Baricitinib nano-cream and preparation method thereof

Abstract

The invention provides a baricitinib nano-cream and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The baricitinib nano-cream provided by the invention comprises a cream matrix and a nano-structure lipid carrier dispersed in the cream matrix, the nano-structure lipid carrier comprises a solid lipid, a liquid lipid and a non-ionic emulsifier, and the types of the solid lipid and the liquid lipid are specifically limited, so that the content of the solid lipid and the liquid lipid in the nano-structure lipid carrier is increased, and the content of the non-ionic emulsifier in the nano-structure lipid carrier is increased. According to the present invention, the solid lipid provides the structure stability, the liquid lipid introduces the lattice defect, such that the solubility and the encapsulation efficiency of the baricitinib or the pharmaceutically acceptable salt thereof are improved so as to improve the release rate and the stability of the baricitinib nano-cream. The nanostructured lipid carrier is dispersed in the cream matrix, so that the permeability and adhesiveness of the baricitinib nanocream can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a baricitinib nanoemulsion cream and a preparation method thereof. BACKGROUND

[0002] Baricitinib is a selective and reversible Janus kinase (JAK) 1 and JAK2 inhibitor, which has application potential in the topical treatment of inflammatory skin diseases (such as atopic dermatitis, psoriasis, alopecia areata). At present, commercially available baricitinib is mostly in the form of oral tablets. However, although oral baricitinib is effective for the treatment of inflammatory skin diseases, it is accompanied by an increased risk of infection, thrombotic events and systemic side effects such as malignant tumors. Transdermal administration has the advantages of high targeting, safety and convenience, but baricitinib is a fat-soluble drug (water solubility <0.1 mg / mL, log P ≈ 1.5), and the skin barrier (stratum corneum) severely limits the transport of the fat-soluble drug baricitinib, resulting in poor transdermal permeability and low bioavailability of baricitinib in traditional external preparations (such as creams and gels). For example, related studies have shown that baricitinib cream or baricitinib gel, by physical dispersion or addition of penetration enhancers (such as polyethylene glycol-7 stearate or glycols), can hardly achieve efficient penetration and controlled release, and the 12h release of baricitinib is often <40%, and the drug is prone to precipitation or poor stability (content decrease >10% after 1 month of storage at 40℃).

[0003] The application of nanotechnology in the field of pharmaceutical preparations provides an innovative approach to solving the solubilization, sustained release, targeted delivery and improvement of bioavailability of poorly soluble drugs. Although nanotechnology has made significant progress in the medical field, the stability, permeability and sustained release effect of the Baricitinib cream in the prior art are poor in actual use, making it difficult for the drug to exert its efficacy and the local treatment effect difficult to meet the demand.

[0004] Therefore, it is urgent to develop a baricitinib nanoemulsion cream that can improve permeability, release and stability and achieve efficient local treatment of inflammatory skin diseases. SUMMARY

[0005] The present application relates to the technical field of pharmaceutical preparations, and in particular to a baricitinib nanoemulsion cream and a preparation method thereof.

[0006] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions: The present application provides a baricitinib nanoemulsion cream, comprising a cream base and a nanostructured lipid carrier dispersed in the cream base. The nanostructured lipid carrier comprises baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid, a liquid lipid, and a non-ionic emulsifier; The solid lipid comprises glyceryl behenate and / or glyceryl stearate; The liquid lipid comprises one or more of caprylic / capric triglyceride, oleic acid, and isopropyl myristate; The baricitinib or the pharmaceutically acceptable salt thereof accounts for 0.2-2.0% of the mass percentage of the baricitinib nanoemulsion cream.

[0007] Preferably, the particle size of the nanostructured lipid carrier is 80-250 nm, the polydispersity index is <0.25, and the encapsulation efficiency is >92%.

[0008] Preferably, the cream base comprises, based on 100% of the mass percentage of the baricitinib nanoemulsion cream, 5.0-15% of a humectant, 0.5-2.0% of a thickening agent, 10-30% of an oil phase, and purified water.

[0009] Preferably, the non-ionic emulsifier comprises poloxamer 188 or Tween 80.

[0010] Preferably, the non-ionic emulsifier accounts for 1.5-3.0% of the mass percentage of the baricitinib nanoemulsion cream.

[0011] Preferably, the mass ratio of the solid lipid to the liquid lipid is 2.5-9:1; and the total mass of the solid lipid and the liquid lipid accounts for 5.0-7.0% of the mass percentage of the baricitinib nanoemulsion cream.

[0012] The application further provides a preparation method of the baricitinib nanoemulsion cream. (1) melt-mixing baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid, and a liquid lipid to obtain a molten oil phase; dissolving a non-ionic emulsifier in water to obtain an aqueous phase; mixing the molten oil phase and the aqueous phase, and then sequentially performing emulsification and homogenization to obtain an NLCs dispersion; (2) mixing the NLCs dispersion obtained in step (1) with a cream base to obtain a baricitinib nanoemulsion cream.

[0013] Preferably, the mass ratio of the molten oil phase to the aqueous phase in step (1) is 1:5-20.

[0014] Preferably, the homogenization in step (1) is high-pressure homogenization, the pressure of the high-pressure homogenization is 600-1200 bar, and the number of cycles of the high-pressure homogenization is 4-8.

[0015] Preferably, the preparation method of the cream base in step (2) comprises: mixing the humectant and the oil phase at 60-70 DEG C to obtain an oil phase base; swelling the thickening agent and purified water at 60-70 DEG C to obtain an aqueous phase base; emulsifying the oil phase base and the aqueous phase base to obtain the cream base.

[0016] The present application provides a baricitinib nano cream, comprising a cream base and nanostructured lipid carriers dispersed in the cream base; the nanostructured lipid carriers comprise baricitinib or a pharmaceutically acceptable salt thereof, solid lipid, liquid lipid and non-ionic emulsifier; the solid lipid comprises glycerol monobehenate and / or glyceryl stearate; the liquid lipid comprises one or more of caprylic / capric triglyceride, oleic acid and isopropyl myristate; the mass percentage of the baricitinib or the pharmaceutically acceptable salt thereof in the baricitinib nano cream is 0.2-2.0%. The baricitinib nano cream provided by the present application comprises a cream base and nanostructured lipid carriers dispersed in the cream base, the nanostructured lipid carriers comprise solid lipid, liquid lipid and non-ionic emulsifier, and the types of solid lipid and liquid lipid are specifically defined, the structural stability is provided by the solid lipid, the solubility and encapsulation efficiency of the baricitinib or the pharmaceutically acceptable salt thereof are improved by introducing lattice defects through the liquid lipid, and then the release rate and stability of the baricitinib nano cream are improved. The nanostructured lipid carriers dispersed in the cream base can improve the permeability and adhesion of the baricitinib nano cream. The results of the examples show that the permeability, release rate and stability of the baricitinib nano cream provided by the present application are significantly improved compared with the comparative examples and the commercially available cream. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 A photo of the baricitinib nano cream prepared in Example 1 of the present application; Figure 2 A particle size distribution curve of the baricitinib nano cream prepared in Example 1 of the present application; Figure 3 A comparison chart of the in-vitro cumulative release curves of the baricitinib nano cream prepared in Example 1 of the present application and the control group. DETAILED DESCRIPTION

[0018] The present application provides a baricitinib nano cream, comprising a cream base and nanostructured lipid carriers dispersed in the cream base; The nanostructured lipid carriers comprise baricitinib or a pharmaceutically acceptable salt thereof, solid lipid, liquid lipid and non-ionic emulsifier; The solid lipid comprises glycerol monobehenate and / or glyceryl stearate; The liquid lipid includes one or more of caprylic / capric triglyceride, oleic acid, and isopropyl myristate. The baricitinib or the pharmaceutically acceptable salt thereof accounts for 0.2-2.0% of the mass percentage of the baricitinib nanoemulsion cream.

[0019] The baricitinib nanoemulsion cream provided by the present application includes a cream base.

[0020] In the present application, the cream base preferably includes 5.0-15% of a humectant, 0.5-2% of a thickening agent, 10-30% of an oil phase, and purified water, based on 100% of the mass percentage of the baricitinib nanoemulsion cream.

[0021] In the present application, the cream base preferably includes 5.0-15% of a humectant. As an embodiment of the present application, the mass percentage of the humectant can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%. In the present application, the humectant preferably includes one or more of glycerin, propylene glycol, butylene glycol, and sorbitol.

[0022] In the present application, the cream base preferably includes 0.5-2.0% of a thickening agent. As an embodiment of the present application, the mass percentage of the thickening agent can be 0.5%, 1.0%, 1.5%, or 2.0%. In the present application, the thickening agent preferably includes one or more of carbomer, xanthan gum, hydroxypropyl methylcellulose (HPMC), and hydroxyethyl cellulose (HEC). The present application can increase the viscosity, prevent the oil-water separation of the cream base, and improve the stability of the cream base by adding the thickening agent.

[0023] In the present application, the cream base preferably includes 10-30% of an oil phase. As an embodiment of the present application, the mass percentage of the oil phase can be 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30%. In the present application, the oil phase is preferably a mixture of petrolatum and cetyl alcohol. In the present application, the mass percentage of the petrolatum and cetyl alcohol is preferably 3-4:1. The present application can form the cream base with the purified water by adding the oil phase.

[0024] In the present application, the cream base preferably includes purified water. In the present application, the mass percentage of the purified water is preferably 60-75%, more preferably 65-70%.

[0025] The baricitinib nanoemulsion cream provided by the present application includes a nanostructured lipid carrier dispersed in the cream base.

[0026] In the present application, the particle size of the nanostructured lipid carrier is preferably 80 to 250 nm, and more preferably 100 to 250 nm. In the present application, the polydispersity index of the nanostructured lipid carrier is preferably <0.25, and more preferably ≤0.21, and the encapsulation efficiency of the nanostructured lipid carrier is preferably >92%, and more preferably ≥93.5%. The present application controls the parameters of the nanostructured lipid carrier within the above range, and the lipid carrier of the nano size can improve the penetration of the baricitinib nano cream and the adhesion of the cream.

[0027] In the present application, the nanostructured lipid carrier includes baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid, a liquid lipid, and a non-ionic emulsifier.

[0028] In the present application, the baricitinib or a pharmaceutically acceptable salt thereof is used as an active pharmaceutical ingredient of the baricitinib nano cream. In the present application, the molecular weight of the baricitinib is preferably 371.42 Da, and the water solubility of the baricitinib is preferably 0.357 to 0.46 mg / mL (25℃), and more preferably 0.4 mg / mL. The present application does not have a special limitation on the type of the pharmaceutically acceptable salt of the baricitinib, and any conventional pharmaceutically acceptable salt of the baricitinib can be used.

[0029] In the present application, the baricitinib or a pharmaceutically acceptable salt thereof accounts for 0.2 to 2.0% of the mass percentage of the baricitinib nano cream. As an embodiment of the present application, the baricitinib or a pharmaceutically acceptable salt thereof can account for 0.2%, 0.5%, 1.0%, 1.5%, or 2.0% of the mass percentage of the baricitinib nano cream. The present application controls the mass percentage of the baricitinib or a pharmaceutically acceptable salt thereof in the baricitinib nano cream within the above range, which can ensure the therapeutic effect of the baricitinib nano cream without increasing the irritation.

[0030] In the present application, the solid lipid includes glyceryl behenate and / or glyceryl stearate, and preferably glyceryl behenate or glyceryl stearate. In the present application, the glyceryl stearate preferably includes one or more of glyceryl monostearate, glyceryl distearate, or glyceryl tristearate. The present application uses the above-mentioned solid lipid, which can provide structural stability to the nanostructured lipid carrier.

[0031] In the present application, the liquid lipid includes one or more of caprylic / capric triglyceride, oleic acid, and isopropyl myristate, and preferably caprylic / capric triglyceride or oleic acid. The present application uses the above-mentioned liquid lipid, which can introduce lattice defects. The present application can improve the solubility of the baricitinib drug and the encapsulation efficiency by adding the solid lipid and the liquid lipid.

[0032] In the present application, the total mass of the solid lipid and the liquid lipid preferably accounts for 5.0-7.0% of the mass percentage of the baricitinib nanoemulsion cream, more preferably 5.5-7.0%. In the present application, the mass ratio of the solid lipid to the liquid lipid is preferably 3-9:1. As an embodiment of the present application, the mass ratio of the solid lipid to the liquid lipid can be 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1. The present application controls the amount of solid lipid and liquid lipid in the above range, which is more conducive to improving the solubility and encapsulation efficiency of baricitinib drugs.

[0033] In the present application, the non-ionic emulsifier preferably includes poloxamer 188 or Tween 80. In the present application, the non-ionic emulsifier preferably accounts for 1.5-3.0% of the mass percentage of the baricitinib nanoemulsion cream. As an embodiment of the present application, the non-ionic emulsifier can account for 1.5%, 2.0% or 3.0% of the mass percentage of the baricitinib nanoemulsion cream. The present application can form nanostructured lipid carriers by adding a non-ionic emulsifier.

[0034] The present application also provides a preparation method of the baricitinib nanoemulsion cream described in the above technical solutions, comprising the following steps: (1) melt-mixing baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid and a liquid lipid to obtain a molten oil phase; dissolving a non-ionic emulsifier in water to obtain an aqueous phase; mixing the molten oil phase with the aqueous phase, and then sequentially performing emulsification and homogenization to obtain an NLCs dispersion; (2) mixing the NLCs dispersion obtained in step (1) with a cream base to obtain a baricitinib nanoemulsion cream.

[0035] The present application melt-mixes baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid and a liquid lipid to obtain a molten oil phase.

[0036] In the present application, the temperature of the melt-mixing is preferably 70-80°C, more preferably 75-80°C. The present application can melt the solid lipid at the above temperature and mix it uniformly with baricitinib or a pharmaceutically acceptable salt thereof and the liquid lipid.

[0037] The present application dissolves a non-ionic emulsifier in water to obtain an aqueous phase.

[0038] In the present application, the mass ratio of the molten oil phase and the aqueous phase is preferably 1:5-20. As an embodiment of the present application, the mass ratio of the molten oil phase and the aqueous phase can be 1:5, 1:6, 1:10, 1:14, 1:15, 1:17 or 1:20. The present application controls the mass ratio of the molten oil phase and the aqueous phase in the above range, and can form nanostructured lipid carriers.

[0039] The present application does not have special limitations on the method for mixing the molten oil phase and the aqueous phase, and the two can be uniformly mixed.

[0040] In the present application, the emulsification method is preferably high-speed shearing emulsification. In an embodiment of the present application, the rotation speed of the high-speed shearing emulsification can be 10,000 rpm; the time of the high-speed shearing emulsification is preferably 2-5 min, more preferably 3-5 min.

[0041] In the present application, the homogenization is preferably high-pressure homogenization, and the pressure of the high-pressure homogenization is preferably 600-1,200 bar, more preferably 1,000-1,200 bar; the number of cycles of the high-pressure homogenization is preferably 4-8 times, more preferably 5-7 times.

[0042] After obtaining the NLCs dispersion, the present application mixes the NLCs dispersion with a cream base to obtain a baricitinib nanoemulsion cream.

[0043] In the present application, the preparation method of the cream base preferably comprises: mixing a humectant and an oil phase at 60-70°C to obtain an oil phase base; swelling a thickening agent and purified water at 60-70°C to obtain an aqueous phase base; and emulsifying the oil phase base and the aqueous phase base to obtain a cream base. The present application does not have special limitations on the operation method of the emulsification, and the oil phase base and the aqueous phase base are sufficiently emulsified to form a stable cream base.

[0044] The present application does not have special limitations on the method for mixing the NLCs dispersion and the cream base, and the NLCs dispersion can be uniformly dispersed in the cream base. In an embodiment of the present application, the method for mixing the NLCs dispersion and the cream base can be homogenization, and the time of the homogenization can be 5 min.

[0045] The method provided by the present application is simple to operate, and the prepared baricitinib nanoemulsion cream comprises a cream base and nanostructured lipid carriers dispersed in the cream base. Solid lipids are used to provide structural stability, and liquid lipids are used to introduce crystal lattice defects, thereby improving the solubility and encapsulation efficiency of baricitinib or a pharmaceutically acceptable salt thereof, and further improving the release degree and stability of the baricitinib nanoemulsion cream. The present application disperses nanostructured lipid carriers in a cream base, and can improve the permeability and adhesion of the baricitinib nanoemulsion cream.

[0046] The application further provides application of the baricitinib nanoemulsion cream or the baricitinib nanoemulsion cream prepared by the preparation method as a topical external medicine for treating inflammatory skin diseases.

[0047] In the application, the inflammatory skin diseases are preferably atopic dermatitis, psoriasis or alopecia areata.

[0048] The application of the baricitinib nanoemulsion cream as a topical external medicine for treating inflammatory skin diseases is not particularly limited, and conventional methods of application of topical external medicines can be used.

[0049] The baricitinib nanoemulsion cream provided by the application has excellent permeability, release rate and stability, and can be used as a topical external medicine for treating inflammatory skin diseases.

[0050] The technical solutions in the application will be described clearly and completely below with reference to the embodiments in the application. Obviously, the described embodiments are only some of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the application.

[0051] Embodiment 1 A baricitinib nanoemulsion cream, which is composed of a cream base and a nanostructured lipid carrier dispersed in the cream base; The nanostructured lipid carrier is composed of baricitinib, a solid lipid (glyceryl monomontanate), a liquid lipid (glyceryl caprylate / caprate) and a non-ionic emulsifier (poloxamer 188); The total mass of the solid lipid and the liquid lipid accounts for 7.0% of the mass percentage of the baricitinib nanoemulsion cream; and the mass ratio of the solid lipid to the liquid lipid is 2.5:1; The non-ionic emulsifier accounts for 2.0% of the mass percentage of the baricitinib nanoemulsion cream; The baricitinib accounts for 1.0% of the mass percentage of the baricitinib nanoemulsion cream; The cream base is composed of a humectant (glycerol) 10%, a thickening agent (carbomer) 1.0%, an oil phase vaseline 15%, cetyl alcohol 5.0% and the balance of purified water (69%).

[0052] The preparation method of the baricitinib nanoemulsion cream is as follows: (1) 1.0 g of baricitinib (molecular weight 371.42 Da, water solubility 0.4 mg / mL), 5.0 g of glyceryl monomontanate and 2.0 g of glyceryl caprylate / caprate are heated to 75℃ for melt mixing to obtain a melt oil phase; Poloxamer 188 2.0 g was dissolved in 48 g purified water heated to 75℃ to dissolve to obtain an aqueous phase; The aqueous phase was added to the oil phase, emulsified by high speed shearing for 3 min at 10000 rpm, and then high pressure homogenized 6 times under 800 bar pressure to obtain an NLCs dispersion with pH value of 6.0; (2) Vaseline 15.0 g, cetyl alcohol 5.0 g were heated to 65℃ to form an oil phase matrix; the balance of purified water was heated to 65℃ to form an aqueous phase matrix; the oil phase matrix and the aqueous phase matrix were emulsified, and cooled to room temperature to obtain a cream matrix; The NLCs dispersion obtained in step (1) was mixed with the cream matrix, and homogenized for 5 min to obtain a baricitinib nano cream.

[0053] The photo of the baricitinib nano cream prepared in Example 1 is shown in Figure 1 It can be seen from Figure 1 that the baricitinib nano cream prepared in this example is a uniform white semi-solid, without stratification or precipitation (no change after 40℃ stability test).

[0054] The particle size distribution curve of the baricitinib nano cream prepared in Example 1 measured by dynamic light scattering (DLS) is shown in Figure 2 It can be seen from Figure 2 that the average particle size of the baricitinib nano cream prepared in Example 1 is about 160 nm, and PDI = 0.21.

[0055] The comparison chart of the in vitro cumulative release curves of the baricitinib nano cream prepared in Example 1 and the control group is shown in Figure 3 The control group is a baricitinib aqueous solution (concentration of 1 mg / mL). It can be seen from Figure 3 that the sustained release effect of the baricitinib nano cream prepared in Example 1 is obviously improved.

[0056] Example 2 A baricitinib nano cream, which is composed of a cream matrix and nanostructured lipid carriers dispersed in the cream matrix; The nanostructured lipid carriers are composed of baricitinib, solid lipid (glyceryl monostearate), liquid lipid (isopropyl myristate) and non-ionic emulsifier (Tween 80); The total mass percentage of the solid lipid and the liquid lipid in the baricitinib nano cream is 5.5%; the mass ratio of the solid lipid to the liquid lipid is 2.67:1; The mass percentage of the non-ionic emulsifier in the baricitinib nano cream is 2.0%; The baricitinib accounts for 0.5% of the mass percentage of the baricitinib nanoemulsion cream; The cream base is composed of a humectant (glycerin) 8.0%, a thickening agent (carbomer) 0.8%, an oil phase vaseline 12.0%, cetyl alcohol 4.0%, and the balance purified water.

[0057] The preparation method of the baricitinib nanoemulsion cream is as follows: (1) 0.5g baricitinib (molecular weight 371.42Da, water solubility 0.4mg / mL), glyceryl monostearate 4.0g and isopropyl myristate 1.5g are heated to 75℃ for melting and mixing to obtain a molten oil phase; Tween 80 2.0g is dissolved in 98g purified water heated to 75℃ to obtain an aqueous phase; The aqueous phase is added to the oil phase, and high-speed shearing emulsification is carried out at 10000rpm for 3min, followed by high-pressure homogenization at 1000bar for 7 times, and cooling to obtain an NLCs dispersion with pH 6.0; (2) Vaseline 15.0g, cetyl alcohol 4.0g are heated to 65℃ to form an oil phase base; carbomer is swelled in the balance of purified water and heated to 65℃ to form an aqueous phase base; the oil phase base and the aqueous phase base are emulsified, and cooled to room temperature to obtain a cream base; The NLCs dispersion obtained in step (1) is mixed with the cream base, and homogenized for 5min to obtain a baricitinib nanoemulsion cream.

[0058] The test results of the baricitinib nanoemulsion cream prepared in this example are as follows: average particle size 115nm, PDI 0.19, encapsulation efficiency 94.2%; 12h release rate 70.5%; transdermal penetration amount (24h); stability: particle size change <4% at 40℃ for 3 months; pig ear skin model shows that the 24h penetration amount is 3 times higher than that of the commercially available ordinary cream (15.6 μg / cm 2 ).

[0059] Example 3 A baricitinib nanoemulsion cream is composed of a cream base and a nanostructured lipid carrier dispersed in the cream base; The nanostructured lipid carrier is composed of baricitinib, solid lipid (glyceryl behenate), liquid lipid (caprylic / capric triglyceride) and non-ionic emulsifier (poloxamer 188); The total mass of the solid lipid and the liquid lipid accounts for 7.2% of the mass percentage of the baricitinib nanoemulsion cream; the mass ratio of the solid lipid to the liquid lipid is 5:1; The non-ionic emulsifier accounts for 2.0% of the mass percentage of the baricitinib nanoemulsion cream; The baricitinib accounts for 1.0% of the mass percentage of the baricitinib nanoemulsion cream; The cream base is composed of a humectant (glycerin) 10%, a thickening agent (carbomer) 1.0%, an oil phase vaseline 15%, cetyl alcohol 5.0%, and the balance purified water.

[0060] The preparation method of the baricitinib nanoemulsion cream is as follows: (1) 1.0g baricitinib (molecular weight 371.42Da, water solubility 0.4mg / mL), glyceryl behenate 6.0g and caprylic / capric triglyceride 1.2g are heated to 75℃ for melt mixing to obtain a melt oil phase; Poloxamer 188 2.0g is dissolved in 98g purified water and heated to 75℃ for dissolution to obtain an aqueous phase; The aqueous phase is added to the oil phase, which is emulsified at 10000rpm for 3min, and then homogenized at 800bar pressure for 6 times, and cooled to obtain an NLCs dispersion with pH 6.0; (2) Vaseline 15.0g, cetyl alcohol 5.0g are heated to 65℃ to form an oil phase base; carbomer is swelled in the balance of purified water and heated to 65℃ to form an aqueous phase base; the oil phase base and the aqueous phase base are emulsified, and cooled to room temperature to obtain a cream base; The NLCs dispersion obtained in step (1) is mixed with the cream base, and homogenized for 5min to obtain a baricitinib nanoemulsion cream.

[0061] The test results of the baricitinib nanoemulsion cream prepared in this example are as follows: particle size 148nm, PDI 0.23, encapsulation efficiency 92.8%; release rate 66%; penetration amount 46μg / cm 2 .

[0062] Comparative Example 1 A baricitinib nanoemulsion cream is composed of a cream base and baricitinib dispersed in the cream base; The baricitinib accounts for 1.0% of the mass percentage of the baricitinib nanoemulsion cream; The cream base is composed of a humectant (glycerin) 10%, a thickening agent (carbomer) 1.0%, an oil phase vaseline 15%, cetyl alcohol 5.0%, and the balance purified water.

[0063] The preparation method of the baricitinib nanoemulsion cream is as follows: Vaseline 15.0g, cetyl alcohol 5.0g are heated to 65℃ to form an oil phase base; carbomer is swelled in the balance of purified water and heated to 65℃ to form an aqueous phase base; the oil phase base and the aqueous phase base are emulsified, and cooled to room temperature to obtain a cream base; 1.0g baricitinib is mixed with the cream base, and homogenized for 5min to obtain a baricitinib nanoemulsion cream.

[0064] The test results of the baricitinib nano cream prepared in this comparative example: uneven drug distribution, content decreased by 12% after 1 month at 40℃; wide particle size distribution (>500nm), release rate 32%; permeation amount 18μg / cm 2 , poor stability (significant precipitation).

[0065] Comparative Example 2 A baricitinib nano cream, consisting of a cream base and nanostructured lipid carriers dispersed in the cream base; The nanostructured lipid carriers consist of baricitinib, solid lipid (glyceryl behenate) and non-ionic emulsifier (poloxamer 188); The mass percentage of the solid lipid in the baricitinib nano cream is 7%; The mass percentage of the non-ionic emulsifier in the baricitinib nano cream is 2.0%; The mass percentage of the baricitinib in the baricitinib nano cream is 1.0%; The cream base consists of humectant (glycerin) 10%, thickening agent (carbomer) 1.0%, oil phase vaseline 15%, cetyl alcohol 5.0% and the balance purified water.

[0066] The preparation method of the baricitinib nano cream is as follows: (1) 1.0g baricitinib (molecular weight 371.42Da, water solubility 0.4mg / mL) and glyceryl behenate 5.0g are heated to 75℃ for melt mixing to obtain a melt oil phase; Poloxamer 188 2.0g is dissolved in 98g purified water heated to 75℃ to obtain an aqueous phase; The aqueous phase is added to the oil phase, which is emulsified at 10000rpm for 3min, followed by high pressure homogenization at 800bar for 6 times, and cooled to obtain an NLCs dispersion with pH 6.0; (2) Vaseline 15.0g and cetyl alcohol 5.0g are heated to 65℃ to form an oil phase base; carbomer is swelled in the balance of purified water and heated to 65℃ to form an aqueous phase base; the oil phase base and the aqueous phase base are emulsified, and cooled to room temperature to obtain a cream base; The NLCs dispersion obtained in step (1) is mixed with the cream base, and homogenized for 5min to obtain a baricitinib nano cream.

[0067] The test results of the baricitinib nano cream prepared in this comparative example: particle size 385nm, PDI 0.42, encapsulation efficiency 65.8%; release rate 45%; permeation amount 28μg / cm 2 , indicating that liquid lipid is the key to improving drug loading and permeation.

[0068] The test results of examples 1~2, comparative examples 1~2 and the commercially available cream (reference CN112168774A) are compared as shown in Table 1.

[0069] Table 1 Comparison of test results of different baricitinib nano cream

[0070] From the above results, it can be seen that the permeability, release rate and stability of the baricitinib nano cream provided by the present application are significantly improved compared with the comparative examples and the commercially available cream, which is because the baricitinib nano cream provided by the present application comprises a cream base and a nanostructured lipid carrier dispersed in the cream base, the nanostructured lipid carrier comprises a solid lipid, a liquid lipid and a non-ionic emulsifier, and the types of solid lipid and liquid lipid are specifically limited, so that the solid lipid provides structural stability, the liquid lipid introduces lattice defects, improves the solubility and encapsulation efficiency of baricitinib or its pharmaceutically acceptable salt, and further improves the release rate and stability of the baricitinib nano cream. The nanostructured lipid carrier dispersed in the cream base can significantly improve the permeability and adhesion of the baricitinib nano cream, improve the local drug delivery efficiency of baricitinib, and is suitable for treating atopic dermatitis, psoriasis and other inflammatory skin diseases.

[0071] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered within the scope of protection of the present application.

Claims

1. A baricitinib nano cream characterized in that, The cream base and the nanostructured lipid carrier dispersed in the cream base; The nanostructured lipid carrier comprises baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid, a liquid lipid and a non-ionic emulsifier; The solid lipid comprises glyceryl behenate and / or glyceryl stearate; The liquid lipid comprises one or more of caprylic / capric triglyceride, oleic acid and isopropyl myristate; The baricitinib or the pharmaceutically acceptable salt thereof accounts for 0.2-2.0% of the mass percentage of the baricitinib nano-cream.

2. The baricitinib nano cream of claim 1, wherein, The nanostructured lipid carrier has a particle size of 80-250 nm, a polydispersity index <0.25 and an encapsulation efficiency >92%.

3. The baricitinib nano cream of claim 1, wherein, The cream base comprises, based on 100% of the mass percentage of the baricitinib nano-cream, 5.0-15% of a humectant, 0.5-2% of a thickening agent, 10-30% of an oil phase and purified water.

4. The baricitinib nano cream of claim 1, wherein, The non-ionic emulsifier comprises poloxamer 188 or Tween 80.

5. The baricitinib nano cream of claim 1 or 4, wherein, The non-ionic emulsifier accounts for 1.5-3.0% of the mass percentage of the baricitinib nano-cream.

6. The baricitinib nano cream of claim 1 or 4, wherein, The mass ratio of the solid lipid to the liquid lipid is 2.5-9:1, and the total mass of the solid lipid and the liquid lipid accounts for 5.0-7.0% of the mass percentage of the baricitinib nano-cream.

7. A process for the preparation of the baricitinib nano cream of any one of claims 1 to 6, characterized in that, The method comprises the following steps: (1) melt-mixing baricitinib or a pharmaceutically acceptable salt thereof, a solid lipid and a liquid lipid to obtain a molten oil phase; dissolving a non-ionic emulsifier in water to obtain an aqueous phase; mixing the molten oil phase with the aqueous phase, and then sequentially performing emulsification and homogenization to obtain an NLCs dispersion; (2) mixing the NLCs dispersion obtained in step (1) with a cream base to obtain a baricitinib nano-cream.

8. The production method according to claim 7, characterized by, The mass ratio of the molten oil phase to the aqueous phase in step (1) is 1:5-20.

9. The preparation method according to claim 7, characterized in that, The homogenization in step (1) is high-pressure homogenization, the pressure of the high-pressure homogenization is 600-1200 bar, and the high-pressure homogenization is performed for 4-8 cycles.

10. The preparation method according to claim 7, characterized in that, The preparation method of the cream base in step (2) comprises: mixing a humectant and an oil phase at 60-70°C to obtain an oil phase base; swelling a thickening agent and purified water at 60-70°C to obtain an aqueous phase base; and emulsifying the oil phase base and the aqueous phase base to obtain a cream base.

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