A poorly soluble drug osmotic pump controlled release tablet and a method for preparing the same

Abstract

The present application relates to a kind of poorly soluble drug osmotic pump controlled-release tablets and its preparation method, the osmotic pump controlled-release tablets include tablet core, semi-permeable membrane coating and release hole, the tablet core includes solid dispersion of poorly soluble drug and penetration agent, the solid dispersion of poorly soluble drug includes poorly soluble drug and carrier, the poorly soluble drug is selected from nicardipine, nifedipine, felodipine and their pharmaceutically acceptable salt, the carrier is selected from organic acid substance.Compared with prior art, the poorly soluble drug osmotic pump controlled-release tablets of the present application greatly improves the drug solubility, without using a large amount of penetration agent or other excipients in tablet core, drug loading is increased, and tablet core will not be too large;In vivo release greatly improves;Preparation process is simple, equipment requirement and cost are low, and easy to industrialization.

Description

A poorly soluble drug osmotic pump controlled-release tablet and its preparation method Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an osmotic pump controlled-release tablet for a poorly soluble drug and a preparation method thereof. Background Art

[0002] Sustained-release formulations can significantly reduce the frequency of medication administration, reduce fluctuations in blood drug concentrations, minimize discomfort caused by peaks and troughs, reduce toxic side effects, and improve patient compliance. Among them, osmotic pump-controlled-release formulations are considered the most ideal oral sustained-release dosage form because they can deliver a sustained, stable, and constant release rate, unaffected by variable gastrointestinal factors such as motility, pH, and gastric emptying time. Osmotic pumps can be categorized into single-chamber osmotic pumps, push-pull osmotic pumps (multi-chamber osmotic pumps), and microporous membrane osmotic pumps, depending on the solubility characteristics of different drugs. Single-chamber osmotic pumps are suitable for water-soluble drugs (5-10%) and offer advantages such as simple preparation and stable release rates. However, they have high requirements for drug solubility, and currently few products are on the market. Poorly soluble drugs are generally designed as multi-chamber osmotic pumps, consisting of a drug-containing core and push-pull layers to increase release dynamics. For example, the early marketed product, the "Nifedipine Osmotic Pump Tablet," is a multi-chamber osmotic pump tablet. However, this dosage form is complex to prepare, requiring multiple tableting cycles and laser identification and drilling. It also places extremely high demands on excipients and process equipment, making industrialization challenging. Therefore, effectively improving the solubility of poorly soluble drugs and developing single-chamber osmotic pump drug delivery systems is of great significance.

[0003] Due to solubility issues, the cumulative release of poorly soluble drugs directly formulated into single-chamber osmotic pumps is low (Study on Nicardipine Hydrochloride Osmotic Pump Controlled-Release Tablets, Zheng Qilan, Shenyang Pharmaceutical University, Master's Thesis). Therefore, drug solubilization and permeation enhancement methods are often used, such as solid dispersions and cyclodextrin inclusion complexes, to improve the solubility of poorly soluble drugs. Furthermore, appropriate permeation enhancers are selected to increase the intra-chamber osmotic pressure and viscosity, enabling the development of single-chamber osmotic pump formulations for poorly soluble drugs. In current research, solid dispersions and cyclodextrin inclusion complexes often utilize polymer carrier materials, such as PVPK30, PEG, poloxamer, and cyclodextrin, typically in dosages of 1 to 5 times the drug. After the intermediate is prepared, permeation enhancers and fillers are added to compress the tablet core, which is then coated to prepare the osmotic pump tablet. For example, some scholars prepared a solid dispersion of curcumin and PVPK30 in a weight ratio of 1:4, and added the permeation enhancer NaCl and the suspending agent CMC-Na to prepare a monolayer osmotic pump preparation with a cumulative release greater than 90% (Preparation and prescription optimization of curcumin solid dispersion monolayer osmotic pump controlled-release tablets, Yan Wei, Hu Chunxia, ​​Zhang Zhiqiang, Chinese Patent Medicine, 2019, 1768-1772); another example is that some scholars used inclusion technology to prepare baicalein into an inclusion complex, with a weight ratio of baicalein to dimethyl-β-cyclodextrin of 1:5, and further added the permeation enhancer NaCl and the suspending agent CMC-Na to prepare a monolayer osmotic pump with a cumulative release of more than 80% (Study on the preparation process of baicalein inclusion complex monolayer osmotic pump tablets, Zheng Xiangtao, Hao Haijun, Han Ru, et al., Journal of Second Military Medical University, 2015, 513-517). However, adding large amounts of functional excipients to improve drug solubility can result in excessive tablet weight, hindering subsequent coating and post-marketing administration. Furthermore, the drug dosage in osmotic pump formulations is higher than in conventional formulations, making excessive use of excipients unrealistic. Therefore, controlling the amount of functional excipients while improving drug solubility is crucial for the process feasibility of the formulation.

[0004] Although it was reported earlier that a single-chamber osmotic pump prepared by directly combining a poorly soluble drug, a suspending agent, and an osmotic agent in a certain ratio achieved good release effects, it was unclear whether this method was applicable to specific drug crystal forms. At the same time, the inventors' previous research found that organic acids can effectively solubilize and enhance the penetration of certain poorly soluble drugs. By using organic acids as penetration enhancers to prepare tablet cores containing poorly soluble drugs and employing simple single-layer osmotic pump technology, the drug release rate in water was significantly improved, with a 24-hour drug release rate of over 90% (Patent No.: (ZL200510065906.2; Preparation of Nicardipine Hydrochloride Monolayer Osmotic Pump Tablets and Investigation of Their In Vitro Release Behavior, Ma Rui, Wang Hongliang, Liu Yuling et al., 2011, China Pharmacy, 1967-1969) However, for some drugs or drug crystal forms, the above methods still cannot effectively improve solubility, and more complex processes such as double-layer osmotic pump formulations are required. The addition of a booster layer requires a large amount of functional excipients, increases the weight of the tablet core, and complicates the formulation and preparation process. Therefore, more suitable methods are needed to further improve drug solubility.

[0005] Summary of the Invention

[0006] To address these issues, the inventors unexpectedly discovered that using organic acids as carriers to form solid dispersions of poorly soluble drugs further improves their solubility in organic acid solutions. Furthermore, compared to using polymeric carrier materials, using organic acids as carriers can significantly reduce the amount of carrier material used, making it easier to control the amount of excipients used in the formulation and improving process feasibility.

[0007] In view of this, the present invention provides, on one hand, an osmotic pump controlled-release tablet for a poorly soluble drug, the osmotic pump controlled-release tablet comprising a tablet core, a semipermeable membrane coating, and a drug release hole, the tablet core comprising a poorly soluble drug solid dispersion and a permeation enhancer, the poorly soluble drug solid dispersion comprising a poorly soluble drug and a carrier;

[0008] The poorly soluble drug is selected from nicardipine, nifedipine, felodipine, and pharmaceutically acceptable salts thereof, and the carrier is selected from organic acids. The resulting osmotic pump controlled-release tablets have greatly improved solubility, eliminate the need for a large amount of penetration enhancers or other excipients in the tablet core, increase drug loading, and minimize tablet size. In vivo release is significantly improved, and the preparation process is simple, with low equipment requirements and costs, making them easy to industrialize.

[0009] The osmotic pump controlled-release tablets of the present invention include single-layer, double-layer or multi-layer osmotic pump controlled-release tablets.

[0010] According to some embodiments of the present invention, the penetration enhancer is selected from an organic acid or a combination of an organic acid with any one or more of sodium chloride, mannitol, and lactose. The inventors have found through a large number of experimental studies that the use of organic acids as penetration enhancers can greatly improve drug solubility. However, excessive solubility of some drugs may cause the drug to be released too quickly, thereby reducing the efficacy of the medication. In some embodiments, selecting an organic acid or a combination of an organic acid with any one or more of sodium chloride, mannitol, and lactose as a penetration enhancer can control the drug release rate within an appropriate range, thereby achieving the purpose of controlled release.

[0011] According to some embodiments of the present invention, the organic acid substance in the carrier is selected from citric acid, fumaric acid, succinic acid, tartaric acid, bile acid, lecithin or deoxycholic acid, preferably selected from citric acid, fumaric acid or succinic acid, and more preferably citric acid.

[0012] According to some embodiments of the present invention, the organic acid substance in the penetration enhancer is selected from citric acid, fumaric acid, succinic acid, tartaric acid, bile acid, lecithin or deoxycholic acid, preferably selected from citric acid, fumaric acid or succinic acid, and more preferably citric acid.

[0013] According to some embodiments of the present invention, the organic acid substances in the carrier and the penetration enhancer are the same organic acid, for example, the organic acid substances in the carrier and the penetration enhancer are both citric acid, or alternatively, the organic acid substances in the carrier and the penetration enhancer are different organic acids.

[0014] According to some embodiments of the present invention, the poorly soluble drug of the present invention is nicardipine hydrochloride, and more preferably α-crystalline nicardipine, β-crystalline nicardipine, or a mixed crystal of the two.

[0015] According to some embodiments of the present invention, the weight ratio of the poorly soluble drug to the carrier in the solid dispersion is 1:(0.1-1), or 1:(0.1-0.8), or 1:(0.1-0.6), or 1:(0.1-0.4), or 1:(0.1-0.3), or 1:(0.1-0.25), or 1:(0.1-0.2); or 1:(0.15-1), or 1:(0.15-0.8), or 1:(0.15-0.6), or 1:(0.15-0.4), or 1:(0.15-0.3), or 1:(0.15-0.25); or 1:(0.19-0.6); or 1: (0.19-0.56); or 1:(0.2-0.56); or 1:(0.2-1), or 1:(0.2-0.8), or 1:(0.2-0.6), or 1:(0.2-0.4), or 1:(0.2-0.3), or 1:(0.2-0.25); or 1:(0.25-1), or 1:(0.25-0.8), or 1:(0.25-0.6), or 1:(0.25-0.4), or 1:(0.25-0.3); or 1:(0.3-1), or 1:(0.3-0.8), or 1:(0.3-0.6), or 1:(0.3-0.4). The inventors have found through a large number of experiments that the use of the smaller carrier weight in the present invention can greatly improve the solubility of poorly soluble drugs, thereby greatly reducing the amount of excipients in the tablets.

[0016] According to some embodiments of the present invention, the penetration enhancer is selected from organic acids, preferably, the organic acid is citric acid. According to some embodiments of the present invention, the penetration enhancer accounts for 10-70% of the total weight of the tablet core, preferably 20-60%.

[0017] In the poorly soluble drug osmotic pump controlled-release tablet of the present invention, the tablet core may further comprise an excipient selected from fillers, disintegrants, diluents, binders or lubricants.

[0018] According to some embodiments of the present invention, the semipermeable membrane coating accounts for 5-12% by weight of the tablet, preferably 5-10% by weight.

[0019] According to some embodiments of the present invention, the semipermeable membrane coating is composed of a film-forming material and a plasticizer. Preferably, the weight ratio of the film-forming material to the plasticizer is 9 to 99:1.

[0020] On the other hand, the present invention provides a poorly soluble drug solid dispersion comprising a poorly soluble drug and a carrier material; the poorly soluble drug is selected from nicardipine, nifedipine, felodipine and pharmaceutically acceptable salts thereof, and the carrier material is selected from organic acids;

[0021] Optionally, the organic acid substance is selected from citric acid, fumaric acid, succinic acid, tartaric acid, bile acid, lecithin or deoxycholic acid; preferably selected from citric acid, fumaric acid or succinic acid, and more preferably citric acid.

[0022] In another aspect, the present invention provides a method for preparing a poorly soluble drug osmotic pump controlled-release tablet, comprising the following steps:

[0023] a) preparing a poorly soluble drug solid dispersion by a solvent method;

[0024] b) mixing the solid dispersion with a penetration enhancer, and optionally adding an appropriate amount of other excipients;

[0025] c) Direct tablet compression or tablet core compression after granulation;

[0026] d) Wrapped with a semi-permeable membrane and punched with holes by laser or machinery.

[0027] Preferably, the solvent method comprises the steps of: dissolving the drug and the carrier in an organic solvent, removing the organic solvent under reduced pressure until foaming occurs, rotary evaporation, sieving, and vacuum drying to obtain,

[0028] Preferably, the organic solvent is selected from ethanol, methanol and tert-butanol, more preferably methanol.

[0029] Optionally, the solvent method comprises the steps of: dissolving the drug and the carrier in an organic solvent, spray drying to remove the organic solvent, and vacuum drying to obtain the drug, wherein the organic solvent is selected from ethanol, methanol, and tert-butanol, preferably methanol.

[0030] Optionally, the solvent method comprises the steps of: dissolving the drug and the carrier in an organic solvent, and removing the organic solvent by freeze-drying, wherein the organic solvent is selected from tert-butanol.

[0031] The preparation process of the osmotic pump tablet provided by the present invention comprises a solid dispersion of a poorly soluble drug and an organic acid, and an organic acid and other suitable excipients are added to prepare a tablet core, which is then further processed to obtain an osmotic pump controlled-release tablet. In the prescription, the poorly soluble drug and the organic acid are prepared into a solid dispersion, and the organic acid is used as a penetration enhancer, which can greatly improve the solubility of the poorly soluble drug. At the same time, the amount of excipients such as the carrier and the penetration enhancer can be controlled at a low level, thereby overcoming the problem of insufficient drug loading or an overly large tablet core. At the same time, the preparation process is simple and easy to implement, and has the advantages of good quality controllability, low equipment requirements, and easy industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG1 is an XRD diffraction pattern of Nic (nicardipine hydrochloride) drug, FIG1A: XRD diffraction pattern of α-Nic; FIG1B: XRD diffraction pattern of β-Nic.

[0033] Figure 2 is the XRD diffraction pattern of Nic / citric acid (w / w 1:0.37) solid dispersion, Figure 2A: XRD diffraction pattern of α-Nic / citric acid solid dispersion, Figure 2B: XRD diffraction pattern of β-Nic / citric acid solid dispersion.

[0034] Figure 3 is the XRD diffraction pattern of β-Nic / PVPK30 solid dispersion, a, XRD diffraction pattern of β-Nic; b, XRD diffraction pattern of PVPK30; c, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:1) physical mixture; d, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:3) physical mixture; e, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:5) physical mixture; f, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:1) solid dispersion; g, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:3) solid dispersion; h, XRD diffraction pattern of β-Nic / PVPK30 (w / w 1:5) solid dispersion.

[0035] Figure 4 is the XRD diffraction pattern of β-Nic / PEG6000 solid dispersion, a, β crystal form of Nic; b, XRD diffraction pattern of PEG6000; c, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:1) physical mixture; d, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:3) physical mixture; e, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:5) physical mixture; f, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:1) solid dispersion; g, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:3) solid dispersion; h, XRD diffraction pattern of β-Nic / PEG6000 (w / w1:5) solid dispersion.

[0036] Figure 5 is the XRD diffraction pattern of β-Nic / SDF68 solid dispersion, a, XRD diffraction pattern of β-crystal of Nic; b, XRD diffraction pattern of SDF68; c, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:1) physical mixture; d, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:3) physical mixture; e, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:5) physical mixture; f, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:1) solid dispersion; g, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:3) solid dispersion; h, XRD diffraction pattern of β-Nic / SDF68 (w / w 1:5) solid dispersion.

[0037] FIG6 is a graph showing the release curves of the Nic osmotic pump tablets and the Perl sustained-release capsules of the present invention.

[0038] FIG7 is a graph showing the release curves of Nic solid dispersion monolayer osmotic pump tablets using different penetration enhancers.

[0039] FIG8 is a graph showing the release curves of Nic solid dispersion osmotic pump tablets using different penetration enhancer combinations.

[0040] FIG9 is a graph showing the release curves of Nic solid dispersion osmotic pump tablets prepared with different ratios of citric acid penetration enhancer.

[0041] FIG10 is a graph showing the release curves of Nic solid dispersion osmotic pumps with different coating compositions.

[0042] FIG11 is a graph showing the release curves of Nic solid dispersion osmotic pump tablets with different coating weight gains.

[0043] FIG12 is a drug-time curve of the blood drug concentration of the Nic osmotic pump tablets and the Perl sustained-release capsules of the present invention in beagle dogs.

[0044] FIG13 is a graph showing the release curves of osmotic pump tablets prepared using nicardipine hydrochloride as a raw material and nicardipine hydrochloride solid dispersion as a raw material. DETAILED DESCRIPTION

[0045] The present invention will be further described in detail below by means of the accompanying drawings and Examples. Through these exemplary descriptions, the characteristics and advantages of the present invention will become more clear and distinct. Any embodiment described herein as an example need not be interpreted as being superior or better than other embodiments.

[0046] Example 1 Preparation of Nicardipine Hydrochloride (Nic) Solid Dispersion and XRD Analysis of Solid Dispersion

[0047] Preparation of solid dispersions

[0048] Using nicardipine hydrochloride as a model drug, organic acids (including succinic acid, fumaric acid, and citric acid), PVPK30, PEG6000, and Pluronic F68 were selected as carrier materials. Solid dispersions were prepared using the solvent method (with organic acids and PVPK30 as carrier materials) and the solvent-melt method (with PEG6000 and Pluronic F68 as carrier materials). The preparation method of the nicardipine solid dispersion is as follows:

[0049] Solvent method: Weigh the nicardipine hydrochloride raw material and carrier material in multiple amounts, add 5-20 times the amount of methanol, remove the organic solvent under reduced pressure until foaming occurs, continue rotary evaporation (40°C water bath, 60 rpm) for 3 hours, pass through a 100-mesh sieve, and vacuum dry at 40°C for 12 hours to obtain;

[0050] Solvent-melting method: weigh the drug, dissolve it in 5-20 times the amount of methanol, melt the carrier material in a water bath according to the proportion, add the drug solution to the carrier solution, stir rapidly, evaporate the methanol, solidify at -20℃, vacuum dry at room temperature for 48h, and dry and grind the solid to obtain it.

[0051] Solid dispersion XRD analysis

[0052] Appropriate amounts of Nic's β or α crystal form, solid dispersion, and corresponding physical mixture were subjected to XRD analysis to observe the crystal diffraction peaks. Detection conditions: Cu-Kα radiation source, graphite monochromator, tube voltage 40 kV, tube current 200 mA, diffraction range 3° < 2θ < 60°, step size 0.02, and dwell time of 0.2 s per step.

[0053] The results in Figures 1 and 2 show that Nic (α, β crystal form) has many characteristic crystal diffraction peaks, indicating that it is in a crystalline state. However, in the solid dispersion formed with the carrier, the crystalline diffraction peaks of the drug completely disappear, suggesting that after the drug forms a solid dispersion with the carrier, the crystal characteristics of Nic itself are suppressed and it exists in an amorphous state.

[0054] The results in Figure 3 show that Nic exhibits numerous characteristic crystal diffraction peaks, indicating its crystalline state, while the carrier material PVP K30 is amorphous. Crystalline diffraction peaks of the drug are visible in the physical mixture, with no new peaks generated, indicating a simple physical mixing of the two. In solid dispersions formed at varying drug / carrier material PVP K30 dosage ratios, the drug's crystalline diffraction peaks completely disappear, revealing characteristic peaks similar to those of the carrier material. Nic's inherent crystal characteristics are suppressed, remaining in an amorphous state, suggesting that solid dispersions can form when the drug and PVP K30 are present at all three ratios.

[0055] The results in Figure 4 show that Nic exhibits numerous characteristic crystal diffraction peaks, indicating its crystalline state. The carrier material, PEG 6000, exhibits a crystalline state. In the physical mixture, both the drug's crystal diffraction peaks and the carrier's characteristic peaks are visible, with no new peaks generated. However, in solid dispersions formed at varying drug-carrier ratios, the drug's crystalline diffraction peaks completely disappear, revealing characteristic peaks similar to those of the carrier material. This suggests that after the solid dispersion of the drug and carrier forms, Nic's inherent crystal characteristics are suppressed, resulting in an amorphous state.

[0056] The results in Figure 5 show that Nic exhibits numerous characteristic crystal diffraction peaks, indicating its crystalline state. The carrier material, SDF68, also exhibits a crystalline state. In the physical mixture, both the drug's crystal diffraction peaks and the carrier's characteristic peaks are visible, with no new peaks generated. However, in solid dispersions formed with varying drug-carrier ratios, the drug's crystalline diffraction peaks completely disappear, revealing characteristic peaks similar to those of the carrier material. This suggests that after the drug and carrier form a solid dispersion, Nic's inherent crystal characteristics are suppressed, resulting in an amorphous state.

[0057] Example 2 Solubility determination of Nicardipine hydrochloride (Nic) solid dispersion

[0058] An appropriate amount of the solid dispersion powder prepared in Example 1 (equivalent to 20 mg of drug) was weighed and added to 1 mL of water or 1 mL of saturated citric acid solution. The mixture was immediately shaken in an air shaker at 37°C for 2 hours. After the drug dissolved, an equal amount of the solid dispersion powder was added and shaken for 2 hours. This process was repeated until insoluble solids appeared in the solution. The solubility of the solid dispersion in 37°C water and saturated citric acid was measured.

[0059] Table 1 Solubility of nicardipine hydrochloride drug and solid dispersion in water and organic acid solvents

[0060]

[0061]

[0062] The results showed that the solubility of nicardipine hydrochloride solid dispersions prepared using different carriers in water or citric acid was significantly higher than that of the drug itself in water or citric acid. The solubility of the nicardipine hydrochloride / citric acid solid dispersion in citric acid was significantly higher than that of the nicardipine / polymer solid dispersion in citric acid. Solid dispersions using organic acids as carriers exhibited a higher drug-loading ratio.

[0063] Example 3 Investigation of solvents for preparing solid dispersions

[0064] Using β-nicardipine hydrochloride as a model drug and citric acid as a carrier material, nicardipine-citric acid solid dispersions were prepared using ethanol, 95% ethanol, ethyl acetate, dichloromethane, and methanol as solvents according to the above solvent method. The feasibility of the preparation was investigated and the residual solvent content was determined by gas chromatography. The results are shown in Table 2 below:

[0065] Table 2 Preparation solvent investigation results

[0066]

[0067] Example 4 Preparation and Release Testing of Osmotic Pump Tablets

[0068] Nicardipine hydrochloride (β-crystalline form) and anhydrous citric acid were prepared at a drug-to-carrier ratio (w / w) of 1:0.37 according to the solvent method in Example 1 to prepare a Nicardipine / citric acid solid dispersion. Osmotic pump tablet preparation 1 was prepared according to the formulation 1 listed in Table 3 below.

[0069] Table 3 Tablet composition of prescription 1

[0070] Nic / citric acid solid dispersion 109.6mg citric acid 130.4mg microcrystalline cellulose 160mg PVPK306mg PVPP6mg magnesium stearate 3mg

[0071] Nicardipine hydrochloride (β-crystalline form) and anhydrous citric acid were prepared at a drug-to-carrier ratio (w / w) of 1:0.19 according to the solvent method in Example 1 to prepare a Nicardipine / citric acid solid dispersion. Osmotic pump tablet preparation 2 was prepared according to the formulation 2 listed in Table 4 below.

[0072] Table 4 Tablet composition of prescription 2

[0073] Nic / citric acid solid dispersion 95.2mg citric acid 144.8mg microcrystalline cellulose 160mg PVPK306mg PVPP6mg magnesium stearate 3mg

[0074] The coating composition and preparation method of Formulation 1 and Formulation 2 are the same, as follows.

[0075] Coating composition: The coating liquid is an acetone-water (90:10) mixed solution of Opadry CA with a solid content of 8%

[0076] Preparation method:

[0077] (1) Tablet preparation

[0078] The prescribed amount of materials was weighed, passed through a 100-mesh sieve, sieved and mixed, and 95% ethanol solution was added to prepare a soft material. The granules were sieved with a 30-mesh sieve and dried at 60°C for 1 hour. The granules were sieved with a 30-mesh sieve, and magnesium stearate was added and mixed. The tablets were compressed on a single-punch tablet press with a punch of 10 mm and a hardness of 10 kgf to obtain tablet cores (labeled amount of nicardipine hydrochloride 80 mg).

[0079] (2) Coating and punching

[0080] Preparation of coating solution: 8% coating powder (Opadry CA), 92% solution (including 10% water, 90% acetone), stir with a stirring paddle for more than 4 hours until uniform and nearly clear, and remove dust.

[0081] Coating parameters: hot air 1200rpm; exhaust 2500rpm; coating temperature 28°C; main machine speed 10rpm / min; flow rate 8ml / min; atomizing pressure 0.2MPa; spray gun pressure 0.2MPa.

[0082] Coating by pan coating method: the average coating weight gain is 7.5%, and the tablets are dried and cured in a constant temperature box at 40°C for 12 hours. A drug release hole with a hole diameter of 0.6 mm is punched on one side of the tablet using a laser puncher to obtain 80 mg of nicardipine hydrochloride osmotic pump controlled-release tablets.

[0083] The in vitro release test was conducted using commercially available nicardipine hydrochloride sustained-release tablets (Pel) as the reference preparation. Six tablets of preparation 1, preparation 2, and the reference preparation were taken, and the test was carried out according to the first method of 0931 of the General Rules for Preparations of Part IV of the Chinese Pharmacopoeia 2015. Water was used as the release medium. 5 ml of the solution was collected at 2, 4, 6, 8, 10, 12, and 24 hours, respectively. The solution was filtered through a 0.45 μm filter membrane, and an equal volume of release medium was added at the same temperature. An appropriate amount of the filtrate was taken and tested under the following conditions:

[0084] Chromatographic conditions: chromatographic column Kromasil C18 (250×4.6 mm, 5 μm), mobile phase composed of 0.016 mol / L potassium hydrogen phosphate and potassium dihydrogen phosphate buffer solution (pH 6.8) as the aqueous phase and methanol as the organic phase, aqueous phase:organic phase = 28:72, detection wavelength 236 nm, column temperature 40°C, flow rate 1.0 ml / min, injection volume 20 μL.

[0085] Preparation of control solution: Take an appropriate amount of nicardipine hydrochloride reference substance, add methanol and ultrasonically dissolve it to prepare a reference solution containing 50 μg of nicardipine hydrochloride per 1 ml.

[0086] Sample determination method: Accurately measure the sample solution and reference solution respectively, perform HPLC detection, record the peak area, and calculate the nicardipine hydrochloride content according to the external standard method.

[0087] Cumulative release was calculated based on the sample content at each sampling point, and release curves were plotted. The results are shown in Figure 6. The results show that both Formulations 1 and 2 released the drug completely after 24 hours, with steady release within 12 hours. The commercially available Nic sustained-release capsules showed a significant burst release, with a 24-hour release rate of less than 50%. Compared with the commercially available Nic sustained-release capsules, Formulations 1 and 2 showed complete in vitro release and excellent sustained-release characteristics.

[0088] Example 5 Investigation of different penetration enhancers

[0089] To investigate the release of osmotic pump tablets containing citric acid, lactose, and sodium chloride as penetration enhancers, the microcrystalline cellulose and citric acid in the tablet core of Prescription 1 were replaced with equal weights of citric acid, lactose, and sodium chloride. All other conditions remained the same. Solid dispersions and osmotic pump tablets were prepared according to the preparation method of Prescription 1 in Example 4. The cumulative release of the osmotic pump tablets at different time points was measured according to the method of Example 4. The results ( Figure 7 ) show significant differences in the release curves of the different penetration enhancers (accounting for 69.98% of the total tablet weight). The sodium chloride group showed almost no release over 24 hours, the lactose group had a cumulative release of approximately 20% over 24 hours, and the citric acid group had a cumulative release of greater than 80% over 24 hours.

[0090] Example 6 Investigation of different penetration enhancer combinations

[0091] To investigate the release profiles of osmotic pump tablets containing combinations of citric acid and different penetration enhancers, the solid dispersion and osmotic pump tablets were prepared according to the method of Example 4 for Prescription 1, replacing the microcrystalline cellulose in the tablet core with equal weights of mannitol and lactose monohydrate. All other conditions remained the same. The cumulative release profiles of the osmotic pump tablets were measured at different time points using the method of Example 4. The results ( Figure 8 ) showed similar release profiles for the different penetration enhancer combinations (accounting for 69.98% of the total tablet core weight).

[0092] Example 7 Investigation of the Dosage of Penetration Enhancer

[0093] Following the preparation method of Formulation 1 in Example 4, the total weight of microcrystalline cellulose and citric acid remained unchanged, and the weights of other components remained unchanged. The amount of citric acid, a penetration enhancer, was adjusted to 0%, 12.1%, 22%, 31.3%, 40%, 60%, and 69.98% of the tablet core weight. Release was measured according to the method of Example 4, and release curves were plotted as shown in Figure 9. The results showed that when the penetration enhancer citric acid was used at a 0% ratio, the cumulative release of the osmotic pump tablets over 0-24 hours was less than 80%; when the ratio was 12.1%, the release of the osmotic pump tablets was greater than 65%; and when the ratio was 22%, 31.3%, 40%, 60%, and 70%, the cumulative release of the osmotic pump tablets over 0-24 hours was greater than 80%. During the preparation process, it was found that when the citric acid ratio was 70%, the soft material prepared was too sticky, which was not conducive to the preparation of wet granules.

[0094] Example 8 Ratio of film-forming material to polyethylene glycol in film coating material

[0095] Anhydrous citric acid was used as a carrier, and the weight ratio of drug to carrier was 1:0.19. The solid dispersion was prepared according to the preparation process in Example 1. The tablet cores were prepared according to the prescription 1 in Example 4. The tablet cores were coated according to the following coating composition:

[0096] Coating composition 1: The weight ratio of cellulose acetate to polyethylene glycol is 90:10, and the coating solution is prepared using 90% acetone aqueous solution.

[0097] Coating composition 2: The weight ratio of cellulose acetate to polyethylene glycol is 95:5, and the coating solution is prepared using 90% acetone aqueous solution.

[0098] Coating composition 3: The weight ratio of cellulose acetate to polyethylene glycol is 99:1, and the coating solution is prepared using a 90% acetone aqueous solution.

[0099] The coating weight gain was 7.5%, and tablets with different coating compositions were taken for release test. The results (Figure 10) showed that the 24h cumulative release results of osmotic pump tablets with different coating compositions were consistent, all greater than 80%.

[0100] Example 9 Investigation of coating weight gain

[0101] Osmotic pump tablet cores were prepared according to the method of Recipe 1 in Example 4 and then coated with Opadry CA, with average weight gains of 5%, 7.5%, and 9.5%, respectively. Release was measured and release curves were plotted according to the method of Example 4.

[0102] The results (Figure 11) show that the cumulative release rate of the osmotic pump tablets with a coating weight gain of 9.5% is close to 80% in the 0-24h period; the cumulative release rates of the osmotic pump tablets with a coating weight gain of 5% and 7.5% are very close, both greater than 80%, and the release rate of the osmotic pump tablets with a coating weight gain of 7.5% is more stable in the 0-24h period.

[0103] Example 10 Stability Study

[0104] Preparation 1 prepared in Example 4 was subjected to an influencing factor investigation and an accelerated test to investigate changes in the nicardipine hydrochloride content and related substances in the sample, and to investigate the release rate at different sampling points under accelerated conditions.

[0105] Influencing factor test: Preparation 1 was placed in a sealed clean container and placed at 60°C for 10 days. Samples were taken on the 5th and 10th days to detect the content and related substances.

[0106] Preparation 1 was placed in a sealed container at a constant humidity of 25°C and RH 90±5%. Samples were taken on the 5th and 10th days to detect the content and related substances.

[0107] Take preparation 1, place it in a light box, and place it under the condition of illumination of 4500Lx±500Lx. Take samples on the 5th and 10th days to detect the content and related substances.

[0108] Accelerated test: Take three batches of preparation 1, seal them, place them at 40℃ under dry conditions, and take samples in 1, 2 and 3 months respectively to test the content, related substances and release rate.

[0109] Properties: Visual inspection.

[0110] Determination of content and related substances: Take three tablets of Preparation 1, remove the coating, grind them into powder, take an appropriate amount of powder, accurately weigh it (approximately equivalent to 25 mg of nicardipine hydrochloride), place it in a 50 ml brown volumetric flask, add about 30 ml of methanol, sonicate for 15 minutes to disperse it evenly, let it cool to room temperature, add mobile phase to dilute to the scale, shake well, filter, and take the filtrate for sampling to determine the related substances; accurately transfer 1 ml of the filtrate to a 10 ml brown volumetric flask, dilute to the scale, shake well, and directly sample to determine the Nic content.

[0111] Release Determination: Osmotic pump tablets were assayed according to Method 1, Part IV, General Rules for Preparations, 0931, of the 2015 edition of the Chinese Pharmacopoeia, using water, pH 2.0 solution, and pH 4.0 as release media at 37°C. Filter 5 ml of the solution through a 0.45 μm microporous membrane at 2, 4, 6, 8, 10, 12, and 24 hours. Simultaneously, an equal volume of release medium was added at the same temperature. The filtrate was then collected and the absorption peak area at a wavelength of 236 nm was measured using high-performance liquid chromatography (HPLC) (see below). The release rate of nicardipine hydrochloride from the osmotic pump tablets was calculated using the external standard method.

[0112] Chromatographic conditions: chromatographic column Kromasil C18 (250×4.6 mm, 5 μm), mobile phase composed of 0.016 mol / L potassium hydrogen phosphate and potassium dihydrogen phosphate buffer solution (pH 6.8) as the aqueous phase and methanol as the organic phase, aqueous phase:organic phase = 28:72, detection wavelength 236 nm, column temperature 40°C, flow rate 1.0 ml / min, injection volume 20 μL.

[0113] Preparation of control solution: Take an appropriate amount of nicardipine hydrochloride reference substance, add methanol and ultrasonically dissolve it to prepare a reference substance solution containing 0.5 mg of nicardipine hydrochloride per 1 ml for the determination of related substances; dilute the above solution to a reference substance solution containing 50 μg of nicardipine hydrochloride per 1 ml for the determination of content and release rate.

[0114] Table 5 Sample content and related substance determination results

[0115]

[0116] The results showed that under conditions of high temperature, high humidity and light, the drug content and related substances did not change significantly.

[0117] Table 6 Accelerated test results

[0118]

[0119] The above results show that after 3 months of acceleration, the drug content, related substances and drug release rate of Preparation 1 did not change significantly, and the quality was stable.

[0120] Example 11 Pharmacokinetic Study

[0121] Test drug

[0122] Reference preparation: Nicardipine hydrochloride sustained-release capsules (perdipine, Per), 40 mg / capsule.

[0123] Test preparation: Nicardipine hydrochloride osmotic pump tablets (NicT, preparation 1), 80 mg / tablet.

[0124] Test animals

[0125] Six healthy beagle dogs (half male and half female), weighing 7-10 kg, were divided into two groups: Group A had three dogs, two males and one female; Group B had three dogs, two males and one female.

[0126] Three, two females and one male.

[0127] Medication and blood collection

[0128] Beagle dogs had not been given any drugs for three weeks. They were fasted for 12 hours before drug administration. They were weighed and blood drawn in the morning before drug administration.

[0129] Group A received one Perel Capsule, and Group B received one 80mg NicT tablet, taken with 30ml of water. Care was taken to maintain the integrity of the osmotic pump tablet during administration. At 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after administration, 2ml of blood was collected from a sodium heparin-coated centrifuge tube in Group A. The blood was centrifuged at 3000 rpm for 10 minutes, and the plasma was separated and stored frozen at -70°C. Blood was collected from Group B at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after administration. After a one-week washout period, dosing was crossover (Group A received one 80mg NicT tablet, and Group B received one Perel Capsule).

[0130] Plasma sample pretreatment

[0131] Take 0.2 ml of plasma and place it in a 1.5 ml stoppered centrifuge tube. Add 20 μl of internal standard solution (1.25 μg / ml) and vortex for 40 seconds. Add 0.8 ml of tert-butyl methyl ether and vortex for 4 minutes to mix. Centrifuge at 12000 rpm × 10 minutes. Take the organic layer and place it in another 1.5 ml centrifuge tube. Centrifuge and concentrate at 25°C until evaporated. Redissolve it in 100 μl of mobile phase, vortex and mix. Centrifuge at 12000 rpm × 10 minutes. Take the supernatant and inject it directly. Determine by high performance liquid chromatography-mass spectrometry (HPLC-MS / MS).

[0132] HPLC-MS / MS determination

[0133] Chromatographic conditions: Agilent Eclipse XDB-C18 column (4.6×150 mm, 5 μm); mobile phase: methanol:0.1% formic acid solution, gradient elution, flow rate: 0.6 ml / min, gradient as shown in the table below, stop time: 7 min; post time: 6 min; column temperature: 50°C; injection volume: 5 μl.

[0134] Table 7 Column elution conditions

[0135] Time (min) Methanol (%) 0.1% formic acid aqueous solution (%) 07030495569556.017030

[0136] Mass spectrometry conditions: An ESI+ source was used with a drying gas flow rate of 9 L / min, a drying gas temperature of 300°C, and a capillary voltage of 5500 V. Primary and secondary mass spectrometry analysis was performed in MRM mode. The following ions were used for quantitative and qualitative analysis: F = 140, CE = 20, nicardipine hydrochloride [M+H]+ m / z 480.2 → 315.1 (quantitative), m / z 480.2 → 148.0 (qualitative); F = 80, CE = 20, internal standard nimodipine [M+H]+ m / z 419.0 → 301.1 (quantitative), m / z 419.0 → 343.0 (qualitative).

[0137] Test results

[0138] Based on the measured blood drug concentrations, a concentration-time curve was plotted (Figure 12). The results showed that the blood drug concentration of Perel in beagle dogs fluctuated between 0 and 20 ng / ml, showing a bimodal curve. The blood drug concentration of Formulation 1 (80 mg) fluctuated between 0 and 15 ng / ml, showing a unimodal curve. The blood drug concentration was relatively stable, indicating that it has a controlled release effect within 2 to 10 hours in beagle dogs.

[0139] The main pharmacokinetic parameters calculated by the statistical moment method are shown in Table 8.

[0140] Table 8 Pharmacokinetic parameters of Nic at different doses

[0141]

[0142] The data show that compared with the commercially available Perl sustained-release capsules, Formulation 1 achieved a delayed peak Tmax in beagle dogs (from 1 / 3 hour to approximately 7 hours), a more gradual blood concentration, and a significantly prolonged mean residence time (MRT), demonstrating controlled-release characteristics. Bioavailability was significantly improved.

[0143] Comparative Example 1 Comparison of the release rate of osmotic pump tablets prepared with Nic solid dispersion and Nic raw material

[0144] Osmotic pumps (Groups 1 and 2) were prepared using nicardipine hydrochloride (α and β crystal forms) as raw materials according to the following formula. At the same time, nicardipine hydrochloride (α and β crystal forms) and anhydrous citric acid were taken at a drug-to-carrier ratio (w / w) of 1:0.37. According to the method in Example 1, a Nic / citric acid solid dispersion was first prepared, and then osmotic pumps (Groups 3 and 4) were prepared according to the following formula. The release curves of the four groups of samples were measured according to the method in Example 4, as shown in Figure 13.

[0145] Table 9 Comparative Example Prescription

[0146]

[0147] The results in Figure 13 show that the release rates of ordinary single-layer osmotic pump tablets prepared with α-crystalline and β-crystalline raw materials are both lower than 25%; while the release rate of improved single-layer osmotic pump tablets prepared with the corresponding citric acid solid dispersion as the intermediate carrier reaches 80%.

[0148] The present invention has been described above with reference to preferred embodiments, but these embodiments are merely exemplary and serve only as illustrations. On this basis, various replacements and improvements can be made to the present invention, all of which fall within the scope of protection of the present invention.

Claims

1. An osmotic pump controlled-release tablet of a poorly soluble drug, characterized in that, the osmotic pump controlled-release tablet comprises a tablet core, a semipermeable membrane coating and a drug release hole, the tablet core contains a poorly soluble drug solid dispersion and a penetration enhancer, and the poorly soluble drug solid dispersion contains a poorly soluble drug and a carrier; the poorly soluble drug is selected from nicardipine, nifedipine, felodipine and their pharmaceutically acceptable salts, and the carrier is selected from organic acid substances.

2. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 1, characterized in that, the penetration enhancer is selected from organic acid substances or a combination of any one or more of organic acid substances and sodium chloride, mannitol, lactose.

3. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 1 or 2, characterized in that, the organic acid substances are selected from citric acid, fumaric acid, succinic acid, tartaric acid, cholic acid, lecithin or deoxycholic acid.

4. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 3, characterized in that, the organic acid substances are selected from citric acid, fumaric acid or succinic acid.

5. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 3, characterized in that, the organic acid substance is citric acid.

6. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 1, characterized in that, the penetration enhancer is citric acid.

7. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 1, characterized in that, the poorly soluble drug is nicardipine.

8. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 7, characterized in that, the poorly soluble drug is α-crystalline nicardipine, β-crystalline nicardipine or a mixed crystal of both.

9. The osmotic pump controlled-release tablet of a poorly soluble drug according to any one of claims 1, 7-8, characterized in that, the weight ratio of the poorly soluble drug to the carrier in the solid dispersion is 1:(0.1-1).

10. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 9, characterized in that, the weight ratio of the poorly soluble drug to the carrier in the solid dispersion is 1:(0.1-0.8).

11. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 9, characterized in that, the weight ratio of the poorly soluble drug to the carrier in the solid dispersion is 1:(0.15-0.6).

12. The osmotic pump controlled-release tablet of a poorly soluble drug according to any one of claims 1-6, characterized in that, the penetration enhancer accounts for 10-70% of the total weight of the tablet core.

13. The osmotic pump controlled-release tablet of a poorly soluble drug according to claim 12, characterized in that, the penetration enhancer accounts for 20-60% of the total weight of the tablet core.

14. A poorly soluble drug solid dispersion, characterized in that, it contains a poorly soluble drug and a carrier material; the poorly soluble drug is selected from nicardipine, nifedipine, felodipine and their pharmaceutically acceptable salts, and the carrier material is selected from organic acid substances.

15. The poorly soluble drug solid dispersion according to claim 14, characterized in that, the organic acid substances are selected from citric acid, fumaric acid, succinic acid, tartaric acid, cholic acid, lecithin or deoxycholic acid.

16. The poorly soluble drug solid dispersion according to claim 14, wherein, the organic acid substances are selected from citric acid, fumaric acid or succinic acid.

17. The poorly soluble drug solid dispersion according to claim 14, wherein, the organic acid substance is citric acid.

18. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to any one of claims 1-13, comprising the following steps: a) preparing a poorly soluble drug solid dispersion by a solvent method; b) mixing the solid dispersion with a penetration enhancer, and optionally adding an appropriate amount of other excipients; c) directly tabletting or granulating and then pressing the tablet core; d) coating an outer semi-permeable membrane and punching holes by laser or mechanically.

19. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to claim 18, wherein, the steps of the solvent method include: dissolving the drug and the carrier in an organic solvent, removing the organic solvent under reduced pressure until foaming, rotary evaporation, sieving, and vacuum drying to obtain; the organic solvent is selected from ethanol, methanol, and tert-butanol.

20. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to claim 19, wherein, the organic solvent is methanol.

21. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to claim 18, wherein, the steps of the solvent method include: dissolving the drug and the carrier in an organic solvent, spray drying to remove the organic solvent, and vacuum drying to obtain, the organic solvent is selected from ethanol, methanol, and tert-butanol.

22. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to claim 21, wherein, the organic solvent is methanol.

23. The preparation method of the osmotic pump controlled release tablet of the poorly soluble drug according to claim 18, wherein, the steps of the solvent method include: dissolving the drug and the carrier in an organic solvent, and removing the organic solvent by freeze-drying method to obtain, the organic solvent is tert-butanol.

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