Diclofenac sodium pharmaceutical preparation as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal preparations, and provides a diclofenac sodium medicinal preparation as well as a preparation method and application thereof. The diclofenac sodium pharmaceutical preparation is prepared from the following components in parts by weight: 1 to 10 parts of diclofenac sodium, 5 to 10 parts of cationic lipid, 1 to 5 parts of PEGylated lipid and 0.1 to 5 parts of a surfactant. The active component diclofenac sodium in the pharmaceutical preparation is delivered through liposome, so that the preparation is endowed with a better transdermal absorption effect; meanwhile, an excellent controlled release effect is achieved, so that the blood concentration is more stable, and the liposome microcapsule is encapsulated, so that the stimulation to the stomach and intestine is effectively reduced, and the compliance of a patient can be effectively improved; the pharmaceutical preparation not only can be prepared into an external transdermal patch, but also can be prepared into an oral controlled-release preparation, and is wide in application.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and provides a diclofenac sodium pharmaceutical preparation, a preparation method thereof, and an application thereof. Background Art

[0002] Diclofenac sodium is a non-steroidal anti-inflammatory drug, which is mainly used in clinical practice for the treatment of rheumatoid arthritis and rheumatoid arthritis, and also has certain curative effects on some diseases such as osteoarthritis, mild to moderate pain, primary dysmenorrhea, fever, bursitis, and acute gout. Oral drugs are likely to cause gastrointestinal reactions. On the one hand, sustained-release preparations can be prepared to effectively control the drug release rate and reduce the gastrointestinal, liver, and kidney adverse reactions caused by high blood drug concentrations; on the other hand, transdermal drug delivery methods can also be used to eliminate its irritation to the gastrointestinal tract. However, transdermal absorption is restricted by the stratum corneum, and the transdermal rate is relatively small, so penetration enhancement technology is required to improve the transdermal drug release effect.

[0003] Currently, regarding the diclofenac sodium sustained-release preparation, Chinese Patent Application No. CN119112821A discloses a diclofenac sodium sustained-release tablet and a preparation method thereof, which include the following components: diclofenac sodium, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, mannitol, organic acid salts, glidants, and lubricants. Through the improvement of excipients, the stable release of the active ingredient is achieved, and the sustained-release effect is excellent, and a 24-hour sustained-release effect can be achieved.

[0004] For diclofenac sodium patches, chemical penetration enhancers are mainly used to improve the transdermal effect. Currently, chemical penetration enhancers include organic solvents (such as ethanol, propylene glycol, fatty acid esters, etc.), organic acids / fatty alcohols (such as oleic acid, linoleic acid, lauryl alcohol, etc.), azone and its derivatives, surfactants (such as cationic, anionic, non-ionic surfactants, Tweens, Spans, etc.), horny moisturizers and softeners (such as urea, salicylic acid, etc.), and terpenes (such as menthol, limonene, camphor, etc.). For example, Chinese Patent Application Nos. CN1489996A, CN107669661A, CN113813370A, etc. all use the above chemical penetration enhancers to prepare diclofenac sodium patches. The local drug concentration at the patch application site is much higher than the blood drug concentration, with a long action time and no irritation. However, direct transdermal drug delivery still has problems such as fast drug release and short maintenance time, which in turn lead to large irritation, and is thus restricted to a certain extent in clinical use.

[0005] Flexible nano-liposomes are a new type of transdermal drug delivery carrier. They can not only achieve the sustained-release effect of drugs, but also effectively improve the transdermal absorption effect of macromolecular drugs and enhance drug utilization. The prior art (Fan Rong, Liang Qinghua, Wang Juan, Tang Tao, Xiong Xingui, Chen Jiang. Effect of transdermal absorption of diclofenac sodium by flexible nano-liposomes [J]. Journal of Clinical Rehabilitative Tissue Engineering Research, 2007, 11(22): 4355-4358) has disclosed that liposomes can increase the humidification and hydration of the stratum corneum, change the structure between keratinocytes, disorder the arrangement of hydrophobic tails in the lipid bilayer, and drugs enter the intercellular matrix through diffusion and other effects. At the same time, the phospholipids of liposomes fuse with the lipid layer in the epidermal lipid barrier, changing the lipid composition and structure of the stratum corneum to form a flat granular structure, reversing its barrier function, and liposomes encapsulating drugs can smoothly pass through the gaps between these lipid particles, thus promoting the transdermal absorption of drugs. In addition, liposomes can enter the deep skin and subcutaneous tissues through sebaceous glands, sweat glands, hair follicles or even directly penetrate the stratum corneum of the skin to achieve transdermal effects.

[0006] However, when using liposomes as a carrier to encapsulate diclofenac sodium for transdermal drug delivery, its drug release effect is unknown. If it can achieve a sustained-release or even controlled-release effect while increasing the transdermal effect, it is expected to be applied to transdermal patches and oral sustained-release preparations at the same time, which is of great significance for expanding the application of diclofenac sodium drug preparations. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention provides a diclofenac sodium drug preparation, its preparation method and application. The diclofenac sodium of the present invention uses a cationic lipid combined with a PEGylated lipid composite liposome as a delivery carrier. The prepared preparation has excellent transdermal absorption effect and sustained-release and controlled-release effects, with excellent comprehensive performance, and can be used for oral sustained-release preparations or transdermal patches, and has a wide range of applications.

[0008] The present invention is realized by the following scheme: One aspect of the present invention is to provide a diclofenac sodium drug preparation, which includes, by mass fraction: 0.5-2 parts of diclofenac sodium, 5-10 parts of cationic lipid, 1-5 parts of PEGylated lipid, and 0.01-0.5 parts of cationic surfactant; The cationic lipid is one or more of trimethyl-2,3-dioleyloxypropylammonium chloride (DOTMA), trimethyl-2,3-dioleyloxypropylammonium bromide (DOTPA), dimethyl-2,3-dioleyloxypropyl-2-(2-sperminecarboxamido)ethylammonium trifluoroacetate (DOSPA), dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide (DORI), dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide (DORIE), dimethyl-3-hydroxypropyl-2,3-dioleyloxypropylammonium bromide (DORIE-HP), dimethyl-4-hydroxybutyl-2,3-dioleyloxypropylammonium bromide (DORIE-HB), and dimethyl-5-hydroxypentyl-2,3-dioleyloxypropylammonium bromide (DORIE-HPc).

[0009] The PEGylated lipid is one or more of dimyristoyl phosphatidylcholine polyethylene glycol (DMPC-mPEG), dipalmitoyl phosphatidylcholine polyethylene glycol (DPPC-mPEG), distearoyl phosphatidylcholine polyethylene glycol (DSPC-mPEG), dimyristoyl phosphatidyl polyethylene glycol (DMPE-mPEG), dipalmitoyl phosphatidyl polyethylene glycol (DPPE-mPEG), and distearoyl phosphatidyl polyethylene glycol (DSPE-mPEG).

[0010] In some preferred embodiments of the present invention, the cationic lipid is trimethyl-2,3-dioleyloxypropylammonium bromide and / or dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide.

[0011] Compared with the cationic lipid containing an oleoxy group, the diclofenac sodium liposome preparation prepared using the cationic lipid containing an acyloxy group has a more suitable sustained-release effect, which may depend on the presence of the olefin unsaturated bond and the cis-trans isomerization thereof, which affects the permeability of the lipid membrane. Although the sustained-release effect is good, the initial release is too slow, resulting in an extended onset time. To achieve a better controlled-release effect, the cationic lipid is preferably trimethyl-2,3-dioleyloxypropylammonium bromide and / or dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide containing an acyloxy group.

[0012] In some preferred embodiments of the present invention, the PEGylated lipid is one or more of DMPC-mPEG, DPPC-mPEG, and DSPC-mPEG.

[0013] Preferably, the cationic surfactant is one or more of dodecyl trimethyl ammonium chloride (DTAC), dodecyl trimethyl ammonium bromide (DTAB), dodecyl dimethyl benzyl ammonium chloride (DDBAC), tetradecyl trimethyl ammonium chloride (TTAC), tetradecyl trimethyl ammonium bromide (TTAB), tetradecyl dimethyl benzyl ammonium chloride (TDBAC), cetyl trimethyl ammonium chloride (CTAC), cetyl trimethyl ammonium bromide (CTAB), and cetyl dimethyl benzyl ammonium chloride (16-BAC).

[0014] In some preferred embodiments of the present invention, the diclofenac sodium pharmaceutical preparation further comprises: sucrose octasulfate. As an auxiliary lipid, sucrose octasulfate is used in combination with cationic lipid and PEGylated lipid, which can not only improve the stability of liposome particles, but also improve the encapsulation efficiency of liposomes for the active pharmaceutical ingredient.

[0015] More preferably, the mass ratio of the cationic lipid, PEGylated lipid to sucrose octasulfate is 1:0.5 - 1:0.05 - 0.5.

[0016] The second aspect of the present invention is to provide a preparation method of the diclofenac sodium pharmaceutical preparation described above, which specifically comprises the following steps: (1) Add the cationic lipid and PEGylated lipid to an organic solvent, with or without sucrose octasulfate, and dissolve them thoroughly to obtain a mixed lipid solution; (2) Remove the organic solvent from the mixed lipid solution to form a lipid film; (3) Take diclofenac sodium and a surfactant and dissolve them in physiological saline or buffer solution. After dissolution, add them to the lipid film and hydrate to obtain a liposome suspension; (4) Perform ultrasonic micronization treatment on the liposome suspension and dry it to obtain the product.

[0017] Further, the total amount of the cationic lipid, PEGylated lipid and / or sucrose octasulfate in the mixed lipid solution is 0.5 - 2.5 g / mL; the concentration of diclofenac sodium in physiological saline or buffer solution is 0.01 - 0.5 g / mL.

[0018] Further, the organic solvent is selected from one or more of methanol, tert-butanol, chloroform, and cyclohexane.

[0019] Further, in step (3), the hydration temperature is 50 - 70 °C and the hydration time is 40 - 60 min.

[0020] The third aspect of the present invention is to provide the application of the diclofenac sodium pharmaceutical preparation described above or the diclofenac ammonium preparation prepared by the preparation method described above in the preparation of drugs for treating arthritis.

[0021] Furthermore, the arthritis includes any one of osteoarthritis, rheumatoid arthritis and rheumatoid arthritis.

[0022] Furthermore, the drug is any one of an oral sustained-release preparation or an external transdermal patch.

[0023] Compared with the prior art, the present invention has the following beneficial effects: (1) The positively charged cationic liposomes and cationic surfactants in the diclofenac sodium lipid delivery system of the present invention have stronger affinity with the negatively charged skin and can be taken up by cells more quickly, thereby improving the transdermal performance of the flexible liposomes; further, the PEG-modified lipids are used to improve the stability of the liposome particles, and through stable encapsulation, the transdermal effect and sustained-release effect are simultaneously improved; (2) The present invention further optimizes the cationic lipids to enable the preparation to exert a more excellent controlled release effect, which is beneficial to the stability of blood drug concentration and thus improves patient compliance; (3) The present invention, in combination with specific auxiliary lipids, also effectively improves the encapsulation effect of the active ingredients of the drug, providing a prerequisite for achieving long-term efficacy and controlled release; (4) The preparation process of the diclofenac sodium nanolipid preparation of the present invention is simple and efficient; and a high encapsulation rate can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The dissolution curves of the diclofenac sodium pharmaceutical preparations of each embodiment and the control preparation; Figure 2 The dissolution curves of the diclofenac sodium pharmaceutical preparations of each comparative example and Example 6 are shown. DETAILED DESCRIPTION

[0025] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0026] Example 1 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 5 g of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide and 5 g of DMPC-mPEG and add them to 20 mL of a methanol / chloroform (V / V=1:1) mixed solvent and fully dissolve them to obtain a mixed lipid solution; (2) removing the solvent from the mixed lipid solution by rotary evaporation at 60°C to form a lipid film; (3) Take 2 g of diclofenac sodium and 0.05 g of tetradecyltrimethylammonium chloride, dissolve them in 20 mL of physiological saline. After dissolution, add a lipid membrane and hydrate at 50 °C for 60 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0027] Example 2 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 7 g of trimethyl-2,3-dioleyloxypropylammonium bromide and 3 g of DPPC-mPEG, add them to 10 mL of chloroform solvent, and dissolve them fully to obtain a mixed lipid solution; (2) Rotate and evaporate to remove the solvent in the mixed lipid solution at 60 °C to form a lipid membrane; (3) Take 2 g of diclofenac sodium and 0.2 g of cetyltrimethylammonium bromide, dissolve them in 40 mL of physiological saline. After dissolution, add a lipid membrane and hydrate at 60 °C for 50 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0028] Example 3 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 9 g of dimethyl-5-hydroxyamyl-2,3-dioleoyloxypropylammonium bromide and 1 g of DSPC-mPEG, add them to 5 mL of a mixed solvent of tert-butanol / cyclohexane (V / V = 4:1), and dissolve them fully to obtain a mixed lipid solution; (2) Rotate and evaporate to remove the solvent in the mixed lipid solution at 60 °C to form a lipid membrane; (3) Take 2 g of diclofenac sodium and 0.01 g of dodecyltrimethylammonium bromide, dissolve them in 10 mL of physiological saline. After dissolution, add a lipid membrane and hydrate at 70 °C for 40 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0029] Example 4 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 5 g of dimethyl-5-hydroxyamyl-2,3-dioleoyloxypropylammonium bromide and 5 g of DMPC-mPEG, add them to 20 mL of a mixed solvent of methanol / chloroform (V / V = 1:1), and dissolve them fully to obtain a mixed lipid solution; (2) Rotate and evaporate to remove the solvent in the mixed lipid solution at 60 °C to form a lipid film; (3) Take 2 g of diclofenac sodium and 0.05 g of tetradecyltrimethylammonium chloride, dissolve them in 20 mL of physiological saline. After dissolution, add to the lipid film and hydrate at 50 °C for 50 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0030] Example 5 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 5 g of dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide and 5 g of DMPE-mPEG, add them to 20 mL of a methanol / chloroform (V / V = 1:1) mixed solvent, and dissolve them thoroughly to obtain a mixed lipid solution; (2) Rotate and evaporate to remove the solvent in the mixed lipid solution at 60 °C to form a lipid film; (3) Take 2 g of diclofenac sodium and 0.05 g of tetradecyltrimethylammonium chloride, dissolve them in 20 mL of physiological saline. After dissolution, add to the lipid film and hydrate at 50 °C for 50 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0031] Example 6 A diclofenac sodium pharmaceutical preparation, the preparation method is as follows: (1) Take 5 g of dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide, 5 g of DMPC-mPEG and 0.2 g of sucrose octasulfate, add them to 20 mL of a methanol / chloroform (V / V = 1:1) mixed solvent, and dissolve them thoroughly to obtain a mixed lipid solution; (2) Rotate and evaporate to remove the solvent in the mixed lipid solution at 60 °C to form a lipid film; (3) Take 2 g of diclofenac sodium and 0.05 g of tetradecyltrimethylammonium chloride, dissolve them in 20 mL of physiological saline. After dissolution, add to the lipid film and hydrate at 50 °C for 60 min to obtain a liposome suspension; (4) Subject the liposome suspension to ultrasonic (250 W) micronization treatment for 20 min, filter through a 0.22 μm filter membrane, and freeze-dry to obtain the product.

[0032] Comparative Example 1 Compared with Example 6, the difference is only that DMPC-mPEG is not added, and the dosage of dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide is adjusted to 10 g.

[0033] Comparative Example 2 Compared with Example 6, the difference is only that dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide is not added, and the dosage of DMPC-mPEG is adjusted to 10 g.

[0034] Comparative Example 3 Compared with Example 6, the difference is only that dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide is replaced with an equal amount of dimethyldioctadecylammonium bromide.

[0035] Comparative Example 4 Compared with Example 6, the difference is only that the cationic surfactant tetradecyltrimethylammonium chloride is not contained, and the dosage of dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide is adjusted to 5.05 g.

[0036] Comparative Example 5 Compared with Example 6, the difference is only that the dosage of dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide is adjusted to 4 g, and the dosage of DMPC-mPEG is adjusted to 6 g.

[0037] Test Example 1 The diclofenac sodium pharmaceutical preparations prepared in Examples 1-6 and Comparative Examples 1-5 were characterized as follows: (1) Encapsulation efficiency: 0.5 g of the freeze-dried diclofenac sodium pharmaceutical preparation was added to 10 mL of a methanol / chloroform (V / V = 1:1) mixed solvent and dissolved completely, and then the total drug concentration was measured. Then, centrifugation was carried out at 4 °C and 100,000 rpm for 2 h. The supernatant was taken to measure the drug content in the supernatant, which was the free drug concentration. Encapsulation efficiency (%) = (1 - free drug concentration) / total drug concentration.

[0038] The drug concentration was measured by high performance liquid chromatography, and the chromatographic conditions were as follows: Chromatographic column: LBondapak C18 (300 mm × 3.9 mm, 10 μm); mobile phase: methanol-water-glacial acetic acid (66:34:36); flow rate: 1.0 mL / min; detection wavelength: 281 nm; column temperature: 2 °C.

[0039] (2) Particle size: 0.5 mg of the freeze-dried diclofenac sodium pharmaceutical preparation was added to 2 mL of deionized water, and it was oscillated to disperse it completely, and then its particle size and polydispersity index PDI were measured by a particle size analyzer.

[0040] The above characterization results are shown in Table 1.

[0041] Table 1 Results of lipid encapsulation efficiency, particle size and PDI of diclofenac sodium ( , n = 3)

[0042] Note: Compared with Example 6, * P <0.05, ** P <0.01, *** P <0.005.

[0043] It can be seen from the above table that the diclofenac sodium prepared in the examples of the present invention achieved an encapsulation efficiency of more than 97%. Although some of the comparative examples also achieved a comparable encapsulation effect, the particle size was relatively large and the polydispersity coefficient was higher. Due to the particle size difference, the transdermal effect became worse and the dissolution became slower.

[0044] Test Example 2 The transdermal effect of the diclofenac sodium pharmaceutical preparation was verified by an in vitro transdermal test. The specific method is as follows: (1) Preparation of excised rat skin: The abdominal hair of SD rats (body weight 180 - 200 g) was removed with an 80 g / L sodium sulfide solution, the skin was washed with physiological saline, and the rats were naturally raised for 24 h. They were sacrificed after anesthesia before the experiment the next day. The abdominal skin was dissected and the subcutaneous fat and tissues were separated. The intact skin was selected and soaked in physiological saline, and stored in the refrigerator at 12 h for later use; (2) Transdermal diffusion test: The rat skin was placed in a Franz diffusion cell (effective diffusion area: 2.8 cm 2 , thickness about 600 μm), with the stratum corneum facing the supply chamber and the dermis facing the receiving chamber. The receiving solution was 30 mL of physiological saline, and the constant temperature water bath was (37 ± 1) °C, and the rotation speed of the magnetic stirrer was 100 rpm. The diclofenac sodium prepared in each example and comparative example was redissolved with methanol / chloroform (V / V = 1:1) to prepare a solution containing 2 mg of diclofenac sodium, which was evenly coated on the surface of the stratum corneum. Samples of 1 mL were taken from the receiving chamber at 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h (while supplementing 1 mL of physiological saline at the same temperature), filtered through a 0.45 μm microporous filter membrane, and the concentration of diclofenac sodium was determined by high performance liquid chromatography. The transdermal permeation rate and cumulative permeation amount were calculated. The results are shown in Table 2.

[0045] Table 2 In vitro transdermal effect of diclofenac sodium pharmaceutical preparation ( , n = 3)

[0046] Note: Compared with Example 6, * P <0.05, ** P <0.01, *** P <0.005.

[0047] As can be seen from the above table, in Examples 1-5, the diclofenac sodium pharmaceutical preparations prepared by the combined use of cationic lipid and PEGylated lipid have excellent transdermal properties. In Example 6, the auxiliary lipid is further increased, and the transdermal effect is further improved. Compared with Example 6, in Comparative Examples 1 and 2, when there is only cationic lipid or PEGylated lipid, the effect significantly decreases, indicating that the two have a significant synergistic effect in improving the transdermal property of diclofenac sodium.

[0048] Test Example 3 According to the "Chinese Pharmacopoeia" 2020 edition, according to the dissolution and release determination method (General Rule 0931, Method 1), using pH 6.8 phosphate buffer solution as the dissolution medium, the rotation speed is 100 rpm, the medium temperature is 37±5°C, 1 mL of samples are taken at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h and 24 h respectively, filtered through a 0.45 μm microporous filter membrane, and the same temperature and the same volume of release medium are replenished in time. The content of diclofenac sodium in the dissolution medium of the diclofenac sodium pharmaceutical preparations and the control preparation (commercially available diclofenac sodium sustained-release tablets) prepared in each example and comparative example was tested by high performance liquid chromatography (the specific conditions are the same as those in Test Example 1), and the cumulative dissolution was calculated. The results are shown in Table 3; the dissolution curve is shown in Figure 1 and Figure 2 .

[0049] Table 3 Dissolution of Diclofenac Sodium Pharmaceutical Preparations

[0050] From the above table and Figure 1 、 Figure 2 it can be seen that the diclofenac sodium pharmaceutical preparation prepared by the present invention can achieve the sustained-release effect of the control preparation (diclofenac sodium sustained-release tablets). Compared with the control preparation, the dissolution curve of the diclofenac sodium prepared by the present invention is more inclined to a constant rate, achieving a controlled release effect while ensuring a long-acting release for 24 h. At the same time, the inventor also found that compared with the cationic lipid containing acyloxy group, although the cationic lipid containing alkenyloxy group also has a comparable sustained-release effect, the release is slower in the early stage (before 12 h), and the onset of action is slow.

[0051] In addition, compared with Example 6, the sustained-release effects of Comparative Examples 2 and 3 become worse. It can be seen that the presence of cationic lipid and its specific type have a great influence on the sustained-release effect of the diclofenac sodium pharmaceutical preparation.

[0052] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art does not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A diclofenac sodium pharmaceutical preparation, characterized in that: The components include, by weight: 0.5-2 parts of diclofenac sodium, 5-10 parts of cationic lipid, 1-5 parts of PEGylated lipid and 0.01-0.5 parts of cationic surfactant; The cationic lipid is one or more of trimethyl-2,3-dioleyloxypropylammonium chloride, trimethyl-2,3-dioleyloxypropylammonium bromide, dimethyl-2,3-dioleyloxypropyl-2-(2-sperminecarboxamido)ethylammonium trifluoroacetate, dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide, dimethyl-2-hydroxyethyl-2,3-dioleyloxypropylammonium bromide, dimethyl-3-hydroxypropyl-2,3-dioleyloxypropylammonium bromide, dimethyl-4-hydroxybutyl-2,3-dioleyloxypropylammonium bromide and dimethyl-5-hydroxypentyl-2,3-dioleyloxypropylammonium bromide; The PEGylated lipid is one or more of DMPC-mPEG, DPPC-mPEG, DSPC-mPEG, DMPE-mPEG, DPPE-mPEG and DSPE-mPEG.

2. The diclofenac sodium pharmaceutical preparation according to claim 1, characterized in that The cationic lipid is trimethyl-2,3-dioleoyloxypropylammonium bromide and / or dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide; The PEGylated lipid is one or more of DMPC-mPEG, DPPC-mPEG and DSPC-mPEG.

3. The diclofenac sodium pharmaceutical preparation according to claim 1, characterized in that The surfactant is one or more of dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyldimethylbenzylammonium chloride, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyldimethylbenzylammonium chloride, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide and hexadecyldimethylbenzylammonium chloride.

4. The diclofenac sodium pharmaceutical preparation according to any one of claims 1 to 3, characterized in that: The diclofenac sodium pharmaceutical preparation also includes: sodium sucrose octasulfate.

5. The diclofenac sodium pharmaceutical preparation according to claim 4, characterized in that: The mass ratio of the cationic lipid, the PEGylated lipid and sodium sucrose octasulfate is 1:0.5-1:0.05-0.

5.

6. The method for preparing the diclofenac sodium pharmaceutical preparation according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) adding cationic lipids and PEGylated lipids into an organic solvent, and adding or not adding sodium sucrose octasulfate, and fully dissolving them to obtain a mixed lipid solution; (2) removing the organic solvent from the mixed lipid solution to form a lipid film; (3) dissolving diclofenac sodium and a surfactant in physiological saline or a buffer solution, adding a lipid film after dissolution to hydrate the film to obtain a liposome suspension; (4) The liposome suspension is subjected to ultrasonic micronization treatment and dried to obtain the liposome suspension.

7. The preparation method according to claim 6, characterized in that: The total concentration of cationic lipids, PEGylated lipids and / or sodium sucrose octasulfate in the mixed lipid solution is 0.5-2.5 g / mL; the concentration of diclofenac sodium in physiological saline or buffer is 0.01-0.5 g / mL; and the organic solvent is selected from one or more of methanol, tert-butanol, chloroform and cyclohexane.

8. The preparation method according to claim 6, characterized in that: In step (3), the hydration temperature is 50-70°C and the hydration time is 40-60 minutes.

9. Use of the diclofenac sodium pharmaceutical preparation according to any one of claims 1 to 5 or the diclofenac ammonium preparation prepared by the preparation method according to any one of claims 6 to 8 in preparing a drug for treating arthritis, characterized in that: The arthritis includes any one of osteoarthritis, rheumatoid arthritis and rheumatoid arthritis.

10. The use according to claim 9, characterized in that: The drug is any one of an internal sustained-release preparation and an external transdermal patch.

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