A ramelteon sublingual film and a method of preparing the same

Abstract

The application provides a ramelteon sublingual film and a preparation method thereof. The sublingual film comprises at least ramelteon, a film-forming material, and one or more of a plasticizer, a disintegrant, a flavoring agent or a sweetening agent, and a stabilizer, wherein the ramelteon is in an amorphous state. The application develops the ramelteon into a sublingual film for the first time, so that the ramelteon can be administered through the sublingual mucosa. The ramelteon in the application exists in an amorphous state, is more easily absorbed, has a molecular-level dispersion in the film, is less likely to aggregate and recrystallize, has better stability and solubility, can be completely dissolved in water within 1 min, is rapidly absorbed by the oral mucosa, achieves the purpose of rapid onset, has an absolute bioavailability of greater than 30%, has a bioavailability obviously higher than that of an original tablet and a common film, has a faster onset, has no food effect, has low cost, and has small side effects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically a rametamide sublingual film preparation and its preparation method. Background Technology

[0002] Rametamide is an oral hypnotic drug developed by Takeda Pharmaceutical Company of Japan and approved by the US FDA in July 2005. It is the first melatonin receptor agonist used in clinical treatment of insomnia. It is mainly used to treat insomnia with difficulty falling asleep, and it also has a definite effect on chronic insomnia and short-term insomnia.

[0003] Ramelteamide is a melatonin receptor agonist with high affinity for melatonin MT1 and MT2 receptors, exhibiting specific and complete agonistic activity against these receptors, but not against MT3 receptors. Furthermore, it does not bind to neurotransmitter receptors such as GABA receptor complexes and, within certain limits, does not interfere with the activity of most enzymes. Therefore, it avoids the attention deficit, addiction, and dependence associated with GABA-containing drugs. Its main metabolite, M-II, is present in 20-100 times greater quantities than the parent compound, but its activity is lower, with affinity for MT1 and MT2 receptors approximately one-fifth and one-tenth, respectively. Compared to the parent drug, its pharmacological activity is reduced by approximately 17-25 times. Other metabolites are inactive.

[0004] Currently, ramelteinamide is marketed as a tablet. Clinical data shows that after oral administration, ramelteinamide is rapidly absorbed, with a median time to peak concentration of approximately 0.75 (0.5-1.5) hours. At least 84% is absorbed after oral administration. However, due to the first-pass effect, its absolute bioavailability is only 1.4%. Furthermore, when taken with a high-fat meal, the AUC is 31% higher than when administered on an empty stomach, Cmax is 22% lower, and the median Tmax is delayed by 45 minutes. Therefore, developing a new route of administration, selecting a suitable dosage form, avoiding the first-pass effect, improving bioavailability, eliminating food effects, and shortening the time to peak concentration are key to developing novel ramelteinamide formulations.

[0005] Chinese patent CN110996938A discloses a rameltein amide 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 rameltein amide. 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 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.

[0007] 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.

[0008] In summary, the disadvantages of existing ramelteamide formulations are: (1) obvious gritty sensation after administration and poor compliance; (2) complex process, poor safety, long production cycle and high energy consumption; (3) serious loss after disintegration, inaccurate dosage and large individual differences; (4) the active pharmaceutical ingredient is in crystalline state and has low solubility in saliva. Summary of the Invention

[0009] To address the aforementioned technical problems, this invention provides a rametamide sublingual film preparation and its preparation method.

[0010] The technical solution of the present invention is as follows:

[0011] A sublingual film preparation, the sublingual film preparation comprising at least ramelteinamide, a film-forming material, and one or more of a plasticizer, a disintegrant, a flavoring agent or sweetener, and a stabilizer, wherein the ramelteinamide is in an amorphous state.

[0012] In the aforementioned sublingual film preparation, ramelteamide is dispersed in a molecular state within the film preparation.

[0013] The sublingual film preparation contains 0.1-5% ramelteamide by weight.

[0014] The sublingual film has a thickness of 5-1000 μm, preferably 10-500 μm, and a weight of 10-400 mg, preferably 10-100 mg.

[0015] The sublingual film preparation, by weight, comprises at least 0.1-5 parts by weight of ramelteamide, 10-99 parts by weight of film-forming material, 0.1-20 parts by weight of plasticizer, 0.1-20 parts by weight of disintegrant, 0.1-10 parts by weight of flavoring agent or sweetener, and 0.0-10 parts by weight of stabilizer.

[0016] The sublingual film agent wherein the film-forming material is selected from one or more of copovidone, soluplus, povidone, hydroxypropyl methylcellulose, polyvinyl alcohol, polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose, and hydroxyethyl cellulose; preferably, the film-forming material is selected from at least one of copovidone, polyoxyethylene, and soluplus; more preferably, the film-forming material is selected from copovidone and polyoxyethylene.

[0017] In the sublingual film preparation, the weight ratio of the copovidone to the polyoxyethylene is 1:(0.25-4); preferably, the weight ratio of the copovidone to the polyoxyethylene is 1:(0.5-2).

[0018] The plasticizer in the sublingual film is selected from one or more of polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, sorbitol, mannitol, and dibutyl phthalate.

[0019] The disintegrant in the sublingual film is selected from one or more of the following: low-substituted hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, starch, methylcellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, polycrylene potassium, and microcrystalline cellulose.

[0020] The sweetener in the sublingual film is selected from one or more of aspartame, mannitol, glycerin, fructose, xylitol, sucralose, sorbitol, saccharin, sodium saccharin, stevioside, sucrose, acetylsupan potassium, maltitol, sodium cyclophosphamide, aliquots, and lacritol.

[0021] The sublingual film preparation wherein the flavoring agent is selected from one or more of menthol, sodium citrate, trehalose, anhydrous citric acid, flavoring, ethyl propionate, and diethyl malonate.

[0022] The stabilizer in the sublingual film is selected from one or more of the following: butylated hydroxyanisole, citric acid, butylated hydroxytoluene, sodium ascorbate, vitamins, sodium sulfite, and fumaric acid.

[0023] The method for preparing the sublingual film includes at least the following steps:

[0024] (1) Weigh the rameltein, film-forming material, plasticizer, disintegrant, flavoring agent or sweetener, and stabilizer and add them to the mixer for mixing;

[0025] (2) Add the mixture into the hot melt extrusion equipment at a speed of 0.01-100 kg / h. After extrusion, stretch the mixture into a film using a film stretching machine. Adjust the rotation speed of the film stretching machine to obtain films of different thicknesses and widths.

[0026] (3) The prepared membrane is cut into membranes of different sizes and shapes using a membrane cutting machine.

[0027] The present invention has the following beneficial effects:

[0028] This invention is the first to develop ramelteline into a sublingual film formulation, allowing for drug delivery via the sublingual mucosa. The ramelteline in this invention exists in an amorphous state, making it easier to absorb. The ramelteline in the film is dispersed at the molecular level, resulting in better absorption. The drug is less prone to aggregation and recrystallization, exhibiting better stability and solubility. It can completely dissolve in water within 1 minute and is rapidly absorbed by the oral mucosa, achieving rapid onset of action. Its absolute bioavailability is >30%, significantly higher than that of the original tablets and ordinary films. It has a faster onset of action, no food effect, low cost, and few side effects.

[0029] The pharmaceutical composition of the present invention is applied under the tongue of the subject, and the drug is absorbed through the oral mucosa and enters the bloodstream. The absorption is rapid, and compared with the original tablet (Tmax about 45 min), the time to peak blood concentration is greatly shortened (Tmax about 7 min). It is similar to the injection. Moreover, the pharmaceutical composition of the present invention is not affected by food, has no gritty feeling, and does not require drinking water, which greatly improves patient compliance.

[0030] This invention employs a novel film-forming process that enables continuous production, with a short production cycle, high output, low energy consumption, small production space, low cost, and is more environmentally friendly and safer as it does not use organic solvents. Compared to solvent-based film-forming agents that cannot form molecular distribution, the amorphous film-forming agent of this invention has a faster solubility rate, faster sublingual mucosal absorption, faster onset of action, better stability, and is less prone to crystallization. Detailed Implementation

[0031] Comparative Example 1

[0032] The prescription is shown in the table below. The dosage of rameltein is 0.8 mg, with a single dose of 1 ml, and a batch size of 1000 vials. The amounts (in g) and weight percentages of each component are as follows:

[0033]

[0034]

[0035] Preparation method: Take about 900ml of water for injection, add sodium chloride, stir to dissolve, then add ramelteamide and stir until completely dissolved. Make up to 1000ml with water for injection, and divide into 1000 vials, each containing 1ml.

[0036] Comparative Example 2

[0037] Prepare blank film as a crystal form comparison sample. Amount of each component (unit: g):

[0038]

[0039] Process:

[0040] According to the prescription, copovidone, polyoxyethylene, cross-linked povidone, sucralose, sorbitol, and butylated hydroxytoluene are added to a mixer and mixed at 12 rpm for 5 minutes. Then, the mixture is added to the feeder of a hot melt extruder. The barrel temperature is set to 80℃, 100℃, 130℃, 140℃, 140℃, 140℃, 140℃, 140℃, and 140℃, the die temperature is 140℃, the film stretching speed is 2, and the screw speed is 50 rpm. After film formation, the film is cut into appropriate sizes and shapes and packaged.

[0041] Example 1

[0042] The prescription is shown in the table below. Based on ramelteinamide at a strength of 2mg, with a single tablet weighing 40mg, and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0043]

[0044] Process:

[0045] According to the prescription, add rameltetinamide, soluplus, polyoxyethylene, microcrystalline cellulose, and sodium saccharin to a mixer and mix at 12 rpm for 5 minutes. Then, add the mixture to the feeder of a hot melt extruder. Slowly add glycerin to the barrel using a peristaltic pump. Set the barrel temperature to 80℃, 100℃, 120℃, 130℃, 130℃, 130℃, 130℃, 130℃, and 130℃. Set the die temperature to 130℃, the film stretching speed to 3, and the screw speed to 20 rpm. After film formation, cut the film to the appropriate size and shape and package it.

[0046] result:

[0047] The rametamide orally disintegrating film prepared according to the above formula and process has good film-forming properties, a smooth surface, uniform color, fast disintegration rate, good mechanical properties, and the drug exists in an amorphous state.

[0048] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0049]

[0050]

[0051] Tensile test data

[0052] Serial Number Thickness / mm Tensile strength / MPa 1 0.07 20.15 2 0.07 21.87 3 0.07 20.56

[0053] Example 2

[0054] The prescription is shown in the table below. Based on ramelteinamide at a strength of 2mg, with a single tablet weighing 40mg, and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0055]

[0056] Process:

[0057] According to the prescription, ramelteamide, hydroxypropyl methylcellulose, and aspartame are added to a mixer and mixed at 12 rpm for 5 minutes. Then, the mixture is added to the feeder of a hot melt extruder. Propylene glycol is slowly added to the barrel using a peristaltic pump. The barrel temperature is set to 100℃, 150℃, 170℃, 170℃, 170℃, 170℃, 170℃, 170℃, and the die temperature is 170℃. The film stretching speed is 2, and the screw speed is 20 rpm. After film formation, the film is cut into appropriate sizes and shapes and packaged.

[0058] result:

[0059] The ramelteamide film prepared according to the above formula and process has good film-forming properties, a smooth surface, uniform color, fast disintegration rate, good mechanical properties, and the drug exists in an amorphous state.

[0060] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0061] Serial Number Thickness / mm Disintegration time / s 1 0.05 30 2 0.05 35 3 0.05 38 4 0.05 33 5 0.05 34 6 0.05 35

[0062] Tensile test data

[0063] Serial Number Thickness / mm Tensile strength / MPa 1 0.05 31.46 2 0.05 35.70 3 0.05 32.91

[0064] Example 3

[0065] The prescription is shown in the table below. Based on ramelteinamide at a strength of 2mg, with a single tablet weighing 40mg, and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0066]

[0067]

[0068] Process:

[0069] According to the prescription, add ramelteamide, soluplus, sorbitol, croscarmellose sodium and sucralose to a mixer and mix at 12 rpm for 5 minutes. Then add the mixture to the feeder of a hot melt extruder, setting the barrel temperature to 50℃, 70℃, 90℃, 100℃, 100℃, 100℃, 100℃, 100℃, 100℃, the die temperature to 100℃, the film stretching speed to 1.5, and the screw speed to 20 rpm. After film formation, cut the film into appropriate sizes and shapes and package it.

[0070] result:

[0071] The ramelteamide film prepared according to the above formula and process has good film-forming properties and fast disintegration rate, but the surface has particles and the drug exists in crystal form.

[0072] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0073] Dissolution curve

[0074]

[0075]

[0076]

[0077] Tensile test data

[0078] Serial Number Thickness / mm Tensile strength / MPa 1 0.07 18.97 2 0.07 20.11 3 0.07 18.77

[0079] Example 4

[0080] Films of different thicknesses were prepared, and the differences in mechanical properties, dissolution, and disintegration time of films of different thicknesses were compared. The batch size was 1000 tablets. The dosage of each component (unit: g) was as follows:

[0081]

[0082] Process:

[0083] According to the prescription, ramelteinamide, copovidone, polyoxyethylene, cross-linked povidone, sucralose, sorbitol, and butylated hydroxytoluene are added to a mixer and mixed at 12 rpm for 5 minutes. Then, the mixture is added to the feeder of a hot melt extruder. The barrel temperature is set to 80℃, 100℃, 130℃, 140℃, 140℃, 140℃, 140℃, 140℃, and 140℃, the die temperature is 140℃, the screw speed is 50 rpm, and the film stretching speed is adjusted within the range of 1-5 to obtain film agents of different thicknesses. After film formation, the film is cut into appropriate sizes and shapes and packaged.

[0084] result:

[0085] The ramelteamide films of various thicknesses prepared according to the above formula and process have good film-forming properties, smooth surfaces, and uniform color.

[0086] Dissolution curve

[0087]

[0088] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0089]

[0090]

[0091] Tensile test data

[0092]

[0093] Films can be formed with a thickness of 10-500μm and have good film-forming properties. However, 10μm films are already relatively soft and have relatively low mechanical properties. If the thickness is further reduced, it will affect the transportation and administration of the film. Due to the large thickness of 500μm, the disintegration time is close to 5 minutes (Chinese Pharmacopoeia 2020 edition).

[0094] Example 5

[0095] Different specifications of film formulations were prepared, the effects of different proportions of active pharmaceutical ingredients on film properties were compared, and the absorption in animals was evaluated. The percentages of each component (unit: %) are shown in the table below.

[0096] Prescription 1: 0.1mg strength, 100mg tablet weight, 0.1% raw material content, 1000 tablets per batch.

[0097] Prescription 2: 0.3mg strength, 30mg tablet weight, 1.0% raw material content, batch size 1000 tablets.

[0098] Prescription 3: 0.8mg strength, 20mg tablet weight, 4.0% raw material content, batch size 1000 tablets.

[0099] Prescription 4: 2.0mg strength, 40mg tablet weight, 5.0% raw material content, batch size 1000 tablets

[0100] Prescription 5: 8.0mg strength, 80mg tablet weight, 10.0% raw material content, batch size 1000 tablets.

[0101]

[0102] Process:

[0103] According to the prescription, rameltein, copovidone, polyoxyethylene, crospovidone, sucralose, sorbitol, and butylated hydroxytoluene are added to a mixer and mixed at 12 rpm for 5 minutes. Then, the mixture is added to the feed feeder of a hot melt extruder. The barrel temperature is set to 80℃, 100℃, 130℃, 140℃, 140℃, 140℃, 140℃, 140℃, 140℃, the die temperature is 140℃, the film stretching speed is 2.5, and the screw speed is 50 rpm. After film formation, the film is cut into appropriate sizes and shapes and packaged.

[0104] result:

[0105] The ramelteamide film prepared according to the above formula and process has good film-forming properties, a smooth surface, uniform color, and a fast disintegration rate.

[0106] Dissolution curve

[0107]

[0108]

[0109] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0110]

[0111] Tensile test data

[0112]

[0113] Stability testing: After packaging, the samples were placed at 60℃ / RH75% and the relevant substances were tested after 1 week and 2 weeks, respectively. The total impurity results are shown in the table below:

[0114]

[0115] The results of Example 5 show that the disintegration time of formulations with different drug loadings is not significantly different (the difference is mainly due to the thickness). All formulations disintegrate rapidly and dissolve quickly. The results of the rapid stability test show that the stability of all five formulations is good and no significant degradation has occurred.

[0116] Example 6

[0117] Films with different proportions of film-forming materials were prepared, and the effects of these proportions on film properties were compared. The batch size was 1000 sheets. The amounts of each component (in g) were as follows:

[0118] Prescription 6: 0.8mg strength, 20mg tablet weight, 4.0% raw material content, batch size 1000 tablets.

[0119] Prescription 7: 0.4mg strength, 10mg tablet weight, 4.0% raw material content, batch size 1000 tablets

[0120]

[0121] Process:

[0122] According to the prescription, add ramelteamide, copovidone, polyoxyethylene, crospovidone, sucralose, sorbitol, and butylated hydroxytoluene to a mixer and mix at 12 rpm for 5 minutes. Then, add the mixture to the feeder of a hot melt extruder. Set the barrel temperature to 80℃, 100℃, 130℃, 140℃, 140℃, 140℃, 140℃, 140℃, 140℃, and 140℃, the die temperature to 140℃, the film stretching speed to 2, and the screw speed to 50 rpm. After film formation, cut the film into appropriate sizes and shapes and package it.

[0123] result:

[0124] The ramelteamide film prepared according to the above formula and process has good film-forming properties, a smooth surface, uniform color, and a fast disintegration rate.

[0125] Disintegration time: Determined using the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia.

[0126]

[0127] Tensile test data

[0128]

[0129] Films can be formed when the mixing ratio of copovidone and polyoxyethylene is in the range of 1:(0.25-4), and the process is feasible. Films with a high proportion of copovidone have high mechanical strength but slightly poor extensibility; films with a high proportion of polyoxyethylene have low mechanical strength and poor extensibility.

[0130] Example 7

[0131] Six healthy male Beagle dogs, weighing (12±1.0) kg, were selected. They were not given any medication for 14 days prior to the experiment. Fasting began at 20:00 the day before the experiment. On the day of the experiment, the drugs were administered intravenously (comparative sample 1), orally (original ROZEREM, 8 mg), and sublingually (prescriptions 2, 3, 4, and 5) at 9:00 AM. Blood drug concentrations were measured. After the measurement, the dogs were washed out for 14 days, and the administration was repeated once more, with blood drug concentrations measured again. Tmax, Cmax, and AUC were compared for different routes of administration. Sampling times were 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 6 h.

[0132]

[0133] Data from Example 7 show that oral absorption increases the bioavailability of ramelteamide. Compared to the oral original tablet, the sublingual membrane showed a nearly 29-fold increase in relative bioavailability, and the time to peak concentration was shortened to 7 minutes, similar to that of the injectable form. This indicates that the performance of this patented sublingual membrane is superior to the original tablet, requiring only a smaller dose to achieve the same effect and promoting faster sleep onset.

[0134] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention are included within the protection scope of the present invention.

Claims

1. A sublingual film, characterized in that, The product comprises, by weight, 0.1-5 parts of ramelteinamide, 10-99 parts of film-forming material, 0.1-20 parts of plasticizer, 0.1-20 parts of disintegrant, 0.1-10 parts of flavoring agent, and 0.0-10 parts of stabilizer; wherein the ramelteinamide is in an amorphous state. The weight percentage of ramelteamide is 0.1-5%; wherein the film-forming material is a copolyvinylpyrrolidone and polyoxyethylene in a weight ratio of 1:(0.5-2), and the thickness of the film is 50-100μm.

2. The sublingual film according to claim 1, characterized in that... Rametamide in film formulations is dispersed at the molecular level.

3. The sublingual film according to claim 1, characterized in that, The weight of the film agent is 10-400 mg.

4. The sublingual film according to claim 3, characterized in that, The weight of the film agent is 10-100 mg.

5. The sublingual film according to claim 1, characterized in that, The plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, sorbitol, mannitol, and dibutyl phthalate.

6. The sublingual film according to claim 1, characterized in that, The disintegrant is selected from one or more of the following: low-substituted hydroxypropyl methylcellulose, starch, methylcellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, polycrylene potassium, and microcrystalline cellulose.

7. The sublingual film according to claim 1, characterized in that, The flavoring agent is a sweetener, which is selected from one or more of aspartame, mannitol, glycerol, fructose, xylitol, sucralose, sorbitol, saccharin, sodium saccharin, stevioside, sucrose, acetylsupan potassium, maltitol, sodium cyclolactic acid, aliquots, and lacritol.

8. The sublingual film according to claim 1, characterized in that, The flavoring agent is selected from one or more of menthol, sodium citrate, trehalose, anhydrous citric acid, flavoring, ethyl propionate, and diethyl malonate.

9. The sublingual film according to claim 1, characterized in that, The stabilizer is selected from one or more of the following: butylated hydroxyanisole, citric acid, butylated hydroxytoluene, sodium ascorbate, vitamins, sodium sulfite, and fumaric acid.

10. The method for preparing the sublingual film according to any one of claims 1-9, characterized in that, Includes the following steps: (1) Weigh rameltein, film-forming material, plasticizer, disintegrant, flavoring agent and stabilizer and add them to the mixer for mixing; (2) Add the mixture to the hot melt extrusion equipment at a speed of 0.01-100 kg / h, and stretch it into a film using a film stretching machine after extrusion. Adjust the rotation speed of the film stretching machine to obtain films of different thicknesses and widths; (3) Cut the prepared film into films of different sizes and shapes using a film cutting machine.

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