Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

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Intranasal medication delivery technique discussion - abstracted references


Aoki, F. Y. and J. C. Crowley (1976). "Distribution and removal of human serum albumin-technetium 99m instilled intranasally." Br J Clin Pharmacol 3(5): 869-78.

The efficacy of antiviral drugs and vaccines administered intranasally may depend upon the technique of application. The distribution and time-course of removal of human serum albumin-technetium 99m (HSA-Tc 99m)-instilled intranasally were studied in eleven healthy volunteers using a gamma camera and an anterior sodium iodide scintillation detector. In 100 randomized studies material was delivered as drops in the supine position or as a spray to seated subjects. A significantly higher proportion of 'good' distributions (62 in 73 tests) was obtained with drops compared with spray (1 in 27). The volume administered was varied between 0.10 ml and 0.75 ml and the concentration of HSA was changed from 3 to 30% with no significant effect upon the distribution of time-course of removal; pertechnetate in isotonic saline was distributed and removed in a manner comparable to HSA-Tc 99m. Activity recorded by the detector showed an initial rapid fall associated with removal of most of the material from the nasal cavity, followed by a slower decline associated with the removal of material mainly from the anterior region of the nose. A multidose study confirmed that frequent administration by drops is required to maintain a high level of activity in the nasal cavity. Using this technique it should be possible to correlate measurements of antiviral efficacy and vaccines take-rates with certain characteristics of intranasal applicators; such studies may lead to the design of better devices.

Bjorkman, S., G. Rigemar, et al. (1997). "Pharmacokinetics of midazolam given as an intranasal spray to adult surgical patients." Br J Anaesth 79(5): 575-80.

The aim of this study was to determine the bioavailability and absorption kinetics of midazolam given as an intranasal (i.n.) spray. In addition, plasma concentrations of the active metabolite, 1-hydroxymidazolam, were measured to give an indication of enteral absorption. An i.v. and i.n. midazolam dose were given in a crossover study to 14 adult surgical patients. Individual uptake profiles of i.n. midazolam were estimated by numerical deconvolution. After an i.n. dose of 0.15 mg kg-1, maximum arterial plasma concentrations were 192 (SD 48) micrograms litre-1 at 14 (2) min. Uptake of midazolam was rapid and bioavailability was 83 (15)%. Formation of the 1-hydroxy metabolite after i.n. administration did not exceed that after the i.v. dose. This demonstrates that under optimal conditions absorption of midazolam via the nasal mucosa was virtually complete. In this case little midazolam was swallowed and subjected to first-pass metabolism in the liver and therefore pharmacologically important amounts of active metabolite were not produced. Routinely administering i.n. midazolam under the assumption that the bioavailability is approximately 50% (as reported previously in the literature) may lead to overdosing in some patients.

Bommer, R. (1999). "Latest advances in nasal drug-delivery technology." Med Device Technol 10(4): 22-28.

Nasal delivery devices are not only limited to local medical therapy. The nasal route is an alternative to invasive or oral drug administration. The penetration of bioactive molecules through the nasal mucosa has been shown to achieve good bioavailability, and nasal sprays offer patients greater convenience. This article reviews some of the latest devices for liquid and dry-powder formulations, including preservative-free systems, and the business benefits they offer.

Bryant, M. L., P. Brown, et al. (1999). "Comparison of the clearance of radiolabelled nose drops and nasal spray as mucosally delivered vaccine." Nucl Med Commun 20(2): 171-4.

The distribution and nasal clearance of 99Tcm-labelled albumin (18.5 MBq), used as a mucosal vaccine surrogate for FluMist, was determined in three volunteers. The subjects were randomized in a cross-over clinical study design to receive either large-particle aerosal (nasal spray) followed by nose drops, or nose drops followed by the nasal spray, 1 week apart. Gamma scintigraphy was used to measure the distribution and clearance. The 'vaccine' delivered as drops was cleared from the nose into the oesophagus and upper stomach at very variable rates. In contrast, the nasal spray was uniformly distributed and cleared from the nasopharynx with a 50% mean clearance time of 50 min (range 40-60 min) and was not detected in the lungs.

Chien, Y. W., K. S. E. Su, et al. (1989). "Chapeter 3: Physicochemical, biopharmaceutical, and toxicophysiological considerations." Nasal Systemic Drug Delivery, Dekker, New York: 39-90.

Daley-Yates, P. T. and R. C. Baker (2001). "Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations." Br J Clin Pharmacol 51(1): 103-5.

AIMS: To measure and compare the systemic bioavailability of fluticasone propionate aqueous nasal spray and a new nasal drop formulation, using a sensitive analytical method and high dose regimen. METHODS: Volunteers received four 800 microg doses of fluticasone propionate as a nasal spray or drops over 2 days, separated by an 8 h dose interval. On day 2, blood samples were collected for assay of fluticasone propionate plasma concentrations. RESULTS: The mean systemic exposure, for both formulations was 8.5 pg x ml(-1) x h (drops) and 67.5 pg x ml(-1) x h (spray). Mean absolute bioavailabilities were estimated to be 0.06% (drops) and 0.51% (spray), by reference to historical intravenous data. CONCLUSIONS: Both formulations exhibited low systemic bioavailability, even at 12 times the normal daily dose. The bioavailability from the nasal drops was approximately eight times lower than from the nasal spray.

David, G. F., C. P. Puri, et al. (1981). "Bioavailability of progesterone enhanced by intranasal spraying." Experientia 37(5): 533-4.

The bioavailability of progesterone (P) in terms of area under time-concentration curve and maximal concentration in the serum and cerebrospinal fluid was studied in adult ovariectomized rhesus monkeys following the administration of P as a nasal spray, i.v. or i.m. injections, nasal or eye drops. The bioavailability of P in both the body fluids was found to be considerably higher following its being sprayed intranasally.

Habib, A. R., A. Thamboo, et al. (2013). "The effect of head position on the distribution of topical nasal medication using the Mucosal Atomization Device: a cadaver study." Int Forum Allergy Rhinol 3(12): 958-962.

  BACKGROUND: The Mucosal Atomization Device (MAD) distributes medication throughout the paranasal sinuses for patients with chronic rhinosinusitis (CRS). Determining the optimal head position is important to ensure maximal delivery of medication to the sinus cavities. The objective of this work was to determine the effect of the lying-head-back (LHB) and head-down and forward (HDF) position, on the distribution of topical nasal medication via MAD in cadaver specimens. METHODS: Twenty specimens having received complete functional endoscopic sinus dissection were chosen. The MAD was used to administer 2 mL of fluorescein-impregnated saline solution through the nose in both the LHB and HDF positions. Fluorescein was identified on 11 predetermined anatomical areas using a blue light filter. Three blinded investigators assessed endoscopic images to determine the presence of fluorescein. RESULTS: A total of 440 anatomical locations (n = 20 cadavers) received administration of the fluorescein nasal spray in the LHB or HDF position. LHB position had significantly greater total distribution to all pertinent anatomical sites than the HDF position (76% vs 41%; p < 0.001; 95% confidence interval [CI], 0.26-0.44). The proportion of staining was significantly greater for the ethmoid (p = 0.11; 95% CI, 0.05-0.66), frontal (p < 0.01; 95% CI, 0.20-0.80), and sphenoid sinuses (p = 0.03; 95% CI, 0.07-0.73) when compared to the HDF position. CONCLUSION: A greater distribution of medication to the sinonasal cavities was observed in the LHB position compared to the HDF position. These areas are of particular clinical relevance in postsurgical patients with refractory CRS.

Hardy, J. G., S. W. Lee, et al. (1985). "Intranasal drug delivery by spray and drops." J Pharm Pharmacol 37(5): 294-7.

A solution of 99mTc-labelled human serum albumin was administered into the nose as a spray and as one or three drops. The patterns of deposition and the rates of clearance in normal subjects were monitored by gamma scintigraphy. The spray was deposited mainly in the atrium, and cleared slowly into the pharynx. The single drop spread more extensively than the spray, while the three drops were sufficient to cover most of the walls of the nasal cavity. Clearance was faster following administration of the drops. These factors have implications when designing dosage regimens for drugs administered by the intranasal route.

Harris, A. S., E. Svensson, et al. (1988). "Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin." J Pharm Sci 77(5): 405-8.

The effect of methylcellulose on the particle size distribution and dosing accuracy of pre-metered spray pump devices containing the peptide desmopressin (DDAVP) was investigated. Using gamma scintigraphy, the influence of methylcellulose on the in vivo deposition and clearance of nasal solutions administered as drops or spray was studied. Nasal formulations containing 0, 0.25, and 0.50% methylcellulose produced a dose-related increase in average particle size from 51 micron for 0% to 81 and 200 micron for 0.25 and 0.50% methylcellulose, respectively. However, no effect was observed on the dosing accuracy of the spray pumps. The addition of methylcellulose gave a more localized in vivo deposition in the anterior region of the nasal vestibule. However, the net effect on clearance followed a biphasic pattern which showed an increase in retention time for the 0.25% solution, followed by a decrease in retention time and faster clearance time for the 0.50% solution. The spray delivers well-controlled doses to the nasal cavity. These findings show that viscosity, particle size, and nasal clearance are important parameters in the design of nasal delivery systems.

Henry, R. J., N. Ruano, et al. (1998). "A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration." Pediatr Dent 20(5): 321-6.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.

Hoekman, J. D. and R. J. Ho (2011). "Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats." Anesth Analg 113(3): 641-651.

                BACKGROUND: Centrally acting opioid analgesics such as morphine and fentanyl are effective, but their efficacy is often limited by a delayed response or side effects resulting from systemic first pass before reaching the brain and the central nervous system (CNS). It is generally accepted that drugs applied to the nasal cavity can directly access the brain and the CNS, which could provide therapeutic advantages such as rapid onset and lower systemic exposure. The olfactory region of the nasal cavity has been implicated in facilitating this direct nose-to-CNS transfer. If the fraction of opioid administered to the olfactory region could be improved, there could be a larger fraction of drug directly delivered to the CNS, mediating greater therapeutic benefit. METHODS: We have developed a pressurized olfactory delivery (POD) device to consistently and noninvasively deposit a majority of drug on the olfactory region of the nasal cavity in Sprague-Dawley rats. Using the tail-flick latency test and analysis of plasma and CNS tissue drug exposure, we compared distribution and efficacy of the opioids morphine and fentanyl administered to the nasal olfactory region with the POD device or the nasal respiratory region with nose drops or systemically via intraperitoneal injection. RESULTS: Compared with nose drop administration, POD administration of morphine resulted in a significantly higher overall therapeutic effect (area under the curve [over the time course] [AUC](effect)) without a significant increase in plasma drug exposure (AUC(plasma)). POD of morphine resulted in a nose-to-CNS direct transport percentage of 38% to 55%. POD of fentanyl led to a faster (5 vs 10 minutes) and more intense analgesic effect compared with nasal respiratory administration. Unlike intraperitoneal injection or nose drop administration, both morphine and fentanyl given by the POD device to olfactory nasal epithelium exhibited clockwise (plasma) versus effect hysteresis after nasal POD administration, consistent with a direct nose-to-CNS drug transport mechanism. CONCLUSIONS: Deposition of opioids to the olfactory region within the nasal cavity could have a significant impact on drug distribution and pharmacodynamic effect, and thus should be considered in future nasally administered opioid studies.

Li, B. L., N. Zhang, et al. (2016). "A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops." Anaesthesia 71(5): 522-528.

Intranasal dexmedetomidine has been used successfully for sedation in children. A mucosal atomisation device delivers an atomised solution to the nasal mucosa which facilitates rapid and effective delivery of medication to the systemic circulation. We compared intranasal delivery of dexmedetomidine in a dose of 3 by either atomiser or drops from a syringe in children < 3 years old undergoing transthoracic echocardiography. Two hundred and seventy-nine children were randomly assigned to one or other group. One hundred and thirty-seven children received dexmedetomidine by atomiser and 142 by drops. The successful sedation rate was 82.5% (95% CI 75.3-87.9%) and 84.5% (95% CI 77.7-89.5%) for atomiser and drops, respectively (p = 0.569). Sedation tended to be less successful in older children (p = 0.028, OR 0.949, 95% CI 0.916-0.983). There were no significant complications. We conclude that both modes of dexmedetomidine administration are equally effective, although increasing age of the child was associated with a decreased likelihood of successful sedation.

McCormick, A. S., V. L. Thomas, et al. (2008). "Plasma concentrations and sedation scores after nebulized and intranasal midazolam in healthy volunteers." Br J Anaesth 100(5): 631-6.

            BACKGROUND: An efficacious, reliable, and non-invasive route of administration for midazolam, a drug used for sedation and pre-anaesthetic medication, would have obvious advantages. This study compares two potential methods of administering midazolam by the nasal and nebulized routes. METHODS: Midazolam (0.2 mg kg(-1)) was given by both nebulizer and nasally by liquid instillation to 10 healthy volunteers in a randomized, double-blind crossover study. Plasma concentrations of midazolam, Ramsay sedation scores, visual analogue scores, critical flicker fusion frequency, and parameters of cardiovascular and respiratory function were measured over 60 min and summarized using 'area under the curve'. RESULTS: Nasal instillation caused more sedation than nebulized administration. This was demonstrated by higher Ramsay sedation scores (P=0.005), lower visual analogue scores (P<0.001), and lower critical flicker fusion frequency (P<0.02). Nasal instillation was associated with higher plasma concentrations of midazolam (P<0.001). Unpleasant symptoms were recorded by six volunteers in the intranasal and one in the nebulized group (P=0.06). CONCLUSIONS: There was some evidence that midazolam caused less discomfort when given by nebulizer compared with intranasally. Comparative bioavailability of midazolam, estimated by the ratio (nebulized:nasal) of area under the 60 min plasma concentration curve, was 1:2.9. A higher dose may need to be administered for adequate pre-anaesthetic medication when midazolam is given by nebulizer.

Merkus, P., F. A. Ebbens, et al. (2006). "The 'best method' of topical nasal drug delivery: comparison of seven techniques." Rhinology 44(2): 102-107.

  OBJECTIVE: To determine whether there is a 'best' technique for delivering drugs to the middle meatus. DESIGN: Single-blind cross-over study in healthy individuals using endoscopic video-imaging. PARTICIPANTS: A dyed test formulation was administered intranasally on seven non-sequential days to ten healthy individuals with no 'nasal' history. The participants were recruited through advertisement. MAIN OUTCOME MEASURES: Comparison of seven different techniques, 20 nostrils and 140 endoscopic videos for the deposition patterns of dyed test formulation. Analysis was possible in 90% of all endoscopic videos. Three head positions were tested for both nasal drops and nasal sprays. RESULTS: Deposition of dyed test formulation near the middle meatus was observed in 43% of all observations. No significant differences were observed in terms of delivery between any of the seven techniques. CONCLUSIONS: Our study suggests there may not be a single 'best' technique for topical nasal drug delivery. A more individual approach to topical nasal drug treatment, taking anatomy and head position into account would seem to be more appropriate.

Merkus, P., F. A. Ebbens, et al. (2006). "Influence of anatomy and head position on intranasal drug deposition." Eur Arch Otorhinolaryngol 263(9): 827-832.

The objective of this study was to determine the influence of individual anatomical differences on intranasal drug deposition. The data of a comparison of seven different administration techniques in ten healthy volunteers was used in this single-blind crossover pilot study. After intranasal administration of a dyed test formulation, endoscopic video imaging was done on seven non-sequential days. The deposition pattern per individual around the head of the middle turbinate was analyzed for each technique and correlated with the individual anatomy. Decreased deposition of dyed test formulation in the target area around the head of the middle turbinate was observed in the presence of minor septal deviations, narrow nasal valve areas, or inferior turbinate hypertrophy; a lateral head position helps to bypass a minor septal deviation. Although results are preliminary, we conclude that anatomy and head position are important factors in the deposition of topical nasal drugs and may be the key to improving individual local nasal (steroid) treatment.

Mygind, N. (1979). "Nasal Allergy, 2nd edition." Blackwell, Oxford, England: 257-270.

Mygind, N. and S. Vesterhauge (1978). "Aerosol distribution in the nose." Rhinology 16(2): 79-88.

Using a cast of the human nose the intranasal distribution of drugs, delivered from pressurized aerosols and nebulizers was studied. The results indicate that a pressurized aerosol should be used twice in each nostril to give an acceptable drug distribution, and also that an automized pump is preferable for a plastic-bottle nebulizer with regard to drug distribution.

Singh, R., A. Pareek, et al. (2016). "Post-operative analgesic efficacy of fentanyl via different routes – A comparative study of nebulisation, intranasal and intravenous routes." IAIM 3(6): 16-22.

Background: Pain is main post operative adverse outcomes causing patient distress, prolonging hospital stay, and increasing the incidence of admissions after surgery. Study was done to assess and compare the post-operative analgesic effects of fentanyl via nebulisation, intranasal and intravenous routes to provide better analgesia, anxiolysis and sedation to the patient. Materials and methods: After approval from ethical committee of SPMC, Bikaner and written informed valid consent from patients, sixty patients of either sex belonging to ASA class I and II, were randomised into three group (Group I - Nebulised Fentanyl, Group II - Intranasal Fentanyl, Group III - Intravenous Fentanyl). With all aseptic precaution, subarachnoid block was instilated via 23/25 gauze spinal needle by injecting sufficient dose of bupivacaine heavy 5% to achieve an adequate sensory and motor block for the proposed surgery. When patient complained pain 1st time, fentanyl was given via nebulisation in group I, intranasal in group II, and intravenous in group III with dose 4 mcg/kg, 1.5 mcg/kg, 2 mcg/kg respectively. Patients were assessed for pain by VAS score. For statistical data, SPSS 10.0 software was used. Results: In present study, Ramsay sedation score, patient satisfaction score and duration of analgesia was better in group II as compared to group I and III. Group III had lesser time of onset of analgesia in comparison to group II and I respectively.

Tsikoudas, A. and J. J. Homer (2001). "The delivery of topical nasal sprays and drops to the middle meatus: a semiquantitative analysis." Clin Otolaryngol 26(4): 294-7.

The distribution of nasal drugs specifically to the middle meatus is of vital importance in the treatment of rhinosinusitis and nasal polyposis. It is widely assumed that the intranasal distribution is superior with nasal drops rather than spray delivery. However, a comparison of nasal spray and drop delivery specifically to this area has not been studied before. This study aims to compare semiquantitatively the intranasal distribution of nasal sprays and drops to the middle meatus in vivo. A novel method was used whereby a neurosurgical patty was placed in the middle meatus. Topical nasal drops and aqueous sprays dyed with methylene blue (0.1% v/v) were administered in a standardized fashion in normal volunteers. The subsequent absorption of administered dye was classified on a four-point scale. A randomized prospective cross-over design was used for the study. We found that there was no difference in the delivery of nasal drug to the middle meatus between either method of drug administration (P > 0.2). The perceived superiority of nasal drops may therefore be as a result of the acknowledged systemic effect of betamethasone drops.

Xie, Z., W. Shen, et al. (2017). "Sedation effects of intranasal dexmedetomidine delivered as sprays versus drops on pediatric response to venous cannulation." Am J Emerg Med 35(8): 1126-1130.

            OBJECTIVES: Mucosal atomization device (MAD) was designed to increase the bioavailability of intranasal medications by facilitating absorption, the present study aimed to evaluate and compare the sedation effects of intranasal dexmedetomidine delivered as drops versus sprays on pediatric responses to intravenous cannulation. METHODS: One hundred and six pediatric patients (aged from 2 to 5years) scheduled for elective ophthalmic surgery were intranasally received a dose of 2mug/kg in 20mul/kg of dexmedetomidine for sedation to reduce response to venous cannulation. The patients were randomized into syringe group and MAD group in which dexmedetomidine was delivered as drops or sprays via syringe or MAD respectively. The primary outcome was the response to peripheral vein cannulation assessed by the FLACC scores (faces, legs, activity, cry and consolability) 30min after intranasal administration of dexmedetomidine. The secondary outcomes included acceptance for intranasal medication, sedation onset time, and needle insertion times and any adverse event at the preoperative holding area. RESULTS: The FLACC scores in MAD group were significantly decreased than that treated by drops (P=0.021). The acceptance for intranasal administration between both groups was comparable (P>0.05), the onset time and the incidences in two and more times of needle insertion did not differ significantly between syringe and MAD groups (all P>0.05). None of patients were required to clinically intervene in heart rates reduction and none suffered respiratory depression after administrations of dexmedetomidine in either group. CONCLUSION: Intranasal dexmedetomidine by sprays offers better sedation effects to reduce responses to venous cannulation than drops.