Overview

I-CAN™ Technology was originally invented to provide effective and safe transport of proprietary nanoparticle technology, CellInject™, through mucous layer to mucosal surfaces with final goal to ensure highest possible bioavailability of the applied active substances.

Clinical proof 1

Nasal mucoadhesiveness test of I-CAN™ system on healthy volunteers

Aim:
To demonstrate the increased retention time of I-CAN™ system after application on mucosal surface in comparison with nonadhesive lipid nanoparticle dispersion or with mucoadhesive polymer solution.
Nasal mucoadhesiveness test of I-CAN™ system on healthy volunteers.

Aim
To demonstrate the increased retention time of I-CAN™ system after application on mucosal surface in comparison with nonadhesive lipid nanoparticle dispersion or with mucoadhesive polymer solution.
STUDY DESIGN

Twelve healthy subjects (8 men) age ranged between 24 and 60, mean 40 years signed informed consent for their participation in the study. None of them suffered from any clinically significant chronic diseases, nor did any of them take medicines on regular basis. None of the subjects was currently smoking and no one had suffered a viral respiratory infection within the past month. ENT examination did not reveal any local structural abnormalities or inflammatory disorders.
Assessments were done in separate visits at 7 days apart. During visits double blind randomized comparisons were made between nasal clearance times of I-CAN™ and RS solutions of Stevia.

NASAL CLEARANCE MEASUREMENTS

Briefly, 100 μL of I-CAN™ Technology system, containing 0.2% Stevia (natural substitution of saccharine) or Reference solution 1 (RS1, isotonic saline, containing 0.2% Stevia) or Reference solution 2 (RS2, Mucoadhesive isotonic solution of 0.2% Stevia) were applied via nasal spray with mechanical pump device in the vestibule of both nostrils at which point timing was started. Subjects were instructed to swallow only at the prompt of the investigator performing the chronometry with a stopwatch. After the first minute with the head bending down, subjects were told to straighten up and swallowed every 30 seconds until they sensed sweet taste in their mouth.
Fig. 1. Nasal Clearance Times for I-CAN™ system compared to reference solutions, RS1 and RS2
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I-CAN™ Technology expresses delayed clearance time (see Fig.1) compared to RS1 and RS2, 9.58 (± 0.94) min. vs. 5.13 (± 0.69) min. vs 6.04 (±0.68). While the clearance time with RS2, which contains 0.2% mucoadhesive polymer, was not found significantly different from that of RS1, I-CAN™ Technology, which also contained 0.2% of the same mucoadhesive polymer, showed 87% increase compared to RS1 (p < 0.001). The delayed clearance of I-CAN™ Technology suggests that the mucoadhesive polymer alone is not the only factor in the composition determining the high Mucoadhesion of I-CAN™ Technology, but the cumulative effect of dispersion components.
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STUDY CONCLUSION:

The small amount of mucoadhesive polymer at level of 0.2% increased substantially the retention time of the applied dose (87% increase), but not the viscosity (just 1.05 cP increase at 33°C for I-CAN™ Technology).

I-CAN™ Technology has lower viscosity and higher mucoadhesiveness from those of water solutions of mucoadhesive polymer with the same concentration (0.2%). The said differences allow I-CAN™ Technology to flow better, to be easily sprayed, to mix better with the mucus secretions, to cover a larger mucosal surface and to stay longer over the mucosa ensuring higher bioavailability.

Clinical proof 2
Clinical research study of I-CAN™ Technology loaded with low dosed mometasone furoate at dose 2.5 mcg per 100 mcl spray.
Aim:
This clinical study has been designed and conducted with the following aims:

  • To prove the author’s original concept for high efficiency of I-CAN™ Technology, loaded with API.

  • To study the effect of nasal spray, containing low dosed Mometasone furoate, loaded on I-CAN™ Technology.

STUDY DESIGN

  • I-CAN™ Technology composition of Mometasone furoate was formulated in spray form delivering dose of 2.5 µg per spray.
  • 12 outpatients (8 women and 4 men, aged between 18 and 69 years) at the Department of Immunology and Allergology at the National Center of Infectious and Parasitic Diseases, diagnosed with perennial allergic rhinitis gave informed consent to volunteer for the study and were instructed to spray the preparation twice in each nostril on “as needed” basis but no more than 4 times a day.
  • The study was designed as open, single medication (no reference product) in two periods, ten days each, with seven days washout. The washout period was used to collect information about expected left-over (depo) effect of the new medication.
  • The symptoms (except the time for free nasal breathing) were evaluated by Visual Analogue Scale (VAS), ranged between 0 (lack of symptom) and 100 (full expression of the symptom).
  • The studied symptoms were:

    - (time for) free nasal breathing after using the spray
    - secretion from the nose
    - itching in the nose
    - nasal congestion
    - sneezing
    - eye irritation


During the clinical testing, the overall health condition (or condition change) of the patients was observed. Patients were phone called once daily in line with the measures for strict daily control on medication application and duly recording in patient cards.
RESULTS:
2.1 Time for Free Nasal Breathing (TFNB)
The results are shown in Fig. 2, Serie M. Significant improvement in nasal symptom between day 0 (baseline) and day 10 and day 20 (p < 0.001). 5.6h Mean TFNB was recorded in the patients diaries on day 20 of the study. The TFNB reached duration plateau on day 7 of Period I whereas it was observed as early as on day 3 of Period II. Strong positive correlation (Pearson r = 0.92) was found between periods. Left-over effect of 294 % above the baseline was observed on day 0 of Period II. No nasal rebound swelling was achieved during the test.

Clinical proof 3
Clinical research study of I-CAN™ Technology loaded with a low dosed combination Mometasone furoate/Xylometazoline at dose 2.5 mcg/5 mcg per 100 mcl sprays.
Aim:
This clinical study has been designed and conducted with the following aims:

  • To prove the author’s original concept for high efficiency of low dosed API combinations loaded on I-CAN™ Technology.

  • To study the effect of nasal spray, containing low dosed API combination Mometasone/ Xylometazoline, loaded on I-CAN™ Technology.

STUDY DESIGN

  • I-CAN™ Technology composition of Mometasone furoate/Xylometazoline was formulated in spray form delivering dose of 2.5 mcg/5.0 mcg per spray.
  • 17 outpatients (10 women and 7 men, aged between 18 and 69 years), at the Department of Immunology and Allergology at the National Center of Infectious and Parasitic Diseases, diagnosed with perennial allergic rhinitis gave informed consent to volunteer for the study and were instructed to spray the preparation twice in each nostril on “as needed” basis but no more than 4 times a day.
  • The study was designed as open, single medication (no reference product) in two periods, ten days each, with seven days washout. The washout period was used to collect information about expected left-over (depo) effect of the new medication and on the other hand – to observe for eventual rebound swelling after the day 7 usually related with use of the decongestant.
  • The symptoms were evaluated by Visual Analogue Scale (VAS), ranged between 0 (lack of symptom) and 100 (full expression of the symptom).
  • The studied symptoms were:

    - (time for) free nasal breathing after using the spray
    - secretion from the nose
    - itching in the nose
    - nasal congestion
    - sneezing
    - eye irritation

    During the clinical testing, the overall health condition (or condition change) of the patients was observed. Patients were phone called once daily in line with the measures for strict daily control on medication application and duly recording in patient cards.
RESULTS:
3.1 Time for Free Nasal Breathing (TFNB)
The results are shown in Fig. 2, Serie M/X. Significant improvement in nasal symptom between day 0 and day 10 and day 20 (p < 0.001). 15h Mean TFNB was recorded in the patients diaries on day 20 of the study. The TFNB gradually increased during the treatment periods. Strong positive correlation (Pearson r = 0.87) was found between periods. Left-over effect of 625% above the baseline was observed on day 0 of Period II. No nasal rebound swelling was achieved during the test.
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Fig. 2. Time for free nasal breathing (TFNB) after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.

… Clinical proof 2

2.2 Nasal secretion score during medication periods
The results are shown in Fig. 3, Serie M. Significant improvement (p < 0.05) in the nasal symptom was observed. The maximum effect was achieved on day 4 of Period I and on day 3 of Period II. Strong positive correlation (Pearson r = 0.77) was found between periods. Left-over effect of 32% decrease from baseline was observed on day 0 of Period II.

… Clinical proof 3

3.2 Nasal secretion score during medication periods
The results are shown in Fig. 3, Serie M/X. Significant improvement (p < 0.05) in the nasal symptom was observed. While the symptom score decreased gradually during Period I, it reached its minimum on day 7 of Period II. Strong positive correlation (Pearson r = 0.82) was found between periods. Left-over effect of 25% decrease from from baseline was observed on day 0 of Period II.
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Fig. 3. Nasal secretion score after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.

… Clinical proof 2

2.3 Nasal Itching during the medication periods
The results are shown in Fig. 4, Serie M. Itching practically disappeared through the days of period I. The symptom was gradually decreased until the end of Period I, whereas it reached minimum on day 6 on Period II and remained unchanged. Strong positive correlation (Pearson r = 0.83) was found between periods. Left-over effect of 26% decrease from the symptom baseline was observed on day 0 of Period II.

… Clinical proof 3

3.3 Nasal Itching during the medication periods
The results are shown in Fig. 4, Serie M/X. Itching practically disappeared through the days of period I. The symptom was gradually decreased until day 9 of Period I, whereas it reached minimum on day 4 and remained unchanged until the end of Period II. Weak positive correlation (Pearson r = 0.35) was found between periods. Left-over effect of 17% decrease from the baseline was observed on day 0 of Period II.
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Fig. 4. Nasal itching score after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.

… Clinical proof 2

2.4 Nasal congestion score during the medication periods
The results are shown in Fig. 5, Serie M. Feeling of nasal congestion was significantly reduced (p < 0.05) during the medication with 50% reduction of the symptom on day 20. The symptom was gradually decreased during the periods. Moderate positive correlation (Pearson r = 0.64) was found between periods. Left-over effect of 23% decrease from the baseline was observed on day 0 of Period II.

… Clinical proof 3

3.4 Nasal congestion score during the medication periods
The results are shown in Fig. 5, Serie M/X. Feeling of nasal congestion was significantly reduced (p < 0,05) during the medication with 78% reduction of the symptom on day 20. The symptom was gradually decreased during the periods. Moderate positive correlation (Pearson r = 0.73) was found between periods. Left-over effect of 43% decrease from the baseline was observed on day 0 of Period II.
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Fig. 5. Nasal congestion score after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.

… Clinical proof 2

2.5 Sneezing during the medication periods
The results are shown in Fig. 6, Serie M. Sneezing was significantly improved (p < 0.05) during the course of medication. Gradual decrease was observed during the treatment periods. Moderate positive correlation (Pearson r = 0.69) was found between periods. Left-over effect of 31% decrease from the baseline was observed on day 0 of Period II.

… Clinical proof 3

3.5 Sneezing during the medication periods
The results are shown in Fig. 6, Serie M/X. Sneezing was practically eliminated during the course of medication. The minimum of symptom score was reached on day 7 of Period I and on day 2 of Period II. Weak positive correlation (Pearson r = 0.12) was found between periods. Left-over effect of 57% decrease from the baseline was observed on day 0 of Period II.
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Fig. 6. Sneezing score after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.

… Clinical proof 2

2.6 Eye irritation during the medication
The results are shown in Fig. 7, Serie M. Eye irritation was practically eliminated during medication. Moderate positive correlation (Pearson r = 0.71) was found between periods. Left-over effect of 27% decrease from the baseline was observed on day 0 of Period II.

… Clinical proof 3

3.6 Eye irritation during the medication
The results are shown in Fig. 7, Serie M/X. Eye irritation was practically eliminated during the course of medication. Weak positive correlation (Pearson r = 0.26) was found between periods. Left-over effect of 68% decrease from the baseline was observed on day 0 of Period II.
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Fig. 7. Eye irritation score after medication with I-CAN™ Technology loaded with Mometasone, 2.5 mcg (Serie M, n=12, squares) or Mometasone/Xylometazoline, 2.5/5.0 mcg, (Serie M/X, n=17, rhombi), Mean +/- SE. p value represents the level of significance in the difference between Series M and M/X.
Clinical proof 2 - STUDY CONCLUSION:

The study demonstrated high efficacy, left-over (depo) effect of more than 7 days, and excellent tolerability with no adverse effects during the test period of I-CAN™ Technology of Mometasone furoate at dose 2.5 mcg per spray on the symptoms of perennial allergic rhinitis.
Clinical proof 3 - STUDY CONCLUSION:

The study demonstrated high efficacy, left-over (depo) effect of more than 7 days, and excellent tolerability with no adverse effects during the test period of I-CAN™ Technology of Mometasone furoate/Xylometazoline at dose 2.5 mcg/5.0 mcg per spray on the symptoms of perennial allergic rhinitis.

Explanation of the added value of local sympathomimetic in the low dosed combination Mometasone/Xylometazoline versus monotherapy with Mometasone when used with I-CAN™ Technology

Both the Series M and M/X significantly increased the TFNB (fig. 2), still I-CAN™ Technology loaded with the combination showed faster and 2.5 times longer effect reaching 15 hours at the end of the treatment after a single dose. The significantly higher initial times at day 0 of the Period II compared to the day 0 of Period I relate to long lasting depo effect of I-CAN™ Technology. During the 7 days wash-out period TFNB with Serie M significantly dropped but still stayed at 294% above the baseline; the same index for Serie M/X was 625% corresponding to more than double the effect of the combination. Serie M reaches a plateau after the day 3 of the tested periods, while the Serie M/X gradually and constantly increased the TFNB reaching 15 hours on day 20.

Since nasal congestion is one of the down-sides of corticosteroid monotherapy, it was expected that the combination with decongestant should treat this symptom faster and stronger. What was yet unexpected was the achievement of long lasting effect of more than 7 days (after 10 days of treatment) with the short acting alfa mimetic xylometazoline (the effect is generally accepted to last up to 5-6h). The level of significance (p value) for each symptom was calculated (figs. 2-7) for Series M and M/X, comparing the data populations. As expected the TFNB and the feeling of nasal congestion showed significant differences with p < 0.0001 because of the added value of Xylometazoline. Unexpectedly the combination gave better control on sneezing (p = 0.0005). For the rest of the symptoms significance between the Series was not found.

There are described methods in the prior art for prolongation the effect of nasally administered APIs with the use of mucoadhesion, but duration of the effect for 7 days and more could not be explained solely with this phenomenon. In fact, the mucoadhesion with I-CAN technology has been used to prolong the time for contact of the lipid particles as carriers of API with the nasal mucosa and subsequently to provide high degree of absorption. As digestion of the particles happen within the cells, the only way the absorbed particles to produce effect is intracellular degradation of the lipid and release the free API. It is expected that such a transport system will be effective for APIs with intracellular mechanism of action. That’s why the choice of corticosteroid (mometasone) is thought reasonable. On the other hand, the high efficacy of xylometazoline delivered within cell was unexpected, yet at levels 20 times lower than the therapeutic ones since its mechanism of action is outer cell membrane alpha-adrenergic receptor mediated.


  • I-CAN™ Technology ensures prolonged action in two stages:
    1. By Mucoadhesion to reach high bioavailability.
    2. By slow degradation within cells, resulting in long lasting (more than 7 days) effect.


  • Xylometazoline encapsulated in I-CAN™ Technology shows 20 times (and more) stronger effect
    due to the high bioavailability and slow degradation of the particles within the cells. Incidents of mucosal ischemia in the course of treatment are unlikely due to the intimate mechanism of API delivery: any state of mucosal/cell oxygen insufficiency should strongly decrease mitochondrial function (and vice versa) and consequently slow down particles digestion and API delivery. This way the delivered amount of the decongestant could be “self-regulated” and never overdosed. This assumption can explain the immediate relief in patients with light to moderate allergic rhinitis and the observed lag in effect in the treatment of more severe states associated with acute inflammation.

GENERAL CONCLUSION


  • I-CAN™ Technology allows 20 times and more reduction in the single dose and additionally 2 to 4 times in the daily dose applications. This reduction has definite explanation and mechanism of pharmacological action, based on increase in the efficiency by pharmaceutical technology means.
  • The added value with insertion of sympathomimetic in low dose, in combination with low dosed corticosteroid both incorporated in the lipid phase in the I-CAN™ Technology system consists of highly effective, nontoxic, well tolerable, long lasting medication of allergic rhinitis, completely covering all the symptoms of allergic rhinitis.
  • The use of corticosteroid in a dose 20 times lower than the therapeutic single dose, the use of combination of corticosteroid plus decongestant (xylometazoline) in dose levels at least 20 times lower than the therapeutic single ones can only possess detectable therapeutic effect when encapsulated within a special carrier system, such as the CellInject particle technology, integrated in I-CAN™ Technology.
  • The decrease in doses of corticosteroid and decongestant (up to 80 times on a daily base) eliminates the adverse reactions, related with the typical use of the same medications. This is especially important in the pediatrics and in all cases when a long-term therapy, reduction in the adverse reactions and the toxic effects is needed.