Nasal soft mist delivery device, method and use

Abstract

The application discloses a nasal cavity soft mist drug delivery device, method and application, relates to the technical field of drug delivery, and comprises a drug delivery main body and a spray adapter. The method comprises the following steps: assembling the drug delivery main body and the spray adapter; placing or inverting the assembled device, and inserting the top end of the spray adapter into the nasal cavity; and extruding the cavity filled with air of the drug delivery main body, so that the drug generates soft mist through a micropore chip built in the spray adapter, and the soft mist enters the nasal cavity to deliver the drug. The nasal cavity soft mist drug delivery device can be applied to rhinitis, allergy, vomiting and central nervous system related indications. The single-dose sterile solution or suspension liquid without preservatives produced through blowing, filling and sealing can be efficiently and rapidly atomized into slow-moving soft mist, the atomized liquid droplets are small in size and uniform in distribution, and can be diffused and deposited in all intranasal regions.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of drug delivery, in particular to a nasal soft mist drug delivery device, method and application. BACKGROUND

[0002] The human intranasal drug delivery area can be roughly divided into five parts, which are region one olfactory area, region two middle turbinate, region three inferior turbinate, region four nasopharyngeal area and region five nasal vestibule. For many years, due to the influence of local drug delivery mechanism and the particle size and speed of the drug spray of the nasal drug delivery device, the action area of the nasal spray is mainly concentrated in the nasal vestibule, and the treatment field of the nasal spray is mainly concentrated in the field of rhinitis and allergy, and the drugs are mainly antihistamines and hormones. With the in-depth study of intranasal drug delivery area, drugs can enter the central nervous system through the nasal-brain drug delivery pathway, and the treatment field of the nasal spray is expected to expand to vomiting and central nervous system, such as headache (including migraine), epilepsy, Parkinson's disease, Huntington's disease, Alzheimer's disease, motion sickness, cerebrovascular disease (including stroke and cerebral infarction, etc.), traumatic brain injury, spinal cord injury, anxiety, depression, insomnia, drowsiness, neuroinfection and neuroimmunity (including meningitis, AIDS, cerebral malaria and multiple sclerosis, etc.), neurodevelopmental disorders, schizophrenia, brainstem glioma, opioid addiction, dry eye syndrome and attention deficit hyperactivity disorder (ADHD) and other diseases.

[0003] The key technical difficulty of the drug entering the central nervous system through the nasal-brain drug delivery pathway is that the drug needs to be atomized into a soft mist with a certain particle size range in the nasal cavity. The liquid droplet particle size distribution range of the spray device of the various nasal sprays on the market is relatively wide, most of the liquid droplet particle size is greater than 50 μm, and the drug liquid spray speed is fast, which leads to a large amount of drug liquid droplets deposited in the nasal vestibule area during drug delivery, and the coverage of the remaining functional areas is very low, which greatly affects the bioavailability of the drug, and seriously affects the efficacy of the nasal spray for central nervous system indications. In addition, most of the various nasal sprays on the market are multi-dose systems, and bacteriostatic agents need to be added in the drug liquid to ensure the sterility during the use of the drug, and the irritation of the bacteriostatic agent limits the use of the nasal spray in sensitive patients, elderly patients and infant patients. Therefore, single-dose sterile nasal sprays without preservatives have significant compliance advantages and broad market prospects.

[0004] Therefore, a nasal soft mist drug delivery method and device are being developed, capable of atomizing liquid drugs into soft mist with small particle size (5-500μm), uniform distribution, and slow movement. This expands the nasal delivery area from the nasal vestibule to the olfactory region, middle turbinate, inferior turbinate, and nasopharynx, significantly improving the bioavailability of various central nervous system nasal spray drugs. It also expands the indications for nasal delivery to include conditions such as vomiting, headache (including migraine), epilepsy, Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, motion sickness, cerebrovascular diseases (including stroke and cerebral infarction), traumatic brain injury, spinal cord injury, anxiety, depression, insomnia, somnolence, neuroinfections and neuroimmunological diseases (including meningitis, AIDS, cerebral malaria, and multiple sclerosis), neurodevelopmental disorders, schizophrenia, encephalomalacia, opioid addiction, dry eye syndrome, and attention deficit hyperactivity disorder (ADHD). In addition, preservative-free single-dose nasal sprays ensure compliance and portability for sensitive patients, elderly patients, and infants. Summary of the Invention

[0005] This invention addresses the problems existing in the prior art by providing a nasal soft mist delivery method and device.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for administering a soft mist through the nasal cavity includes the following steps:

[0008] Step 1: Assemble the drug delivery unit and the spray adapter;

[0009] Step 2: Place the assembled device flat or upside down, and insert the tip of the spray adapter into the nasal cavity;

[0010] Step 3: Squeeze the flat or inverted drug delivery unit, which has an air-filled cavity. The drug is delivered into the nasal cavity by generating a soft mist through the microporous chip built into the spray adapter.

[0011] Based on the above technical solution, the drug delivery body is a structure containing a drug produced by blow-fill-seal, and the drug is a single-dose sterile solution or suspension without preservatives.

[0012] Based on the above technical solution, the generated soft mist particle size range is 5-500μm, preferably 20-150μm.

[0013] Based on the above technical scheme, further, the drug includes various nasal spray drugs for allergy and rhinitis, various nasal spray drugs for vomiting, various nasal spray drugs for headache (including migraine), various drugs for epilepsy, various drugs for Parkinson's disease, various drugs for Huntington's disease, various drugs for amyotrophic lateral sclerosis, various drugs for Alzheimer's disease, various drugs for motion sickness, various drugs for cerebrovascular disease (including stroke and cerebral infarction, etc.), various drugs for traumatic brain injury, various drugs for spinal cord injury, various drugs for anxiety, various drugs for depression, various drugs for insomnia, various drugs for drowsiness, various drugs for neuroinfection and neuroimmunity (including meningitis, AIDS, cerebral malaria, and multiple sclerosis, etc.), various drugs for neurodevelopmental disorders, various drugs for schizophrenia, various drugs for medulloblastoma, various drugs for opioid addiction, various drugs for dry eye syndrome, and various drugs for attention deficit hyperactivity disorder (ADHD).

[0014] Based on the above technical scheme, further, the drug includes various drugs for rhinitis and allergy, such as azelastine, dexamethasone, ipratropium bromide, mometasone, olopatadine, fluticasone, beclomethasone, budesonide, ciclesonide, oxymetazoline, xylometazoline, naphazoline, loratadine, cetirizine, cromolyn sodium, olopatadine, epinastine, rupatadine, ketotifen, pemirolast, phenyltoloxamine, carebastine, rimegepant, epinastine, betahistine, and pharmaceutically acceptable salts thereof, etc.

[0015] Based on the above technical scheme, further, the drug includes various drugs for vomiting, such as difenidol, metoclopramide, domperidone, promethazine, buclizine, meclizine, chlorcyclizine, cinnarizine, flunarizine, scopolamine, trihexyphenidyl, difenidol, chlorpromazine, mosapride, ondansetron, alosetron, palonosetron, itasetron, azasetron, ramosetron, indisetron, dolasetron, granisetron, tropisetron, aprepitant, casopitant, netupitant, fosaprepitant, maropitant, metoclopramide, domperidone, itopride, clomipride, lorazepam, dexamethasone, and pharmaceutically acceptable salts thereof, etc.

[0016] Based on the above technical scheme, further, the drug includes various drugs for migraine, such as zolmitriptan, sumatriptan, rizatriptan, eletriptan, lamiditan, celecoxib, sodium valproate, ibuprofen, flunarizine, propranolol, almotriptan, riamitriptan, dihydroergotamine, aspirin, caffeine, acetaminophen, ibuprofen, ubrogepant, rimegepant, metoclopramide, prochlorperazine, propranolol, metoprolol, verapamil, amitriptyline, sodium valproate, topiramate, CGRP monoclonal antibody and its pharmaceutically acceptable salt, etc.

[0017] Based on the above technical scheme, further, the drug includes various drugs for epilepsy, such as diazepam, clonazepam, nitrazepam, clonazepam, midazolam, lacosamide, phenobarbital, sodium valproate, primidone, amobarbital, fenfluramine, zonisamide, topiramate, isopropyl adrenaline, gabapentin, lamotrigine, riluzole, flunarizine, sodium valproate and topiramate, oxcarbazepine, denzicol, nafimidone, everolimus, sodium valproate, mephenytoin, ethotoin, fosphenytoin sodium, stiripentol, brivaracetam, primidone, carbamate, carbamazepine, ethosuximide, methyl ethosuximide, phenyl ethosuximide, trimethadione, methoheptazine, lufuramide, sodium valproate, phenyl acetyl urea, phenyl butyl urea, clorazepate, levetiracetam, clonazepam, perampanel, zonisamide, retigabine, acetazolamide, sultiam, paraformaldehyde, vanillin, chloral hydrate, lidocaine phenytoin sodium and its pharmaceutically acceptable salt, etc.

[0018] Based on the above technical scheme, further, the drug includes various drugs for Parkinson's disease, such as levodopa, carbidopa, pramipexole, opipramol, talipexole, trihexyphenidyl, rotigotine, biperiden, entacapone, ropinirole, apomorphine, cabergoline, ictotrazone, pimavanserin, safinamide, selegiline, rasagiline, zonisamide, droxidopa, fendolatane, adamantane and its pharmaceutically acceptable salt, etc.

[0019] Based on the above technical scheme, further, the drug includes various drugs for Huntington's disease, such as trihexyphenidyl, levodopa, selegiline, levodopa, ropinirole, baclofen, aripiprazole, chlorpromazine, haloperidol, risperidone, olanzapine, clozapine and its pharmaceutically acceptable salt, etc.

[0020] Based on the above technical scheme, further, the drug includes various drugs for amyotrophic lateral sclerosis, such as riluzole, edaravone, butylphthalide, vitamin E, gabapentin and its pharmaceutically acceptable salt, etc.

[0021] Based on the above technical scheme, further, the drug includes various drugs for Alzheimer's disease, such as flurbiprofen, memantine, donepezil, galantamine hydrochloride, galantamine, rivastigmine, rivastigmine, rivastigmine, vitamin E, omega-3 fatty acids, curcumin, ginkgo, melatonin and its pharmaceutically acceptable salts, etc.

[0022] Based on the above technical scheme, further, the drug includes various drugs for motion sickness, such as acetyl leucine, benadryl, dyphylline, sodium bicarbonate and its pharmaceutically acceptable salts, etc.

[0023] Based on the above technical scheme, further, the drug includes various drugs for stroke, such as edaravone, dextromethorphan, butylphthalide, citicoline, ganglioside, oxiracetam, alinacin, nervonic acid, methylcobalamin, cerebrolysis, neurotropin, brain protein, guaibezit, mouse nerve production factor, aspirin, oryzanol, vitamin B1, vitamin B6, vitamin B12, resveratrol and its pharmaceutically acceptable salts, etc.

[0024] Based on the above technical scheme, further, the drug includes various drugs for traumatic brain injury, such as loxoprofen, acetaminophen, ibuprofen, betahistine, flunarizine hydrochloride, piracetam, oxiracetam, mannitol, sulbactam, monosialic tetrahexose ganglioside sodium, mannitol, sorbitol, cimetidine and its pharmaceutically acceptable salts, etc.

[0025] Based on the above technical scheme, further, the drug includes various drugs for spinal cord injury, such as methylprednisolone, methylprednisolone, ganglioside, hyoscine, methylcobalamin, mannitol, dextran, furosemide and its pharmaceutically acceptable salts, etc.

[0026] Based on the above technical scheme, further, the drug includes various drugs for anxiety, such as escitalopram, duloxetine, diazepam, lorazepam, oxazepam, clonazepam, sertraline, paroxetine, fluoxetine, venlafaxine, mirtazapine, alprazolam, buspirone, chlordiazepoxide, escitalopram, chlorpromazine, buspirone and its pharmaceutically acceptable salts, etc.

[0027] Based on the above technical scheme, further, the drug includes various drugs for depression, such as ketamine, bupropion, duloxetine, venlafaxine, desvenlafaxine, sertraline, escitalopram, fluvoxamine, dextromethorphan, lumefanuron, milnacipran, levomilnacipran, maprotiline, vortioxetine, modafinil, salt paroxetine, trazodone, amitriptyline, zopiclone, citalopram, selegiline, vilazodone, milnacipran, imipramine, quetiapine, escitalopram, fluoxetine, mirtazapine, vortioxetine, vilazodone, desipramine, amitriptyline, doxepin, desipramine, phenylbutazone, isocarboxazid, selegiline, aripiprazole, quetiapine, lithium and pharmaceutically acceptable salts thereof.

[0028] Based on the above technical scheme, further, the drug includes various drugs for insomnia, such as diazepam, flurazepam, prazepam, clorazepate, chlormezanone, midazolam, chloral hydrate, diazepam, estazolam, alprazolam, triazolam, zolpidem tartrate, zaleplon, zopiclone and pharmaceutically acceptable salts thereof.

[0029] Based on the above technical scheme, further, the drug includes various drugs for sleepiness, such as methylphenidate, modafinil, amphetamine, pimozide, ritalin, venlafaxine, fluoxetine, hydroxybutyric acid, and calcium, magnesium, potassium and pharmaceutically acceptable salts thereof.

[0030] Based on the above technical scheme, further, the drug includes various drugs for neuroinfection and neuroimmunity, such as nerve growth factor, ganglioside, butylphthalate, mecobalamin, acyclovir, ganciclovir, prednisone, different kinds of antibiotics and pharmaceutically acceptable salts thereof.

[0031] Based on the above technical scheme, further, the drug includes various drugs for neurodevelopmental disorders, such as oxiracetam, piracetam, such as ganglioside, citicoline, vitamin B1 and pharmaceutically acceptable salts thereof.

[0032] Based on the above technical scheme, further, the drug includes various drugs for schizophrenia, such as chlorpromazine, perphenazine, fluphenazine, thioridazine, haloperidol, pimozide, chlorprothixene, sulpiride, risperidone, clozapine, olanzapine, quetiapine, asenapine, brexpiprazole, cariprazine, iloperidone, lumefanuron, lurasidone, paliperidone, aripiprazole, ziprasidone, perospirone, zanomeline, trospium chloride and pharmaceutically acceptable salts thereof.

[0033] Based on the above technical scheme, further, the drug includes various drugs for brain stem glioma, such as PD-1 / PD-L1 monoclonal antibody, bevacizumab, cellular immunotherapy drug, oncolytic virus drug, bevacizumab, EGFR, dabrafenib / trametinib, temozolomide, biricnib, obitexan, Enzastaurin, Paxalisi, NMS-03305293, ASC40, JL15003, SDT-101 and pharmaceutically acceptable salts thereof.

[0034] Based on the above technical scheme, further, the drug also includes various drugs for opioid addiction, such as naloxone, nalmefene, clonidine, buprenorphine, clonidine, methadone, codeine, oxazepam, alprazolam, temazepam, diazepam, nitrazepam, lobe, nicotinic acid, doxapram and pharmaceutically acceptable salts thereof.

[0035] Based on the above technical scheme, further, the drug includes various drugs for dry eye, such as varenicline and pharmaceutically acceptable salts thereof.

[0036] Based on the above technical scheme, further, the drug includes various drugs for attention deficit hyperactivity disorder (ADHD), such as dextroamphetamine, bupropion, desipramine, imipramine, nortriptyline, protriptyline, lysine amphetamines, methylphenidate, dexmethylphenidate, atomoxetine, guanfacine, clonidine, lisdexamfetamine and pharmaceutically acceptable salts thereof.

[0037] A nasal cavity soft mist drug delivery device, comprising a drug delivery body and a spray adapter; the spray adapter is connected with the drug delivery body, and the drug delivery body is provided with a first cavity and a second cavity in communication; the spray adapter is loaded with a microporous chip, and the drug in the cavity is delivered through the microporous chip.

[0038] Based on the above technical scheme, further, it also includes a connecting piece for connecting the drug delivery body and the spray adapter, the spray adapter is also provided with a guide part, the connecting piece is provided with a through hole, the guide part is arranged in the through hole, one end of the guide part is a pointed structure, the inner wall of the through hole is provided with a first limiting part and a second limiting part, and a first groove structure is arranged between the first limiting part and the second limiting part, the end part of the drug delivery body is provided with a first convex part, the first convex part is matched with the first groove, the outer surface of the drug delivery body is provided with a second convex part, a second groove is opened on the connecting piece, and one end of the second convex part is extended and limited into the second groove.

[0039] Based on the above technical scheme, further, the end part of the drug delivery body is provided with an external thread structure, the spray adapter is provided with an internal thread structure, and the drug delivery body and the spray adapter are directly connected through the thread structure.

[0040] Based on the above technical scheme, further, a plurality of injection holes are arranged on the microporous chip, and the diameter of the injection hole ranges from 1 to 100 microns.

[0041] Based on the above technical scheme, further, the size, size and material of the administration main body are adjusted according to actual needs, and the material of the administration main body is selected from but not limited to polyethylene, LDPE, LLDPE, HDPE and polypropylene.

[0042] The application of a nasal cavity soft mist administration device is applied to rhinitis, allergy, vomiting and central nervous system related indications.

[0043] Based on the above technical scheme, further, the central nervous system related indications include but are not limited to headache (including migraine), epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, motion sickness, cerebrovascular disease (including stroke and cerebral infarction, etc.), traumatic brain injury, spinal cord injury, anxiety, depression, insomnia, sleepiness, neurological infection and neuroimmunity (including meningitis, AIDS, cerebral malaria and multiple sclerosis, etc.), neurological developmental disorder, schizophrenia, brainstem glioma, opioid addiction, dry eye, attention deficit hyperactivity disorder (ADHD) and other diseases.

[0044] Compared with the prior art, the present application has the following beneficial effects:

[0045] The present application provides a nasal cavity soft mist administration device, method and application, which is portable, can efficiently and quickly atomize single-dose preservative-free sterile solution or suspension into slow-moving soft mist, the droplet size after atomization is small and uniform (5-500 microns), and more diffusion and deposition can be achieved in all intranasal regions, thereby significantly improving the total coverage rate of each intranasal region of the patient, and greatly improving the bioavailability of the drug. Secondly, compared with most multi-dose nasal sprays on the market, the nasal cavity soft mist delivery has obvious advantages, and provides an effective solution for sensitive patients, elderly patients and infant patients. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 It is a front view of the nasal cavity soft mist administration device of the present application;

[0047] Figure 2 It is a side view of Figure 1

[0048] Figure 3 It is a partial structure schematic view of Figure 2

[0049] Figure 4 It is a structure schematic view of assembling a plurality of administration devices of the present application;

[0050] Figure 5 ​​Front view of the administration device without the connecting member of the present application;

[0051] Figure 6 Side view of the administration device without the connecting member of the present application;

[0052] Figure 7 Structure diagram of multiple administration devices without the connecting member of the present application;

[0053] Figure 8 Particle size distribution diagram of sample 1 of the present application;

[0054] Figure 9 Particle size distribution diagram of sample 2 of the present application;

[0055] The reference signs: 1. administration body; 2. spray adapter; 3. micropore chip; 4. connecting member; 5. labeling part; 6. guiding part; 7. first limiting part; 8. second limiting part; 9. first groove; 10. first convex part; 11. second convex part; 12. second groove; 13. tip structure; 14. first cavity; 15. second cavity; 16. end cap; 17. recess. DETAILED DESCRIPTION

[0056] The technical features of each embodiment of the present application can be combined accordingly without conflict. In order to make the above-mentioned objects, features and advantages of the present application more apparent, the specific embodiments of the present application will be described in detail below with reference to the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced without the specific details. In other instances, well-known methods have not been described in detail in order not to obscure the present application. The technical features of each embodiment of the present application can be combined accordingly without conflict.

[0057] In the description of the present application, it should be understood that when an element is considered to be “connected” to another element, it can be directly connected to the other element or indirectly connected to the other element with an intermediate element. In contrast, when an element is considered to be “directly” connected to another element, there is no intermediate element. In the description of the present application, it should be understood that the terms “first”, “second” are only used for distinguishing description purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features with “first”, “second” can explicitly or implicitly include at least one of the features.

[0058] Example 1

[0059] As Figures 1-7As shown, a nasal cavity soft mist administration device comprises an administration main body 1 and a spray adapter 2; the spray adapter 2 is connected with the end of the administration main body 1; the administration main body 1 is provided with a recess 17, which divides the internal cavity of the administration main body 1 into a first containing cavity 14 and a second containing cavity 15 in communication; the spray adapter 2 is loaded with a microporous chip 3, which is directly opposite the end position of the administration main body 1. One embodiment is as shown in Figure 1 The spray adapter 2 is connected with the end of the administration main body 1 through a connecting piece 4; another embodiment is as shown in Figure 5 The spray adapter 2 is directly screwed with the end of the administration main body 1 through a threaded structure.

[0060] Specifically, the microporous chip 3 is provided with a plurality of spray holes, the diameter of the spray holes ranges from 1 μm to 100 μm, preferably from 1 μm to 30 μm. It needs to be explained that the microporous chip 3 refers to a structure that has spray holes of specified size on a chip material of silicon base, carbon base, copper, stainless steel, etc., by setting the pore size of the spray holes of different sizes, the liquid medicine in the internal cavity can be sprayed out in the form of soft mist of different sizes, which is a conventional phenomenon in the art. The connecting piece 4 is provided with an external threaded structure, the inside of the spray adapter 2 is an internal threaded structure, the connecting piece 4 and the spray adapter 2 are screwed together. The spray adapter 2 is also provided with a guide part 6, the connecting piece 4 is provided with a through hole, the guide part 6 is arranged in the through hole, and one end of the guide part 6 is a pointed structure 13, the pointed structure 13 is provided with a liquid outlet hole, the pointed structure 13 is provided to facilitate the communication between the spray adapter 2 and the administration main body 1, in use, the pointed structure 13 is inserted into the end of the administration main body 1, the structure is inclined to insert the top of the spray adapter 2 into the nasal cavity, the medicine in the administration main body 1 flows into the first containing cavity 14, and then enters the spray adapter 2 through the liquid outlet hole of the pointed structure 13, by extruding the second containing cavity 15, a pressure is formed, the solution entering the spray adapter 2 is then sprayed out through the spray holes on the microporous chip 3 under the action of the pressure. The inner wall of the through hole is provided with a first limiting part 7 and a second limiting part 8, and a first groove 9 structure is arranged between the first limiting part 7 and the second limiting part 8. The inner wall of the connecting piece 4 is provided with an inclined angle on one side wall of the second limiting part 8, the inclined structure is arranged to facilitate the installation of the end of the administration main body 1 and the connecting piece 4, and to avoid unnecessary damage to the end of the administration main body 1 and the connecting piece 4 due to excessive friction. The end of the administration main body 1 is provided with a first protrusion 10, which cooperates with the first groove 9. The lower end of the administration main body 1 is provided with a labeling part 5, which is pasted with an information label. The outer surface of the administration main body 1 is provided with a second protrusion 11, the connecting piece 4 is provided with a second groove 12, and one end of the second protrusion 11 extends and limits into the second groove 12.

[0061] The size and material of the administration body 1 can be adjusted according to actual needs, for example, the material of the administration body 1 can be selected from polyethylene, LDPE, LLDPE, HDPE, polypropylene, etc., and the liquid medicine in the administration body 1 is a sterile liquid preparation without adding a bacteriostatic agent. The bottle type, size and internal volume of the small bottle made of LDPE and other materials can be adjusted to meet the dosage requirements of different medicines.

[0062] The administration operation principle of the device is as follows: before use, the end cap 16 at the upper end of the administration body 1 for sealing is unscrewed, and the spray adapter 2 is directly screwed with the end part of the administration body 1. It should be noted that whether it is a soft material or a hard material, the spray adapter 2 can be screwed with the end part of the administration body 1, or the spray adapter 2 is connected with the end part of the administration body 1 through the bayonet structure of the connecting piece 4. When the connecting piece 4 is used, the connecting piece 4 is installed on the upper end of the administration body 1, the first limiting part 7, the second limiting part 8 and the first groove 9 of the connecting piece 4 are engaged with the first protruding part 10 of the administration body 1, and the second groove 12 of the connecting piece 4 is engaged with the second protruding part 11 of the administration body 1. The spray adapter 2 is inserted into the passage of the connecting piece 4, and the spray adapter 2 pierces the top of the administration body 1 through the pointed end structure 13 and is inserted into the administration body 1. Specifically, during use, the administration body 1 is inverted or placed horizontally, so that the medicine in the second cavity 15 of the administration body 1 enters the first cavity 14, and the upper end of the spray adapter 2 is inserted into the nasal cavity. Head up, tilt the administration device, so that the medicine is concentrated in the first cavity 14 of the administration body, manually squeeze the second cavity 15 of the administration body 1, the medicine enters the spray adapter 2 through the pores on the pointed end structure 13 of the spray adapter 2, the medicine is atomized to produce soft mist through the micro-pore chip 3, and the medicine enters the nasal cavity to realize administration. It should be noted that the pressure of manual extrusion is greater than 80Kpa, which has been verified to be sufficient to realize the ejection of the medicine through the spray hole and the generation of liquid droplets or soft mist. Further, the meaning of soft mist in this embodiment is that the droplet size is small, the spray speed is slow, and the single spray lasts for a long time. The output mist is called "soft mist". In the extrusion process of the device, the soft mist is generated by the collision of the structure such as the spray hole size and the spray adapter 2, and the target particle size of the output soft mist is 5-500μm, and the best range is 20-150μm.

[0063] Embodiment 2

[0064] A nasal cavity soft mist administration method, comprising the following steps: step 1: assembling the administration body and the spray adapter;

[0065] Step 2: Place the assembled device flat or upside down and insert the tip of the spray adapter into the nasal cavity; Step 3: Squeeze the cavity of the flat or upside down administration body filled with air, and the drug generates a soft mist through the microporous chip inside the spray adapter, enters the nasal cavity and delivers the drug. The generated soft mist has a particle size range of 5-500 μm, preferably 20-150 μm.

[0066] The drug includes one or more of various nasal spray drugs for allergies and rhinitis, various nasal spray drugs for vomiting, various nasal spray drugs for headaches (including migraines), various drugs for epilepsy, various drugs for Parkinson's disease, various drugs for Huntington's disease, various drugs for amyotrophic lateral sclerosis, various drugs for Alzheimer's disease, various drugs for motion sickness, various drugs for cerebrovascular disease (including stroke and cerebral infarction, etc.), various drugs for traumatic brain injury, various drugs for spinal cord injury, various drugs for anxiety, various drugs for depression, various drugs for insomnia, various drugs for drowsiness, various drugs for neuroinfection and neuroimmunity (including meningitis, AIDS, cerebral malaria, and multiple sclerosis, etc.), various drugs for neurodevelopmental disorders, various drugs for schizophrenia, various drugs for medulloblastoma, various drugs for opioid addiction, various drugs for dry eye syndrome, and various drugs for attention deficit hyperactivity disorder (ADHD).

[0067] Further, the drug includes various drugs for rhinitis and allergies, such as azelastine, dexamethasone, ipratropium bromide, mometasone, olopatadine, fluticasone, beclomethasone, budesonide, ciclesonide, oxymetazoline, xylometazoline, naphazoline, loratadine, cetirizine, cromolyn sodium, olopatadine, epinastine, rupatadine, ketotifen, pemirolast, phenylamine, carbinoxamine, remacemide, epinastine, betahistine, and pharmaceutically acceptable salts thereof, etc.

[0068] Further, the drug includes various drugs for vomiting, such as difenidol, metoclopramide, domperidone, promethazine, buclizine, meclizine, chlorcyclizine, cinnarizine, flunarizine, hyoscine, trihexyphenidyl, difenidol, chlorpromazine, mosapride, ondansetron, alosetron, palonosetron, itasetron, azasetron, ramucirumab, indisetron, dolasetron, granisetron, tropisetron, aprepitant, casopitant, netupitant, fosaprepitant, maropitant, metoclopramide, domperidone, itopride, clorpromide, lorazepam, dexamethasone, and pharmaceutically acceptable salts thereof, etc.

[0069] Still further, the drug includes various drugs for migraine, such as zolmitriptan, sumatriptan, rizatriptan, eletriptan, lamotrigine, celecoxib, sodium valproate, ibuprofen, flunarizine, propranolol, almotriptan, riamitriptan, dihydroergotamine, aspirin, caffeine, acetaminophen, ibuprofen, ubrogepant, rimegepant, metoclopramide, prochlorperazine, propranolol, metoprolol, verapamil, amitriptyline, sodium valproate, topiramate, CGRP monoclonal antibody, and pharmaceutically acceptable salts thereof, etc.

[0070] Still further, the drug includes various drugs for epilepsy, such as diazepam, clonazepam, nitrazepam, clonazepam, midazolam, lacosamide, phenobarbital, sodium valproate, primidone, amobarbital, fenfluramine, zonisamide, topiramate, isoprenaline, gabapentin, lamotrigine, retigabine, remacemide, flunarizine, riluzole, sodium valproate and topiramate, oxcarbazepine, denzicol, nafimidone, everolimus, sodium valproate, mephenytoin, ethotoin, fosphenytoin sodium, stiripentol, brivaracetam, primidone, carbamate, carbamazepine, ethosuximide, methsuximide, phenylsuximide, trimethadione, methprylon, levetiracetam, phenacemide, pheneturide, clorazepate, levetiracetam, clonazepam, perampanel, zonisamide, retigabine, acetazolamide, sulthiame, paraformaldehyde, vanillin, chloral hydrate, lidocaine phenytoin sodium, and pharmaceutically acceptable salts thereof, etc.

[0071] Still further, the drug includes various drugs for Parkinson's disease, such as levodopa, carbidopa, pramipexole, opipramol, talipexole, trihexyphenidyl, rotigotine, biperiden, piribedil, entacapone, ropinirole, apomorphine, cabergoline, ictiracetam, pimavanserin, safinamide, selegiline, rasagiline, zonisamide, droxidopa, fendolatadine, adamantane, and pharmaceutically acceptable salts thereof, etc.

[0072] Still further, the drug includes various drugs for Huntington's disease, such as trihexyphenidyl, levodopa, selegiline, levodopa, ropinirole, baclofen, aripiprazole, chlorpromazine, haloperidol, risperidone, olanzapine, clozapine, and pharmaceutically acceptable salts thereof, etc.

[0073] Still further, the drug includes various drugs for amyotrophic lateral sclerosis, such as riluzole, edaravone, butylphthalide, vitamin E, gabapentin, and pharmaceutically acceptable salts thereof, etc.

[0074] Still further, the drug includes various drugs for Alzheimer's, such as flurbiprofen, memantine, donepezil, galantamine hydrochloride, galantamine, rivastigmine, rivastigmine, encainide, vitamin E, omega-3 fatty acids, curcumin, ginkgo, melatonin, and pharmaceutically acceptable salts thereof.

[0075] Still further, the drug includes various drugs for motion sickness, such as acetyl leucine, benadryl, dyphylline, sodium bicarbonate, and pharmaceutically acceptable salts thereof.

[0076] Still further, the drug includes various drugs for stroke, such as edaravone, dexpanthenol, butylphthalide, citicoline, ganglioside, oxiracetam, alinacin, nervonic acid, methylcobalamin, cerebrolysis, neurotropin, cerebroprotein, guanfacine, murine neurotrophic factor, aspirin, oryzanol, vitamin B1, vitamin B6, vitamin B12, resveratrol, and pharmaceutically acceptable salts thereof.

[0077] Still further, the drug includes various drugs for traumatic brain injury, such as loxoprofen, acetaminophen, ibuprofen, betahistine, flunarizine hydrochloride, piracetam, oxiracetam, mannitol, sulbactam, monosialotetrahexosyl ganglioside sodium, mannitol, sorbitol, cimetidine, and pharmaceutically acceptable salts thereof.

[0078] Still further, the drug includes various drugs for spinal cord injury, such as methylprednisolone, methylprednisolone, ganglioside, hyoscine, methylcobalamin, mannitol, dextran, furosemide, and pharmaceutically acceptable salts thereof.

[0079] Still further, the drug includes various drugs for anxiety, such as escitalopram, duloxetine, diazepam, lorazepam, oxazepam, clonazepam, sertraline, paroxetine, fluvoxamine, venlafaxine, mirtazapine, alprazolam, buspirone, chlordiazepoxide, escitalopram, imipramine, and pharmaceutically acceptable salts thereof.

[0080] Still further, the drug includes various drugs for depression, such as ketamine, bupropion, duloxetine, venlafaxine, desvenlafaxine, sertraline, escitalopram, fluvoxamine, dextromethorphan, lumiracoxib, milnacipran, levomilnacipran, maprotiline, vortioxetine, modafinil, salparoxetine, trazodone, amitriptyline, zopiclone, citalopram, selegiline, vilazodone, milnacipran, imipramine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, vilazodone, bupropion, nortriptyline, amitriptyline, doxepin, desipramine, tranylcypromine, phenylbutazone, isocarboxazid, selegiline, aripiprazole, quetiapine, lithium, and pharmaceutically acceptable salts thereof.

[0081] Further, the drug includes various drugs for insomnia, such as diazepam, flurazepam, prazepam, loprazolam, chloral hydrate, estazolam, alprazolam, triazolam, zolpidem tartrate, zaleplon, zopiclone, and pharmaceutically acceptable salts thereof, etc.

[0082] Further, the drug includes various drugs for sleepiness, such as methylphenidate, modafinil, amphetamine, pirenoxol, lisdexamfetamine, venlafaxine, fluoxetine, hydroxybutyric acid, and potassium calcium magnesium, and pharmaceutically acceptable salts thereof, etc.

[0083] Further, the drug includes various drugs for neuroinfection and neuroimmunity, such as nerve growth factor, ganglioside, butylphthalate, mecobalamin, acyclovir, ganciclovir, prednisone, different kinds of antibiotics, and pharmaceutically acceptable salts thereof, etc.

[0084] Further, the drug includes various drugs for neurodevelopmental disorders, such as olatcitabine, piracetam, ganglioside, citicoline, vitamin B1, and pharmaceutically acceptable salts thereof, etc.

[0085] Further, the drug includes various drugs for schizophrenia, such as chlorpromazine, perphenazine, fluphenazine, thioridazine, haloperidol, pimozide, chlorprothixene, sulpiride, risperidone, clozapine, olanzapine, quetiapine, asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, paliperidone, aripiprazole, ziprasidone, perospirone, zanomeline, trospium chloride, and pharmaceutically acceptable salts thereof, etc.

[0086] Further, the drug includes various drugs for brainstem glioma, such as PD-1 / PD-L1 monoclonal antibody, bevacizumab, cellular immunotherapy drug, oncolytic virus drug, bevacizumab, EGFR, dabrafenib / trametinib, temozolomide, berzosertib, obitrexate, Enzastaurin, Paxalisi, NMS-03305293, ASC40, JL15003, SDT-101, and pharmaceutically acceptable salts thereof, etc.

[0087] Further, the drug also includes various drugs for opioid addiction, such as naloxone, nalmefene, clonidine, buprenorphine, clonidine, methadone, codeine, oxazepam, alprazolam, temazepam, diazepam, nitrazepam, lobe, nikethamide, doxapram, and pharmaceutically acceptable salts thereof, etc.

[0088] Further, the drug includes various drugs for dry eye, such as varenicline, and pharmaceutically acceptable salts thereof, etc.

[0089] Further, the medicament includes various medicaments for attention deficit hyperactivity disorder (ADHD), such as dextroamphetamine, bupropion, desipramine, imipramine, nortriptyline, thionessazine, lysine amphetamines, methylphenidate, dexmethylphenidate, atomoxetine, guanfacine, clonidine, lisdexamfetamine, and pharmaceutically acceptable salts thereof.

[0090] The particle size distribution of the mist after atomization of sumatriptan is compared between the present device, method, and existing commercially available devices, as follows:

[0091] 1. Sumatriptan nasal spray liquid is prepared, as shown in Table 1, and is filled into a small bottle of LDPE or the like produced by blow-filling-sealing, that is, into a main body for administration, and a nasal spray adapter is connected to the small bottle of LDPE or the like, serving as sample 1. Another sumatriptan nasal spray liquid is filled into a commercially available nasal spray device, serving as sample 2. The particle size distribution of the mist of the two samples is determined by a new Palteck laser particle size tester, and is compared. The results are shown in Table 2.

[0092] Table 1: Sumatriptan nasal spray liquid

[0093]

[0094] Table 2

[0095]

[0096] According to the results in the above table, compared with the atomization effect of the spray device of the commercially available nasal spray under the same conditions, in combination with the data of D10-D90, for example, the D90 of the present nasal cavity soft mist administration device is 24.67 μm, and the D50 is 16.05 μm, while the D90 of the commercially available device is 78.02 μm, and the D50 is 35.84 μm. The particle size distribution range of the mist atomized by the nasal cavity soft mist administration device in the present scheme is relatively narrow, and the uniformity has a significant advantage. Moreover, the particle size range of the mist sprayed by the present device meets the set range.

[0097] Example 3

[0098] Based on the administration method described in Example 1 and Example 2, the particle size distribution of azelastine hydrochloride and fluticasone propionate medicaments is compared between the nasal cavity soft mist administration device and the commercially available nasal inhalation device, and the specific analysis is as follows: azelastine hydrochloride and fluticasone propionate nasal spray is prepared, as shown in Table 3, and is filled into a small bottle of LDPE or the like of the nasal cavity soft mist administration device, and a nasal spray adapter is connected to the small bottle of LDPE or the like, serving as sample 3. Another azelastine hydrochloride and fluticasone propionate nasal spray is filled into a commercially available nasal spray device, serving as sample 4. The particle size distribution of the mist of the two samples is determined by a new Palteck laser particle size tester, and is compared. The results are shown in Table 4.

[0099] Table 3 Azelastine hydrochloride nasal spray liquid

[0100]

[0101] Table 4

[0102]

[0103] According to the above table results, compared with the atomization effect of the spray device of the commercially available nasal spray under the same conditions, combined with the D10-D90 data, for example, the D90 of the nasal cavity soft mist drug delivery device is 26.06 μm, and the D50 is 16.04 μm, while the D90 of the commercially available device is 77.95 μm, and the D50 is 36.07 μm. The nasal cavity soft mist drug delivery device in the present scheme has a narrow and uniform particle size distribution. And the particle size range of the mist sprayed by the device meets the set range.

[0104] Example 4

[0105] Based on Example 1 and Example 2, combined with the comparison of the mist droplet size distribution of the nasal cavity soft mist drug delivery device and the commercially available device for budesonide drug, the specific analysis is as follows: budesonide nasal spray is prepared, as shown in Table 5, and is filled into a small bottle of LDPE and the like, and the nasal spray adapter is connected with the small bottle of LDPE and the like, as sample 5. Another budesonide nasal spray is filled into a commercially available nasal spray device, as sample 6. The mist droplet size distribution of the two samples is determined by a new Patek laser particle size tester, and compared. The results are shown in Table 6.

[0106] Table 5 Budesonide nasal spray liquid

[0107]

[0108] Table 6

[0109]

[0110] According to the above table results, compared with the atomization effect of the spray device of the commercially available nasal spray under the same conditions, combined with the D10-D90 data, for example, the D90 of the nasal cavity soft mist drug delivery device is 26.06 μm, and the D50 is 16.04 μm, while the D90 of the commercially available device is 77.95 μm, and the D50 is 36.07 μm. The nasal cavity soft mist drug delivery device in the present scheme has a narrow and uniform particle size distribution. And the particle size range of the mist sprayed by the device meets the set range.

[0111] Example 5

[0112] Based on Example 1 and Example 2, the nasal soft mist drug delivery device is compared with the commercially available device in terms of the droplet size distribution of fluticasone propionate after atomization. The specific analysis is as follows: fluticasone propionate nasal spray is prepared, as shown in Table 7, and filled into a small bottle made of LDPE or the like for the nasal soft mist drug delivery device. The nasal spray adapter is connected to the small bottle made of LDPE or the like, serving as sample 7. Fluticasone propionate nasal spray is filled into a commercially available nasal spray device, serving as sample 8. The droplet size distribution of the two samples is determined by a new Partek laser particle size tester, and compared. The results are shown in Table 8.

[0113] Table 7 Fluticasone propionate nasal spray liquid

[0114]

[0115] Table 8

[0116]

[0117] According to the results in the above table, compared with the atomization effect of the commercially available nasal spray device under the same conditions, the D10-D90 data show that the D90 of the nasal soft mist drug delivery device is 24.67 μm, and the D50 is 16.05 μm. The D90 of the commercially available device is 80.14 μm, and the D50 is 37.21 μm. The nasal soft mist drug delivery device has a narrow droplet size distribution and a significant advantage in uniformity. The droplet size range sprayed by the device meets the set range.

[0118] Example 6

[0119] Based on Example 1 and Example 2, the nasal soft mist drug delivery device is compared with the commercially available device in terms of the droplet size distribution of granisetron hydrochloride after atomization. The specific analysis is as follows: granisetron hydrochloride nasal spray is prepared, as shown in Table 9, and filled into a small bottle made of LDPE or the like for the nasal soft mist drug delivery device. The nasal spray adapter is connected to the small bottle made of LDPE or the like, serving as sample 9. Granisetron hydrochloride nasal spray is filled into a commercially available nasal spray device, serving as sample 10. The droplet size distribution of the two samples is determined by a new Partek laser particle size tester, and compared. The results are shown in Table 10.

[0120] Table 9 Granisetron hydrochloride nasal spray liquid

[0121]

[0122] Table 10

[0123]

[0124] According to the results of the above table, compared with the spray droplets generated by the spray device of the commercially available nasal spray under the same conditions, the data combined with D10-D90, for example, the D90 of the nasal cavity soft mist drug delivery device is 23.15 μm, and the D50 is 17.24 μm, while the D90 of the commercially available device is 72.39 μm, and the D50 is 36.28 μm. The nasal cavity soft mist drug delivery device in the present scheme has a narrow and uniform particle size distribution of the atomized mist droplets. And the particle size range of the mist droplets sprayed by the device meets the set range.

[0125] Example 7

[0126] Based on Examples 1 and 2, the nasal cavity soft mist drug delivery device was characterized by the distribution in the intranasal region after drug delivery, as follows:

[0127] A certain amount of calcein powder was dissolved in 1 mol / L sodium hydroxide solution and mixed with 25% glycerol solution to prepare a fluorescent indicator solution with a certain viscosity. The nasal cavity soft mist drug delivery device was filled with the solution, and the silicone nasal cavity model was simulated for nasal spray drug delivery (sample 11) using the device. A UV lamp was used as the light source, and the fluorescent imaging was collected in a dark room by a digital camera, so as to directly display the distribution of the drug in the intranasal region.

[0128] From the actual imaging results, the soft mist after atomization of the single-dose nasal cavity soft mist drug delivery device of the present scheme has a very high area coverage in the intranasal region. Except for the nasopharynx region, the olfactory region, the middle turbinate region, the inferior turbinate region and the nasal vestibule have good distribution, which indicates that the drug can exert its effect in each region.

[0129] Example 8

[0130] Based on Examples 1 and 2, the distribution after nasal spray drug delivery by the nasal cavity soft mist drug delivery device and the commercially available nasal spray device was compared, as follows:

[0131] The fluorescent indicator solution prepared in Example 7 was filled into the nasal cavity soft mist drug delivery device (sample 12) and the commercially available nasal spray device (sample 13), respectively, and the silicone nasal cavity model was subjected to nasal spray drug delivery. A UV lamp was used as the UV light source, and the fluorescent imaging photos of different groups were collected in a dark room by a digital camera. The pictures were analyzed by software, and the coverage of each region was calculated, so as to compare the intranasal region distribution of different devices after nasal spray drug delivery. The results are shown in Table 11.

[0132] Table 11

[0133]

[0134] From the imaging contrast results of the obtained silicone nasal cavity model, it can be seen that, compared with the commercially available nasal spray device, the nasal spray soft mist drug delivery device of the present scheme not only has a coverage rate in the nasal vestibule that can reach the coverage rate of the commercially available device, but also has a significant advantage in total coverage rate and single coverage rate in other areas (except the nasopharynx area), which shows that the nasal soft mist drug delivery device of the present scheme can greatly improve the bioavailability of various nasal sprays, especially central nervous system nasal sprays.

[0135] In summary, the present scheme provides a better solution for various commercially available nasal sprays, especially central nervous system nasal sprays. The single-dose nasal soft mist drug delivery device of the present scheme can atomize the drug solution into soft mist with small particle size (5-500 μm), uniform distribution, and slow movement, preferably in the particle size range of 20-150 μm, which significantly improves the bioavailability of such drugs. In addition, compared with most multi-dose nasal sprays on the market, the nasal soft mist delivery has a significant advantage, providing an effective solution for sensitive patients, elderly patients, and infant patients.

[0136] Example 9

[0137] Based on Examples 1 and 2, the application of a nasal soft mist drug delivery device is applied to rhinitis, anti-allergy, and central nervous system related indications. Specifically, the central nervous system related indications include but are not limited to headache (including migraine), epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, motion sickness, cerebrovascular disease (including stroke and cerebral infarction, etc.), traumatic brain injury, spinal cord injury, anxiety, depression, insomnia, sleepiness, neurological infection and neuroimmunity (including meningitis, AIDS, cerebral malaria, and multiple sclerosis, etc.), neurodevelopmental disorders, schizophrenia, brainstem glioma, opioid addiction, dry eye syndrome, attention deficit hyperactivity disorder (ADHD), etc.

[0138] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A nasal soft mist drug delivery device employing a nasal soft mist drug delivery method, characterized by, The drug delivery device is used for delivering central nervous system drugs, comprising a drug delivery body and a spray adapter; the spray adapter is connected with the drug delivery body, and the drug delivery body is provided with a first cavity and a second cavity in communication; the spray adapter is loaded with a microporous chip, and the drug in the cavity is delivered through the microporous chip; Further comprising a connecting piece for connecting the drug delivery body and the spray adapter, the spray adapter is further provided with a guide part, the connecting piece is provided with a through hole, the guide part is arranged in the through hole, and one end of the guide part is a pointed structure, The inner wall of the through hole is provided with a first limiting part and a second limiting part, and a first groove structure is arranged between the first limiting part and the second limiting part, the end part of the drug delivery body is provided with a first protruding part, the first protruding part is matched with the first groove, the outer surface of the drug delivery body is provided with a second protruding part, a second groove is arranged on the connecting piece, and one end of the second protruding part is extended and limited into the second groove; and an inner wall of the connecting piece is provided with an inclined angle on one side wall of the second limiting part; The microporous chip is provided with a plurality of spray holes, and the diameter of the spray holes ranges from 1 μm to 100 μm; The generated soft mist particle size ranges from 10 μm to 50 μm; The drug delivery method comprises the following steps: Step 1: Assemble the drug delivery body and the spray adapter; Step 2: Place or invert the assembled device, and insert the top end of the spray adapter into the nasal cavity; Step 3: Squeeze the cavity filled with air of the drug delivery body placed or inverted, the drug generates soft mist through the microporous chip built-in the spray adapter, and the soft mist enters the nasal cavity for drug delivery.

2. A nasal soft mist delivery device according to claim 1, wherein, The end part of the drug delivery body is provided with an external thread structure, the spray adapter is provided with an internal thread structure, and the drug delivery body and the spray adapter are directly connected through the thread structure.

3. The nasal soft mist dispensing device of claim 1, wherein, The size, size and material of the drug delivery body are adjusted according to actual requirements, and the material selection of the drug delivery body includes polyethylene, LDPE, LLDPE, HDPE and polypropylene.

4. The nasal soft mist drug delivery device according to claim 1, wherein the drug delivery body is a structure filled with drugs produced by blow molding and sealing, and the drugs are single-dose sterile solutions or suspensions without preservatives.

5. The nasal soft mist drug delivery device according to claim 1, wherein the drugs include one or more of various drugs for vomiting, various drugs for headache, various drugs for epilepsy, various drugs for Parkinson's disease, various drugs for Huntington's disease, various drugs for amyotrophic lateral sclerosis, various drugs for Alzheimer's disease, various drugs for motion sickness, various drugs for cerebrovascular disease, various drugs for traumatic brain injury, various drugs for spinal cord injury, various drugs for anxiety, various drugs for depression, various drugs for insomnia, various drugs for drowsiness, various drugs for neuroinfection and neuroimmunity, various drugs for neurodevelopmental disorders, various drugs for schizophrenia, various drugs for medulloblastoma, various drugs for opioid addiction, various drugs for dry eye syndrome, and various drugs for attention deficit hyperactivity disorder.

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