation: Midazolam is a drug with high bioavailability BA , reasonable ability to cross the BBB, and easily observed pharmacodynamic effects sedation.

In a three-way crossover study of 12 healthy volunteers, delivery of the same dose of midazolam 3. Alternative transport routes to the brain bypassing the BBB described in animal studies may contribute to the sedative effects [ 32 — 34 , 44 ].

Moreover, direct transport to the brain for both small and large molecules may occur along ensheathed cells forming channels around the olfactory and trigeminal nerves [ 34 , 44 ]. In a randomized, double-blind, parallel group, placebo-controlled study, a single migraine attack was treated in-clinic with two doses of sumatriptan powder 7.

The pain relief rates were similar to historical data SC injection despite much lower systemic exposure [ 90 , 92 ]. However, based on comparisons with historical data on the PK and pharmacodynamics profiles of sumatriptan delivered through different routes, it has been speculated that the rate of systemic absorption of nasal sumatriptan may not alone explain differences in headache response suggesting the potential for an additional route to the site of action as discussed above [ 14 ].

A Phase 3 study is currently in progress www. Fluticasone propionate—chronic rhinosinusitis with nasal polyps: Fluticasone is a topical steroid, available as a standard nasal spray for treatment of rhinitis but often used with limited benefit in the treatment of chronic rhinosinusitis CRS with and without nasal polyps. Combined symptom score, nasal blockage, discomfort, rhinitis symptoms, and sense of smell were all significantly improved [ 87 ]. The highly significant progressive treatment effect of Opt-FP was observed regardless of baseline polyps score.

Previous sinus surgery had no impact on the efficacy. Notably, this is a condition marked by many recent negative placebo-controlled trials [ 96 , 97 ]. This context, in addition to comparison with historical data in similar patient populations, again suggests that breath-powered bi-directional delivery is capable of producing superior deep nasal deposition in clinical practice improved targeting of the middle meatus in this case which can translate into improved clinical response Fig.

In contrast to the self-administration with the OptiNose device, the nasal drops were delivered by an assistant inserting the pipette tip in a controlled manner beyond the nasal valve with the neck extended. With development of high-resolution CT and MRI technology, it has become possible to generate accurate 3D reconstructions of the complex nasal anatomy Fig.

The field of computational fluid dynamics CFD is rapidly progressing in medicine and has enabled CFD simulations of nasal aerodynamics and deposition patterns [ 98 — ]. The greatly improved density of the grids used and algorithms, along with much faster computers available for simulation, now allow implementation of more realistic conditions. For example, recent publications describe algorithms to simulate septal abnormalities, post-surgical changes, as well as heat and water exchange, and to more accurately simulate the true properties of aerosol generation and plume characteristics [ 99 — ].

Undoubtedly, as the quality and capabilities increase, CFD simulations will play an increasingly important role and allow for realistic simulation of nasal physiology and drug delivery. A more detailed review of this exciting field is outside the scope of this review. The progress in imaging and reconstruction software has also made it possible to make physical models in rigid materials by modern 3D printing techniques like stereolithography with correct nasal geometry and dimensions.

Casts made in softer material like silicone may offer advantages in terms of more realistic device cast interface. However, caution is necessary because even the softer silicone casts do not realistically represent the nasal valve dynamics, the cyclic physiological changes of the mucosa, or reflect the in vivo surface properties of the nasal mucosa, including the impact on mucocliliary clearance [ ].

An in depth review of in vitro drug delivery simulation performed in nasal casts is also outside the scope of this review, but some comments related to recent work are included to highlight issues related to the interpretation and predictive value of results obtained with nasal delivery devices in cast studies.

Three recent publications report in detail on the effect of breathing patterns, formulation, spray pump variables, and the site of deposition in a particular commercially available silicone cast Koken Co. An interesting gel coating method that changes color in contact with the liquid allowing quantification of deposition by photometric analysis of deposition images is described [ ].

In the most recent work, different insertion depth, spray angle, and plume characteristics cone angle and particle size distribution were studied.

Data on the dimensions of the cast are not presented in these reports; however, it is critical to note that the Koken cast is, according to the manufacturer, primarily an educational tool and that it therefore has a flat transparent septum to enable visualization of complicated nasal structures. Inspection of the nasal valve area and objective measurements of the dimensions reveals that the dimensions at the valve area are several-fold larger than the average human valve dimensions and outside the normal range [ ].

It is suggested in these recent publications that casts studies have potential for establishing in vivo bioequivalence and as indicators of critical quality attributes [ 65 ]. While an admirable goal, the lack of validation of all cast dimensions coupled with the inability of the cast to reproduce important dynamic aspects of nasal anatomy and physiology discussed previously, certainly casts doubt on the ability to achieve this objective with the Koken cast, and potentially any rigid nasal cast.

Nevertheless, the use of ever-improving casts coupled with innovative techniques such as photometrics may be very useful in development of new nasal delivery devices. Reliance on standards published by FDA for performance of spray pumps may seem appropriate for comparison of nasal delivery devices; however, published analysis also suggests that the in vitro measurements in the FDA guidance related to performance of spray pumps are not clinically relevant [ 2 ].

Thus, in light of current methodological and technological limitations, human in vivo deposition and clearance studies, and relevant human clinical trials, allowing regional deposition quantification and direct clinical comparisons, respectively, are still ultimately required. A recent review concludes that although both in vitro studies and in vivo imaging methods may be of value during the device development stages, ultimately, randomized placebo-controlled trials quantifying both symptoms and functional parameters are required to determine drug delivery efficiency of different devices [ 42 ].

A number of gamma deposition studies, a study using radiopaque contrast, and studies using colored dyes confirm that administration with conventional spray pumps, pMDIs, nebulizers, and powder devices all result in deposition mainly in the anterior non-ciliated segments of the nose anterior to and at the narrow nasal valve, which is regarded suboptimal for clinical efficacy where deep and broad nasal deposition is required [ 13 , 43 , 63 , 66 , 72 , 79 , ].

Colored dyes may offer a quick and inexpensive semi-quantitative assessment of deposition and clearance, and a number of studies have assessed deposition patterns with dyes with the goal of improving deposition and the clinical outcome of delivery with spray pumps and drops [ 43 , , ]. Although results vary, the effect of different body positions and administration techniques appears to have limited impact on initial deposition patterns.

Lack of patient compliance further reduces the clinical usefulness of these delivery techniques. More detailed assessment of drug deposition using regional gamma-deposition patterns have added to the understanding of deposition and clearance patterns and how they may have an impact on the clinical outcomes [ 13 , 14 , 66 , 70 , 72 ]. Improved methods for positioning and re-positioning of the test subjects and the use of radiolabeled gases and MRI overlay allow regional quantification of nasal deposition and outcomes [ 66 , 70 ].

Furthermore, in contrast to earlier studies, proper correction for regional differences in tissue attenuation in the different nasal segments and between the nose and lungs is now being performed [ 13 , 14 , 70 ]. This review only addresses in vivo gamma-deposition studies dealing with some key aspects related to the in vivo performance of nasal delivery devices that normally get limited attention.

One factor too often neglected when comparing deposition studies is whether the delivery procedure was performed by the subjects themselves or by an assistant. Clearly, delivery by the subjects is much closer to the real-life situation, but inevitably introduces more variability. In most gamma-deposition studies, a trained assistant inserts the spray device and performs the actuation according to a strict protocol.

This was the case in a study assessing deposition of radiolabeled cromoglycate substantial delivery beyond the nasal valve along the nasal floor was observed [ ]. In contrast, in a study with radiolabeled insulin where the spray was actuated by the subjects themselves, it was noted that individual administration technique resulted in the majority of doses being deposited in the anterior rather than the posterior nasal cavity in five out of six subjects, with the dose then being cleared via the nares rather than the nasopharynx [ ].

Contrary to expectations, no sign of systemic absorption of insulin was observed, and the authors commented that this effect of individual administration technique raises a separate question on the usefulness of nasal spray doses for delivery of insulin intended for systemic absorption [ ]. Gamma studies must be performed in a controlled setting where subjects are more likely to adhere to instructions for use of the devices than in real life. It is very common to observe that subjects during, or immediately after, administration of drug using nasal devices intuitively sniff to avoid the concentrated anterior liquid deposition from dripping out and down on the upper lips.

Sometimes, the anteriorly deposited surplus is wiped off, as has been observed in gamma-deposition studies [ ]. This phenomenon has also been observed after delivery with nebulizers [ 14 , 72 ]. Recent studies offering regional clearance curves for four or six nasal segments highlight that the initial site of deposition has a major impact on the clearance rates and that determination of overall nasal clearance is a very crude and potentially misleading measure that does not predict clinical performance [ 13 , 14 ].

Interestingly, a recent review on pulmonary drug delivery states that total lung deposition appears to be a poor predictor of clinical outcome; rather, regional deposition needs to be assessed to predict therapeutic effectiveness [ ].

However, the regional deposition patterns divided in four nasal segments reveal that this difference is primarily a result of anterior retention in the predominantly non-ciliated anterior two nasal quadrants following hand-actuated spray delivery.

The results from the study described above comparing deposition and clearance after delivery from the same spray pump actuated in different manners show that the initial site of deposition has a profound impact on the clearance rates [ 3 , 13 , 14 ]. Interestingly, McLean et al. The first phase occurs within the first minute after administration and is particularly evident following delivery of large concentrated volumes that rapidly pass along the floor of the nose to the pharynx to be swallowed.

This applies in particular to delivery of drops and can contribute to explaining the much lower absorption of desmopressin delivered as drops, but also applies to spray delivery with higher spray volumes [ 3 , 14 , 51 , ]. The initial and very rapid removal may not always be recognized, as the initial gamma image often includes averaging of registration of counts over a 2-min period due to the relatively small dose of radioactivity used for ethical reasons [ 14 ].

Consequently, depending on whether the substance in question has local action, is intended for systemic absorption, for N2B transport, or a combination, the primary goal is frequently to maximize exposure to the ciliated mucosa beyond the nasal valve.

One strategy for enhanced exposure is to slow clearance by thixotropic or bioadhesive agents or agents which slow ciliary action in order to increase the residence time in this region or by adding absorption enhancer if systemic absorption is the objective [ 78 , ]. The goal should be to reduce the amount of drug quickly passing through the nose to be swallowed in the first phase, to reduce the amount deposited outside the nose, and to increase the amount bypassing the nasal valve and the nasal respiratory mucosal surface covered.

For locally acting anti-inflammatory drugs like steroids and antihistamines, as well as for vaccines, the non-ciliated surface of the vestibule is not the target [ 42 ]. However, recent publications continue to advocate concentrated anterior deposition and retention as desirable and a key advantage of the novel HFA-based nasal pMDI with topically acting drug [ ]. A recent publication even claims that the anterior retention following pMDI delivery provides evidence for enhanced efficacy, which seems to be in conflict with the prevailing opinion [ 42 , ].

The nose is attractive for delivery of many drugs and vaccines, but the potential has not been fully realized. Inherent challenges related to the nasal anatomy, physiology, and aerodynamics that may severely limit the potential and clinical efficiency are not widely understood. The small and dynamic dimensions of the nasal cavity and the anterior anatomy are among the most important hurdles for more efficient nasal drug delivery. Despite important improvements in the technical device attributes that can offer more reproducible and reliable in vitro performance, this has to a limited extent translated into improved clinical performance.

While in vitro performance testing is undoubtedly of value for product quality assessment, predictive value for in vivo clinical performance is highly questionable [ 2 ]. CFD simulations of nasal aerodynamics and cast studies may be of value in the developmental stages of device design, and future advances may improve their predictive value.

Human in vivo deposition and clearance studies can be very important, providing valuable information particularly if recent advances allowing regional quantification and tissue attenuation correction are employed [ 14 , 70 , ]. Still, delivery by trained assistants in controlled environments may not adequately reflect the device performance in the clinical setting.

Even the most advanced nebulizer technologies introduced have shown poor delivery efficiency, with undesirable localized delivery in the non-ciliated anterior nasal region and along the floor of the nose and problems with inhalation exposure of the lungs [ 72 ]. This delivery technology can be combined with a variety of dispersion technologies for both liquids and powders, and promises to expand the possibilities of nasal drug delivery.

Djupesland is a founder, CSO and shareholder of OptiNose, a commercial company developing nasal delivery devices. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.

National Center for Biotechnology Information , U. Drug Delivery and Translational Research. Drug Deliv Transl Res. Published online Oct Per Gisle Djupesland. Author information Copyright and License information Disclaimer. OptiNose, Oslo, Norway. Per Gisle Djupesland, Email: on. Corresponding author. This article has been cited by other articles in PMC.

Abstract Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis. Introduction Intuitively, the nose offers easy access to a large mucosal surface well suited for drug- and vaccine delivery. Nasal anatomy and physiology influencing drug delivery Regulation of nasal airflow Nasal breathing is vital for most animals and also for human neonates in the first weeks of life.

The nasal mucosa—filtration and clearance The region anterior to the valve called the vestibule is lined by non-ciliated squamous epithelium that in the valve region gradually transitions into ciliated epithelium typical of the ciliated respiratory epithelium posterior to the valve region [ 4 , 19 ]. Open in a separate window. The complex anatomy of the nasal airways and paranasal sinuses. Nasal and sinus vasculature and lymphatic system For nasally delivered substances, the site of deposition may influence the extent and route of absorption along with the target organ distribution.

Innervation of the nasal mucosa The nose is also a delicate and advanced sensory organ designed to provide us with the greatest pleasures, but also to warn and protect us against dangers. The sensitivity of the nasal mucosa as a limiting factor In addition to the limited access, obstacles imposed by its small dimensions and dynamics, the high sensitivity of the mucosa in the vestibule and in the valve area is very relevant to nasal drug delivery.

Targeted nasal delivery For most purposes, a broad distribution of the drug on the mucosal surfaces appears desirable for drugs intended for local action or systemic absorption and for vaccines [ 3 ]. Nasal drug delivery devices The details and principles of the mechanics of particle generation for the different types of nasal aerosols have been described in detail by Vidgren and Kublik [ 3 ] in their comprehensive review from and will only be briefly described here, with focus instead on technological features directly impacting particle deposition and on new and emerging technologies and devices.

Table 1 Overview of the main types of liquid and powder delivery devices, their key characteristics, and examples of some key marketed nasal products and emerging devices and drug—device combination products in clinical development. Devices for liquid formulations The liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered. Drops delivered with pipette Drops and vapor delivery are probably the oldest forms of nasal delivery.

Delivery of liquid with rhinyle catheter and squirt tube A simple way for a physician or trained assistant to deposit drug in the nose is to insert the tip of a fine catheter or micropipette to the desired area under visual control and squirt the liquid into the desired location. Squeeze bottles Squeeze bottles are mainly used to deliver some over-the-counter OTC products like topical decongestants.

Single- and duo-dose spray devices Metered-dose spray pumps require priming and some degree of overfill to maintain dose conformity for the labeled number of doses. Nasal pressurized metered-dose inhalers pMDIs Most drugs intended for local nasal action are delivered by spray pumps, but some have also been delivered as nasal aerosols produced by pMDIs. Mismatch between geometry of anterior nose and the spray plume The pressure created by the force actuating a spray pump drives the liquid through the swirl chamber at the tip of the applicator and out through the circular nozzle orifice [ 64 ].

Powered nebulizers and atomizers Nebulizers use compressed gasses air, oxygen, and nitrogen or ultrasonic or mechanical power to break up medical solutions and suspensions into small aerosol droplets that can be directly inhaled into the mouth or nose. VibrENT pulsation membrane nebulizer A new nebulizer intended for delivery to the nose and sinuses in patients with chronic rhinosinusitis utilizing a pulsating aerosol generated via a perforated vibrating membrane has recently been introduced VibrENT PARI Pharma GmbH.

Clinical relevance of deposition results with nebulizers Lung deposition and relatively low nasal delivery fractions are issues with nasal nebulizers. ViaNase atomizer A handheld battery-driven atomizer intended for nasal drug delivery has been introduced ViaNase by Kurve Technology Inc. Impel nitrogen-driven atomizer A nasal atomizer driven by highly pressurized nitrogen gas is under development by Impel Inc. Powder devices Powder medication formulations can offer advantages, including greater stability than liquid formulations and potential that preservatives may not be required.

Nasal powder insufflators Trimel www. Assessment of nasal deposition and clearance—clinical aspects CFD simulations With development of high-resolution CT and MRI technology, it has become possible to generate accurate 3D reconstructions of the complex nasal anatomy Fig. Deposition studies in casts The progress in imaging and reconstruction software has also made it possible to make physical models in rigid materials by modern 3D printing techniques like stereolithography with correct nasal geometry and dimensions.

In vivo assessment of deposition and clearance A number of gamma deposition studies, a study using radiopaque contrast, and studies using colored dyes confirm that administration with conventional spray pumps, pMDIs, nebulizers, and powder devices all result in deposition mainly in the anterior non-ciliated segments of the nose anterior to and at the narrow nasal valve, which is regarded suboptimal for clinical efficacy where deep and broad nasal deposition is required [ 13 , 43 , 63 , 66 , 72 , 79 , ].

Impact of delivery instructions, patient compliance, and body position One factor too often neglected when comparing deposition studies is whether the delivery procedure was performed by the subjects themselves or by an assistant.

Overall versus regional clearance patterns Gamma studies must be performed in a controlled setting where subjects are more likely to adhere to instructions for use of the devices than in real life. Impact of site of delivery and volume on deposition and clearance The results from the study described above comparing deposition and clearance after delivery from the same spray pump actuated in different manners show that the initial site of deposition has a profound impact on the clearance rates [ 3 , 13 , 14 ].

Conclusions The nose is attractive for delivery of many drugs and vaccines, but the potential has not been fully realized. Conflict of interest P. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.

References 1. FDA US FDA draft guidance for industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays. Accessed July Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, absorption and biologic response. J Aerosol Med. Medications using the new nasal technology are becoming more and more prevalent due to their rapid absorption in the nasal passages. The main use of nasal sprays has been for delivery of a drug or drugs, generally to alleviate cold or allergy symptoms such as nasal congestion.

Though the delivery methods vary, most nasal sprays function by instilling a fine mist into the nostril using a hand operated pump mechanism. The three main types available are: antihistamines, corticosteroids, and topical decongestants.

As well, some nasal sprays need to be shaken. Check with your pharmacist to see whether your nasal spray needs to be primed or shaken. If your spray needs to be primed before using, spray it a few times into the air and keep it well away from your eyes. Keep the bottle pointing upright, and point the tip toward the back and outer side of the nose.

Remember to breathe in deeply through your nose as you depress the applicator, and breathe out through your mouth after each spray. Nasal Delivery Technology is becoming more popular as pharmacists across the globe utilize the technology to deliver a continuous variety of medications.

Nasal Delivery New Technology Spray. Advances in nasal delivery technology have bought to life a longer lasting sex spray for men.

Nasal sprays or nasal mists as some people call them are used to delivery various medications via the nasal passage.

The Aspirair device is similar to an asthma inhaler, and administers apomorphine to help erectile dysfunction. Because the drug is breathed in, it hits the bloodstream more quickly and delivers a swifter response. Scientists believe even this rapid response time could be halved to four minutes if higher doses are used. Trials on 35 patients by Vectura, a British company specialising in developing inhaled drug treatments, revealed 59 per cent of men given a higher dose of the drug and 49 per cent on a lower dose had erections eight minutes after using the spray.

More extensive trials will now take place. Monday, Oct 28th 5-Day Forecast. Viagra, by contrast, which is swallowed in pill form, can take up to an hour to work. Share or comment on this article:. Most watched News videos Brexiteer attacks Caroline Voaden for calling for a People's Vote Ambulances continue transporting people found dead in lorry 'Knifeman' held down on floor at Oxford Road station in Manchester Police arrest 'knifeman' at Manchester Oxford Road station Bystanders take action against armed robbers in Shepherd's Bush Black Range Rover shatters glass of jewellers in Shepherd's Bush Metro passenger distracted by phone falls onto tracks in Madrid Simba the lion is saved from 'canned hunting' and finds new home Peter Wilson prepares for first ever landing of Stealth Fighter Tragic moment two young girls are found murdered in their home Bodies of two young girls are found at a home in Perth Excruciating moment couple are told by stewardess to stop having sex.

Bing Site Web Enter search term: Search. Doctors in China claim smartphone-addicted man was left 'temporarily blind after suffering an eye stroke due A deadly pandemic could sweep the world in hours and kill millions because NO country is fully prepared, Emotional moment girl, 13, with life-limiting cystic fibrosis breaks down in tears of joy as her mother Forget ambulances Study of rush-hour traffic in New York reveals the gadgets get to Forgetting to pay your bills on time may be a warning sign of Alzheimer's 'because an inability to keep on Terminally-ill boy who was diagnosed with dementia at just SIX can no longer recognises his heartbroken College cuts your chances of becoming an alcoholic in HALF: New study finds that every four extra years of Stop sharing breastmilk!

Gisele Bundchen is all-smiles as she gets into the Halloween spirit at the pumpkin patch with daughter Vivian Seemed to be having a blast Meghan King Edmonds is feeling 'so raw' amid divorce from husband Jim She swore she was happy to be curvy - now she's suddenly lost three stone. Patmore aka Lesley Nicol teases Maggie Smith's return in the film's sequel in the works Liam Gallagher's daughter Molly Moorish changes Instagram handle to include his surname a year after their reconciliation Kanye West buys poo emoji cushion for his infamously minimal home while shopping in NY Meghan King Edmonds' husband Jim files for divorce Back to top Home News U.

Nasal delivery technology impotence