A pharmaceutical preparation of diclofenac sodium and a preparation method and application thereof

Abstract

The present application relates to the technical field of pharmaceutical preparations, and provides a diclofenac sodium pharmaceutical preparation, a preparation method and application thereof.The diclofenac sodium pharmaceutical preparation comprises, in terms of weight fraction, 1-10 parts of diclofenac sodium, 5-10 parts of cationic lipids, 1-5 parts of PEGylated lipids and 0.1-5 parts of a surfactant.The active ingredient diclofenac sodium in the pharmaceutical preparation is delivered by liposomes, which endows the preparation with better transdermal absorption effect;at the same time, the pharmaceutical preparation also has excellent controlled release effect, so that the blood drug concentration is more stable, and the diclofenac sodium is encapsulated in the liposome microcapsules, which effectively reduces the stimulation to the gastrointestinal tract and can effectively improve the patient compliance; the pharmaceutical preparation can be prepared into not only an external transdermal patch, but also an oral controlled release preparation, and has wide application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and provides a diclofenac sodium pharmaceutical formulation, its preparation method, and its application. Background Technology

[0002] Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) primarily used clinically to treat rheumatoid arthritis and osteoarthritis. It also shows some efficacy in treating other conditions such as osteoarthritis, mild to moderate pain, primary dysmenorrhea, fever, bursitis, and acute gout. Oral administration can easily cause gastrointestinal reactions. On the one hand, sustained-release formulations can be developed to effectively control the drug release rate and reduce gastrointestinal, hepatic, and renal adverse reactions caused by high blood drug concentrations. On the other hand, transdermal administration can be used to eliminate gastrointestinal irritation. However, transdermal absorption is limited by the stratum corneum, resulting in a relatively low transdermal rate. Therefore, permeation-enhancing techniques are needed to improve the transdermal drug release effect.

[0003] Currently, regarding diclofenac sodium sustained-release formulations, Chinese invention patent application number CN119112821A discloses a diclofenac sodium sustained-release tablet and its preparation method, comprising the following components: diclofenac sodium, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, mannitol, organic acid salts, gliding agent, and lubricant. Through the improvement of excipients, it achieves stable release of active ingredients and excellent sustained-release effect, which can reach a sustained-release effect of 24 hours.

[0004] Diclofenac sodium patches primarily utilize chemical penetration enhancers to improve transdermal efficacy. These chemical penetration enhancers currently include organic solvents (such as ethanol, propylene glycol, and fatty acid esters), organic acids / fatty alcohols (such as oleic acid, linoleic acid, and lauryl alcohol), azones and their derivatives, surfactants (such as cationic, anionic, and nonionic surfactants, Tween and Span surfactants), keratin moisturizers and softeners (such as urea and salicylic acid), and terpenes (such as menthol, limonene, and camphor). Chinese invention patent applications CN1489996A, CN107669661A, and CN113813370A all employ these chemical penetration enhancers to prepare diclofenac sodium patches. The local drug concentration at the application site is significantly higher than the blood drug concentration, resulting in a longer duration of action and less irritation. However, direct transdermal administration also presents challenges such as rapid drug release, short duration of action, and consequently, high irritation, limiting its clinical application.

[0005] Flexible nanoliposomes are a novel transdermal drug delivery carrier that can not only achieve sustained drug release but also effectively improve the transdermal absorption of macromolecular drugs and enhance drug utilization. Existing technology (Fan Rong, Liang Qinghua, Wang Juan, Tang Tao, Xiong Xingui, Chen Jiang. Effect of flexible nanoliposomes on transdermal absorption of diclofenac sodium [J]. Chinese Journal of Tissue Engineering Research and Clinical Rehabilitation, 2007, 11(22): 4355-4358) discloses that liposomes can increase the humidification and hydration of the stratum corneum, change the structure between keratinocytes, and disrupt the arrangement of hydrophobic tails in the lipid bilayer, allowing drugs to enter the intercellular matrix through diffusion and other mechanisms; 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 allowing liposomes encapsulated with drugs to pass smoothly through the gaps between these lipid particles, thereby promoting transdermal drug absorption; in addition, liposomes can penetrate the stratum corneum through sebaceous glands, sweat glands, hair follicles, or even directly into the deep layers of the skin and subcutaneous tissue to achieve transdermal effects.

[0006] However, the drug release effect of diclofenac sodium when encapsulated and administered transdermally using liposomes is still unknown. If sustained or even controlled release can be achieved while increasing transdermal effect, it is expected to be applied to both transdermal patches and oral sustained-release formulations, which is of great significance for expanding the application of diclofenac sodium drug formulations. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a diclofenac sodium pharmaceutical formulation, its preparation method, and its application. The diclofenac sodium of this invention uses cationic lipids combined with PEGylated lipid complex liposomes as a delivery carrier. The resulting formulation has excellent transdermal absorption and sustained-release / controlled-release effects, exhibiting superior overall performance. It can be used in oral sustained-release formulations or transdermal patches and has a wide range of applications.

[0008] This invention is achieved through the following scheme:

[0009] One aspect of the present invention is that it provides a diclofenac sodium pharmaceutical formulation comprising, by weight parts: 0.5-2 parts diclofenac sodium, 5-10 parts cationic lipids, 1-5 parts PEGylated lipids, and 0.01-0.5 parts cationic surfactants;

[0010] The cationic lipid is one or more of the following: trimethyl-2,3-diolenooxypropylammonium chloride (DOTMA), trimethyl-2,3-diolenooxypropylammonium bromide (DOTPA), dimethyl-2,3-diolenooxypropyl-2-(2-sperminecarbamoylamino)ethylammonium trifluoroacetate (DOSPA), dimethyl-2-hydroxyethyl-2,3-diolenooxypropylammonium bromide (DORI), dimethyl-2-hydroxyethyl-2,3-diolenooxypropylammonium bromide (DORIE), dimethyl-3-hydroxypropyl-2,3-diolenooxypropylammonium bromide (DORIE-HP), dimethyl-4-hydroxybutyl-2,3-diolenooxypropylammonium bromide (DORIE-HB), and dimethyl-5-hydroxypentyl-2,3-diolenooxypropylammonium bromide (DORIE-HPc).

[0011] The PEGylated lipid is one or more of the following: dimyristoyl phosphatidylcholine polyethylene glycol (DMPC-mPEG), dipalmitoyl phosphatidylcholine polyethylene glycol (DPPC-mPEG), distearyl phosphatidylcholine polyethylene glycol (DSPC-mPEG), dimyristoyl phosphatidyl polyethylene glycol (DMPE-mPEG), dipalmitoyl phosphatidyl polyethylene glycol (DPPE-mPEG), and distearyl phosphatidyl polyethylene glycol (DSPE-mPEG).

[0012] In some preferred embodiments of the present invention, the cationic lipid is trimethyl-2,3-dioleoyloxypropylammonium bromide and / or dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide.

[0013] Compared to cationic lipids containing olefin groups, diclofenac sodium liposome formulations prepared using cationic lipids containing acyl groups have a more suitable sustained-release effect. This may be due to the presence of olefin unsaturated bonds and their cis-trans isomerization, which affects the permeability of the lipid membrane. Although the sustained-release effect is better, the initial release is too slow, resulting in a prolonged onset time. To achieve a better controlled-release effect, the preferred cationic lipids are trimethyl-2,3-dioleoyloxypropylammonium bromide and / or dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide containing acyl groups.

[0014] In some preferred embodiments of the present invention, the PEGylated lipid is one or more of DMPC-mPEG, DPPC-mPEG and DSPC-mPEG.

[0015] Preferably, the cationic surfactant is one or more of the following: dodecyltrimethylammonium chloride (DTAC), dodecyltrimethylammonium bromide (DTAB), dodecyl dimethylbenzylammonium chloride (DDBAC), tetradecyltrimethylammonium chloride (TTAC), tetradecyltrimethylammonium bromide (TTAB), tetradecyl dimethylbenzylammonium chloride (TDBAC), hexadecyltrimethylammonium chloride (CTAC), hexadecyltrimethylammonium bromide (CTAB), and hexadecyl dimethylbenzylammonium chloride (16-BAC).

[0016] In some preferred embodiments of the present invention, the diclofenac sodium pharmaceutical formulation further includes sodium sucrose octasulfate. Sodium sucrose octasulfate, as an auxiliary lipid, is used in combination with cationic lipids and PEGylated lipids, which not only improves the stability of liposome particles but also increases the encapsulation efficiency of the active pharmaceutical ingredient by the liposomes.

[0017] More preferably, the mass ratio of the cationic lipid, the PEGylated lipid and sodium sucrose octasulfate is 1:0.5-1:0.05-0.5.

[0018] A second aspect of the present invention is to provide a method for preparing any of the above-described diclofenac sodium pharmaceutical preparations, specifically comprising the following steps:

[0019] (1) Add cationic lipids and PEGylated lipids to an organic solvent, with or without the addition of sodium sucrose octasulfate, and dissolve them thoroughly to obtain a mixed lipid solution;

[0020] (2) Remove the organic solvent from the mixed lipid solution to form a lipid membrane;

[0021] (3) Dissolve diclofenac sodium and surfactant in physiological saline or buffer solution, add lipid membrane after dissolution, and hydrate to obtain liposome suspension;

[0022] (4) The liposome suspension is subjected to ultrasonic micronization and dried to obtain the final product.

[0023] Furthermore, 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 solution is 0.01-0.5 g / mL.

[0024] Furthermore, the organic solvent is selected from one or more of methanol, tert-butanol, chloroform, and cyclohexane.

[0025] Furthermore, in step (3), the hydration temperature is 50-70℃ and the hydration time is 40-60min.

[0026] A third aspect of the present invention is that it provides the use of any of the above-described diclofenac sodium pharmaceutical preparations or diclofenac ammonium preparations prepared by any of the above-described preparation methods in the preparation of a drug for treating arthritis.

[0027] Furthermore, the arthritis includes any one of osteoarthritis, rheumatoid arthritis, and osteoarthritis.

[0028] Furthermore, the drug is either an oral sustained-release preparation or a topical transdermal patch.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) In the diclofenac sodium lipid delivery system of the present invention, the positively charged cationic liposomes and cationic surfactants have a stronger affinity for 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 improve the stability of the liposome particles, and through stable encapsulation, the transdermal effect and sustained release effect are simultaneously improved.

[0031] (2) By further optimizing the cationic lipids, the present invention enables the formulation to exert a better controlled release effect, which is conducive to the stability of blood drug concentration and thus improves patient compliance.

[0032] (3) With the cooperation of specific auxiliary lipids, the present invention also effectively improves the encapsulation effect of the active pharmaceutical ingredient, providing a prerequisite for achieving long-lasting and controlled release;

[0033] (4) The preparation process of the diclofenac sodium nanolipid formulation of the present invention is simple and efficient; and can achieve a high encapsulation rate. Attached Figure Description

[0034] Figure 1 The dissolution curves of the diclofenac sodium drug formulation and the control formulation in each embodiment are shown.

[0035] Figure 2 The dissolution curves are for the diclofenac sodium drug formulations of each comparative example and Example 6. Detailed Implementation

[0036] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0037] Example 1

[0038] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0039] (1) Take 5g of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide and 5g of DMPC-mPEG and add them to 20mL of methanol / chloroform (V / V=1:1) mixed solvent, dissolve them completely to obtain a mixed lipid solution;

[0040] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0041] (3) Dissolve 2g of diclofenac sodium and 0.05g of tetradecyltrimethylammonium chloride in 20mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 50℃ for 60min to obtain a liposome suspension.

[0042] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0043] Example 2

[0044] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0045] (1) Take 7g of trimethyl-2,3-dioleoyloxypropylammonium bromide and 3g of DPPC-mPEG and add them to 10mL of chloroform solvent. Dissolve them completely to obtain a mixed lipid solution.

[0046] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0047] (3) Dissolve 2g of diclofenac sodium and 0.2g of hexadecyltrimethylammonium bromide in 40mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 60℃ for 50min to obtain a liposome suspension.

[0048] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0049] Example 3

[0050] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0051] (1) Take 9g of dimethyl-5-hydroxypentyl-2,3-dioleenooxypropylammonium bromide and 1g of DSPC-mPEG and add them to 5mL of tert-butanol / cyclohexane (V / V=4:1) mixed solvent and dissolve them completely to obtain a mixed lipid solution;

[0052] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0053] (3) Dissolve 2g of diclofenac sodium and 0.01g of dodecyltrimethylammonium bromide in 10mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 70℃ for 40min to obtain a liposome suspension.

[0054] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0055] Example 4

[0056] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0057] (1) Take 5g of dimethyl-5-hydroxypentyl-2,3-dioleenooxypropylammonium bromide and 5g of DMPC-mPEG and add them to 20mL of methanol / chloroform (V / V=1:1) mixed solvent and dissolve them completely to obtain a mixed lipid solution;

[0058] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0059] (3) Dissolve 2g of diclofenac sodium and 0.05g of tetradecyltrimethylammonium chloride in 20mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 50℃ for 50min to obtain a liposome suspension.

[0060] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0061] Example 5

[0062] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0063] (1) Take 5g of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide and 5g of DMPE-mPEG and add them to 20mL of methanol / chloroform (V / V=1:1) mixed solvent, dissolve them completely to obtain a mixed lipid solution;

[0064] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0065] (3) Dissolve 2g of diclofenac sodium and 0.05g of tetradecyltrimethylammonium chloride in 20mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 50℃ for 50min to obtain a liposome suspension.

[0066] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0067] Example 6

[0068] A diclofenac sodium pharmaceutical preparation, the preparation method of which is as follows:

[0069] (1) Take 5g of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide, 5g of DMPC-mPEG and 0.2g of sodium sucrose octasulfate and add them to 20mL of methanol / chloroform (V / V=1:1) mixed solvent and dissolve them completely to obtain a mixed lipid solution;

[0070] (2) The solvent in the mixed lipid solution is removed by rotary evaporation at 60°C to form a lipid film;

[0071] (3) Dissolve 2g of diclofenac sodium and 0.05g of tetradecyltrimethylammonium chloride in 20mL of physiological saline. After dissolving, add the lipid membrane and hydrate at 50℃ for 60min to obtain a liposome suspension.

[0072] (4) The liposome suspension was subjected to ultrasonic (250W) micronization for 20 min, filtered through a 0.22μm filter membrane, and freeze-dried to obtain the final product.

[0073] Comparative Example 1

[0074] Compared with Example 6, the only difference is that DMPC-mPEG is not added, and the amount of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide is adjusted to 10g.

[0075] Comparative Example 2

[0076] Compared with Example 6, the only difference is that dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide is not added, and the amount of DMPC-mPEG is adjusted to 10g.

[0077] Comparative Example 3

[0078] Compared with Example 6, the only difference is that dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide is replaced with an equal amount of dioctadecyldimethylammonium bromide.

[0079] Comparative Example 4

[0080] Compared to Example 6, the only difference is that the cationic surfactant tetradecyltrimethylammonium chloride is not included, and the amount of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide is adjusted to 5.05g.

[0081] Comparative Example 5

[0082] Compared with Example 6, the only difference is that the amount of dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide was adjusted to 4g and the amount of DMPC-mPEG was adjusted to 6g.

[0083] Test Example 1

[0084] The diclofenac sodium pharmaceutical preparations prepared in Examples 1-6 and Comparative Examples 1-5 were characterized as follows:

[0085] (1) Encapsulation efficiency: 0.5 g of the lyophilized diclofenac sodium preparation was dissolved in 10 mL of methanol / chloroform (V / V=1:1) mixture and the total drug concentration was determined. Then, the mixture was centrifuged at 4℃ and 100,000 rpm for 2 h. The supernatant was taken and the drug content in the supernatant was determined, which is the free drug concentration. Encapsulation efficiency (%) = (1 - free drug concentration) / total drug concentration.

[0086] Drug concentration was determined by high performance liquid chromatography (HPLC) under the following chromatographic conditions:

[0087] 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.

[0088] (2) Particle size: Take 0.5 mg of the freeze-dried diclofenac sodium drug preparation and add it to 2 mL of deionized water. Shake to disperse it fully and use a particle size analyzer to determine its particle size and polydispersity index (PDI).

[0089] The characterization results are shown in Table 1.

[0090] Table 1. Diclofenac sodium lipid encapsulation efficiency, particle size, and PDI results ( (n=3)

[0091]

[0092] Note: Compared with Example 6, * P <0.05, ** P <0.01, *** P <0.005.

[0093] As can be seen from the table above, the diclofenac sodium prepared in the embodiments of the present invention achieved an encapsulation rate of over 97%. Although some comparative examples also achieved a similar encapsulation effect, the particle size was relatively large and the polydispersity index was higher. Due to the difference in particle size, the transdermal effect was also reduced and the dissolution was slower.

[0094] Test Example 2

[0095] The transdermal efficacy of diclofenac sodium formulation was verified by in vitro transdermal testing, and the specific method is as follows:

[0096] (1) Preparation of isolated rat skin: SD rats (180-200g) were dehaired on the abdomen with 80g / L sodium sulfide solution, the skin was washed with physiological saline, and they were naturally fed for 24 hours. They were anesthetized and sacrificed the next day before the experiment. The abdominal skin was peeled off and the subcutaneous fat and tissue were separated. Undamaged skin was selected and soaked in physiological saline and refrigerated for 12 hours before use.

[0097] (2) Transdermal diffusion test: Mouse skin was placed in a Franz diffusion cell (effective diffusion area of ​​2.8 cm²). 2 The stratum corneum was approximately 600 μm thick. The stratum corneum faced the supply chamber, and the dermis faced the receiving chamber. The receiving solution was 30 mL of physiological saline. The temperature was maintained at (37±1) ℃ in a constant-temperature water bath, and the magnetic stirrer was set at 100 rpm. The diclofenac sodium prepared in each comparative example was redissolved in methanol / chloroform (V / V=1:1) to prepare a solution containing 2 mg of diclofenac sodium. The solution was uniformly coated on the surface of the stratum corneum. 1 mL samples were taken from the receiving chamber at 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h (1 mL of physiological saline at the same temperature was added simultaneously). The samples were filtered through a 0.45 μm microporous membrane, and the concentration of diclofenac sodium was determined by high-performance liquid chromatography. The transdermal permeation rate and cumulative permeation volume were calculated. The results are shown in Table 2.

[0098] Table 2. In vitro transdermal efficacy of diclofenac sodium formulations ( (n=3)

[0099]

[0100] Note: Compared with Example 6, * P <0.05, ** P <0.01, *** P <0.005.

[0101] As can be seen from the table above, the diclofenac sodium drug formulations prepared by the combined use of cationic lipids and PEGylated lipids in Examples 1-5 have excellent transdermal properties. Example 6 further increases the use of auxiliary lipids, which further enhances the transdermal effect. Compared with Example 6, the effects of Comparative Examples 1 and 2, which only use cationic lipids or PEGylated lipids, are significantly reduced, indicating that the two have a significant synergistic effect in improving the transdermal properties of diclofenac sodium.

[0102] Test Example 3

[0103] According to the 2020 edition of the Chinese Pharmacopoeia, the method for determining dissolution and release (General Rule 0931, Method 1) was used. A pH 6.8 phosphate buffer solution was used as the dissolution medium, the rotation speed was 100 rpm, and the medium temperature was 37±5℃. Samples of 1 mL were taken at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h, filtered through a 0.45 μm microporous membrane, and the same volume and temperature of release medium were replenished promptly. High-performance liquid chromatography (HPLC) was used (specific conditions were the same as in Test Example 1) to test the diclofenac sodium content in the dissolution medium of the diclofenac sodium drug preparations prepared in each example and comparative example, as well as the control preparation (commercially available diclofenac sodium sustained-release tablets). The cumulative dissolution rate was calculated, and the results are shown in Table 3. The dissolution curves are shown in Table 3. Figure 1 and Figure 2 .

[0104] Table 3 Dissolution of diclofenac sodium drug formulations

[0105]

[0106] From the above table and Figure 1 , Figure 2 It can be seen that the diclofenac sodium drug formulation prepared by this invention can achieve the sustained-release effect of the control formulation (diclofenac sodium sustained-release tablets). Compared with the control formulation, the dissolution curve of the diclofenac sodium prepared by this invention is more constant, achieving a controlled-release effect while ensuring a long-lasting release over 24 hours. The inventors also found that, compared with acyl-containing cationic lipids, although olefin-containing cationic lipids also have a considerable sustained-release effect, their release is slower in the early stage (before 12 hours), resulting in a slower onset of action.

[0107] Furthermore, compared with Example 6, the sustained-release effect of Comparative Examples 2 and 3 was worse, indicating that the presence of cationic lipids and their specific types have a significant impact on the sustained-release effect of diclofenac sodium drug formulations.

[0108] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A pharmaceutical formulation of diclofenac sodium characterized in that, According to the mass fraction, it comprises: diclofenac sodium 0.5-2 parts, cationic lipid 5-10 parts, PEGylated lipid 1-5 parts and cationic surfactant 0.01-0.5 parts; The cationic lipid is one or more of trimethyl-2,3-dioleyloxypropyl ammonium chloride, trimethyl-2,3-dioleoyloxypropyl ammonium bromide, dimethyl-2,3-dioleyloxypropyl-2-(2-argininecarboxamido)ethyl ammonium trifluoroacetate, dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropyl ammonium bromide, dimethyl-2-hydroxyethyl-2,3-dioleyloxypropyl ammonium bromide, dimethyl-3-hydroxypropyl-2,3-dioleyloxypropyl ammonium bromide, dimethyl-4-hydroxybutyl-2,3-dioleyloxypropyl ammonium bromide and dimethyl-5-hydroxypentyl-2,3-dioleyloxypropyl ammonium bromide; The PEGylated lipid is one or more of DMPC-mPEG, DPPC-mPEG, DSPC-mPEG, DMPE-mPEG, DPPE-mPEG and DSPE-mPEG; The diclofenac sodium drug preparation comprises the following steps: (1) adding cationic lipid and PEGylated lipid into organic solvent, dissolving thoroughly to obtain mixed lipid solution; (2) removing organic solvent in the mixed lipid solution to form lipid film; (3) dissolving diclofenac sodium and cationic surfactant in physiological saline or buffer solution, adding the lipid film after dissolving to hydrate, obtaining liposome suspension; (4) performing ultrasonic micro-fining treatment on the liposome suspension, drying to obtain the product.

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

3. The diclofenac sodium pharmaceutical formulation according to claim 1, characterized in that, The cationic 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 formulation according to any one of claims 1-3, characterized in that, The diclofenac sodium drug preparation further comprises sodium sucrose octasulfate.

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

5.

6. The process for the preparation of diclofenac sodium pharmaceutical formulations according to any one of claims 1-5, characterized in that, The steps comprise: (1) adding cationic lipid and PEGylated lipid into organic solvent, adding or not adding sodium sucrose octasulfate, dissolving thoroughly to obtain mixed lipid solution; (2) removing organic solvent in the mixed lipid solution to form lipid film; (3) dissolving diclofenac sodium and cationic surfactant in physiological saline or buffer solution, adding the lipid film after dissolving to hydrate, obtaining liposome suspension; (4) performing ultrasonic micro-fining treatment on the liposome suspension, drying to obtain the product.

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

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

9. Use of a pharmaceutical formulation of diclofenac sodium according to any one of claims 1 to 5 or a pharmaceutical formulation of diclofenac sodium prepared according to the process of any one of claims 6 to 8 for the manufacture of a medicament for the treatment of arthritis, characterized in that, The arthritis includes any one of osteoarthritis, rheumatic arthritis and rheumatoid arthritis; and the medicine is an external transdermal patch.

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