Novel pediatric composition of nasal dexmedetomidine

Abstract

The present invention relates to a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

Description

[0001] NOVEL PEDIATRIC COMPOSITION OF NASAL DEXMEDETOMIDINE

[0002] Technical field

[0003] The present invention relates to a composition of dexmedetomidine for intranasal administration to a human child by nasal spray, such as for use in a method for sedation of a human child via intranasal administration. In addition, the present invention concerns a nasal spray device comprising the composition.

[0004] The present invention also relates to a method for preoperative sedation of a human child before anaesthesia comprising administering to said child an effective dosage of the composition as well as a method for preoperative sedation of a human child before anaesthesia comprising administering to said child an effective dosage of the composition, and further for reducing emergence agitation in the recovery period after anaesthesia.

[0005] Background Art

[0006] Millions of children annually undergo anaesthesia for surgical or diagnostic procedures. Preoperative sedation for prevention of anxiety related to induction of anaesthesia, including placement of a peripheral venous catheter for intravenous anaesthetics or inhala- tional anaesthetics by mask, is very common. It is estimated that at least 30% of paediatric patients undergoing anaesthesia will require preoperative sedation. Agitation in the recovery period after anaesthesia, often referred to as “emergence agitation” (a dysregulated state of consciousness) is a common side effect to anaesthesia in paediatric patients occurring in approximately 25% (range 10-80%) of paediatric patients undergoing anaesthesia. Emergence agitation may be reduced by alpha-2-agonists e.g. dexmedetomidine administered before or during anaesthesia.

[0007] The most common premedication is benzodiazepines administered rectally or orally. The benzodiazepine midazolam given by the oral route of administration is often used, e.g., the midazolam solution for injection mixed with a syrup to attempt to mask the bitter and unpleasant taste. However, the taste does not become “child-friendly”. Due to the bitter taste of midazolam, the rate of compliance among children to the administration of oral midazolam intake remains variable and it is often difficult to mask the intervention sufficiently. No marketed drug product as a nasal spray exists for preoperative sedation of children before anaesthesia. In clinical practice drug products containing the active ingredient dexmedetomidine (an alpha-2-agonist) are marketed as solutions for injection for sedation of adults in intensive care departments and used intranasally off-label as preoperative sedation of children. Even though, dexmedetomidine is administered intranasally it is not marketed as an intranasal drug formulation nor approved for children. Also, the intranasal use of the solution for injection is far from optimal, since dosing according to body weight in paediatric patients includes unfeasible large dosing volumes with the risk of run-off to the throat, affecting efficacy and safety. The time to onset when using the marketed dexmedetomidine solution for injection (PRECEDEX or DEXDOR) off-label for intranasal administration is stated in the literature to be about 30 min or more, however, that is not feasible in clinical practice when timing premedication in children before anaesthesia and surgery. Preferable onset time for premedication should be less than 20 min.. Also, the solution (that is PRECEDEX or DEXDOR) for injection has no buffer for controlling pH and tonicity.

[0008] Summary of the Disclosure

[0009] The present inventors have experienced that there is an unmet medical need for development of new drug formulations for sedation, such as preoperative or presurgical sedation, of a human child before anaesthesia as well as reducing emergence agitation during the recovery period in a human child. Furthermore, dexmedetomidine has mild analgesic properties. The available treatment options for sedation before anaesthesia are insufficient and not available in drug formulations suitable for paediatric patients. Due to the lack of suitable drug formulations, drugs intended for intravenous administration are often administered intranasally off-label. The use of drug products containing the active ingredient dexmedetomidine as a solution for injection used intranasally is far from optimal, since dosing according to body weight results in unfeasible large dosing volumes with the risk of run-off to the throat, affecting efficacy and safety. The time to onset, that is defined as the time from administration to the nostrils of a child to the sedative effect sets in, is not feasible for marketed dexmedetomidine solution for injection (PRECEDEX or DEXDOR) administered off- label intranasally prior to anaesthesia and surgery in a busy clinical practice. Thus, the aim of the composition for intranasal administration to a human child by nasal spray of the present invention is to provide a solution that has a considerable shorter time to onset, preferably 20 minutes or less, which will make the use of a dexmedetomidine nasal spray a strong improvement over the known techniques for sedation of children. The shorter time to onset of the present invention is believed to be due to at least a higher concentration compared to PRECEDEX / DEXDOR, administration in smaller volumes than required by using the solutions for injection, and administration via a nasal spray device in contrast to the usual nose drops or use of mucosal atomizing device (MAD device) with a nozzle tip (and an user-dependent aerosol) for intranasal administration. This provides an improved distribution over the nasal mucosa most likely leading to faster absorption through the nasal mucosa and thus faster onset of effect.

[0010] A solution of dexmedetomidine for intranasal administration is needle-free, easy to administer and is absorbed directly to the systemic blood supply, avoiding hepatic first-pass metabolism. Furthermore, the dose is titratable.

[0011] Moreover, administration of sedative medicine to children, in particular small children under age 2, usually requires an authorized practitioner, such as a physician, to be in charge of or at least supervising or monitoring administration of sedative medicine, such as any of the above-described medicines and administration routes, even in ambulatory and emergency settings.

[0012] The present invention concerns in one aspect a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

[0013] The present composition of the invention is easy to administer and is absorbed directly to the systemic blood supply, avoiding hepatic first-pass metabolism. This also contributes to a faster onset of effect. Furthermore, the composition is without preservatives and stable for storage at room temperature and can be stored for later use.

[0014] In one embodiment the solution has a tonicity of 250-340 mOsm / kg, preferably a constant tonicity between 250-340 mOsm / kg.

[0015] In a further embodiment the solution is isotonic (290-300 mOsm / kg) to human blood plasma.

[0016] In a still further embodiment, (a) is a salt of dexmedetomidine.

[0017] In a further embodiment, (a) is a HC1 salt of dexmedetomidine.

[0018] In a still further embodiment, the buffer is a phosphate buffer and / or a Citric acid buffer. In a further embodiment, the buffer is a phosphate buffer.

[0019] In a still further embodiment, the buffer is a Citric acid buffer.

[0020] In a further embodiment the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0021] In a still further embodiment, the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0022] In a further embodiment, the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0023] In a still further embodiment, the composition is without any preservatives.

[0024] In a further embodiment, the buffer maintains pH from 5.0-6.7 in the solution.

[0025] In a still further embodiment, the buffer maintains pH from 5.5-6.5 in the solution.

[0026] In a still further embodiment, the composition is storage stable and suitable for a nasal spray device.

[0027] In a further embodiment, the composition comprises dexmedetomidine as the free base and an acid.

[0028] In a still further embodiment, the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0029] Each of the above embodiments of the composition should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0030] In a second aspect the present invention concerns a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution for use in a method for sedation of a human child before anesthesia.

[0031] In an embodiment of the second aspect the solution has a tonicity of 250-340 mOsm / kg.

[0032] In a further embodiment of the second aspect the solution is isotonic (290-300 mOsm / kg) to human blood plasma.

[0033] In a still further embodiment of the second aspect (a) is a salt of dexmedetomidine.

[0034] In a further embodiment of the second aspect (a) is a HC1 salt of dexmedetomidine.

[0035] In a still further embodiment of the second aspect the buffer is a phosphate buffer and / or a Citric acid buffer. In a further embodiment of the second aspect the buffer is a phosphate buffer.

[0036] In a still further embodiment of the second aspect the buffer is a Citric acid buffer.

[0037] In a further embodiment of the second aspect the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0038] In a still further embodiment of the second aspect the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0039] In a further embodiment of the second aspect the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0040] In a still further embodiment of the second aspect the composition is without any preservatives.

[0041] In a further embodiment of the second aspect the buffer maintains pH from 5.0 to 6.7, preferably 5.5-6.5 in the solution.

[0042] In a still further embodiment of the second aspect the composition is storage stable and suitable for a nasal spray device.

[0043] In a further embodiment of the second aspect the composition comprises dexmedetomidine as the free base and an acid.

[0044] In a still further embodiment of the second aspect the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0045] Each of the above embodiments of the second aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0046] In a third aspect the present invention concerns a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution for use in a method for reducing emergence agitation in a human child in a recovery period following anaesthesia.

[0047] In an embodiment of the third aspect the solution has a tonicity of 250-340 mOsm / kg.

[0048] In a further embodiment of the third aspect the solution is isotonic (290-300 mOsm / kg) to human blood plasma.

[0049] In a still further embodiment of the third aspect (a) is a salt of dexmedetomidine.

[0050] In a further embodiment of the third aspect (a) is a HC1 salt of dexmedetomidine. In a still further embodiment of the third aspect the buffer is a phosphate buffer and / or a Citric acid buffer.

[0051] In a further embodiment of the third aspect the buffer is a phosphate buffer.

[0052] In a still further embodiment of the third aspect the buffer is a Citric acid buffer.

[0053] In a further embodiment of the third aspect the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0054] In a still further embodiment of the third aspect the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0055] In a further embodiment of the third aspect the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0056] In a still further embodiment of the third aspect the composition is without any preservatives.

[0057] In a further embodiment of the third aspect the buffer maintains pH from 5.0 to 6.7, preferably 5.5-6.5 in the solution.

[0058] In a still further embodiment of the third aspect the composition is storage stable and suitable for a nasal spray device.

[0059] In a further embodiment of the third aspect the composition comprises dexmedetomidine as the free base and an acid.

[0060] In a still further embodiment of the third aspect the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0061] Each of the above embodiments of the third aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0062] In a fourth aspect the present invention concerns a nasal spray device comprising a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

[0063] In an embodiment of the fourth aspect the solution has a tonicity of 250-340 mOsm / kg. Typically, the solution has a constant tonicity between 250-340 mOsm / kg. Such as a tonicity of 290-300 mOsm / kg.

[0064] In a further embodiment of the fourth aspect the solution is isotonic (290-300 mOsm / kg) to human blood plasma. In a still further embodiment of the fourth aspect (a) is a salt of dexmedetomidine.

[0065] In a further embodiment of the fourth aspect (a) is a HC1 salt of dexmedetomidine.

[0066] In a still further embodiment of the fourth aspect the buffer is a phosphate buffer and / or a Citric acid buffer.

[0067] In a further embodiment of the fourth aspect the buffer is a phosphate buffer.

[0068] In a still further embodiment of the fourth aspect the buffer is a Citric acid buffer.

[0069] In a further embodiment of the fourth aspect the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0070] In a still further embodiment of the fourth aspect the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0071] In a further embodiment of the fourth aspect the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0072] In a still further embodiment of the fourth aspect the composition is without any preservatives.

[0073] In a further embodiment of the fourth aspect the buffer maintains pH from 5.0-6.7 in the solution.

[0074] In a further embodiment of the fourth aspect the buffer maintains pH from 5.5-6.5 in the solution.

[0075] In a still further embodiment of the fourth aspect the composition is storage stable and suitable for a nasal spray device.

[0076] In a further embodiment of the fourth aspect the composition comprises dexmedetomidine as the free base and an acid.

[0077] In a still further embodiment of the fourth aspect the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0078] In a further embodiment the nasal spray device of the fourth aspect is adapted to deliver a dosing volume of 25-150 pl per actuation.

[0079] In a still further embodiment, the nasal spray device of the fourth aspect is adapted to deliver a dosing volume of 50-100 pl per actuation.

[0080] Each of the above embodiments of the fourth aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention. In a fifth aspect the present invention relates to a nasal spray device comprising a composition wherein the composition comprises an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution, for use in a method for sedation of a human child before anaesthesia.

[0081] In an embodiment of the fifth aspect the human child is under 18 years.

[0082] In a further embodiment of the fifth aspect the human child is under 2 year.

[0083] In a still further embodiment of the fifth aspect the human child is under 1 year.

[0084] In a further embodiment of the fifth aspect the human child is between / i year and 2 years.

[0085] In a still further embodiment of the fifth aspect the child weighs below 60 kg, such as below 50 kg, such as below 35 kg, such as below 25 kg, e.g. below 10 kg.

[0086] In a further embodiment of the fifth aspect the solution has a tonicity of 250-340 mOsm / kg.

[0087] In a further embodiment of the fifth aspect the solution is isotonic (290-300 mOsm / kg) to human blood plasma.

[0088] In a still further embodiment of the fifth aspect (a) is a salt of dexmedetomidine.

[0089] In a further embodiment of the fifth aspect (a) is a HC1 salt of dexmedetomidine.

[0090] In a still further embodiment of the fifth aspect the buffer is a phosphate buffer and / or a Citric acid buffer.

[0091] In a further embodiment of the fifth aspect the buffer is a phosphate buffer.

[0092] In a still further embodiment of the fifth aspect the buffer is a Citric acid buffer.

[0093] In a further embodiment of the fifth aspect the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0094] In a still further embodiment of the fifth aspect the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0095] In a further embodiment of the fifth aspect the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0096] In a still further embodiment of the fifth aspect the composition is without any preservatives.

[0097] In a further embodiment of the fifth aspect the buffer maintains pH from 5.0-6.7, such as pH from 5.5-6.5 in the solution. In a still further embodiment of the fifth aspect the composition is storage stable and suitable for a nasal spray device.

[0098] In a further embodiment of the fifth aspect the composition comprises dexmedetomidine as the free base and an acid.

[0099] In a still further embodiment of the fifth aspect the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0100] In a further embodiment the nasal spray device of the fifth aspect is adapted to deliver a dosing volume of 25-150 pl per actuation.

[0101] In a still further embodiment, the nasal spray device of the fifth aspect is adapted to deliver a dosing volume of 50-100 pl per actuation.

[0102] Each of the above embodiments of the fifth aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0103] In a sixth aspect the present invention relates to a nasal spray device comprising a composition wherein the composition comprises an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution, for use in a method for reducing emergence agitation in a human child in a recovery period following anaesthesia.

[0104] In an embodiment of the sixth aspect the human child is under 18 years.

[0105] In a further embodiment of the sixth aspect the human child is under 2 year.

[0106] In a still further embodiment of the sixth aspect the human child is under 1 year.

[0107] In a further embodiment of the sixth aspect the human child is between / i year and 2 years.

[0108] In a still further embodiment of the sixth aspect the child weighs below 60 kg, such as below 50 kg, such as below 35 kg, such as below 25 kg, e.g. below 10 kg.

[0109] In a further embodiment of the sixth aspect the solution has a tonicity of 250-340 mOsm / kg.

[0110] In a further embodiment of the sixth aspect the solution is isotonic (290-300 mOsm / kg) to human blood plasma.

[0111] In a still further embodiment of the sixth aspect (a) is a salt of dexmedetomidine.

[0112] In a further embodiment of the sixth aspect (a) is a HC1 salt of dexmedetomidine. In a still further embodiment of the sixth aspect the buffer is a phosphate buffer and / or a Citric acid buffer.

[0113] In a further embodiment of the sixth aspect the buffer is a phosphate buffer.

[0114] In a still further embodiment of the sixth aspect the buffer is a Citric acid buffer.

[0115] In a further embodiment of the sixth aspect the buffer is a mixture of a phosphate buffer and a Citric acid buffer.

[0116] In a still further embodiment of the sixth aspect the concentration of (a) is 200-800 pg / ml measured as the free base in the solution.

[0117] In a further embodiment of the sixth aspect the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

[0118] In a still further embodiment of the sixth aspect the composition is without any preservatives.

[0119] In a further embodiment of the sixth aspect the buffer maintains pH from 5.0-6.7, such as pH from 5.5-6.5 in the solution.

[0120] In a still further embodiment of the sixth aspect the composition is storage stable and suitable for a nasal spray device.

[0121] In a further embodiment of the sixth aspect the composition comprises dexmedetomidine as the free base and an acid.

[0122] In a still further embodiment of the sixth aspect the composition comprises dexmedetomidine as the free base and hydrochloric acid.

[0123] In a further embodiment the nasal spray device of the sixth aspect is adapted to deliver a dosing volume of 25-150 pl per actuation.

[0124] In a still further embodiment, the nasal spray device of the sixth aspect is adapted to deliver a dosing volume of 50-100 pl per actuation.

[0125] Each of the above embodiments of the sixth aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0126] In a seventh aspect the present invention relates to a method for sedation of a human child before anaesthesia comprising administering to said child an effective dosage of a composition comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution, from the nasal spray device comprising the composition.

[0127] In an embodiment of the seventh aspect the effective dosage is 2-4 actuations wherein each actuation delivers a dosing volume of 50-100 pl per actuation having a concentration of dexmedetomidine or a salt thereof from 200-800 pg / ml measured as the free base in the solution.

[0128] Each of the above embodiments of the seventh aspect and relevant compositions under the first aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0129] In an eight aspect the present invention relates to a method for reducing emergence agitation in a human child in a recovery period following anaesthesia, comprising administering to said child an effective dosage of a composition comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution, from the nasal spray device comprising the composition.

[0130] Each of the above embodiments of the eight aspect and relevant compositions under the first aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0131] In a ninth aspect the present invention relates to a pre-filled and ready to use nasal spray device comprising a composition wherein the composition comprises an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

[0132] In an embodiment the pre-filled and ready to use nasal spray device of the ninth aspect is for use in a method for sedation of a human child before anaesthesia.

[0133] In another embodiment the pre-filled and ready to use nasal spray device of the ninth aspect is for use in a method for reducing emergence agitation in a human child in a recovery period following anaesthesia.

[0134] Each of the above embodiments of the ninth aspect and relevant compositions under the first aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention. In a tenth aspect the present invention relates to a kit of parts comprising a nasal spray device of the fourth aspect and a composition of the first aspect and a packing.

[0135] Each of the above embodiments of the tenth aspect and the nasal spray device of the fourth aspect and the compositions under the first aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0136] In an eleventh aspect the present invention relates to a kit of parts comprising a nasal spray device of the ninth aspect and the compositions under the first aspect and a packing.

[0137] Each of the above embodiments of the eleventh aspect and the nasal spray device of the ninth aspect and the compositions under the first aspect should be seen as referring to any one of the embodiments described above in any combination unless it is specified that an embodiment relates to a certain aspect or a certain embodiment of the present invention.

[0138] Brief description of drawing

[0139] Figure 1 shows the calibration curve for dexmedetomidine.

[0140] Figure 2 shows percentage (%) relative cell viability of Calu-3 cell monolayers seeded on permeable supports exposed to Zymelin® in different volumes and Dexmedetomidine in different concentrations and volumes

[0141] Detailed description

[0142] In a broad aspect, the present invention concerns a composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

[0143] Local toxicity of the developed solutions of dexmedetomidine in a buffer, such as a phosphate buffer, on a cell line as a model of nasal mucosa was evaluated in terms of the proportion of viable cells after exposure to the different concentrations of the developed solutions of dexmedetomidine. Further details are described below under Experimental.

[0144] As used herein the term “aqueous solution” means a water carrier wherein relevant components are dissolved, and the water is, typically, sterile water.

[0145] As used herein the term “intranasal administration by spray” means administration of an aqueous solution, that is the above mixture of (a) and (b) in solution to a nostril of a human child through a means for spraying, such as a nozzle or tip capable of blowing the composition of the present invention as small droplets, e.g. a mist, into the nostril(s).

[0146] As used herein the term “aqueous solution of (a) and (b) in solution” means that (a) and (b) are mixed together and dissolved in the water.

[0147] A salt of dexmedetomidine may be any acid salt, such as inorganic or organic salts, and is preferably a pharmaceutically acceptable acid addition salt, such as HC1. Solvates, such as hydrates of the above compound or salts are also to be understood as comprised in the term.

[0148] As used herein the term “nasal spray device” means any device adapted for spraying a liquid solution into a nostril of a human child which device is airtight when assembled. In particular and as used herein the nasal spray device has a body part containing a composition of the present invention and a pump system with a nozzle or other spray function for administration via the nasal delivery route (the nostrils of a human child), and this device is typically assembled (ia. pre-assembled) and ready for use in a human child. Furthermore, “a nasal spray device” means that the nasal spray device containing the composition of the present invention can be stored for a sufficient period of time, such as 1 month, 3 months or one year, and is ready to be used by e.g. a health care professional or a physician at a hospital and a healthcare setting. The device may also be a kit of parts comprising a body part holding the composition of the present invention e.g. a glass bottle with a thread or snapping means and a pump system for spraying, wherein said pump system is adapted to provide a nasal spray device which is sealed and airtight and can be stored. An example of such a pump system for use as part of the device is available from Aptar Pharma a part of the Aptar Group, such as a CPS vented dip tube (a versatile spray pump), (see for instance: http: / / www.aptar.com / pharma / prescription-division / products / CPS). The Aptar Group owns intellectual property to these suitable pump systems for intranasal delivery. For instance, the body part may be a container in glass holding a solution of a mixture of (a) and (b). The container closure system used for the product is a mechanical multi dose nasal spray device. The device consists of a vented pump (nasal spray device from Aptar Pharma (see for instance: http: / / www.aptar.com / pharma / prescription-division / products / CPS” or equivalent) and a paediatric actuator mounted on a 3 ml glass v-bottom bottle (u-save bottle “SGD Pharma” or equivalent). The dosing volume of the pump is 50 or 100 microliters. As used herein the term “a dosage volume” or “a dosing volume” used interchangeably, means the liquid dosage volume containing the composition comprising water and active compounds delivered from the device to a nostril. The preferred dosage volume to a nostril is from 0.05-0.1 ml.

[0149] In a further embodiment the composition of the present invention in a nasal spray device has a volume from 25 pl to 5 ml, such as a volume from 50 pl to 5 ml. Typically, the volume is from 0.1 to 3 ml. Preferably, the volume is from 0.5 to 3 ml, such as 2 ml.

[0150] As used herein the term “a volume” means the total volume of liquid water, dissolved compounds, and optionally additives dissolved therein. Thus, any undissolved compound or other additive is not considered part of the volume.

[0151] In a further embodiment the solution contains a buffer that is able to maintain pH at a constant level between 4 and 7. Thus, e.g. pH may be 4, 4.5, 5, 5.5, 6, 6.5, or 7, typically 5.0-6.5. The buffer may be any suitable buffer, such as a phosphate buffer or a Citric acid buffer.

[0152] As used herein the term “a buffer” means a buffer or a mixture of buffers, that is pharmaceutically acceptable, such as a buffer approved by an authority such as EMA or FDA for administration to a human child.

[0153] As used herein the term “a constant tonicity” means keeping osmolality within a range of 10 mOsm / kg is considered constant, and for instance isotonic to human blood plasma is considered constant within 290-300 mOsm / kg to human blood plasma.

[0154] As used herein the term “treatment” and “treating” as used herein means the management and care of a human child for the purpose of sedation and / or reducing emergence agitation as described herein. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound for preoperative sedation of a human child, in particular before anaesthesia, and / or for reducing emergence agitation in a human child following preoperative sedation, in particular before anaesthesia.

[0155] In a further aspect the present invention relates to a pre-filled and ready to use nasal spray device comprising the composition of the present invention. The term “prefilled and ready to use” means a nasal spray device containing the composition of the present invention and which is sealed and can be stored until use, wherein storage is at least 2 weeks at room temperature. In a further embodiment the pre-filled and ready to use nasal spray device of the present invention is for use in an emergency vehicle, such as an ambulance.

[0156] In a preferred treatment regimen wherein the nasal spray device of the present invention is used, a dosage volume of 0.05-0.5 ml is administered to a nostril of a human child. Typically, the dosage volume is 0.05-0.1 ml per spray / actuation. In another embodiment the dosage volume of 0.05-0.1 ml per spray is administered in each nostril, such as two - four times, each spray in each nostril immediately following each other until effective dosage is obtained according to weight of human child.

[0157] Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

[0158] The above embodiments should be seen as referring to any one of the aspects (such as ‘composition’, ‘nasal spray device’, ‘method for preoperative sedation of a human child before anaesthesia’ or ‘method for reducing emergence agitation in a human child following preoperative sedation before anaesthesia’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

[0159] All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0160] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0161] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0162] The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Thus, the terms “a” and “an” means “one or more” or “at least one” and are used interchangeably during the text.

[0163] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by "about," where appropriate).

[0164] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0165] The use of any and all examples, or exemplary language (e.g., “such as”, “typically, “preferably”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

[0166] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and / or enforceability of such patent documents.

[0167] The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0168] This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.

[0169] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. Experimental 1

[0170] The aim was to determine the solubility and short-term stability of dexmedetomidine in two buffer systems in order to develop concentrated solutions of dexmedetomidine (200- 600 pg / mL) that are feasible for intranasal administration for dosing of pediatric patients ranging from 10-60 kg preferably with a maximum of approximately four sprays of 0.05 to 0.1 mL The current commercially available injectable formulation of dexmedetomidine has a concentration of 100 pg / mL and the dose required for intranasal administration is 2-3 pg / kg. With the current IV formulation the dose volume is too high for intranasal use (optimally 50- 100 pL per spray / actuation for pediatric patients). Therefore, two formulations of either 200 pg / mL and 300 pg / mL or 400 pg / mL and 600 pg / mL are required in order to deliver the appropriate dose of dexmedetomidine in 1-4 sprays in nostrils of pediatric patients ranging from 10-60 kg.

[0171] MATERIALS

[0172] Table 1 gives an overview of the chemicals and solvents used in this study. Table 1 : Chemicals used in this study

[0173] METHODS

[0174] Sample and buffer preparation

[0175] Two buffers were used for the stability study:

[0176] 1. 30 mM citrate buffer, 110 mM NaCl, pH 5.5.

[0177] The osmolality of this buffer was 283 mOsm / kg as measured by freezing point depression.

[0178] 2. 60 mM phosphate buffer, 90 mM NaCl, pH 6.5.

[0179] The osmolality of this buffer was 290 mOsm / kg as measured by freezing point depression.

[0180] The buffers were prepared in ultrapure water (Milli-Q® Reference A+ System, Merck) with a resistivity of 18.2 MQ cm and filtered (0.22 pm, Qmax cellulose acetate, Frisenette). Stock solutions of Dexmedetomidine hydrochloride (Dex-HCl) were prepared by dissolving 15.6 mg in 22.0 mL phosphate buffer and 15.4 mg in 21.7 mL citrate buffer giving a concentration of Dex-HCL of 709 pg / mL corresponding to a concentration of dexmedetomidine free base (Dex) of 600 pg / mL. Samples of 600, 400, 300, and 200 pg / mL dexmedetomidine were prepared in each of the two buffers by dilution with the respective buffer (see Table 2).

[0181] Table 2. Table of stock concentrations of Dex- HCl, dilutions, and Dex concentrations in the final formulations.

[0182] Six vials were prepared for each concentration, amounting to 24 vials per buffer. Samples were aliquoted into autoclaved vials and crimped. Five of the six vials were incubated at 25 °C, while one vial was incubated at 5 °C (see Table 3). RH means Relative Humidity.

[0183] Table 3. Vial preparation setup

[0184] Sample Dex cone. Temperature (ambient RH) Number p / mL 25 °C 5 °C of vials

[0185] 1 600 5 1 6

[0186] 2 400 5 1 6

[0187] 3 300 5 1 6

[0188] 4 200 5 1 6

[0189] Samples were pulled after 2, 3, 7, 10, and 14 days. At every pull point, the samples were visually inspected, and pH and osmolality measurements were carried out. Subsequently, the samples were frozen at -20 °C and stored until day 14. RP-HPLC measurements were carried out at t° and after 14 days.

[0190] 1.1 RP-HPLC method

[0191] An HPLC method was developed for dexmedetomidine, and a calibration curve was prepared in triplicate (see

[0192] Brief description of drawing

[0193] Figure 1).

[0194] Samples were measured by RP-HPLC at t°. At each of the pull points the sample was frozen and stored until day 14, where all samples were thawed at measured by RP-HPLC. A calibration curve for quantification of dexmedetomidine was freshly prepared in triplicate at t° and after 14 days.

[0195] RP-HPLC

[0196] HPLC system: Vanquish Flex, Thermo Fischer

[0197] Column: Kinetex 2.6 pm EVO C18 100A 100 x 4.6 mm, Phenomenex

[0198] Column temperature: 40°C

[0199] Buffer A: 50 mM phosphate buffer pH 7.0

[0200] Buffer B: Acetonitrile

[0201] Flow: 0.7 mL / min, isocratic 33% B

[0202] Runtime: 10 min

[0203] Detection wavelength: 220 nm

[0204] RESULTS AND DISCUSSION

[0205] Solubility study

[0206] Initially, dexmedetomidine was dissolved to 1 mg / mL in ultrapure water and in Phosphate buffered saline (PBS) buffer pH 7.2. The compound dissolved readily in both solvents and the pH was measured to 5.7 and 6.9, in ultrapure water and PBS buffer, respectively. Following this simple test, the solubility was assessed by adding dexmedetomidine in excess to 30 mM citrate buffer with 110 mMNaCl, pH 5.5 (280 mOsm / kg) and to 30 mM phosphate buffer with 120 mM NaCl, pH 6.5 (281 mOsm / kg). The solubility was determined by quantification of the supernatant by RP-HPLC measurements. A 35 % higher solubility was found for phosphate buffer pH 6.5 (65.1 mg / mL) as compared to citrate buffer pH 5.5 (48.1 mg / mL). However, the observed solubility of dexmedetomidine was >100% higher in phosphate buffer and >80 % higher in citrate buffer than the highest target concentration of dexmedetomidine (600 pg / mL). Therefore, solubility was not considered a risk factor for any of the buffer systems in question.

[0207] Chemical stability study

[0208] The stability of dexmedetomidine samples of 600, 400, 300, and 200 pg / mL in two buffers were evaluated throughout 14 days incubation at 25 °C with five pull points at day 2, 3, 7, 10, and 14. One vial of each concentration in each buffer were placed at 5 °C for reference and samples at day 14. At every pull point, the visual observations were noted and the pH and osmolality were measured. The samples appeared clear and colorless at all times with no visible precipitation. The osmolality and pH data can be found in Table 4. The pH was stable with a variation across samples of ±0.1 pH units and the osmolality varied by approximately ±2 mOsm / kg, which are within the expected error margins for these types of measurements.

[0209] RP-HPLC data for all pull point can be found in Table 5. The dexmedetomidine concentration fell within 2% variation from the nominal concentration across the five pull points. No significant degradation was observed.

[0210] Table 4. Osmolality measurements on the day of the pull point for all samples in citrate buffer pH 5.5 and in phosphate buffer pH 6.5. Each measurement was done in technical triplicates (n=3).

[0211] Table 5. Concentration of all samples taken at the different pull points and stored frozen until day 14. The % recovery indicates the difference from the target concentration (600, 400, 300, and 200 pg / mL).

[0212] Above shows the concentration of dexmedetomidine at different pull points during 14 days of incubation at 25 °C in citrate buffer pH 5.5 (left) and in phosphate buffer pH 6.5 (right) as measured by RP-HPLC. One vial of each concentration in each buffer was placed at 5 °C for reference. Notice that the t° samples were measured at t° and the remaining samples were frozen at -20 °C at their respective pull point and measured by RP-HPLC at the 14D pull point (the 14D samples were not frozen).

[0213] CONCLUSION

[0214] Dexmedetomidine was soluble to 48 mg / mL 30 mM citrate buffer with 110 mM NaCl, pH 5.5 (280 mOsm / kg) and to 65 mg / mL in 30 mM phosphate buffer with 120 mM NaCl, pH 6.5 (281 mOsm / kg). With the highest target concentration of dexmedetomidine in the intended pediatric formulation development being 600 pg / mL, both buffer systems were considered suitable with regards to solubility.

[0215] Samples of 600, 400, 300, and 200 pg / mL in the two buffer systems were incubated at 25 °C for 14 days. The pH was stable with a variation across samples of ±0.1 pH units and the osmolality varied by approximately ±2 mOsm / kg. The dexmedetomidine concentration fell within 2% variation from the nominal concentration across the five pull points. No significant degradation was observed.

[0216] Experimental 2 The aim was to evaluate the local toxicity of the developed solutions of dexmedetomidine in phosphate buffer on a Calu-3 cell line as a model of nasal mucosa. Toxicity was evaluated in terms of the proportion of viable cells after exposure to the different concentrations of the developed solutions of dexmedetomidine.

[0217] Solutions of dexmedetomidine in phosphate buffer were developed (Experimental 1). The solutions are intended for intranasal administration in paediatric patients. The relevant concentrations tested were dexmedetomidine 200 pg / ml, dexmedetomidine 300 pg / ml, dexmedetomidine 400 pg / ml and dexmedetomidine 600 pg / ml and in concentrations well above therapeutic concentrations (dexmedetomidine 1000 pg / ml and dexmedetomidine 1200 pg / ml). Before the initiation of clinical trials, the local toxicity of the solutions was tested in a Calu-3 cell line as a model of the nasal mucosa. The Calu-3 cell line is a well-established model for testing local toxicity of drug products at the nasal mucosa [ref: 1-4],

[0218] Publications of the use of intranasal dexmedetomidine used the commercially available product containing dexmedetomidine 100 pg / ml and reported it well tolerated by paediatric patients.

[0219] In the study set-up concentrations of dexmedetomidine and the volumes tested resembles the intended dosing in paediatric patients.

[0220] Evaluation of Dexmedetomidine local toxicity

[0221] During the cell study, monolayers of Calu-3 cells were used to evaluate the toxicity of Dexmedetomidine. The evaluation was conducted by comparing the marketed product Zymelin® (xylometazoline) that does not contain preservatives and are approved as over- the-counter medication for children in Denmark. Zymelin® was applied on the calu-3 cells in different volumes (where’s 150 pL corresponds to the therapeutic / recommended dose) and Dexmedetomidine was applied in different volumes and concentrations (see tables 1-3). The cells were exposed to the test solution for a total duration of 2 hours followed by the toxicity assessment using the MTS / PMS assay.

[0222] Brief description of the MTS / PMS assay:

[0223] This assay evaluated the metabolic activity and viability of cells. The assay involved the conversion of the tetrazolium salt MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) to a purple formazan in the presence of phenazine methosulfate (PMS). The enzymes responsible were NADPH-de- pendent dehydrogenases, which were active in viable cells. The absorbance of the resulting formazan solution was proportional to the number of viable cells and were quantified using a spectrophotometer at 490-500 nm detection range.

[0224] Table 1 : Experimental transwell setup for the toxic evaluation of Dexmedetomidine compared to Zymelin® (0.5 mg / ml non conserved solution). Zymelin® is applied in different volumes, in triplicates, on calu-3 monolayers.

[0225] Table 2: Experimental transwell setup for the toxic evaluation of Dexmedetomidine compared to Zymelin® (0.5 mg / ml non conserved solution). Dexmedetomidine is applied in different volumes and concentrations, in triplicates, on calu-3 monolayers.

[0226] Table 3: Experimental transwell setup for the toxic evaluation of Dexmedetomidine compared to Zymelin® (0.5 mg / ml non conserved solution). Dexmedetomidine is applied in different volumes and concentrations, in triplicates, on calu-3 monolayers.

[0227] Materials

[0228] Calu-3 cells (human cancer lung cells, broncho-tracheal submucosal gland cell line) were bought from ATCC (HTB-55), LACDR (Leiden / Amsterdam Center for Drug Research). All culture plates were from sigma Merck KGaA (Darmstadt, Germany). Additional chemicals and reagents used in this study are available from Sigma Merck KGaA, Orifarm Healthcare, Supelco, Alfa Aesar, HACH and Gibco.

[0229] Method

[0230] Sample and buffer preparations Phosphate buffer Saline (PBS): 60 mM phosphate buffer, 90 mM NaCl were prepared. Briefly, the buffer was prepared in ultrapure water (Milli-Q® Reference A+ System, Merck) with a resistivity of 18.2 MQ cm and filtered (0.22 pm, Qmax cellulose acetate, Frisenette). The pH was adjusted to 6.5 with IM NaOH or HC1 and the osmolality of this buffer was 290 mOsm / kg as measured by freezing point depression on an Osmometer (Loser Messtechnik, Berlin, Germany).

[0231] Sample preparation- Dexmedetomidine solutions:

[0232] A fresh stock solution of Dex-HCl was prepared by dissolving 10,0 mg in 1.0 mL phosphate buffer resulting in a concentration of Dex-HCl of 10 mg / mL corresponding to a concentration of Dex free base of 8460 pg / mL on the experimental day. Samples of 600, 400, 300, and 200 pg / mL Dex free base were prepared by diluting the stock with phosphate buffer and tested in different volumes (see table 5).

[0233] Table 5. Table of stock concentrations of Dex-HCl, dilutions, and Dex concentrations in the final formulations including the apical volume tested on Calu-3 cell monolayers.

[0234] Sample preparation- Zymelin® solutions: Zymelin® (0,5 mg / ml, unpreserved) were used directly from the original package and the container was unsealed on the experimental day. Different volumes of Zymelin® were tested as listed in table 6.

[0235] Table 6. Apical volumes tested of Zymelin (0,5 mg / ml, unconserved) test solutions on Calu- 3 cell monolayers.

[0236] Cell culture

[0237] Calu-3 cells were maintained in Corning Costar Polystyrene culture flasks (75 cm2surface area) in Dulbecco's Modified Eagle Medium (DMEM) - High glucose, supplemented with penicillin (100 U / ml), streptomycin (100 pg / ml), L-glutamine (2mM) and fetal bovine serum (FBS) (10% v / v). The cells were incubated in an incubator (37°C, 5% CO2) and the growth media was changed every second day until they reached a confluence of 90% followed by trypsinization. Briefly, the cells were detached from the culture flask by treatment with a trypsin-ethylenediaminetetraacetic acid (EDTA) solution (5 mg / ml and 2 mg / ml respectively) for 8 min. After cell detachment, the enzymatic activity was stopped by the addition of growth media and the cells were then diluted appropriately for a new maintenance flask (0.8-0.9-106cells / flask) and experimental plates. For the experimental plates, Calu-3 cells were seeded in T12 permeable supports (1.12 cm2surface area), pre-coated with a collagen solution (18.9 pg / ml), with a seeding density of 0.9-105cells / well. The cells were incubated in an incubator (37°C, 5% CO2) with media change every second day until experimental use on day 16.

[0238] Evaluating the toxicity of Dexmedetomidine using the MTS-PMS assay

[0239] Following 2h exposure of Dex (see table 5 for volumes and concentrations) and Zymelin® (see table 6 for volumes), the relative cell viability was examined using the MTS-PMS assay. Briefly, the test solutions were removed, and the cells were washed twice with preheated PBS (37°C). 300 pL of MTS / PMS solution (240 pg / mL MTS, 4.8 pg / mL PMS in PBS) were added to each well and was incubated for 30-45 mins on a shaking table (50 RPM, 37°C). The absorbance was then measured at 492 nm using a FLUOstar OPTIMA plate reader (BMG Labtech, Ortenberg, Germany). As viable and dead cell control, wells of Calu-3 cells only exposed to PBS for 2h was used as the viable control, and the MTS / PMS start solution were used as the dead cell control (with no formation of the purple formazan). The relative percentage (%) viability of the cells was calculated using the following equation:

[0240] Where AAnalyteis the absorbance Calu-3 cells treated with the test solutions, Aviabieis the absorbance of Calu-3 cells only exposed to PBS and ADeadis the absorbance of the MTS / PMS start solution with no formazan formation.

[0241] Statistical analysis

[0242] Data analysis was performed in Microsoft Office Excel version 2501 (Microsoft, Redmond, WA, USA) and GraphPad Prism version 9.4.1 (Graphpad Software, San Diego, CA, USA) for unpaired T-test for statistical analysis and data plotting. Significant effects were considered on statistics with P<0,05. On data presentation, N was used to indicate the number of experimental repetition and n was used to indicate the number of individual replicates within the same experiment.

[0243] Results and discussion

[0244] Relevant clinical doses of Dexmedetomidine showed no significant local cell toxicity on Calu-3 cell monolayers compared to therapeutic doses of Zymelin® and the control tested cells

[0245] Evaluating the toxic effect on Calu-3 cell monolayers after 2h exposure to the test solutions (Zymelin® and Dex) (figure 1) showed no significant decrease in the percentage relative cell viability for the Dex solution up to concentrations of lOOOpg / ml (P>0,05).

[0246] Figure 2: Percentage (%) relative cell viability of Calu-3 cell monolayers seeded on T12 permeable supports exposed to Zymelin® in different volumes (150, 200, 300 and 400 pL) and Dexmedetomidine in different concentrations and volumes (300 pL 200 pg / ml, 400 pL 300 pg / ml, 150 pL 400 pg / ml, 200 pL 600 pg / ml, 150 pL 1000 pg / ml, 300 pL 1200 pg / ml and 400 pL 1200 pg / ml) for 2h. The % relative cell viability is calculated based on cells treated with PBS pH 6.5 only (CTR) and MTS / PMS base solution with no formazan formation (data not shown in figure). Results is presented as mean ± SEM, N=3, n=9. ns=non- significant, *:P=<0,05, ***:P=0,0002, ****:P=<0,0001.

[0247] Exceeding the 1000 pg / ml concentration mark began to affect the Celu-3 cell viability as indicated on figure 2, P=0,0015 and P=0,0002 for Dex (300 pL, 1200 pg / ml) and Dex (400 pL, 1200 pg / ml) respectively. Comparing relevant Zymelin® therapeutic doses (150 pL) with Dex (300 pL, 200 pg / ml) showed no significant difference (P>0,05).

[0248] It, however, became evident through visual observations that the Zymelin® test solutions affected the cells very differently compared to all the Dex test solutions. After 2h incubation, during the removal of especially the high volume Zymelin® test solutions (300 and 400 pL) it was observed that the Calu-3 cells were not well-attached to the surface of the permeable supports and could easily be removed by the sheer stress of moving liquids. This was indeed also true during the MTS / PMS assay, as the MTS / PMS solutions was not clear but in fact a bit cloudy when transferred for the absorbance measurements. These findings suggest that the Zymelin® formulation are negatively affecting the Calu-3 cells ability to adhere to the surface and keep the monolayer integrity and potentially also affect the Calu-3 cell viability after 2h incubation. These observations could explain the high viability variation observed for the Zymelin® test solutions encountered throughout this study (figure 2). The de-attachment of Calu-3 cell monolayers were not observed with any of the Dex test solutions and indeed suggest a promising potential for Dex formulations up to concentrations of 1000 pg / ml intended for nasal administration in paediatric patients.

[0249] Conclusion

[0250] In conclusion, solutions of dexmedetomidine (200 pg / ml, 300 pg / ml, 400 pg / ml, 600 pg / ml and 1000 pg / ml) in phosphate buffer pH 6.5 showed no significant local cell toxicity on Calu-3 cell monolayers compared to therapeutic doses of Zymelin® and the control.

[0251] References

[0252] 1. Dimova S, Brewster ME, Noppe M, Jorissen M, Augustijns P. The use of human nasal in vitro cell systems during drug discovery and development. Toxicol Vitr. 2005; 19(1): 107— 22.

[0253] 2. Inoue D, Furubayashi T, Tanaka A, Sakane T, Sugano K. Quantitative estimation of drug permeation through nasal mucosa using in vitro membrane permeability across Calu-3 cell layers for predicting in vivo bioavailability after intranasal administration to rats. Eur J Pharm Biopharm [Internet], 2020; 149(February): 145-53. Available from: https: / / doi.Org / 10.1016 / j.ejpb.2020.02.004

[0254] 3. Salade L, Wauthoz N, Goole J, Amighi K. How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods. Int J Pharm [Internet], 2019;561(Feb- ruary):47-65. Available from: https: / / doi.Org / 10.1016 / j.ijpharm.2019.02.026

[0255] 4. Furubayashi T, Inoue D, Nishiyama N, Tanaka A, Yutani R, Kimura S, et al. Comparison of various cell lines and three-dimensional mucociliary tissue model systems to estimate drug permeability using an in vitro transport study to predict nasal drug absorption in rats. Pharmaceutics. 2020; 12(1).

Claims

WE CLAIM:

1. A composition for intranasal administration to a human child by nasal spray comprising an aqueous solution of (a) dexmedetomidine or a salt thereof and (b) a buffer, wherein the buffer maintains pH from 4-7 in the solution.

2. The composition of claim 1 wherein the solution has a constant tonicity between 250-340 mOsm / kg .

3. The composition of claim 1 or 2 wherein (a) is a salt of dexmedetomidine, such as a HC1 salt of dexmedetomidine.

4. The composition of any one of claims 1-3 wherein the buffer is a phosphate buffer and / or a Citric acid buffer.

5. The composition of any one of claims 1-4 wherein the concentration of (a) is 200-800 pg / ml measured as the free base in the solution, such as the concentration of (a) is 200-600 pg / ml measured as the free base in the solution.

6. The composition of any one of claims 1-5 without any preservatives.

7. The composition of any one of claims 1-6 wherein the buffer maintains pH from 5.0-6.7 in the solution.

8. The composition of any one of claims 1-7 is storage stable and suitable for a nasal spray device.

9. The composition of any one of claims 1-8 comprising dexmedetomidine as the free base and an acid, typically hydrochloric acid.

10. The composition of any one of claims 1-9 for use in a method for sedation of a human child before anaesthesia.

11. The composition of any one of claims 1-10 for use in a method for reducing emergence agitation in a human child in a recovery period following anaesthesia.

12. A nasal spray device comprising the composition of any one of claims 1-11.

13. The nasal spray device of claim 12 adapted to deliver a dosing volume of 25-150 pl per actuation, typically 50-100 pl per actuation.

14. A nasal spray device comprising the composition of any one of claims 1-11 for use in a method for sedation of a human child before anaesthesia.

15. A nasal spray device comprising the composition of any one of claims 1-10 for reducing emergence agitation in a human child in a recovery period following anaesthesia.

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