Intranasal Gel Research Articles

Formulation and Evaluation of Fish Oil-based Rizatriptan Microemulsion for Intranasal Migraine Treatment

In the present study microemulsion based intranasal gel of rizatriptan using fish oil was prepared for treatment and management of migraine to sustain the drug release and improve the drug residence time in nasal cavity. Fish oil is reported to have antimigraine activity hence it has been used in the present formulation along with cremophore EL as surfactant and Transcutol P as co-surfactant. The pseudoternary phase diagram plotted with these components shown the microemulsion existence region in ratio of (1:9-9:1) surfactant and co-surfactant. The optimized micro-emulsion contained fish oil (45.29%), cremophore E/transcutol P (2:1) and was characterized for pH (6.3±0.02), viscosity (114 ± 3.00cp), % transmittance (99.5 ± 1.01), refractive index (1.335±0.01),). The prepared microemulsion gels were optimized and characterized for in-vitro studies, pH, drug content, rheological studies and stability study. The release of rizatriptan from micro-emulsion gel prepared from carbopol 934 (98.01%) was found to be higher and prolonged than plain gel. Thus, microemulsion based gel was able to prolong drug releaseand improve drug residence time in the nasal cavity.

Formulation and evaluation of thermoreversible mucoadhesive in-situ gel for intranasal delivery of naratriptan hydrochloride

Intractable migraine presents a significant treatment challenge due to associated throbbing or pulsating headache, which affects one half of the head and lasts from 2 to 72 h. Naratriptan hydrochloride is an approved drug molecule for migraine headaches, but its use is limited due to its poor bioavailability, reoccurrence of migraine and lesser half-life requiring frequent dosing. Therefore, the objective of present study was to formulate a thermoreversible intranasal gel for drug targeting directly to brain via olfactory lobe pathway thereby improving bioavailability. Gels were formulated by using poloxamer 407 as thermoreversible polymer and carbopol 934 as mucoadhesive polymer. Formulated gels were characterized for gelation temperature, gel strength, mucoadhesive strength, viscosity, in-vitro drug release and ex-vivo permeation study using sheep nasal mucosa. In-vitro and ex-vivo drug release studies suggested that the release rate was directly proportional to the concentration of carbopol 934, whereas poloxamer 407 reduced the rate of drug release. Histopathology study of sheep nasal mucosa showed no signs of damage to columnar epithelial cells, confirming non-toxic nature of the formulated gel. Stability studies performed as per ICH guidelines [Q1A (R2)] suggested that the gels were stable.

Optimization of combinational intranasal drug delivery system for the management of migraine by using statistical design

Migraine is a chronic disorder characterized by significant headache and various associated symptoms which worsen with exertion. Zolmitriptan approved for use in the acute treatment of migraine and related vascular headaches but are limited by high pain recurrence due to rapid drug elimination. Combinationalformulationof triptans and a nonsteroidal anti-inflammatory drug may provide a quicker and longer duration of relief from the subsequent pain during the attack. In this study, we formulate a Zolmitriptan (ZT) & ketorolac tromethamine (KT) loaded thermo reversible in-situ mucoadhesive intranasal gel (TMISG) formulation which gels at the nasal mucosal temperature and contains a bioadhesive polymer (Xyloglucan) that lengthens the residence time will enhance the bioavailability of the combinational drugs. This study uses Box-Behnken design for the first time to develop, optimize the TMISG and assess factors affecting the critical quality attributes. Histopathological study of the nasal mucosa suggested that the formulation was safe for nasal administration. The statistical difference in absolute bioavailability between oral and intranasal route suggested that intranasal route had almost 21% increases in bioavailability for ZT and for KT there was 16% increase over oral formulations. Optimized formulation would help mitigate migraine associated symptoms much better over the currently available formulations.

Formulation and evaluation of thermoreversible, mucoadhesive in situ intranasal gel of rizatriptan benzoate

The present study was aimed to formulate and evaluate in situ thermoreversible intranasal gel of an antimigraine drug rizatriptan benzoate. The poloxamer 407 and carbopol 934 were used as thermoreversible and mucoadhesive polymers respectively. The gels were prepared with cold method. The phase transition temperature was determined with visual method. The gels were evaluated for their pH, mucoadhesive strength, in vitro release and ex vivo drug permeation through goat nasal mucosa. The histopathological study of the nasal mucosa was carried out to check for its damage during drug permeation. The 18 % w/v poloxamer solution was found to be showing phase transition at physiologic conditions (34–35 °C). As the percentage of carbopol 934 was increased from 0.1 to 0.5 % w/v the gelling temperature was found to be decreased. All formulations were showing mucoadhesive strength above 4,000 dynes/cm2. Drug permeation studies have indicated that the drug permeation rate can be increased by using carbopol 934 above 0.3 % w/v concentration. The histopathological evaluation of nasal mucosa after drug permeation study has not shown any evidence of damage. Thus in situ thermoreversible mucoadhesive gel of rizatriptan benzoate can be a promising approach to treat migraine.

Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration

The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8–70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.

Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization

Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson’s disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934 P and chitosan). The formulations were evaluated for sol–gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28–33 °C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p < 0.05) improvement in bioavailability (four- to six-folds) of the drug from intranasal gels than oral solution. Chronic exposure studies in Wistar rats showed that these intranasal gels were non-irritant and non-toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p < 0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.

Nasal Gel and Olfactory Cleft

ObjectiveTo evaluate whether a nasal gel, administered using a radial-hole inhaler, reaches the olfactory cleft, and if a different administration method influences distribution. Material and methodSixteen healthy volunteers underwent a nasal endoscopy at 1 and 7min after the administration of a intranasal gel, with a different method in each fossa. ResultsNo dye deposition was identified at the olfactory cleft, middle turbinate or middle meatus. In all cases the gel was identified at the nasal vestibule. On the right side, the second most frequent dye identification area was the inferior turbinate, with a rate of 87% at the first minute and 75% at 7min. It was followed by the septum (75% and 62%) and the inferior meatus (6.2% and 12.5%). On the left side, the second most frequent stained area was the septum (18.7% and 13.5%), followed by the inferior meatus (6.5% and 65%). No inferior turbinate staining was found in the left side. There was a significant difference in the deposition rate at the septum (P<.01) and inferior turbinate (P<.001), when both administration methods were compared. ConclusionsNo nasal gel, administered using a radial-hole inhaler, was found at the olfactory cleft, middle turbinate or middle meatus. Gel distribution was located at the anterior and inferior portion of the nose, independent of the administration method used. Significantly different gel distribution rates were found at the septum and inferior turbinate when the 2 administration methods were compared.

Gel nasal y hendidura olfatoria

ObjectiveTo evaluate whether a nasal gel, administrated using a radial-hole inhaler, reaches the olfactory cleft and if a different administration method influences distribution. Material and methodSixteen healthy volunteers underwent a nasal endoscopy at 1 and 7minutes after the administration of a intranasal gel, with a different method in each fossa. ResultsNo dye deposition was identified at the olfactory cleft, middle turbinate or middle meatus. In all cases the gel was identified at the nasal vestibule. On the right side, the second most frequent dye identification area was the inferior turbinate, with a rate of 87% at the first minute and 75% at 7 minutes. It was followed by the septum (75 and 62%) and the inferior meatus (6.2 and 12.5%). On the left side, the second most frequent stained area was the septum (18.7 and 13.5%), followed by the inferior meatus (6.5 and 65%). No inferior turbinate staining was found in the left side. There was a significant difference in the deposition rate at the septum (P<.01) and inferior turbinate (P<.001), when both administration methods were compared. ConclusionsNo nasal gel, administrated using a radial-hole inhaler, was found at the olfactory cleft, middle turbinate or middle meatus. Gel distribution was located at the anterior and inferior portion of the nose, independent of the administration method used. Significantly different gel distribution rates were found at the septum and inferior turbinate when the 2 administration methods were compared.

Enhancement of the intranasal delivery of insulin via a novel mucoadhesive Carbopol gel

The objectives of this study were to develop an intranasal insulin gel using Carbopol homogenization rather than neutralization and to examine the effectiveness of the gel compared with a subcutaneous injection. Four factors, namely the molecular weight of polyethylene glycol (PEG), the concentration of Carbopol, the temperature of preparation and the type of absorption enhancer, were evaluated for their effect on viscosity and in-vitro insulin release. Bioavailability of insulin from selected formulations was compared with an intranasal solution and subcutaneous injection in rabbits. Increasing the molecular weight of PEG and Carbopol concentration increased the gel viscosity and changed the release mechanism from diffusion to case II transport. Applying heat during preparation resulted in a lower viscosity gel and increased the in-vitro insulin release. Among the two enhancers studied, sodium deoxycholate resulted in a higher viscosity gel than Tween 80. In vivo, the intranasal gel showed a stronger and longer hypoglycaemic effect with 1.7- and 3.1-fold higher maximum decrease in blood glucose level and area above the curve, respectively, compared with the subcutaneous injection. The homogenized Carbopol intranasal gel could be an efficient noninvasive way for insulin delivery but selection of gel components and method of preparation are critical for achieving the most desired effect.

Intranasal Cobalamin: A Warning-Reply

In Reply.— Dr Heimburger states that the summary report of Nature's Bounty's clinical studies indicates that the rise in serum cobalamin level after a single 400-μg intranasal dose approximates that from a 100-μg intramuscular dose. Dr Heimburger then suggests that the use of an intranasal gel would have a compliance advantage over daily oral cobalamin and would not entail the inconvenience or cost of intramuscular injections. He concludes that the use of Ener-B, with proper monitoring of cobalamin status, should be considered by physicians treating patients with pernicious anemia. It is the Food and Drug Administration's (FDA) position that Ener-B Intra-Nasal Gel is a drug, a new drug, and is illegally marketed. The FDA has consistently regulated parenteral vitamin-mineral and topically administered nutritional products as drugs. On February 26, 1987, the FDA sent a regulatory letter to Nature's Bounty informing them that Ener-B was an unapproved new drug and was

Intranasal Cobalamin: A Warning

To the Editor.— The Commentary by Dr Lederle 1 and the accompanying editorial of Drs Hathcock and Troendle 2 provide a straightforward and compelling argument for the use of oral cobalamin for the treatment of pernicious anemia whenever possible. In my experience, the vicissitudes and costs of monthly intramuscular cobalamin injections often result in discontinuation of the therapy entirely, putting patients at risk for recurrent deficiency. Oral therapy should ameliorate this problem. However, there may be another alternative that the authors did not describe, and of which few physicians are aware: nasal cobalamin. For a number of years, an intranasal cyanocobalamin gel called Ener-B has been available over the counter. It is sold in packages of 12 unit-dose tubes, each containing 400 μg of cyanocobalamin. The manufacturer (Nature's Bounty, 90 Orville Dr, Bohemia, NY 11716) has targeted the product at the health-foods market and has not promoted it among physicians