An asenapine maleate buccal adhesive film formulation, and a preparation method and use thereof

Abstract

The application relates to a preparation method and use of an asenapine maleate oral adhesive film, and belongs to the field of pharmaceutical preparations, in particular to an asenapine maleate self-nanoemulsion oral adhesive film and an asenapine maleate nanocrystal oral adhesive film preparation. The self-nanoemulsion can improve the solubility of asenapine maleate, the low surface tension of the self-nanoemulsion is beneficial to permeating a mucosa hydration layer, the mucosa absorption is enhanced, the nanocrystal can improve the solubility and dissolution rate of API, the drug concentration gradient near the oral mucosa is increased, the diffusion and oral absorption of the drug are promoted. The oral adhesive film can adhere to the sublingual part and rapidly release the drug, the drug is absorbed through rich submucosal blood vessels and directly enters the systemic circulation, the metabolism of the drug in the gastrointestinal tract and the liver is avoided, and the oral bioavailability is enhanced.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method and application of an asenapine maleate self-nanoemulsion oral adhesive film and an asenapine maleate nanocrystal oral adhesive film preparation. Background Art

[0002] Schizophrenia is a chronic mental disorder characterized by abnormal behavior and confusion with reality. Patients experience positive symptoms characterized by hallucinations, negative symptoms characterized by diminished emotional expression and lack of motivation, and cognitive deficits characterized by impaired learning and memory. Patients experience difficulty integrating into social and family life, distort reality, and even develop antisocial tendencies. Common patient compliance issues contribute to the high relapse rate, resulting in intermittent illness, poor long-term treatment efficacy, and incomplete symptom relief. Severe episodes can lead to violent tendencies, including suicidal and disabling behaviors. This not only deeply distresses patients but also places a heavy burden on families and society. Schizophrenia is estimated to be a major contributor to the burden of mental illness, accounting for 15% of total healthcare expenditures. The disorder typically begins in young adulthood and reduces life expectancy by 10 years. Its early onset, prolonged course, and high relapse rate make schizophrenia one of the most burdensome and costly illnesses worldwide.

[0003] Currently, the main treatment for schizophrenia remains medication, primarily with atypical antipsychotics such as olanzapine and risperidone. However, these drugs are associated with serious adverse reactions with long-term use. Asenapine maleate, a newer atypical antipsychotic, offers a wider range of indications, better tolerability, lower toxicity, and side effects compared to olanzapine and risperidone. It can also be used for the emergency treatment of adult patients, offering broad application prospects and clinical efficacy.

[0004] Asenapine Maleate (ASM), also known as asenapine, has the structural formula (3aRS, 12bRS)-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxepin [4,5-c]pyrrole is an atypical antipsychotic drug belonging to the dibenzoxazolidine pyrrole class. It appears as a white powder with a molecular formula of C 17 H 16ClNO·C4H4O4, the structural formula is shown in formula (I). This drug belongs to BCS class II drugs, is poorly soluble in water, and is easily soluble in ethanol, methanol, acetone, etc., with a logP of 4.9 and a pKa value of 8.6 (25°C). ASM is mainly directly glucuronidated by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) and cytochrome P450 1A2 (CYP1A2). Nearly 38 metabolites have been identified, but none of them show clinically relevant activity, and none can cross the blood-brain barrier. ASM interacts with a wide range of receptors in the body, but its exact mechanism of action is still unclear. In schizophrenia, it shows effects on dopamine D2 and 5-HT 2A receptor antagonism, and also D1, D3, D 2A 、D 2B It has a high affinity for D4 receptors and also interacts with serotonin receptor subtypes, including 5-HT7, 5-HT 5A , 5-HT 1A , 5-HT 1B , 5-HT 2C , 5-HT 2B , 5-HT 2A and 5-HT6, in most cases ASM behaves as an antagonist and can be used to treat acute schizophrenia, acute mania in adults and bipolar mania in children.

[0005]

[0006] Asenapine maleate undergoes extensive hepatic and gastrointestinal metabolism, resulting in an oral bioavailability of less than 2%. Schering-Plough's sublingual tablet (Saphris) increases bioavailability to 35% via sublingual administration. However, the preparation, transportation, and storage costs of sublingual tablets are high, and patient compliance is low (no food or water should be consumed for 10 minutes after taking the tablet). To address these challenges faced by clinical formulations, an oral formulation with improved absorption, rapid onset, and high patient compliance is needed.

[0007] The oral mucosal drug delivery system refers to a new drug delivery system in which the preparation acts on the oral cavity to exert local treatment or is directly absorbed into the systemic circulation through the oral mucosa to exert systemic treatment. It has been regarded as an effective alternative to conventional oral and parenteral administration. The oral physiological environment is mild, with a near-neutral pH and low enzyme activity. Drugs are absorbed through the mucosa without first-pass metabolism in the liver. It is characterized by convenient administration, easy removal, and high patient compliance. Compared with other mucosa, the oral mucosa is not easily damaged, has rapid cell renewal and repair, has certain permeability, firmness, and strong resistance to mechanical irritation, and has a stronger tolerance to potential allergens, which can reduce irreversible irritation or damage caused by drug administration.

[0008] So far, some invention patents have provided methods for preparing orally dissolving asenapine maleate films to simplify the preparation process and improve oral absorption. Patent CN 104000800 A discloses an orally dissolving asenapine maleate film. Compared with sublingual tablets, its preparation process is simple and packaging, transportation and storage are convenient. However, organic solvents (ethanol or acetone) are used in the preparation process. In industrial production, a large amount of organic solvents will volatilize, and the final system has the problem of organic solvent residues. Patent CN102657635A discloses a method for preparing a sponge-like asenapine sublingual film with micropores. The film uses silicon dioxide as a pore-forming agent. Micropores are formed on the surface of the film by high-temperature volatilization of the organic solvent. This film will form a large amount of organic solvent residues, and the film uniformity is difficult to control due to the uneven distribution of the number of micropores, making it difficult to ensure the accuracy of the dosage. Asenapine maleate has poor water solubility and is extensively metabolized in the body, while the sublingual mucosa can significantly increase its oral bioavailability. However, the above methods do not improve the solubility of the drug, and all have the problem of short sublingual residence time, which cannot fundamentally improve the oral absorption of the drug.

[0009] Self-nanoemulsion systems are a new technology in the field of pharmaceutical formulations. Asenapine maleate self-nanoemulsion drug delivery formulations can be prepared by dissolving asenapine maleate in a mixture of one or more oils, surfactants, and co-surfactants. When a self-nanoemulsion system comes into contact with water, it spontaneously emulsifies, forming micron- or nanometer-sized droplets, known as self-microemulsion systems and self-nanoemulsion systems, respectively. Because the drug (API) in a self-nanoemulsion system is already dissolved, it can bypass the dissolution process compared to solid APIs, resulting in a faster dissolution or penetration rate. This effectively addresses the poor water solubility and low bioavailability of asenapine maleate. Compared to emulsions, self-emulsifying drug delivery systems are thermodynamically stable, have more stable physicochemical properties, and are easier to prepare. Under appropriate temperatures and moderate movement in the oral cavity or gastrointestinal tract, they rapidly emulsify to form fine microemulsions, thereby increasing drug solubility, permeability, and bioavailability. However, in actual production and use, there are problems such as high production costs, poor transportation and storage, and low drug loading. The use of large doses of surfactants can also cause mucosal irritation. They are generally encapsulated in capsules for oral administration, with a single dosage form and prone to problems such as capsule-shell compatibility, drug precipitation, and leakage. By solidifying the liquid self-emulsifying system in different ways to form a solid self-emulsifying system, the stability of the drug can be significantly improved, effectively improving the shortcomings of liquid preparations in production, storage, and transportation, and increasing the dosage form selection and expanding the scope of drug application.

[0010] Nanocrystal drugs (NCs) are crystalline or amorphous drugs with a size less than 1 μm, no carrier, and a small amount of stabilizer. Typically, NCs exist as crystalline dispersed particles. When dispersed in a liquid, they are called nanosuspensions, which consist of nanocrystals, stabilizers, and a liquid dispersion medium. Nanosuspensions significantly improve the solubility and dissolution rate of drugs by reducing the particle size of the API. They offer advantages such as simple formulation, high safety, high bioavailability, and high drug loading. Nanosuspensions can improve drug solubility and enhance drug penetration and diffusion through the oral mucosa. Orally dissolving films can circumvent extensive metabolism in the liver and gastrointestinal tract. The combination of these two can effectively enhance the oral bioavailability of poorly soluble drugs, representing a novel, efficient, low-cost, and easy-to-prepare delivery method. Furthermore, the physical stability of nanosuspensions is a major challenge in their development and application. Orally dissolving films can solidify nanosuspensions, improving their stability while maintaining the rapid-release properties of the formulation, providing a new option for solidifying nanosuspensions.

[0011] At present, there are relatively few reports on self-nanoemulsions and nanocrystalline oral films in China. Patent CN 113209052 A discloses a cannabidiol self-nanoemulsion buccal film that can significantly increase the drug's in vitro dissolution rate and oral mucosal permeation rate; Patent CN 109172547A discloses a self-microemulsifying oral fast-dissolving film for pets and its preparation method. For many drugs with strong fat solubility, good permeability, and low oral bioavailability, the core problem has not been improved or solved. Traditional oral administration methods have a significant first-pass effect and low bioavailability. The oral mucosal drug delivery system is a new drug delivery route developed to replace the traditional systemic administration route. Compared with the traditional oral administration route, the drug can be absorbed through the oral mucosa and directly enter the systemic circulation, thereby avoiding degradation by gastrointestinal enzymes and the first-pass effect of the liver. The drug can reach an effective blood concentration more quickly, increasing drug absorption and improving drug bioavailability. Compared with the gastrointestinal absorption route, the dosage can be reduced and related side effects can be reduced; oral films have suitable mechanical properties and are easy to transport and store; they have accurate dosage and good taste, which can improve patient compliance with medication and are especially suitable for the elderly, mentally ill patients and children with dysphagia.

[0012] So far, no patents related to asenapine maleate self-nanoemulsion oral adhesive film and nanocrystalline oral adhesive film have been reported. Summary of the Invention

[0013] Based on the physicochemical properties of the drug itself, the advantages and limitations of existing preparations, and the advantages of combining self-nanoemulsions and nanosuspensions with oral mucosal administration, the present invention aims to provide asenapine maleate self-nanoemulsion oral adhesive film and asenapine maleate nanocrystal oral adhesive film preparations. These preparations can improve the solubility of the API and have the advantages of high drug loading, rapid onset of action, rapid absorption, and high bioavailability. In addition, the preparations have excellent mechanical properties and are convenient for storage, transportation, and use.

[0014] The asenapine maleate self-nanoemulsion oral adhesive film preparation of the present invention is mainly composed of an asenapine maleate self-nanoemulsion system, a film-forming material, an adhesive material, a solid adsorbent, and a taste-masking agent. The self-nanoemulsion oral adhesive film preparation is prepared by dissolving asenapine maleate in the self-nanoemulsion system, adsorbing it on the solid adsorbent, and then dispersing it in the film-forming material to form an oral adhesive film. The self-nanoemulsion system comprises an oil phase, an emulsifier, and a co-emulsifier. The droplet size of the self-nanoemulsion system is 10 to 300 nm, preferably 20 to 150 nm.

[0015] The particle size of the emulsion droplets formed after the preparation is re-dissolved is 10 to 300 nm, preferably 20 to 150 nm.

[0016] The content of the self-nanoemulsification system in the asenapine maleate self-nanoemulsification oral adhesive film preparation is 1-80% w / w, preferably 3-70% w / w, and more preferably 10-60% w / w.

[0017] The oil phase contained in the self-nanoemulsion system refers to a pharmaceutically acceptable oil or oily substance selected from the group consisting of soybean oil, castor oil, corn oil, olive oil, sesame oil, sunflower oil, peanut oil, long-chain monoglycerides, long-chain triglycerides, medium-chain triglycerides, caprylic capric triglycerides, caprylic capric mono- and diglycerides, monooleic glyceride, monolinoleic glyceride, glyceryl monolinoleate, propylene glycol fatty acid esters, propylene glycol monolaurate, caprylic / capric / succinic triglyceride, vitamin E, fatty acids and fatty acid esters, mineral oil, or any combination thereof.

[0018] In the self-nanoemulsion oral adhesive film preparation of the present invention, the hydrophilic-hydrophobic balance (HLB value) of the oil phase is 8 to 18. The content of the oil phase in the self-nanoemulsion system is 5-75% w / w, preferably 10-60% w / w, more preferably 15-50% w / w.

[0019] The self-nanoemulsion system in the self-nanoemulsion oral adhesive film preparation provided by the present invention also contains an emulsifier, which adopts various pharmaceutically acceptable non-ionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants or any combination thereof. Specifically selected from perfluorooctane sulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate and other alkyl sulfates, sodium lauryl ether sulfate (SLES) and alkylbenzene sulfonate, Tween 20 or 80, Span 80 or 85, poloxamer, caprylic acid capric acid polyethylene glycol glyceride, polyoxyethylene (35) castor oil ELP, polyoxyethylene ether castor oil, polyoxyethylene ether hydrogenated castor oil, fatty acid polyethylene glycol glyceride, polyoxyethylene dehydrated sorbitan fatty acid ester and phospholipids. The hydrophilic-hydrophobic balance value (HLB value) of the surfactant is 11 to 16.

[0020] The content of the emulsifier in the self-nanoemulsification system is 10-50% w / w, preferably 20-45% w / w.

[0021] The self-nanoemulsifying system in the self-nanoemulsifying oral adhesive film preparation provided by the present invention further comprises an emulsifier. The emulsifier is selected from one or more of ethanol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, 1-hexanol, 2-hexanol, 1-octanol, 2-octanol, fusel oil, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether, tetrahydrofuran glycol ether, and glycerol.

[0022] The content of the co-emulsifier in the self-nanoemulsification system is 3-30% w / w, preferably 5-40% w / w.

[0023] The solid adsorbent used in the self-nanoemulsion oral adhesive film preparation of the present invention is a pharmaceutically acceptable solid adsorbent, selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, talc, silicon dioxide, mannitol, PEG 4000 and PEG 6000.

[0024] The present invention provides an asenapine maleate nanocrystalline oral adhesive film preparation primarily composed of an asenapine maleate nanosuspension, a film-forming material, an adhesive material, a plasticizer, and a taste-masking agent. The asenapine maleate nanosuspension is prepared by wet grinding and then dispersed in a film-forming adhesive to form a bioadhesive film. The nanoparticles formed after reconstitution have a particle size of 10 to 500 nm, preferably 20 to 350 nm.

[0025] The nanosuspension is prepared from a drug and a stabilizer. The nanosuspension comprises 10-60% w / v of the asenapine maleate nanocrystal oral adhesive film preparation, and the nanosuspension particle size ranges from 10 to 400 nm. The concentration of asenapine maleate in the nanosuspension is 1%-6% w / v, preferably 1%-3% w / v. The volume ratio of the nanosuspension to the film-forming adhesive is 3:7. The stabilizer is selected from one or two of Tween 20, Tween 80, poloxamer 188, hypromellose, sodium lauryl sulfate, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), preferably Soluplus.

[0026] Furthermore, the concentration of the stabilizer Soluplus is 0.25%-5% w / v, preferably 0.5%-1% w / v;

[0027] In the nanocrystalline oral adhesive film preparation of the present invention, the plasticizer is selected from any one of polyethylene glycol 400, glycerol, 1,2-propylene glycol, silicone oil, mannitol, and sorbitol, or a mixture of any two of them in any proportion, preferably polyethylene glycol 400 or glycerol.

[0028] In the two oral adhesive film preparations described in the present invention, the taste masking agent is sucralose.

[0029] The film-forming material used in the present invention is a pharmaceutically acceptable polymer film-forming material, including a water-soluble polymer, a water-insoluble polymer, or a combination of one or more water-soluble polymers and / or water-insoluble polymers. The film-forming material is specifically selected from one or a combination of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone (PVP) K90, polyvinyl alcohol-polyethylene glycol copolymer, xanthan gum, tragacanth gum, sodium alginate, and pullulan.

[0030] Furthermore, the content of the film-forming material of the present invention is 10%-60% w / v, preferably 10%-40% w / v.

[0031] The adhesive material used in the present invention is a pharmaceutically acceptable bioadhesive material, including one or two of sodium carboxymethyl cellulose, carbomer, polycarbophil, chitosan, polyvinyl pyrrolidone (PVP) K90, carrageenan, xanthan gum, gelatin, guar gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, copolymer of acrylic acid and alkyl acrylate, sodium hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose.

[0032] Furthermore, the content of the adhesive material of the present invention is 1%-20% w / v, preferably 2%-20% w / v.

[0033] Furthermore, in the formulation of the asenapine maleate self-nanoemulsion oral adhesive film, the mass ratio of asenapine maleate, propylene glycol monocaprylate, polyoxyethylene (35) castor oil ELP and diethylene glycol monoethyl ether is 28:360:296:148.

[0034] Furthermore, the prescription of the asenapine maleate self-nanoemulsion oral adhesive film is:

[0035]

[0036] The dosage of the asenapine maleate self-nanoemulsion oral adhesive film preparation prepared by the present invention is 2.5 mg / tablet, and the above prescription is for a batch of 1000 tablets.

[0037] The present invention also provides a method for preparing an asenapine maleate self-nanoemulsion oral adhesive film preparation, which is specifically as follows:

[0038] a. Mix the drug with the oil phase, emulsifier and co-emulsifier, and stir in a 37°C water bath to fully dissolve the drug to form an asenapine maleate self-nanoemulsion system;

[0039] b. Disperse the film-forming material and the adhesive material in water and stir to dissolve to form a uniform film-forming adhesive;

[0040] c. The asenapine maleate from the nanoemulsion system of step a was poured into the film-forming glue of step b under stirring at room temperature. After the nanoemulsion was formed, a solid adsorbent was added and stirred until uniformly dispersed to allow sufficient adsorption;

[0041] d. Add pigment, taste masking agent, etc., stir evenly at room temperature, let stand to degas, and use a film coating machine to spread the film. Set the scraper height to 1.0 mm and the coating speed to 20 mm / s. After coating, dry at 40°C for 2 h. After the temperature returns to room temperature, demold to obtain the asenapine maleate self-nanoemulsion oral adhesive film preparation.

[0042] The asenapine maleate self-nanoemulsion oral adhesive film preparation provided by the present invention is prepared by adjusting the ratios and amounts of the oil phase, emulsifier, co-emulsifier, and asenapine maleate in the self-nanoemulsion system, and screening the optimal formulation of the asenapine maleate self-nanoemulsion by examining the particle size, PDI, emulsification ability, and stability of the self-nanoemulsion system. The film-forming material and solid adsorbent are determined by examining the film's appearance, mechanical properties, and formulation compatibility. The adhesive material is determined based on adhesion, in vitro retention time, mechanical properties, and formulation compatibility. The optimal formulation of the asenapine maleate self-nanoemulsion oral adhesive film preparation is determined by examining the film's drug loading, particle size change after reconstitution, film appearance, and mechanical properties.

[0043] In the present invention, in the formulation of the cenapine maleate nanocrystal oral adhesive film preparation, the mass ratio of asenapine maleate to Soluplus is 360:60.

[0044] Furthermore, the prescription of the asenapine maleate nanocrystalline oral adhesive film is:

[0045]

[0046] The dosage of the asenapine maleate nanocrystalline oral adhesive film preparation prepared by the present invention is 2.5 mg / tablet, and the above prescription is for a batch of 1000 tablets.

[0047] The present invention also provides a method for preparing an asenapine maleate nanocrystalline oral adhesive film preparation, which is specifically as follows:

[0048] a. The drug, stabilizer, grinding medium and grinding beads were weighed in appropriate amounts according to the ratio of each prescription and placed in a grinding tube, mixed evenly to form a coarse suspension, and asenapine maleate nanosuspension was prepared by wet grinding;

[0049] b. Disperse the film-forming material and the adhesive material in water and stir to dissolve to form a uniform film-forming adhesive;

[0050] c. Pour the asenapine maleate nanosuspension of step a into the film-forming glue of step b under stirring at room temperature and stir evenly;

[0051] d. Add plasticizer, taste masking agent and pigment, stir evenly at room temperature, let stand to degas, and use a film coating machine to spread the film. Set the scraper height to 1.0 mm and the coating speed to 20 mm / s. After coating, dry at 40°C for 2 h. After the temperature returns to room temperature, demold to obtain the asenapine maleate nanocrystal oral adhesive film preparation.

[0052] The asenapine maleate nanocrystalline oral adhesive film provided by the present invention is prepared by adjusting the drug concentration, stabilizer type and concentration, and bead size in the nanosuspension formula, and further selecting the grinding time, grinding frequency, and other factors to determine the preparation process of the nanosuspension. Based on the self-nanoemulsion oral adhesive film, the nanocrystalline oral adhesive film is further formulated, and the plasticizer and nanosuspension dosage are selected. Finally, the asenapine maleate nanocrystalline oral adhesive film is coated.

[0053] The asenapine maleate oral adhesive film preparation of the present invention can be used for treating acute schizophrenia, acute mania in adults and bipolar mania in children.

[0054] The present invention has the following beneficial effects compared to the prior art:

[0055] 1. Provide the process and formulation for two formulations of asenapine maleate: self-nanoemulsion and nanosuspension. These two nanoformulations can improve drug mucosal absorption by improving drug solubility and dissolution, promoting drug diffusion in the mucus layer, increasing oral mucosal absorption and penetration, and prolonging drug retention time, thereby enhancing oral bioavailability. Both can be combined with oral adhesive membranes to achieve drug delivery through the sublingual mucosa. The drug is absorbed directly into the bloodstream through the abundant submucosal blood vessels, avoiding gastrointestinal degradation and the first-pass effect in the liver, thereby improving the oral absorption efficiency of ASM.

[0056] 2. The asenapine maleate oral adhesive film formulation provided by the present invention rapidly hydrates upon contact with a small amount of saliva, adhering to the oral mucosa and resisting detachment. Mental illness patients experience extreme emotional instability, and some patients hide or spit out medication. The oral adhesive film eliminates the need for swallowing and rapidly adheres to and releases the drug after sublingual administration. This formulation can quickly exert its efficacy and stabilize patients' moods, significantly improving medication compliance.

[0057] 3. The present invention creatively introduces a solid adsorbent for absorbing the self-nanoemulsion, which can improve the mechanical properties of the self-nanoemulsion oral adhesive film. The combination of self-nanoemulsion and nanosuspension with oral film also provides a new option for the solidification method of the above preparations, which can effectively solve the long-standing problems of poor stability and low patient compliance of self-nanoemulsion and nanosuspension.

[0058] 4. This invention combines self-nanoemulsion technology and nanocrystals with an oral adhesive membrane. The self-nanoemulsion improves the solubility of asenapine maleate. Its lower surface tension facilitates penetration through the mucosal hydration layer, enhancing mucosal absorption. The nanocrystals increase the solubility and dissolution rate of the API, increasing the drug concentration gradient near the oral mucosa, promoting drug diffusion and oral absorption. The oral adhesive membrane adheres to the tongue and rapidly releases the drug. The drug is absorbed directly into the systemic circulation through the abundant submucosal blood vessels, avoiding metabolism in the gastrointestinal tract and liver, thereby enhancing oral bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 The particle size distribution of asenapine maleate self-nanoemulsion oral adhesive film preparation after redissolution in water;

[0060] Figure 2 The particle size distribution of asenapine maleate nanocrystalline oral adhesive film preparation after redissolution in water;

[0061] Figure 3 The in vitro dissolution curves of asenapine maleate self-nanoemulsion oral adhesive film and asenapine maleate nanocrystal oral adhesive film preparations are shown;

[0062] Figure 4In vivo pharmacokinetic and blood concentration curves of asenapine maleate self-nanoemulsion oral adhesive film and asenapine maleate nanocrystal oral adhesive film preparations. DETAILED DESCRIPTION

[0063] The present invention is described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments obtained without creative work all fall within the scope of protection of the present invention.

[0064] Example 1

[0065] Preparation of Asenapine Maleate Self-nanoemulsion

[0066] 1. Screening of oil phase, emulsifier and co-emulsifier

[0067] Solubility determination of asenapine maleate in different oil phases, emulsifiers and co-emulsifiers: The equilibrium solubility determination was performed using the classic shake flask method. 1 g of the oil phase, emulsifier, and co-emulsifier were added to a centrifuge tube, and then 1 mg of asenapine maleate was added to each centrifuge tube. The tubes were vortexed for 2 minutes, and an appropriate amount of asenapine maleate was added according to the solubility conditions so that visible drug solids were always present in the oil phase. The tubes were shaken in a 37°C constant temperature water bath for 48 hours (100 rpm), removed and centrifuged (13000 rpm, 20 minutes); 0.3 mL of the supernatant was aspirated and transferred to a 10 mL volumetric flask, and the mobile phase was added to the mark. An appropriate amount of the solution was filtered through a 0.45 μm microporous membrane, and the filtrate was added to an injection bottle. The drug solubility was determined by high performance liquid chromatography. The solubility determination results of ASM in different oil phases, emulsifiers, and co-emulsifiers are shown in Table 1.

[0068] Table 1 Solubility of ASM in different oil phases, emulsifiers and co-emulsifiers

[0069]

[0070] The screened oil phase, emulsifiers and co-emulsifiers include caprylic and capric mono- and diglycerides, polyoxyethylene (35) castor oil, diethylene glycol monoethyl ether, medium chain glycerides, soybean oil, caprylic and capric macrogol glycerides, peppermint oil, Tween 20, Tween 60, Tween 80, sesame oil, oleyl alcohol, polyethanol-7-stearate, polyoxyethylene 40 hydrogenated castor oil, PEG400, oleoyl polyoxyethylene glyceride, lauric macrogol glyceride, and propylene glycol monocaprylate.

[0071] 2. Self-nanoemulsion prescription screening

[0072] The oil phase, emulsifier and co-emulsifier were determined by combining solubility and pseudo-ternary phase diagram. The proportion of each component was determined according to the particle size, PDI, emulsification time, transmittance and emulsion stability of the self-nanoemulsion. The final self-nanoemulsion formula was: propylene glycol monocaprylate (45.0%), polyoxyethylene (35) castor oil (37.0%) and diethylene glycol monoethyl ether (18.0%). The measured particle size was 45.54±0.75nm, PDI was 0.18±0.05, and the drug loading was 3.5%.

[0073] Example 2

[0074] Preparation of Asenapine Maleate Nanosuspension

[0075] Asenapine maleate nanosuspension was prepared by wet grinding. An appropriate amount of stabilizer was weighed into a grinding tube, 1 mL of purified water was injected, asenapine maleate was added, and the mixture was shaken to disperse to obtain a coarse suspension. Finally, a certain amount of 0.5 mm zirconium oxide grinding beads was added, the grinding tube was placed in a grinder, and the grinding parameters were adjusted to grind to obtain asenapine maleate nanosuspension.

[0076] The single-factor variable method was used to screen the stabilizer of the nanosuspension and its concentration, grinding time and drug loading, etc. to further optimize the prescription, and a nanosuspension with a drug concentration of 3% w / v and a stabilizer Soluplus concentration of 0.5% w / v was obtained. The grinding time was 60 min, the grinding frequency was 60 Hz, the particle size was 124.20±2.46 nm, and the PDI was 0.13±0.09.

[0077] Example 3

[0078] Preparation of Asenapine Maleate Self-Nanoemulsion Oral Adhesive Films (ASM@SNE-OMFs)

[0079] The present invention uses a solvent casting method to prepare an asenapine maleate self-nanoemulsion oral adhesive film preparation. A film-forming material and an adhesive material are added to purified water in a certain proportion and dissolved, the self-nanoemulsion is added and stirred evenly, a solid adsorbent is added and stirred to fully adsorb the self-nanoemulsion, and finally a taste masking agent is added, and the film is coated and dried to obtain the self-nanoemulsion oral adhesive film preparation. The film-forming materials in this step are preferably hypromellose and polyvinyl alcohol, and the adhesive materials are preferably carbomer 934P, sodium hypromellose, hypromellose K4M, and polyvinylpyrrolidone K90. The film-forming materials and adhesive materials are weighed in appropriate proportions, and the optimal formulation is determined based on the appearance, mechanical properties, and adhesive ability of the film. The drug loading of the film is determined by examining the drug content and particle size changes.

[0080] Table 2 Investigation of drug loading of asenapine maleate self-nanoemulsion oral adhesive film preparation

[0081]

[0082] Example 4

[0083] Preparation of Asenapine Maleate Nanocrystal Oral Adhesive Film Formulation (ASM@NC-OMFs)

[0084] The present invention adopts solvent casting method to prepare asenapine maleate nanocrystal oral adhesive film preparation. Film-forming material and adhesive material are added to purified water in a certain proportion and dissolved, and then nanosuspension is added and stirred evenly. Finally, taste masking agent and plasticizer are added and stirred thoroughly so that the film-forming glue is evenly dispersed. The coating is dried to obtain the nanocrystal oral adhesive film preparation. The film-forming material and adhesive material of asenapine maleate nanocrystal oral adhesive film are based on self-nanoemulsion oral adhesive film, and the two are basically the same. However, since the self-nanoemulsion system itself has a large amount of oil phase, it can play the role of plasticizer. Therefore, plasticizer is not added, while nanocrystal oral adhesive film needs to add plasticizer to improve the mechanical properties of the film. The volume ratio of nanosuspension and film-forming glue is determined by the drug loading of the film. The results are shown in Table 3.

[0085] Table 3 Investigation of drug loading of asenapine maleate nanocrystal oral adhesive film preparation

[0086]

[0087] The specific prescription is as follows:

[0088] Asenapine maleate self-nanoemulsion oral adhesive film 1

[0089]

[0090] *Used in the formulation but removed during the manufacturing process. Asenapine Maleate Self-Nanoemulsion Oral Adhesive Film 2

[0091]

[0092] *Used in the formulation but removed during the manufacturing process. Asenapine Maleate Self-Nanoemulsion Oral Adhesive Film 3

[0093]

[0094]

[0095] *Used in formulation but removed during processing.

[0096] Asenapine maleate self-nanoemulsion oral adhesive film 4

[0097]

[0098] *Used in the formulation but removed during processing. Formulations 1-4 above were used to compare adhesive materials.

[0099] Asenapine maleate self-nanoemulsion oral adhesive film 5

[0100]

[0101] *Used in the recipe but removed during processing. Recipe 5 is used to compare the film-forming materials with Recipe 1.

[0102] Asenapine Maleate Nanocrystal Oral Adhesive Film 6

[0103]

[0104] *Used in the formulation but removed during processing. Asenapine Maleate Nanocrystalline Oral Adhesive Film 7

[0105]

[0106] *Used in formulation but removed during processing. Formulation 7 was used for comparative adhesive material.

[0107] Asenapine Maleate Nanocrystal Oral Adhesive Film 8

[0108]

[0109] *Used in the formulation but removed during processing. Formulation 8 was used for comparative film forming materials.

[0110] Example 5

[0111] Determination of the thickness of asenapine maleate oral adhesive film preparations

[0112] The coated film was cut into three small films of 2 cm × 3 cm at different positions. The thickness of the two preparations was measured using an electronic micrometer (resolution: 0.001 mm) with a five-point sampling method, i.e., the four corners and the center of the film. The five values ​​were recorded and the average value was calculated to obtain the thickness of the oral adhesive film preparation.

[0113] Example 6

[0114] Mechanical property evaluation

[0115] (1) Determination of tensile strength and elongation at break

[0116] Cut the film into 20mm x 150mm strips and secure both ends to the left and right clamps of the electronic stripping machine. Control the sample's tightness, ensuring it's stretched but not taut. Set the stretching speed to 30mm / min. Once the test begins, the right clamp of the electronic stripping machine automatically moves, recording the sensor's force and elongation. Three parallel measurements are performed, and the average values ​​are recorded. The formulas for calculating the film's tensile strength and elongation at break are as follows:

[0117]

[0118]

[0119] (2) Folding endurance test

[0120] A 2 cm × 3 cm membrane sheet was folded repeatedly at the same position and in the same direction until the membrane sheet broke. The number of folds was recorded and the average value was taken (n=3).

[0121] Example 7

[0122] Adhesion time measurement

[0123] The two oral adhesive films were cut into circular pieces with a diameter of 1.5 cm, lightly moistened with simulated saliva (pH 6.8), and attached to the surface of the porcine buccal membrane. The retention time of the films was measured using a disintegration apparatus (37°C, 50 rpm). The films were moved vertically up and down. During the downward movement, the film and the porcine buccal membrane must be completely submerged in the medium solution. The time it took for the film to dissolve or fall off was recorded as the adhesion time.

[0124] Example 8

[0125] Adhesion force determination

[0126] The adhesion of asenapine maleate self-nanoemulsion oral adhesive films and nanocrystal oral adhesive films was measured using a texture analyzer. Porcine buccal membranes were cut into 1.5 cm × 1.5 cm squares and adhered to the punch of the texture analyzer. The formulations were then placed in a watch glass, moistened with simulated saliva, and placed on the lower support of the texture analyzer. The punch was lowered at a speed of 1 mm / s. When the porcine buccal membrane on the punch contacted the formulation, a force of 0.5 N was applied to the punch for 60 seconds. The punch was then raised at a speed of 1 mm / s to separate the porcine buccal membrane from the formulation. The force at separation was recorded and the adhesion force was calculated. The adhesion of the asenapine maleate self-nanoemulsion oral adhesive films and nanocrystal oral adhesive films, as well as both formulations without PVP K90, was also measured.

[0127] According to Examples 5 to 8, the mechanical properties, adhesion force and adhesion time of asenapine maleate oral adhesive film preparations (F1 SNEDDS-OMFs to F5SNEDDS-OMFs, F6 NC-OMFs to F8 NC-OMFs) (formulations of Examples 1-8) were measured. The results are shown in Table 4.

[0128] As shown in Table 4, the formulations containing carbomer, sodium hypromellose, and K4M (F2 SNEDDS-OMFs, F3 SNEDDS-OMFs, F4 SNEDDS-OMFs, and F7 NC-OMFs) exhibited poor film-forming properties and an unsightly appearance. The results in the table show that, despite their long retention times, the films were thick, with numerous bubbles on the surface. Their folding endurance, elongation at break, and tensile strength were also poor. The formulation containing hypromellose exhibited slightly poor adhesion and holding time. Considering the film thickness, folding endurance, elongation at break, tensile time, adhesion, and holding time parameters, along with the aforementioned requirements, F1 SNEDDS-OMFs and F6 NC-OMFs were ultimately selected as the optimal formulations.

[0129] Table 4 Film formulation characteristics

[0130]

[0131] Example 9

[0132] Determination of particle size of asenapine maleate oral adhesive film preparation after reconstitution / hydration

[0133] The homemade asenapine maleate self-nanoemulsion oral adhesive film and nanocrystalline oral adhesive film preparations were redissolved in water, and their particle sizes were measured and compared with the particle sizes of liquid self-nanoemulsion systems and nanosuspensions containing asenapine maleate. The effects of combining the self-nanoemulsion and nanosuspension with the oral adhesive film and the entire formulation process on the particle size were investigated.

[0134] like Figure 1 As shown in Figure 2, the average particle size of asenapine maleate after reconstitution in the nanoemulsion oral adhesive film preparation was 125.88±2.61nm, and the PDI was 0.17±0.08; Figure 2 As shown in the figure, the average particle size of the asenapine maleate nanocrystal oral adhesive film preparation after reconstitution was 325.10 ± 5.03 nm, and the PDI was 0.30 ± 0.06. This indicates that after loading the asenapine maleate nanoemulsion and nanocrystals into the oral adhesive film, the particle size, although slightly increased, remained within a relatively small range and was uniform. This facilitated the diffusion of the asenapine maleate nanoemulsion and nanocrystals in the mucus layer, enhancing the drug's mucosal permeability.

[0135] Example 10

[0136] Evaluation of in vitro dissolution of asenapine maleate in oral adhesive film

[0137] The present invention designs two oral adhesive films that are both taken sublingually. To simulate the oral environment as much as possible, the present invention selects simulated saliva as the dissolution medium, with a volume of 20 mL. The asenapine maleate self-nanoemulsion oral adhesive film preparation, the asenapine maleate nanocrystal oral adhesive film preparation, and the asenapine maleate API were added to 20 mL of release medium. At 37±1°C and 100 rpm, 1 mL of the medium was sampled at 1, 2, 4, 6, 8, 12, 16, 20, 30, 60, and 120 min (the same amount of the corresponding medium was then replenished at the same temperature). Insoluble impurities were filtered to remove the sample, and 20 μL of the sample was injected into a high-performance liquid chromatograph to determine the drug content and calculate the dissolution rate.

[0138] The results are as follows Figure 3 As shown in the data, the dissolution rates of asenapine maleate from the nanoemulsion oral adhesive film and the asenapine maleate nanocrystal oral adhesive film are basically similar. The nanocrystal oral adhesive film can dissolve 90% within 15 minutes, and the nanoemulsion oral adhesive film can dissolve 92% within 30 minutes, both of which are significantly higher than the asenapine maleate raw material.

[0139] Example 11

[0140] Evaluation of the pharmacokinetics of asenapine maleate in oral mucosa

[0141] The present invention compares the oral bioavailability of three test preparations, ASM@SNE-OMFs, ASM@NC-OMFs, and ASM sublingual tablets, in rats. 18 male SD rats were divided into three groups and fasted for 12 hours before administration, with free access to water. During administration, the rats were anesthetized with ether, and the sublingual membrane and sublingual tablets were delivered under the rats' tongues using tweezers and moistened with 0.2 mL of simulated saliva. The control dose for the three groups was 2.4 mg / kg. 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, 0.5 mL of blood was collected into a 0.5 mL centrifuge tube rinsed with sodium heparin solution, centrifuged at 13,000 rpm for 5 min, and the supernatant plasma was collected.

[0142] The plasma samples were extracted by liquid-liquid extraction and analyzed by UPLC-MS / MS.

[0143] Blood drug concentration curve Figure 4 The pharmacokinetic data are shown in Table 5. When asenapine maleate sublingual tablets were used as the reference preparation, the AUC of asenapine maleate self-nanoemulsion oral adhesive film was (0-24h) and C max The AUC of asenapine maleate nanocrystal oral adhesive film was increased by 1.39 times and 1.45 times respectively. (0-24h) and C maxThe AUC of ASM@SNE-OMFs and ASM@NC-OMFs compared with ASM sublingual tablets were improved by 1.27 times and 1.33 times respectively. (0-24h) and C max There were significant differences, indicating that ASM@SNE-OMFs and ASM@NC-OMFs could significantly improve the oral bioavailability of ASM.

[0144] Table 5 Pharmacokinetic parameters

[0145]

[0146] *p<0.05, comparing ASM@SNE-OMFs and ASM@NC-OMFs with ASM sublingual tablets.

Claims

1. An asenapine maleate self-nanoemulsion oral adhesive film preparation, characterized in that: The invention mainly consists of a self-nanoemulsion system of asenapine maleate, a film-forming material, an adhesive material, a solid adsorbent and a taste masking agent; the self-nanoemulsion oral adhesive film preparation is prepared by dissolving asenapine maleate in the self-nanoemulsion system, adsorbing the asenapine maleate in the film-forming material after adsorption by the solid adsorbent to form an oral adhesive film; the self-nanoemulsion system comprises an oil phase, an emulsifier and an auxiliary emulsifier, wherein the oil phase, the emulsifier and the auxiliary emulsifier are propylene glycol monocaprylate, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether respectively; the oil phase is in the self-nanoemulsion system. The content of the emulsifier in the self-nanoemulsion system is 15-50% w / w, the content of the emulsifier in the self-nanoemulsion system is 20-45% w / w, and the content of the co-emulsifier in the self-nanoemulsion system is 5-40% w / w; the film-forming material is selected from hydroxypropyl methylcellulose and polyvinyl alcohol; the adhesive material is selected from carbomer 934P, sodium hydroxypropyl methylcellulose, hydroxypropyl methylcellulose K4M and polyvinyl pyrrolidone K90; the solid adsorbent is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, talc, silicon dioxide, mannitol, PEG4000 and PEG 6000; the droplet particle size formed after the preparation is reconstituted is 10-300 nm; the content of the self-nanoemulsion system in the asenapine maleate self-nanoemulsion oral adhesive film preparation is 10-60% w / w.

2. A maleic acid asenapine self-nanoemulsion oral adhesive film preparation according to claim 1, characterized in that, The mass ratio of asenapine maleate, propylene glycol monocaprylate, polyoxyethylene (35) castor oil ELP and diethylene glycol monoethyl ether is 28:360:296:148; the formula of the asenapine maleate self-nanoemulsion oral adhesive film preparation is: The dosage of the asenapine maleate self-nanoemulsion oral adhesive film preparation is 2.5 mg / tablet.

3. The method for preparing the asenapine maleate self-nanoemulsion oral adhesive film preparation according to claim 1, wherein: Follow these steps: a. Mix the drug with the oil phase, emulsifier and co-emulsifier, and stir in a 37°C water bath to fully dissolve the drug to form an asenapine maleate self-nanoemulsion system; b. Disperse the film-forming material and the adhesive material in water and stir to dissolve to form a uniform film-forming adhesive; c. The asenapine maleate from the nanoemulsion system of step a was poured into the film-forming glue of step b under stirring at room temperature. After the nanoemulsion was formed, a solid adsorbent was added and stirred until uniformly dispersed to allow sufficient adsorption; d. Add taste masking agent and pigment, stir evenly at room temperature, let stand to degas, use a coating machine to lay the film, set the scraper height and coating speed, dry at 40 ° C after coating, wait for the temperature to return to room temperature, and demold to obtain asenapine maleate self-nanoemulsion oral adhesive film preparation.

4. An asenapine maleate nanocrystal oral adhesive film preparation, characterized in that: The invention mainly consists of asenapine maleate nanosuspension, film-forming material, adhesive material, plasticizer and taste masking agent; the asenapine maleate nanosuspension is prepared by wet grinding with drug and stabilizer as raw materials, and the nanosuspension is dispersed in film-forming glue to form a bioadhesive film; the concentration of asenapine maleate in the nanosuspension is 1-6% w / v, the stabilizer is polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer The concentration is 0.25-5% w / v; the film-forming material is selected from hypromellose and polyvinyl alcohol; the adhesive material is selected from carbomer 934P, hypromellose sodium, hypromellose K4M and polyvinyl pyrrolidone K90; the plasticizer is selected from any one of polyethylene glycol 400, glycerol, 1,2-propylene glycol, silicone oil, mannitol, and sorbitol, or a mixture of any two of them in any proportion; the nanoparticles formed after reconstitution of the preparation have a particle size of 10 to 500 nm.

5. The asenapine maleate nanocrystal oral adhesive film preparation according to claim 4, characterized in that: The particle size of the nanosuspension is 10-400 nm. The concentration of asenapine maleate in the nanosuspension is 3% w / v; the concentration of the stabilizer is 0.5% w / v.

6. The asenapine maleate self-nanoemulsion oral adhesive film preparation according to claim 1 or the asenapine maleate nanocrystal oral adhesive film preparation according to claim 4, characterized in that: The content of the film-forming material is 10-60% w / v; the content of the adhesion material is 1-20% w / v.

7. The oral adhesive film preparation of cenapine maleate nanocrystals according to claim 4, characterized in that: The mass ratio of asenapine maleate to the stabilizer polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 360:60; the formula of the asenapine maleate nanocrystalline oral adhesive film preparation is: The dosage of the asenapine maleate nanocrystal oral adhesive film preparation is 2.5 mg / tablet.

8. The method for preparing the asenapine maleate nanocrystalline oral adhesive film preparation according to claim 4, characterized in that: Follow these steps: a. The drug, stabilizer, grinding medium and grinding beads were weighed according to the ratio of each prescription and placed in a grinding tube, mixed evenly to form a coarse suspension, and asenapine maleate nanosuspension was prepared by wet grinding; b. Disperse the film-forming material and the adhesive material in water and stir to dissolve to form a uniform film-forming adhesive; c. Pour the asenapine maleate nanosuspension of step a into the film-forming glue of step b under stirring at room temperature and stir evenly; d. Add plasticizer, taste masking agent and pigment, stir evenly at room temperature, let stand to degas, use a film coating machine to spread the film, set the scraper height and coating speed, dry at 40 ° C after coating, wait until the temperature returns to room temperature, and demold to obtain asenapine maleate nanocrystal oral adhesive film preparation.

9. Use of the asenapine maleate self-nanoemulsion oral adhesive film preparation according to claim 1 or the asenapine maleate nanocrystal oral adhesive film preparation according to claim 4 in the preparation of a drug for treating acute schizophrenia, acute mania in adults and bipolar mania in children.

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