Meloxicam oral instant film preparation as well as preparation method and application thereof

Abstract

The invention discloses a meloxicam oral instant film preparation which comprises the following raw material components in percentage by mass: 0.1-20% of meloxicam, 0.5-15% of an oil phase, 5-40% of a surfactant, 30-60% of a polymer film-forming agent, 5-20% of a plasticizer, 5-20% of a filler and 5-20% of a disintegrating agent. In the invention, an oil phase and a surfactant form an oil phase system, the oil phase system and meloxicam are added into an aqueous solution of other components to form a nano-emulsion system, and the meloxicam oral instant film preparation is prepared. By using a mixed oil phase system composed of an oil phase and a surfactant, the solubility of meloxicam can be effectively improved. Meanwhile, the medicine (meloxicam) in the nano-emulsion system is in a dissolved state and in an amorphous state, compared with dissolution of crystal-form medicine, the medicine in the nano-emulsion system can directly skip the dissolution process and present a high dissolution rate, and the problems that meloxicam is poor in water solubility, slow in effect and low in bioavailability can be effectively solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a meloxicam oral instant film formulation, its preparation method, and its application. Background Technology

[0002] Meloxicam, also known as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, is a known nonsteroidal anti-inflammatory drug (NSAID) with superior efficacy compared to traditional non-selective NSAIDs. Traditional NSAIDs inhibit prostaglandin synthesis by inhibiting cyclooxygenase activity. Most adverse reactions of NSAIDs are caused by inhibition of type I cyclooxygenase (COX-1); however, meloxicam has greater inhibitory activity on type II cyclooxygenase (COX-2) than COX-1, effectively reducing the side effects of COX-1 inhibition.

[0003] To expand the application range of meloxicam formulations, researchers have developed various meloxicam formulations. Chinese patent document CN1233323C discloses a meloxicam orally disintegrating tablet, with meloxicam as the active ingredient and excipients including lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, sodium bicarbonate, citric acid, aspartame, flavoring, and magnesium stearate. This orally disintegrating tablet is prepared using a wet granulation process, and the resulting tablet disintegrates within 30 seconds in the oral cavity, offering benefits to the elderly, infants, and those with swallowing difficulties.

[0004] Chinese patent document CN116350595A discloses a meloxicam-containing tablet, comprising, by weight, the following components: component A at 11-34 parts, starch at 30-60 parts, dextrin at 20-40 parts, and lubricant at 0.02-0.2 parts. Component A includes 1-4 parts meloxicam and 10-30 parts glucose, wherein the meloxicam has a particle size of 20-30 μm and the glucose has a particle size of 50-100 μm. Using this technical solution, by preparing meloxicam and glucose as component A and mixing it with other excipients such as starch and dextrin, the solubility and bioavailability of meloxicam tablets can be significantly improved. However, the tablet administration method does not improve patient compliance.

[0005] Oral transdermal patches are a novel oral drug delivery method, developed based on transdermal patch technology. Placed in the mouth without drinking water or chewing, they dissolve or break down within one minute, offering advantages such as high flexibility and patient compliance. As a type of film-based delivery system, oral films can replace tablets, syrups, or suppositories because they avoid swallowing large amounts of liquid, making them particularly suitable for pediatricians, the elderly, and those with chronic diseases requiring long-term medication. Oral film delivery does not damage normal tissue. These polymer films, used for local or systemic absorption, enter the bloodstream through the dense network of capillaries in the oral mucosa or under the tongue. They reduce or avoid drug degradation caused by exposure to the acidic and enzymatic environments of the digestive tract, thereby minimizing the first-pass effect in the liver and improving drug bioavailability. These advantages make oral films a very promising drug delivery method.

[0006] In recent years, with the development of polymer film-forming materials and the improvement of pharmaceutical manufacturing technology, the process and manufacturing level of oral films have been continuously improving, and more and more drugs are being prepared into oral films and launched into the market. Chinese patent document CN115300486A discloses a meloxicam orally disintegrating film, comprising the following components by mass percentage: meloxicam 40%~55%; polymer film-forming agent 30%~50%; defoamer 1%~15%; plasticizer 1%~20%; flavoring agent 1%~20%; the polymer film-forming agent is a mixture of hydroxypropyl cellulose and polyethylene oxide. This invention selects hydroxypropyl cellulose and polyethylene oxide as polymer film-forming agents for meloxicam film formation; this can significantly improve the drug loading of the orally disintegrating film and promote the dissolution rate of meloxicam, while avoiding bubbles and particles on the surface of the orally disintegrating film. However, this preparation method requires the use of the organic solvent ethanol, and the amount of ethanol used is related to the uniformity of the slurry: the more ethanol used in the preparation process, the better the uniformity. Too much water results in a rough and uneven film; however, the greater the amount of ethanol used, the worse the safety of industrial production, requiring the installation of explosion-proof devices.

[0007] Therefore, there is an urgent need to find a meloxicam formulation that can take effect quickly, directly reach the lesion, and is portable and easy to store. At the same time, the manufacturing process of the formulation also needs to be simple and convenient. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a meloxicam oral instant-dissolving film formulation. The use of a specific oil phase can improve the solubility of meloxicam. Simultaneously, this oral instant-dissolving film formulation can increase the dissolution rate of the oral film and promote the dissolution of meloxicam in an acidic medium. Furthermore, it can rapidly disintegrate in the mouth, be quickly absorbed, and has a pleasant taste.

[0009] A meloxicam oral instant film formulation, by weight percentage, comprises: 0.1%~20% meloxicam, 0.5%~15% oil phase, 5%~40% surfactant, 30%~60% polymeric film-forming agent, 5%~20% plasticizer, 5%~20% filler, and 5%~20% disintegrant; The oil phase is at least one of oleyl alcohol, oleic acid, isopropyl myristate, triacetin, glyceryl monodecanoate, medium-chain triglycerides, castor oil, glyceryl monostearate, glyceryl monooleate, octanoic acid / decanoic acid mixed glyceryl monosaccharide, glyceryl monolaurate, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The surfactant is at least one of polyethylene glycol oleate, Tween 80, polyethylene glycol 15-hydroxystearate, polyoxyethylene hydrogenated castor oil, polyethylene glycol glycerol octanoate and caprylic / capric acid, and poloxamer.

[0010] In this invention, an oil phase and a surfactant form an oil phase system. The oil phase system and meloxicam are added to an aqueous solution of other components to form a nanoemulsion system, thus preparing a meloxicam oral fast-dissolving film formulation. Using a mixed oil phase system composed of an oil phase and a surfactant can effectively improve the solubility of meloxicam. Simultaneously, the drug (meloxicam) in the nanoemulsion system is in a dissolved state, exhibiting an amorphous form. Compared to the dissolution of crystalline drugs, the drug in the nanoemulsion system can directly skip the dissolution process, exhibiting a rapid dissolution rate, which can effectively solve the problems of poor water solubility, slow onset of action, and low bioavailability of meloxicam.

[0011] Preferably, the oil phase is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or triacetin, and the surfactant is Tween 80.

[0012] More preferably, the mass ratio of the oil phase to the surfactant is 3~8%:5~35.

[0013] In this invention, by selecting a specific combination of oil phase and surfactant, the solubility of meloxicam can be effectively increased to 25 mg / mL, which is 162 times that of the aqueous phase (the solubility of meloxicam in the aqueous phase is 0.154 mg / mL).

[0014] Preferably, the polymeric film-forming agent is at least one selected from polyvinyl alcohol, gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and pullulan.

[0015] Preferably, the plasticizer is at least one selected from glycerol, propylene glycol, polyethylene glycol, diethyl phthalate, ethyl citrate, and glyceryl triacetate.

[0016] Preferably, the filler is at least one selected from pregelatinized starch, pea starch, hydroxypropyl starch, maltose, dextrin, and mannitol.

[0017] Preferably, the disintegrant is at least one selected from crospovidone, methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0018] A disintegrant is added to the formulation to ensure rapid disintegration of the resulting film, with a disintegration time of less than 30 seconds. This not only improves the solubility of the poorly soluble drug meloxicam and the drug loading capacity of the oral instant film formulation, but also achieves rapid disintegration, further enhancing the quality of the oral instant film formulation and providing patients with a higher-quality product.

[0019] Preferably, the meloxicam oral instant film preparation further includes a flavoring agent, which is at least one selected from glucose, sucralose, cyclamate, saccharin, aspartame, peppermint flavoring, sweet orange flavoring, tangerine flavoring, and strawberry flavoring, and the amount of the flavoring agent added is 0.05% to 6%.

[0020] Compared with ordinary oral instant-dissolving films and tablets, the meloxicam oral instant-dissolving film preparation provided by this invention can improve drug solubility, effectively mask the unpleasant taste of the drug, and is convenient to take, thereby improving patient compliance.

[0021] More preferably, the raw material components of the meloxicam oral instant film preparation include: 1.63% meloxicam, 3.81% oil phase, 31.72% surfactant, 35.91% polymeric film-forming agent, 7.24% plasticizer, 10.88% filler, 7.18% disintegrant, and 1.63% flavoring agent.

[0022] This invention also provides a method for preparing the above-mentioned meloxicam oral instant film formulation. This method combines the advantages of both nanoemulsion systems and oral instant film formulations. It uses phosphate buffer to prepare the aqueous solution required for the nanoemulsion system, which can form a uniform, clear and stable nanoemulsion system. This method can achieve the goals of rapid onset of action, improved bioavailability and improved medication adherence. Moreover, the preparation method is simple and convenient and does not require the use of complex instruments.

[0023] A method for preparing a meloxicam oral instant-dissolving film formulation includes the following steps: (1) Prepare a phosphate buffer solution by adding plasticizer and flavoring agent, stirring until a homogeneous solution is obtained; (2) Mix the oil phase and surfactant evenly and add them to the aqueous solution obtained in step (1) to obtain a mixed system; (3) Add meloxicam to the mixture obtained in step (2), heat and stir to obtain a nanoemulsion system; (4) Add polymeric film-forming agent, filler and disintegrant to the nanoemulsion system of step (3), heat and stir to obtain film liquid; (5) The membrane liquid obtained in step (4) is coated on the substrate and dried to obtain meloxicam oral instant film preparation.

[0024] Preferably, in step (1), the phosphate buffer solution is a mixed solution of sodium hydroxide and potassium dihydrogen phosphate, wherein the mass ratio of sodium hydroxide to potassium dihydrogen phosphate is 0.1~0.2:1.

[0025] Nanoemulsion systems obtained using deionized water require a large dosage of the film to achieve the required drug loading, which is not conducive to patient administration. In this invention, a phosphate buffer solution at pH 6.8 is used to form a homogeneous, clear, and stable nanoemulsion system, and the solubility of meloxicam in this system is 15 times that of the pure water nanoemulsion system. The nanoemulsion system prepared using this method significantly improves the solubility of meloxicam, effectively increasing the drug loading of meloxicam oral instant-dissolving film formulations.

[0026] Preferably, in steps (3) and (4), the heating and stirring is carried out at 50~70 °C for 1~3 h.

[0027] The present invention also provides the use of the above-mentioned meloxicam oral instant film formulation in the preparation of drugs for treating osteoarthritis or rheumatoid arthritis.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) Meloxicam is a poorly soluble drug. The oral fast-dissolving film formulation of meloxicam prepared by the present invention using a specific oil phase can improve the solubility of meloxicam. At the same time, the dissolution rate and cumulative dissolution amount of the oral fast-dissolving film formulation in acidic media are better than those of tablets, which can help increase the exposure of meloxicam and thus improve its bioavailability.

[0029] (2) The preparation process provided by the present invention does not contain organic solvents, is simple to operate, does not require complex instruments and equipment, and has low site requirements. By combining the nanoemulsion system with the oral fast-dissolving film formulation, the nanoemulsion solution containing meloxicam is stably and uniformly dispersed in the film-forming agent, which can achieve the purpose of rapid onset of action, improved bioavailability and improved medication compliance.

[0030] (3) The meloxicam oral instant film preparation provided by the present invention disperses rapidly in the oral cavity and has a good taste without mucosal irritation; it provides convenience for special populations such as patients with swallowing disorders and the elderly, and can improve the drug adaptability and safety of special populations, and can be better applied to the preparation of drugs for the treatment of osteoarthritis or rheumatoid arthritis. Attached Figure Description

[0031] Figure 1 The image shows the appearance of the meloxicam oral instant film preparation obtained in Example 1.

[0032] Figure 2 The image shows the X-ray powder diffraction patterns of the meloxicam oral instant film preparation and the meloxicam active pharmaceutical ingredient obtained in Example 1.

[0033] Figure 3 The values ​​represent the cumulative dissolution amounts of the meloxicam oral instant film prepared in Example 1 and commercially available meloxicam tablets in different media, where A to C are buffer media at pH 1.2, pH 4.0, and pH 4, respectively. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0035] All raw materials used in this invention are commercially available.

[0036] Example 1 The composition formula is shown in Table 1.

[0037] Table 1: Composition and Formulation of Example 1 The preparation method is as follows: (1) Dissolve 0.048 g sodium hydroxide and 0.348 g potassium dihydrogen phosphate in 30 mL of water to obtain phosphate buffer (pH 6.8). Add sucralose, sweet orange flavoring and polyethylene glycol 400 to the buffer and stir until homogeneous to obtain an aqueous solution. (2) Mix triacetylglycerol and Tween 80 evenly and add them to the aqueous solution obtained in step (1) to obtain a mixed system; (3) Add meloxicam to the mixture obtained in step (2), heat and stir at 65 °C for 30 min to obtain a nanoemulsion system; (4) Polyvinyl alcohol 1788, low-substituted hydroxypropyl cellulose and pregelatinized starch were added to the nanoemulsion system of step (3), and the mixture was heated and stirred at 65 °C for 2 h to obtain the membrane solution. (5) The film solution obtained in step (4) is coated onto the substrate to a thickness of 0.45 mm. After drying at 50 °C for 1.5 h, it is peeled off from the substrate and cut into meloxicam oral instant film preparations of uniform size. Its appearance is as follows: Figure 1 As shown.

[0038] Example 2 The composition formula is shown in Table 2.

[0039] Table 2: Composition and Formulation of Example 2 The preparation method is as follows: (1) Dissolve 0.08 g sodium hydroxide and 0.58 g potassium dihydrogen phosphate in 30 mL of water to obtain phosphate buffer (pH 6.8). Add sucralose, orange flavoring and polyethylene glycol 400 to the buffer and stir until homogeneous to obtain an aqueous solution. (2) Mix the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and Tween 80 evenly, and add them to the aqueous solution obtained in step (1) to obtain a mixed system; (3) Add meloxicam to the mixture obtained in step (2), heat and stir at 65 °C for 30 min to obtain a nanoemulsion system; (4) Add gelatin, sodium carboxymethyl starch and pregelatinized starch to the nanoemulsion system of step (3), and heat and stir at 65 °C for 2 h to obtain the membrane solution; (5) The film liquid obtained in step (4) is coated on the substrate with a thickness of 0.5 mm. After drying at 50 °C for 1.5 h, it is peeled off from the substrate and cut into meloxicam oral instant film preparations with uniform size.

[0040] Example 3 The composition formula is shown in Table 3.

[0041] Table 3: Composition and Formulation of Example 3 The preparation method is the same as in Example 2.

[0042] Example 4 The composition formula is shown in Table 4.

[0043] Table 4: Composition and Formulation of Example 4 The preparation method is as follows: (1) Dissolve 0.024 g sodium hydroxide and 0.174 g potassium dihydrogen phosphate in 30 mL of water to obtain phosphate buffer (pH 6.8). Add sucralose, strawberry flavoring and polyethylene glycol 400 to the buffer and stir until homogeneous to obtain an aqueous solution. (2) Mix triacetylglycerol and Tween 80 evenly and add them to the aqueous solution obtained in step (1) to obtain a mixed system; (3) Add meloxicam to the mixture obtained in step (2), heat and stir at 65 °C for 30 min to obtain a nanoemulsion system; (4) Polyvinyl alcohol 1788, low-substituted hydroxypropyl cellulose and pregelatinized starch were added to the nanoemulsion system of step (3), and the mixture was heated and stirred at 65 °C for 2 h to obtain the membrane solution. (5) The film liquid obtained in step (4) is coated on the substrate with a thickness of 0.5 mm. After drying at 50 °C for 1.5 h, it is peeled off from the substrate and cut into meloxicam oral instant film preparations with uniform size.

[0044] Performance testing I. Disintegration Time Limit Take three tablets of the meloxicam oral dissolving film prepared in Example 1, and use 10 mL of PBS solution with pH=6.8 as the dissolution medium. The film is heated at 37 °C and rotated at 30 r / min. The time is recorded from the moment the oral dissolving film comes into contact with the dissolution medium. The measurement is repeated three times.

[0045] Table 5: In vitro disintegration time test of meloxicam oral instant film formulation Test results show that meloxicam oral instant film formulation disintegrates rapidly in vitro, releasing its contents in about 30 seconds, demonstrating good disintegration properties.

[0046] II. Solid-state performance testing of meloxicam oral instant film formulation The meloxicam oral instant film preparation and meloxicam active pharmaceutical ingredient obtained in Example 1 were subjected to X-ray powder diffraction (XRPD) tests to understand the solid form of the active pharmaceutical ingredient in the film preparation.

[0047] Figure 2 The image shows X-ray powder diffraction patterns of the meloxicam oral instant film preparation and the meloxicam active pharmaceutical ingredient prepared in Example 1, wherein the meloxicam in the meloxicam oral instant film preparation exists in an amorphous state.

[0048] III. Dissolution Performance Test of Meloxicam Oral Fast-Dissolving Film Formulation Three tablets of the meloxicam oral dissolving film prepared in Example 1 and three commercially available meloxicam tablets (20 mg specification) were taken. Dissolution profiles of the oral dissolving film and commercially available tablets were examined according to the provisions of the Chinese Pharmacopoeia (2020 Edition), referring to General Chapter 0931, Method I. The specific method was as follows: 50 revolutions using a paddle method; the dissolution medium was 100 mL of buffer solutions with pH 1.2, pH 4.0, and pH 4; and the dissolution samples were detected using a UV spectrophotometer at a wavelength of 320 nm.

[0049] Figure 3The figures represent the cumulative dissolution amounts of the meloxicam oral instant-dissolving film prepared in Example 1 and commercially available meloxicam tablets in different media, where A to C are buffer media at pH 1.2, pH 4.0, and pH 4, respectively. Compared to commercially available tablets, the meloxicam oral instant-dissolving film formulation exhibits a faster dissolution rate and a larger cumulative dissolution amount in acidic media.

[0050] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A meloxicam oral instant-dissolving film formulation, characterized in that, By mass percentage, its raw material components include: 0.1%~20% meloxicam, 0.5%~15% oil phase, 5%~40% surfactant, 30%~60% polymeric film-forming agent, 5%~20% plasticizer, 5%~20% filler, and 5%~20% disintegrant; The oil phase is at least one of oleyl alcohol, oleic acid, isopropyl myristate, triacetin, glyceryl monodecanoate, medium-chain triglycerides, castor oil, glyceryl monostearate, glyceryl monooleate, octanoic acid / decanoic acid mixed glyceryl monosaccharide, glyceryl monolaurate, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The surfactant is at least one of polyethylene glycol oleate, Tween 80, polyethylene glycol 15-hydroxystearate, polyoxyethylene hydrogenated castor oil, polyethylene glycol glycerol octanoate and caprylic / capric acid, and poloxamer.

2. The meloxicam oral instant-dissolving film formulation according to claim 1, characterized in that, The oil phase is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or triacetin, and the surfactant is Tween 80.

3. The meloxicam oral instant-dissolving film formulation according to claim 2, characterized in that, The mass ratio of the oil phase to the surfactant is 3~8:5~35.

4. The meloxicam oral instant-dissolving film formulation according to claim 1, characterized in that, The polymeric film-forming agent is at least one of polyvinyl alcohol, gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and pullulan. The plasticizer is at least one of glycerol, propylene glycol, polyethylene glycol, diethyl phthalate, ethyl citrate, and glyceryl triacetate. The filler is at least one of pregelatinized starch, pea starch, hydroxypropyl starch, maltose, dextrin, and mannitol; The disintegrant is at least one of crospovidone, methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

5. The meloxicam oral instant-dissolving film formulation according to claim 1, characterized in that, The meloxicam oral instant film formulation also includes a flavoring agent, which is at least one of glucose, sucralose, cyclamate, saccharin, aspartame, peppermint flavoring, sweet orange flavoring, tangerine flavoring, and strawberry flavoring, and the amount of the flavoring agent added is 0.05% to 6.0%.

6. The meloxicam oral instant-dissolving film formulation according to claim 5, characterized in that, The raw material components of the meloxicam oral instant film preparation include: 1.63% meloxicam, 3.81% oil phase, 31.72% surfactant, 35.91% polymeric film-forming agent, 7.24% plasticizer, 10.88% filler, 7.18% disintegrant, and 1.63% flavoring agent.

7. The method for preparing the meloxicam oral instant-dissolving film formulation according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Prepare a phosphate buffer solution by adding plasticizer and flavoring agent, stirring until a uniform aqueous solution is obtained; (2) Mix the oil phase and surfactant evenly and add them to the aqueous solution obtained in step (1) to obtain a mixed system; (3) Add meloxicam to the mixture obtained in step (2), heat and stir to obtain a nanoemulsion system; (4) Add polymeric film-forming agent, filler and disintegrant to the nanoemulsion system of step (3), heat and stir to obtain film liquid; (5) The membrane liquid obtained in step (4) is coated on the substrate and dried to obtain meloxicam oral instant film preparation.

8. The method for preparing the meloxicam oral instant-dissolving film formulation according to claim 7, characterized in that, In step (1), the phosphate buffer solution is a mixed solution of sodium hydroxide and potassium dihydrogen phosphate, and the mass ratio of sodium hydroxide to potassium dihydrogen phosphate is 0.1~0.2:

1.

9. The method for preparing the meloxicam oral instant film formulation according to claim 7, characterized in that, In steps (3) and (4), the heating and stirring are performed at 50-70 °C for 1-3 h.

10. The use of the meloxicam oral instant film formulation according to any one of claims 1 to 6 in the preparation of a medicament for treating osteoarthritis or rheumatoid arthritis.

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