Polymer auxiliary material for medicine, preparation method of polymer auxiliary material and medicine preparation

Abstract

The invention relates to the technical field of solid medicine preparations, in particular to a polymer auxiliary material for medicine, a preparation method of the polymer auxiliary material and a medicine preparation. The polymer auxiliary material for the medicine comprises a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5-4): 1, the number-average molecular weight of the polyethylene glycol is greater than or equal to 1000Da. According to the polymer auxiliary material, the solubility of insoluble drugs can be increased, and quick release and slow / controlled release of the drugs are realized; the dissolution characteristic of a water-soluble medicine can be improved (burst release is avoided, near-zero-level release is realized, and dissolution is not influenced by a medium and a stirring rate), and meanwhile, the storage stability of a medicinal preparation can be enhanced.

Description

Technical Field

[0001] The present invention relates to the technical field of solid pharmaceutical preparations, and in particular to a polymer excipient for medicines, a preparation method thereof, and a pharmaceutical preparation. Background Art

[0002] Currently, oral solid preparations face several key challenges in the field of poorly soluble drug delivery: difficulty in drug solubilization, low bioavailability, and poor sustained and controlled release effects. Traditional solubilization strategies (including solvent methods, micelles, emulsions, inclusion compounds, solid dispersions, and nanocrystals) all have certain technical limitations, and generally have problems such as complex prescriptions and high process requirements. In addition, oral sustained-release tablets with high-viscosity water-soluble polymers (such as hydroxypropyl methylcellulose, HPMC) as the skeleton have the risk of drug burst release in actual applications, and the release rate is greatly affected by the dissolution medium and stirring rate, making it difficult to achieve zero-order release of the drug. In order to control the release rate, it is necessary to rely on complex prescriptions and processes such as multi-layer coatings or osmotic pumps, which are costly. These technical bottlenecks have seriously restricted the clinical efficacy of poorly soluble drugs and product development.

[0003] Polylactide (PLA) is a synthetic, biodegradable polymer whose ester bonds can be hydrolyzed in aqueous environments to form non-toxic hydroxycarboxylic acids, which are then metabolized to water and carbon dioxide through the citric acid cycle. PLA has been approved by the U.S. Food and Drug Administration for use as a drug carrier system due to its excellent biodegradability, good mechanical properties, and low immunogenicity. Currently, commercial PLA-based formulations mainly include drug-loaded micelles, long-acting microspheres, and implants, which have promising applications in the delivery of peptides, anticancer drugs, and other drugs. However, PLA's hydrophobicity, difficulty in regulating its degradation rate, and limited loading capacity for polar drugs have limited 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 crystallization properties. The resulting PLA-PEG amphiphilic copolymer has the following advantages: (1) high solubility and bioavailability of 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 through the reticuloendothelial system; and (5) good safety. Currently, PLA-PEG nanoparticles have been successfully used in the delivery system of vaccines, protein drugs, and gene drugs, which can enhance drug efficacy and reduce drug resistance.

[0004] However, PLA-PEG is susceptible to hydrolysis and degradation, and has poor storage stability at room temperature. Currently, the application and research of PLA-PEG mostly focuses on injections, with limited exploration and application in the oral field. To date, there are no commercial oral formulations.

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

[0006] The object of the present invention is to provide a polymer excipient for drugs, a preparation method thereof, and a pharmaceutical preparation. The polymer excipient of the present invention has good storage stability, drug solubilization and sustained-release effects, and can be used to prepare oral pharmaceutical preparations.

[0007] In order to achieve the above-mentioned purpose of the present invention, the first aspect of the present invention provides a polymer excipient for drugs, comprising a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5-4):1; the number average molecular weight of the polyethylene glycol is ≥1000Da.

[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 block is 1000-3000 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da. Furthermore, the number average molecular weight of the polyethylene glycol is 1000-10000 Da.

[0009] In a specific embodiment of the present invention, the molecular weight of the polyethylene glycol block in the polylactic acid-polyethylene glycol block copolymer is 6000-8000 Da. Furthermore, 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 a diblock copolymer PLA-PEG and a 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 single block 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 single block (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 single block (i.e., the average molecular weight of each polylactic acid single block) 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 single block 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 single block 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, in the polylactic acid-polyethylene glycol block copolymer, the polylactic acid block includes at least one of a PLLA block and a 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 a specific embodiment of the present invention, at least one of hydroxypropyl methylcellulose, microcrystalline cellulose, ethyl cellulose, povidone, lactose, hydroxypropyl cellulose, polyacrylic acid, polyvinyl alcohol, cross-linked polyvinyl pyrrolidone and carboxymethyl cellulose is further included.

[0019] The second aspect of the present invention provides a method for preparing the polymer excipient for medicine according to the first aspect of the present invention, comprising the following steps: uniformly melting and mixing the polylactic acid-polyethylene glycol block copolymer and polyethylene glycol, and cooling.

[0020] In a specific embodiment of the present invention, the preparation method includes: melt-mixing the first copolymer and part of the polyethylene glycol to obtain a first mixture; melt-mixing the second copolymer and the remaining polyethylene glycol to obtain a second mixture; melt-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] The third aspect of the present invention provides a pharmaceutical preparation comprising a drug and any one of the polymer excipients for drugs according to 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 a tablet and a capsule.

[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: 9% to 55% of the drug, 15% to 50% of a polymer excipient for the drug, 15% to 50% of other pharmaceutical excipients, and 0% to 1% of magnesium stearate. Furthermore, 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 polyvinyl pyrrolidone, and carboxymethyl cellulose.

[0027] In a specific embodiment of the present invention, the viscosity of a 2 wt % 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 present invention has the following beneficial effects:

[0029] (1) The polymer excipient of the present invention, by compounding a polylactic acid-polyethylene glycol block copolymer with 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, and can achieve rapid release or sustained release effects while solubilizing the oral drugs.

[0030] (2) The polymer excipients of the present invention, by compounding polylactic acid-polyethylene glycol block copolymer and polyethylene glycol, can be used as a drug sustained-release skeleton material, which can improve the sudden release of water-soluble drugs; combined with other excipients, it can further regulate the dissolution of the drug, and a dissolution curve with a near-zero-order release can be obtained. The drug release process is not affected by the release medium and the stirring rate, and the storage stability of the preparation can be improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

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

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

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

[0035] Figure 4 This is a dissolution curve of the solubilized rapid-release 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 diagram of a diltiazem hydrochloride matrix sustained-release preparation using HPMC of different viscosities provided in Example 6 of the present invention;

[0039] Figure 8 This is a dissolution curve of the diltiazem hydrochloride matrix sustained-release preparation using different excipients provided in Example 7 of the present invention;

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

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

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

[0043] Figure 12 This is a dissolution curve diagram of the diltiazem hydrochloride matrix sustained-release preparation provided in Example 7 of the present invention after storage at different temperatures for 3 months;

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

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

[0046] Figure 15 This is a dissolution curve of the diltiazem hydrochloride matrix sustained-release preparation provided in Example 11 of the present invention. DETAILED DESCRIPTION

[0047] The technical scheme of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. Those who do not specify specific conditions in the embodiments are carried out according to normal conditions or the conditions recommended by the manufacturer. Those whose reagents or instruments are not specified by the manufacturer are conventional products that can be purchased commercially.

[0048] The molecular weights in the present invention are considered to be weight average molecular weights unless otherwise specified. If additional specifications are given, the specifications shall prevail.

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

[0050] The present invention achieves a material suitable for solubilizing poorly soluble drugs and serving as a sustained-release matrix material by compounding a polylactic acid-polyethylene glycol block copolymer with polyethylene glycol at a certain ratio. For example, in different embodiments, the mass ratio of the polylactic acid-polyethylene glycol block copolymer to the 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 solubilization of poorly soluble drugs and providing a sustained-release matrix material.

[0051] The polymer excipient of the present invention regulates the number-average molecular weight of polyethylene glycol to meet a number-average molecular weight of 1000 Da or higher, thereby ensuring the polymer excipient's melting point, compatibility with the capsule shell, and tableting performance. The present invention has found that when the number-average molecular weight of the polyethylene glycol used is less than 1000 Da, the mixture with the polylactic acid-polyethylene glycol block copolymer has a low melting point, is incompatible with HPMC and the gelatin capsule shell, and cannot be tableted, cannot be made into a solid pharmaceutical preparation, and cannot achieve effects such as sustained-release or controlled-release.

[0052] The polylactic acid block portion of the present invention includes a homopolymer of left-handed (L-) lactide, right-handed (D-) lactide, racemic (D, L-) lactide, meso- (meso-) lactide or a copolymer of at least two 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 block is 1000-3000 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da. Furthermore, the number average molecular weight of the polyethylene glycol is 1000-10000 Da.

[0054] In a polylactic acid-polyethylene glycol block copolymer, the average molecular weight of a polylactic acid block is the average molecular weight of each polylactic acid block. For example, when the polylactic acid-polyethylene glycol block copolymer is a diblock copolymer of PLA-PEG, the average molecular weight of the polylactic acid block is the molecular weight of the polylactic acid block; when the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer of PLA-PEG-PLA, the average molecular weight of the polylactic acid block is the average molecular weight of each polylactic acid block.

[0055] When the average molecular weight of the polylactic acid single block, the molecular weight of the polyethylene glycol block and the number average molecular weight of the polyethylene glycol in the polylactic acid-polyethylene glycol block copolymer respectively meet the above ranges, it is more conducive to solubilizing the drug. For example, in different embodiments, in the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid single block can be 1000Da, 1200Da, 1500Da, 1800Da, 2000Da, 2200Da, 2500Da, 2800Da, 3000Da or a range consisting of any two thereof; the molecular weight of the polyethylene glycol block can be 1500Da, 2000Da, 2500Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 5500Da, 6000Da, 7000Da, 8000Da, 9000Da, 10000Da, 11000Da, 12000Da, 15000Da, 18000Da, 2000Da, 2200Da, 2500Da, 2800Da, 3000Da or a range consisting of any two thereof; 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 a range consisting of any two thereof;

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

[0057] In a specific embodiment of the present invention, in the polylactic acid-polyethylene glycol block copolymer, the molecular weight of the polyethylene glycol block is 6000 to 8000 Da. Furthermore, the number average molecular weight of the polyethylene glycol is 4000 to 10000 Da. When the molecular weight of the polyethylene glycol block is 6000 Da or more, the melting point of the polymer is higher. Further, when combined with polyethylene glycol having a number average molecular weight of 4000 Da or more, the melting point of the polymer excipient is increased while regulating 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 comprises at least one of a diblock copolymer PLA-PEG and a triblock copolymer PLA-PEG-PLA, wherein the diblock copolymer PLA-PEG is PLA-MePEG.

[0059] The present invention further regulates the polymer excipients according to the different requirements of solubilization quick release and solubilization slow and controlled release effects.

[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 single block is 1000-2100 Da, for example, it can be 1000 Da, 1200 Da, 1500 Da, 1800 Da, 2000 Da, 2100 Da or a range consisting of any two thereof; the molecular weight of the polyethylene glycol block is 2000-8000 Da, for example, it can be 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da or a range consisting of 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 single block is 1000-2100Da, and the molecular weight of the polyethylene glycol block is 2000-8000Da; when the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer PLA-PEG-PLA, the average molecular weight of the polylactic acid single block is 1000-1800Da, and the molecular weight of the polyethylene glycol block is 3000-8000Da. The present invention has found that the polymer excipient obtained by blending a copolymer of a polylactic acid block with relatively low molecular weight and polyethylene glycol is easier to disperse and dissolve while ensuring drug solubilization, thereby obtaining a solubilized rapid-release dosage form. For example, it can effectively solubilize poorly soluble drugs such as indomethacin, nimodipine, and nifedipine, and the resulting capsules or tablets have a good rapid-dissolving effect.

[0061] In order to further increase the release rate, the proportion of polyethylene glycol is increased within the mass ratio 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 reduced within the number average molecular weight range of 1000-10000 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 single block is 2200-3000 Da, for example, it can be 2200 Da, 2400 Da, 2500 Da, 2600 Da, 2800 Da, 3000 Da or a range consisting of any two thereof; the molecular weight of the polyethylene glycol block is 2000-10000 Da, for example, it can be 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da or a range consisting of any two thereof. The present invention has found that a copolymer of a polylactic acid block having a relatively high molecular weight is difficult to dissolve or insoluble in water. The polymer excipient obtained by blending the copolymer with polyethylene glycol can disperse relatively slowly in water while ensuring drug solubilization. Thus, a solubilized sustained-release dosage form can be obtained. 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] In order 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 number average molecular weight range of 1000-10000 Da.

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

[0065] Common water-soluble drugs formulated into matrix-based sustained-release tablets often risk burst release, preventing zero-order release, and significantly affecting dissolution due to factors such as the medium. The present invention innovatively discovered that a composite of 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 burst release and other issues. The present invention further regulates the polymer excipients to address the demand for matrix materials for sustained-release water-soluble drugs.

[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 single block is ≥2000Da, preferably 2000-5000Da, for example, 2000Da, 2500Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, or a range consisting of any two thereof; the molecular weight of the polyethylene glycol block is 6000-8000Da, for example, 6000Da, 6500Da, 7000Da, 7500Da, 8000Da, or a range consisting of any two thereof. The use of a polylactic acid-polyethylene glycol block copolymer that meets the above conditions is more conducive to improving the skeleton stability; among them, the use of a copolymer with a higher molecular weight polylactic acid block can significantly reduce the effect of stirring rate on dissolution.

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

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

[0069] It is understood that the PLLA block and the PDLA block can be introduced from the same polylactic acid-polyethylene glycol block copolymer, or 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 and second copolymers 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 excipient of the present invention is used as a sustained-release matrix material, it can be used to prepare diltiazem hydrochloride, levetiracetam matrix-type sustained-release preparations, etc. In addition, when the polymer excipient of the present invention is used as a sustained-release matrix material, it can also provide sustained-release of water-insoluble drugs, such as apremilast.

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

[0074] The polymer excipient of the present invention is compounded with low-viscosity HPMC. When preparing the diltiazem hydrochloride skeleton-type sustained-release preparation, the dissolution exhibits near-zero-order release without burst release, and the dissolution is not affected by the medium.

[0075] The second aspect of the present invention provides a method for preparing the polymer excipient for medicine according to the first aspect of the present invention, comprising the following steps: uniformly melting and mixing the polylactic acid-polyethylene glycol block copolymer and polyethylene glycol, and cooling.

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

[0077] In a specific embodiment of the present invention, the mass ratio of the first mixture to the second mixture is 1:(0.5-2), 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 a range consisting of any two thereof.

[0078] In a specific embodiment of the present invention, the mass ratio of part of the polyethylene glycol to the balance of polyethylene glycol is 1:(0.5-2), 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 a range consisting of any two thereof.

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

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

[0081] The third aspect of the present invention provides a pharmaceutical preparation comprising a drug and any one of the polymer excipients for drugs according to the first aspect of the present invention.

[0082] In a specific embodiment of the present invention, the pharmaceutical preparation is a solid-state preparation. Furthermore, the pharmaceutical preparation comprises at least one of a tablet and a capsule. The tablets of the present invention can be prepared using conventional solid-state tablet processes, such as blending, granulation, drying, tableting, and coating. The capsules of the present invention can be prepared by uniformly mixing the drug with a polymer excipient under molten conditions and then filling the capsule.

[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 includes the following components by mass percentage: 9% to 55% of drug, 15% to 50% of polymer excipients for drug, 15% to 50% of other pharmaceutical excipients and 0% to 1% of magnesium stearate. For example, in different embodiments, in the pharmaceutical preparation, the amount of each component can be as follows, calculated in percentage by mass: the amount of the drug can be 9%, 10%, 12%, 15%, 17%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or a range consisting of any two thereof; the amount of the polymer excipient used for the drug can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or a range consisting of any two thereof; the amount of other pharmaceutical excipients can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or a range consisting of any two thereof; the amount of magnesium stearate can be 0%, 0.2%, 0.5%, 0.8%, 1% or a range consisting of any two thereof.

[0086] In a specific embodiment 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 polyvinyl pyrrolidone and carboxymethyl cellulose.

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

[0088] In a specific embodiment of the present invention, the pharmaceutical preparation comprises the following components by mass: 3% to 8% of the drug, 40% to 50% of a polymer excipient for the drug, 45% to 55% of microcrystalline cellulose, and 0% to 4% of cross-linked polyvinyl pyrrolidone. Preferably, the pharmaceutical preparation comprises the following components by mass: 4% to 6% of the drug, 42% to 46% of a polymer excipient for the drug, 47% to 51% of microcrystalline cellulose, and 1% to 3% of cross-linked polyvinyl pyrrolidone. Furthermore, the drug is apremilast.

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

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

[0091] mLA: meso-lactide;

[0092] LLA: L-lactide;

[0093] DLA: D-lactide, right-rotatory 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 below, W represents the molecular weight of PEG, and Y and Z represent the mass fractions (wt%) of L-lactide and PEG in the polymer, respectively;

[0104] In the PDLA-PEG-PDLA WY / Z mentioned below, W represents the molecular weight of PEG, and Y and Z represent the mass fractions (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 carried out with reference to the Chinese patent application with publication number CN120059147A.

[0107] The present invention provides a method for preparing a polylactic acid-polyethylene glycol block copolymer, which can 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; and after the PEG or MePEG is melted, applying vacuum for a predetermined period of time while stirring to remove residual water and other volatiles from the PEG or MePEG. After heating to 130°C, D-lactide and / or L-lactide are added, respectively. After melting, a catalyst is added, and a polymerization reaction is completed under stirring under predetermined conditions to obtain a block copolymer. After each addition, the flask is briefly evacuated, for example for 30 minutes, and then sealed.

[0108] The preparation parameters for the various block copolymers used in the examples of the present invention are shown in Table 1. The physical and chemical properties of the resulting 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 is based on Chinese patent application publication number CN120059147A. The DSC testing method involves weighing approximately 20 mg of sample into a crucible and scanning the temperature from -20°C to 100°C at a heating rate of 10°C / 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, the preparation method of PDLA-PEG-PDLA 6000-43 / 57 refers to Example 14 in CN120059147A, and the preparation method of PLLA-PEG-PLLA The preparation method of PDLLA / LLA-PEG-PDLLA / LLA 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 weight of the polylactic acid single block, 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 single block is calculated as follows: polylactic acid block calculated molecular weight = polyethylene glycol molecular weight × (X+Y) / Z. For triblock PLA-PEG-PLA, the average molecular weight of the polylactic acid single block is the average of the calculated molecular weights of the polylactic acid single blocks = polyethylene glycol molecular weight × (X+Y) / Z / 2.

[0117] Water solubility testing method: Shake the polymer in a sufficient volume of 10mM PBS at 37°C, pH 7.4, at a water / polymer ratio of 100mL / 1g. Observe for dissolution and dispersion. Readily soluble / dispersible: dissolves / disperses within 4 hours; slowly soluble / slowly dispersible: dissolves / disperses within 4 hours and within 24 hours; insoluble: no significant dissolution or dispersion within 24 hours. Subsequent water solubility testing methods are similar.

[0118] Example 1

[0119] This embodiment provides a method for preparing a polymer excipient for use in medicine, comprising the following steps:

[0120] Polyethylene glycol PEG and polylactic acid-polyethylene glycol block copolymer are melted and uniformly mixed at 80° C. to obtain a mixture, which is then cooled to room temperature to obtain a polymer excipient.

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

[0122] Table 3 Relevant information of polymer excipients

[0123]

[0124]

[0125]

[0126] Example 2

[0127] This embodiment provides a method for preparing a polymer excipient for use in medicine, comprising the following steps:

[0128] 50 g of polyethylene glycol PEG and 50 g of the first block copolymer were melted and mixed uniformly at 80° C. to obtain a first mixture; 50 g of polyethylene glycol PEG and 50 g of the 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 excipient.

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

[0130] Table 4 Relevant information of polymer excipients

[0131]

[0132] Example 3

[0133] This embodiment provides a method for preparing a solubilized rapid-release drug, comprising 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 bottle, stir magnetically at 80°C for about 10 minutes to mix evenly, then add a certain amount of drug, continue magnetic stirring for about 20-30 minutes to mix evenly, and then divide into No. 0 HPMC capsules (except for capsules numbered 3-4 with a filling amount of 300 mg, the filling amount of the other numbered capsules is 560-600 mg).

[0135] The preparation parameter information of different solubilized rapid-release drugs in this example is shown in Figure 5.

[0136] Table 5 Preparation parameter information of solubilized immediate release drugs

[0137]

[0138] Example 4

[0139] This embodiment provides a method for preparing various solubilized sustained-release drugs, comprising the following steps:

[0140] Apremilast Solubilized Sustained-Release Capsules 1: Weigh 9.5 g of polyethylene glycol PEG (Mn = 4000 Da) and vacuum evacuate at 130°C to remove moisture for 2 hours. After vacuuming, add 9.5 g of PLLA-PEG-PLLA 6000-43 / 57 and stir for approximately 10 minutes until completely melted. Then add 1 g of apremilast and magnetically stir at 130°C for approximately 20 minutes until completely melted and mixed. The mixture is then dispensed into size 0 HPMC capsules, controlling the loading to 560-600 mg.

[0141] Apremilast Solubilized Sustained-Release Capsules 2: Weigh 47.5 g of polyethylene glycol PEG (Mn = 4000 Da) and vacuum evacuate at 130°C to remove moisture for 2 h. After vacuuming, add 47.5 g of PDLLA / LLA-PEG-PDLLA / LLA 6000-22 / 22 / 56 and stir for approximately 10 min until completely melted. Then add 5 g of apremilast and magnetically stir at 130°C for approximately 20 min until completely melted and mixed. The mixture is then dispensed into size 0 HPMC capsules, controlling the loading to be between 560 and 600 mg.

[0142] Nifedipine solubilized sustained-release capsules 1: Fully melt 45 g of polyethylene glycol PEG (Mn = 6000 Da) and 45 g of PLLA-PEG-PLLA 6000-43 / 57 at 80°C and mix thoroughly to obtain a mixture. Then, take 47.5 g of the mixture and stir with 2.5 g of nifedipine at 130°C for about 20 min to mix evenly. Then, divide the mixture into No. 0 HPMC capsules, controlling the filling amount to 560-600 mg.

[0143] Nifedipine Solubilized Sustained-Release Capsules 2: 45 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 45 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to obtain a first mixture. 45 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 45 g of PDLA-PEG-PDLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to obtain a second mixture. The first and second mixtures were weighed in a 1:1 mass ratio, melted and mixed at 80°C. 47.5 g of the above mixture was mixed with 2.5 g of nifedipine by stirring at 130°C for approximately 20 minutes, and then dispensed into size 0 HPMC capsules, controlling the dosage to be between 560 and 600 mg.

[0144] Example 5

[0145] This embodiment provides a method for preparing various matrix-type sustained-release drugs, each comprising the following steps:

[0146] Levetiracetam matrix sustained-release tablets 1: 20 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 20 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a first mixture; 20 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 20 g of PDLA-PEG-PDLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a second mixture; the first and second mixtures were then mixed at a mass ratio of 1:1 at 80°C, cooled, pulverized, and sieved to obtain a polymer excipient. 12 g of levetiracetam was thoroughly blended with 4 g of the polymer excipient, 5.9 g of hydroxypropyl methylcellulose (HPMC4000, 2% aqueous solution viscosity 4000 mPa·s at 20°C), and 0.1 g of magnesium stearate, and tableted using a single-punch tablet press. The punch did not stick. The average diameter is 8 mm, the tablet weight is 303 mg, and the hardness is 71.2 N.

[0147] Levetiracetam Matrix Sustained-Release Tablets 2: 40 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 40 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 12 g of levetiracetam was thoroughly blended with 4 g of the polymer excipient, 5.9 g of hydroxypropyl methylcellulose (HPMC4000, 2% aqueous solution viscosity 4000 mPa·s at 20°C), and 0.1 g of magnesium stearate. The tablets were compressed in a single-punch tablet press with a non-stick punch. The tablets had an average diameter of 8 mm, a weight of 310 mg, and a hardness of 100.3 N.

[0148] Diltiazem hydrochloride matrix sustained-release tablets 1: 0.75 g of polyethylene glycol PEG (Mn = 6000 Da) and 0.75 g of PLLA-PEG-PLLA 6000-43 / 57 were fully melted and mixed at 80° C. to prepare a first mixture; 0.75 g of polyethylene glycol PEG (Mn = 6000 Da) and 0.75 g of PDLA-PEG-PDLA 6000-43 / 57 were fully melted and mixed at 80° C. to prepare a second mixture; the first mixture and the second mixture were then mixed at a mass ratio of 1:1 at 80° C., and then cooled, pulverized, and sieved to obtain a polymer excipient. 4g of diltiazem hydrochloride was thoroughly blended with 3g of polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05g of magnesium stearate. The mixture was then compressed into tablets using a single punch press. The punch did not stick. The tablets had an average diameter of 8mm, a weight of 281mg, and a hardness of 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 thoroughly melted and mixed at 80°C. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 4g of diltiazem hydrochloride was thoroughly blended with 3g of the polymer excipient, 2.95g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05g of magnesium stearate. The tablets were compressed using a single-punch tablet press with a non-stick punch. The tablets had an average diameter of 8mm, a weight of 293mg, and a hardness of 70N.

[0150] Example 6

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

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

[0153] Among them, HPMC4000, HPMC50, HPMC30, HPMC15, and HPMC6 were used to prepare diltiazem hydrochloride matrix sustained-release tablets according to the above method, and were named HPMC4000 sustained-release tablets, HPMC50 sustained-release tablets, HPMC30 sustained-release tablets, HPMC15 sustained-release tablets, and HPMC6 sustained-release tablets, respectively. During tableting, the punches did not stick. The HPMC4000 sustained-release tablets had an average diameter of 8 mm, a tablet weight of 294 mg, and a hardness of 160.8 N; the HPMC50 sustained-release tablets had an average diameter of 8 mm, a tablet weight of 294 mg, and a hardness of 70 N; the HPMC30 sustained-release tablets had an average diameter of 8 mm, a tablet weight of 285 mg, and a hardness of 95.4 N; the HPMC15 sustained-release tablets had an average diameter of 8 mm, a tablet weight of 283 mg, and a hardness of 115 N; and the HPMC6 sustained-release tablets had an average diameter of 8 mm, a tablet weight of 283 mg, and a hardness of 97.7 N.

[0154] Example 7

[0155] This embodiment provides a method for preparing various matrix-type sustained-release drugs, each comprising the following steps:

[0156] Diltiazem hydrochloride matrix sustained-release tablets (MCC) formulation: 50g of polyethylene glycol (PEG) (Mn=6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a first mixture. 50g of polyethylene glycol (PEG) (Mn=6000Da) and 50g of PDLA-PEG-PDLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a second mixture. The first and second mixtures were then mixed at a mass ratio of 1:1 at 80°C, cooled, pulverized, and sieved to obtain the polymer excipient. 20g of diltiazem hydrochloride, 40g of the polymer excipient, 40g of microcrystalline cellulose, and 0.2g of magnesium stearate were thoroughly blended and compressed in a single-punch tablet press. The punches did not stick. The tablets had an average diameter of 8mm and weighed 308mg.

[0157] Formula for diltiazem hydrochloride matrix sustained-release tablets: 50g of polyethylene glycol (PEG) (Mn=6000Da) and 50g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a first mixture; 50g of polyethylene glycol (PEG) (Mn=6000Da) and 50g of PDLA-PEG-PDLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a second mixture; the first and second mixtures were then mixed at a mass ratio of 1:1 at 80°C, cooled, pulverized, 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 were thoroughly blended and compressed in a single-punch tablet press. The punch did not stick. The average diameter is 8 mm, the tablet weight is 292 mg, and the hardness is 144.4 N.

[0158] Formula of diltiazem hydrochloride matrix sustained-release tablets hydroxypropyl methylcellulose (HPMC30): 50 g of polyethylene glycol PEG (Mn=6000Da) and 50 g of PLLA-PEG-PLLA 6000-43 / 57 are fully melted and mixed at 80°C to prepare a first mixture; 50 g of polyethylene glycol PEG (Mn=6000Da) and 50 g of PDLA-PEG-PDLA 6000-43 / 57 are fully melted and mixed at 80°C to prepare a second mixture; the first mixture and the second mixture are then mixed at a mass ratio of 1:1 at a temperature of 80°C, and then cooled, pulverized, and sieved to obtain a polymer excipient. 2g of diltiazem hydrochloride, 4g of polymer excipient, 3.95g of hydroxypropyl methylcellulose (HPMC30, 2% aqueous solution viscosity 30 mPa·s at 20°C), and 0.02g of magnesium stearate were thoroughly blended and compressed into tablets using a single punch press. The punch did not stick. The tablets had an average diameter of 8mm, a weight of 275mg, and a hardness of 89.1N.

[0159] Example 8

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

[0161] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 1: 20 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 20 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a first mixture; 20 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 20 g of PDLA-PEG-PDLA 6000-43 / 57 were thoroughly melted and mixed at 80°C to form a second mixture; the first and second mixtures were then mixed at a mass ratio of 1:1 at 80°C, cooled, pulverized, and sieved to obtain a polymer excipient. 4 g of diltiazem hydrochloride, 3 g of the polymer excipient, 2.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and tableted using a single-punch tablet press. The punch did not stick. The average diameter is 8 mm, the tablet weight is 299 mg, and the hardness is 97.5 N.

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

[0163] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 3: 27 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 27 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 130°C. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 4 g of diltiazem hydrochloride, 3 g of the polymer excipient, 2.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press. The punch did not stick. The tablets had an average diameter of 8 mm, a weight of 299 mg, and a hardness of 122.3 N.

[0164] Example 9

[0165] This embodiment provides a method for preparing various matrix-type sustained-release drugs, each comprising the following steps:

[0166] Apremilast Matrix Sustained-Release Tablets 1: Melt 3g of polyethylene glycol (PEG) (Mn=6000Da) and 6g of PLLA-PEG-PLLA6000-43 / 57 at 80°C and mix thoroughly. Add 1g of apremilast and mix thoroughly. Cool and pulverize to obtain a powder. Thoroughly mix 3.7g of the powder, 3.7g of microcrystalline cellulose, and 0.14g of cross-linked polyvinyl pyrrolidone and press into a single-punch tablet press. The tablets have an average diameter of 8mm and weigh 248mg.

[0167] Apremilast Matrix Sustained-Release Tablets 2: Melt 2.5g of polyethylene glycol (PEG) (Mn=6000Da) and 5.5g of PLLA-PEG-PLLA 6000-43 / 57 at 80°C and mix thoroughly. Add 1g of apremilast and mix thoroughly. Cool and pulverize to obtain a powder. Thoroughly mix 2.2g of the powder, 2.2g of microcrystalline cellulose, and 0.09g of cross-linked polyvinyl pyrrolidone and press into a single-punch tablet machine for tableting. The tablets have an average diameter of 8mm and weigh 248mg.

[0168] Apremilast Matrix Sustained-Release Tablets 3: 4.5 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 4.5 g of PLLA-PEG-PLLA 6000-43 / 57 were thoroughly melted and mixed at 80°C. 1 g of apremilast was added and mixed thoroughly. The mixture was then cooled and pulverized to obtain a powder. 2.6 g of the powder was thoroughly mixed with 2.6 g of microcrystalline cellulose and 0.1 g of cross-linked polyvinyl pyrrolidone and compressed into tablets using a single punch. The tablets had an average diameter of 8 mm and a weight of 255 mg.

[0169] Example 10

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

[0171] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 1: 960 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 960 g of PLLA-PEG-PLLA 6000-50 / 50 were thoroughly melted and mixed at 110°C to form a mixture. The mixture was then cooled, pulverized, and sieved to obtain the polymer excipient. 1 g of diltiazem hydrochloride, 4.5 g of the polymer excipient, 4.45 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press with a non-stick punch. The tablets had an average diameter of 8 mm, a weight of 322 mg, and a hardness of 91.6 N.

[0172] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 2: 960 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 960 g of PLLA-PEG-PLLA 6000-50 / 50 were thoroughly melted and mixed at 110°C to form a mixture. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 2 g of diltiazem hydrochloride, 4 g of the polymer excipient, 3.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press with a non-stick punch. The tablets had an average diameter of 8 mm, a weight of 322 mg, and a hardness of 77.6 N.

[0173] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 3: 960 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 960 g of PLLA-PEG-PLLA 6000-50 / 50 were thoroughly melted and mixed at 110°C to form a mixture. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 4 g of diltiazem hydrochloride, 4 g of the polymer excipient, 1.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press. The punch did not stick. The tablets had an average diameter of 8 mm, a weight of 302 mg, and a hardness of 110.0 N.

[0174] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 4: 960 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 960 g of PLLA-PEG-PLLA 6000-50 / 50 were thoroughly melted and mixed at 110°C to form a mixture. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 4 g of diltiazem hydrochloride, 2 g of the polymer excipient, 3.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press. The punch did not stick. The tablets had an average diameter of 8 mm, a weight of 314 mg, and a hardness of 115.0 N.

[0175] Diltiazem Hydrochloride Matrix Sustained-Release Tablets 5: 960 g of polyethylene glycol (PEG) (Mn = 6000 Da) and 960 g of PLLA-PEG-PLLA 6000-50 / 50 were thoroughly melted and mixed at 110°C to form a mixture. The mixture was then cooled, pulverized, and sieved to obtain a polymer excipient. 4 g of diltiazem hydrochloride, 3 g of the polymer excipient, 2.95 g of hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity 50 mPa·s at 20°C), and 0.05 g of magnesium stearate were thoroughly blended and compressed into tablets using a single-punch tablet press. The punch did not stick. The tablets had an average diameter of 8 mm, a weight of 285 mg, and a hardness of 78.6 N.

[0176] Example 11

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

[0178] 960g polyethylene glycol PEG (Mn=6000Da) and 960g PLLA-PEG-PLLA 6000-50 / 50 are fully melted and mixed at 110°C to make a mixture, then pulverized and sieved to obtain a polymer excipient after cooling. 4g diltiazem hydrochloride, 3g polymer excipient, 2.95g hydroxypropyl methylcellulose (HPMC50, 2% aqueous solution viscosity is 50mPa·s at 20°C) and 0.05g magnesium stearate are fully blended, and three blended powders are prepared in parallel. The powders are respectively put into a single punch tablet press and tableted, and the punch does not stick. The first batch has an average diameter of 8mm, a tablet weight of 293mg, and a hardness of 77.8N; the second batch has an average diameter of 8mm, a tablet weight of 292mg, and a hardness of 75.4N; and the third batch has an average diameter of 8mm, a tablet weight of 296mg, and a hardness of 74.8N.

[0179] Experimental Example 1

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

[0181] Table 6 Accelerated stability test results

[0182]

[0183] Experimental Example 2

[0184] Dissolution testing was performed on different drug formulations. The dissolution conditions and test methods are shown in Tables 7 and 8. Subsequent testing was performed according to the methods in Tables 7 and 8 unless additional dissolution conditions were specified.

[0185] Table 7 Dissolution conditions of different drug preparations

[0186]

[0187] Table 8 Detection methods for different drug preparations

[0188]

[0189] The dissolution of the solubilized rapid-release 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 FIG. Figure 4 The dissolution of Apremilast Solubilized Sustained-Release Capsules 1, Apremilast Solubilized Sustained-Release Capsules 2, Nifedipine Solubilized Sustained-Release Capsules 1, and Nifedipine Solubilized Sustained-Release Capsules 2 prepared in Example 4 was tested by the above method. The dissolution curves are shown in FIG. Figure 5 The dissolution of levetiracetam skeleton sustained-release tablets 1, levetiracetam skeleton sustained-release tablets 2, diltiazem hydrochloride skeleton sustained-release tablets 1, and diltiazem hydrochloride skeleton sustained-release tablets 2 prepared in Example 5 was tested using the above method. The dissolution curves are shown in FIG. Figure 6 .from Figure 6 It can be seen that the diltiazem hydrochloride matrix sustained-release tablets 2 prepared in Example 5 exhibited a dissolution curve of nearly zero-order release. The dissolution of the diltiazem hydrochloride matrix sustained-release drugs with different viscosities of HPMC prepared in Example 6 was tested using the above method. The dissolution curves are shown in FIG. Figure 7 The dissolution of the diltiazem hydrochloride matrix sustained-release drug prepared in Example 7 using different excipients was tested using the above method. The dissolution curves are shown in Figure 8 .

[0190] The dissolution of the diltiazem hydrochloride matrix sustained-release tablet 1 prepared in Example 8 was tested using the above method in different dissolution media. The media in the dissolution conditions were replaced with 900 mL of pH = 1 (0.1 mol / L hydrochloric acid solution), 20 mM pH = 4.5 acetate buffer saline solution, 20 mM pH = 6.8 phosphate buffer saline 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 Figure 5. Figure 9 .

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

[0192] The dissolution of the diltiazem hydrochloride matrix sustained-release tablet 3 prepared in Example 8 was tested in different dissolution media using the above method. The media in the dissolution conditions were replaced with 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. The dissolution curves are shown in FIG. Figure 11 .

[0193] The above method was used to prepare the diltiazem hydrochloride matrix sustained-release tablets of microcrystalline cellulose (MCC) in Example 7. After storage at different temperature conditions for 3 months, a dissolution test was performed. The dissolution curves are shown in FIG. Figure 12 .

[0194] The dissolution of Apremilast skeleton sustained-release tablets 1, Apremilast skeleton sustained-release tablets 2, and Apremilast skeleton sustained-release tablets 3 prepared in Example 9 was tested by the above method. The dissolution curves are shown in FIG. Figure 13 .

[0195] The dissolution of diltiazem hydrochloride matrix sustained-release tablets 1 to 5 prepared in Example 10 was tested using the above method. The dissolution curves are shown in FIG. Figure 14 The dissolution of the diltiazem hydrochloride matrix sustained-release tablets prepared in parallel with Example 11 was tested using the above method. The dissolution curve is shown in FIG. Figure 15 , indicating that the pharmaceutical preparation of the present invention has good reproducibility.

[0196] The above test results show that the polymer excipients of the present invention can increase the solubility of poorly soluble drugs and achieve rapid release and sustained release of drugs; they can also improve the dissolution characteristics of water-soluble drugs (avoiding burst release, achieving near-zero-order release, and dissolution is not affected by the medium and stirring rate), and at the same time enhance the storage stability of drug preparations.

[0197] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements 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 polymer excipient for a drug, characterized in that: The invention comprises a polylactic acid-polyethylene glycol block copolymer and polyethylene glycol in a mass ratio of (0.5-4):1; the number average molecular weight of the polyethylene glycol is ≥1000Da.

2. The polymer excipient for medicine according to claim 1, characterized in that In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid single block is 1000-3000 Da, and the molecular weight of the polyethylene glycol block is 1500-8000 Da; Preferably, the number average molecular weight of the polyethylene glycol is 1000 to 10000 Da.

3. The polymer excipient for pharmaceutical use according to claim 1 or 2, characterized in that: In the polylactic acid-polyethylene glycol block copolymer, the molecular weight of the polyethylene glycol block is 6000 to 8000 Da; Preferably, the number average molecular weight of the polyethylene glycol is 4000 to 10000 Da.

4. The polymer excipient for medicine according to claim 2, characterized in that: In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid single block is 1000-2100 Da, and the molecular weight of the polyethylene glycol block is 2000-8000 Da; Preferably, when the polylactic acid-polyethylene glycol block copolymer is a triblock copolymer PLA-PEG-PLA, the average molecular weight of the polylactic acid single block is 1000-1800 Da, and the molecular weight of the polyethylene glycol block is 3000-8000 Da.

5. The polymer excipient for medicine according to claim 2, characterized in that: In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid single block is 2200-3000 Da, and the molecular weight of the polyethylene glycol block is 2000-10000 Da.

6. The polymer excipient for pharmaceutical use according to claim 1 or 2, characterized in that: In the polylactic acid-polyethylene glycol block copolymer, the average molecular weight of the polylactic acid single block is ≥2000 Da, and the molecular weight of the polyethylene glycol block is 6000-8000 Da; Preferably, the average molecular weight of the polylactic acid single block is 2000 to 5000 Da; Preferably, the number average molecular weight of the polyethylene glycol is 4000 to 10000 Da.

7. The polymer excipient for medicine according to claim 6, characterized in that: In the polylactic acid-polyethylene glycol block copolymer, the polylactic acid block includes at least one of a PLLA block and a PDLA block; Preferably, 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 a diblock copolymer PLLA-PEG and a triblock copolymer PLLA-PEG-PLLA, and the second copolymer is selected from at least one of a PDLA-PEG and a triblock copolymer PDLA-PEG-PDLA; Preferably, the mass ratio of the first copolymer to the second copolymer is 1:(0.5-2).

8. The polymer excipient for medicine according to claim 6, 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 polyvinyl pyrrolidone, and carboxymethyl cellulose.

9. The method for preparing a polymer excipient for pharmaceutical use according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: melting and uniformly mixing the polylactic acid-polyethylene glycol block copolymer and the polyethylene glycol, and cooling.

10. A pharmaceutical preparation, characterized in that Comprising a drug and the polymer excipient for drug according to any one of claims 1 to 8; Preferably, the pharmaceutical preparation is a solid preparation; Preferably, the pharmaceutical preparation is an oral preparation; Preferably, the drug comprises at least one of indomethacin, nimodipine, nifedipine, apremilast, diltiazem hydrochloride, levetiracetam, and fenofibrate; Preferably, the pharmaceutical preparation comprises the following components by mass percentage: 9% to 55% of the drug, 15% to 50% of the polymer excipient for the drug, 15% to 50% of other pharmaceutical excipients and 0% to 1% of magnesium stearate; Preferably, 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 polyvinyl pyrrolidone and carboxymethyl cellulose; Preferably, the viscosity of a 2 wt % aqueous solution of the hydroxypropyl methylcellulose at 20° C. is ≤4000 mPa·s.

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