Ramelteon liquid preparation as well as preparation method and application thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a ramelteon liquid preparation as well as a preparation method and application thereof. The preparation comprises the following components: ramelteon, a first solvent, a second solvent and a third solvent, and optionally comprises one or more of water, a solubilizer, a surfactant, a polymer film-forming material, a plasticizer, a flavoring agent and a diluent. The preparation is high in stability, convenient to take and high in bioavailability, effectively overcomes the defects in the prior art, and has commercial application value.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a ramelteon liquid preparation and a preparation method and use thereof. Background Art

[0002] Ramelteon is the first melatonin receptor agonist for the clinical treatment of insomnia developed by Takeda in Japan in 1996, entered clinical trials in 1999, and was approved by the FDA for marketing in the United States in 2005. It is mainly used to treat insomnia with difficulty falling asleep, and has a definite effect on chronic insomnia and short-term insomnia. Ramelteon is a potent MT1 / MT2 receptor agonist. Compared with melatonin, it has higher affinity and selectivity for MT1 and MT2 receptors, and has a specific and complete agonist effect on MT1 and MT2 receptors, but not on MT3 receptors. At the same time, its receptor affinity for other neurotransmitters in the central nervous system is also relatively limited. It does not bind to neurotransmitter receptors such as GABA receptor complexes, and does not interfere with the activity of most enzymes within a certain range, which can avoid distraction, drug addiction or dependence caused by the use of GABA drugs. Therefore, ramelteon is also the first non-addictive insomnia treatment drug that has not been listed as a special control, and is a strong competitor in the new drugs for the treatment of insomnia.

[0003] Although ramelteon has the above advantages in efficacy and pharmacology, due to its poor water solubility, most of the current ramelteon preparations are oral tablets, such as ordinary tablets, orodisintegrating tablets, dispersible tablets, sustained-release tablets, etc. These dosage forms are basically absorbed in the digestive tract and can be metabolized by multiple cytochrome P-450 (CYP450) isozymes including CYP1A2, CYP2C subfamily and CYP3A4. There is a strong first-pass effect in the liver, poor absorption in the body, large individual differences, low oral bioavailability, and the absolute bioavailability of the original tablet is about 1.8% (0.5%~12%), and the original is a highly variable drug. In order to solve this problem, new dosage forms such as sublingual tablets and sublingual membranes have been developed. Compared with the aforementioned oral tablets, these new dosage forms can effectively reduce the adverse effects of the first-pass effect of the liver, but they do not really enhance the solubility of ramelteon in the dosage form. Therefore, there is still room for improvement in the bioavailability of ramelteon preparations, and the existing preparations are absorbed slowly in the human body. The existing sublingual preparation of ramelteon needs to stay under the tongue for a relatively long time, which will cause a certain foreign body sensation when used and will bring many inconveniences to daily eating and drinking, which will reduce the patient's compliance to a certain extent. Summary of the invention

[0004] Based on this, it is necessary to provide a ramelteon preparation (ramelteon liquid preparation) for transmucosal administration with good solubility, quick and convenient administration, high bioavailability and high stability, as well as a preparation method and use thereof.

[0005] In one aspect of the present invention, there is provided a ramelteon preparation (preferably a ramelteon liquid preparation) for transmucosal administration, comprising the following components: ramelteon and excipients; The auxiliary materials include one or more of solvents, solubilizers, surfactants, polymer film-forming materials, plasticizers, flavoring agents and diluents.

[0006] In the present invention, the ramelteon liquid preparation is a specific form of the ramelteon preparation for transmucosal administration, and the ramelteon liquid preparation is also a mode of administration for transmucosal administration.

[0007] In some embodiments, the solvent includes one or more of diethylene glycol monoethyl ether, ethanol, isopropanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, glycerol, propylene glycol, and hexylene glycol.

[0008] In some embodiments, the solubilizer includes polyoxyethylene 35 castor oil (EL35), polyoxyethylene 40 hydrogenated castor oil (RH40), polysorbate 60, polysorbate 80, sodium lauryl sulfate, poloxamer 188, poloxamer 237, poloxamer 338, caprylic acid capric acid macrogol glyceride, 15-hydroxystearate macrogol ester, sodium dodecylbenzene sulfonate, sodium dioctyl succinate sulfonate, lecithin , Sorbitan fatty acid, polyoxyethylene 40 stearate, PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2-hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) One or more of dioleate, propylene glycol monolaurate, propylene glycol monomyristate, dipropylene glycol dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol dicaprate, dipropylene glycol dipelargonate, propylene glycol bis(9, 10-epoxystearate), propylene glycol monoisostearate, propylene glycol heneicosate, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogol glycerides, lauroyl macrogol glycerides, stearoyl macrogol glycerides, capryl macrogol glycerides, medium chain triglycerides, polyglyceryl-3 diisostearate, polyglyceryl oleate, ethylene glycol palmitostearate, diisopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide and diethylene glycol monoethyl ether.

[0009] In some embodiments, the surfactant is at least one or more of polysorbate and sorbitan fatty acid ester. Further, the surfactant is one or more of polysorbate-60, polysorbate-80, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan and polyoxyethylene (20) sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitan monooleate.

[0010] In some embodiments, the polymer film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, pullulan, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum, and gum arabic.

[0011] In some embodiments, the plasticizer is selected from one or more of polyethylene glycol, polypropylene glycol, glycerol, and triethyl citrate.

[0012] In some embodiments, the flavoring agent is selected from one or more of sucralose, aspartame, saccharin sodium, sugar alcohol, acesulfame potassium, steviol glycosides, citric acid, citric acid, malic acid, stevioside, glycyrrhizin, tea polyphenols, phytic acid, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, thaumatin, and grape flavor. Examples of sugar alcohols include D-mannitol, maltitol, erythritol, reduced isomaltulose, lactitol, and xylitol.

[0013] In some embodiments, the diluent includes one or more of water, glycerin, ginger oil, eucalyptus, terpenes, pH buffer, and liquid oil.

[0014] In some embodiments, the ramelteon preparation for transmucosal administration comprises, by weight percentage: 0.01% to 10% ramelteon, 30% to 70% solvent, 0% to 50% solubilizer, and 15% to 75% diluent.

[0015] In some embodiments, the ramelteon preparation for transmucosal administration comprises, by weight percentage: 0.01% to 10% ramelteon, 10% to 70% solvent, 0% to 50% solubilizer, 15% to 75% diluent and 0.001 to 5% flavoring agent.

[0016] In some embodiments, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of ramelteon is: 0.01-50% or 0.5%-5%. Further, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of ramelteon is: 0.01%, 0.05%, 0.1%, 0.5%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0017] In some embodiments, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of the solvent is 20-99%; further, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of the solvent is: 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 58%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 76%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.

[0018] In some embodiments, the solvents are grouped as follows: The first group of solvents includes one or more of diethylene glycol monoethyl ether (carbitol), ethanol and isopropanol, The second group of solvents includes one or more of polyethylene glycol 200, polyethylene glycol 400 (PEG400) and polyethylene glycol 600, The third group of solvents includes one or two of propylene glycol, glycerol, and hexylene glycol; The solvent is selected from one or more of the first group of solvents, the second group of solvents and the third group of solvents, for example, the first group of solvents and the second group of solvents are included at the same time, or the first group of solvents, the second group of solvents and the third group of solvents are included at the same time.

[0019] In some embodiments, when the solvent simultaneously comprises a combination of two solvents, that is, a combination of the first group of solvents and the second group of solvents, a combination of the first group of solvents and the third group of solvents, and a combination of the second group of solvents and the third group of solvents, each solvent accounts for 0 to 50% by weight, and the total proportion in the transmucosal ramelteon preparation does not exceed 98%; when the solvent simultaneously comprises three solvents, that is, the first group of solvents, the second group of solvents and the third group of solvents, each solvent accounts for 1 to 45% by weight, and the total proportion in the transmucosal ramelteon preparation does not exceed 80%.

[0020] Furthermore, the proportions of the first group of solvents, the second group of solvents and the third group of solvents are each independently: 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 49.9%.

[0021] In some embodiments, the solvent is any one of the following: Group (1) ethanol and polyethylene glycol 400; Group (2) diethylene glycol monoethyl ether and polyethylene glycol 400; Group (3) diethylene glycol monoethyl ether, polyethylene glycol 400 and 1,2-propylene glycol; Group (4) ethanol and 1,2-propylene glycol; Group (5) ethanol, polyethylene glycol 400 and 1,2-propylene glycol.

[0022] In some embodiments, the solvent is any one of the following groups by weight percentage: Group (1) ethanol 15%-50% and polyethylene glycol 400 6%-50%; Group (2) diethylene glycol monoethyl ether 15%~25% and polyethylene glycol 400 20%~50%; Group (3) diethylene glycol monoethyl ether 15%-25%, polyethylene glycol 400 20%-45% and 1,2-propylene glycol 1%-20%; Group (4) 30-50% ethanol and 5-20% 1,2-propylene glycol; Group (5) ethanol 25-50%, polyethylene glycol 400 1-15% and 1,2-propylene glycol 1-15%.

[0023] In some embodiments, the solvent is 1-30% diethylene glycol monoethyl ether, 5-70% polyethylene glycol 400, and 0.5-25% 1,2-propylene glycol, by weight percentage.

[0024] In some embodiments, the solvent is 5-70% ethanol, 0.5%-25% polyethylene glycol 400 and 0.5%-25% 1,2-propylene glycol, by weight percentage, and optionally further comprises water.

[0025] In some embodiments, in the ramelteon preparation for transmucosal administration, the polymer film-forming material accounts for 20-90% by weight.

[0026] In some embodiments, the solubilizing agent in the ramelteon preparation for transmucosal administration is 0-99% by weight; further, the solubilizing agent in the ramelteon preparation for transmucosal administration is 0%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 8 5%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 58%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 76%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.

[0027] In some embodiments, in the ramelteon preparation for transmucosal administration, the diluent accounts for 0-99% by weight.

[0028] In some embodiments, in the ramelteon preparation for transmucosal administration, the surfactant accounts for 1-50% by weight.

[0029] In some embodiments, in the ramelteon preparation for transmucosal administration, the plasticizer accounts for 0.1-50% by weight.

[0030] In some embodiments, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of the flavoring agent is: 0.001-50% or 0.001-2%; further, the ramelteon preparation for transmucosal administration, by weight percentage, the proportion of the flavoring agent is: 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%.

[0031] In some embodiments, the colorant in the ramelteon preparation for transmucosal administration, by weight percentage, accounts for 0.001-10%; further, the colorant in the ramelteon preparation for transmucosal administration, by weight percentage, accounts for 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0032] The present invention can effectively improve the solubility of ramelteon in diluents such as water by selecting a specific type of composite solvent, optionally supplemented with a specific type of solubilizer, and formulating according to a certain mass ratio, so that it can be prepared into a liquid preparation that can be administered through the mucosa and quickly absorbed, solving the problem of poor bioavailability of the preparation caused by the poor solubility of ramelteon in the traditional technology, or poor patient compliance caused by inconvenience in taking. In addition, through the combination of solvents of specific components, the stability of the ramelteon liquid preparation is guaranteed, the generation of impurities in the ramelteon liquid preparation is reduced, and its storage stability is improved, making it valuable for commercial application.

[0033] The appropriate solvent combination can further improve and balance the performance of various aspects of the ramelteon preparation of the present invention, so that the solubility of ramelteon in the preparation, the stability of the preparation and the safety of the preparation can be at a good level, while maintaining the viscosity of the preparation within an appropriate range, so that the irritation of the preparation is low, thereby greatly improving the taking experience of the preparation without affecting the efficacy of the preparation, and can further improve the patient's compliance with medication.

[0034] In some embodiments, in the ramelteon preparation for transmucosal administration, the concentration of ramelteon is 1 mg / mL to 50 mg / mL. Optionally, the concentration of ramelteon in the preparation can also be, for example, 2 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 38 mg / mL, 40 mg / mL, 42 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL or 48 mg / mL.

[0035] In some embodiments, the ramelteon preparation for transmucosal administration is a film, a spray, an aerosol or drops. Further, it is an oral film, an oral spray, a nasal spray or a sublingual spray. The spray can be, for example, an oral spray or a nasal spray. Among them, the oral spray can be, for example, a sublingual spray. Developed as a sublingual spray, the first-pass effect can be avoided and the absorption of the prototype drug can be increased. The sublingual spray has good compliance for patients with dysphagia, the elderly, etc.

[0036] Another aspect of the present invention provides a method for preparing a ramelteon preparation for transmucosal administration, comprising the following steps: mixing ramelteon and an excipient (a solvent, optionally including a solubilizer); or After ramelteon, the solvent and the solubilizer are mixed, a diluent and / or a flavoring agent are optionally added and mixed.

[0037] In some embodiments, the preparation method comprises the following steps: mixing ramelteon, a first group of solvents and a second group of solvents, then adding a solubilizer and mixing, and finally adding a diluent and mixing.

[0038] Ramelteon, the first group of solvents and the second group of solvents are mixed, and then the diluent and / or flavoring agent are added and mixed.

[0039] Ramelteon, the first group of solvents and the second group of solvents are mixed, and then the third group of solvents and optionally a solubilizer are added and mixed, and finally the diluent is added and mixed.

[0040] Ramelteon, the first group of solvents and the second group of solvents are mixed, and then the third group of solvents and flavoring agents are added and mixed, and finally the diluent is added and mixed.

[0041] In view of the problems that ramelteon adopts solid preparation in the prior art and has low bioavailability and first-pass effect when taken orally, the present invention provides a ramelteon liquid preparation, and more specifically provides a ramelteon liquid preparation for sublingual administration.

[0042] The present invention further, since ramelteon is insoluble in water, the prepared liquid preparation needs to meet the requirements of preparation solubility and stability. Through experiments, a specific solvent combination is used to make the prepared ramelteon liquid preparation have better solubility and stability, so that it has the value of applicability. Therefore, the present invention first provides a ramelteon liquid preparation, which is administered through the nasal or sublingual mucosa in the form of a mist or drops, and solves the technical problems of first-pass effect and bioavailability of oral ramelteon; then, a ramelteon liquid preparation composed of specific components is used to ensure the solubility and stability of the active component of ramelteon, so that it has commercial and promotion value.

[0043] A ramelteon liquid preparation comprises: ramelteon, a first solvent, a second solvent, and a third solvent; wherein the first solvent is one or more of ethanol, carbitol, and isopropanol, the second solvent is polyethylene glycol, and the third solvent is one or more of propylene glycol, glycerol, and hexylene glycol.

[0044] Preferably, the first solvent is ethanol or carbitol, the second solvent is polyethylene glycol with a number average molecular weight of 200-600 (preferably 300-500), and the third solvent is propylene glycol.

[0045] Preferably, the first solvent is ethanol or carbitol, the second solvent is polyethylene glycol 400, and the third solvent is 1,2-propylene glycol.

[0046] In a further preferred embodiment of the present invention, when the first solvent is ethanol, the raw material composition of the preparation includes, by weight percentage: Ramelteon 0.01% to 10%, preferably 0.05% to 8%, more preferably 0.1% to 5%; Ethanol 10-70%, preferably 15-65%, more preferably 20-60%; Polyethylene glycol 1-25%, preferably 2-20%, more preferably 3-15%; 1,2-Propanediol 1-25%, preferably 2-20%, more preferably 3-15%.

[0047] Optionally, the preparation further comprises: 25-85% water, preferably 30-75%, more preferably 35-65%.

[0048] In a further preferred embodiment of the present invention, when the first solvent is carbitol, the specific composition of the raw materials of the preparation includes, by weight percentage: Ramelteon 0.01% to 10%, preferably 0.05% to 8%, more preferably 0.1% to 5%; Carbitol 1-30%, preferably 3-25%, more preferably 5-20%; Polyethylene glycol 10-70%, preferably 15-65%, more preferably 18-60%; 1,2-Propanediol 1-35%, preferably 2-30%, more preferably 3-25%.

[0049] Optionally, the preparation further comprises: 25-85% water, preferably 30-75%, more preferably 35-65%.

[0050] In a further preferred embodiment of the present invention, the preparation further comprises a solubilizer. Preferably, the solubilizer is polyoxyethylene 35 castor oil and / or polyoxyethylene 40 hydrogenated castor oil. Preferably, the mass ratio of the amount of the solubilizer added to the first solvent is 1:1 to 3, preferably 1:1.2 to 2.8.

[0051] In a further preferred embodiment of the present invention, the preparation may further optionally include one or more of the following auxiliary agents: a surfactant, a polymer film-forming material, a plasticizer, a flavoring agent, and a diluent.

[0052] Preferably, the surfactant is one or more of polysorbate and sorbitan fatty acid ester.

[0053] Preferably, the polymer film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, pullulan, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum and gum arabic.

[0054] Preferably, the plasticizer is selected from one or more of polyethylene glycol, polypropylene glycol, glycerol and triethyl citrate.

[0055] Preferably, the flavoring agent is selected from one or more of sucralose, aspartame, saccharin sodium, sugar alcohol, acesulfame potassium, steviol glycosides, citric acid, citric acid, malic acid, stevioside, glycyrrhizin, tea polyphenols, phytic acid, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, thaumatin, and grape flavor.

[0056] Preferably, the diluent comprises one or more of glycerol, ginger oil, eucalyptol, terpene, buffer and liquid oil.

[0057] In a further preferred embodiment of the present invention, the ramelteon liquid preparation is selected from one of the following groups: Group (1): ramelteon 0.1%~5%, ethanol 25~50%, 1,2-propylene glycol 1~10%, PEG400 1~10%, citric acid 0.001%~0.01%, menthol 0.01~0.1%, saccharin sodium 0.001~0.01%, water 35~50%; Group (2): ramelteon 0.1%-5%, carbitol 5-20%, PEG400 20-60%, 1,2-propylene glycol 10-25%, citric acid 0.001%-0.01%, menthol 0.01-0.1%, saccharin sodium 0.001-0.01%, water 35-65%; Group (3): ramelteon 0.1%~5%, ethanol 25~60%, PEG400 1~15%, 1,2-propylene glycol 1~15%, water 35~65%.

[0058] In the present invention, the preparation is a mist or drops. Preferably, the preparation is a spray or aerosol. Preferably, the preparation is a spray or aerosol for intranasal or sublingual administration.

[0059] In the present invention, the number average molecular weight of polyethylene glycol is 200 to 600, preferably 250 to 550, and more preferably 300 to 500. For example, the number average molecular weight of polyethylene glycol is 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600.

[0060] The invention provides a method for preparing a ramelteon liquid preparation, comprising the following steps: uniformly mixing ramelteon, a first solvent, a second solvent and a third solvent to obtain the ramelteon liquid preparation.

[0061] Preferably, after mixing ramelteon, the first solvent, the second solvent, the third solvent and optionally water and a solubilizer, one or more of a surfactant, a polymer film-forming material, a plasticizer, a flavoring agent and a diluent are optionally added and mixed to obtain a ramelteon liquid preparation.

[0062] The present invention provides a use of a ramelteon liquid preparation in preparing a medicament for treating insomnia. The ramelteon liquid preparation is made into a spray or aerosol for intranasal or sublingual administration for treating insomnia. The spray or aerosol for intranasal or sublingual administration is a medicament for treating insomnia.

[0063] The preparation method of the ramelteon liquid preparation of the present invention is simple to operate, and only the components need to be mixed at room temperature. The mixing can be stirred by a stirrer, or the reaction container can be manually shaken, etc., so that the auxiliary materials and ramelteon can be dissolved and mixed with each other, which is easy to industrially expand production and has low requirements on production equipment. The reaction container used in the embodiment of the present invention can be a beaker, etc.

[0064] In the present invention, relative to the active ingredient ramelteon, the first solvent, the second solvent, the third solvent, the solubilizer, the surfactant, the polymer film-forming material, the plasticizer, the flavoring agent and the diluent can be collectively referred to as excipients.

[0065] In another aspect of the present invention, there is provided use of the ramelteon preparation for transmucosal administration described in any of the aforementioned embodiments in the preparation of a medicament for treating insomnia.

[0066] The present invention can effectively improve the solubility of ramelteon in diluents such as water by selecting a specific type of composite solvent and optionally other excipients, and formulating according to a certain mass ratio, so that it can be prepared into a liquid preparation that can be quickly administered through the mucosa, solving the problem of poor bioavailability of preparations caused by poor solubility of ramelteon in traditional technologies, or poor patient compliance caused by inconvenience in taking. Furthermore, the present invention solves the problem of poor stability of ramelteon liquid by selecting a mixed solvent composed of specific components, and adopts the technical solution of the present invention, so that the ramelteon liquid preparation can be stably present, so that it has the basis and conditions for popularization and application.

[0067] The preparation method of the ramelteon liquid preparation of the present invention is simple to operate, and only requires mixing the components at room temperature, is easy to industrially scale up production, and has low requirements on production equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 This is the average blood concentration-time curve of ramelteon in the plasma of SD rats after a single sublingual administration of the test drug and a single administration of the control drug; Figure 2 This is the average blood drug concentration-time curve of the metabolite M-Ⅱ in the plasma of SD rats after a single administration of the test drug and a single oral administration of the control drug. DETAILED DESCRIPTION

[0069] For ease of understanding of the present invention, the present invention will be described more fully below with reference to relevant embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0070] In addition, the terms "first", "second", and "third" are used for descriptive purposes only and are not to be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first", "second", and "third" may explicitly or implicitly include at least one of the features. In the description of the invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0072] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0073] In the present invention, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0074] The percentage concentrations involved in the present invention, unless otherwise specified, refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of the component.

[0075] The temperature parameters in the present invention, if not specifically limited, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument.

[0076] In the present invention, "optionally" means to be performed or not performed, that is, to be added or not added.

[0077] The ramelteon of the present invention has an English name of ramelteon, a CAS number of 196597-26-9, and a systematic name of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide.

[0078] It can be understood that in order to bring a better smell or taste, or to achieve other functions (such as preservation, etc.), one or more other pharmaceutically acceptable excipients may be introduced into the ramelteon liquid preparation of the present invention, such as benzoic acid and its salts, parabens, sorbic acid, chlorobutanol, ethylparaben, benzyl alcohol, phenylethyl alcohol, thimerosal, chlorhexidine acetate and quaternary ammonium compound cationic surfactants and other preservatives, or sucrose, invert sugar, glucose, fructose, dextran, mannitol, xylitol, disodium glycyrrhizinate, trisodium glycyrrhizinate, steviol glycosides, saccharin sodium, peppermint oil, menthol, orange peel tincture, citric acid, tartaric acid and lactic acid and other flavoring agents, or glucose, lactose, dextran, sorbitol, mannitol and its inorganic salts and other osmotic pressure regulators.

[0079] The present invention is further described in detail below in conjunction with specific examples and comparative examples. For experimental parameters not specified in the following specific examples, reference is given to the instructions given in the present application document, and reference may also be made to the experimental manual of the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer. It is understood that the instruments and raw materials used in the following examples are more specific, and in other specific embodiments, they may not be limited thereto. The weight of the relevant components mentioned in the embodiments of the present invention specification can not only refer to the specific content of each component, but also represent the proportional relationship of the weight between each component. Therefore, as long as the content of the relevant components of the embodiments of the present invention specification is proportionally enlarged or reduced, it is within the scope disclosed in the embodiments of the present invention specification. Specifically, the weight described in the embodiments of the present invention specification can be mass units known in the chemical and chemical fields such as μg, mg, g, and kg.

[0080] Source of reagents: Ramelteon (raw materials used in the examples, all commercially available ramelteon can be used in the present invention): Zhejiang Aoxiang Pharmaceutical Co., Ltd., 100.0%; ramelteon tablets (reference preparation, for reference comparison only): Takeda Pharmaceutical Co., Ltd.; ethanol: anhydrous ethanol, Hunan Xiangyikang Pharmaceutical Co., Ltd.; carbitol: Gattefosse SAS; PEG400: Jiangxi Ipsen Pharmaceutical Co., Ltd.; glycerol: Shandong Ruisheng Pharmaceutical Excipients Co., Ltd.; 1,2-propylene glycol: Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; EL35: BASF SE; RH40: BASF SE; glycerol (batch number: GY20210702 Shandong Ruisheng Pharmaceutical Excipients Co., Ltd.). Example 1

[0081] A. Screening of experimental prescriptions Prepare the materials according to Table 1, mix ramelteon, the first group of solvents and the second group of solvents, then add the third group of solvents (if any) and the solubilizer (if any) in sequence, and finally add the diluent to 10 mL, mix and dissolve, and prepare the ramelteon liquid preparation.

[0082] Table 1 Prescription screening

[0083] B. Stability test The preparation prepared in step A was subjected to a stability test at 2°C to 8°C to examine the precipitation of ramelteon in the preparation after being placed for a certain period of time, as shown in Table 2.

[0084] Table 2 Prescription stability

[0085] It is explained that the stability observation time of the present invention is 60 days. If ramelteon is precipitated, the precipitation time is the time of observation record; if it is precipitated immediately, it means that ramelteon is precipitated during preparation or within half an hour; if it is placed for 1 day, it means that after the ramelteon preparation is configured, ramelteon is precipitated in the preparation within 1 day. Recording that there is no precipitation for 14 days indicates that there is no precipitation of solid ramelteon in the ramelteon preparation within 14 days, and ramelteon begins to precipitate from the 15th day. Recording that there is no precipitation for 25 days indicates that there is no precipitation of solid ramelteon in the ramelteon preparation within 25 days, and ramelteon begins to precipitate from the 26th day. Recording that there is no precipitation for 60 days indicates that there is no solid ramelteon precipitation in the ramelteon preparation throughout the stability observation experiment.

[0086] From prescriptions 1 to 2, it can be seen that when there is no solubilizer and the third group of solvents, ramelteon will be directly precipitated during preparation, and the solubility is very poor. After introducing EL35 as a solubilizer into the prescription, if the types and dosages of each component are appropriate, ramelteon will not precipitate even if it is placed for 10 to 30 days (prescriptions 5 to 6). However, if the dosage of the solvent is not appropriate, even if the preparation can remain stable for a short time during preparation, ramelteon will precipitate after being placed for 1 to 2 days (prescriptions 3 to 4, 7 to 8).

[0087] Considering the irritation of ethanol and the sensitivity of some people, carbitol (diethylene glycol monoethyl ether) is used instead of ethanol. However, the solubility effect of carbitol may be slightly inferior to that of ethanol. Therefore, simply replacing the components without adjusting the dosage will also lead to a decrease in the stability of the preparation (prescriptions 9~10). If the dosage of PEG400 is increased, the stability of the preparation can be improved, so that it can remain stable after 30 days (prescription 11).

[0088] However, when the dosage of PEG400 is too much, the viscosity of the preparation will increase, which may lead to a decrease in the efficacy or feeling of use. Therefore, it is considered to keep the dosage of PEG400 unchanged at 20 times the dosage of ramelteon, and introduce the third group of solvents to make the preparation still stable when using 10 times the dosage of carbitol and 20 times the dosage of ramelteon. In prescription 12, glycerol is used as the third group of solvents, and the preparation precipitates after being placed for 7 days, while in prescription 13, 1,2-propylene glycol is used as the third group of solvents, and the preparation remains stable after being placed for 7 days. It can be seen that the right type of third group of solvents is the key to further improving the performance of the stability of the preparation.

[0089] Through further screening, the dosage of 1,2-propylene glycol can be reduced to 4-5 times the dosage of ramelteon (prescriptions 15-16), but when it is as low as 3 times, the preparation will precipitate after 7 days (prescription 14); if the dosage of EL35 is reduced to 10 times that of ramelteon, the stability of the preparation will also decrease, and ramelteon will precipitate after 2 days (prescription 17); if the dosage of PEG400 is reduced to 10 times that of ramelteon, the stability of the preparation will also decrease, and ramelteon will precipitate after 2 days (prescription 18). It can be seen that the appropriate amount of excipients has an important influence on the stability of the preparation.

[0090] The solubilizer EL35 was replaced by RH40, and the dosage remained unchanged, and the stability of the preparation was not significantly affected (Formulation 19).

[0091] Considering that the solubilizers EL35 and RH40 have a strong odor and are not adaptable when used for sublingual spray, the present invention further screens other composition technical solutions of the ramelteon liquid preparation that does not use a solubilizer.

[0092] From prescriptions 21-25, it can be seen that in the absence of the second group of solvents, the combination of ethanol, glycerol and diluent has a greater impact on the stability of the preparation.

[0093] It can be seen from prescriptions 26-30 that by reducing the amount of propylene glycol and increasing PEG400, the stability of the preparation can be effectively improved.

[0094] It can be seen from prescriptions 31-45 that adjusting the dosage of the first solvent, the second solvent, and the third solvent respectively has an impact on the stability of the ramelteon liquid preparation. The dosage of the first solvent, the second solvent, and the third solvent is controlled within a reasonable range, which can ensure the stability of the prepared ramelteon liquid preparation.

[0095] C. Accelerated test The prescription product in Example 1 was subjected to an accelerated test and placed under accelerated conditions (40±2°C, RH75%±5°C) for 1 month. The detection of impurities is shown in Table 3 below.

[0096] Table 3 Impurity analysis of the prescription after accelerated testing

[0097] Note: ND means not detected.

[0098] From the detection of impurities in the prescriptions, it can be seen that compared with day 0, the impurity D of ramelteon in prescription 15 increased rapidly, but was within the limit (<0.5%), and the total impurities increased slightly, also within the limit (≤1.0%). The impurity D and total impurities of ramelteon in prescriptions 33, 37-44, and 46 fluctuated in a large range. It can be seen that the use of ethanol or carbitol as the main solvent and the combination of screening other solvents (polyethylene glycol 400 and propylene glycol) to synergistically dissolve ramelteon affect the stability of the prepared sublingual spray. By controlling the composition of the solvent system in ramelteon and the amount of various solvents, the growth of impurity D can be effectively controlled.

[0099] The present invention obtains two technical routes through experimental screening, one of which is a solvent system using a solubilizer; the other is a method of constructing a stable ramelteon liquid system by combining a plurality of solvents without using a solubilizer, and selecting three solvents with specific components to form a mixed solvent system, thereby avoiding the use of a solubilizer (EL35 and RH40 both have a strong odor), and the prepared ramelteon liquid preparation can have better stability only by combining solvents with specific components.

[0100] Example 2 Weigh 100 mg of ramelteon into a reaction container, add 1000 mg of diethylene glycol monoethyl ether and 2000 mg of PEG400, then add 2000 mg of EL35 and 400 mg of propylene glycol, and finally add water to 10 ml and mix to dissolve.

[0101] Example 3 Weigh 100 mg of ramelteon into a reaction container, add 1000 mg of diethylene glycol monoethyl ether and 2000 mg of PEG400, then add 2000 mg of EL35 and 500 mg of propylene glycol, and finally add water to 10 ml and mix to dissolve.

[0102] Example 4 Weigh 100 mg of ramelteon in a reaction container, add 1000 mg of diethylene glycol monoethyl ether and 2000 mg of PEG400, then add 2000 mg of EL35 and 500 mg of propylene glycol, and finally add water to 10 ml and mix and dissolve. Example 5

[0103] Prescription: Weigh 100 mg of ramelteon in a reaction container, add 1000 mg of diethylene glycol monoethyl ether and 3000 mg of PEG400, then add 2000 mg of EL35, and finally add water to 10 ml and mix to dissolve. Example 6

[0104] Weigh 100 mg of ramelteon in a reaction container, add 1000 mg of diethylene glycol monoethyl ether and 2000 mg of PEG400, then add 2000 mg of EL35 and 1000 mg of propylene glycol, and finally add water to 10 ml and mix to dissolve. Example 7

[0105] Weigh 100 mg of ramelteon into a reaction container, add 2000 mg of ethanol and 2000 mg of PEG400, then add 2000 mg of EL35, and finally add water to 10 ml, mix and dissolve.

[0106] Example 8 Weigh 100 mg of ramelteon into a reaction container, add 1000 mg of ethanol and 2000 mg of PEG400, then add 2000 mg of EL35, and finally add water to 10 ml, mix and dissolve.

[0107] Example 9 Weigh 100 mg of ramelteon into a reaction container, add 4000 mg of ethanol and 500 mg of PEG400, then add 500 mg of 1,2-propylene glycol, add 0.5 mg of citric acid, 3 mg of menthol and 0.5 mg of saccharin sodium, and finally add water to 10 ml and mix to dissolve.

[0108] Example 10 Weigh 100 mg of ramelteon into a reaction container, add 3500 mg of ethanol and 1000 mg of PEG400, then add 500 mg of propylene glycol, add 0.4 mg of citric acid, 2 mg of menthol and 1 mg of saccharin sodium, and finally add water to 10 ml and mix to dissolve.

[0109] Example 11 Effect test of human pilot experiment Experimental design: A randomized, open, single-dose, two-preparation, two-cycle, 7-day washout human pilot study design was adopted. The ramelteon sublingual spray preparation prepared in Prescription 33 of Example 1 of the present application was used as the test drug (T).

[0110] Test drug (T): 2 sprays of ramelteon sublingual spray were administered on an empty stomach, with a dosage of approximately 200 μL (containing 4 mg of ramelteon).

[0111] Reference preparation (R): 2 tablets of ramelteon tablets (containing 16 mg of ramelteon) are administered once on an empty stomach with 240 mL of water. As shown in Table 4:

[0112] With reference to the original experimental design and combined with the characteristics of the self-developed preparation, the sampling time points were designed as follows: 0h, 0.17h, 0.33h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h; 4mL of venous blood was collected each time in a sodium heparin blood collection tube. Centrifugation conditions: 1700 g; 4°C; 10 min.

[0113] Biological sample analysis Basis: The drug instructions show that ramelteon is a melatonin receptor agonist, and the parent drug and its metabolite M-Ⅱ are both active ingredients.

[0114] Detection indicators: The concentrations of ramelteon and M-Ⅱ in serum were determined by LC-MS / MS method.

[0115] Evaluation indicators: Cmax, AUClast, and AUCinf of ramelteon and its main active metabolite M-Ⅱ.

[0116] The average test results of ramelteon (0-12h) are shown in Table 5:

[0117] The AUC of the original drug after the subjects took the test drug on an empty stomach was 13.13 ng•h / mL, and the AUC of the original drug after taking the reference preparation was 11.92 ng•h / mL. After dose conversion, the bioavailability of the original drug in the test drug increased by about 8 times.

[0118] The average test results (0-12h) of metabolite M-II are shown in Table 6:

[0119] The AUC of M-II was 39.15 ng•h / mL after the subjects took the test drug on an empty stomach, and the AUC of M-II was 485.86 ng•h / mL after taking the reference preparation. After dose conversion, the bioavailability of the metabolite M-II in the test drug was about 0.64 times that of the reference preparation.

[0120] Ramelteon tablets mainly exert their pharmacological effects through the prototype drug and its metabolite M-II. The efficacy of M-II is lower than that of the original drug (17 to 25 times lower), but the exposure is significantly higher than that of the original drug (20 to 100 times higher). Sublingual spray avoids first-pass elimination, resulting in a reduction in the exposure of M-II in the body. The data show that the absorption of the test preparation is improved compared with the reference preparation, and the absorption of the prototype drug of the test preparation is better than that of the reference preparation (relative bioavailability is increased by about 8 times). The bioavailability of the sublingual spray developed in the prior art CN110996938A in beagle dogs is only 3.4 times that of the reference preparation (after conversion). It can be seen that the sublingual spray prepared in this application has made significant progress.

[0121] Example 12 Pharmacokinetic study in SD rats A single-cycle inter-group control administration was conducted to compare the pharmacokinetic properties of SD rats after single oral administration of ramelteon tablet suspension (reference preparation, control group) and sublingual administration of sublingual spray of Prescription 33 of Example 1 (test preparation, test group) under fasting conditions; the effects of different administration methods on the pharmacokinetic characteristics of ramelteon and its metabolites in vivo under fasting conditions were investigated.

[0122] The trial adopted a single-dose, single-cycle, inter-group controlled trial design.

[0123] Twelve SD rats, half male and half female, weighing 180 g to 260 g, were randomly divided into a control group and a test group, with 6 rats in each group. The control group was gavaged with a single dose of ramelteon tablet suspension at a dose of 1 mg / kg; the test group was given a single sublingual spray of 0.25 mg / kg.

[0124] 0.3 mL of whole blood was collected from the jugular vein at 0 h before administration and 0.083 h, 0.17 h, 0.25 h, 0.5 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, and 4.0 h after administration. The collected venous blood was placed in an EP tube with EDTA-K2 anticoagulant, shaken and placed in an ice water bath for centrifugation. The concentrations of ramelteon and its metabolite M-II in plasma samples were determined by LC-MS / MS.

[0125] SD rats were given a single oral gavage of the reference preparation R and a single sublingual administration of the test preparation T in a single-cycle, intergroup controlled trial. The main pharmacokinetic parameters of ramelteon and its metabolites in plasma are shown in Table 7 below.

[0126] Table 7 Main pharmacokinetic parameters of ramelteon and its metabolite M-II in plasma of SD rats after single administration (n=6, mean±SD)

[0127] The average AUC of the prototype drug in plasma after a single sublingual administration of the test formulation (0.25 mg / kg) to SD rats 0-t 91.97 ng·h·mL -1 , the average AUC of the prototype drug in plasma after a single oral administration of the reference preparation (1 mg / kg) 0-t 63.80 ng·h·mL -1 After dose conversion, the bioavailability of the original drug of the test preparation is about 5.77 times that of the reference preparation. That is, when SD rats were given sublingual ramelteon sublingual spray, the exposure of ramelteon in the animals was much higher than that of ramelteon suspension. The average AUC of the metabolite M-II of the test preparation (0.25 mg / kg) 0-t 17.07 ng·h·mL -1 , the average AUC of the metabolite M-II of the reference preparation (1 mg / kg) 0-t 87.46 ng·h·mL -1 After dose conversion, the bioavailability of the test preparation metabolite M-II is about 0.78 times that of the reference preparation. That is, when the test preparation is sublingually administered to SD rats, the exposure of the metabolite M-II in the animal body is lower than that of the reference preparation.

[0128] The peak concentration (Cmax) of ramelteon original drug in the control group was approximately 1.42 times that of the metabolite M-II, and the exposure (AUC 0-t ) is about 0.73 times that of the metabolite M-II. The peak concentration (Cmax) of ramelteon original drug in the test group was about 13.56 times that of the metabolite M-II, and the exposure amount (AUC 0-t ) is about 5.39 times that of the metabolite M-II. That is, compared with the control group, sublingual administration of the test preparation to SD rats can significantly reduce the peak concentration and exposure of the metabolite M-II and reduce the first-pass effect of the drug.

[0129] Conclusion: Compared with the control group, sublingual spray of the test preparation can significantly increase the bioavailability of the original drug in the plasma of SD rats, reduce the exposure of the metabolite M-II, and reduce the first-pass effect of the drug.

[0130] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0131] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A ramelteon liquid preparation, characterized in that: The preparation comprises: ramelteon, a first solvent, a second solvent and a third solvent; wherein the first solvent is one or more of ethanol, carbitol and isopropanol, the second solvent is polyethylene glycol, and the third solvent is one or more of propylene glycol, glycerol and hexylene glycol.

2. The ramelteon liquid preparation according to claim 1, characterized in that: The first solvent is ethanol or carbitol, the second solvent is polyethylene glycol with a number average molecular weight of 200 to 600 (preferably 300 to 500), and the third solvent is propylene glycol; Preferably, the first solvent is ethanol or carbitol, the second solvent is polyethylene glycol 400, and the third solvent is 1,2-propylene glycol.

3. The ramelteon liquid preparation according to claim 2, characterized in that: When the first solvent is ethanol, the raw material composition of the preparation includes, by weight percentage: Ramelteon 0.01% to 10%, preferably 0.05% to 8%, more preferably 0.1% to 5%; Ethanol 10-70%, preferably 15-65%, more preferably 20-60%; Polyethylene glycol 1-25%, preferably 2-20%, more preferably 3-15%; 1,2-propylene glycol 1-25%, preferably 2-20%, more preferably 3-15%; When the first solvent is carbitol, the specific composition of the raw materials of the preparation includes, by weight percentage: Ramelteon 0.01% to 10%, preferably 0.05% to 8%, more preferably 0.1% to 5%; Carbitol 1-30%, preferably 3-25%, more preferably 5-20%; Polyethylene glycol 10-70%, preferably 15-65%, more preferably 18-60%; 1,2-Propanediol 1-35%, preferably 2-30%, more preferably 3-25%.

4. The ramelteon liquid preparation according to any one of claims 1 to 3, characterized in that: The formulation also includes water and / or a solubilizer; Preferably, the solubilizing agent is polyoxyethylene 35 castor oil and / or polyoxyethylene 40 hydrogenated castor oil; Preferably, the mass ratio of the added amount of the solubilizer to the added amount of the first solvent is 1:1-3, preferably 1:1.2-2.

8.

5. The ramelteon liquid preparation according to any one of claims 1 to 4, characterized in that: The preparation may also optionally include one or more of the following auxiliary agents: a surfactant, a polymer film-forming material, a plasticizer, a flavoring agent, and a diluent.

6. The ramelteon liquid preparation according to claim 5, characterized in that: The surfactant is one or more of polysorbate and sorbitan fatty acid ester; The polymer film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, pullulan, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum, and gum arabic; The plasticizer is selected from one or more of polyethylene glycol, polypropylene glycol, glycerol, and triethyl citrate; The flavoring agent is selected from one or more of sucralose, aspartame, saccharin sodium, sugar alcohol, acesulfame potassium, steviol glycoside, citric acid, citric acid, malic acid, stevioside, glycyrrhizin, tea polyphenols, phytic acid, mint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, thaumatin, and grape flavor; The diluent includes one or more of glycerin, ginger oil, eucalyptus, terpene, buffer and liquid oil.

7. The ramelteon liquid preparation according to claim 1, characterized in that: The ramelteon liquid preparation is selected from one of the following groups: Group (1): ramelteon 0.1%~5%, ethanol 25~50%, 1,2-propylene glycol 1~10%, PEG400 1~10%, citric acid 0.001%~0.01%, menthol 0.01~0.1%, saccharin sodium 0.001~0.01%, water 35~50%; Group (2): ramelteon 0.1%-5%, carbitol 5-20%, PEG400 20-60%, 1,2-propylene glycol 10-25%, citric acid 0.001%-0.01%, menthol 0.01-0.1%, saccharin sodium 0.001-0.01%, water 35-65%; Group (3): ramelteon 0.1%~5%, ethanol 25~60%, PEG400 1~15%, 1,2-propylene glycol 1~15%, water 35~65%.

8. The ramelteon liquid preparation according to any one of claims 1 to 7, characterized in that: The preparation is in the form of a mist or drops; Preferably, the preparation is a spray or an aerosol.

9. A method for preparing the ramelteon liquid preparation according to any one of claims 1 to 8, comprising the following steps: Evenly mixing ramelteon, the first solvent, the second solvent, and the third solvent to obtain a ramelteon liquid preparation; Preferably, after mixing ramelteon, the first solvent, the second solvent, the third solvent and optionally water and a solubilizer, one or more of a surfactant, a polymer film-forming material, a plasticizer, a flavoring agent and a diluent are optionally added and mixed to obtain a ramelteon liquid preparation.

10. Use of the ramelteon liquid preparation according to any one of claims 1 to 8 in the preparation of a medicament for treating insomnia.

Images