New combination drug for pediatric use

Abstract

The present invention relates to an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and analogs, in solution. The present invention also relates to (a) an aqueous composition for intranasal administration by spray comprising sufentanil, its salts and / or analogs, in solution, and (b) an aqueous composition for intranasal administration by spray comprising ketamine, its salts and / or analogs, in solution, for use in a method for treating or preventing pain in children. The compositions are useful for treating or preventing pain in children 17 years of age or younger. The compositions are delivered from a nasal spray device to treat or prevent pain, such as procedural pain, in children.

Description

[Technical field]

[0001] The present invention relates to (a) an aqueous composition for intranasal administration by spray comprising sufentanil, its salts and / or analogues in solution, and (b) an aqueous composition for intranasal administration by spray comprising ketamine, its salts and / or analogues in solution. The combination of these compositions is useful in a method for the treatment or prevention of pain in children. In particular, the aqueous composition is for use in a method for the treatment or prevention of pain in children, and is administered by a nasal spray device. The present invention further relates to a pre-filled, ready-to-use nasal spray device, a kit of parts, and an emergency vehicle comprising the nasal spray device or the kit of parts. The present invention also relates to a method for treating or preventing pain in children. [Background technology]

[0002] Children attending hospitals experience painful procedures that can leave lasting negative impressions. Procedures range from simple venipuncture to more invasive procedures such as drainage tubes and burn dressing removal. Children who have experienced procedural pain once are more likely to have increased pain during future painful procedures (Blount et al). Furthermore, procedural pain in children is often underestimated and undertreated (Blount et al). Several drug options are available for pharmacological management, including opioids, nitrous oxide, and local anesthetics. However, pediatric formulations that allow for accurate dosing and are acceptable to children are often lacking.

[0003] Intranasal administration provides direct access to the systemic circulation and may be an acceptable route of administration for children (Hadley et al. and Kendall et al.). In children, intranasal midazolam (Rey et al.), sufentanil (Henderson et al.; Karl et al.; Absl et al.; and Zedie et al.), and ketamine (Absl et al.; Weber et al.; Weksler et al.; and Diaz et al.) have been used for anesthetic premedication, and combinations of sufentanil / midazolam or ketamine / midazolam have been used for anesthetic premedication and postoperative analgesia (Roelofse et al.). The analgesic effects of intranasal ketorolac (Drover et al.), diamorphine (Kendall et al.), and fentanyl (Borland et al.) have also been investigated in children.

[0004] According to Nielsen et al, Pediatric Anesthesia 24 (2014), “Intranasal Sufentanil / Ketamine analgesia in children”, p.170-180, there is a lack of pediatric formulations that are accurately dosed, acceptable to children, and have a rapid onset of analgesia. The authors concluded that sufentanil / ketamine nasal spray provides rapid analgesia with minor side effects for a variety of painful procedures and has promising characteristics for use in pediatric procedural pain management.

[0005] US2004092531 describes an active substance combination comprising as active substance component a) at least one opioid compound having a fentanyl type structure and / or its enantiomers and / or diastereomers and / or at least one corresponding pharma- ceutically acceptable salt, and as active substance component b) ketamine and / or at least one physiologically acceptable salt thereof. The weight ratio of active substance component a) to active substance component b) is in the range of 1:20 to 1:1500. The invention also relates to pharmaceutical preparations and medicaments comprising the active substance combination of the invention, as well as the use of said active substance combination for the manufacture of medicaments. There appears to be no disclosure of the combined use of sufentanil and ketamine at low doses and for the treatment of pain by intranasal administration in children.

[0006] US6825203 describes a topical pharmaceutical composition incorporating at least one local anesthetic and at least one opioid analgesic, and a method for providing pain relief to a subject through topical administration of the composition in an amount and for a period of time sufficient to synergistically enhance the antinociceptive response. In particular, disclosed is a topical pharmaceutical composition comprising: i) a topical dosage form selected from the group consisting of gels, lotions, creams, oils, emulsions, and ointments; and ii) a synergistically effective amount of morphine and lidocaine, the ratio of morphine to lidocaine being about 1:0.1 to about 1:2.4, with morphine in an amount ranging from about 0.01% to about 25% and lidocaine in an amount ranging from about 0.01% to about 25%. There appears to be no disclosure of a combination of sufentanil and ketamine in low doses for the treatment of pain in children by intranasal administration. Summary of the Invention [Problem to be solved by the invention]

[0007] The inventors have experienced that there exists an unmet medical need for the treatment or prevention of pain, particularly procedural pain, in children 17 years of age or younger. None of the available drugs and / or routes of administration are sufficient and in many respects do not actually solve the problem of pain in children. In particular, the problem of relieving pain in children who are in dire need of pain treatment but who do not have a facility such as a hospital or a doctor nearby who can obtain pain relief medication has been identified and solved. Furthermore, the combination of the present invention has a fast onset of therapeutic effect and does not require needles. Furthermore, the administration of pain relief medication to children, particularly children under the age of 2, usually requires that an authorized practitioner, such as a physician, be responsible for or at least supervise or monitor the administration of the pain relief medication, such as any of the above-mentioned drugs and routes of administration, even in an outpatient or emergency setting. The combination of the present invention is easy to administer and is absorbed directly into the systemic blood supply, avoiding hepatic first-pass metabolism. Furthermore, the dosage is titratable. [Means for solving the problem]

[0008] The present invention in one aspect relates to an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs, in solution. Preferably, (a) is sufentanil, such as sufentanil citrate, and (b) is ketamine, such as ketamine hydrochloride. Typically, (a) and (b) are present in a weight ratio (a):(b) of 1:5000 to 1:500, where the weights of (a) and (b) are calculated on the free compounds. The aqueous solution usually has a total volume of 25 μl to 5 ml, and the solution contains a buffer, such as a phosphate buffer, to maintain a pH of 4 to 8, for example 4 to 6 or 5 to 7. Sufentanil, calculated as the free base, is present in a concentration of 25 to 200 μg / ml, and ketamine, calculated as the free base, is present in a concentration of 25 to 200 mg / ml. The aqueous solutions are preferably sterile or contain preservatives added to the compositions.

[0009] In a further aspect, the present invention relates to a composition as described above for use in a method for the treatment or prevention of pain in a child. The composition is administered via a nasal spray device. When administered to a child, the dose volume is 0.05-0.5 ml, for example 0.05-0.1 ml, typically 1 or 2 dose volumes are administered to relieve pain. The child is preferably under 18 years of age, and the present invention is effective for children under 2 years of age, or under 1 year of age. Children may vary in weight, but the present invention is effective for children weighing less than 60 kg.

[0010] In a further aspect, the present invention relates to a pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution, such as any one of the embodiments of the composition described above. In particular, the pre-filled, ready-to-use nasal spray device is suitable for use in emergency vehicles, such as ambulances, and may be handled by emergency medical personnel. When present in an emergency vehicle, the pre-filled, ready-to-use nasal spray device is pre-assembled and included in a kit of parts along with packaging.

[0011] In a further aspect, the present invention relates to a kit of parts comprising a pre-filled, ready-to-use nasal spray device as described above and packaging.

[0012] Additionally, such pre-filled, ready-to-use nasal spray devices or kits of parts may be carried in emergency vehicles, such as ambulances, and handled by emergency medical personnel without medical supervision.

[0013] In a further aspect, the present invention relates to a method of treating or preventing pain in a child comprising administering to the child from a pre-filled, ready-to-use nasal spray device an effective amount of an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogues, and (b) ketamine, its salts and / or analogues in solution. In particular, the pre-filled, ready-to-use nasal spray device is located in an emergency vehicle, typically an ambulance.

[0014] In a further aspect, the present invention relates to an aqueous composition for intranasal administration by spray comprising (a) sufentanil, a salt and / or analogue thereof, in solution, and (b) ketamine, a salt and / or analogue thereof, in solution, for use in a method for the treatment or prevention of pain in a child.

[0015] In a further aspect, the present invention relates to a pre-filled, ready-to-use nasal spray device comprising the composition of the present invention.

[0016] In a further aspect, the present invention relates to a pre-filled, ready-to-use nasal spray device comprising the composition of the present invention for use in emergency vehicles, such as ambulances.

[0017] In yet another aspect, the present invention relates to a kit of parts comprising a pre-filled, ready-to-use nasal spray device containing the composition of the present invention and packaging.

[0018] In a further aspect, the invention relates to an emergency vehicle equipped with a pre-filled, ready-to-use nasal spray device comprising the composition of the invention, or a kit of parts comprising a pre-filled, ready-to-use nasal spray device comprising the composition of the invention and packaging.

[0019] In a further aspect, the present invention relates to a method of treating or preventing pain in a child comprising administering to the child an effective amount of a composition of the present invention from a pre-filled, ready-to-use nasal spray device comprising the composition of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description In a broad aspect, the present invention relates to an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogues, and (b) ketamine, its salts and / or analogues, in solution.

[0021] The term "aqueous composition" as used herein means a liquid composition in which the carrier is water, such as sterile water. Herein, other additive(s) may be added that may be required depending on the drug to be dissolved, such as solubility enhancer(s), preservative(s), etc.

[0022] As used herein, the term "intranasal administration by spray" refers to administration of an aqueous composition, such as the above mixture of (a) and (b) in solution, or the above mixture of (a) in solution and (b) in solution from separate containers, to the nostrils of a human subject via a spraying means, such as a nozzle or tip, capable of blowing the composition into the nostrils as small droplets.

[0023] As used herein, the term "a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution" means that (a) and (b) are combined together and dissolved in water. Thus, the solution contains both (a) and (b), but one solution does not contain (a) and another solution contains (b).

[0024] The term "(a) sufentanil, its salts and / or analogs" as used herein means sufentanil, a salt of sufentanil, an analog of sufentanil, or an analog of a salt of sufentanil, or a mixture of two or more thereof. Sufentanil has the systematic (IUPAC) name N-[4-(methoxymethyl)-1-(2-thiofuran-2-ylethyl)-4-piperidyl]-N-phenylpropanamide and is a well-known drug as a pain reliever. The salt of sufentanil may be any acid salt, such as an inorganic salt or an organic salt, and is preferably a pharma- ceutically acceptable acid addition salt, such as a citrate salt. An analog of sufentanil or its salt is a compound that has a pain-relieving effect similar to that of sufentanil. One of the analogs of sufentanil is fentanyl, which has the systematic (IUPAC) name N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide and is well-known as a pain reliever. Another analog of sufentanil is alfentanil, which has the systematic (IUPAC) name N-{1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetrazol-1-yl)ethyl]-4-(methoxymethyl)piperidin-4-yl}N-phenylpropanamide and is well known as a pain relieving agent. Solvates, such as hydrates, of the above compounds or salts are also understood to be included in this term.

[0025] The term "(b) ketamine, its salts and / or analogs" as used herein means ketamine, a salt of ketamine, an analog of ketamine, an analog of a salt of ketamine, or a mixture of two or more thereof. Ketamine has the systematic (IUPAC) name (RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and is well known as an anesthetic and analgesic. The salt of ketamine may be any acid salt, such as an inorganic salt or an organic salt, and is preferably a pharma- ceutically acceptable acid addition salt, such as hydrochloride. An analog of ketamine or its salt is a compound having an anesthetic action similar to ketamine. One analog of ketamine is S-ketamine, which has the systematic (IUPAC) name (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and is a well known anesthetic. Solvates, such as hydrates, of the above compounds or salts are also understood to be included in this term.

[0026] In one embodiment, (a) and (b) are present in a weight ratio (a):(b) of 1:5000 to 1:500, where the weights of (a) and (b) are calculated on the free compounds. In a further embodiment, the weight ratio (a):(b) is about 1:4000 to 1:750. In another embodiment, the weight ratio (a):(b) is about 1:2000 to 1:750. Typically, the weight ratio (a):(b) is about 1:1000.

[0027] In a further embodiment, (a) is sufentanil or a salt thereof. Typically, (a) is a pharma- ceutically acceptable acid addition salt of sufentanil. Preferably, (a) is sufentanil citrate.

[0028] In a further embodiment, (a) is fentanyl or a salt thereof. Typically, (a) is a pharma- ceutically acceptable acid addition salt of fentanyl. Preferably, (a) is fentanyl citrate.

[0029] In a further embodiment, (a) is alfentanil or a salt thereof. Typically, (a) is a pharma- ceutically acceptable acid addition salt of alfentanil. Preferably, (a) is alfentanil hydrochloride.

[0030] In a further embodiment, (b) is ketamine or a salt thereof. Typically, (b) is a pharma- ceutically acceptable acid addition salt of ketamine. Preferably, (b) is ketamine hydrochloride.

[0031] In a further embodiment, (b) is S-ketamine or a salt thereof. Typically, (b) is a pharma- ceutically acceptable acid addition salt of S-ketamine. Preferably, (b) is S-ketamine hydrochloride.

[0032] In a further embodiment, the composition of the invention has a volume of 25 μl to 5 ml, for example a volume of 50 μl to 5 ml. Typically, the volume is 0.1 to 2 ml. Preferably, the volume is 0.5 to 2 ml, for example 1 ml.

[0033] As used herein, the term "volume" refers to the combined volume of liquid water, dissolved compounds such as sufentanil or ketamine, and optionally any additives dissolved therein, such as buffers. Thus, undissolved compounds or other additives are not considered part of the volume.

[0034] In a further embodiment, the solution comprises a buffer. The buffer is capable of maintaining the pH at a constant level, for example a pH between 4 and 8. Thus, for example, the pH may be 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8, typically 5.5 to 6.5, for example about 4 to 6. The buffer may be any suitable buffer, such as a phosphate buffer or a citrate buffer.

[0035] In a further embodiment, the concentration of (a) is 25-200 μg / ml. Typically, the concentration of (a) is 40-150 μg / ml, for example, 40-100 μg / ml, for example, 50-70 μg / ml. In a further embodiment, the concentration of (a) is 65-85 μg / ml. In a further embodiment, the concentration of (a) is 80-100 μg / ml. In a further embodiment, the concentration of (a) is 140-160 μg / ml.

[0036] In a further embodiment, the concentration of (b) is 25-200 mg / ml. Typically, the concentration of (b) is 40-150 mg / ml, such as 40-100 mg / ml, for example 50-70 mg / ml. In a further embodiment, the concentration of (b) is 65-85 mg / ml. In a further embodiment, the concentration of (b) is 80-100 mg / ml. In a further embodiment, the concentration of (b) is 140-160 mg / ml.

[0037] In a further embodiment, the compositions of the invention further comprise additional pharma- ceutically acceptable additives, such as preservatives. Alternatively, the compositions of the invention may also be sterilized to provide a sterile composition.

[0038] In a further aspect, the invention relates to an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution for use in a method for the treatment or prevention of pain in a child. The above-mentioned embodiments for the composition also apply to this aspect. In a further embodiment, the composition is administered via a nasal spray device, such as a pre-filled, ready-to-use nasal spray device. In a further embodiment, a dosage volume of 0.05-0.5 ml is administered to a nostril of a human subject. Typically, the dosage volume is 0.05-0.1 ml. In a further embodiment, a dosage volume of 0.05-0.3 ml is administered once. In another embodiment, a dosage volume of 0.05-0.3 ml is administered twice, typically 10 minutes apart, to each nostril. In a further embodiment, the composition of the invention is for use in a method for preventing pain in a child. In a further embodiment, the pain is procedural pain. In yet another embodiment, the pain is acute pain. In further embodiments, the pain is treated acute pain. In yet another embodiment, the child is 17 years old or younger. In certain embodiments, the child is less than 2 years old, such as less than 1 year old, for example, between 3 and 6 months old. In further embodiments, the child weighs less than 60 kg. In some embodiments, the child weighs less than 50 kg, such as less than 35 kg, less than 25 kg, less than 10 kg, all of which constitute individual embodiments of the present invention.

[0039] The term "nasal spray device" as used herein means any device adapted to spray a liquid solution into the nostrils of a human subject, which device is airtight when assembled. In particular, as used herein, a "pre-filled, ready-to-use nasal spray device" means a nasal spray device having a body portion containing the composition of the present invention and a pump system having a nozzle or other spraying feature for administration via the nasal delivery route, which device is typically assembled (i.e., pre-assembled) and ready for immediate use in a human subject, particularly a child. Furthermore, a "pre-filled, ready-to-use 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, e.g., one month, three months, or one year, and can be used immediately, e.g., by a paramedic in an ambulance. The device can be used, e.g., by a paramedic, without the need for an authorized practitioner, such as a doctor. The device can also be a kit of parts including a body portion holding the composition of the present invention, e.g., a glass bottle with a thread or snap means, and a pump system for spraying, which pump system is adapted to provide a nasal spray device that can be stored in a closed and airtight manner. Examples of such pump systems for use as part of a device are available from Aptar Pharma, part of the Aptar Group, e.g., the CPS Vented Dip Tube (Multi-Use Spray Pump), (see, e.g., http: / / www.aptar.com / pharma / prescription-division / products / CPS). The Aptar Group holds the intellectual property for these pump systems suitable for intranasal administration. For example, the body portion may be a glass container and may consist of one chamber that holds a solution of the mixture of (a) and (b), or two separate chambers, one that holds (a) in solution and the other that holds (b) in solution.

[0040] As used herein, the term "dose volume" refers to the liquid dose volume, including water and a composition including active compounds, such as sufentanil and ketamine, delivered from the device to the nostril. A typical dose volume is 0.05-0.5 ml, for example, 0.05-0.1 ml.

[0041] The term "pediatric pain" as used herein means pain of any origin in children aged 17 years or younger. Preferably, the pain is procedural pain, acute pain, or both. Examples of procedural pain are pain caused by a medical or diagnostic procedure, such as drawing blood, placing peripheral venous access, placing a nasogastric tube, reducing a fracture, suturing a small laceration, removing a chest or other drain, etc. Examples of acute pain are acute pain in children and adolescents aged 1 to 18 years in hospital or prehospital settings, surgery pain, dental pain, burn pain, pain from a medical or diagnostic procedure, pain from trauma in prehospital settings, etc.

[0042] The terms "treatment" and "treating" as used herein refer to the management and care of a pediatric subject for the purposes of treatment and / or combating pain, such as acute pain. The terms are intended to include the full range of treatments for a given condition suffered by a patient, including, for example, the administration of an active compound to alleviate pain, particularly procedural pain or acute pain or both, as well as to prevent pain. Prevention here can be understood as the management and care of a pediatric subject to alleviate or eliminate pain, including the administration of an active compound to prevent the onset of pain.

[0043] In a further aspect, the present invention relates to a pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray, the aqueous composition comprising a mixture of (a) sufentanil, its salts and / or analogues, and (b) ketamine, its salts and / or analogues in solution. The above-mentioned embodiments relating to the composition also apply to this aspect. In a further embodiment, the pre-filled, ready-to-use nasal spray device of the present invention is for use in an emergency vehicle, such as an ambulance.

[0044] In a further aspect, the present invention relates to a kit of parts comprising a pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray, the composition comprising a mixture of (a) sufentanil, its salts and / or analogues, and (b) ketamine, its salts and / or analogues in solution, and packaging, in which the embodiments described above for the composition also apply.

[0045] In a further aspect, the present invention relates to an emergency vehicle comprising a pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogues, and (b) ketamine, its salts and / or analogues in solution, and optionally packaging. The embodiments described above for the composition also apply in this aspect.

[0046] In a further aspect, the present invention relates to a method of treating or preventing pain in a child comprising administering to the child an effective amount of an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution from a pre-filled, ready-to-use nasal spray device of the present invention. In a further embodiment, a pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution is placed in an emergency vehicle, such as an ambulance. In a further embodiment, the pre-filled, ready-to-use nasal spray device comprising an aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil, its salts and / or analogs, and (b) ketamine, its salts and / or analogs in solution is handled by a paramedic. The embodiments relating to the composition described above also apply to this aspect.

[0047] In a further aspect, the invention relates to an aqueous composition for intranasal administration by spray comprising (a) sufentanil, its salts and / or analogues in solution. In one embodiment, (a) is sufentanil or a salt thereof. Typically, (a) is a pharmaceutically acceptable acid addition salt of sufentanil. Preferably, (a) is sufentanil citrate. In a further embodiment, (a) is fentanyl or a salt thereof. Typically, (a) is a pharmaceutically acceptable acid addition salt of fentanyl. Preferably, (a) is fentanyl citrate. In a further embodiment, (a) is alfentanil or a salt thereof. Typically, (a) is a pharmaceutically acceptable acid addition salt of alfentanil. Preferably, (a) is alfentanil hydrochloride. In a further embodiment, the composition of the invention has a volume of between 25 μl and 5 ml. Typically, the volume is between 0.1 and 2 ml. Preferably, the volume is 0.5-2 ml, for example 1 ml. In a further embodiment, the solution comprises a buffer. The buffer is capable of maintaining the pH at a constant level, for example a pH between 4 and 8. Thus, for example, the pH may be 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8, typically 5.0-6.5, for example about 6. The buffer may be any suitable buffer, such as a phosphate buffer or a citrate buffer. In a further embodiment, the concentration of (a) is 25-200 μg / ml. Typically, the concentration of (a) is 40-150 μg / ml, for example 40-100 μg / ml, for example 50-70 μg / ml. In a further embodiment, the concentration of (a) is 65-85 μg / ml. In a further embodiment, the concentration of (a) is 80-100 μg / ml. In a further embodiment, the concentration of (a) is 140-160 μg / ml. In a further embodiment, the compositions of the invention further comprise additional pharma- ceutically acceptable additives, such as preservatives. Alternatively, the compositions of the invention may also be sterilized to provide a sterile composition.

[0048] In a further aspect, the present invention relates to an aqueous composition for intranasal administration by spray comprising (b) ketamine, its salts and / or analogues in solution. In one embodiment, (b) is ketamine or a salt thereof. Typically, (b) is a pharma- ceutically acceptable acid addition salt of ketamine. Preferably, (b) is ketamine hydrochloride. In a further embodiment, (b) is S-ketamine or a salt thereof. Typically, (b) is a pharma- ceutically acceptable acid addition salt of S-ketamine. Preferably, (b) is S-ketamine hydrochloride. In a further embodiment, the composition of the present invention has a volume of 25 μl to 5 ml. Typically, the volume is 0.1 to 2 ml. Preferably, the volume is 0.5 to 2 ml, for example 1 ml. In a further embodiment, the solution comprises a buffer. The buffer is capable of maintaining the pH at a constant level, for example a pH between 4 and 8. Thus, for example, the pH may be 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8, typically 5.0 to 6.5, for example about 6. The buffer may be any suitable buffer, such as a phosphate buffer or a citrate buffer. In a further embodiment, the concentration of (b) is 25 to 200 mg / ml. Typically, the concentration of (b) is 40 to 150 μg / ml, such as 40 to 100 μg / ml, for example 50 to 70 μg / ml. In a further embodiment, the concentration of (b) is 65 to 85 mg / ml. In a further embodiment, the concentration of (b) is 80 to 100 mg / ml. In a further embodiment, the concentration of (b) is 140 to 160 mg / ml. In a further embodiment, the composition of the invention further comprises an additional pharma- ceutically acceptable additive, such as a preservative. Alternatively, the composition of the invention may be sterilized to provide a sterile composition.

[0049] In a broader aspect, the present invention relates to (a) an aqueous composition comprising sufentanil, its salts and / or analogues in solution for intranasal administration by spray, and (b) an aqueous composition comprising ketamine, its salts and / or analogues in solution for intranasal administration by spray, for use in a method for the treatment or prevention of pain in a child.

[0050] It should be clear that although the experiments herein are carried out by using mixtures of (a) and (b) in solution, such mixtures can be carried out after (a) and (b) exit the spray for intranasal administration, or can be carried out in a mixing chamber as part of a device for intranasal administration by spray, or even from separate nasal spray devices, one containing (a) and another containing (b).

[0051] In an embodiment, the composition is administered via a pre-filled, ready-to-use nasal spray device. In a further embodiment, the device comprises a first chamber for (a) and a second chamber for (b). In a further embodiment, the device comprises an additional chamber for mixing (a) and (b) prior to intranasal administration by spray. In another embodiment, the device is configured to deliver (a) and (b) separately and simultaneously by intranasal administration by spray.

[0052] In this respect, the embodiments described above for the aqueous composition comprising (a) or (b) also apply, In a further embodiment, the composition is administered via a nasal spray device, for example a pre-filled, ready to use nasal spray device, typically a pre-assembled, pre-filled, ready to use nasal spray device.

[0053] In a further embodiment, a dose volume of 0.05-0.5 ml including (a) and a dose volume of 0.05-0.5 ml including (b) are administered to a nostril of a human subject. Typically, the dose volume is 0.05-0.3 ml including (a). Typically, the dose volume is 0.05-0.3 ml including (b). In a further embodiment, a dose volume of 0.05-0.1 ml including (a) and a dose volume of 0.05-0.1 ml including (b) are administered once. In another embodiment, a dose volume of 0.05-0.1 ml including (a) and a dose volume of 0.05-0.1 ml including (b) are administered twice, typically 10 minutes apart, to each nostril. In a further embodiment, the composition of the invention is for use in a method for preventing pain in a child. In a further embodiment, the pain is procedural pain. In yet another embodiment, the pain is acute pain. In a further embodiment, the pain is procedural acute pain. In further embodiments, the child is 17 years of age or younger, e.g., less than 17 years of age. In certain embodiments, the child is less than 2 years of age, e.g., less than 1 year of age, e.g., between 3 and 6 months of age. In further embodiments, the child weighs less than 60 kg. In some embodiments, the child weighs less than 50 kg, e.g., less than 35 kg, less than 25 kg, less than 10 kg, all of which constitute individual embodiments of the present invention.

[0054] In a further aspect, the present invention relates to a pre-filled, ready to use nasal spray device comprising (a) an aqueous composition for intranasal administration by spray comprising sufentanil, its salts and / or analogues thereof in solution, and (b) an aqueous composition for intranasal administration by spray comprising ketamine, its salts and / or analogues thereof in solution. In an embodiment, the pre-filled, ready to use nasal spray device is for use in an emergency vehicle, such as an ambulance. The above-mentioned embodiments for the composition also apply to this aspect.

[0055] In a further aspect, the present invention relates to a kit of parts comprising the pre-filled, ready-to-use nasal spray device of the present invention and packaging. The above-mentioned embodiments for the composition also apply to this aspect.

[0056] In a further aspect, the present invention relates to an emergency vehicle comprising a pre-filled, ready-to-use nasal spray device of the present invention or a kit of parts of the present invention. The embodiments described above for the composition also apply in this aspect.

[0057] In a further aspect, the present invention relates to a method for treating or preventing pain in a child comprising administering to the child an effective amount of (a) an aqueous composition for intranasal administration by spray comprising sufentanil, its salts and / or analogues thereof in solution, and (b) an aqueous composition for intranasal administration by spray comprising ketamine, its salts and / or analogues thereof in solution from a pre-filled, ready to use nasal spray device of the present invention. In an embodiment, the pre-filled, ready to use nasal spray device of the present invention is located in an emergency vehicle. In a further embodiment, the pre-filled, ready to use nasal spray device of the present invention is handled by emergency medical personnel.

[0058] Further embodiments of the processes are described in the experimental section herein, with each individual process as well as each starting material constituting an embodiment that may form part of an embodiment.

[0059] The above embodiments should be considered to refer to any one of the embodiments described herein, as well as any one of the aspects described herein (such as "methods for treatment," "pharmaceutical compositions," or "compositions for use in methods"), unless it is specified that the embodiment relates to a particular aspect or aspects of the invention.

[0060] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each individual reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0061] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0062] 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.

[0063] As used in the context of describing the invention, the terms "a," "an," "the," and similar references are intended to be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0064] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range, unless otherwise stated herein, and each separate numerical value is incorporated herein as if set forth individually herein. Unless otherwise indicated, all precise values ​​provided herein represent corresponding approximations (e.g., all precise exemplary values ​​provided with respect to a particular coefficient or measurement can also be considered to provide corresponding approximation measurements, modified by "about" as appropriate).

[0065] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0066] The use of any and all examples or exemplary language (e.g., "for example," "etc.") provided herein is intended merely to facilitate a better understanding of the invention and does not pose a limitation on the scope of the invention unless specifically stated otherwise. No language in the specification should be construed as indicating any element as essential to the practice of the invention unless expressly stated.

[0067] Citation and incorporation of patent documents herein is done for convenience only and does not reflect any opinion regarding the validity, patentability, and / or enforceability of such patent documents.

[0068] A 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 similar aspects or embodiments of the invention that "consists of," "consists essentially of," or "substantially comprises" that particular element, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0069] This invention includes all modifications and equivalents of the subject matter recited in the embodiments or claims presented herein to the maximum extent permitted by applicable law.

[0070] The present invention is further illustrated by the following examples, which should not 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. EXAMPLES

[0071] experiment Four different strengths / concentrations of formulations are prepared for use in clinical trials. Aqueous compositions of a) sufentanil and (b) ketamine in phosphate buffer are prepared by 1) dissolving (c) NaH2PO4 and Na2HPO4 in purified water followed by sterilization in an autoclave at 121°C (249°F) with high pressure saturated steam, 2) dissolving the relevant contents of (a) and (b) in (c), and (d) filtering the solution of (a)+(b)+(c) through a 0.22 μm filter and filling into nasal spray device vials or bottles. The container closure system used for this product is a mechanical multi-drug nasal spray device. It consists of a vent pump (Aptar Pharma nasal spray device (see e.g., http: / / www.aptar.com / pharma / prescription-division / products / CPS) or equivalent) and a pediatric actuator attached to a 3 ml glass V-bottom bottle (u-save bottle "SGD Pharma" or equivalent). The pump dose volume is 100 microliters. This intranasal formulation (d) is being used in a clinical trial with 50 pediatric patients aged 1-18 years. The study is designed to investigate the pharmacokinetics, analgesic efficacy, and safety of the intranasal formulation (d) for procedural pain in children using Aptar Pharma's nasal spray device (see, for example, http: / / www.aptar.com / pharma / prescription-division / products / CPS). The prefilled, ready-to-use nasal spray in two strengths / concentrations with pump dose volumes of 50 or 100 microliters (Table 1) will be tested during clinical development including the following clinical trial plans in which (d) will be used: 1) Safety, feasibility, and efficacy study with 300 pediatric patients aged 1-18 years in a prehospital setting; In this study, a single dose of intranasal sufentanil / ketamine was administered, with target doses of 0.5 μg / kg sufentanil and 0.5 mg / kg ketamine, which could be repeated 10-15 minutes later if sufficient analgesia was not achieved.2) An ancillary safety study is being conducted to evaluate the safety and tolerability of intranasal sufentanil / ketamine using retrospective data from 10 years of routine clinical practice in children aged 1-17 years who require analgesia / sedation with intranasal administration of sufentanil and / or s-ketamine injections for procedural pain / sedation. In this non-interventional study, data from approximately 3000 medical procedures are available, with intranasal doses of sufentanil at approximately 0.5 μg / kg and / or s-ketamine at approximately 0.5 mg / kg. 3) A bioavailability study to evaluate the absolute bioavailability of intranasal sufentanil / ketamine in 13 healthy volunteers. The study is designed as a randomized, open-label, single-dose, three-period crossover study administering doses of intranasal sufentanil 10 μg / ketamine 10 mg, intravenous sufentanil 10 μg or intravenous ketamine 10 mg. 4) An efficacy, concentration-effect and dose-response study in 220 patients undergoing third molar extraction to evaluate the effect of intranasal sufentanil / ketamine combination versus intranasal sufentanil or intranasal ketamine or placebo, and to evaluate the concentration-effect relationship. A randomized, double-blind, 4-arm (principal intervention), 2-dose (1-hour interval) parallel-group design. 5) A pharmacokinetic study in 25 pediatric patients aged 1-2 years undergoing elective surgery and requiring pre-anesthetic premedication. This open-label study will administer a single dose of intranasal sufentanil / ketamine and target doses of intranasal sufentanil / ketamine of 0.5-0.7 μg / kg sufentanil and 0.5-0.7 mg / kg ketamine (target dose) as premedication to evaluate estimates of pharmacokinetic parameters in this age group.

[0072] [Table 1]

[0073] References 1) Blount RL, Piira T, Cohen LL, et al. Pediatric procedural pain. Behav Modif 2006;30:24-49 2) Hadley G, Maconochie I, Jackson AA. Survey of intranasal medication use in the paediatric emergency setting in England and Wales. Emerg Med J 2010;27:553-554. 3) Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001;322:261-265. 4) Rey E, Delaunay L, Pons G, et al. Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol 1991;41:355-357. 5) Henderson JM, Brodsky DA, Fisher DM, et al. Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil. Anesthesiology 1988;68:671-675. 6) Karl HW, Keifer AT, Rosenberger JL, et al. Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients. Anesthesiology 1992;76:209-215 7)Abrams R, Morrison JE, Villasenor A, et al.Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures.Anesth Prog 1993;40:63-66 8) Zedie N, Amory DW, Wagner BK, et al. Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther 1996;59:341-3488) 9) Weber F, Wulf H, el Saeidi G. Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children. Can J Anaesth 2003;50:470-475 10) Weksler N, Ovadia L, Muati G, et al. Nasal ketamine for paediatric premedication. Can J Anaesth 1993;40:119-121. 11) Diaz JH. Intranasal ketamine preinduction of paediatric outpatients. Paediatr Anaesth 1997;7:273-278. 12) Roelofse JA, Shipton EA, de la Harpe CJ, et al. Intranasal sufentanil / midazolam versus ketamine / midazolam for analgesia / sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog 2004;51:114-121 13) Drover DR, Hammer GB, Anderson BJ. The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients. Anesth Analg 2012;114:1270-1276. 14) Borland M, Jacobs I, King B, et al. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49:335-340 15) Nielsen et al, Pediatric Anesthesia 24 (2014), “Intranasal Sufentanil / Ketamine analgesia in children”, p.170-180 (Intranasal Sufentanil / Ketamine analgesia in children)

Claims

1. 1. An aqueous composition for intranasal administration by spray comprising a mixture of (a) sufentanil or a salt thereof, and (b) ketamine or a salt thereof, in solution, wherein the solution comprises a buffer that maintains a pH between 4 and 8.

2. 2. The composition of claim 1, wherein (a) and (b) are present in a weight ratio (a):(b) of 1:5000 to 1:500, wherein the weights of (a) and (b) are calculated on the free compounds.

3. The composition of claim 2, wherein (a) and (b) are present in a weight ratio (a):(b) of about 1:1000.

4. 4. The composition of any one of claims 1 to 3, wherein (a) is sufentanil citrate and (b) is ketamine hydrochloride.

5. The composition according to any one of claims 1 to 4, having a volume of from 25 μl to 5 ml.

6. The composition described in claim 5 having a volume of 1 to 2 ml.

7. The composition of any one of claims 1 to 6, wherein the solution comprises a buffer that maintains a pH of from 4 to 6.

8. The composition described in claim 7, wherein the buffer is a phosphate buffer or a citrate buffer.

9. The composition according to any one of claims 1 to 8, wherein the concentration of (a) is from 25 to 200 µg / ml and the concentration of (b) is from 25 to 200 mg / ml.

10. 10. The composition according to claim 9, wherein the concentration of (a) is 50 to 70 μg / ml and the concentration of (b) is 50 to 70 mg / ml.

11. The composition of claim 10, wherein the concentration of (a) is 60 μg / ml and the concentration of (b) is 60 mg / ml.

12. 10. The composition of claim 9, wherein the concentration of (a) is 80-100 μg / ml and the concentration of (b) is 80-100 mg / ml.

13. The composition of claim 12, wherein the concentration of (a) is 90 μg / ml and the concentration of (b) is 90 mg / ml.

14. A composition according to any one of claims 1 to 13 for use in a method for the treatment or prevention of pain in children.

15. The composition of claim 14, wherein the composition is administered via a nasal spray device.

16. The composition of claim 15, wherein the nasal spray device is a pre-filled, ready-to-use nasal spray device.

17. The composition of any one of claims 14 to 16, wherein a dosage volume of the composition of 0.05 to 0.5 ml is administered.

18. A composition according to any one of claims 14 to 17 for use in a method for preventing pain in children.

19. The composition according to any one of claims 14 to 18, wherein the pain is procedural pain.

20. The composition of claim 19, wherein the procedural pain is procedural pain selected from pain caused by a medical procedure or a diagnostic procedure.

21. The composition of claim 20, wherein the medical or diagnostic procedure is drawing blood, placing peripheral venous access, placing a nasogastric tube, reducing a fracture, suturing a small laceration, or removing a chest or other drain.

22. The composition according to any one of claims 14 to 21, wherein the pain is acute pain.

23. The composition of claim 22, wherein the acute pain is selected from surgical pain, dental pain, burn pain, pain caused by a medical or diagnostic procedure, pain in a pre-hospital setting, or acute pain in children and adolescents aged 1 to 18 years in a hospital or pre-hospital setting.

24. The composition described in claim 23, wherein the pain in the pre-hospital setting is pain caused by a traumatic injury in the pre-hospital setting.

25. A pre-filled, ready to use nasal spray device comprising a composition according to any one of claims 1 to 13.

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