Melatonin composition

Abstract

The invention discloses a melatonin composition. The melatonin composition is characterized by comprising a particle core and a double-layer coating coated on the surface of the particle core. The particle core is composed of melatonin, mannitol, hydroxypropyl cellulose and silicon dioxide, and uniform distribution and stable release are ensured. The double-layer coating comprises an inner damp-proof protection layer and an outer pH sensitive controlled release layer, the inner damp-proof protection layer is prepared from at least one of ethyl cellulose or polyvinyl alcohol or an aminomethacrylate-methyl acrylate copolymer, humidity and oxygen are effectively shielded, and the storage stability is improved; the outer pH-sensitive controlled release layer is prepared from a methacrylic acid-ethyl methacrylate copolymer or a mixture of the methacrylic acid-ethyl methacrylate copolymer, so that double-phase release is realized: about 30% of melatonin is quickly released in the stomach, and quick falling asleep is helped; 70% of the sustained release in the small intestine environment is remained, and the drug effect is prolonged. The composition has the advantages of quick effect, long-acting maintenance, high stability and wide applicability, obviously improves the defects of the traditional melatonin preparation, and is suitable for improving the sleep quality.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a melatonin composition. Background Art

[0002] Melatonin is an endogenous hormone secreted by the pineal gland, which plays an important role in regulating circadian rhythm and improving sleep quality. With the accelerated pace of modern life and the widespread use of electronic devices, sleep disorders are becoming increasingly common. Melatonin, as a safer sleep aid, has been widely used around the world. However, traditional melatonin preparations have many deficiencies in terms of dissolution and absorption rate, stability, and gastrointestinal adaptability, as shown below:

[0003] 1. Dissolution and absorption rates are unbalanced:

[0004] Rapid release problem: Existing melatonin preparations are mostly in the form of ordinary tablets or capsules. Some products release melatonin quickly within a short period of time after taking it, causing a rapid increase in blood drug concentration. Although it can produce a short-term sedative effect, it is difficult to maintain sleep quality for a long time.

[0005] Problems with sustained-release preparations: Although some sustained-release tablets extend the release time, the initial release is insufficient, making it difficult for the drug to take effect quickly, which affects the patient's ability to fall asleep. Existing preparations are difficult to simultaneously meet the requirements of rapid onset and long-term maintenance.

[0006] 2. Stability issues:

[0007] Melatonin sensitivity: Melatonin molecules are sensitive to light, humidity and oxygen, and are prone to degradation during storage, resulting in reduced efficacy. Some preparations on the market are not treated with special protective coatings and are easily affected by environmental factors, making it difficult to ensure product quality during long-term storage and transportation.

[0008] 3. Gastrointestinal environmental impact:

[0009] Influence of pH value: The release of existing common melatonin preparations in the gastrointestinal tract is greatly affected by pH value. Some products dissolve too quickly in the stomach, causing melatonin to be quickly absorbed in the stomach and blood drug concentration to increase rapidly. However, due to the lack of subsequent sustained-release process, the efficacy is difficult to maintain for a long time.

[0010] Differences in bioavailability: The bioavailability of melatonin is greatly affected by individual differences. If the release rate is not properly controlled, it may lead to unstable efficacy.

[0011] 4. Limitations of existing technologies:

[0012] Ordinary tablets or capsules: It is difficult to take into account both the requirements of rapid onset of effect and sustained release, and they have poor stability and are easily affected by environmental factors.

[0013] Microencapsulation: Although it can improve stability and controlled release effect, inappropriate selection of microencapsulation materials may affect the dissolution curve.

[0014] Single-layer controlled release coating: Although it can delay the release of melatonin, due to the lack of an initial rapid release mechanism, the onset time of the drug is long, which is not conducive to patients falling asleep quickly. Summary of the Invention

[0015] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the specification of this application, to avoid obscuring the purpose of this part, the abstract of the specification, and the title of the invention, and such simplifications or omissions shall not be used to limit the scope of the present invention.

[0016] Therefore, to solve the above technical problems, the present invention provides the following technical solution: A melatonin composition, whose basic structure includes a particle core and a double-layer coating covering its surface; the particle core is composed of melatonin, mannitol, hydroxypropyl cellulose, and silicon dioxide in an optimal ratio, where:

[0017] Melatonin: 0.2% (1mg / 500mg);

[0018] Mannitol: 94.8% (474mg / 500mg);

[0019] Hydroxypropyl cellulose: 3% (15mg / 500mg);

[0020] Silicon dioxide: 2% (10mg / 500mg);

[0021] The total mass of the particle core is fixed at 500mg;

[0022] On this basis, a double-layer coating is applied successively through a fluidized bed coating process. The double-layer coating is applied successively through a fluidized bed coating process. First, an inner moisture-proof protective layer is applied, and then an outer pH-sensitive controlled release layer is applied to ensure that the coating is uniform, continuous, and has excellent adhesion. Specifically:

[0023] Inner moisture-proof protective layer: It is made of a polymer (such as ethyl cellulose, copolymer of amino methacrylate - methyl acrylate, or polyvinyl alcohol), and its mass ratio is controlled within 2% - 5% of the core weight; the inner moisture-proof protective layer in the double-layer coating not only improves the shielding effect of melatonin against moisture and oxygen, but also effectively reduces the degradation rate of melatonin caused by environmental factors, thus significantly improving the storage stability of the composition.

[0024] Outer pH-sensitive controlled-release layer: It is made of polymers (such as copolymers of methacrylic acid and ethyl methacrylate, copolymers of methacrylic acid and methyl methacrylate, or mixtures thereof), and its mass ratio is controlled at 3% - 8% of the core weight; the outer pH-sensitive controlled-release layer in the double-layer coating is made of polymers selected from copolymers of methacrylic acid and ethyl methacrylate, copolymers of methacrylic acid and methyl methacrylate, or mixtures thereof, and its mass ratio accounts for 3% - 8% of the double-layer coating weight. It partially dissolves and achieves rapid release at a pH value lower than the predetermined value (such as pH < 5.5), and releases slowly at a higher pH value.

[0025] Therefore, in the present invention, the composition of the final product can meet:

[0026] The proportion of the particle core in the finished product is 88.50% - 95.2%;

[0027] The proportion of the double-layer coating in the finished product is 4.4% - 12.4%.

[0028] As a preferred embodiment of the melatonin composition of the present invention, wherein: the outer pH-sensitive controlled-release layer in the double-layer coating partially dissolves in the stomach (pH about 1.0 - 3.0), so that a certain proportion of melatonin is released in the initial stage, and at the same time, it slowly dissolves in the small intestine (pH about 5.5 - 7.5) environment to provide a sustained release effect.

[0029] As a preferred embodiment of the melatonin composition of the present invention, wherein: the composition exhibits a biphasic release characteristic after oral administration. Specifically: an initial rapid release is achieved within 15 minutes after administration, so that about 30% of melatonin is rapidly released; the remaining 70% of melatonin is continuously released within 4 hours to extend the drug effect time.

[0030] As a preferred embodiment of the melatonin composition of the present invention, wherein: the cumulative dissolution degree of the composition in the aqueous medium meets: more than 90% is reached within 5 minutes, more than 95% is reached within 15 minutes, and it is completely dissolved within 30 minutes. At the same time, the dissolution curve meets the requirements of the biphasic release design.

[0031] Advantages of the present invention:

[0032] 1. Through the biphasic release mechanism, the present invention solves the problem that traditional preparations are difficult to balance rapid onset and long-term maintenance; specifically, about 30% of melatonin is released within 15 minutes to achieve rapid onset and help patients fall asleep as soon as possible; the remaining 70% of melatonin is continuously released within 4 hours to maintain the blood drug concentration, reduce nocturnal awakening, and improve the sleep maintenance ability; compared with ordinary tablets or sustained-release tablets, the present invention can more accurately control the change of blood drug concentration and provide a better sleep quality improvement plan.

[0033] 2. Through the design of the inner moisture-proof protective coating, the present invention significantly improves the stability of melatonin and extends the storage period of the product; the inner moisture-proof protective layer (made of ethyl cellulose or polyvinyl alcohol) effectively prevents the degradation of melatonin by environmental humidity and oxygen.

[0034] 3. By introducing an inner moisture-proof protective layer and an outer pH-sensitive controlled-release layer outside the particle core, the present invention breaks through the limitations of the single controlled-release coating in the prior art; specifically, through the design of the pH-sensitive controlled-release coating, the release characteristics of melatonin in different gastrointestinal environments are optimized, and the influence of individual differences on the drug effect is reduced; the outer pH-sensitive controlled-release layer is partially dissolved in the stomach (pH 1.0 - 3.0) to achieve rapid initial release; it is slowly dissolved in the small intestine (pH 5.5 - 7.5) environment to provide a sustained release effect.

[0035] 4. Since the pH-sensitive controlled-release coating can gradually release melatonin at different pH values, the composition of the present invention ensures a stable release curve in the gastrointestinal environments of different individuals, enabling patients of different ages and with different digestive functions to obtain a stable drug effect, and having wide applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings. Among them:

[0037] Figure 1 It is the process flow chart of the preparation of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0038] In order to make the above objects, features, and advantages of the present invention more obvious and understandable, the following will describe the specific embodiments of the present invention in detail with reference to the drawings of the specification.

[0039] Many specific details are set forth in the following description in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0040] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that can be included in at least one implementation manner of the present invention. The "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor is it a separate or selectively exclusive embodiment from other embodiments.

[0041] Example 1

[0042] This is the first embodiment of the present invention, which provides a melatonin composition. The specific application embodiments of this composition are as follows:

[0043] 1. Particle core:

[0044] Melatonin: 1 mg (accounting for 0.2%). Through scientific proportioning, it can be evenly distributed in the particle system and released in the gastrointestinal tract according to the established release curve;

[0045] Mannitol: 474 mg (accounting for 94.8%). As the main excipient, it not only helps to improve the taste, but also promotes the disintegration and dissolution of the particles in water, enabling melatonin to be released faster in the gastrointestinal tract and improving the bioavailability.

[0046] Hydroxypropyl cellulose: 15 mg (accounting for 3%); it imparts appropriate adhesiveness to the particles, enhances the mechanical strength of the particles, ensures the uniformity and stability of the particles, and at the same time plays a certain sustained-release role during the release process, prolonging the drug effect;

[0047] Silica: 10 mg (accounting for 2%); it improves the fluidity of the powder, reduces the hygroscopicity of the particles, improves the storage stability of the preparation, prevents the occurrence of caking problems, and improves the feasibility of the production process;

[0048] → Total core mass: 500 mg;

[0049] 2. Double-layer coating:

[0050] Based on the weight of the core:

[0051] Inner moisture-proof protective layer: Ethyl cellulose is selected, taking 3% of the core mass, that is, 15 mg. Using ethyl cellulose as the moisture-proof coating can effectively shield the external humidity and oxygen, prevent the degradation of melatonin, and improve the storage stability; this layer can also avoid premature dissolution, ensure that the outer pH-sensitive coating can take effect at the predetermined site, and enhance the controlled-release effect;

[0052] Outer pH-sensitive controlled-release layer: Methacrylic acid-ethyl methacrylate copolymer (soluble at pH 5.5) is selected, taking 5% of the core mass, that is, 25 mg, so that the coating is partially dissolved in the stomach (pH 1.0 - 3.0) and releases 30% of melatonin within 15 minutes to quickly help fall asleep; it gradually disintegrates in the small intestine (pH 5.5 - 7.5) environment and continuously releases the remaining 70% within 4 hours, enabling melatonin to maintain a relatively long blood drug concentration, prolonging the drug effect, and reducing the occurrence of nocturnal awakening; it gradually disintegrates in the small intestine (pH 5.5 - 7.5) environment and continuously releases the remaining 70% within 4 hours, enabling melatonin to maintain a relatively long blood drug concentration, prolonging the drug effect, and reducing the occurrence of nocturnal awakening.

[0053] → Total mass of double-layer coating: 15 mg + 25 mg = 40 mg

[0054] Final product composition

[0055] Total mass = Core (500 mg) + Coating (40 mg) = 540 mg

[0056] Proportion of particle core ≈ 92.6% (500 / 540 × 100), meeting the range of 88.50% - 95.2%;

[0057] Proportion of double-layer coating ≈ 7.4% (40 / 540 × 100), meeting the range of 4.4% - 12.4%.

[0058] Proportion of particle core is 92.6%, proportion of double-layer coating is 7.4

[0059] The present invention, through the precise ratio of 92.6% particle core + 7.4% double-layer coating, strictly controlled within the standard ranges of 88.50% - 95.2% and 4.4% - 12.4%, ensures the stability of the formulation, facilitates industrial mass production, realizes the three core technical advantages of rapid onset, sustained release maintenance, and high stability, has better efficacy control, higher stability, and better bioavailability compared with the prior art, and has significant application value in the field of melatonin preparations.

[0060] Example 2

[0061] As shown in the Figure 1 accompanying drawings, this is the second embodiment of the present invention. The difference between this embodiment and the first embodiment is that this embodiment provides a preparation process for the above composition, which is specifically as follows:

[0062] 1. Raw material pretreatment: Sieve each component in the example in advance to ensure uniform particle size; premix melatonin to ensure uniform dispersion.

[0063] 2. Preparation of core particles: Mix melatonin, mannitol, hydroxypropyl cellulose, and silicon dioxide evenly according to the above ratio, and use wet granulation or direct compression molding to obtain core particles.

[0064] 3. Coating process, specifically as follows:

[0065] Apply successively using fluidized bed coating technology:

[0066] First, spray the inner moisture-proof protective layer (using ethyl cellulose solution), with the target coating mass of 15 mg.

[0067] After the inner layer is dried, then spray the outer pH-sensitive controlled release layer (using methyl methacrylate - ethyl methacrylate copolymer solution), with the target coating mass of 25 mg.

[0068] During the spraying process, the spraying rate, temperature, and atomization parameters need to be strictly controlled to ensure that the coating is uniform, continuous, and has good adhesion.

[0069] 4. Drying and Quality Inspection

[0070] Dry the particles after coating, and the loss on drying should be less than 2.0%;

[0071] Perform particle size, content uniformity, dissolution, and stability tests to ensure that the dissolution of the product is ≥90% within 5 minutes, ≥95% within 15 minutes, and completely dissolved within 30 minutes. At the same time, it should meet the requirements of the biphasic release design, that is, about 30% of the initial release within 15 minutes, and the remaining 70% of melatonin is continuously released within 4 hours.

[0072] In this embodiment, through the double-layer coating design, part of the melatonin is rapidly released in the stomach to assist in falling asleep quickly; the remaining amount is continuously released in the small intestine to prolong the drug effect and help improve sleep quality; the inner moisture-proof layer effectively reduces the influence of moisture and oxygen in the environment on melatonin and improves the storage stability of the product; the fluidized bed coating technology is used to achieve precise coating, ensuring the consistency of products between batches and being suitable for large-scale industrial production.

[0073] Example 3

[0074] This is the third embodiment of the present invention. On the basis of Embodiments 1-2, the materials and process parameters of the double-layer coating are further optimized to meet different clinical needs and improve the product stability, as follows:

[0075] 1. Formula and Composition:

[0076] 1.1. The particle core is the same as that in Example 1, and the core components are in the following proportions:

[0077] Melatonin: 1 mg (0.2%);

[0078] Mannitol: 474 mg (94.8%);

[0079] Hydroxypropyl cellulose: 15 mg (3%);

[0080] Silicon dioxide: 10 mg (2%);

[0081] Total core mass: 500 mg.

[0082] 1.2. Double-layer coating. In this embodiment, different coating material combinations are used:

[0083] Inner moisture-proof protective layer: Polyvinyl alcohol is selected, and the coating quality is controlled at 4% (20 mg) of the core mass to enhance the moisture barrier effect;

[0084] Outer pH-sensitive controlled release layer: A mixture of methacrylic acid-methyl methacrylate copolymer (Chinese name: methacrylic acid-methyl methacrylate copolymer (soluble at pH 7.0)) and methacrylic acid-ethyl methacrylate copolymer is selected. After optimizing the mixing ratio, the total coating mass is 6% (30 mg) of the core mass, aiming to regulate the dissolution curve, so that the release ratio in the stomach is slightly lower (about 30% within 15 minutes), and the release is more stable in the small intestine environment.

[0085] 1.3. The final product composition is as follows:

[0086] Total mass = 500 mg (core) + 15 mg + 25 mg = 550 mg

[0087] The proportion of the particle core is approximately 90.9%, and the proportion of the coating is approximately 9.1%, both meeting the predetermined range.

[0088] 2. The preparation process is as follows:

[0089] 2.1. Preparation of core particles;

[0090] Same as Example 1, raw materials are mixed and wet granulation or tableting is carried out to obtain 500 mg core particles.

[0091] 2.2. Application of double-layer coating;

[0092] The fluidized bed technology is adopted, specifically as follows:

[0093] First, a polyvinyl alcohol solution is sprayed to form an inner moisture-proof layer (target mass 15 mg).

[0094] After the inner layer is dried, the outer mixed coating is sprayed (the outer controlled release layer material in this example is selected from methacrylic acid-ethyl methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer or their mixture, target mass 25 mg) to regulate the dissolution rate in different pH environments.

[0095] The coating uniformity and drying process are controlled to ensure firm adhesion and good mechanical properties.

[0096] 2.3. Drying and detection

[0097] After the coating is completed, hot air drying is carried out, and the loss on drying, particle size distribution, content uniformity and in vitro dissolution of the particles are detected. The in vitro dissolution test shows that about 25% is released within 15 minutes in the gastric simulation fluid (pH 1.0 - 3.0), and the cumulative release reaches 100% within 4 hours in the small intestine simulation fluid (pH 5.5 - 7.5), meeting the expected biphasic release design.

[0098] 3. In this example:

[0099] In this embodiment, by adopting a hybrid outer coating, the release rate in the stomach and small intestine can be further optimized, making the initial release ratio slightly lower than that in Embodiment 1, which is suitable for treatment scenarios requiring slow release and further prolongs the drug effect.

[0100] This embodiment uses polyvinyl alcohol as the inner layer material, which can provide better moisture shielding effect compared with ethyl cellulose and is suitable for storage and transportation in high humidity environments.

[0101] On the basis of Embodiment 2, this embodiment optimizes the process parameters, enabling the product to exhibit an ideal release curve in different pH environments, providing technical support for personalized treatment in clinical practice for different patient needs (such as sleep disorders and circadian rhythm disorders).

[0102] Compared with the prior art, the present invention has significant technical advantages in the following aspects:

[0103] 1. Synergistic effect of the double-layer coating structure

[0104] By introducing a double-layer coating design of an inner moisture-proof protective layer and an outer pH-sensitive controlled-release layer on the basis of a fixed core formula, the present invention not only ensures the stability of the product in harsh environments but also realizes the biphasic release of the drug. This structural combination is not a simple process stacking in the prior art but an overall optimization in terms of formulation, coating material selection, and process control, which can significantly improve the drug effect and safety.

[0105] 2. Integration of cross-field materials and processes

[0106] The present invention combines the drug controlled-release technology with an advanced fluidized bed coating process. In view of the sensitivity of melatonin to light and humidity, a specially designed moisture-proof coating is adopted to effectively reduce the drug degradation rate. At the same time, the release of the drug in the gastrointestinal tract is regulated through the pH-sensitive controlled-release layer, achieving a balance between rapid onset and sustained release and providing an unprecedented overall solution.

[0107] 2. Precise coating amount control;

[0108] By setting the coating ratios of 2% - 5% for the inner layer and 3% - 8% for the outer layer, it is ensured that the ratio of the core to the coating in the final product is stably within the reasonable range of 88.50% - 95.2% and 4.4% - 12.4%, guaranteeing the consistency of drug release for each dosage unit.

[0109] 3. Biphasic release design;

[0110] In clinical applications, the blood drug peak can be quickly reached, and at the same time, the drug effect time is prolonged, which helps to improve the difficulty of patients falling asleep and maintain sleep quality.

[0111] 4. Dual guarantee of moisture-proof and controlled release;

[0112] It improves the stability of the product during transportation and storage, reduces the risk of efficacy loss, and has high practical value and commercial promotion prospects.

[0113] Multiple embodiments of the present invention are based on actual detection data and process optimization schemes, which not only ensure the effectiveness of the core formula but also achieve the biphasic release of the drug and the improvement of environmental stability through the double-layer coating design. This technical solution combines material selection, precise control of the coating amount, and the fluidized bed process, overcoming the problems of uneven release and easy degradation existing in traditional melatonin preparations and significantly improving the clinical drug administration experience.

[0114] Example 4

[0115] This is the fourth embodiment of the present invention. The purpose of this embodiment is to study the stability and dissolution behavior of melatonin granules prepared by the double-layer coating technology under different environmental conditions through experiments, and compare them with existing ordinary melatonin tablets to verify the superiority of the moisture-proof protection + pH-dependent controlled release design of the present invention.

[0116] 1 Experimental preparation and implementation process

[0117] 1.1 Materials and equipment

[0118] Experimental samples: Double-layer coated melatonin granules of the present invention (core + double-layer coating);

[0119] Control samples: Commercially available ordinary melatonin tablets (without double-layer coating);

[0120] Main reagents: Ethyl cellulose, methyl methacrylate-ethyl methacrylate copolymer;

[0121] Experimental equipment: Dissolution tester (USP II type), HPLC, high-temperature and high-humidity chamber, fluidized bed coater;

[0122] 1.2 Preparation of particle core (500 mg / unit particle)

[0123] 1.21 Mixing

[0124] Weigh the raw and auxiliary materials according to the following ratio: Melatonin: 1 mg (0.2%), Mannitol: 474 mg (94.8%)

[0125] Hydroxypropyl cellulose: 15 mg (3%), Silicon dioxide: 10 mg (2%). Stir with a high-speed mixer (rotation speed 500 rpm) for 15 minutes to ensure uniform distribution.

[0126] 1.22 Granulation

[0127] Use wet granulation, add an appropriate amount of purified water, and control the humidity at 8% - 10%;

[0128] Screening is carried out using a 40-mesh sieve to ensure that the particle size is between 100 - 500 μm, improving uniformity;

[0129] 1.23 Drying

[0130] Dry at 50 °C for 2 hours to make the loss on drying less than 2.0% to prevent the degradation of melatonin.

[0131] 1.3 Application of double-layer coating (target coating mass 40 mg)

[0132] Inner moisture-proof protective layer (15 mg, ethyl cellulose);

[0133] Coating solution: 5% ethanol solution of ethyl cellulose;

[0134] Fluidized bed coater parameters:

[0135] Feed rate: 3 mL / min; Spray pressure: 1.5 bar; Inlet air temperature: 40 °C;

[0136] Target coating mass: 15 mg, forming a uniform moisture-proof barrier to reduce the sensitivity of melatonin to humidity and oxygen;

[0137] Outer pH-sensitive controlled-release layer (25 mg, solution of methyl methacrylate - ethyl methacrylate copolymer);

[0138] Coating solution: 10% ethanol solution of methacrylic acid copolymer;

[0139] Fluidized bed coater parameters:

[0140] Feed rate: 4 mL / min; Spray pressure: 1.8 bar; Inlet air temperature: 45 °C;

[0141] Target coating mass: 25 mg, ensuring that the particles are insoluble below pH 5.5 and gradually release above pH 5.5 to achieve controlled release in the small intestine.

[0142] 1.4 In vitro dissolution test

[0143] Take 6 groups of samples and conduct dissolution detection under different pH conditions (pH 1.2 and pH 6.8).

[0144] 1.5 Stability test

[0145] Store the samples in a high humidity (75% RH), high temperature (40 °C) and light-proof environment for 30 days, regularly measure the drug degradation rate, and compare the stability of the present invention with that of ordinary tablets;

[0146] 2 The test comparison data of this example are shown in the following table;

[0147] The following table records the dissolution, stability, and key quality parameters under different conditions;

[0148]

[0149] 3. Data analysis and demonstration of beneficial effects

[0150] 3.1. Optimize the release curve to improve the stability of drug efficacy;

[0151] Ordinary tablets release 85% within 15 minutes, which may lead to too high a blood drug concentration of melatonin in a short time, affecting the normal circadian rhythm.

[0152] The granules of the present invention only release 30% within 15 minutes, but continuously release 70% within 4 hours, meeting the needs of the human circadian rhythm, helping patients fall asleep quickly and maintain stable sleep quality.

[0153] 2. The moisture-proof coating improves stability and extends the shelf life;

[0154] Ordinary tablets degrade by 10% in a high-humidity and high-temperature environment, resulting in a large loss of active ingredients.

[0155] The degradation rate of the granules of the present invention is only 2%, indicating that the moisture-proof coating significantly improves the environmental tolerance and extends the storage period.

[0156] 3. Improve the powder flowability to enhance production adaptability;

[0157] The angle of repose changes from 45° to 30°, significantly improving the powder flowability, reducing caking during the production process, and enhancing the automated production efficiency.

[0158] 4. Optimize the taste and solubility to improve the taking experience;

[0159] Traditional tablets are prone to turbidity after dissolving in water, affecting the patient's taking experience.

[0160] The granules of the present invention are clearer after dissolution, enhancing the visual and sensory quality of the product and improving patient compliance.

[0161] The test data show that compared with the existing ordinary melatonin tablets, the present invention has better controlled-release performance, stability, and industrial production adaptability. Through a scientific and reasonable double-layer coating design, it provides an improved solution with both innovation and practicality. The present invention has made significant technological progress in drug controlled-release technology, stability optimization, and taking experience.

[0162] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A melatonin composition, characterized in that: Comprising A particle core, comprising the following components: melatonin, mannitol, hydroxypropyl cellulose, and silicon dioxide; A double-layer coating covering the surface of the particle core, the double-layer coating comprising an inner moisture-proof protective layer and an outer pH-sensitive controlled-release layer to achieve biphasic release and improve environmental stability.

2. The melatonin composition according to claim 1, wherein: The particle core and the double-layer coating in the composition are composed in the following mass ratio: the particle core is 88.50% - 95.2%, the proportion of the double-layer coating in the finished product is 4.4% - 12.4%, and the total mass percentage of the particle core and the double-layer coating is 100%.

3. The melatonin composition according to claim 2, wherein: The particle core is composed of melatonin, mannitol, hydroxypropyl cellulose, and silicon dioxide in the following mass ratio: melatonin is 0.2%, mannitol is 94.8%, hydroxypropyl cellulose is 3%, and silicon dioxide is 2%, and the total mass percentage of the above components is 100%.

4. The melatonin composition according to claim 3, wherein: The double-layer coating is applied sequentially by a fluidized bed coating process. First, the inner moisture-proof protective layer is applied, and then the outer pH-sensitive controlled-release layer is applied to ensure that the coating is uniform, continuous, and has excellent adhesion.

5. The melatonin composition according to claim 4, characterized in that: The inner moisture-proof protective layer in the double-layer coating is made of a polymer selected from at least one of ethyl cellulose, copolymer of amino methacrylate - methyl acrylate, or polyvinyl alcohol, and its mass ratio accounts for 2% - 5% of the weight of the double-layer coating.

6. The melatonin composition according to claim 5, wherein: The inner moisture-proof protective layer in the double-layer coating not only improves the shielding effect of melatonin against moisture and oxygen, but also effectively reduces the degradation rate of melatonin caused by environmental factors, thereby significantly improving the storage stability of the composition.

7. The melatonin composition according to claim 6, wherein: The outer pH-sensitive controlled-release layer in the double-layer coating is made of a polymer selected from copolymer of methacrylic acid - ethyl methacrylate, copolymer of methacrylic acid - methyl methacrylate, or a mixture thereof, and its mass ratio accounts for 3% - 8% of the weight of the double-layer coating; this pH-sensitive controlled-release layer partially dissolves in an environment with a pH value lower than a predetermined value to achieve rapid release, and slowly dissolves at a higher pH value to extend the drug release time.

8. The melatonin composition according to claim 7, wherein: The outer pH-sensitive controlled-release layer in the double-layer coating partially dissolves in the stomach, enabling the composition to release a certain proportion of melatonin initially, and at the same time slowly dissolves in the small intestine environment to provide a sustained release effect.

9. The melatonin composition according to claim 8, wherein: The composition exhibits biphasic release characteristics after oral administration. Specifically: rapid initial release is achieved within 15 minutes after administration, enabling 30% of melatonin to be rapidly released; the remaining 70% of melatonin is continuously released within 4 hours to extend the drug efficacy time.

10. The melatonin composition according to claim 9, characterized in that: The cumulative dissolution of the composition in an aqueous medium meets the following requirements: reaching more than 90% within 5 minutes, reaching more than 95% within 15 minutes, and being completely dissolved within 30 minutes. At the same time, the dissolution curve conforms to the design requirements of biphasic release.

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