Ramelteon preparation for mucosal administration as well as preparation method and application of ramelteon preparation

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a ramelteon preparation for mucosal administration as well as a preparation method and application of the ramelteon preparation. The preparation is prepared by dissolving ramelteon and a solid dispersion material in a pharmaceutically acceptable solvent, and spraying, coating, adsorbing or absorbing on other auxiliary materials in the form of a medicine-containing solution. According to the preparation, ramelteon is uniformly dispersed in other auxiliary materials in a highly dispersed state such as a molecular state, an amorphous state and the like to form a dispersion system existing in a solid form, so that ramelteon can be absorbed through sublingual mucosa, metabolism in gastrointestinal tracts and livers is favorably avoided, the bioavailability of ramelteon is improved, and the bioavailability of ramelteon is improved. Most defects of oral absorption can be well overcome; the preparation process is simple and quick, and the production cost of the medicine is effectively reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and in particular to a ramelteamide preparation administered via mucosal route, its preparation method, and its uses. Background Technology

[0002] Ramelteline, developed by Takeda Pharmaceutical Company of Japan in 1996, entered clinical trials in 1999, and was approved by the FDA for marketing in the United States in 2005, is the first melatonin receptor agonist used clinically to treat insomnia. It is primarily used to treat difficulty falling asleep, but also shows efficacy for chronic and short-term insomnia. Ramelteline is a potent MT1 / MT2 receptor agonist. Compared to melatonin, it has higher affinity and selectivity for MT1 and MT2 receptors, exhibiting specific and complete agonistic effects on these receptors without interacting with MT3 receptors. Simultaneously, it has limited affinity for receptors of other neurotransmitters in the central nervous system, 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, thus avoiding the distraction, addiction, or dependence caused by GABA-based drugs. Therefore, ramelteline is also the first non-addictive insomnia treatment drug not listed as a specially regulated drug, making it a strong competitor among new insomnia treatments.

[0003] Despite the aforementioned advantages in efficacy and pharmacology, ramelteamide's poor water solubility has limited its availability. Currently, most ramelteamide formulations are oral tablets, such as immediate-release tablets, orally disintegrating tablets, dispersible tablets, and sustained-release tablets. These formulations are primarily absorbed through the digestive tract and are metabolized by various cytochrome P-450 (CYP450) isoenzymes, including CYP1A2, CYP2C subfamily, and CYP3A4. This results in a strong first-pass effect in the liver, poor absorption in vivo, significant individual variability, and low oral bioavailability. The absolute bioavailability of the original tablets is approximately 1.8% (0.5%–12%), and the original drug is highly variable. To address this issue, new formulations such as sublingual tablets and sublingual films have been developed. These new formulations effectively mitigate the adverse effects of the first-pass effect compared to oral tablets, but they do not significantly improve the solubility of ramelteamide in the formulation. Therefore, there is still room for improvement in the bioavailability of ramelteamide formulations, and existing formulations are absorbed slowly in the human body. The existing sublingual formulation of ramelteamide needs to remain under the tongue for a relatively long time, which can cause a foreign body sensation and make daily eating and drinking inconvenient, thus reducing patient compliance to some extent.

[0004] Chinese patent CN103429223A discloses a rameltetinamide oral mucosal absorption formulation, including sublingual or oral administration. The formulation uses a large amount of insoluble excipients microcrystalline cellulose and pregelatinized starch, resulting in a noticeable gritty sensation during administration. Furthermore, it lacks a taste mask, leading to poor patient compliance. The preparation process uses a fluidized bed, which is cumbersome and energy-intensive. The median time to peak concentration is approximately 0.6 (0.5-0.8) h, indicating a relatively slow onset of action.

[0005] CN110996938A discloses a ramelteinamide composition, which, when administered via a mucosal delivery system (including intranasal or sublingual), avoids the first-pass effect of the liver. The formulation incorporates sulfobutyl ether-β-cyclodextrin to form an inclusion complex, thereby improving the solubility of ramelteinamide. The process employs wet granulation using ethanol as a solvent; the process steps are cumbersome, the use of organic solvents pollutes the environment and poses an explosion risk, the prepared granules are relatively hard, resulting in a noticeable gritty sensation in the oral cavity and poor patient compliance.

[0006] Chinese patent CN112190555A discloses a ramelteamide sublingual tablet and its preparation method. Both ramelteamide and excipients require sieving, which easily generates dust. Excessive inhalation of this dust by laboratory personnel can cause drowsiness and pose a production safety issue. Furthermore, the ball milling process for ramelteamide and mannitol is cumbersome and unsuitable for industrial production. Sublingual tablets are thicker than sublingual membranes, dissolve slowly, and are easily lost with saliva. Summary of the Invention

[0007] Therefore, it is necessary to provide a rameltetinamide formulation with good solubility, rapid and convenient administration, and high bioavailability via mucosal administration, along with its preparation method and uses. Sublingual mucosal administration of rameltetinamide can effectively avoid the first-pass effect caused by hepatic metabolism, without reducing the bioavailability of rameltetinamide. Sublingual rameltetinamide formulations will have greater application value, and formulation methods can not only improve bioavailability but also enhance patient compliance. The goal is to develop a rameltetinamide sublingual tablet that improves bioavailability by uniformly dispersing the active drug in a highly dispersed state (molecular, amorphous, etc.) among other excipients, forming a dispersion system existing in solid form. The preparation process is simple and rapid, effectively reducing the production cost of the drug, avoiding the first-pass effect, reducing the dosage of rameltetinamide, improving efficacy, reducing side effects, and facilitating clinical use while improving patient compliance.

[0008] In one aspect, the present invention provides a ramelteamide formulation administered via a mucosa, comprising the following components: ramelteamide and excipients, wherein the excipients include a core excipient and an external excipient;

[0009] The excipients include one or more of solvents, solubilizers, surfactants, polymeric film-forming materials, plasticizers, binders, fillers, disintegrants, lubricants, flavoring agents, and diluents. The excipients have a particle size from about 3 micrometers to about 30 micrometers.

[0010] In some embodiments, the ramelteinamide and the binder are dissolved in a pharmaceutically acceptable solvent and remain dissolved to form a drug-containing solution, which is sprayed, coated, absorbed, or adsorbed onto the drug core excipient, and the active drug remains dispersed in the drug core excipient in the final composition to facilitate dissolution.

[0011] In some embodiments, the solvent includes one or more of diethylene glycol monoethyl ether, ethanol, water, isopropanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, glycerol, propylene glycol, and hexanediol. Preferably, the solution prepared by the solvent can be formed from an aqueous solvent, a non-aqueous solvent, or a mixture thereof. When rameltein is coated, adsorbed, or absorbed onto the carrier, it is in solution, and the solvent is volatile and can be removed by drying or other methods. Rameltein is essentially insoluble in purified water but has high solubility in organic solvents such as anhydrous ethanol and propylene glycol; therefore, an aqueous ethanol solution can be considered as the solvent.

[0012] In some embodiments, the mass concentration of rameltein in the drug-containing solution is 0.5% to 30%, preferably 0.5% to 5%, more preferably 1% to 4.5%, further preferably 1.5% to 4%, and even more preferably 2% to 3.5%, for example 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, and 4%. In some embodiments, the concentration of the solid dispersion material in the drug-containing solution is 1% to 30%, preferably 4% to 10%, more preferably 4.5% to 9%, further preferably 5% to 8.5%, and even more preferably 5.5% to 8%, for example 4%, 5%, 6%, 6.25%, 6.5%, 7%, 8%, 9%, or 10%.

[0013] 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, polyethylene glycol glyceryl caprylate, polyethylene glycol 15-hydroxystearate, sodium dodecylbenzene sulfonate, sodium dioctyl succinate sulfonate, lecithin, fatty acid sorbitan, 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, and propylene glycol distearate. Propylene glycol dioctanoate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propylene glycol monolaurate, propylene glycol monomyristate, dipropylene glycol dinonanoate, polypropylene glycol monobutyl ether oleate, propylene glycol dinonanoate, propylene glycol didecanoate, dipropylene glycol dinonanoate, propylene glycol bis(9,10-epoxystearate), propylene glycol monoisostearate, propylene glycol icosanoate, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl polyethylene glycol glycerol, lauroyl polyethylene glycol glycerol, stearoyl polyethylene glycol glycerol, octyl polyethylene glycol glycerol, medium-chain triglycerides, polyglycerol-3 diisostearate, polyglycerol oleate, ethylene glycol palmitate, diisopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide, and diethylene glycol monoethyl ether.

[0014] 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) sorbitol monolaurate, polyoxyethylene (20) sorbitol monopalmitate, polyoxyethylene (20) sorbitol, polyoxyethylene (20) sorbitol monooleate, sorbitol monolaurate, sorbitol monopalmitate, sorbitol monostearate, sorbitol tristearate, and sorbitol monooleate.

[0015] In some embodiments, the polymeric film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyoxyethylene, polyvinylpyrrolidone, pullulan, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum, and gum arabic.

[0016] In some embodiments, the plasticizer is selected from one or more of polyethylene glycol, polypropylene glycol, glycerin, and triethyl citrate.

[0017] In some embodiments, the adhesive is selected from one or more of pregelatinized starch, starch, sucrose, gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (including hydroxypropyl methylcellulose E3, E5, E30, E50), copovidone, polyvinylpyrrolidone (such as povidone K30), amylopectin, dextrin, maltodextrin, cyclodextrin (including α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin), methylcellulose, ethylcellulose, polyethylene glycol 4000, and polyethylene glycol 6000; further, the viscosity of the hydroxypropyl cellulose is 5-10 mPs or higher.

[0018] In some embodiments, the filler is selected from one or more of the following: eutectic, lactose (including lactose of 100 mesh, 120 mesh, and 200 mesh), lactose monohydrate, cellulose lactose, modified starch, pregelatinized starch, corn starch, potato starch, starch, carboxymethyl starch, talc, gum arabic powder, crystalline cellulose, sugar powder, magnesium stearate, mannitol, mannitol (including D-mannitol sugar), xylitol, sorbitol, erythritol, light silicic anhydride, magnesium carbonate, calcium carbonate, L-cysteine, sucrose, glucose, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, microcrystalline cellulose, dextrin, and potato starch.

[0019] In some embodiments, the disintegrant is selected from one or more of PVPP, sodium carboxymethyl starch, amino acids, starch, corn starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, croscarmellose polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, sodium carboxymethyl starch, polyvinylpyrrolidone, and croscarmellose calcium.

[0020] In some embodiments, the lubricant is selected from one or more of magnesium lauryl sulfate, magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose esters of fatty acids, micronized silica gel, hydrogenated vegetable oil, polyethylene glycol 6000, polyethylene glycol 4000, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearoyl fumarate, boric acid, sodium lauryl sulfate, and glyceryl behenate.

[0021] In some embodiments, the flavoring agent is selected from one or more of sucralose, aspartame, sodium saccharin, sugar alcohols, acesulfame potassium, steviol glycosides, citric acid, citric acid, malic acid, steviol glycosides, glycyrrhizin, tea polyphenols, phytic acid, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, sematriol, grape flavor, simple syrup, mannitol, sorbitol, sodium saccharin, aspartame, sucralose, steviol glycosides, glucose, xylitol, maltitol, sodium citrate, and tripotassium citrate. Examples of sugar alcohols include D-mannitol, maltitol, erythritol, reduced isomaltulose, lactitol, and xylitol.

[0022] In some embodiments, the ramelteinamide formulation administered via mucosal delivery comprises, by weight percentage, 0.01% to 50% or 0.5% to 5%. Further, the ramelteinamide formulation administered via mucosal delivery comprises, by weight percentage, 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%.

[0023] In some embodiments, the ramelteamide formulation administered via mucosal delivery comprises, by weight percentage, 20% to 90% of the polymeric film-forming material; further, the ramelteamide formulation administered via mucosal delivery comprises, by weight percentage, 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%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, or 90%.

[0024] In some embodiments, the solubilizer in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 0-99%; further, the solubilizer in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 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%, 2 6%, 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%.

[0025] In some embodiments, the surfactant in the mucosal-administered ramelteamide formulation comprises, by weight percentage, 1-50%; further, the surfactant in the mucosal-administered ramelteamide formulation comprises, by weight percentage, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 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%.

[0026] In some embodiments, the plasticizer in the mucosal-administered ramelteamide formulation comprises, by weight percentage, 0.1% to 50%; further, the plasticizer in the mucosal-administered ramelteamide formulation comprises, by weight percentage, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 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%.

[0027] In some embodiments, the flavoring agent in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 0.001–50% or 0.001–2%; further, the flavoring agent in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 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%.

[0028] In some embodiments, the colorant in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 0.001–10%; further, the colorant in the mucosal administration of ramelteamide formulation comprises, by weight percentage, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0029] In some embodiments, the transmucosal rameltein formulation includes: rameltein, binder, filler, disintegrant, flavoring agent, and lubricant.

[0030] In some embodiments, the transmucosal ramelteamide formulation comprises, by weight percentage: 0.01%–10% ramelteamide, 5%–40% binder, 15%–80% filler, 5%–40% disintegrant, 0.01%–5% flavoring agent, and 0.01%–5% lubricant.

[0031] In some embodiments, the transmucosal ramelteamide formulation comprises, by weight percentage: ramelteamide 1%–5%, binder 10–25%, filler 55–70%, disintegrant 10–25%, flavoring agent 0.1%–1.5%, and lubricant 0.1%–1.5%.

[0032] Further, the ramelteamide formulation administered via mucosal delivery comprises, by weight percentage, 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%, or 10%; and the adhesive comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%. The percentages of the filler are: 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%; the percentages of the filler are: 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%, 55%, 58%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 76%, or 80%; the proportion of the disintegrant is: 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%, or 40%; The flavoring agent comprises 0.01%, 0.05%, 0.1%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the total content; the lubricant comprises 0.5-1%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the total content.

[0033] In some embodiments, the mucosal administration of ramelteamide formulation comprises, by weight percentage: ramelteamide 2.5-3.5%, binder 3-16.67%, filler 62.67%, disintegrant 8-16.17%, flavoring agent 0.1-1%, and lubricant 0.50-1%. In some embodiments, the mucosal administration of ramelteamide formulation comprises: ramelteamide, croscarmellose sodium, and povidone.

[0034] In some embodiments, the transmucosal rameltein formulation includes: rameltein, binder, filler, disintegrant, flavoring agent, and lubricant.

[0035] The adhesive is one or more of the following: povidone, pregelatinized starch, starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (including hydroxypropyl methylcellulose E3, E5, E30, E50), copovidone, polyvinylpyrrolidone (such as povidone K30), amylopectin, dextrin, maltodextrin, cyclodextrin (including α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin), methylcellulose, ethylcellulose, polyethylene glycol 4000, and polyethylene glycol 6000.

[0036] The filler is at least one of mannitol and lactose; the disintegrant is selected from one of crospovidone sodium carboxymethyl cellulose, crospovidone, or a mixture of crospovidone and crospovidone sodium carboxymethyl cellulose.

[0037] The flavoring agent is at least one of sodium saccharin and citric acid; the lubricant is magnesium stearate.

[0038] In some embodiments, the ramelteamide formulation is administered sublingually via the sublingual mucosa, with each tablet containing 0.01–5 mg or 0.01–1.5 mg of ramelteamide. For example, tablets may also be available in doses of 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mg, administered 1–3 times daily, preferably once daily.

[0039] On the one hand, a ramelteinamide formulation administered via mucosal delivery is prepared by dissolving ramelteinamide and a solid dispersion material in a pharmaceutically acceptable solvent, and then spraying, coating, adsorbing, or absorbing it onto other excipients in the form of a drug-containing solution.

[0040] Furthermore, the mass ratio of rameltein to the solid dispersion material is 1:1 to 1:6, preferably 1:1 to 5, and more preferably 1:1, 1:2, 1:3, 1:4, etc.

[0041] Furthermore, the other excipients are selected from one or more of solubilizers, surfactants, polymeric film-forming materials, plasticizers, binders, fillers, disintegrants, lubricants, flavoring agents, and diluents. Other excipients and solid dispersion materials have the definitions described in this invention, and will not be repeated here.

[0042] When the ramelteamide formulation of the present invention, administered via the sublingual mucosa, is a tablet, preferably, the weight of the formulation is about 20-200 mg.

[0043] When the ramelteamide formulation of the present invention, administered sublingually, is in the form of a tablet, its absolute hardness is generally at least 1.0 N / mm². 2 Preferably at least 1.5 N / mm 2 More preferably at least 2.0 N / mm 2 When the ramelteamide formulation of the present invention, administered sublingually, is in the form of a tablet, its absolute hardness generally does not exceed 5.0 N / mm². 2 .

[0044] When the ramelteamide formulation of the present invention administered via sublingual mucosa is a tablet, the disintegration time is generally no more than 30 seconds, preferably no more than 15 seconds, and more preferably no more than 10 seconds. When the ramelteamide formulation of the present invention administered via sublingual mucosa is a tablet, the disintegration time is generally not less than 1 second. In the ramelteamide formulation of the present invention administered via sublingual mucosa, the inclusion of the above-mentioned components capable of preventing disintegration in the granules can improve disintegration characteristics. In addition, coating the components preventing disintegration with sugar or sugar alcohol can ensure the pathway for water to penetrate into the formulation, thereby obtaining high disintegration characteristics. The ramelteamide formulation administered via sublingual mucosa of the present invention can achieve good disintegration characteristics and good formulation stiffness.

[0045] The ramelteamide of the present invention is sprayed onto the excipients / other excipients in a dissolved form, and can be directly absorbed into the bloodstream through the sublingual mucosa without being dissolved in oral saliva or the aqueous environment of the gastrointestinal tract, thus achieving rapid onset of action and higher and more sustained bioavailability.

[0046] In another aspect, the present invention provides a method for preparing a ramelteamide formulation administered via mucosal delivery, comprising the following steps:

[0047] S1: Preparation of drug-containing solution: Dissolve the solid dispersion material and ramettel in a solvent to prepare a drug-containing solution;

[0048] S2: Premixing and preheating: Premixing and preheating the first filler and the first disintegrant to obtain a premix;

[0049] S3: One-step granulation: Set the instrument parameters, spray the drug-containing solution into the premix, complete the granulation and drying, and granulation;

[0050] S4: Total blending: After mixing the granulated granules, flavoring agent, second filler and second disintegrant, lubricant is added and the mixture is then blended to obtain total blended granules;

[0051] S5: Tableting: The total mixture of particles is compressed into tablets to obtain tablets.

[0052] Furthermore, the drug-containing solution refers to the solution obtained by first dissolving the adhesive and rameltein in anhydrous ethanol, stirring to dissolve, and then adding pure water.

[0053] Furthermore, the parameters for premixing and preheating include: an inlet air temperature of 70–75°C, a fan frequency of 20–25 Hz, and an air volume of 15–30 m³ / h. 3 / h.

[0054] Furthermore, the instrument parameters for the one-step granulation include: peristaltic pump speed of 15-28 rpm, spray gun pressure of 1.5 bar, preheating temperature of 40-45°C, and air inlet temperature of 50-55°C.

[0055] Furthermore, the drying process continues until the moisture content is measured to be below 4%. Furthermore, the granulation process involves passing the granules through a 24-mesh sieve.

[0056] Furthermore, the mass ratio of the first disintegrant to the second disintegrant is 1:6 to 8, preferably 1:7 to 7.5.

[0057] Further, the first disintegrant is croscarmellose sodium; the second disintegrant is absent, or is selected from croscarmellose sodium, croscarmellose, or a mixture of croscarmellose and croscarmellose sodium.

[0058] Furthermore, the mass ratio of the first filler to the second filler is 1:2 to 3.5, preferably 1:2.5 to 3.

[0059] Furthermore, the first filler is at least one of mannitol and lactose; the second filler is absent or is mannitol.

[0060] The drug-containing solution is sprayed, coated, adsorbed, or absorbed onto the drug core excipients / other excipients to obtain the drug core. This preparation method ensures that the active drug is uniformly dispersed in the drug core excipients / other excipients, thereby improving drug solubility and bioavailability. During the spraying, coating, adsorption, or absorption process, the active drug and binder in the drug-containing solution can fully penetrate into the pores of the drug core excipients / other excipients, forming a tight bond, allowing the drug core to rapidly disintegrate and release the drug when administered sublingually.

[0061] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above 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.

[0062] The preparation method of the transmucosal rameltemine formulation of the present invention is simple to operate, requiring only mixing of the components at room temperature. The mixing can be achieved by stirring with a stirrer or manually shaking the reaction vessel, etc., to ensure that the excipients and rameltemine are mutually dissolved and mixed. This method is easy to scale up for industrial production and has low requirements for production equipment. The reaction vessel used in the embodiments of the present invention can be a beaker, etc.

[0063] In another aspect, the present invention provides the use of the transmucosal ramelteamide formulation described in any of the foregoing embodiments in the preparation of a medicament for treating insomnia.

[0064] The preparation method of the transmucosal ramelteamide formulation of the present invention is simple to operate, requiring only the mixing of each component at room temperature, and is easy to scale up for industrial production with low requirements for production equipment.

[0065] This invention employs a one-step granulation process to simulate a solid dispersion for preparing ramelteamide sublingual tablets. Ramelteamide is uniformly dispersed in other excipients in a highly dispersed state, such as molecular or amorphous, to form a dispersion system (sublingual tablet) existing in solid form. This allows ramelteamide to be absorbed through the sublingual mucosa, thereby effectively avoiding metabolism in the gastrointestinal tract and liver, thus improving the bioavailability of ramelteamide. This invention can effectively solve most of the shortcomings of oral absorption, improve efficacy and reduce side effects, while facilitating clinical use and improving patient compliance.

[0066] To reduce the influence of food and digestive enzymes on the absorption of ramelteamide, and to change the clinical usage from fasting to increase clinical applicability, while simultaneously reducing the dosage and adverse reactions, the dosage form of the existing tablets has been improved. Ramelteamide has been changed from the original ordinary tablets to sublingual tablets. Sublingual administration effectively avoids first-pass metabolism, reduces the dosage, thereby improving bioavailability, eliminating the influence of food, and reducing the coefficient of variation. Furthermore, it is convenient for patients to take, allowing for self-administration and improving compliance. Ramelteamide sublingual tablets overcome the disadvantage of low absolute bioavailability of ramelteamide tablets, achieving the same blood drug concentration with a lower dosage. Simultaneously, utilizing the advantages of sublingual administration, ramelteamide directly enters the bloodstream after sublingual administration, avoiding the first-pass effect and achieving a faster onset of action.

[0067] Rametamide has been developed into sublingual tablets, a parenteral route of administration. This not only avoids the first-pass effect in the liver and improves the oral bioavailability of rametamide tablets, but also reduces the drug's hepatotoxic side effects. Furthermore, the sublingual mucosa lacks a keratinized layer, allowing the drug to be absorbed primarily through intercellular pathways. This route offers good permeability and a short penetration path, enabling rametamide to directly enter the systemic circulation via capillaries and act throughout the body. In addition, the sublingual administration route is simple and easy to administer, resulting in better compliance for patients with swallowing difficulties and the elderly. Attached Figure Description

[0068] Figure 1 Dissolution curve of the sublingual tablets prepared in Example 12 Detailed Implementation

[0069] To facilitate understanding of the present invention, a more complete description will be given 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. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0070] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of the invention, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified. In the description of the present invention, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0072] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0073] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe features or characteristics, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0074] Unless otherwise specified, all percentage concentrations mentioned in this invention refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0075] Unless otherwise specified, the temperature parameters in this invention can be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows temperature fluctuations within the precision range controlled by the instrument.

[0076] The ramelteon described in this invention, with CAS number 196597-26-9, is systematically named (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide.

[0077] It is understood that, in order to bring better odor or taste, or to achieve other functions (such as preservation), the transmucosal administration of ramelteamide formulation of the present invention may also introduce one or more other pharmaceutically acceptable excipients, such as benzoic acid and its salts, parabens, sorbic acid, chlorobutanol, ethylparaben, benzyl alcohol, phenethyl alcohol, thimerosal, chlorhexidine acetate and quaternary ammonium cationic surfactants, or flavoring agents such as sucrose, invert sugar, glucose, fructose, dextran, mannitol, xylitol, disodium glycyrrhizate, trisodium glycyrrhizate, steviol glycosides, sodium saccharin, peppermint oil, menthol, orange peel tincture, citric acid, tartaric acid and lactic acid, or osmotic pressure regulators such as glucose, lactose, dextran, sorbitol, mannitol and their inorganic salts.

[0078] The present invention will be further described in detail below with reference to specific embodiments and comparative examples. Experimental parameters not specified in the following specific embodiments should first be referred to the guidelines given in this application, and may also be referred to experimental manuals or other experimental methods known in the art, or the experimental conditions recommended by the manufacturer. It is understood that the instruments and raw materials used in the following embodiments are relatively specific, and may not be limited to these in other specific embodiments. The weights of the relevant components mentioned in the embodiments of this invention may not only refer to the specific content of each component, but also to the proportional relationship between the weights of the components. Therefore, any scaling up or down of the content of the relevant components according to the embodiments of this invention is within the scope disclosed in the embodiments of this invention. Specifically, the weights mentioned in the embodiments of this invention may be well-known units of mass in the chemical industry, such as μg, mg, g, and kg.

[0079] Reagent source:

[0080] Rametamide (raw materials used in the examples): Zhejiang Aoxing Pharmaceutical Co., Ltd., 100.0%; Rametamide tablets (reference preparation): Takeda Pharmaceutical Company Ltd.; Ethanol: Anhydrous ethanol, Hunan Xiangyikang Pharmaceutical Co., Ltd.; Carbitol: Gattefosse SAS; PEG400: Jiangxi Ipsen Pharmaceutical Co., Ltd.; Glycerin: Shandong Ruisheng Pharmaceutical Excipients Co., Ltd.; 1,2-Propanediol: Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; EL35: BASF SE; RH40: BASF SE

[0081] Example 1: Preparation of Rametamide Sublingual Tablets

[0082] Single dose: Rametamide 2.00 mg, Povidone K30 10.00 mg, Mannitol 10.00 mg, Croscarmellose Sodium 1.20 mg, Sodium Saccharin 0.30 mg, Citric Acid 0.10 mg, Magnesium Stearate 0.30 mg, Mannitol (direct pressure)

[0083] 27.60 mg, croscarmellose sodium 8.50 mg

[0084] Preparation process:

[0085] ① Preparation of drug-containing solution: Add povidone K30 and rameltein to 32mg of anhydrous ethanol, stir to dissolve, and then add 32mg of purified water to make a clear and transparent solution for later use;

[0086] ② Premixing and preheating: Set the inlet air temperature to 75℃, the fan frequency to 25Hz and the air volume to 20m3 / h, and mix mannitol and croscarmellose sodium in a fluidized bed evenly and preheat to above 40℃;

[0087] ③ One-step granulation: Set the peristaltic pump speed to 25 rpm and the spray gun pressure to 1.5 bar. When the material temperature is preheated to above 40℃, immediately spray in the drug-containing solution. After the drug-containing solution is sprayed, adjust the air inlet temperature to 55℃ for drying. After drying, take about 3g of material for moisture testing. If the moisture content is below 4%, the material can be collected.

[0088] ④ Dry granulation: The obtained dry granules are granulated using a 24-mesh sieve;

[0089] ⑤ Total Mixing: Mix the dry granulated granules, sodium saccharin, citric acid, mannitol (direct compression type), and croscarmellose sodium, and then add magnesium stearate for total mixing to obtain total mixed granules;

[0090] ⑥ Tableting: The total mixture of granules is compressed into tablets using a rotary tablet press to obtain rametamide sublingual tablets.

[0091] Example 2: Preparation of Rametamide Sublingual Tablets

[0092] Single dose: Rametamide 2.00 mg, Povidone K30 10.00 mg, Lactose 10.00 mg, Croscarmellose Sodium 1.20 mg, Sodium Saccharin 0.30 mg, Citric Acid 0.10 mg, Magnesium Stearate 0.30 mg, Mannitol (direct pressure)

[0093] 27.60 mg, crospovidone 8.50 mg

[0094] Preparation process:

[0095] ① Preparation of drug-containing solution: Add povidone K30 and rameltein to 32mg of anhydrous ethanol, stir to dissolve, and then add 32mg of purified water to make a clear and transparent solution for later use;

[0096] ② Premixing and preheating: Set the inlet air temperature to 75℃, fan frequency to 25Hz, and air volume to 30m³ / h. 3 / h, lactose and croscarmellose sodium are mixed evenly in a fluidized bed and preheated to above 40°C;

[0097] ③ One-step granulation: Set the peristaltic pump speed to 15 rpm and the spray gun pressure to 1.5 bar. When the material temperature is preheated to above 40℃, immediately spray in the drug-containing solution. After the drug-containing solution is sprayed, adjust the air inlet temperature to 55℃ for drying. After drying, take about 3g of material for moisture testing. If the moisture content is below 4%, the material can be collected.

[0098] ④ Dry granulation: The obtained dry granules are granulated using a 24-mesh sieve;

[0099] ⑤ Total Mixing: Mix the dry granulated granules, sodium saccharin, citric acid, mannitol (direct compression type), and crospovidone, and then add magnesium stearate for total mixing to obtain total mixed granules;

[0100] ⑥ Tableting: The total mixture of granules is compressed into tablets using a rotary tablet press to obtain rametamide sublingual tablets.

[0101] Example 3: Preparation of Rametamide Sublingual Tablets

[0102] Single dose: Rametamide 2.00 mg, Povidone K30 10.00 mg, Lactose and Mannitol 5.00 mg each, Croscarmellose Sodium 1.20 mg, Sodium Saccharin 0.30 mg, Citric Acid 0.10 mg, Magnesium Stearate 0.30 mg, Mannitol (direct pressure) 27.60 mg, Croscarmellose 4.00 mg, Croscarmellose Sodium 4.50 mg

[0103] Preparation process:

[0104] ① Preparation of drug-containing solution: Add povidone K30 and rameltein to 32mg of anhydrous ethanol, stir to dissolve, and then add 32mg of purified water to make a clear and transparent solution for later use;

[0105] ② Premixing and preheating: Set the inlet air temperature to 75℃, the fan frequency to 25Hz, and the air volume to 15m³ / h. 3 / h, lactose, mannitol and croscarmellose sodium are mixed evenly in a fluidized bed and preheated to above 40°C;

[0106] ③ One-step granulation: Set the peristaltic pump speed to 28 rpm and the spray gun pressure to 1.5 bar. When the material temperature is preheated to above 40℃, immediately spray in the drug-containing solution. After the drug-containing solution is sprayed, adjust the air inlet temperature to 55℃ for drying. After drying, take about 3g of material for moisture testing. If the moisture content is below 4%, the material can be collected.

[0107] ④ Dry granulation: The obtained dry granules are granulated using a 24-mesh sieve;

[0108] ⑤ Total Mixing: Mix the dry granulated granules, sodium saccharin, citric acid, mannitol (direct compression type), crospovidone and crospovidone sodium carboxymethyl cellulose, and then add magnesium stearate for total mixing to obtain total mixed granules;

[0109] ⑥ Tableting: The total mixture of granules is compressed into tablets using a rotary tablet press to obtain rametamide sublingual tablets.

[0110] Example 4

[0111] Single dose: Rametamide 2.00 mg, hydroxypropyl cellulose 4 mg, mannitol 43.6 mg, croscarmellose sodium 9.7 mg, sodium saccharin 0.4 mg, magnesium stearate 0.30 mg.

[0112] Preparation process:

[0113] ① Preparation of drug-containing solution: Add hydroxypropyl cellulose and rameltein to 32 mg of anhydrous ethanol, stir to dissolve, and then add 32 mg of purified water to make a clear and transparent solution for later use;

[0114] ② Premixing and preheating: Set the inlet air temperature to 75℃, the fan frequency to 25Hz, and the air volume to 15m³ / h. 3 / h, mannitol and croscarmellose sodium are mixed evenly in a fluidized bed and preheated to above 40°C;

[0115] ③ One-step granulation: Set the peristaltic pump speed to 28 rpm and the spray gun pressure to 1.5 bar. When the material temperature is preheated to above 40℃, immediately spray in the drug-containing solution. After the drug-containing solution is sprayed, adjust the air inlet temperature to 55-85℃ for drying. After drying, take about 3g of material for moisture testing. If the moisture content is below 4%, the material can be collected.

[0116] ④ Dry granulation: The obtained dry granules are granulated using a 24-mesh sieve;

[0117] ⑤ Total blending: The dry-granulated granules, sodium saccharin, and magnesium stearate are mixed together to obtain total blended granules;

[0118] ⑥ Tableting: The total mixture of granules is compressed into tablets using a rotary tablet press to obtain rametamide sublingual tablets.

[0119] Example 5

[0120] The difference from Example 2 is that povidone K30 is replaced with hydroxypropyl cellulose.

[0121] Example 6

[0122] The difference from Example 3 is that povidone K30 is replaced with hydroxypropyl cellulose.

[0123] Example 7

[0124] The difference from Example 4 is that the preparation process is different.

[0125] Specifically: ② Premixing and preheating: Use up all mannitol and croscarmellose sodium; ⑤ Total mixing: Mix the dry granulated granules and sodium saccharin, then add magnesium stearate for total mixing to obtain total mixed granules.

[0126] Example 8

[0127] The difference from Example 5 is that the preparation process is different.

[0128] Specifically: ② Premixing and preheating: Use up all mannitol and croscarmellose sodium; ⑤ Total mixing: Mix the dry granulated granules and sodium saccharin, then add magnesium stearate for total mixing to obtain total mixed granules.

[0129] Example 9

[0130] The difference from Example 6 is that the preparation process is different.

[0131] Specifically: ② Premixing and preheating: Use up all mannitol and croscarmellose sodium; ⑤ Total mixing: Mix the dry granulated granules and sodium saccharin, then add magnesium stearate for total mixing to obtain total mixed granules.

[0132] Example 10

[0133] Single dose: Rametamide 2.00 mg, Mannitol 45.6 mg, Croscarmellose Sodium 9.7 mg, Sodium Saccharin 2.4 mg, Magnesium Stearate 0.30 mg.

[0134] ① Preparation of drug-containing solution: Dissolve rameltein directly in 34.29 mg of ethanol, add 8.57 mg of purified water to prepare a drug-containing solution for later use;

[0135] ② Premixing and preheating: Set the inlet air temperature to 75℃, the fan frequency to 25Hz and the air volume to 20m3 / h. Mix mannitol, croscarmellose sodium and saccharin sodium evenly in the fluidized bed and preheat to above 40℃.

[0136] ③ One-step granulation: Set the peristaltic pump speed to 25 rpm and the spray gun pressure to 1.5 bar. When the material temperature is preheated to above 40℃, immediately spray in the drug-containing solution. After the drug-containing solution is sprayed, adjust the air inlet temperature to 55-75℃ for drying. After drying, take about 3g of material for moisture testing. If the moisture content is below 4%, the material can be collected.

[0137] ④ Dry granulation: The obtained dry granules are granulated using a 24-mesh sieve;

[0138] ⑤ Total blending: The dry-granulated granules and magnesium stearate are mixed together to obtain total blended granules;

[0139] ⑥ Tableting: The total mixture of granules is compressed into tablets using a rotary tablet press to obtain rametamide sublingual tablets.

[0140] During the tableting process, the tableting hardness is 10-20N. After one-step granulation, the compressibility of the material is not significantly improved. In subsequent examples, hydroxypropyl cellulose is considered to be added as a binder to improve the particle state and granulation effect of the material during the granulation process and improve the compressibility of the material.

[0141] Example 11

[0142] The amount of different binders, such as hydroxypropyl cellulose, used in the one-step granulation process may affect the properties of the granules and the granulation effect, thereby affecting the dissolution of the formulation. Therefore, the amount of hydroxypropyl cellulose used was investigated.

[0143] Example 11-1 Hydroxypropyl cellulose content 3%; Single dose: Rametamide 2.00mg, hydroxypropyl cellulose 1.80mg, mannitol 43.8mg, croscarmellose sodium 9.7mg, sodium saccharin 2.4mg, magnesium stearate 0.30mg.

[0144] Example 11-2: Hydroxypropyl cellulose content 6.67%; Single dose: Rametamide 2.00 mg, Hydroxypropyl cellulose 4 mg, Mannitol 43.6 mg, Croscarmellose sodium 9.7 mg, Sodium saccharin 0.4 mg, Magnesium stearate 0.30 mg.

[0145] The preparation process is the same as in Example 1.

[0146] The sublingual tablets prepared in Examples 11-1 and 11-2 had disintegration times of 47–57 seconds. The dissolution curves of the binder hydroxypropyl cellulose at 3% and 6.67% showed no significant difference, indicating rapid dissolution. Hydroxypropyl cellulose in the formulation can improve the granulation effect and the compressibility of the material. Combining the dissolution curve and material compressibility study results, the effect is better when the amount of hydroxypropyl cellulose is 6.67%.

[0147] Example 12

[0148] The amount of different disintegrants, such as sodium croscarmellose, used in the one-step granulation process may affect the dissolution of the formulation. Therefore, the amount of sodium croscarmellose used was investigated.

[0149] Example 12-1: Croscarmellose sodium contains 8% sodium carboxymethyl cellulose; single dose: rameltein 2.00 mg, hydroxypropyl cellulose 4 mg, mannitol 48.5 mg, croscarmellose sodium 4.8 mg, sodium saccharin 0.4 mg, magnesium stearate 0.30 mg.

[0150] Example 12-2 Hydroxypropyl cellulose content 16.17%; Single dose: rameltein 2.00 mg, hydroxypropyl cellulose 4 mg, mannitol 43.6 mg, croscarmellose sodium 9.7 mg, sodium saccharin 0.4 mg, magnesium stearate 0.30 mg.

[0151] The preparation process is the same as in Example 1.

[0152] The sublingual tablets prepared in Examples 12-1 and 12-2 had a disintegration time of 87–107 s, as shown in the example. Figure 1 As shown, when the dosage of croscarmellose sodium is 16.67%, the dissolution point at 5 min is slightly faster than that of the croscarmellose sodium formulation with a dosage of 8%, both of which are rapid dissolution. Since this product is administered sublingually, disintegration in the oral cavity will affect the absorption of this product. Therefore, the preferred dosage of croscarmellose sodium is 16.67%.

[0153] Example 13

[0154] To improve the taste of this product during sublingual administration, different amounts of sodium saccharin in the prescription were investigated.

[0155] Example 13-1: Sodium saccharin content 0.67%; Single dose: Rametamide 2.00mg, hydroxypropyl cellulose 4mg, mannitol 48.5mg, croscarmellose sodium 4.8mg, sodium saccharin 0.4mg, magnesium stearate 0.60mg.

[0156] Example 13-2 does not contain sodium saccharin.

[0157] The preparation process is the same as in Example 1.

[0158] The sublingual tablets prepared in Examples 13-1 and 13-2 were evaluated for their taste. The taste evaluation was divided into eight levels: very poor (1 point), poor (2 points), slightly poor (3 points), fair (4 points), slightly good (5 points), good (6 points), very good (7 points), and excellent (8 points), as shown in Table 1 below:

[0159]

[0160] Results and Conclusions: Example 13-1 scored highly, with a sodium saccharin content of 0.67%. Adding sodium saccharin as a flavoring agent significantly improves the taste of this product; a sodium saccharin content of 0.67% is preferred.

[0161] Comparative Example 1

[0162] Sublingual tablets were prepared according to the description in Example 3 of patent CN112190555B.

[0163] The sublingual tablets prepared in Example 1 of this application have better content uniformity than those in Comparative Example 1. This is because: First, in the preparation of the sublingual tablets in this application, ramelteline and a binder are dissolved in a solvent, and ramelteline is uniformly dispersed in other excipients in a highly dispersed state such as molecular and amorphous forms, forming a dispersion system in solid form, which can ensure the uniformity of ramelteline and the binder; Second, the drug-containing solution containing ramelteline is dispersed in the disintegrant and filler by spraying, achieving uniform dispersion; Third, the uniformly dispersed particles are further mixed with added fillers and disintegrants to obtain total mixed particles, which are then compressed into tablets, ensuring that the content uniformity of Example 1 of this application is better than that of Comparative Example 1.

[0164] On the other hand, the material in the formulation of Comparative Example 1 has poor compressibility, and the particle state and granulation effect are not good, which need to be improved.

[0165] Through disintegration time testing, it was found that the sublingual tablets prepared in Example 1 of this application exhibited highly uniform dispersion of the active ingredient ramelteamide, which facilitates rapid absorption. Furthermore, stability testing revealed that the prepared tablets showed good stability, with a short disintegration time even after long-term storage.

[0166] Effect Example

[0167] SD rats were administered the sublingual tablet suspension of Example 13-1 (experimental group) via drop-in or the commercially available ramelteinamide tablet suspension via gavage (control group) using a single-dose, single-cycle, intergroup controlled crossover design. Plasma samples were collected at different time points, and the contents of ramelteinamide and its metabolite M-II in plasma at different time points were detected. The main pharmacokinetic parameters were calculated to evaluate the relative bioavailability of ramelteinamide and its metabolite in SD rats after sublingual administration of Example 13-1.

[0168] The trial employed a single-dose, single-cycle, intergroup controlled design.

[0169] Twelve SD rats, half male and half female, weighing 180g-200g, were randomly divided into a control group and an experimental group, with six rats in each group. The control group was given a single oral gavage of ramelteamide tablet suspension at a dose of 1mg / kg; the experimental group was given a single sublingual drip of the sublingual tablet suspension of Example 13-1 at a dose of 0.25mg / kg.

[0170] Whole blood samples of 0.3 mL were collected via the jugular vein at 0 h before administration and at 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 EP tubes containing EDTA-K2 anticoagulant, shaken well, and placed in an ice-water bath for centrifugation. The concentrations of ramelteamide and its metabolite M-II in the plasma samples were determined using LC-MS / MS.

[0171] In a single-cycle, intergroup controlled trial, SD rats were administered the control formulation R by gavage and the test formulation T by sublingual drip. The main pharmacokinetic parameters of rameltein and its metabolites in plasma are shown in Table 2 below.

[0172] Table 2. Major pharmacokinetic parameters of ramelteamide and its metabolite M-II in plasma of SD rats after a single dose (n=6, mean±SD)

[0173]

[0174]

[0175] Mean AUC of the parent drug in plasma of SD rats after a single sublingual administration of the test formulation (0.25 mg / kg) 0-t It is 108.77 ng·h·mL -1 The mean AUC of the original drug in plasma after a single oral administration of the control formulation (1 mg / kg) 0-t It is 68.75 ng·h·mL -1 After dose conversion, the bioavailability of the test formulation was approximately 6.33 times that of the control formulation. This means that in SD rats, sublingual administration of ramelteamide sublingual tablet suspension resulted in significantly higher ramelteamide exposure compared to ramelteamide tablet suspension. The mean AUC of metabolite M-II from the test formulation (0.25 mg / kg) was... 0-t 40.03 ng·h·mL -1 The mean AUC of metabolite M-II in the control formulation (1 mg / kg) 0-t It is 93.84 ng·h·mL -1After dosage conversion, the bioavailability of metabolite M-II in the test formulation was approximately 1.71 times that of the control formulation. This means that when the test formulation was administered sublingually to SD rats, the exposure of metabolite M-II in the animals was slightly higher than that of the control formulation.

[0176] Peak concentration of ramelteamide technical in the control group (C max The exposure to ramelteamide technical grade (AUC) was approximately 1.67 times that of metabolite M-II. 0-t The concentration of rameltein amide (C) was approximately 0.73 times that of its metabolite M-II. The peak concentration of rameltein amide in the test group (C0) was... max The exposure to ramelteamide active ingredient (AUC) was approximately 5.19 times that of its metabolite M-II. 0-t The concentration of the test formulation was approximately 2.72 times that of the metabolite M-II. This means that, compared to the control group, sublingual administration of the test formulation to SD rats significantly reduced the peak concentration and exposure of the metabolite M-II, thus decreasing the first-pass effect of the drug.

[0177] Conclusion: Compared with the control group, HXLMT026 sublingual tablets can significantly improve the bioavailability of the original drug in the plasma of SD rats, reduce the exposure of metabolite M-II, and reduce the first-pass effect of the drug.

[0178] Bioavailability experiments revealed that the bioavailability of the rametamide sublingual tablets prepared in this application was significantly improved compared to the original reference formulation.

[0179] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A transmucosal administration of ramelteamide, characterized in that, It is prepared by dissolving rameltein and a solid dispersion in a pharmaceutically acceptable solvent, and then spraying, coating, adsorbing, or absorbing it onto other excipients in the form of a drug-containing solution.

2. The rameltein formulation according to claim 1, characterized in that, The mass ratio of rameltein to the solid dispersion material is 1:1 to 1:

6.

3. The rameltein formulation according to claim 1, characterized in that, The mass concentration of rameltein in the drug-containing solution is 0.5% to 30%, preferably 1.5% to 4%; The concentration of the solid dispersion material in the drug-containing solution is 1-30%, preferably 4-10%.

4. The rameltein formulation according to claim 1, characterized in that, The solid dispersion material includes a binder selected from one or more of the following: pregelatinized starch, starch, sucrose, gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copovidone, polyvinylpyrrolidone (such as povidone K30), amylopectin, and dextrin. The other excipients are selected from one or more of the following: solubilizers, surfactants, polymeric film-forming materials, plasticizers, adhesives, fillers, disintegrants, lubricants, flavoring agents, and diluents. The filler is selected from one or more of the following: lactose, pregelatinized starch, corn starch, talc, crystalline cellulose, powdered sugar, magnesium stearate, mannitol, xylitol, sorbitol, erythritol, light silicic anhydride, magnesium carbonate, calcium carbonate, and L-cysteine. The disintegrant is selected from one or more of the following: amino acids, starch, corn starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, croscarmellose polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, sodium carboxymethyl starch, polyvinylpyrrolidone, and croscarmellose calcium. The lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose esters of fatty acids, micronized silica gel, and sodium stearoyl fumarate. The flavoring agent is selected from one or more of the following: sucralose, aspartame, sodium saccharin, sugar alcohols, acesulfame potassium, steviol glycosides, citric acid, citric acid, malic acid, steviol glycosides, glycyrrhizin, tea polyphenols, phytic acid, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, sematriol, grape flavor, simple syrup, mannitol, sorbitol, sodium saccharin, aspartame, sucralose, steviol glycosides, glucose, xylitol, maltitol, sodium citrate, and tripotassium citrate. The pharmaceutically acceptable solvent is selected from one or more of diethylene glycol monoethyl ether, ethanol, water, isopropanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, glycerol, propylene glycol, and hexanediol.

5. The rameltein formulation according to claim 1, characterized in that, The transmucosal ramelteamide formulation comprises, by weight percentage: ramelteamide 0.01%–10%, binder 5%–40%, filler 15%–80%, disintegrant 5%–40%, flavoring agent 0.01%–5%, and lubricant 0.01%–5%. Preferably, by weight percentage, it comprises: 1%–5% ramelteamide, 10–25% binder, 55–70% filler, 10–25% disintegrant, 0.1%–1.5% flavoring agent, and 0.1%–1.5% lubricant; Preferably, the transmucosal ramelteamide formulation comprises, by weight percentage: 2.5-3.5% ramelteamide, 3-16.67% binder, 62.67% filler, 8-16.17% disintegrant, 0.1-1% flavoring agent, and 0.50-1% lubricant.

6. The rameltein formulation according to claim 1, characterized in that, The binder is povidone or hydroxypropyl cellulose; the filler is at least one of mannitol and lactose; the disintegrant is selected from sodium croscarmellose, croscarmellose, or a mixture of croscarmellose and sodium croscarmellose; the flavoring agent is at least one of sodium saccharin and citric acid; and the lubricant is magnesium stearate.

7. A method for preparing a ramelteinamide formulation administered via mucosal delivery according to any one of claims 1 to 6, comprising the following steps: S1: Preparation of drug-containing solution: Dissolve the solid dispersion material and ramettel in a solvent to prepare a drug-containing solution; S2: Premixing and preheating: Premixing and preheating the first filler and the first disintegrant to obtain a premix; S3: One-step granulation: Set the instrument parameters, spray the drug-containing solution into the premix, complete the granulation and drying, and granulation; S4: Blending: After mixing the granulated granules, flavoring agent, second filler and second disintegrant, lubricant is added and blending is performed to obtain blended granules; S5: Tableting: The total mixture of particles is compressed into tablets to obtain tablets.

8. The preparation method according to claim 7, characterized in that, The parameters for premixing and preheating include: inlet air temperature of 70–75°C, fan frequency of 20–25 Hz, and air volume of 15–30 m³ / h. 3 / h; More preferably, the instrument parameters for the one-step granulation include: peristaltic pump speed of 15-28 rpm, spray gun pressure of 1.5 bar, preheating temperature of 40℃-45℃, and air inlet temperature of 50-55℃; More preferably, the drying process is carried out until the moisture content is below 4%; more preferably, the granulation process is carried out through a 24-mesh sieve.

9. The preparation method according to claim 7, characterized in that, The mass ratio of the first disintegrant to the second disintegrant is 1:6 to 8, preferably 1:7 to 7.5; More preferably, the first disintegrant is croscarmellose sodium; the second disintegrant is absent, or is selected from croscarmellose sodium, croscarmellose, or a mixture of croscarmellose and croscarmellose sodium; Preferably, the mass ratio of the first filler to the second filler is 1:2 to 3.5, more preferably 1:2.5 to 3; More preferably, the first filler is at least one of mannitol and lactose; the second filler is absent, or is mannitol. Preferably, the solvent is an aqueous ethanol solution, preferably a 50-80% aqueous ethanol solution; The concentration of rameltein in the drug-containing solution is 0.5-5%, preferably 1-4.5%, more preferably 1.5-4%, and even more preferably 2-3.5%, for example 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, and 4%. The concentration of the solid dispersion material in the drug-containing solution is 4-10%, preferably 4.5-9%, more preferably 5-8.5%, and even more preferably 5.5-8%, for example 4%, 5%, 6%, 6.25%, 6.5%, 7%, 8%, 9% or 10%.

10. Use of the ramelteinamide formulation administered via mucosal delivery according to any one of claims 1 to 6, or the ramelteinamide formulation prepared by the preparation method according to any one of claims 7 to 9, in the preparation of a medicament for treating insomnia.

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