BOTULINUM TOXIN FORMULATIONS AND METHODS FOR INTRANASAL DELIVERY THEREOF FOR THE TREATMENT OF ALLERGIC RHINITIS

Abstract

A method for intranasal delivery of a formulation comprising Botulinum toxin for the treatment of allergic rhinitis involved impregnating an absorbent tip of an applicator with the formulation, the applicator having a rigid rod having the absorbent tip at a distal end thereof, and inserting the applicator straight into a nasal cavity of a patient beneath the lower turbinates to target the nasal- or nasopharynx-associated lymphoid tissue (NALT) and the eustachian tube opening zone of the nasopharynx within the nasal cavity with the absorbent tip.

Claims

1. A method for intranasal delivery of a formulation comprising Botulinum toxin for the treatment of allergic rhinitis, the method comprising impregnating an absorbent tip of an applicator with the formulation, the applicator comprising a rigid rod having the absorbent tip at a distal end thereof, the method comprising inserting the applicator straight into a nasal cavity of a patient beneath the lower turbinates to target the nasal- or nasopharynx-associated lymphoid tissue (NALT) and the eustachian tube opening zone of the nasopharynx within the nasal cavity with the absorbent tip.

2. The method as claimed in claim 1, wherein the absorbent tip is cotton.

3. The method as claimed in claim 1, wherein the rigid rod is between 120 mm and 170 mm in length.

4. The method as claimed in claim 3, wherein the rigid rod is approximately 150 mm in length.

5. The method as claimed in claim 1, wherein the absorbent tip is massaged back-and-forth across the NALT and the eustachian tube opening zone.

6. The method as claimed in claim 1, wherein two applicators are used and wherein each applicator is inserted through a respective nostril.

7. The method as claimed in claim 1, further comprising initially targeting the nasal cavity.

8. The method as claimed in claim 1, wherein targeting the nasal cavity comprises targeting inside of the nasal vestibule.

9. The method as claimed in claim 1, wherein targeting the nasal cavity comprises using the applicator to target septal walls and dorsal roof of the nasal spaces.

10. The method as claimed in claim 9, wherein the method comprises sweeping the rigid rod in a cranial direction.

11. The method as claimed in claim 10, further comprising rotating the rigid rod.

12. The method as claimed in claim 7, wherein the nasal cavity is targeted for between 2 and 8 minutes.

13. The method as claimed in claim 7, wherein the nasal cavity is targeted for approximately five minutes.

14. The method as claimed in claim 1, wherein the rigid rod is inserted straight down along the sulcus below the inferior turbinate and/or the middle turbinates.

15. The method as claimed in claim 14, wherein, when inserting the rod along the sulcus, the rod is rotated.

16. The method as claimed in claim 1, wherein the NALT and the eustachian tube opening zone are targeted for more than 10 minutes.

17. The method as claimed in claim 16, wherein the NALT and the eustachian tube opening zone are targeted for more than approximately 15 minutes.

18. The method as claimed in claim 1, wherein the Botulinum toxin is Type A Botulinum toxin.

19. The method as claimed in claim 1, wherein the formulation comprises poloxamer gel.

20. The method as claimed in claim 1, wherein the formulation comprises saline solution.

21. The method as claimed in claim 1, wherein the formulation comprises Lignocaine.

22. The method as claimed in claim 1, wherein the formulation comprises Adrenaline.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Notwithstanding any other forms which may fall within the scope of the present invention, preferred embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings in which:

[0057] FIG. 1 shows a side view of the intranasal spaces; and

[0058] FIG. 2 shows a front view of the intranasal spaces.

DESCRIPTION OF EMBODIMENTS

[0059] Prior to performing the treatment, the physician should review their training materials on the functional anatomy of the mucosa and plan their approach to ensure that the physician is able to reach the NALT and Eustachian tube opening zone of the nasopharynx by accessing the groove or sulcus under the folds of the middle and inferior turbinates, as well as the maxillary ostial opening under the middle turbinate fold.

[0060] An assistant is optional if the physician wishes assistance to provide personal care and reassurance to the patient during the treatment.

[0061] The patient is preferably accommodated into a fully adjustable, motorised treatment chair or bed that may position patient into semi-recumbent (135 degrees), supine (180 degrees, flat) and Trendelenburg (200 degrees, tilted back with downslope) positions.

[0062] A pulse oximeter monitor may be applied to the patient's finger to provide reference to the patient's heart rate (HR) and oxygenation (SaO2) parameters during the treatment. Baseline measurements of HR, SaO2 and Blood Pressure are recorded and documented on the patient case record chart.

[0063] The patient is advised that they may experience all manner of symptoms akin to a typical hayfever ‘attack’ during the treatment, and they are reassured that they will be under direct clinical observation and will be taken care of by the physician.

[0064] The physician may ask the patient to blow their nose into a disposable paper tissue before proceeding further.

[0065] Before commencing, the physician may perform a visual inspection of the external nostrils and adjust any examination lighting to illuminate the nasal space to directly visualise the lower nasal septum and lower turbinates (conchae). The physician may note visible structural anomalies (such as deviated nasal septum), presence of inflammation (very likely), swelling (including presence of possible polyps) and mucous, and consider their impact on the conduct of the treatment protocol.

[0066] The present method may comprise initial preparation wherein the physician is to don a non-sterile disposable glove on their non-dominant hand (that will contact the patient's nose during treatment).

[0067] The physician may dispense the botulinum toxin formulation onto two sterile 150 mm cotton-tipped applicator buds, with half of the supplied volume being applied to each bud.

[0068] The physician may pass both applicators to the patient and ask the patient to initiate first contact of applicator bud into each nostril so that the patient can control the initial sensation and pressure of the bud inside the nostril. The patient may be instructed not to insert the applicators too deeply, other than getting used to the unusual intra-nasal sensation of a foreign body inside the nose.

[0069] Thereafter, the physician may take over control of the applicators in their dominant hand and use their non-dominant, gloved hand to control and adjust the patient's nose to support and control the movements of the applicator tips whilst they are inside the patient's nose.

[0070] The treatment method may comprise the physician using the dominant hand fingers to hold and manipulate the sterile applicators to perform a structured and comprehensive interrogation of each nasal cavity.

[0071] The physician then inserts one applicator into each nostril. Then, preferably using their dominant hand thumb and index/middle fingers, the physician may twirl/twist the applicator to allow each cotton tip to rotate and wipe against the adjacent nasal mucosa, whilst simultaneously advancing and withdrawing the applicator in a cranial-caudal axis to enter and exit the nasal airway spaces.

[0072] The physician may commence the interrogation by initially massaging the inside of the nasal vestibule, just inside the opening to the nostril. This allows easy stretching of the nasal alar as the cotton tip is rotated and wiped around the alar in sweeping circular movements to ensure both the alar aspect and septal aspects of the mucosa are contacted and massaged in this way.

[0073] Thereafter, the physician may commence deeper penetration with the cotton tips, rubbing each along the ‘roof’ of the nasal cavity (under the external dorsum) in the groove adjacent to the septum and the superior or middle turbinate. Such can be done by direct linear sweeps in a cranial direction and straight out again caudally, whilst rotating the applicators within the groove by rolling the applicator rod between their thumb and fingers.

[0074] Whilst gently massaging the whole septal aspect with the applicator cotton tips by wiping and rotating the cotton tips, the physician may determine the position and structure of the turbinates and trace them out by touch.

[0075] The physician may methodically use the applicator cotton tips to trace out, massage and rub into the mucosal lining; repeating the motions into the vestibule, septal walls, and dorsal roof of the nasal spaces. Increased sensitivity may be felt by the patient when applying pressure against a bony surface of the nasal bones versus pressure applied against cartilaginous or soft-tissue surfaces.

[0076] After about 5 minutes of this method, the physician may adjust the patient position into either a flat (supine) or slightly tilted back (Trendelenburg) position and advise the patient that the treatment will proceed to the deeper zone of the nasopharynx structures.

[0077] With the patient's head tilted back, the physician may apply slight pressure on their nasal tip in a cranial direction to expose direct access to a vertical plane in a line from their nostril straight down to their nasopharynx.

[0078] The physician may insert the applicators in a vertical orientation, and gently proceed straight down along the sulcus below the inferior turbinate and/or the middle turbinates to reach the nasopharynx.

[0079] The physician preferably carefully rotates the cotton tips whilst doing this to eventually gain access and bypass any swelling of the turbinate folds.

[0080] The physician then gently passes the applicator directly down until the back of the nasopharynx is reached, whilst preferably rotating the tips as several passes are performed up and down during which the physician may feel the resistance of the turbinate fold at the midpoint.

[0081] This manoeuvre is generally unpleasant for the patient during which the patient may experience a mild gagging sensation or pressure in the ears or teeth or associated pruritus (itching sensations) during this deep massage, so the physician may withdraw the applicators after several passes in response to these observations.

[0082] The physician may repeat all of the above steps several times. Preferably at least three complete interrogations of the whole nasal space, cavities and sulci (grooves) including the nasopharynx NALT region are performed.

[0083] During application, the physician may repeatedly stop and pause in response to patient feedback (direct observation or patient request) or sneezing fits and the like.

[0084] The physician may constantly observe the patient's face to be ready to cease the treatment if patient becomes distressed or suffers from sneezing fits. The physician may compress and pinch the patient nose (with the physician's gloved non-dominant hand) if a sneeze becomes apparent, either until the sneeze has occurred or the sensation has passed (advised by enquiry of the patient).

[0085] Either the physician or an assistant may make observations of the patient's lacrimal gland status (tearfulness) and nasal mucous production and be ready to use disposable paper tissues to dab away tears or mucous in order to keep the patient as comfortable as possible.

[0086] Preferably, the physician ensures at least 15 minutes of contact time during mucosal massaging, excluding any brief stoppage time. Rarely, extended stoppage time is required due to poor patient tolerance and the total treatment time is increased accordingly.

[0087] Both the innervation of the internal nasal space and secondary anxiety within the patient in coping with the treatment sensations, may provoke many physiological reactions in the patient and cause observable changes in their observable physiological state: result, the sympathetic nervous system stimulation may provoke sweating, pallor, tachycardia, fluctuations in blood pressure. Nasal cavity stimulation may provoke itchiness of the throat, eyes, ears; intense sneezing and/or coughing, possibly in fits or singularly; excessive lacrimation (tearfulness) or nasal mucous production (maybe either thick/viscous or thin/frothing) or nasal bleeding (blood nose or epistaxis [very rarely], or blood staining on applicator tips). Furthermore, specific ocular reactions include itchiness; bleariness, puffy-eye with conjunctival oedema; excessive lacrimation and tearfulness. All of these reactions resolve swiftly and spontaneously on completion of the treatment and cessation of the nasal stimulation.

[0088] Post application, the patient may be sat up in the treatment chair/bed, firstly to a semi-recumbent (135 degrees) and then into an upright (90 degrees) position to be recovered and allow the autonomic nervous system to stabilise after the deep stimulation.

[0089] Preferably, the patient is kept seated for 10 minutes and offered either cold water or herbal (peppermint or mint) teas to drink, to assist their recovery.

[0090] The patient may be asked to stand under direct observation of the physician or assistant, to ensure that the patient is stable on their feet in the standing position and there is no risk of a delayed vaso-vagal syncope.

[0091] There are no specific after-care instructions and the patient may return to their usual practices. The patient will have prominent nasal congestion present which mostly resorbs into the nasal linings shortly after the treatment. It is thought that these secretions are containing traces of the Botulinum toxin formulation so the patient is instructed to not blow their nose for at least 15 minutes following procedure completion. Usually, they may do so on leaving the clinic but are asked to delay if possible.

[0092] The present Botulinum toxin formulation may comprise Botulinum toxin Type A. Any of Abobotulinumtoxin A (DYSPORT™), Onabotulinumtoxin A (BOTOX™), or Incobotulinumtoxin A (XEOMIN™), may be used.

[0093] Poloxamer gel (also called Pluronic gel) may be used as a diluent to reconstitute the Botulinum toxin and penetration enhancer carrier base to facilitate mucosal adhesion and topical absorption of the toxin protein. Poloxamer gel is bio-adhesive to mucous membranes and helps the toxin protein to ‘stick’ to the nasal linings.

[0094] The formulation may further comprise a normal saline (Sodium chloride 0.9%) diluent to reconstitute the botulinum toxin.

[0095] The formulation may comprise Lignocaine as a local anaesthetic medication to provide numbing of the nasal mucosa and improve treatment comfort and tolerance by patient.

[0096] Furthermore, the formulation may comprise Adrenaline as a vasoconstrictor medication used to constrict the superficial blood vessels of the nasal mucosa and retard vascular flushing of the medication away from the mucosal surface.

[0097] The present procedure in formulations are only effective against true AR symptoms. Non-allergic rhinitis (or intrinsic rhinitis) is another common disorder that mimics AR with overlapping symptoms and may co-exist with AR as a secondary complication of uncontrolled AR. Thus, it is important for clinical assessment and correct diagnosis so that the treatment is only offered to suitable candidates. Any co-existing non-AR symptoms should be proportionally defined and advised, to ensure the correct expectations are set with the patient.

[0098] The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practise the invention. Thus, the foregoing descriptions of specific embodiments of the invention are presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed as obviously many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, thereby enabling others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the following claims and their equivalents define the scope of the invention.

[0099] The term “approximately” or similar as used herein should be construed as being within 10% of the value stated unless otherwise indicated.