Levobupivacaine oral film and method of preparation thereof

Abstract

The application provides an oral film containing ribociclib and a preparation method thereof. The film is prepared by adding appropriate amounts of carrier materials, plasticizers and other excipients. The application develops ribociclib into an oral film for the first time. Compared with the original research tablet, the dissolution of the oral film is greatly increased. Compared with the tablet, the volume of the film is smaller, the administration is more convenient, the influence of diet is smaller, and the film is not easy to lose.

Description

Technical Field

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

[0002] Leboresen is an orexin OX1 / OX2 receptor antagonist used to treat insomnia characterized by difficulty falling asleep and / or maintaining sleep. Orexin (also known as hypothalamic secretin) is a hypothalamic neuropeptide first reported in the late 1990s. Since then, research has found that orexin can regulate the sleep / wake cycle by maintaining wakefulness and helps regulate appetite and maintain energy homeostasis. Currently, only two insomnia medications target orexin, and leboresen is the second. It was approved for marketing in the United States in December 2019.

[0003] Currently, lebracetam is marketed as a tablet. Clinical data shows that lebracetam is rapidly absorbed after oral administration, with a peak absorption time of approximately 1.0–1.5 hours. Bioavailability data for lebracetam in humans are currently unavailable, but in male rats and monkeys, bioavailability is low, reaching a maximum of only 23%. Lebracetam is primarily metabolized by the CYP3A4 enzyme. Combined with its low bioavailability in animals, this suggests a strong first-pass effect. Diet also affects the absorption of lebracetam. Under feeding conditions, the AUC of lebracetam is 18% lower than that of fasting administration, Cmax is 23% lower, and the median Tmax is delayed by 2 hours. This also restricts patients' freedom to eat before and after medication, reducing patient compliance. Therefore, developing a new route of administration, selecting a suitable dosage form, avoiding the first-pass effect, improving bioavailability, eliminating the food effect, and shortening the time to peak absorption are key to developing novel lebracetam formulations.

[0004] Chinese patent CN114901285A discloses a pharmaceutical composition of leboresen, the final dosage form of which is tablets. It specifies that the particle size of leboresen is D90 less than 64 μm. Dissolution tests show that in a test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen is over 80% within 15 minutes of the start of the dissolution test. Furthermore, in another test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia - pH 6.8, 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen is over 50% within 15 minutes of the start of the dissolution test. However, this patent does not address the issues of low bioavailability of leboresen and its susceptibility to food effects.

[0005] Chinese patent CN114901285A discloses a leboresen soft capsule, the contents of which consist of leboresen, gelatin, and glycerin. This patent solves the problem of low solubility of leboresen tablets. However, in this invention, the soft capsule is still for oral administration, and it cannot solve the problem of low bioavailability caused by the first-pass effect, nor can it solve the problem of inconsistent drug absorption caused by gastric contractions after eating. Furthermore, in soft capsule formulations, the active pharmaceutical ingredient exists in a liquid form after dissolution, which reduces its stability and is not conducive to long-term storage.

[0006] In summary, existing formulations of leboresen have the following main drawbacks: low bioavailability, significant food effect, long onset time, and large individual variability. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention aims to provide an oral film containing Leborresen and its preparation method, wherein the film is prepared by adding appropriate amounts of carrier materials, plasticizers, and other excipients.

[0008] Leboresen is a poorly soluble compound, almost insoluble in water, poorly soluble in 0.1 mol / L hydrochloric acid, and almost insoluble in Britton-Robinson buffer solution at pH 2–7, which is detrimental to its absorption in the intestines. When taken orally, leboresen has a significant food effect, with peak blood concentrations reaching approximately 3–5 hours after eating, which is insufficient to meet the urgent need of insomnia patients for rapid symptom relief.

[0009] By comparing CN114901285A patent, we found that the leboresen tablets prepared by the original manufacturer achieved rapid dissolution in hydrochloric acid within 15 minutes, but only reached 50% dissolution in a pH 6.8 solution within 15 minutes. Considering that leboresen is mainly absorbed in the intestine, the pH 6.8 solution better reflects its true solubility. This slower solubility not only delays the absorption of leboresen in vivo but also limits the development of its film-forming formulation.

[0010] Oral films must disintegrate and be absorbed in the presence of a small amount of saliva. According to common understanding in the pharmaceutical industry, disintegration within 2 minutes is relatively easy. However, the challenge lies in ensuring complete drug dissolution and absorption through the oral mucosa during disintegration. Currently, most oral mucosal tablets produced in the industry are orally disintegrating tablets, meaning they disintegrate in the mouth, with a very small amount absorbed through the mucosa and the majority swallowed and absorbed by the gastrointestinal tract. This type of orally disintegrating film typically achieves the same blood drug concentration as the original drug, improving patient compliance without altering pharmacokinetics or providing superior efficacy. Therefore, this method is not suitable for addressing issues such as low bioavailability and slow onset of action.

[0011] Therefore, the inventors believe that if the route of administration of leboresen can be modified to include sublingual or mucosal administration, the first-pass effect in the liver can be avoided, compliance can be maintained, bioavailability can be greatly improved, the food effect can be eliminated, and individual variability can be reduced. Sublingual or mucosal administration is most commonly done with sublingual tablets, sublingual films, and oral films. Sublingual tablets, due to their small surface area and weaker adhesiveness than films, are prone to slipping and accidental swallowing, and cannot be effectively absorbed through the mucosa.

[0012] Based on this, the present invention proposes a leboresen film preparation, which has good adhesion and rapidly disintegrates and dissolves in a pH 6.8 phosphoric acid solution to ensure that the drug is in molecular form in saliva and can be absorbed through the sublingual membrane or mucosa.

[0013] The technical solution of the present invention is as follows: An oral film, the oral film comprising at least leboresen, a film-forming material, and one or more of a plasticizer, a flavoring agent or sweetener, and a stabilizer.

[0014] The thickness of the oral film is 5-1000 μm, preferably 5-150 μm.

[0015] The oral film formulation has a particle size D of the active pharmaceutical ingredient. 99 <10µm.

[0016] The oral film formulation described herein uses an amorphous active pharmaceutical ingredient.

[0017] The oral film, by weight, comprises at least 1-50 parts by weight of Leboresen, 20-99 parts by weight of film-forming material, 0.1-20 parts by weight of plasticizer, 0.1-10 parts by weight of flavoring agent or sweetener, and 0.1-10 parts by weight of stabilizer.

[0018] The oral film agent wherein the film-forming material is selected from one or more of copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (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.

[0019] The oral film formulation wherein the plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, glyceryl triacetate, triethyl citrate, sorbitol, mannitol, and dibutyl phthalate.

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

[0021] The stabilizer in the oral film is selected from one or more of the following: butylated hydroxyanisole, citric acid, butylated hydroxytoluene, sodium ascorbate, vitamins, sodium sulfite, and fumaric acid.

[0022] The oral film preparation method is a solvent method and a hot melt extrusion method.

[0023] Patients taking films absorbed through the oral mucosa or sublingually must abstain from water. Considering patient compliance, this abstinence period should not exceed half an hour. Therefore, such films must be at least 80% dissolved within half an hour. Ideally, they should dissolve at least 80% within 10-15 minutes.

[0024] The oral film of the present invention completely disintegrates and dissolves in the oral cavity for absorption. Therefore, the small cup method is used to better simulate the dissolution of the drug in a small amount of saliva. However, considering that the compound is a poorly soluble preparation, the reduction of solvent will make it more difficult to release. Therefore, it is difficult to prepare a rapidly dissolving sample by selecting a suitable carrier material, suitable equipment parameters and suitable film thickness.

[0025] Oral films can be prepared using hot-melt extrusion and solvent extraction methods. Both methods allow for uniform dispersion of the compound within the polymer, maximizing surface area and improving the dissolution rate. Both methods can produce both amorphous and non-amorphous oral films. The inventors investigated both amorphous and non-amorphous oral films and unexpectedly discovered that when the active pharmaceutical ingredient (API) is amorphous, it dissolves completely within 10 minutes (dissolution and release rate method III, 37°C, 150 ml, pH 6.8 phosphate buffer). When the API is in particulate form, the particle size (D99) must be less than 10 µm to achieve a dissolution rate greater than 80% within 10 minutes.

[0026] The inventors also investigated the stability of the film-forming agents. Generally, film-forming agents, due to their large specific surface area and the presence of amorphous or extremely small particles in the active pharmaceutical ingredient, exhibit poor stability. However, the inventors unexpectedly discovered that the stability was significantly improved upon adding the plasticizer PEG. In packaged form, the PEG-containing film-forming agents demonstrated good stability, exhibiting no new impurities compared to 0d, and maintaining acceptable dissolution within 6M.

[0027] Leboresen has a bitter taste in the mouth. The present invention adds sucralose, a sweetener, to the leboresen film to mask the unpleasant bitter taste of the drug and improve patient compliance.

[0028] The present invention has the following beneficial effects: (1) For the first time, Leboresen was developed into an oral film. Compared with the original tablets, the oral film dissolves much faster. The film is smaller in size than the tablets, making it more convenient to administer. It is less affected by food and less prone to loss. (2) It is absorbed faster, has less individual variation, takes effect faster, and helps patients fall asleep faster; (3) It has high viscosity when it comes into contact with water, strong adsorption force, in-situ absorption, less loss, and higher bioavailability.

[0029] (4) The film-forming material used is a polymer material, which has high viscosity when exposed to water, strong adhesion, can be absorbed in situ, and is not easy to slip off. Detailed Implementation

[0030] Example 1 The prescription is shown in the table below. Based on Leboresen's strength of 10mg, with a single tablet weighing 50mg and a batch size of 200 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0031] Process: According to the prescription, add Leboresen, polyvinyl alcohol, polyethylene glycol, silicon dioxide and sucralose into a mixer and mix at 10 rpm for 10 min; then add the mixture into the feeder of a hot melt extruder, set the appropriate temperature as the extrusion temperature, and the screw speed to 20 rpm; use different stretching speeds to obtain films of different thicknesses.

[0032] result: Prescriptions 1-4 cannot form a film.

[0033] Prescription 5 can form a film, but its toughness is extremely poor.

[0034] Example 2 The prescription is shown in the table below. Based on Leboresen's strength of 10mg, with a single tablet weighing 50mg and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows: Leibo Reson 20.0 10.0 Polyvinyl alcohol 74.0 37.0 polyethylene glycol 5.0 2.5 Sucralose 1.0 1.0 total 100.0 50.0 Process: According to the prescription, add Leboresen, polyvinyl alcohol, polyethylene glycol and sucralose to a mixer and mix at 10 rpm for 10 minutes. Then add the mixture to the feeder of a hot melt extruder. Set the barrel temperature to 100℃, 140℃, 175℃, 175℃, 175℃, 175℃, 175℃, 175℃, 175℃, and 175℃, the die temperature to 175℃, and the screw speed to 20 rpm. Use different stretching speeds to obtain films of different thicknesses. After film formation, cut the film into appropriate sizes and shapes and package it.

[0035] result: The oral dissolving film of Leborex prepared according to the above prescription and process has good film-forming properties, smooth surface, uniform color, fast disintegration rate, strong adhesion, good mechanical properties, and the drug exists in an amorphous state.

[0036] Disintegration time: The disintegration time test method for oral solid dosage forms in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0037] 1 0.07 18 2 0.07 15 3 0.07 16 4 0.15 22 5 0.15 21 6 0.14 20

[0038] Dissolution results of phosphate solution at pH 6.8 (dissolution and release rate, third method, 150 ml, 37 °C)

[0039] Example 3 The prescription is shown in the table below. Based on Leboresen's strength of 5mg, with a single tablet weighing 50mg and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0040] Process: Leberai airflow pulverized to D 99 <10µm According to the prescription, add Leboresen, copovidone, Soluplus, polyethylene glycol and sucralose to a mixer and mix at 15 rpm for 10 minutes. Then add the mixture to the feeder of a hot melt extruder, setting the barrel temperature to 80℃, 110℃, 145℃, 145℃, 145℃, 145℃, 145℃, 145℃, and 145℃, the die temperature to 145℃, and the screw speed to 20 rpm. Using different stretching speeds, films of different thicknesses are obtained. After film formation, the films are cut into appropriate sizes and shapes and packaged.

[0041] result: The leboresen film preparation based on the above formula and process has good film-forming properties, a smooth surface, uniform color, fast disintegration rate, strong adhesion, good mechanical properties, and the drug exists in a crystalline state.

[0042] Disintegration time: The disintegration time test method for oral solid dosage forms in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0043] 1 0.07 15 2 0.07 13 3 0.07 16 4 0.14 23 5 0.13 20 6 0.13 19

[0044] Dissolution results of phosphate solution at pH 6.8 (dissolution and release rate, third method, 150 ml, 37 °C)

[0045] Example 4 The prescription is shown in the table below. Based on Leboresen's strength of 5mg, with a single tablet weighing 50mg and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows: Leibo Reson 20.0 10.0 Copolyvinylpyrrolidone 28.8 14.4 Polyoxyethylene 45.7 22.85 polyethylene glycol 5.0 2.5 Sucralose 0.5 0.25 total 100.0 50.0 Process: Determination of D in Leboresen raw material 90 It is 35.7µm, D 99 It is 64.8µm.

[0046] According to the prescription, add Leboresen, copovidone, polyoxyethylene, polyethylene glycol and sucralose to a mixer and mix at 15 rpm for 10 minutes. Then add the mixture to the feeder of a hot melt extruder, setting the barrel temperature to 80℃, 110℃, 145℃, 145℃, 145℃, 145℃, 145℃, 145℃, 145℃, the die temperature to 145℃, and the screw speed to 20 rpm. Using different stretching speeds, films of different thicknesses are obtained. After film formation, the films are cut into appropriate sizes and shapes and packaged.

[0047] result: The leboresen film-forming agent prepared according to the above formula and process has good film-forming properties, but the surface is not smooth, with small protrusions, uneven color, fast disintegration rate, slightly weak adhesion, good mechanical properties, and the drug exists in a crystalline state.

[0048] Disintegration time: The disintegration time test method for oral solid dosage forms in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0049] 1 0.07 16 2 0.07 15 3 0.07 13 4 0.14 22 5 0.13 22 6 0.13 22

[0050] Dissolution results of phosphate solution at pH 6.8 (dissolution and release rate, third method, 150 ml, 37 °C)

[0051] Example 5 The prescription is shown in the table below. Based on Leboresen's strength of 5mg, with a single tablet weighing 50mg and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows: Leibo Reson 20.0 10.0 gelatin 70.0 35.0 polyethylene glycol 2.5 1.25 glycerin 7.0 3.5 Sucralose 0.5 0.25 Purified water / 200.0 total 100.0 50.0 Process: The airflow of Leberle was pulverized to D. 99 <10µm Dissolve sucralose, glycerin, and polyethylene glycol in water by stirring. Add gelatin and stir thoroughly. Add Leboresen and stir until dispersed. Coat the solution evenly onto a polyester tape and heat to 80°C to dry, thus preparing a film. After film formation, cut the film into appropriate sizes and shapes and package it.

[0052] result: The Lebo Reigen film-forming agents of various thicknesses prepared according to the above formula and process have good film-forming properties, smooth surface, and uniform color.

[0053] Disintegration time: The disintegration time test method for oral solid dosage forms in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0054] 1 0.05 11 2 0.05 12 3 0.05 13 4 0.14 19 5 0.13 20 6 0.13 20

[0055] Dissolution results of phosphate solution at pH 6.8 (dissolution and release rate, third method, 150 ml, 37 °C)

[0056] Example 6 The prescription is shown in the table below, with the dosage (unit: g) and weight percentage of each component as follows: Leibo Reson 10.0 5.0 Polyvinyl alcohol 84.0 42.0 polyethylene glycol 5.0 2.5 Sucralose 0.5 0.25 BHT 0.5 0.25 total 100.0 50.0 Leboresen 5mg, cut into 50mg portions Leboresen 2.5mg, cut into 25mg portions Process: According to the prescription, add Leboresen, polyvinyl alcohol, polyethylene glycol, BHT and sucralose to a mixer and mix at 10 rpm for 10 minutes. Then add the mixture to the feeder of a hot melt extruder, setting the barrel temperature to 100℃, 140℃, 175℃, 175℃, 175℃, 175℃, 175℃, 175℃, 175℃, the die temperature to 175℃, and the screw speed to 20 rpm. Using different stretching speeds, films of different thicknesses are obtained. After film formation, the films are cut into appropriate sizes and shapes and packaged.

[0057] result: The oral dissolving film of Leborex prepared according to the above prescription and process has good film-forming properties, smooth surface, uniform color, fast disintegration rate, strong adhesion, good mechanical properties, and the drug exists in an amorphous state.

[0058] Disintegration time: The disintegration time test method for oral solid dosage forms in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0059] 5mg-1 0.05 11 5mg-2 0.05 10 5mg-3 0.05 12 2.5mg-1 0.05 10 2.5mg-2 0.05 9 2.5mg-3 0.05 9

[0060] Dissolution results of phosphate solution at pH 6.8 (dissolution and release rate, third method, 150 ml, 37 °C)

[0061] Example 7 Samples with a thickness of 0.05~0.07 mm from each example were placed in a long-term stability chamber (25℃±2℃; 60%RH±5%RH) to determine their stability.

[0062]

[0063] The results showed that the film preparation of the present invention had good stability even when the plasticizer polyethylene glycol was present in the formulation. Compared with 0d, the impurities did not increase significantly, and the dissolution within 6M still met the requirements.

[0064] 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. An oral film, characterized in that, By weight percentage, it comprises 20% Leboresen, 74.5% film-forming material, 5% polyethylene glycol, and 0.5% sweetener; the film-forming material comprises 28.8% copovidone and 45.7% Soluplus; The particle size D of the leboresen active pharmaceutical ingredient in the oral film is specified. 99 <10µm, the oral film is prepared by hot melt extrusion.

2. The oral film according to claim 1, characterized in that, The active pharmaceutical ingredient is amorphous.

3. The oral film according to claim 1, characterized in that, The thickness of the oral film is 5-150 μm.

4. The oral film according to claim 1, characterized in that, The sweetener is sucralose.

5. The oral film according to claim 1, characterized in that: In a pH 6.8 solution, the dissolution rate is greater than 80% after 10 minutes.

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