Sustained-release preparation of inosine and its preparation method and application

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a sustained-release preparation of isopropyl inosine and a preparation method and application thereof, and the sustained-release preparation of isopropyl inosine comprises a tablet core and a coating film covering the tablet core; wherein the tablet core comprises the following components in percentage by mass: 70%-74.35% of isopropyl inosine, 20%-25% of a hydrophilic gel matrix material, 5%-14.35% of a filling agent, 0.5%-2% of a disintegrating agent and 0.15%-0.5% of a lubricant; the coating film comprises the following components in percentage by mass: 70%-75% of a film control material, 10%-20% of a pore-forming agent and 10%-20% of a plasticizer; the weight of the coating film is 5%-8% of the weight of the tablet core. The application provides the sustained-release preparation of isopropyl inosine and a preparation method and application thereof; the sustained-release preparation of isopropyl inosine plays an anti-inflammatory and joint protection role by regulating T / B lymphocyte activity and inhibiting inflammatory factor release, and makes up for the defects of traditional arthritis treatment drugs, i.e. only relieving symptoms and being unable to regulate immune disorders.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulation technology, and in particular to isoproinosine sustained-release formulations, their preparation methods, and applications. Background Technology

[0002] The number of people suffering from arthritis worldwide is enormous, and it continues to rise with an aging population. Arthritis severely impacts patients' quality of life, leading to joint pain, functional impairment, and even disability. Traditional arthritis medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, can relieve symptoms, but they have side effects such as gastrointestinal reactions, liver damage, and kidney injury. Moreover, for some types of arthritis (such as rheumatoid arthritis), there are no effective drugs that can fundamentally alter the course of the disease. Summary of the Invention

[0003] Based on this, this application provides isoproinosine sustained-release formulations, their preparation methods, and applications. The isoproinosine sustained-release formulations exert anti-inflammatory and joint-protective effects by regulating T / B lymphocyte activity and inhibiting the release of inflammatory factors, thus overcoming the shortcomings of traditional arthritis treatments that only relieve symptoms and cannot regulate immune disorders.

[0004] The first aspect of this application provides an isoprotinin sustained-release formulation, comprising a tablet core and a coating film covering the tablet core;

[0005] The chip core comprises the following components by weight percentage:

[0006] Isoproinosine 65%~74.35%;

[0007] Hydrophilic gel skeleton material 20%~25%;

[0008] Filler content: 5%~14.35%;

[0009] Disintegrant 0.5%~2%;

[0010] Lubricant 0.15%~0.5%;

[0011] The coating film comprises the following components by weight percentage:

[0012] Membrane control materials 70%~75%;

[0013] 10%~20% pore-forming agent;

[0014] Plasticizer 10%~20%;

[0015] The weight of the coating film is 5% to 8% of the weight of the tablet core.

[0016] In some embodiments, the hydrophilic gel skeleton material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, calcium alginate, guar gum, and xanthan gum.

[0017] In some embodiments, the filler includes one or more of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, and dicalcium phosphate.

[0018] In some embodiments, the disintegrant includes one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0019] In some embodiments, the lubricant includes one or more of magnesium stearate, calcium stearate, zinc stearate, stearic acid, silica, glyceryl behenate, sodium stearate fumarate, and polyethylene glycol.

[0020] In some embodiments, the isopyrosine sustained-release formulation meets at least one of the following conditions:

[0021] (1) The membrane control material includes one or more of ethyl cellulose and acrylic resin;

[0022] (2) The pore-forming agent includes one or more of hydroxypropyl methylcellulose and polyvinylpyrrolidone;

[0023] (3) Plasticizers include one or more of polyethylene glycol, triethyl citrate, dibutyl sebacate, dioctyl sebacate and di-n-butyl adipate.

[0024] The second aspect of this application provides a method for preparing the isoprotinin sustained-release formulation provided in the first aspect of this application, comprising the following steps:

[0025] After mixing isoproinosine, hydrophilic gel framework material, filler and some disintegrant, hydrophilic gel framework particles are prepared by wet granulation, drying and granulation in sequence.

[0026] The hydrophilic gel skeleton particles, the remaining disintegrants, and the lubricant are mixed to prepare a mixture;

[0027] The mixture is pressed to prepare the core material;

[0028] A coating solution is prepared by dissolving the membrane control material, pore-forming agent, and plasticizer in a solvent; and

[0029] The tablet core is coated with a coating solution to form a coating film on the surface of the tablet core;

[0030] The weight of the coating film is 5% to 8% of the weight of the tablet core.

[0031] In some implementations, the preparation process of the wafer core satisfies at least one of the following conditions:

[0032] (1) Isoproinosine, hydrophilic gel skeleton material, filler and some disintegrant were mixed at a speed of 20 rpm to 30 rpm for 15 min to 20 min;

[0033] (2) In the wet granulation process, water and ethanol are used as wetting agents;

[0034] (3) The drying step includes: placing the wet granules prepared by wet granulation into a fluidized bed dryer, with an inlet air temperature of 55℃~65℃ and a bed temperature of 45℃~50℃, and drying until the moisture loss is ≤2.0%;

[0035] (4) In the pressing process, the gauge pressure is 60MPa~120MPa.

[0036] In some embodiments, the solid content of the coating solution is 10% to 15%.

[0037] The third aspect of this application provides the use of the isoprotinin sustained-release formulation provided in the first aspect of this application in the preparation of a medicament for treating arthritis.

[0038] Compared with traditional technologies, this application has the following advantages:

[0039] The isoprominosine sustained-release formulation provided in this application exerts anti-inflammatory and joint-protective effects from the root cause of immune regulation by regulating T / B lymphocyte activity and inhibiting the release of key inflammatory factors. This overcomes the shortcomings of traditional arthritis treatments, which only relieve symptoms and cannot regulate immune disorders, and effectively improves the progression of arthritis.

[0040] Meanwhile, addressing the technical challenge of achieving stable, long-lasting release of isoprotinin due to its high water solubility and rapid burst release, traditional formulations struggle to achieve this. This application constructs a dual, synergistic sustained-release system consisting of a hydrophilic gel matrix tablet core and a membrane-controlled coating. The inner hydrophilic gel matrix controls the main drug release through diffusion and dissolution, while the outer coating provides an additional diffusion barrier. Through the synergistic effects of multiple mechanisms—diffusion-dissolution-membrane barrier—and the optimal mass ratio of the tablet core and coating, the system jointly regulates the drug release delay and overall release rate, effectively inhibiting the burst release of isoprotinin, resulting in a stable drug release curve, achieving long-lasting and precise drug release, reducing fluctuations in blood drug concentration, and further improving efficacy stability and patient compliance. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments or related technologies of this application, the accompanying drawings used in the description of the embodiments or related technologies will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1 This is a schematic diagram illustrating the preparation method of isoproinosine sustained-release formulation in some embodiments of this application.

[0043] Figure 2 Safranin-Fix-Green staining images of the knee joint in different groups of this application.

[0044] Figure 3 OARSI scores for safranin-fixation-green staining of the knee joint in different groups. Detailed Implementation

[0045] A detailed reference is now provided to embodiments of this application, one or more of which are described below. Each embodiment is provided for explanation and not for limitation. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to this application without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.

[0046] Therefore, this application is intended to cover such modifications and variations falling within the scope of the appended claims and their equivalents. Other objects, features, and aspects of this application are disclosed in or will be apparent from the following detailed description. It will be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of this application.

[0047] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0048] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0049] In this article, when referring to units of data ranges, if a unit is only followed by the right endpoint, it means that the units of the left and right endpoints are the same.

[0050] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0051] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0052] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, if the method includes steps (a) and (b), it means that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, if the method may also include step (c), it means that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0053] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0054] The number of people suffering from arthritis worldwide is enormous, and it continues to rise with an aging population. Arthritis severely impacts patients' quality of life, leading to joint pain, functional impairment, and even disability. Traditional arthritis medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, can relieve symptoms, but they have side effects such as gastrointestinal reactions, liver damage, and kidney injury. Moreover, for some types of arthritis (such as rheumatoid arthritis), there are no effective drugs that can fundamentally alter the course of the disease.

[0055] Based on this, the applicant discovered during the research process that isoprominosine can exert anti-inflammatory and joint-protective effects by regulating T / B lymphocyte activity and inhibiting the release of key inflammatory factors, thus making up for the shortcomings of traditional arthritis treatment drugs that only relieve symptoms and cannot regulate immune disorders.

[0056] However, during the in-depth research, the applicant discovered that common isoprotinin preparations (such as tablets or capsules) often have the problem of dissolving too quickly, resulting in excessively high local drug concentrations, which in turn cause mild gastrointestinal irritation. At the same time, these common isoprotinin preparations have strong hygroscopicity and are quite sensitive to humidity during long-term storage, which greatly reduces the stability of the drug.

[0057] Based on this, the first aspect of this application provides an isoprotinin sustained-release formulation, including a tablet core and a coating film covering the tablet core;

[0058] The chip core comprises the following components by weight percentage:

[0059] Isoproinosine 65%~74.35%;

[0060] Hydrophilic gel skeleton material 20%~25%;

[0061] Filler content: 5%~14.35%;

[0062] Disintegrant 0.5%~2%;

[0063] Lubricant 0.15%~0.5%;

[0064] The coating film comprises the following components by weight percentage:

[0065] Membrane control materials 70%~75%;

[0066] 10%~20% pore-forming agent;

[0067] Plasticizer 10%~20%;

[0068] The weight of the coating film is 5% to 8% of the weight of the tablet core.

[0069] As a non-limiting example, the mass percentage of isoprotinin in the tablet core is 65% to 74.35%, for example, 65%, 68%, 70%, 72%, 74.35%, and any value within the range of any two of the above values. Further, the mass percentage of isoprotinin in the tablet core is 68% to 72%.

[0070] As a non-limiting example, the weight of the coating film is 5% to 8% of the tablet core weight, for example, 5%, 6%, 7%, 8%, and any value within the range of any two of the above values. Further, the weight of the coating film is 5% of the tablet core weight.

[0071] In this application, "isoproinosine" refers to a stable complex (also known as dimepranol acedoben) formed by inosine and N,N-dimethylamino-2-propanol in a 1:3 molar ratio of p-acetaminobenzoate, with the molecular formula C. 52 H 78 N 10 O 17 The molecular weight is 1115.23. Appearance: White or off-white crystalline powder, almost odorless, slightly bitter taste; solubility in water at 25℃ is approximately 90mg / mL~100mg / mL, belonging to the "easily soluble / freely soluble" category in the Chinese Pharmacopoeia; melting point is approximately 140℃~145℃; it is recommended to store in a moisture-proof, sealed container at room temperature under an inert gas atmosphere; CAS: 36703-88-5.

[0072] The isoprominosine sustained-release formulation provided in this application exerts anti-inflammatory and joint-protective effects from the root cause of immune regulation by regulating T / B lymphocyte activity and inhibiting the release of key inflammatory factors. This overcomes the shortcomings of traditional arthritis treatments, which only relieve symptoms and cannot regulate immune disorders, and effectively improves the progression of arthritis.

[0073] Meanwhile, addressing the technical challenge of achieving stable, long-lasting release of isoprotinin due to its high water solubility and rapid burst release, traditional formulations struggle to achieve this. This application constructs a dual, synergistic sustained-release system consisting of a hydrophilic gel matrix tablet core and a membrane-controlled coating. The inner hydrophilic gel matrix controls the main drug release through diffusion and dissolution, while the outer coating provides an additional diffusion barrier. Through the synergistic effects of multiple mechanisms—diffusion-dissolution-membrane barrier—and the optimal mass ratio of the tablet core and coating, the system jointly regulates the drug release delay and overall release rate, effectively inhibiting the burst release of isoprotinin, resulting in a stable drug release curve, achieving long-lasting and precise drug release, reducing fluctuations in blood drug concentration, and further improving efficacy stability and patient compliance.

[0074] In some embodiments, the hydrophilic gel backbone material includes one or more of hydroxypropyl methylcellulose, sodium alginate, calcium alginate, guar gum, and xanthan gum. Further, the hydrophilic gel backbone material is hydroxypropyl methylcellulose.

[0075] Hydroxypropyl methylcellulose includes one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, and hydroxypropyl methylcellulose K100M. Further, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose K15M.

[0076] Hydroxypropyl methylcellulose K15M is a medium viscosity grade cellulose ether. A 2% aqueous solution has a viscosity of 15000 mPa·s at 20°C, which is classified as a medium-high viscosity grade.

[0077] This application utilizes hydroxypropyl methylcellulose of a specific viscosity grade and adjusts its addition amount to effectively control the strength and density of the gel barrier, thereby regulating the initial burst release and overall release time of the drug to achieve a stable and long-lasting release.

[0078] In some embodiments, the filler includes one or more of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, and dicalcium phosphate. Further, the filler is a mixture of microcrystalline cellulose and lactose.

[0079] In some embodiments, the mass ratio of microcrystalline cellulose to lactose is (1.2~2):1, for example, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, and any value within the range of any two of the above values. By combining microcrystalline cellulose (MCC) and anhydrous lactose, the pore structure and hydrophilic / hydrophobic balance of the tablet core are adjusted, thereby optimizing the release curve. While ensuring sufficient compression strength and forming a stable gel matrix, an appropriate amount of initial pores is created, achieving a stable initial release rate and an ideal sustained release rate, avoiding sudden or excessively slow drug release. Microcrystalline cellulose mainly acts as a matrix support and dry binder, enhancing the density of the matrix, slowing water penetration and drug diffusion, and thus delaying release; on the other hand, it provides compressibility and a dry binder, ensuring the hardness and low brittleness of the tablet core. Lactose, as a soluble pore-forming agent, forms hydrophilic pores in the matrix, providing pathways for the diffusion of water and drugs, thereby accelerating the initial drug release rate; at the same time, it regulates the flowability and filling properties of the powder, making it easier to accurately control the tablet core weight.

[0080] In some implementations, microcrystalline cellulose refers to PH102 microcrystalline cellulose or PH103 microcrystalline cellulose.

[0081] In one specific embodiment, microcrystalline cellulose refers to PH102 microcrystalline cellulose with an average particle size of 90 μm, a bulk density of 0.30 g / cm³, and an angle of repose of 42°.

[0082] In some embodiments, the disintegrant includes one or more of crospovidone (PVPP), crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch. More specifically, the disintegrant is crospovidone (PVPP).

[0083] The disintegrant has a mass percentage of 0.5% to 2% in the tablet core, for example, 0.5%, 1%, 1.5%, 2%, or any value within the range of any two of the above values. By setting the mass percentage of the disintegrant to 0.5% to 2%, its rapid water absorption properties are utilized to form microscopic hydrophilic channels in the hydrophilic gel matrix, ensuring initial wetting of the tablet and fine-tuning the initiation phase of drug release, while ensuring that the integrity of the overall sustained-release matrix structure of the hydrophilic gel is not compromised.

[0084] In some embodiments, the lubricant includes one or more of magnesium stearate, calcium stearate, zinc stearate, stearic acid, silica, glyceryl behenate, sodium stearate fumarate, and polyethylene glycol. Further, the lubricant is magnesium stearate.

[0085] The mass percentage of lubricant in the tablet core is 0.15% to 0.5%, for example, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, and any value within the range of any two of the above values. Further, the mass percentage of lubricant in the tablet core is 0.25% to 0.35%. Some traditional sustained-release tablet designs rely on a high proportion of hydrophobic lubricant to form a blocking skeleton. This design endows the lubricant with a "sustaining-release function," but its non-uniform hydrophobic coating effect is difficult to control precisely, often leading to unpredictable release behavior, significant batch-to-batch differences, and potentially incomplete release due to over-coating. Therefore, this application sets the mass percentage of lubricant in a low range of 0.15% to 0.5%, primarily using it to ensure smooth tableting process, without relying on lubricant to achieve controlled release, thus avoiding excessive release deceleration and significant batch-to-batch differences caused by hydrophobic coating; controlled release is achieved by constructing a dual, synergistic sustained-release system of hydrophilic gel skeleton and membrane-controlled coating membrane, obtaining a predictable release curve and better drug release stability with a lower lubricant burden.

[0086] In some embodiments, the membrane control material includes one or more of ethyl cellulose (EC) and acrylic resin. More specifically, the membrane control material is ethyl cellulose (EC).

[0087] In some embodiments, the porogen includes one or more of hydroxypropyl methylcellulose and polyvinylpyrrolidone. Further, the porogen is hydroxypropyl methylcellulose and polyvinylpyrrolidone.

[0088] In some embodiments, the mass ratio of hydroxypropyl methylcellulose to polyvinylpyrrolidone in the porogen is 1:(0.8~1.5).

[0089] In some embodiments, the plasticizer includes one or more of polyethylene glycol, triethyl citrate, dibutyl sebacate, dioctyl sebacate, and di-n-butyl adipate. Further, the plasticizer is polyethylene glycol. Even further, the plasticizer is polyethylene glycol 400 (PEG400).

[0090] like Figure 1 As shown, the second aspect of this application provides a method for preparing the isoprotinin sustained-release formulation provided in the first aspect of this application, comprising the following steps:

[0091] S1. After mixing isoproinosine, hydrophilic gel skeleton material, filler and some disintegrant, the mixture is then subjected to wet granulation, drying and granulation to prepare hydrophilic gel skeleton particles.

[0092] S2. Mix the hydrophilic gel skeleton particles, the remaining disintegrants and lubricants to prepare a mixture.

[0093] S3. Press the mixture to prepare the core.

[0094] S4. Dissolve the membrane control material, pore-forming agent, and plasticizer in a solvent to prepare a coating solution.

[0095] S5. Coating solution is used to coat the tablet core to form a coating film on the surface of the tablet core.

[0096] The weight of the coating film is 5% to 8% of the weight of the tablet core.

[0097] In the preparation of isopyrosine sustained-release formulations, the disintegrant is added in two batches: one batch is added before the wet granulation step (as an internal phase); the other batch is added in the final mixing step after the granulation, drying, and granulation steps (as an external phase). By regulating the spatial distribution of the disintegrant inside and outside the particles, the wetting and pore formation process of the tablet core is synergistically optimized, avoiding rapid disintegration of the tablet core and achieving more controllable and robust release initiation and sustained release behavior.

[0098] In some embodiments, 30% to 70% of the disintegrant is used as an internal phase and 30% to 70% of the disintegrant is used as an external phase. Further, 50% of the disintegrant is used as an internal phase and 50% of the disintegrant is used as an external phase.

[0099] In some embodiments, in S1 above, isoproinosine, hydrophilic gel skeleton material, filler and partial disintegrant are placed in a three-dimensional mixer and mixed at a speed of 20 rpm to 30 rpm for 15 min to 20 min to prepare a premix.

[0100] In some embodiments, during the wet granulation process in S1 above, water and ethanol are used as wetting agents, and the wetting agents are added to the premix by spraying or sprinkling to prepare wet granules.

[0101] In some embodiments, the drying step in S1 above includes: placing the wet granules prepared by wet granulation in a fluidized bed dryer, with an inlet air temperature of 55°C to 65°C and a bed temperature of 45°C to 50°C, and drying until the moisture loss is ≤2.0%.

[0102] In some embodiments, in S2 above, the hydrophilic gel skeleton particles, the remaining disintegrants, and the lubricant are mixed under low shear force for 2 to 3 minutes to prepare a mixture.

[0103] In some embodiments, in the pressing process of S3 above, the gauge pressure is 60MPa~120MPa.

[0104] In some embodiments, the tensile strength σt of the core is 0.8MPa to 1.2MPa, for example 0.8MPa, 0.9MPa, 1MPa, 1.1MPa, 1.2MPa, and any value within the range of any two of the above values.

[0105] In some implementations, the fragility of the chip core is ≤0.5%.

[0106] In some implementations, the wafer core weight RSD is ≤2%.

[0107] In some implementations, the core has a diameter of 8mm to 10mm and a thickness of 3mm to 4mm.

[0108] In some embodiments, the solvent in S4 above is an alcohol solvent. Examples of alcohol solvents include anhydrous ethanol and isopropanol.

[0109] In some embodiments, in S4 above, the solid content of the coating liquid is 10% to 15%, for example 10%, 11%, 12%, 13%, 14%, 15%, and any value within the range of any two of the above values.

[0110] In some embodiments, S5 includes: coating the tablet cores with a coating solution in a coating pan to form a coating film on the surface of the tablet cores. The pan rotation speed is 6 rpm to 12 rpm; the inlet air temperature is 45°C to 55°C; and the material bed temperature is 35°C to 40°C.

[0111] In some implementations, the coating process is carried out in a well-ventilated environment that meets explosion-proof requirements to ensure the safe discharge of solvent vapors.

[0112] In some embodiments, a pretreatment step is included before S1, which includes sieving isoproinosine, hydrophilic gel matrix material, filler and disintegrant; and pre-dissolving membrane control material.

[0113] In one specific embodiment, isoprotinin is passed through an 80-mesh sieve and set aside for later use.

[0114] In one specific embodiment, the hydrophilic gel skeleton material and filler are passed through a 40-60 mesh sieve and are ready for use.

[0115] In one specific embodiment, a portion of the disintegrant is passed through a 40-mesh sieve and set aside for later use.

[0116] In one specific embodiment, the membrane control material is prepared using a mixed solvent of ethanol and isopropanol (volume ratio of 1:1) for later use.

[0117] The third aspect of this application provides the use of the isoprotinin sustained-release formulation provided in the first aspect of this application in the preparation of a medicament for treating arthritis.

[0118] Furthermore, this application provides the following specific embodiments and comparative examples to further illustrate the specific implementation of this application and its advantages.

[0119] Example 1

[0120] (1) Isoproinosine was passed through an 80-mesh sieve and set aside; hydroxypropyl methylcellulose, microcrystalline cellulose and lactose were passed through a 40-mesh sieve and set aside; some cross-linked polyvinylpyrrolidone was passed through a 40-mesh sieve and set aside; 60g of ethyl cellulose was dissolved in ethanol / isopropanol (v:v=1:1) and magnetically stirred for 25min and set aside.

[0121] (2) Weigh 1000g of isoprotinin, 300g of hydroxypropyl methylcellulose, 80g of microcrystalline cellulose, 40g of lactose and 5g of cross-linked polyvinylpyrrolidone and place them in a three-dimensional mixer. Mix at 25 rpm for 15 min to prepare a premix. Add water / ethanol (v:v=8:2) to the premix by spraying and pass it through a 16-mesh sieve to prepare wet particles. Place the wet particles in a fluidized bed dryer with an inlet air temperature of 60℃ and a bed temperature of 50℃. Dry until the moisture loss is ≤2.0%. Granulate the particles through a 16-mesh sieve to prepare hydrophilic gel skeleton particles.

[0122] (3) Add 5g of cross-linked polyvinyl chloride and 5g of magnesium stearate to the hydrophilic gel skeleton particles, and mix them for 3 minutes at 30 rpm using a three-dimensional mixer to prepare a mixture.

[0123] (4) A die of 8mm×8mm is used to press the tablet under a pressure of 80-100MPa to prepare the tablet core. The tablet core has a diameter of 8mm and a thickness of 3mm.

[0124] (5) Add the ethyl cellulose, 4g of hydroxypropyl methylcellulose, 4g of polyvinylpyrrolidone and 12g of polyethylene glycol 400 dissolved in step (1) to anhydrous ethanol to prepare a coating solution. The solid content of the coating solution is 12%.

[0125] (6) Place the coating solution in the coating machine to coat the tablet cores and form a coating film on the surface of the tablet cores. The rotation speed of the pot is 8 rpm; the air inlet temperature is 50°C; the material bed temperature is 38°C; and the weight of the coating film is 5% of the weight of the tablet cores.

[0126] A total of 1000 tablets of isopyrosine sustained-release formulation were produced.

[0127] Example 2

[0128] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that in step (2) of this embodiment, hydroxypropyl methylcellulose is replaced with sodium alginate; and in step (6), the weight of the coating film is 6.5% of the weight of the tablet core.

[0129] Example 3

[0130] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that in step (2) and step (3) of this embodiment, cross-linked polyvinyl ketone is replaced with cross-linked sodium carboxymethyl cellulose; and in step (6), the weight of the coating film is 8% of the weight of the core.

[0131] Example 4

[0132] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the mass percentage of isoproinosine in the core prepared in this embodiment is 70%, the mass percentage of hydrophilic gel skeleton material is 21%, the mass percentage of filler is 7.5%, the mass percentage of disintegrant is 1%, and the mass percentage of lubricant is 0.5%.

[0133] Example 5

[0134] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the mass percentage of isoproinosine in the core prepared in this embodiment is 72%, the mass percentage of hydrophilic gel skeleton material is 20%, the mass percentage of filler is 6.5%, the mass percentage of disintegrant is 1%, and the mass percentage of lubricant is 0.5%.

[0135] Example 6

[0136] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the mass percentage of the membrane control material in the coating film prepared in this embodiment is 70%, the mass percentage of the pore-forming agent is 16%, and the mass percentage of the plasticizer is 14%.

[0137] Example 7

[0138] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the mass percentage of the membrane control material in the coating film prepared in this embodiment is 75%, the mass percentage of the pore-forming agent is 12%, and the mass percentage of the plasticizer is 13%.

[0139] The specific material composition details of Examples 1-7 are shown in Table 1 below.

[0140] Table 1

[0141]

[0142] It should be noted that "weight gain of coating film" in Table 1 refers to the percentage of the weight of the coating film to the weight of the tablet core.

[0143] Comparative Example 1

[0144] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the weight of the coating film in step (6) of this embodiment is 4% of the weight of the core.

[0145] Comparative Example 2

[0146] The preparation methods of this embodiment and Example 1 are basically the same. The main difference is that the weight of the coating film in step (6) of this embodiment is 10% of the weight of the core.

[0147] Comparative Example 3

[0148] Isoproinosine, crospovidone, and micronized silica gel were pulverized and passed through a 120-mesh sieve. 500g of isoproinosine, 40g of crospovidone, and 100g of micronized silica gel were thoroughly mixed. An appropriate amount of hydroxypropyl methylcellulose ethanol solution was added to prepare a soft mass, which was then granulated through a 20-mesh sieve, dried in a ventilated environment at 60℃, and sized through a 16-mesh sieve. The granules were then coated with a moisture-proof coating powder. The pot temperature was controlled at 55℃ and the pot rotation speed was controlled at 50 rpm. A 15% alcohol-soluble coating solution was prepared based on a 11% increase in granule weight. The solution was sprayed at an appropriate flow rate for coating. After coating, the granules were dried, and the resulting granules were compressed into tablets with an appropriate amount of lubricant, magnesium stearate.

[0149] Test case

[0150] (1) Appearance: Check whether the surface of the tablets is smooth and whether there are defects such as spots or cracks. The results are shown in Table 2 below.

[0151] (2) Tablet weight variation: Tested according to the method specified in the Chinese Pharmacopoeia. The results are shown in Table 2 below.

[0152] (3) Hardness: The hardness of the tablets was tested using a hardness tester. The results are shown in Table 2 below.

[0153] (4) Release rate: The paddle method was used with 0.1 mol / L hydrochloric acid solution (900 mL) as the release medium, a rotation speed of 50 r / min, and a temperature of 37℃±0.5℃. Samples were taken at 1 h, 4 h, 8 h, and 12 h to determine the release of isopyrosine. Generally, the release rate was required to be no more than 30% at 1 h, 40%-60% at 4 h, 60%-80% at 8 h, and no less than 90% at 12 h. The results are shown in Table 3 below.

[0154] (5) Release stability test: The accelerated stability (40℃±2℃, 75%RH±5%) and long-term stability (25℃±2℃, 60%RH±5%) of the isoprotinin drug formulations prepared in the examples and comparative examples were investigated. Samples were taken at different time points and their in vitro release was measured. The results are shown in Tables 4-6 below. The dissolution curve similarity (f2) results are shown in Table 7 below and compared with the initial sample (T=0).

[0155] Table 2

[0156]

[0157] Table 3

[0158]

[0159] Table 4

[0160]

[0161] Table 5

[0162]

[0163] Table 6

[0164]

[0165] Table 7

[0166]

[0167] (5) Pharmacodynamic test: The patients were randomly divided into three groups: Sham group: only the knee joint was cut open and exposed, without cutting the medial meniscus and tibial ligament, and without inducing an arthritis model. No drug treatment was given after the operation, and the patients were fed until the end of the experiment as a normal physiological control.

[0168] Model control group (DMM): The medial meniscus tibial ligament was surgically cut to induce medial meniscus instability and establish an osteoarthritis model. No drug intervention was given after modeling, serving as a pathological damage control.

[0169] The treatment group (DMM + INO) used the same surgical procedure as the model control group to establish an osteoarthritis model. One week after modeling, the drug was started at a clinically equivalent dose (4 mg / kg). The drug was dissolved in water to prepare 50 ml of solution, which was changed every two days. The drug was administered continuously for 8 weeks to evaluate the drug's effect on improving arthritis.

[0170] Ten mice were used in each group and fed until week 10. At week 10, an arthritis model was induced by surgery. Drug experiments were conducted on the arthritis mouse models at 4 weeks and 8 weeks post-modeling. The mice were orally administered the isoprominosine sustained-release formulation provided in Example 1 (at an equivalent dose) daily, and periodic evaluations were performed.

[0171] The evaluation method is as follows:

[0172] (1) After the experiment, the mice were euthanized and the knee joints were fixed, decalcified and embedded.

[0173] (2) Section and perform safranin-fix green staining (healthy cartilage is stained red because it contains a lot of proteoglycans, while damaged areas are faded).

[0174] (3) Scoring the slides under a microscope according to the OARSI standard.

[0175] The results are as follows Figure 2 and 3 As shown. Figure 2 The images show safranin-fixative-green staining of the knee joint in different groups. As can be seen from the images, in the sham surgery group (Sham), at 4 and 8 weeks, the cartilage matrix was stained evenly, the tidal line structure was intact, the chondrocytes were arranged regularly, the distribution of each layer was clear, and there was no obvious cartilage damage.

[0176] Model group (DMM): At 4 weeks, the cartilage matrix staining became lighter, the chondrocytes were arranged in a disordered manner, and the tidal line structure began to be destroyed; at 8 weeks, the damage was further aggravated, a large number of necrotic chondrocytes were visible, the cartilage surface was severely damaged, and fibrous gaps appeared in some areas.

[0177] In the treatment group (DMM+INO): at 4 and 8 weeks, the staining of the cartilage matrix was significantly darker than that in the model group, the arrangement of chondrocytes was more regular, the tidal line structure was less damaged, and only a few fibrous gaps were observed. The degree of cartilage damage was significantly less than that in the model group.

[0178] Figure 3 The OARSI scores of the knee joints were determined by Safranin-Fix-Green staining in different groups. The results showed that the OARSI scores of the model group (DMM-4W / DMM-8W) were significantly higher than those of the sham-operated group (Sham-4W / Sham-8W) (*P<0.05, ***P<0.001), indicating that the model group successfully induced cartilage damage.

[0179] Compared with the model group, the OARSI scores of the treatment groups (DMM+INO-4W / DMM+INO-8W) were significantly reduced (**P<0.01, ***P<0.001), and the improvement was more obvious at 8 weeks, indicating that the sustained-release formulation of isopyrosine can significantly reduce the degree of cartilage damage and promote cartilage repair.

[0180] Time-dependent analysis showed that the OARSI score of the model group increased further over time, while the score of the drug-treated group remained at a low level, suggesting that the protective effect of the sustained-release formulation on cartilage is time-dependent.

[0181] Depend on Figure 2-3 It is known that, through oral administration to arthritis mice at 4 and 8 weeks of age, the isoprotinin sustained-release formulation provided in this application significantly promotes the repair of articular cartilage and has a significant effect on improving arthritis.

[0182] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0183] The above embodiments merely illustrate several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A sustained-release formulation of isoprotinin, characterized in that, Includes a wafer core and a coating film covering the wafer core; The chip core comprises the following components by mass percentage: Isoproinosine 65%~74.35%; Hydrophilic gel skeleton material 20%~25%; Filler content: 5%~14.35%; Disintegrant 0.5%~2%; Lubricant 0.15%~0.5%; The coating film comprises the following components by weight percentage: Membrane control materials 70%~75%; 10%~20% pore-forming agent; Plasticizer 10%~20%; The weight of the coating film is 5% to 8% of the weight of the core film.

2. The isoprotinin sustained-release formulation according to claim 1, characterized in that, The hydrophilic gel framework material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, calcium alginate, guar gum, and xanthan gum.

3. The isoprotinin sustained-release formulation according to claim 1, characterized in that, The filler includes one or more of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, and dicalcium phosphate.

4. The isoprotinin sustained-release formulation according to claim 1, characterized in that, The disintegrant includes one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

5. The isoprotinin sustained-release formulation according to claim 1, characterized in that, The lubricant includes one or more of magnesium stearate, calcium stearate, zinc stearate, stearic acid, silicon dioxide, glyceryl behenate, sodium stearate fumarate, and polyethylene glycol.

6. The isoprotinin sustained-release formulation according to claim 1, characterized in that, At least one of the following conditions must be met: (1) The membrane control material includes one or more of ethyl cellulose and acrylic resin; (2) The pore-forming agent includes one or more of hydroxypropyl methylcellulose and polyvinylpyrrolidone; (3) The plasticizer includes one or more of polyethylene glycol, triethyl citrate, dibutyl sebacate, dioctyl sebacate and di-n-butyl adipate.

7. A method for preparing an isoprotinin sustained-release formulation according to any one of claims 1-6, characterized in that, Includes the following steps: The hydrophilic gel skeleton material, filler and partial disintegrant are mixed and then subjected to wet granulation, drying and granulation in sequence to prepare hydrophilic gel skeleton particles. The hydrophilic gel skeleton particles, the remaining disintegrants, and the lubricant are mixed to prepare a mixture; The mixture is pressed to prepare a core. A coating solution is prepared by dissolving membrane control materials, pore-forming agents, and plasticizers in a solvent; as well as The coating solution is used to coat the tablet core, forming a coating film on the surface of the tablet core; The weight of the coating film is 5% to 8% of the weight of the core film.

8. The method for preparing the isoprotinin sustained-release formulation according to claim 7, characterized in that, The preparation process of the wafer core satisfies at least one of the following conditions: (1) The isoprotinin, hydrophilic gel skeleton material, filler and partial disintegrant are mixed at a speed of 20 rpm to 30 rpm for 15 min to 20 min; (2) In the wet granulation process, water and ethanol are used as wetting agents; (3) The drying step includes: placing the wet granules prepared by the wet granulation process into a fluidized bed dryer, with an inlet air temperature of 55℃~65℃ and a bed temperature of 45℃~50℃, and drying until the moisture loss is ≤2.0%; (4) In the pressing process, the gauge pressure is 60MPa~120MPa.

9. The method for preparing the isoprotinin sustained-release formulation according to claim 7, characterized in that, The solid content of the coating solution is 10% to 15%.

10. The use of the isoprotinin sustained-release formulation according to any one of claims 1-6 in the preparation of a medicament for treating arthritis.

Images