Chloramphenicol binary alcohol liposome, external preparation, preparation method and application thereof

Abstract

The application provides a chloramphenicol niosome, an external preparation, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations; the chloramphenicol niosome is a vesicle structure, comprising a lipid bilayer and chloramphenicol wrapped in the lipid bilayer; the chloramphenicol niosome is prepared from raw materials comprising the following components: chloramphenicol, lecithin, ethanol, propylene glycol, Tween-80 and water; and the particle size of the chloramphenicol niosome is less than or equal to 200 nm. In the application, the chloramphenicol niosome is nanoscale, the fluidity of the bilayer membrane is good, the transdermal absorption and permeability are superior, and the chloramphenicol can better penetrate the skin barrier; the gel composed of the chloramphenicol niosome and a gel base has better stability and transdermal absorption, effectively increases the retention rate of chloramphenicol on the skin, and enhances the transdermal penetration effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a chloramphenicol diol plastid, a topical formulation, its preparation method, and its application. Background Technology

[0002] Acne is a common chronic pilosebaceous unit disease that typically occurs on the face and trunk, affecting approximately 9% of the global population (about 85% of patients aged 12–24 and about 50% of patients aged 20–29), and can cause permanent body scarring.

[0003] Chloramphenicol is a broad-spectrum antibacterial agent with the molecular formula C. 11 H 12 Cl2N2O5, with a relative molecular mass of 323, exhibits broad-spectrum antimicrobial activity against aerobic Gram-negative bacteria, Gram-positive bacteria, anaerobic bacteria, Rickettsiae, Spirochetes, and Chlamydiae in vitro. Its mechanism of action involves inhibiting bacterial protein synthesis, resulting in bacteriostatic activity. It is effective against Gram-positive bacteria and has a significant bactericidal effect against Propionibacterium acnes, reducing inflammation at the lesion site. Due to its bone marrow toxicity, the oral and intravenous use of chloramphenicol is currently limited, and it is primarily used to treat eye and ear infections. Chloramphenicol is also commonly used in topical preparations for acne treatment, such as chloramphenicol lotion, chloramphenicol liniment, and chloramphenicol gel; however, these preparations suffer from poor transdermal absorption. Summary of the Invention

[0004] The purpose of this invention is to provide a chloramphenicol diol plasmid, a topical formulation, a method for preparing the same, and its application. The chloramphenicol diol plasmid of this invention can carry chloramphenicol across the skin barrier, exhibiting excellent transdermal absorption and penetration properties.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a chloramphenicol diol corpuscle, wherein the chloramphenicol diol corpuscle has a vesicular structure comprising a lipid bilayer and chloramphenicol encapsulated within the lipid bilayer; the chloramphenicol diol corpuscle is prepared from raw materials comprising the following components: chloramphenicol, lecithin, ethanol, propylene glycol, Tween-80, and water;

[0007] The particle size of the chloramphenicol diol protome is ≤200nm.

[0008] Preferably, the first raw material is used as a solvent, and the chloramphenicol diol proteome comprises the following components at the following concentrations based on the volume of the solvent: chloramphenicol 0.1-0.3 g / 100 mL, lecithin 1-5 g / 100 mL, and Tween-80 0.1-0.2 g / 100 mL;

[0009] The first raw material preferably comprises the following components in parts by volume: 9-20 parts ethanol, 15-28 parts propylene glycol, and 60-70 parts water.

[0010] Preferably, the volume ratio of ethanol to propylene glycol is (3-5):(5-7).

[0011] The present invention also provides a method for preparing the chloramphenicol diol plasmid described in the above scheme, comprising the following steps:

[0012] Chloramphenicol, lecithin, ethanol and propylene glycol were mixed to obtain an alcoholic solution;

[0013] Tween-80 is dissolved in water to obtain a Tween-80 solution;

[0014] The Tween-80 solution was added to the alcohol phase solution to obtain crude chloramphenicol diol morphology;

[0015] The crude chloramphenicol diol plasmid was subjected to ultrasound to obtain chloramphenicol diol plasmid.

[0016] Preferably, the power of the ultrasound is 150-300W.

[0017] The present invention also provides an in vitro formulation of chloramphenicol diol, comprising a gel matrix and chloramphenicol diol; wherein the chloramphenicol diol comprises the chloramphenicol diol described in the above scheme or the chloramphenicol diol prepared by the preparation method.

[0018] Preferably, the gel matrix comprises carbomer.

[0019] This invention also provides a method for preparing the chloramphenicol diol in vitro formulation described above, comprising the following steps:

[0020] The chloramphenicol diol protoplast described above is dispersed in a swollen gel matrix to obtain an in vitro formulation of chloramphenicol diol protoplast.

[0021] Preferably, the swollen gel matrix is ​​a gel matrix swollen with water; the total volume ratio of water used to swell the gel matrix and the chloramphenicol diol body to the mass ratio of the gel matrix is ​​100 mL: (0.6-1.2) g; the volume ratio of water used to swell the gel matrix to the chloramphenicol diol body is 2:1.

[0022] The present invention also provides the use of the chloramphenicol diol protease described in the above-described scheme or the chloramphenicol diol protease prepared by the above-described preparation method or the chloramphenicol diol protease for external use or the chloramphenicol diol protease for external use prepared by the above-described preparation method in the preparation of drugs for the prevention or treatment of acne.

[0023] Compared with the prior art, the present invention has the following significant advantages:

[0024] This invention provides a chloramphenicol diol granule, which has a vesicle structure comprising a lipid bilayer and chloramphenicol encapsulated within the lipid bilayer. The chloramphenicol diol granule is prepared from raw materials comprising the following components: chloramphenicol, lecithin, ethanol, propylene glycol, Tween-80, and water. The particle size of the chloramphenicol diol granule is ≤200 nm. In this invention, the chloramphenicol diol granule is nanoscale, and the lipid bilayer membrane exhibits good fluidity and deformability, resulting in superior transdermal absorption and permeation performance. It can carry chloramphenicol through the skin barrier effectively, thus improving the bioavailability and therapeutic index of chloramphenicol. The use of ethanol and propylene glycol solutions to prepare the diol granule prevents aggregation between the diol granules, reduces volatility, increases stability, and to some extent avoids drug leakage and reduces skin irritation. Compared to chloramphenicol alcohol solutions, the chloramphenicol diol granule encapsulating chloramphenicol in this invention provides better stability and transdermal absorption. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 Electron micrograph of the prepared chloramphenicol diol plometabolite;

[0027] Figure 2 The particle size distribution diagram of the prepared chloramphenicol diol granules;

[0028] Figure 3 The encapsulation efficiency of the prepared chloramphenicol diol protoplasts varies with time.

[0029] Figure 4 The graph shows the cumulative in vitro release of chloramphenicol diol, chloramphenicol alcohol, and chloramphenicol alcohol solution over time.

[0030] Figure 5 The graph shows the change in transdermal permeation of chloramphenicol diol, chloramphenicol alcohol, and chloramphenicol alcohol solution over time.

[0031] Figure 6 The graph shows the change in the cumulative in vitro release of chloramphenicol diol pluripotent gel, chloramphenicol pluripotent gel, and chloramphenicol alcohol solution gel over time.

[0032] Figure 7 The graph shows the change in transdermal penetration over time for chloramphenicol diol pluripotent gel, chloramphenicol pluripotent gel, and chloramphenicol alcohol solution gel. Detailed Implementation

[0033] This invention provides a chloramphenicol diol pluripotent, wherein the chloramphenicol diol pluripotent has a vesicular structure comprising a lipid bilayer and chloramphenicol encapsulated within the lipid bilayer; the chloramphenicol diol pluripotent is prepared from raw materials comprising the following components: chloramphenicol, lecithin, ethanol, propylene glycol, Tween-80, and water; the particle size of the chloramphenicol diol pluripotent is ≤200 nm. In this invention, the particle size of the chloramphenicol diol pluripotent is more preferably 80–120 nm.

[0034] In this invention, using the first raw material as a solvent, the chloramphenicol diol protome further comprises the following components at the following concentrations based on the volume of the solvent: chloramphenicol 0.1-0.3 g / 100 mL, lecithin 1-5 g / 100 mL, and Tween-80 0.1-0.2 g / 100 mL; more preferably, using the first raw material as a solvent, the chloramphenicol diol protome is composed of the following components at the following concentrations based on the volume of the solvent: chloramphenicol 0.1-0.3 g / 100 mL, lecithin 1-5 g / 100 mL, and Tween-80 0.1-0.2 g / 100 mL.

[0035] In this invention, the first raw material is used as a solvent, and the chloramphenicol diol proteome further includes the following components at the following concentrations based on the volume of the solvent: chloramphenicol 0.1-0.15 g / 100 mL, lecithin 1-2 g / 100 mL, and Tween-80 0.1-0.2 g / 100 mL.

[0036] In this invention, the first raw material preferably comprises the following components in parts by volume: 9-20 parts of ethanol, 15-28 parts of propylene glycol, and 60-70 parts of water; more preferably, the first raw material is composed of the following components in parts by volume: 9-20 parts of ethanol, 15-28 parts of propylene glycol, and 60-70 parts of water.

[0037] In this invention, the first raw material comprises 9 to 20 parts of ethanol, more preferably 9 to 16 parts, by volume. The role of the ethanol is to increase the flexibility and fluidity of the lipid bilayer, making it easy to deform during transdermal drug delivery and facilitating its penetration through the gaps in the stratum corneum of the skin.

[0038] In this invention, the first raw material comprises 15 to 28 parts of propylene glycol by volume, more preferably 18 to 24 parts; the role of propylene glycol is to prevent aggregation between diol protons, reduce ethanol volatility, increase stability, avoid drug leakage to a certain extent, reduce skin irritation, form a synergistic effect with ethanol, promote transdermal absorption, and increase the transdermal absorption effect of the drug.

[0039] In this invention, the first raw material comprises 60-70 parts by volume, more preferably 65-70 parts by volume; the water is preferably purified water.

[0040] In this invention, the lecithin is preferably soybean lecithin.

[0041] In this invention, the role of Tween-80 in chloramphenicol diol plasmids is to increase stability and prevent vesicle fusion, thereby reducing vesicle size and enhancing skin permeability.

[0042] In this invention, the volume ratio of ethanol to propylene glycol is further preferably (3-5):(5-7), more preferably 3:7. In this invention, the use of ethanol and propylene glycol to prepare the ethanol-based protoplasm reduces the amount of ethanol used, increases stability, reduces irritation to the skin and mucous membranes, and allows both to synergistically promote transdermal absorption, increasing transdermal drug absorption and improving drug retention in the skin.

[0043] The present invention also provides a method for preparing the chloramphenicol diol plasmid described in the above scheme, comprising the following steps:

[0044] Chloramphenicol, lecithin, ethanol and propylene glycol were mixed to obtain an alcoholic solution;

[0045] Tween-80 is dissolved in water to obtain a Tween-80 solution;

[0046] The Tween-80 solution was added to the alcohol phase solution to obtain crude chloramphenicol diol morphology;

[0047] The crude chloramphenicol diol plasmid was subjected to ultrasound to obtain chloramphenicol diol plasmid.

[0048] This invention involves mixing chloramphenicol, lecithin, ethanol, and propylene glycol to obtain an alcohol phase solution.

[0049] In this invention, the mixing is preferably carried out under water bath conditions; the mixing preferably includes stirring. In this invention, the temperature of the water bath is preferably 25–35°C, more preferably 30°C. In this invention, the stirring speed is preferably 600–800 r / min, more preferably 700 r / min; the stirring time is preferably 10–30 min, further preferably 20–30 min, more preferably 30 min.

[0050] The present invention dissolves Tween-80 in water to obtain a Tween-80 solution.

[0051] In this invention, the purpose of preparing the alcohol phase solution and the Tween-80 solution is that when the Tween-80 solution is added to the alcohol phase, it can increase stability and prevent vesicle fusion.

[0052] After obtaining the alcohol phase solution and the Tween-80 solution, the present invention adds the Tween-80 solution to the alcohol phase solution to obtain crude chloramphenicol binary alcohol body.

[0053] In this invention, the addition of Tween-80 solution to the alcohol phase solution preferably includes: slowly injecting Tween-80 solution into the alcohol phase solution under stirring conditions; the slow injection preferably includes the following steps: drawing the Tween-80 solution into a syringe and slowly injecting it drop by drop into the alcohol phase solution; the stirring speed is the same as described above, and will not be repeated here. In this invention, when Tween-80 solution is added to the alcohol phase solution, phospholipid molecules can automatically form vesicles with a lipid bilayer in water, and encapsulate chloramphenicol within the vesicles.

[0054] After adding the Tween-80 solution to the alcohol phase solution, the present invention preferably further includes stirring and mixing; the stirring speed is the same as the above scheme, and will not be repeated here; the stirring and mixing time is preferably 30 min.

[0055] After obtaining crude chloramphenicol diol morphology, the present invention sonicates the crude chloramphenicol diol morphology to obtain chloramphenicol diol morphology.

[0056] In this invention, the ultrasound is preferably performed under ice bath conditions; the ultrasound power is preferably 100-300W, more preferably 100-200W, and even more preferably 200W; the ultrasound duration is preferably 3-8 minutes, and even more preferably 6 minutes. By employing the above-mentioned ultrasound conditions, this invention can reduce the particle size of the diol liposomes, ensure sufficient and uniform dispersion of vesicles, and avoid damaging the liposomes, thus facilitating drug loading.

[0057] Following the ultrasound, the present invention preferably further includes filtering the ultrasound product; the pore size of the filter membrane used for filtration is preferably 0.22 μm; and the filtration is preferably performed three times. The present invention, by using a 0.22 μm filter membrane, can effectively remove unencapsulated phospholipids and free drugs.

[0058] The present invention also provides an in vitro formulation of chloramphenicol diol, comprising a gel matrix and chloramphenicol diol; wherein the chloramphenicol diol comprises the chloramphenicol diol described in the above scheme or the chloramphenicol diol prepared by the preparation method.

[0059] The present invention also provides a method for preparing the chloramphenicol diol in vitro formulation described in the above scheme, comprising the following steps: dispersing the chloramphenicol diol described in the above scheme in a swollen gel matrix to obtain the chloramphenicol diol in vitro formulation.

[0060] In this invention, the swollen gel matrix is ​​preferably a gel matrix swollen with water; the water is preferably purified water. In this invention, the mass ratio of the total volume of water and chloramphenicol diol used to swell the gel matrix to the mass of the gel matrix is ​​preferably 100 mL:(0.6–1.2) g, more preferably 100 mL:(0.8–1.2) g, and even more preferably 100 mL:1 g. The gel prepared at this ratio has uniform shape, suitable viscosity, and is easy to spread.

[0061] In this invention, the volume ratio of water used for swelling the gel matrix to the chloramphenicol diol colloid is 2:1.

[0062] In this invention, the dispersion step preferably includes adding the diol body to the swollen gel formulation and stirring with a stir bar; this method enables the solution to be uniformly dispersed in the gel matrix.

[0063] In this invention, the gel matrix preferably comprises carbomer, more preferably carbomer 940. After the gel matrix swells, the invention preferably further includes adjusting the pH of the swollen gel matrix to 6-8; under the above pH conditions, it will not irritate the skin and will not affect the physical and chemical stability of the formulation.

[0064] The present invention also provides the application of the chloramphenicol diol protease described in the above-described scheme or the chloramphenicol diol protease prepared by the above-described preparation method or the chloramphenicol diol protease for external use or the chloramphenicol diol protease for external use prepared by the above-described preparation method in the preparation of a drug for treating acne.

[0065] In this invention, the dosage form of the drug preferably includes gel, ointment, lotion or liniment; the drug is preferably administered transdermally during the treatment of acne; the acne preferably includes acne conglobata, acne fulminans, drug-induced acne, premenstrual acne or cosmetic acne.

[0066] To further illustrate the present invention, the chloramphenicol diol plastisol, topical preparation, preparation method, and application provided by the present invention are described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0067] Example 1

[0068] Preparation of chloramphenicol diol plastids

[0069] Chloramphenicol 5mg, soybean lecithin 100mg, Tween-80 0.01mg, ethanol 0.45mL, propylene glycol 1.05mL, purified water 3.5mL.

[0070] Chloramphenicol diol plasti was prepared using an injection-ultrasound method: The prescribed amounts of chloramphenicol, soybean lecithin, ethanol, and propylene glycol were accurately weighed and placed in a vial. The solution was stirred at 700 rpm for 30 minutes in a 30°C water bath until completely dissolved, yielding an alcohol phase solution. Tween-80 was dissolved in water to obtain a Tween-80 solution. Then, in a 30°C water bath, the Tween-80 solution was drawn into a syringe and slowly injected drop by drop into the alcohol phase solution. After complete addition, stirring was continued at 700 rpm for 30 minutes to obtain crude chloramphenicol diol plasti. The crude chloramphenicol diol plasti was ultrasonicated for 6 minutes in an ice bath at 200 W, followed by filtration three times using a 0.22 μm filter membrane to obtain purified chloramphenicol diol plasti. The purified plasti was then sealed and stored at 4°C.

[0071] Example 2

[0072] The raw materials for chloramphenicol diol plastid are: 7.5 mg chloramphenicol, 150 mg soybean lecithin, 0.02 mg Tween-80, 1 mL ethanol, 1 mL propylene glycol, and 3 mL purified water.

[0073] The remaining chloramphenicol diol protoplasts were prepared according to the preparation method in Example 1.

[0074] Example 3

[0075] Electron microscopy and particle size measurement were performed on the chloramphenicol diol granules in Example 1.

[0076] The structure of chloramphenicol diol protoplasts was observed using an HT7700 transmission electron microscope; the particle size of the chloramphenicol diol protoplasts was measured using a Malvern nanoparticle size analyzer.

[0077] The structure of chloramphenicol diol plasmid under an electron microscope is shown below. Figure 1 As shown in the figure, the chloramphenicol diol protoplast of the present invention forms a vesicle structure, wherein the outer layer of the vesicle is a lipid bilayer and the interior of the vesicle is chloramphenicol.

[0078] The particle size distribution of chloramphenicol diol pluripotents is as follows: Figure 2 As shown in the figure, the overall particle size of chloramphenicol diol protons ranges from 61 to 266 nm, with an average particle size of 114 nm; chloramphenicol diol protons with a particle size of 80 to 140 nm account for 71.40%.

[0079] Example 4

[0080] The encapsulation efficiency and drug loading of chloramphenicol diol plasmids in Example 1 were determined.

[0081] 1. Test Methods

[0082] Total drug content determination: Pipette 0.5 mL of chloramphenicol diol liposome into a 10 mL volumetric flask, add methanol to break the emulsion, and sonicate for 10 min. Dilute to the mark and mix thoroughly. Take 2.5 mL of this solution and place it in a 10 mL volumetric flask, then add methanol to the mark. Measure the absorbance of chloramphenicol at 274 nm using a cuvette, and record the absorbance as W. 总 .

[0083] Determination of free drug: Pipette 0.5 mL (from the same batch as the total drug concentration) of chloramphenicol diol into a centrifuge tube and place it in a refrigerated centrifuge. The program is set as follows: centrifugation speed 6000 rpm, time 30 min, temperature 4℃. After centrifugation and standing for 10 min, transfer 0.2 mL of the supernatant to a 10 mL volumetric flask, add methanol, sonicate, and dilute to the mark. Then, take 2.5 mL of this supernatant and transfer it to a 5 mL volumetric flask, and dilute to the mark with methanol. Place an appropriate amount in a cuvette and measure the absorbance of chloramphenicol at 274 nm, denoted as W. 游 .

[0084] Encapsulation efficiency (%) = (W 总 -W 游 ) / W 总 ×100% formula (1).

[0085] Drug loading (%) = (W 总 -W 游 ) / W s ×100% formula (2).

[0086] Equations (1) and (2) represent the formulas for calculating encapsulation efficiency and drug loading, respectively, where W s The total weight of chloramphenicol and soybean lecithin in the chloramphenicol diol plastid formulation in Example 1.

[0087] 2. Test Results

[0088] The results are shown in Table 1 and Figure 3 As shown in the figure, the encapsulation efficiency of chloramphenicol diol plosomes changes over time. Figure 3 As shown, the encapsulation efficiency and drug loading of chloramphenicol diols did not change significantly after being placed at 4°C for 5 days, decreased slightly on the 10th day, and decreased significantly on the 15th day, indicating that the diols have good stability after being placed at 4°C for 10 days.

[0089] Table 1. Changes in encapsulation efficiency and drug loading of chloramphenicol diol plasmids over time.

[0090]

[0091] Example 5: Comparative test of in vitro release of chloramphenicol diol serotonide, chloramphenicol alcohol serotonide, and chloramphenicol alcohol solution.

[0092] 1. Preparation of test materials

[0093] Chloramphenicol diol plasmid prepared according to the scheme of Example 1.

[0094] Chloramphenicol alcohol solution: Weigh 5 mg of chloramphenicol, add 0.45 mL of ethanol and 1.05 mL of propylene glycol, and finally add water to 5 mL to obtain chloramphenicol alcohol solution.

[0095] Chloramphenicol protoplasts: prepared using conventional methods in the art.

[0096] 2. Experimental Methods

[0097] Dialysis bags with a molecular weight cutoff of 3500 were selected, and isotonic PBS buffer with a pH of 7.4 was used as the release medium. The in vitro release rates of chloramphenicol octanoic acid, chloramphenicol alcohol solution, and chloramphenicol diol octanoic acid were analyzed and compared. 200 mL of isotonic PBS buffer was used as the release medium at 32°C with a stirring speed of 300 rpm to ensure good flowability. Samples were taken at 1, 2, 4, 6, 8, 10, 12, 24, and 36 hours, with 1 mL of sample taken each time and 1 mL of isothermal release medium added. The chloramphenicol content was determined using high-performance liquid chromatography (HPLC).

[0098] Chromatographic conditions: SepaChrom C18 reversed-phase column (250 mm × 4.6 mm, 5 μm); mobile phase: 0.01 mol / L sodium heptanesulfonate buffer solution-methanol, wherein the volume ratio of sodium heptanesulfonate buffer solution to methanol is 60:40; flow rate: 1 mL / min; injection volume: 20 μL; column temperature: 30 °C; detection wavelength: 274 nm; the preparation method of the sodium heptanesulfonate buffer solution is as follows: take 6.8 g of potassium dihydrogen phosphate, dissolve and dilute it to 1000 mL with 0.01 mol / L sodium heptanesulfonate solution, add 5 mL of triethylamine, mix well, and adjust the pH value to 2.5 with phosphoric acid.

[0099] 3. Experimental Results

[0100] The results are shown in Table 2 and Figure 4 As shown, the in vitro release curve is shown in the figure. Figure 4 .Depend on Figure 4It is known that chloramphenicol alcohol solution has a relatively rapid release rate, with the release being faster before 6 hours, and the release rate exceeding 70% by 4 hours. After 12 hours, the release tends to stabilize. The drug release from chloramphenicol alcohol octopuses and chloramphenicol diol octopuses is faster in the first 2 hours, possibly due to the release of unencapsulated chloramphenicol. After 2 hours, the release rate begins to slow down, exhibiting a sustained-release effect.

[0101] Table 2. In vitro release of chloramphenicol diol plasmid, chloramphenicol alcohol plasmid, and chloramphenicol alcohol solution at each time point (unit: %)

[0102]

[0103] Example 6: Transdermal Permeation Comparison Test of Chloramphenicol Diol Peptide, Chloramphenicol Alcohol Peptide, and Chloramphenicol Alcohol Solution

[0104] 1. Test materials

[0105] The chloramphenicol diol colloid, chloramphenicol colloid, and chloramphenicol alcohol solution described in Example 5

[0106] 2. Preparation of isolated rat skin

[0107] Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate. Abdominal hair was then carefully shaved with an electric shaver. A small amount of depilatory cream was applied to the shaved area to remove any remaining hair. After depilation, the area was carefully cleaned with a cotton swab dipped in warm water. Twenty-four hours after depilation, the rats were euthanized by cervical dislocation. The abdominal skin was quickly peeled off, and subcutaneous fat and adhesions were carefully removed, taking care to avoid skin damage. The peeled skin was repeatedly rinsed with physiological saline, dried, and stored at -20°C.

[0108] 3. Experimental Methods

[0109] The experiment was conducted using a modified Franz diffusion cell with a diameter of 15 mm and an effective diffusion area of ​​1.77 cm². 2 The receiving cell volume was 10 mL. Before the in vitro transdermal test, a stir bar was placed in the receiving cell, and a constant temperature water bath of 32±0.5℃ was set. The stirring speed was 300 r / min. PBS with a pH of 7.4 was added to the receiving cell as the receiving solution to ensure that the "leakage condition" was met. Frozen mouse skin was thawed with physiological saline and laid flat on the Franz diffusion cell with the stratum corneum facing upwards. It was fixed in place, ensuring that the surface of the receiving solution was in full contact with the skin underneath without air bubbles. 1 mL of chloramphenicol alcohol solution, 1 mL of chloramphenicol alcohol body, and 1 mL of chloramphenicol diol body were added to the supply chamber and laid flat on the skin. 1.0 mL of receiving solution was collected at time points of 1, 2, 4, 6, 9, 12, 24, and 36 hours, and an equal volume of fresh receiving solution at the same temperature was added simultaneously. The transdermal receiving solution of the gel was filtered through a 0.22 μm microporous membrane and analyzed by HPLC.

[0110] After 24 hours of sampling, excess chloramphenicol preparation was gently wiped from the skin surface with filter paper. The skin surface was then rinsed with methanol and saline and blotted dry with filter paper. The skin was cut into small pieces, 1 mL of methanol was added, and homogenization was performed for 10 min. Then, ultrasonic extraction was performed three times, 15 min each time, at a speed of 10000 rpm. -1 Centrifuge for 10 min and analyze the supernatant. Calculate the cumulative transdermal drug delivery (Qn / μg·cm³) according to formula (3). -2 Equation (3) Qn represents the cumulative permeability per unit area (μg / cm²). 2 ), C i V represents the drug concentration (μg / mL) measured at the i-th time point. i C represents the sampling volume (mL) at the i-th time point. n V n Let A be the total drug permeation at time point i-1, and let A be the area of ​​the receiving pool (cm²). 2 In this experiment, V was 10 mL and A = 1.77 cm. 2

[0111] Cumulative permeability

[0112] 3. Experimental Results

[0113] The results are shown in Table 3 and Figure 5 As shown, the in vitro percutaneous permeability curve is shown below. Figure 5 As shown in Table 3, the Qn of the chloramphenicol alcohol solution is 128.63 μg·cm⁻¹. -2 The Qn of chloramphenicol alcohol lyosomes is 174.38 μg·cm⁻¹. -2 The Qn of chloramphenicol diol plasmid is 191.20 μg·cm⁻¹. -2 The cumulative permeability of chloramphenicol alcohol solution and chloramphenicol octopus is lower than that of chloramphenicol diol octopus, possibly because the diol contained in chloramphenicol diol octopus promotes transdermal permeation.

[0114] Table 3. Cumulative permeation per unit area at each time point for chloramphenicol diol plastisol, chloramphenicol alcohol plastisol, and chloramphenicol alcohol solution (unit: μg·cm³). -2 )

[0115]

[0116] Example 7

[0117] The volume ratio of ethanol to propylene glycol is 2:8;

[0118] Chloramphenicol diol plasmids were prepared according to the scheme in Example 1.

[0119] Example 8

[0120] The volume ratio of ethanol to propylene glycol is 4:6;

[0121] Chloramphenicol diol plasmids were prepared according to the scheme in Example 1.

[0122] Example 9

[0123] The volume ratio of ethanol to propylene glycol is 5:5;

[0124] Chloramphenicol diol plasmids were prepared according to the scheme in Example 1.

[0125] Example 10

[0126] Experiments were conducted on the chloramphenicol diol liposomes of Examples 1 and 7-9, with each group repeated three times, to investigate the effect of the mixing volume ratio of ethanol and propylene glycol on the particle size, encapsulation efficiency, drug loading, potential, and PDI (polymer dispersibility index) of the diol liposomes.

[0127] The results are shown in Table 4. The table shows that when the ethanol:propylene glycol ratio is 3:7, the particle size is optimal, the encapsulation efficiency and drug loading are highest, and the particle size distribution is concentrated. Furthermore, compared to ordinary ethanol esters, binary ethanol esters reduce the amount of ethanol used, thus decreasing irritation to the skin and mucous membranes.

[0128] Table 4. Effects of the volume ratio of ethanol to propylene glycol on the particle size, encapsulation efficiency, drug loading, site of action, and PDI of the diol granules.

[0129]

[0130] Example 11

[0131] Chloramphenicol diol morphosomes were prepared according to the scheme in Example 1, except that the power of the ultrasound was 150W.

[0132] Example 12

[0133] Chloramphenicol diol morphosomes were prepared according to the scheme in Example 1, except that the power of the ultrasound was 300W.

[0134] Example 13: Experiments were conducted on chloramphenicol diol granules from Examples 1, 11, and 12 to investigate the effect of ultrasonic power on the particle size and encapsulation efficiency of the chloramphenicol diol granules.

[0135] The results are shown in Table 5. As can be seen from the table, when the ultrasonic power is 200W, the chloramphenicol diol colloids obtained have the smallest particle size and the highest encapsulation efficiency.

[0136] Table 5. Effect of ultrasonic power on chloramphenicol diol granule size and encapsulation efficiency.

[0137]

[0138] Example 14

[0139] Preparation of chloramphenicol diol plogel

[0140] Example 1 prepared 2 mL of chloramphenicol diol plasmid, 4 mL of purified water, and 60 mg of carbomer 940.

[0141] Weigh out the above-prescribed amount of carbomer 940, add it to 4 mL of purified water and let it swell overnight. Adjust the pH to 7 with sodium hydroxide, then add 2 mL of chloramphenicol diol gel and stir well to obtain chloramphenicol diol gel.

[0142] Example 15

[0143] Chloramphenicol diol plasmid in Example 2

[0144] The remaining preparations followed the protocol outlined in Example 14 to prepare chloramphenicol diol liposome gels.

[0145] Example 16 Comparison Test of Different Gel Matrices

[0146] 1. Preparation of different blank gel matrices

[0147] ① Preparation of 1% sodium carboxymethyl cellulose (CMC-Na) gel matrix: Weigh 60 mg of CMC-Na powder and 15 mg of NaOH, add 6 mL of purified water to make it fully swollen, stir evenly, and observe the appearance of the gel.

[0148] ② Preparation of 1% Carbomer 940 (C940) gel matrix: Weigh 60mg of C-940 powder and 15mg of NaOH, add 6mL of purified water to make it fully swollen, stir evenly, and observe the appearance of the gel.

[0149] ③ Preparation of 1% gelatin gel matrix: Weigh 60mg of gelatin, add 6mL of purified water to make it fully swollen, stir evenly, and observe the appearance of the gel.

[0150] ④ Preparation of 1% sodium alginate gel matrix: Weigh 60 mg of sodium alginate, add 6 mL of purified water to make it fully swollen, stir evenly, and observe the appearance of the gel.

[0151] The suitable matrix is ​​selected by comparing the shapeability, color, uniformity, viscosity, spreadability and skin feel of various gel matrices.

[0152] 2. Experimental Results

[0153] The results are shown in Table 6. As can be seen from the table, carbomer and sodium carboxymethyl cellulose can both be formed when preparing blank gels, while sodium alginate cannot be formed. Gelatin gels have a strong granular texture and poor skin compliance. Therefore, sodium alginate and gelatin will not be considered in subsequent preparations of drug-containing gels.

[0154] Table 6 Properties of different gelling agents

[0155]

[0156] Comparative Example 1

[0157] The gel was made of sodium carboxymethyl cellulose (CMC-Na), and the amount of sodium carboxymethyl cellulose added was 1 g / 100 mL based on the total volume of chloramphenicol diol and purified water.

[0158] The remaining preparations were made using the same methods as in Examples 1 and 14. Chloramphenicol diol liposome gels were prepared.

[0159] Comparative Example 2

[0160] Sodium carboxymethyl cellulose was used as the gel, and the amount of sodium carboxymethyl cellulose added was 2g / 100mL based on the total volume of chloramphenicol diol and purified water.

[0161] The remaining preparations were made using the same methods as in Examples 1 and 14. Chloramphenicol diol liposome gels were prepared.

[0162] Comparative Example 3

[0163] The gel used was carbomer-940 (C-940), and the amount of carbomer-940 added was 0.6 g / 100 mL based on the total volume of chloramphenicol diol and purified water.

[0164] The remaining preparations were made using the same methods as in Examples 1 and 14. Chloramphenicol diol liposome gels were prepared.

[0165] Comparative Example 4

[0166] Carbomer-940 was selected for the gel, and the amount of carbomer-940 added was 0.8 g / 100 mL based on the total volume of chloramphenicol diol and purified water.

[0167] The remaining preparations were made using the same methods as in Examples 1 and 14. Chloramphenicol diol liposome gels were prepared.

[0168] Comparative Example 5

[0169] Carbomer-940 was used as the gel, and the amount of carbomer-940 added was 1.2 g / 100 mL based on the total volume of chloramphenicol diol and purified water.

[0170] The remaining preparations were made using the same methods as in Examples 1 and 14. Chloramphenicol diol liposome gels were prepared.

[0171] Example 17

[0172] The molding properties, color, uniformity, viscosity, spreadability, and skin feel of the chloramphenicol diol liposome gels in Example 14 and Comparative Examples 1-5 were examined to screen out suitable gel matrices and concentrations.

[0173] Test results

[0174] The results are shown in Table 7. The table shows that the gel prepared with C-940 at a concentration of 1.0% has a uniform shape, suitable viscosity, and is easy to spread.

[0175] Table 7 Properties of chloramphenicol diol tropoemulsions with different amounts of carbomer and sodium carboxymethyl cellulose.

[0176]

[0177] Example 18: Comparative in vitro release test of chloramphenicol diol pluripotent gel, chloramphenicol pluripotent gel, and chloramphenicol alcohol solution gel.

[0178] 1. Test materials

[0179] The chloramphenicol diol granule, chloramphenicol alcohol granule, and chloramphenicol alcohol solution from Example 5 were prepared into gels according to the scheme in Example 14.

[0180] The remaining tests were conducted according to the test method in Example 5, and will not be repeated here.

[0181] Test results

[0182] The results are shown in Table 8 and Figure 6 As shown, the in vitro release curve is shown in the figure. Figure 6 .Depend on Figure 6 It is known that chloramphenicol alcohol solution gel has a relatively rapid release rate, with a fast release rate before 6 hours, and the release rate exceeding 50% by 4 hours. After 12 hours, the release tends to stabilize. In both chloramphenicol alcohol liposome gel and chloramphenicol diol liposome gel, drug release is rapid in the first 2 hours, possibly due to the release of unencapsulated chloramphenicol. After 2 hours, the release rate begins to slow down. Curve fitting of the cumulative release rate shows that the release process tends towards a first-order equation, exhibiting a sustained-release effect.

[0183] Table 8. In vitro release rates (%) of chloramphenicol diol plastosome gel, chloramphenicol liposome gel, and chloramphenicol alcohol solution gel at each time point.

[0184]

[0185] Table 9. Equations for the in vitro release curves of chloramphenicol diol pluripotent gel, chloramphenicol pluripotent gel, and chloramphenicol alcohol solution gel.

[0186]

[0187]

[0188] Example 19: Transdermal Permeation Comparison Test of Chloramphenicol Diol Plastisol Gel, Chloramphenicol Plastisol Gel, and Chloramphenicol Alcohol Solution Gel

[0189] Chloramphenicol diol pluripotent gel and chloramphenicol pluripotent gel, chloramphenicol alcohol solution gel in Example 18

[0190] The remaining tests were conducted according to the test method in Example 6, and will not be repeated here.

[0191] Test results

[0192] The results are shown in Table 10 and Figure 7 As shown, the in vitro percutaneous permeability curve is shown below. Figure 7 As shown in Table 10, the Qn of the chloramphenicol alcohol solution gel is 101.12 μg·cm⁻¹. -2 The Qn of chloramphenicol protoplast gel is 136.02 μg·cm⁻¹. -2 The Qn of chloramphenicol diol plogel was 154.37 μg·cm⁻¹. -2 The cumulative permeability per unit volume of chloramphenicol alcohol solution gel and chloramphenicol liposome gel is lower than that of chloramphenicol diol liposome gel, possibly because the diol contained in chloramphenicol diol liposome gel promotes transdermal permeation.

[0193] Table 10. Cumulative permeation per unit area at each time point for chloramphenicol diol pluripotent gel, chloramphenicol pluripotent gel, and chloramphenicol alcohol solution gel (unit: μg·cm³). -2 )

[0194]

[0195] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A chloramphenicol dioliposome, characterized by, The chloramphenicol niosome is a vesicular structure, comprising a lipid bilayer and chloramphenicol wrapped in the lipid bilayer; the chloramphenicol niosome is prepared from raw materials of chloramphenicol, lecithin, ethanol, propylene glycol, Tween-80 and water; The particle size of the chloramphenicol niosome is ≤200 nm; The chloramphenicol niosome is composed of the following components at the following concentrations, based on the volume of the first raw material as a solvent: chloramphenicol 0.1-0.3 g / 100 mL, lecithin 1-5 g / 100 mL, Tween-80 0.1-0.2 g / 100 mL; The first raw material is composed of the following components in the following volume fractions: ethanol 9-20 parts, propylene glycol 15-28 parts and water 60-70 parts; The volume ratio of the ethanol and propylene glycol is 3:

7.

2. The method of claim 1, wherein the chloramphenicol liposome is prepared by the steps of, The method comprises the following steps: Mixing chloramphenicol, lecithin, ethanol and propylene glycol to obtain an alcohol-phase solution; Dissolving Tween-80 in water to obtain a Tween-80 solution; Adding the Tween-80 solution to the alcohol-phase solution to obtain crude chloramphenicol niosomes; Ultrasonicating the crude chloramphenicol niosomes to obtain chloramphenicol niosomes.

3. The method of claim 2, wherein, The power of the ultrasonication is 150-300 W.

4. A chloramphenicol ointment for external use, characterized by comprising, The gel base comprises carbomer.

5. The chloramphenicol gel formulation according to claim 4, wherein The method comprises the following steps:

6. The method for preparing the external preparation of chloramphenicol liposome of claim 4 or 5, characterized in that, Dispersing the chloramphenicol niosomes in the swollen gel base to obtain a chloramphenicol niosome external preparation. The swollen gel base is a gel base swollen with water; the ratio of the total volume of the water used to swell the gel base and the chloramphenicol niosomes to the mass of the gel base is 100 mL:(0.6-1.2) g; the volume ratio of the water used to swell the gel base to the chloramphenicol niosomes is 2:

1.

7. The production method according to claim 6, wherein 8. Use of the chloramphenicol niosome of claim 1 or prepared by the method of claim 2 or 3, or the chloramphenicol niosome external preparation of any one of claims 4 or 5 or prepared by the method of claim 6 or 7 in the preparation of a medicament for preventing or treating acne. ​

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