Polymeric excipients for pharmaceuticals and methods for their preparation, pharmaceutical formulations

Abstract

The present application relates to the technical field of solid pharmaceutical preparation, in particular to a polymer excipient for medicine, a preparation method thereof and a pharmaceutical preparation. The polymer excipient for medicine comprises polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5-4):1, and the number average molecular weight of the polyethylene glycol is greater than or equal to 1000 Da. The polymer excipient can increase the solubility of poorly soluble drugs, realize the immediate release, sustained and controlled release of the drugs, improve the dissolution characteristics of water-soluble drugs (avoid burst release, realize near zero-order release, and the dissolution is not affected by the medium and stirring rate), and enhance the storage stability of the pharmaceutical preparation.

Description

Technical Field

[0001] This invention relates to the field of solid pharmaceutical preparations, and in particular to a polymeric excipient for pharmaceuticals, its preparation method, and pharmaceutical preparations. Background Technology

[0002] Currently, oral solid dosage forms face several key challenges in the delivery of poorly soluble drugs: difficulty in drug solubilization, low bioavailability, and unsatisfactory sustained-release and controlled-release effects. Traditional solubilization strategies (including solvent methods, micelles, emulsions, inclusion complexes, solid dispersions, and nanocrystals) all have certain technical limitations and generally suffer from complex formulations and demanding process requirements. Furthermore, oral sustained-release and controlled-release tablets with high-viscosity water-soluble polymers (such as hydroxypropyl methylcellulose, HPMC) as the backbone pose a risk of burst release in practical applications, and the release rate is significantly affected by the dissolution medium and stirring rate, making it difficult to achieve zero-order release. Controlling the release rate requires complex formulations and processes such as multi-layer coatings or osmotic pumps, resulting in high costs. These technical bottlenecks severely restrict the clinical efficacy and product development of poorly soluble drugs.

[0003] Polylactide (PLA) is a synthetic biodegradable polymer whose ester bonds can be hydrolyzed in an aqueous environment to produce non-toxic hydroxycarboxylic acids, which are then metabolized into water and carbon dioxide via the citric acid cycle. PLA has been approved by the U.S. Food and Drug Administration (FDA) for use in drug delivery systems due to its excellent biodegradability, good mechanical properties, and low immunogenicity. Currently, commercially available PLA-based formulations mainly include drug-loaded micelles, long-acting microspheres, and implants, which have promising applications in the delivery of peptides and anticancer drugs. However, PLA's hydrophobicity, difficulty in controlling its degradation rate, and limited capacity for loading polar drugs restrict its application in oral formulations and other fields. To overcome these limitations, researchers copolymerized hydrophilic polyethylene glycol (PEG) with PLA, significantly improving the material's hydrophilicity, degradation rate, and crystallinity. The resulting PLA-PEG amphiphilic copolymer has the following advantages: (1) high solubility and high bioavailability for poorly soluble drugs; (2) high drug loading and encapsulation efficiency; (3) small particle size helps enhance targeting; (4) prolonged drug circulation time by avoiding clearance by the reticuloendothelial system; and (5) good safety. Currently, PLA-PEG nanoparticles have been successfully applied to delivery systems for vaccines, protein drugs, and gene drugs, enhancing efficacy and reducing drug resistance.

[0004] However, PLA-PEG is easily hydrolyzed and degraded, and has poor stability when stored at room temperature. Currently, most applications and research on PLA-PEG focus on injectable formulations, with limited exploration and application in the oral field. To date, there are no commercially available oral formulations.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The purpose of this invention is to provide polymer excipients for pharmaceuticals, methods for their preparation, and pharmaceutical formulations. The polymer excipients of this invention have good storage stability, drug solubilization, and sustained-release effects, and can be used to prepare oral pharmaceutical formulations.

[0007] To achieve the above-mentioned objectives of the present invention, a first aspect of the present invention provides a polymeric excipient for a pharmaceutical product, comprising a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5 to 4):1; wherein the polyethylene glycol has a number average molecular weight ≥ 1000 Da.

[0008] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-3000 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da. Further, the number-average molecular weight of the polyethylene glycol is 1000-10000 Da.

[0009] In a specific embodiment of the present invention, the polyethylene glycol block copolymer has a molecular weight of 6000-8000 Da for the polyethylene glycol blocks. Further, the number-average molecular weight of the polyethylene glycol is 4000-10000 Da.

[0010] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes at least one of diblock copolymer PLA-PEG and triblock copolymer PLA-PEG-PLA.

[0011] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-2100 Da, and the molecular weight of the polyethylene glycol block is 2000-8000 Da. Further, when the polylactic acid-polyethylene glycol block copolymer is a diblock copolymer PLA-PEG, the average molecular weight of the polylactic acid monoblock (i.e., the molecular weight of the polylactic acid block) is 1000-2100 Da, and the molecular weight of the polyethylene glycol block is 2000-8000 Da; when the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer PLA-PEG-PLA, the average molecular weight of the polylactic acid monoblock (i.e., the average molecular weight of each polylactic acid monoblock) is 1000-1800 Da, and the molecular weight of the polyethylene glycol block is 3000-8000 Da.

[0012] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 2200-3000 Da, and the molecular weight of the polyethylene glycol block is 2000-10000 Da.

[0013] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is ≥2000 Da, preferably 2000-5000 Da; the molecular weight of the polyethylene glycol block is 6000-8000 Da.

[0014] In a specific embodiment of the present invention, the number-average molecular weight of the polyethylene glycol is 4000 to 10000 Da.

[0015] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes at least one of PLLA block and PDLA block.

[0016] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes a first copolymer and a second copolymer; the first copolymer is selected from at least one of the diblock copolymer PLLA-PEG and the triblock copolymer PLLA-PEG-PLLA, and the second copolymer is selected from at least one of the PDLA-PEG and the triblock copolymer PDLA-PEG-PDLA.

[0017] In a specific embodiment of the present invention, the mass ratio of the first copolymer to the second copolymer is 1:(0.5-2), preferably 1:1.

[0018] In specific embodiments of the present invention, at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose is also included.

[0019] The second aspect of the present invention provides a method for preparing a polymeric excipient for a pharmaceutical product according to the first aspect of the present invention, comprising the following steps: melting and mixing polylactic acid-polyethylene glycol block copolymer with polyethylene glycol until homogeneous, and then cooling.

[0020] In a specific embodiment of the present invention, the preparation method includes: melting and mixing a first copolymer with a portion of polyethylene glycol to obtain a first mixture; melting and mixing a second copolymer with the remaining polyethylene glycol to obtain a second mixture; melting and mixing the first mixture and the second mixture to obtain a second mixture; and cooling.

[0021] In a specific embodiment of the present invention, the mass ratio of the first mixture to the second mixture is 1:(0.5-2).

[0022] A third aspect of the present invention provides a pharmaceutical formulation comprising a drug and any of the polymeric excipients for a drug as described in the first aspect of the present invention.

[0023] In a specific embodiment of the present invention, the pharmaceutical preparation is a solid preparation. Further, the pharmaceutical preparation includes at least one of tablets and capsules.

[0024] In a specific embodiment of the present invention, the pharmaceutical preparation is an oral preparation.

[0025] In a specific embodiment of the present invention, the drug includes at least one of indomethacin, nimodipine, nifedipine, apremilast, diltiazem hydrochloride, levetiracetam, and fenofibrate.

[0026] In a specific embodiment of the present invention, the pharmaceutical preparation comprises the following components by mass percentage: 9%–55% of the drug, 15%–50% of polymeric excipients for the drug, 15%–50% of other pharmaceutical excipients, and 0%–1% of magnesium stearate. Further, the other pharmaceutical excipients include at least one selected from hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose.

[0027] In a specific embodiment of the present invention, the viscosity of the 2wt% aqueous solution of hydroxypropyl methylcellulose at 20°C is ≤4000 mPa·s, preferably 6 to 4000 mPa·s.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] (1) The polymer excipient of the present invention, through the compounding of polylactic acid-polyethylene glycol block copolymer and polyethylene glycol, can increase the solubility of poorly soluble drugs and has good storage stability; furthermore, the composition of the polymer excipient is optimized for different oral drugs, which can achieve the effects of immediate release or sustained release while solubilizing oral drugs.

[0030] (2) The polymer excipients of the present invention, through the compounding of polylactic acid-polyethylene glycol block copolymer and polyethylene glycol, can be used as drug sustained-release skeleton materials, which can improve the burst release of water-soluble drugs; when used in combination with other excipients, drug dissolution can be further adjusted, and a dissolution curve with near-zero release can be obtained. The drug release process is not affected by the release medium and stirring rate, and the storage stability of the formulation can be improved. Attached Figure Description

[0031] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0032] Figure 1 GPC test graphs of polymer excipient 2-1 provided in Example 1 of the present invention at different times in a stability study at 40°C;

[0033] Figure 2 HPLC test chromatograms of polymer excipient 2-1 provided in Example 1 of the present invention at different times in a stability study at 40°C;

[0034] Figure 3 DSC test charts of polymer excipient 2-1 provided in Example 1 of the present invention at different times in a stability study at 40°C;

[0035] Figure 4 This is a dissolution curve of the solubilized and rapidly released drug provided in Example 3 of the present invention;

[0036] Figure 5 This is a dissolution curve of the solubilized sustained-release drug provided in Example 4 of the present invention;

[0037] Figure 6 This is a dissolution curve of the matrix-type sustained-release drug provided in Example 5 of the present invention;

[0038] Figure 7 This is a dissolution curve of a diltiazem hydrochloride skeleton-type sustained-release formulation using HPMC of different viscosities, provided in Example 6 of the present invention.

[0039] Figure 8 This is a dissolution curve of a diltiazem hydrochloride skeleton-type sustained-release formulation using different excipients, provided in Example 7 of the present invention.

[0040] Figure 9 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 8 of the present invention in different media;

[0041] Figure 10 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 8 of the present invention at different stirring rates;

[0042] Figure 11 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 8 of the present invention in different dissolution media;

[0043] Figure 12 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 7 of the present invention after being stored at different temperatures for 3 months.

[0044] Figure 13 This is a dissolution curve of the apremilast matrix-type sustained-release formulation provided in Example 9 of the present invention;

[0045] Figure 14 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 10 of the present invention;

[0046] Figure 15 This is a dissolution curve of the diltiazem hydrochloride skeleton-type sustained-release formulation provided in Example 11 of the present invention. Detailed Implementation

[0047] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0048] Unless otherwise specified, the molecular weights used in this invention are considered to be weight-average molecular weights; where additional explanations are given, those explanations shall prevail.

[0049] The first aspect of the present invention provides a polymeric excipient for a pharmaceutical product, comprising a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5 to 4):1; wherein the number average molecular weight of the polyethylene glycol is ≥1000 Da.

[0050] This invention, through a specific ratio of polylactic acid-polyethylene glycol block copolymer (PLA-PEG) to polyethylene glycol, achieves a solution suitable for solubilizing poorly soluble drugs and serving as a sustained-release matrix material. In different embodiments, the mass ratio of PLA-PEG to polyethylene glycol can be 0.5:1, 0.8:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, or any combination thereof, thereby facilitating the solubilization of poorly soluble drugs and achieving sustained-release effects as a matrix material.

[0051] The polymer excipients of this invention, by controlling the number-average molecular weight of polyethylene glycol to ensure it is ≥1000 Da, guarantee the melting point, compatibility with capsule shells, and tableting performance of the polymer excipients. This invention's research found that when the number-average molecular weight of the polyethylene glycol used is below 1000 Da, the mixture with polylactic acid-polyethylene glycol block copolymer has a low melting point, is incompatible with HPMC and gelatin capsule shells, cannot be tableted, cannot be made into solid dosage forms, and cannot achieve sustained-release or controlled-release effects.

[0052] The polylactic acid block portion of the present invention comprises homopolymers of levorotatory (L-)lactide, dextrorotatory (D-)lactide, racemic (D,L-)lactide, and meso-lactide, or copolymers thereof. The polyethylene glycol of the present invention includes, but is not limited to, polyethylene glycol and polyethylene glycol monomethyl ether.

[0053] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-3000 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da. Further, the number average molecular weight of the polyethylene glycol is 1000-10000 Da.

[0054] In polylactic acid (PLA)-polyethylene glycol (PEG) block copolymers, the average molecular weight of a PLA monoblock refers to the average molecular weight of each PLA monoblock. For example, when the PLA-PEG block copolymer is a diblock copolymer, the average molecular weight of the PLA monoblock is the same as the molecular weight of the PLA block; when the PLA-PEG block copolymer is a triblock copolymer, the average molecular weight of the PLA monoblock is the average molecular weight of each PLA monoblock.

[0055] When the average molecular weight of the polylactic acid monoblocks, the molecular weight of the polyethylene glycol blocks, and the number-average molecular weight of the polyethylene glycol in the polylactic acid-polyethylene glycol block copolymer meet the aforementioned ranges, it is more conducive to the solubilization of drugs. For example, in different embodiments, the average molecular weight of the polylactic acid monoblocks in the polylactic acid-polyethylene glycol block copolymer can be within the range of 1000 Da, 1200 Da, 1500 Da, 1800 Da, 2000 Da, 2200 Da, 2500 Da, 2800 Da, 3000 Da, or any combination thereof; the molecular weight of the polyethylene glycol blocks can be within the range of 1500 Da, 2000 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 5500 Da, 6000 Da. The range of 6500Da, 7000Da, 7500Da, 8000Da, or any two of these; the number average molecular weight of polyethylene glycol can be 1000Da, 1500Da, 2000Da, 2500Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 5500Da, 6000Da, 6500Da, 7000Da, 7500Da, 8000Da, 8500Da, 9000Da, 9500Da, 10000Da, or any two of these.

[0056] It is understood that the polymer excipients of the present invention cover cases including two or more polylactic acid-polyethylene glycol block copolymers, cases including two or more polyethylene glycols, and cases including two or more polylactic acid-polyethylene glycol block copolymers and two or more polyethylene glycols, as long as the polylactic acid-polyethylene glycol block copolymers and polyethylene glycols each meet the above conditions, and the ratio of the two meets the above conditions.

[0057] In a specific embodiment of the present invention, the polyethylene glycol block copolymer has a molecular weight of 6000–8000 Da for the polyethylene glycol blocks. Further, the number-average molecular weight of the polyethylene glycol is 4000–10000 Da. When the molecular weight of the polyethylene glycol blocks is above 6000 Da, the polymer has a higher melting point. Further, by combining it with polyethylene glycol having a number-average molecular weight above 4000 Da, the melting point of the polymer excipient is increased while adjusting the dissolution and dispersion of the polymer excipient and the drug release rate, thereby improving the storage stability of the polymer excipient.

[0058] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes at least one of a diblock copolymer PLA-PEG and a triblock copolymer PLA-PEG-PLA. The diblock copolymer PLA-PEG is PLA-MePEG.

[0059] This invention further regulates polymer excipients to meet different needs for solubilization and rapid release versus solubilization and controlled release.

[0060] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-2100 Da, for example, it can be a range of 1000 Da, 1200 Da, 1500 Da, 1800 Da, 2000 Da, 2100 Da or any two thereof; the molecular weight of the polyethylene glycol block is 2000-8000 Da, for example, it can be a range of 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da or any two thereof. Furthermore, when the polylactic acid-polyethylene glycol block copolymer is a diblock copolymer PLA-PEG, the average molecular weight of the polylactic acid monoblock is 1000–2100 Da, and the molecular weight of the polyethylene glycol block is 2000–8000 Da; when the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer PLA-PEG-PLA, the average molecular weight of the polylactic acid monoblock is 1000–1800 Da, and the molecular weight of the polyethylene glycol block is 3000–8000 Da. This invention has found that polymer excipients obtained by blending copolymers with relatively low molecular weight polylactic acid blocks and polyethylene glycol can better disperse and dissolve drugs while ensuring drug solubilization. This allows for the acquisition of solubilized and rapid-release dosage forms. For example, it can effectively solubilize poorly soluble drugs such as indomethacin, nimodipine, and nifedipine, resulting in capsules or tablets with good rapid-dissolving effects.

[0061] To further improve the release rate, the proportion of polyethylene glycol is increased within the mass ratio range of polylactic acid-polyethylene glycol block copolymer to polyethylene glycol of (0.5 to 4):1; and / or, the number average molecular weight of polyethylene glycol is decreased within the range of 1000 to 10000 Da.

[0062] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 2200-3000 Da, for example, it can be a range of 2200 Da, 2400 Da, 2500 Da, 2600 Da, 2800 Da, 3000 Da or any two thereof; the molecular weight of the polyethylene glycol block is 2000-10000 Da, for example, it can be a range of 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da or any two thereof. This invention has discovered that copolymers with relatively high molecular weight polylactic acid blocks are difficult to dissolve or insoluble in water. When blended with polyethylene glycol, the resulting polymer excipients can disperse relatively slowly in water while ensuring drug solubilization. This allows for the preparation of solubilized and controlled-release dosage forms. For example, it can effectively solubilize poorly soluble drugs such as nifedipine and apremilast, and the resulting capsules or tablets have good solubilization and controlled-release effects.

[0063] To further reduce the release rate and improve the sustained-release effect, the proportion of polyethylene glycol is reduced within the mass ratio range of polylactic acid-polyethylene glycol block copolymer to polyethylene glycol of (0.5-4):1; and / or, the number average molecular weight of polyethylene glycol is increased within the range of 1000-10000 Da.

[0064] For the purpose of solubilization, the drug to be solubilized can be melt-blended with polymer excipients to obtain a uniformly dispersed formulation.

[0065] When common water-soluble drugs are formulated into matrix-type sustained-release tablets, there is often a risk of drug burst release due to dissolution, failing to achieve zero-order release, and dissolution is significantly affected by the medium. This invention creatively discovers that using a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol as a sustained-release matrix material can effectively control the release of water-soluble drugs, avoiding problems such as burst release. This invention further addresses the needs of sustained-release matrix materials for water-soluble drugs by regulating the polymer excipients.

[0066] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is ≥2000 Da, preferably 2000–5000 Da, for example, it can be 2000 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, or any combination thereof; the molecular weight of the polyethylene glycol block is 6000–8000 Da, for example, it can be 6000 Da, 6500 Da, 7000 Da, 7500 Da, 8000 Da, or any combination thereof. Using a polylactic acid-polyethylene glycol block copolymer that meets the above conditions is more conducive to improving the stability of the skeleton; in particular, using a copolymer with a higher molecular weight polylactic acid block can significantly reduce the influence of stirring rate on dissolution.

[0067] In a specific embodiment of the present invention, the number average molecular weight of polyethylene glycol is 4000 to 10000 Da, for example, it can be 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da or any combination thereof.

[0068] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes at least one of PLLA block and PDLA block.

[0069] It is understandable that PLLA and PDLA blocks can be introduced from the same polylactic acid-polyethylene glycol block copolymer, or they can be introduced from two or more polylactic acid-polyethylene glycol block copolymers respectively.

[0070] In a specific embodiment of the present invention, the polylactic acid-polyethylene glycol block copolymer includes a first copolymer and a second copolymer; the first copolymer is selected from at least one of the diblock copolymer PLLA-PEG and the triblock copolymer PLLA-PEG-PLLA, and the second copolymer is selected from at least one of the PDLA-PEG and the triblock copolymer PDLA-PEG-PDLA.

[0071] In a specific embodiment of the present invention, the mass ratio of the first copolymer to the second copolymer is 1:(0.5-2), preferably 1:1. Furthermore, the average molecular weight of the polylactic acid monoblocks in the first copolymer and the second copolymer is the same. This further helps to improve the melting point and stability of the polymer excipient and regulate the release rate.

[0072] When the polymer excipients of this invention are used as sustained-release matrix materials, they can be used to prepare sustained-release formulations of diltiazem hydrochloride, levetiracetam, etc. Furthermore, when the polymer excipients of this invention are used as sustained-release matrix materials, they can also be used for the sustained-release of non-water-soluble drugs, such as apremilast.

[0073] In specific embodiments of the present invention, at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose is also included. Further, low-viscosity hydroxypropyl methylcellulose is included, wherein a 2 wt% aqueous solution of hydroxypropyl methylcellulose has a viscosity ≤4000 mPa·s at 20°C. For example, the low-viscosity hydroxypropyl methylcellulose is at least one of HPMC 4000, HPMC 50, HPMC 30, HPMC 15, and HPMC 6.

[0074] When the polymer excipients of the present invention are combined with low-viscosity HPMC to prepare diltiazem hydrochloride skeleton-type sustained-release formulations, the dissolution exhibits near-zero-order release with no burst release phenomenon, and the dissolution is not affected by the medium.

[0075] The second aspect of the present invention provides a method for preparing a polymeric excipient for a pharmaceutical product according to the first aspect of the present invention, comprising the following steps: melting and mixing polylactic acid-polyethylene glycol block copolymer with polyethylene glycol until homogeneous, and then cooling.

[0076] In a specific embodiment of the present invention, the preparation method includes: melting and mixing a first copolymer with a portion of polyethylene glycol to obtain a first mixture; melting and mixing a second copolymer with the remaining polyethylene glycol to obtain a second mixture; melting and mixing the first mixture and the second mixture to obtain a second mixture; and cooling.

[0077] In a specific embodiment of the present invention, the mass ratio of the first mixture to the second mixture is 1:(0.5 to 2), for example, it can be a range of 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2 or any two of them.

[0078] In a specific embodiment of the present invention, the mass ratio of a portion of polyethylene glycol to the balance of polyethylene glycol is 1:(0.5 to 2), for example, it can be 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2 or any combination thereof.

[0079] In a specific embodiment of the present invention, the melting and mixing temperature is 80–150°C, for example, it can be a range of 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, 130°C, 150°C, or any combination thereof. In actual operation, the melting and mixing temperature can be conventionally adjusted according to the melting points of polyethylene glycol and copolymers to ensure uniform mixing.

[0080] In a specific embodiment of the present invention, the preparation method further includes: grinding and sieving the cooled material. The specific particle size can be adjusted conventionally according to the requirements of the formulation.

[0081] A third aspect of the present invention provides a pharmaceutical formulation comprising a drug and any of the polymeric excipients for a drug according to the first aspect of the present invention.

[0082] In a specific embodiment of the present invention, the pharmaceutical preparation is a solid preparation. Further, the pharmaceutical preparation includes at least one of tablets and capsules. The tablets of the present invention can be prepared using conventional solid tablet processes, such as blending, granulation, drying, compression, and coating; the capsules of the present invention can be prepared by uniformly mixing the drug and polymer excipients under molten conditions and then filling them into capsules.

[0083] In a specific embodiment of the present invention, the pharmaceutical preparation is an oral preparation.

[0084] In a specific embodiment of the present invention, the drug includes at least one of indomethacin, nimodipine, nifedipine, apremilast, diltiazem hydrochloride, levetiracetam, and fenofibrate.

[0085] In a specific embodiment of the present invention, the pharmaceutical preparation comprises the following components by mass percentage: 9% to 55% of the drug, 15% to 50% of polymeric excipients for the drug, 15% to 50% of other pharmaceutical excipients, and 0% to 1% of magnesium stearate. In different embodiments, the amounts of each component in the pharmaceutical preparation, by mass percentage, may be as follows: the amount of the drug may be 9%, 10%, 12%, 15%, 17%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or any combination thereof; the amount of the polymeric excipient used in the drug may be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or any combination thereof; the amount of other pharmaceutical excipients may be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or any combination thereof; and the amount of magnesium stearate may be 0%, 0.2%, 0.5%, 0.8%, 1%, or any combination thereof.

[0086] In specific embodiments of the present invention, other pharmaceutical excipients include at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose.

[0087] In a specific embodiment of the present invention, the pharmaceutical formulation comprises, by mass percentage, the following components: 35%–45% of the drug, 25%–35% of polymeric excipients for the drug, 25%–35% of hydroxypropyl methylcellulose, and 0%–1% of magnesium stearate. Further, the viscosity of a 2 wt% aqueous solution of hydroxypropyl methylcellulose at 20°C is ≤4000 mPa·s, for example, including but not limited to at least one of HPMC 4000, HPMC 50, HPMC 30, HPMC 15, and HPMC 6, preferably HPMC 50. Further, the drug is diltiazem hydrochloride.

[0088] In a specific embodiment of the present invention, the pharmaceutical formulation comprises, by weight percentage, the following components: 3%–8% of the drug, 40%–50% of polymeric excipients for the drug, 45%–55% of microcrystalline cellulose, and 0%–4% of cross-linked polyvinylpyrrolidone. Preferably, the pharmaceutical formulation comprises, by weight percentage, the following components: 4%–6% of the drug, 42%–46% of polymeric excipients for the drug, 47%–51% of microcrystalline cellulose, and 1%–3% of cross-linked polyvinylpyrrolidone. Further, the drug is apremilast.

[0089] The Chinese meanings or full names of some of the English abbreviations mentioned in this document are as follows:

[0090] DLLA: D,L-lactide, racemic lactide;

[0091] mLA: meso-lactide;

[0092] LLA: L-lactide, L-lactide;

[0093] DLA: D-lactide, dextrorotatory lactide;

[0094] MePEG: methoxy polyethylene glycol, polyethylene glycol monomethyl ether;

[0095] PEG: polyethylene glycol, containing at least one hydroxyl group;

[0096] PLLA: poly(L-lactide);

[0097] PDLA: poly(D-lactide);

[0098] PDLLA / LLA: poly(D,L-lactide-co-L-lactide);

[0099] PDLLA / LLA-PEG-PDLLA / LLA: poly(D,L-lactide-co-L-lactide)-block-polyethylene glycol-block-poly(D,L-lactide-co-L-lactide);

[0100] PLLA-PEG-PLLA: poly(L-lactide)-block-polyethylene glycol-block-poly(L-lactide);

[0101] PDLA-PEG-PDLA: poly(D-lactide)-block-polyethylene glycol-block-poly(D-lactide);

[0102] In the PDLLA / LLA-PEG-PDLLA / LLA WX / Y / Z mentioned below, W represents the molecular weight of PEG, and X, Y and Z represent the mass fractions (wt%) of D, L-lactide, L-lactide and PEG in the polymer, respectively.

[0103] In the PLLA-PEG-PLLA WY / Z mentioned later, W represents the molecular weight of PEG, and Y and Z represent the mass fraction (wt%) of L-lactide and PEG in the polymer, respectively.

[0104] In the PDLA-PEG-PDLA WY / Z mentioned later, W represents the molecular weight of PEG, and Y and Z represent the mass fraction (wt%) of D-lactide and PEG in the polymer, respectively.

[0105] In the PDLLA / LLA-MePEG WX / Y / Z mentioned below, W represents the molecular weight of MePEG, and X, Y and Z represent the mass fractions (wt%) of D, L-lactide, L-lactide and MePEG in the polymer, respectively.

[0106] The preparation method of the polylactic acid-polyethylene glycol block copolymer of the present invention can be referred to Chinese patent application with publication number CN120059147A.

[0107] This invention provides a method for preparing polylactic acid-polyethylene glycol block copolymers, which may include the following steps: adding PEG or MePEG to a clean flask equipped with a magnetic stirrer. Immersing the flask in an oil bath at 110–130°C, after the PEG or MePEG melts, applying vacuum for a certain period of time while stirring to remove residual moisture and other volatiles from the PEG or MePEG. After heating to 130°C, adding D, L-lactide and / or L-lactide respectively, and after melting, adding a catalyst, and stirring under certain conditions to complete the polymerization reaction, obtaining the block copolymer. After each addition of material, a brief evacuation is performed, such as for 30 minutes, followed by sealing.

[0108] The preparation parameters of the multiple block copolymers involved in the embodiments of the present invention are shown in Table 1, and the physicochemical properties of the obtained multiple block copolymers are shown in Table 2. The weight-average molecular weight (Mw) was determined by GPC, and the melting point was determined by DSC. The GPC testing method refers to Chinese patent application publication number CN120059147A. The DSC testing method includes: weighing approximately 20 mg of sample into a crucible, a temperature scan range of -20℃ to 100℃, and a heating rate of 10℃ / min.

[0109] Table 1 Preparation parameters of block copolymers

[0110]

[0111]

[0112] The preparation method of PDLLA / LLA-PEG-PDLLA / LLA 6000-18 / 18 / 64 refers to Example 19 in CN120059147A; the preparation method of PLLA-PEG-PLLA 6000-30 / 70 refers to Example 20 in CN120059147A; the preparation method of PDLA-PEG-PDLA 6000-30 / 70 refers to Example 21 in CN120059147A; the preparation method of PLLA-PEG-PLLA 6000-43 / 57 refers to Example 13 in CN120059147A; and the preparation method of PDLA-PEG-PDLA 6000-43 / 57 refers to Example 14 in CN120059147A. The preparation method of 6000-36 / 64 refers to Example 18 in CN120059147A; the preparation method of PDLLA / LLA-PEG-PDLLA / LLA 6000-7.2 / 28.4 / 64 refers to Example 17 in CN120059147A; the preparation method of PDLLA / LLA-PEG-PDLLA / LLA 6000-8.6 / 34.4 / 57 refers to Example 16 in CN120059147A; and the preparation method of PDLLA / LLA-PEG-PDLLA / LLA 6000-14.3 / 28.7 / 57 refers to Example 15 in CN120059147A.

[0113] Table 2 Physicochemical properties of block copolymers

[0114]

[0115]

[0116] Note: In the calculated molecular weight of block copolymers, the first and third (if any) numbers are the calculated molecular weights of the polylactic acid monoblocks, and the second number is the molecular weight of the polyethylene glycol block. For diblock PLA-PEG, the average molecular weight of the polylactic acid monoblock is the calculated molecular weight of the polylactic acid block = polyethylene glycol molecular weight × (X+Y) / Z. For triblock PLA-PEG-PLA, the average molecular weight of the polylactic acid monoblock is the average of the calculated molecular weights of each polylactic acid monoblock = polyethylene glycol molecular weight × (X+Y) / Z / 2.

[0117] Water solubility test method: Place the polymer in sufficient volume of 37℃, pH 7.4 10mM PBS and shake. The water / polymer ratio (v / w) is 100mL / 1g. Observe the dissolution and dispersion. Easily soluble / easily dispersible: dissolves / disperses within 4 hours; Slowly soluble / slowly dispersed: dissolves / disperses within 24 hours but more than 4 hours; Insoluble: no significant dissolution or dispersion within 24 hours. Subsequent water solubility tests are conducted similarly.

[0118] Example 1

[0119] This embodiment provides a method for preparing polymeric excipients for pharmaceuticals, comprising the following steps:

[0120] Polyethylene glycol (PEG) and polylactic acid-polyethylene glycol block copolymer were melted and mixed uniformly at 80°C to obtain a mixture, which was then cooled to room temperature to obtain a polymer auxiliary material.

[0121] The preparation parameters and physicochemical properties of the different polymer excipients in this embodiment are shown in Table 3.

[0122] Table 3. Relevant information on polymer excipients

[0123]

[0124]

[0125]

[0126] Example 2

[0127] This embodiment provides a method for preparing polymeric excipients for pharmaceuticals, comprising the following steps:

[0128] 50g of polyethylene glycol (PEG) and 50g of a first block copolymer were melted and mixed uniformly at 80°C to obtain a first mixture; 50g of PEG and 50g of a second block copolymer were melted and mixed uniformly at 80°C to obtain a second mixture; the first mixture and the second mixture were weighed at a mass ratio of 1:1, then melted and mixed uniformly at 80°C, and cooled to room temperature to obtain a polymer auxiliary material.

[0129] The preparation parameters and physicochemical properties of the different polymer excipients in this embodiment are shown in Table 4.

[0130] Table 4. Relevant information on polymer excipients

[0131]

[0132] Example 3

[0133] This embodiment provides a method for preparing a solubilized and rapidly released drug, including the following steps:

[0134] Weigh a certain amount of polylactic acid-polyethylene glycol block copolymer and a certain amount of polyethylene glycol PEG into a reaction flask, and mix them evenly by magnetic stirring at 80°C for about 10 minutes. Then add a certain amount of drug and continue to mix evenly by magnetic stirring for about 20 to 30 minutes. Then dispense the mixture into HPMC capsules of number 0 (except for capsules numbered 3-4, which have a content of 300 mg, the other numbered capsules have a content of 560 to 600 mg).

[0135] The preparation parameters for different solubilized and rapidly released drugs in this embodiment are shown in Figure 5.

[0136] Table 5. Preparation parameters for solubilized and rapidly released drugs.

[0137]

[0138] Example 4

[0139] This embodiment provides a variety of methods for preparing solubilized, sustained-release, and controlled-release drugs, including the following steps:

[0140] Aprepitant Solubilized Sustained-Release Capsules 1: Weigh 9.5g of polyethylene glycol (PEG) (Mn = 4000Da) and remove moisture by vacuum degassing at 130℃ for 2 hours. After degassing, add 9.5g of PLLA-PEG-PLLA 6000-43 / 57 and stir for about 10 minutes until completely melted. Then add 1g of aprepitant and stir magnetically at 130℃ for about 20 minutes until completely melted and mixed. Then dispense into No. 0 HPMC capsules, controlling the fill weight to be between 560 and 600mg.

[0141] Aprepitant Solubilized Sustained-Release Capsules 2: Weigh 47.5g of polyethylene glycol (PEG) (Mn = 4000Da) and remove moisture by vacuum degassing at 130℃ for 2 hours. After degassing, add 47.5g of PDLLA / LLA-PEG-PDLLA / LLA 6000-22 / 22 / 56 and stir for about 10 minutes until completely melted. Then add 5g of aprepitant and stir magnetically at 130℃ for about 20 minutes until completely melted and mixed. Then dispense into HPMC capsules of size 0, controlling the fill weight to be between 560 and 600mg.

[0142] Nifedipine Solubilized Sustained-Release Capsules 1: 45g of polyethylene glycol (PEG) (Mn = 6000Da) and 45g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃ to obtain a mixture. Then, 47.5g of the mixture was mixed with 2.5g of nifedipine at 130℃ for about 20 minutes to obtain a uniform mixture. The mixture was then dispensed into HPMC capsules of size 0, with the fill weight controlled between 560 and 600mg.

[0143] Nifedipine Solubilized Sustained-Release Capsules 2: 45g of polyethylene glycol (PEG) (Mn = 6000 Da) and 45g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃ to obtain a first mixture; 45g of polyethylene glycol (PEG) (Mn = 6000 Da) and 45g of PDLA-PEG-PDLA 6000-43 / 57 were fully melted and mixed at 80℃ to obtain a second mixture; the first and second mixtures were weighed at a mass ratio of 1:1, and then melted and mixed evenly at 80℃. 47.5g of the aforementioned evenly mixed material was mixed with 2.5g of nifedipine and stirred at 130℃ for about 20 minutes until evenly mixed. The mixture was then dispensed into No. 0 HPMC capsules, with the fill weight controlled between 560 and 600 mg.

[0144] Example 5

[0145] This embodiment provides methods for preparing various matrix-based sustained-release and controlled-release drugs, each including the following steps:

[0146] Levetiracetam matrix-type sustained-release tablets 1: 20g of polyethylene glycol PEG (Mn=6000Da) and 20g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃ to prepare a first mixture; 20g of polyethylene glycol PEG (Mn=6000Da) and 20g of PDLA-PEG-PDLA 6000-43 / 57 were fully melted and mixed at 80℃ to prepare a second mixture; the first mixture and the second mixture were then mixed evenly at 80℃ at a mass ratio of 1:1, cooled, powdered, and sieved to obtain the polymer excipient. 12g of levetiracetam was fully mixed with 4g of the polymer excipient, 5.9g of hydroxypropyl methylcellulose (HPMC4000, 2% aqueous solution viscosity 4000mpa·s at 20℃), and 0.1g of magnesium stearate, and then fed into a single-punch tablet press for tableting, ensuring the punch did not stick. Average diameter 8mm, tablet weight 303mg, hardness 71.2N.

[0147] Levetiracetam matrix-type sustained-release tablets 2: 40g of polyethylene glycol (PEG) (Mn = 6000 Da) and 40g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃, then cooled, powdered, and sieved to obtain the polymer excipient. 12g of levetiracetam was thoroughly mixed with 4g of the polymer excipient, 5.9g of hydroxypropyl methylcellulose (HPMC4000, 2% aqueous solution viscosity 4000 mPa·s at 20℃), and 0.1g of magnesium stearate. The mixture was then fed into a single-punch tablet press for tableting, ensuring the punch did not stick. The average diameter was 8mm, the tablet weight was 310mg, and the hardness was 100.3N.

[0148] Diltiazem hydrochloride matrix sustained-release tablets 1: 0.75g polyethylene glycol PEG (Mn=6000Da) and 0.75g PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a first mixture; 0.75g polyethylene glycol PEG (Mn=6000Da) and 0.75g PDLA-PEG-PDLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a second mixture; the first mixture and the second mixture are then mixed evenly at 80℃ at a mass ratio of 1:1, cooled, powdered, and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of polymer excipients, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and then fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 281mg, and the hardness was 97.5N.

[0149] Diltiazem hydrochloride matrix sustained-release tablets 2: 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃, then cooled, powdered, and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of the polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting, ensuring the punch did not stick. Average diameter 8mm, tablet weight 293mg, hardness 70N.

[0150] Example 6

[0151] This embodiment provides a method for preparing a matrix-based sustained-release drug using HPMC of different viscosities, including the following steps:

[0152] 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃, then cooled, pulverized, and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of the polymer excipient, 0.05g of magnesium stearate, and 2.95g of hydroxypropyl methylcellulose were thoroughly mixed and then fed into a single-punch tablet press for tableting.

[0153] Diltiazem hydrochloride matrix-type sustained-release tablets were prepared using HPMC4000, HPMC50, HPMC30, HPMC15, and HPMC6 respectively, and named HPMC4000 sustained-release tablets, HPMC50 sustained-release tablets, HPMC30 sustained-release tablets, HPMC15 sustained-release tablets, and HPMC6 sustained-release tablets, respectively. During tablet compression, the punch did not stick to any of the tablets. The average diameter of the HPMC4000 sustained-release tablet was 8 mm, the tablet weight was 294 mg, and the hardness was 160.8 N; the average diameter of the HPMC50 sustained-release tablet was 8 mm, the tablet weight was 294 mg, and the hardness was 70 N; the average diameter of the HPMC30 sustained-release tablet was 8 mm, the tablet weight was 285 mg, and the hardness was 95.4 N; the average diameter of the HPMC15 sustained-release tablet was 8 mm, the tablet weight was 283 mg, and the hardness was 115 N; and the average diameter of the HPMC6 sustained-release tablet was 8 mm, the tablet weight was 283 mg, and the hardness was 97.7 N.

[0154] Example 7

[0155] This embodiment provides methods for preparing various matrix-based sustained-release and controlled-release drugs, each including the following steps:

[0156] The formulation of diltiazem hydrochloride matrix-type sustained-release tablets containing microcrystalline cellulose (MCC) is as follows: 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a first mixture; 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PDLA-PEG-PDLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a second mixture; the first and second mixtures are then mixed uniformly at 80℃ at a mass ratio of 1:1, cooled, pulverized, and sieved to obtain the polymer excipient. 20g of diltiazem hydrochloride, 40g of polymer excipient, 40g of microcrystalline cellulose, and 0.2g of magnesium stearate are thoroughly mixed and fed into a single-punch tablet press for tableting, ensuring the punch does not stick. The average diameter is 8mm, and the tablet weight is 308mg.

[0157] The formulation of Diltiazem hydrochloride matrix-type sustained-release tablets containing lactose is as follows: 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a first mixture; 50g of polyethylene glycol (PEG) (Mn = 6000Da) and 50g of PDLA-PEG-PDLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a second mixture; the first and second mixtures are then mixed evenly at 80℃ at a mass ratio of 1:1, cooled, powdered, and sieved to obtain the polymer excipient. 2g of Diltiazem hydrochloride, 4g of the polymer excipient, 3.95g of lactose, and 0.02g of magnesium stearate are thoroughly mixed and fed into a single-punch tablet press for tableting, ensuring the punch does not stick. Average diameter 8mm, tablet weight 292mg, hardness 144.4N.

[0158] The formulation of hydroxypropyl methylcellulose (HPMC30) in diltiazem hydrochloride matrix sustained-release tablets is as follows: 50g of polyethylene glycol PEG (Mn=6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a first mixture; 50g of polyethylene glycol PEG (Mn=6000Da) and 50g of PDLA-PEG-PDLA 6000-43 / 57 are fully melted and mixed at 80℃ to prepare a second mixture; the first mixture and the second mixture are then mixed evenly at 80℃ at a mass ratio of 1:1, cooled, powdered, and sieved to obtain the polymer excipient. 2g of diltiazem hydrochloride, 4g of polymer excipients, 3.95g of hydroxypropyl methylcellulose (HPMC30, 2% aqueous solution viscosity 30mpa·s at 20℃), and 0.02g of magnesium stearate were thoroughly mixed and then fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 275mg, and the hardness was 89.1N.

[0159] Example 8

[0160] This embodiment provides a method for preparing a matrix-based sustained-release drug, which includes the following steps:

[0161] Diltiazem hydrochloride matrix sustained-release tablets 1: 20g of polyethylene glycol PEG (Mn=6000Da) and 20g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃ to prepare a first mixture; 20g of polyethylene glycol PEG (Mn=6000Da) and 20g of PDLA-PEG-PDLA 6000-43 / 57 were fully melted and mixed at 80℃ to prepare a second mixture; the first and second mixtures were then mixed evenly at 80℃ at a mass ratio of 1:1, cooled, powdered, and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting, ensuring the punch did not stick. Average diameter 8mm, tablet weight 299mg, hardness 97.5N.

[0162] Diltiazem hydrochloride matrix-type sustained-release tablet 2 was prepared according to the preparation method of Diltiazem hydrochloride matrix-type sustained-release tablet 1. The tablets had an average diameter of 8 mm, a weight of 300 mg, and a hardness of 97.5 N.

[0163] Diltiazem hydrochloride matrix sustained-release tablets 3: 27g of polyethylene glycol (PEG) (Mn = 6000Da) and 27g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 130℃, then cooled, powdered, and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting, ensuring the punch did not stick. Average diameter 8mm, tablet weight 299mg, hardness 122.3N.

[0164] Example 9

[0165] This embodiment provides methods for preparing various matrix-based sustained-release and controlled-release drugs, each including the following steps:

[0166] Aprepitant matrix-type sustained-release tablets 1: 3g of polyethylene glycol (PEG) (Mn = 6000 Da) and 6g of PLLA-PEG-PLLA6000-43 / 57 were fully melted and mixed at 80℃. 1g of aprepitant was added and mixed thoroughly. After cooling, the mixture was pulverized to obtain a powder. 3.7g of the powder, 3.7g of microcrystalline cellulose, and 0.14g of cross-linked polyvinylpyrrolidone were thoroughly mixed and fed into a single-punch tablet press for tableting. The average diameter was 8mm, and the tablet weight was 248mg.

[0167] Aprepitant matrix-type sustained-release tablets 2: 2.5g of polyethylene glycol (PEG) (Mn = 6000Da) and 5.5g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80℃. 1g of aprepitant was added and mixed thoroughly. After cooling, the mixture was pulverized to obtain a powder. 2.2g of the powder, 2.2g of microcrystalline cellulose, and 0.09g of cross-linked polyvinylpyrrolidone were thoroughly mixed and fed into a single-punch tablet press for tableting. The average diameter was 8mm, and the tablet weight was 248mg.

[0168] Aprepitant matrix-type sustained-release tablets 3: 4.5g of polyethylene glycol (PEG) (Mn = 6000Da) and 4.5g of PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80℃. 1g of aprepitant is added and mixed thoroughly. After cooling, the mixture is pulverized to obtain a powder. 2.6g of the powder, 2.6g of microcrystalline cellulose, and 0.1g of cross-linked polyvinylpyrrolidone are thoroughly mixed and fed into a single-punch tablet press for tableting. The average diameter is 8mm, and the tablet weight is 255mg.

[0169] Example 10

[0170] This embodiment provides a method for preparing matrix-based sustained-release drugs with different drug loadings or different excipient ratios, which includes the following steps:

[0171] Diltiazem hydrochloride matrix sustained-release tablets 1: 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 1g of diltiazem hydrochloride, 4.5g of polymer excipient, 4.45g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 322mg, and the hardness was 91.6N.

[0172] Diltiazem hydrochloride matrix sustained-release tablets 2: 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 2g of diltiazem hydrochloride, 4g of polymer excipient, 3.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 322mg, and the hardness was 77.6N.

[0173] Diltiazem hydrochloride matrix sustained-release tablets 3: 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 4g of polymer excipient, 1.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 302mg, and the hardness was 110.0N.

[0174] Diltiazem hydrochloride matrix sustained-release tablets 4: 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 2g of polymer excipient, 3.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tablet press for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 314mg, and the hardness was 115.0N.

[0175] Diltiazem hydrochloride matrix sustained-release tablets 5: 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly mixed and fed into a single-punch tableting machine for tableting. The punch did not stick. The average diameter was 8mm, the tablet weight was 285mg, and the hardness was 78.6N.

[0176] Example 11

[0177] This embodiment provides a method for preparing a matrix-based sustained-release drug, which includes the following steps:

[0178] 960g of polyethylene glycol (PEG) (Mn = 6000Da) and 960g of PLLA-PEG-PLLA 6000-50 / 50 were fully melted and mixed at 110℃ to form a mixture. After cooling, the mixture was pulverized and sieved to obtain the polymer excipient. 4g of diltiazem hydrochloride, 3g of the polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity of 50mpa·s at 20℃), and 0.05g of magnesium stearate were thoroughly blended to prepare three parallel blend powders. These powders were then fed into a single-punch tablet press for tableting, ensuring the punch did not stick. The first batch had an average diameter of 8mm, a tablet weight of 293mg, and a hardness of 77.8N; the second batch had an average diameter of 8mm, a tablet weight of 292mg, and a hardness of 75.4N; and the third batch had an average diameter of 8mm, a tablet weight of 296mg, and a hardness of 74.8N.

[0179] Experimental Example 1

[0180] Accelerated stability tests were conducted at 40°C on the block copolymer PLLA-PEG-PLLA 6000-43 / 57, polymer excipients numbered 1-13 in Example 1, and polymer excipients numbered 2-1 in Example 2 (samples were taken at day 0, month 1, and month 3). The results are shown in Table 6. Mw and PD were determined by GPC testing, LMWS content by HPLC testing, and melting point by DSC testing. Taking polymer excipients numbered 1-13 in Example 1 as an example, their GPC, HPLC, and DSC test results are shown in Table 6. Figures 1-3 The GPC and HPLC testing methods refer to Chinese patent application publication number CN120059147A. The DSC testing method includes: weighing approximately 20 mg of sample into a crucible, with a temperature scan range of -20℃ to 100℃; and a heating rate of 10℃ / min.

[0181] Table 6. Results of Accelerated Stability Test

[0182]

[0183] Experimental Example 2

[0184] Dissolution of different drug formulations was tested, and the dissolution conditions and testing methods are shown in Tables 7 and 8. Unless otherwise specified, subsequent tests shall be conducted according to the methods described in Tables 7 and 8.

[0185] Table 7 Dissolution conditions for different drug formulations

[0186]

[0187] Table 8. Detection methods for different drug formulations

[0188]

[0189] The dissolution of the solubilized and rapidly released drugs numbered 3-1, 3-2, 3-3, 3-4, and 3-5 prepared in Example 3 was tested using the above method. The dissolution curves are shown in the figure. Figure 4 The dissolution of aprepitant solubilized sustained-release capsules 1, aprepitant solubilized sustained-release capsules 2, nifedipine solubilized sustained-release capsules 1, and nifedipine solubilized sustained-release capsules 2 prepared in Example 4 was tested using the above method. The dissolution curves are shown in the figure. Figure 5 The dissolution of levetiracetam matrix-based sustained-release tablets 1, levetiracetam matrix-based sustained-release tablets 2, diltiazem hydrochloride matrix-based sustained-release tablets 1, and diltiazem hydrochloride matrix-based sustained-release tablets 2 prepared in Example 5 was tested using the above method. The dissolution curves are shown in the figure. Figure 6 .from Figure 6 It can be seen that the diltiazem hydrochloride matrix-type sustained-release tablets 2 prepared in Example 5 exhibit a near-zero-order release dissolution curve. The dissolution of diltiazem hydrochloride matrix-type sustained-release drugs with different viscosities of HPMC prepared in Example 6 was tested using the above method, and the dissolution curves are shown in [Figure 6]. Figure 7 The dissolution of the diltiazem hydrochloride matrix-type sustained-release drugs prepared in Example 7 using different excipients was tested using the above method. The dissolution curves are shown in the figure. Figure 8 .

[0190] The dissolution of the diltiazem hydrochloride matrix sustained-release tablets 1 prepared in Example 8 was tested in different dissolution media using the above method. The media in the dissolution conditions were changed to 900 mL of pH=1 (0.1 mol / L hydrochloric acid solution), 20 mM pH=4.5 acetate buffer solution, 20 mM pH=6.8 phosphate buffer solution, water, 5 vol.% ethanol + pH=1 (0.1 mol / L hydrochloric acid solution), and 10 vol.% ethanol + pH=1 (0.1 mol / L hydrochloric acid solution). The dissolution curves are shown in the figure. Figure 9 .

[0191] The dissolution of diltiazem hydrochloride matrix-type sustained-release tablets 2 and 3 prepared in Example 8 was tested at different stirring rates using the above method. The stirring rates in the dissolution conditions were changed to 25 rpm, 60 rpm, and 150 rpm, respectively. The dissolution curves are shown in the figure. Figure 10 .

[0192] The dissolution of the diltiazem hydrochloride matrix sustained-release tablets 3 prepared in Example 8 was tested in different dissolution media using the above method. The media in the dissolution conditions were changed to 900 mL of pH=1 (0.1 mol / L hydrochloric acid solution), 20 mM pH=4.5 acetate buffer solution, 20 mM pH=6.8 phosphate buffer solution, and water, respectively. The dissolution curves are shown in the figure. Figure 11 .

[0193] The diltiazem hydrochloride matrix-type sustained-release tablets microcrystalline cellulose (MCC) formulation prepared in Example 7 were stored at different temperature conditions for 3 months using the above method, and dissolution tests were performed. The dissolution curves are shown in the figure. Figure 12 .

[0194] The dissolution of apremilast matrix-based sustained-release tablets 1, 2, and 3 prepared in Example 9 was tested using the above method. The dissolution curves are shown in the figure. Figure 13 .

[0195] The dissolution of the diltiazem hydrochloride matrix-type sustained-release tablets 1-5 prepared in Example 10 was tested using the above method. The dissolution curves are shown in the figure. Figure 14 The dissolution of the diltiazem hydrochloride matrix-type sustained-release tablets prepared in parallel in Example 11 was tested using the above method. The dissolution curves are shown in the figure. Figure 15 This demonstrates that the pharmaceutical formulation of the present invention has good reproducibility.

[0196] The test results above show that the polymer excipients of the present invention can increase the solubility of poorly soluble drugs, enabling rapid release and controlled release of drugs; they can also improve the dissolution characteristics of water-soluble drugs (avoiding burst release, achieving near-zero-order release, and dissolution unaffected by the medium and stirring rate), and enhance the storage stability of drug formulations.

[0197] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polymeric excipient for pharmaceuticals, characterized in that, It includes a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5-4):1; wherein the number average molecular weight of the polyethylene glycol is 1000-10000 Da; In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-4500 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da.

2. The polymeric excipient for pharmaceuticals according to claim 1, characterized in that, In the polylactic acid-polyethylene glycol block copolymer, the molecular weight of the polyethylene glycol block is 6000-8000 Da.

3. The polymeric excipient for pharmaceuticals according to claim 1 or 2, characterized in that, The number-average molecular weight of the polyethylene glycol is 4000–10000 Da.

4. The polymeric excipient for pharmaceuticals according to claim 1, characterized in that, In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 1000-2100 Da, and the molecular weight of the polyethylene glycol block is 2000-8000 Da.

5. The polymeric excipient for pharmaceuticals according to claim 1, characterized in that, When the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer PLA-PEG-PLA, the average molecular weight of the polylactic acid monoblock is 1000-1800 Da, and the molecular weight of the polyethylene glycol block is 3000-8000 Da.

6. The polymeric excipient for pharmaceuticals according to claim 1, characterized in that, In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 2200-3000 Da, and the molecular weight of the polyethylene glycol block is 2000-8000 Da.

7. The polymeric excipient for pharmaceuticals according to claim 1, characterized in that, In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid monoblock is 2000-3000 Da, and the molecular weight of the polyethylene glycol block is 6000-8000 Da.

8. The polymeric excipient for pharmaceuticals according to claim 7, characterized in that, In the polylactic acid-polyethylene glycol block copolymer, the polylactic acid blocks include at least one of PLLA blocks and PDLA blocks.

9. The polymeric excipient for pharmaceuticals according to claim 8, characterized in that, The polylactic acid-polyethylene glycol block copolymer includes a first copolymer and a second copolymer; the first copolymer is selected from at least one of the diblock copolymer PLLA-PEG and the triblock copolymer PLLA-PEG-PLLA, and the second copolymer is selected from at least one of the PDLA-PEG and the triblock copolymer PDLA-PEG-PDLA.

10. The polymeric excipient for a pharmaceutical according to claim 9, characterized in that, The mass ratio of the first copolymer to the second copolymer is 1:(0.5~2).

11. The polymeric excipient for a pharmaceutical according to claim 7, characterized in that, It also includes at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose.

12. The method for preparing the polymeric excipient for a pharmaceutical product according to any one of claims 1 to 11, characterized in that, The process includes the following steps: polylactic acid-polyethylene glycol block copolymer and polyethylene glycol are melt-mixed and uniformly, and then cooled.

13. A pharmaceutical preparation, characterized in that, Includes pharmaceuticals and polymeric excipients for pharmaceuticals as described in any one of claims 1 to 11.

14. The pharmaceutical preparation according to claim 13, characterized in that, The pharmaceutical preparation is a solid preparation.

15. The pharmaceutical preparation according to claim 13, characterized in that, The pharmaceutical preparation is an oral preparation.

16. The pharmaceutical preparation according to claim 13, characterized in that, The drug includes at least one of indomethacin, nimodipine, nifedipine, apremilast, diltiazem hydrochloride, levetiracetam, and fenofibrate.

17. The pharmaceutical preparation according to claim 13, characterized in that, The pharmaceutical preparation comprises the following components by weight percentage: 9%–55% drug, 15%–50% polymeric excipients for the drug, 15%–50% other pharmaceutical excipients, and 0%–1% magnesium stearate; The other pharmaceutical excipients include at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose.

18. The pharmaceutical preparation according to claim 17, characterized in that, The viscosity of the 2wt% aqueous solution of the hydroxypropyl methylcellulose at 20°C is ≤4000 mPa·s.

Images