Dabrafenib Transdermal Preparation Composition and Preparation Method of Dabrafenib Transdermal Preparation

Abstract

The present invention relates to a dacarbazine transdermal preparation composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The dacarbazine transdermal preparation composition described in the present invention comprises dacarbazine, a transdermal penetration enhancer, a solvent and a solubilizer. The dacarbazine transdermal preparation composition of the present invention has a high transdermal absorption rate and effectively avoids irritation to the gastrointestinal tract; the present invention also provides a simple and feasible preparation method for the dacarbazine transdermal preparation.

Description

Technical Field

[0001] The present invention relates to a dabrafenib transdermal preparation composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Dabrafenib is an effective drug for treating melanoma, which is a targeted BRAF tyrosine kinase inhibitor and has inhibitory effects on BRAF V600E, BRAF V600K, and BRAF V600D.

[0003] There are relatively few reports on dabrafenib-related drugs. CN201611112050.4 discloses a sustained-release tablet of dabrafenib mesylate and a preparation method thereof. The sustained-release tablet of dabrafenib mesylate is prepared from the following raw and auxiliary materials: 1 part of dabrafenib mesylate, 0.3 - 0.9 part of sustained-release matrix material, 0.05 - 0.11 part of glidant, 1.1 - 3.1 parts of filler, and 1 - 6 parts of binder. The main drug, dabrafenib mesylate, in the sustained-release tablet of dabrafenib mesylate prepared according to the present invention is slowly released, and the release period is up to 12 hours. Therefore, this product can reduce the number of administrations compared with traditional capsules; the main drug, dabrafenib mesylate, in this product is slowly released, which can provide a stable and lasting effective blood drug concentration, avoid or reduce the peak-valley phenomenon of blood drug concentration, and is beneficial to improving the safety of drug use. At the same time, this product has good stability and a shelf life of up to 24 months.

[0004] The administration route of the commercially available dabrafenib is basically oral, and it has relatively large side effects after oral administration; when administered orally to reach the lesion site, not only is the efficiency low and the specificity poor, but also it will cause liver toxicity, gastrointestinal irritation, etc. The transdermal absorption of drugs is affected by the drug properties and skin barrier, resulting in a low absorption rate of transdermal preparations. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art and provide a dabrafenib transdermal preparation composition with a high transdermal absorption rate and effectively avoiding irritation to the gastrointestinal tract; the present invention also provides a simple and feasible preparation method for the dabrafenib transdermal preparation.

[0006] The dabrafenib transdermal preparation composition described in the present invention comprises dabrafenib, a transdermal penetration enhancer, a solvent, and a solubilizer.

[0007] Preferably, the transdermal penetration enhancer is azone, borneol, oleic acid, or peppermint oil.

[0008] Preferably, the solvent is one or more of isopropyl alcohol, methanol, acetone, ethyl acetate, tert-butanol, or dimethyl sulfoxide.

[0009] Preferably, the solubilizer is lecithin.

[0010] Preferably, the mass content of the transdermal penetration enhancer is 0.5-30%, and the mass content of the solubilizer is 0.5-30%, based on the total mass of the preparation.

[0011] More preferably, the mass content of the transdermal penetration enhancer is 5-20%, and the mass content of the solvent is 5-20%.

[0012] The dabrafenib transdermal preparation composition further comprises a preservative and a gelling agent.

[0013] Preferably, the gelling agent is carbomer, hydroxypropyl cellulose, ethyl cellulose, hard fat, glycerol or polyethylene glycol.

[0014] Preferably, the preservative is sodium benzoate, benzalkonium chloride, benzalkonium bromide, chlorobutanol or benzoic acid.

[0015] The method for preparing the dabrafenib transdermal preparation comprises the following steps:

[0016] (1) Dissolve dabrafenib in a solvent to prepare a dabrafenib solution with a mass concentration of 5-50%;

[0017] (2) Add a gelling agent, a transdermal penetration enhancer, a solubilizer and a preservative, and heat and stir to obtain a matrix solution;

[0018] (3) Add the dabrafenib solution prepared in step (1) to the matrix solution under stirring, stir, and obtain a cream after cooling;

[0019] (4) Add the cooled cream into a composite hose, seal it, and obtain the dabrafenib transdermal preparation.

[0020] In vitro permeation test:

[0021] For the transdermal experiment, the skin of rats is selected, the in vitro permeation device is a Franz diffusion cell, the sampling time is 3, 6, 12 hours, the diffusion area of the Franz diffusion cell is 4.5 cm 2 , and the volume of the receiving chamber is 13 mL.

[0022] In the present invention, dabrafenib is prepared into a transdermal preparation and directly applied to the lesion site. Since the water solubility of dabrafenib is poor, dabrafenib is dissolved in an organic solvent and mixed with a matrix. The transdermal preparation prepared by adding a certain amount of azone and lecithin to the matrix can significantly increase the skin permeability. Among them, azone is a relatively common penetration enhancer, and lecithin can be used as a solubilizer for dabrafenib. After solubilizing the raw materials and then permeating, the permeation efficiency can be improved.

[0023] In this invention, in vitro transdermal tests were conducted to compare the permeation of drugs using different penetration enhancers. The test results showed that the co - use of azone and lecithin can significantly improve the drug permeation rate.

[0024] Compared with the prior art, this invention has the following beneficial effects:

[0025] (1) The dabrafenib transdermal preparation composition described in this invention has a high transdermal absorption rate and high specificity;

[0026] (2) This invention also provides a simple and feasible method for preparing the dabrafenib transdermal preparation. Detailed implementation mode

[0027] The following is a further description of the present invention in combination with examples, but it does not limit the implementation of the present invention. Example 1

[0028] Table 1 Prescription

[0029]

[0030]

[0031] Preparation process:

[0032] (1) Dissolve 10 g of dabrafenib in 40 g of isopropanol.

[0033] (2) Heat 10 g of glycerol, 10 g of azone, 7 g of lecithin, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high - speed homogenizer for 10 minutes, add the isopropanol solution containing dabrafenib, and continue to stir for 10 minutes.

[0034] (3) After standing and cooling, fill it into a pre - prepared composite hose and seal it. Then the dabrafenib cream is obtained.

[0035] Test results:

[0036] The permeation rate was detected using a transdermal absorption diffusion cell, and the results are shown in Table 2.

[0037] Table 2 Permeation rate test results

[0038] Time (hours) Dabrafenib Concentration (mg / mL) 3 0.015 6 0.033 12 0.043

[0039] Example 2

[0040] Without adding lecithin, after preparing samples using the commonly used transdermal penetration enhancer azone and oleic acid, relevant transdermal tests were carried out.

[0041] Table 3 Prescription

[0042]

[0043] Preparation process:

[0044] (1) Dissolve 10 g of dabrafenib in 40 g of isopropyl alcohol.

[0045] (2) Heat 10 g of glycerol, 17 g of azone or oleic acid, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high-speed homogenizer for 10 minutes, add the isopropyl alcohol solution containing dabrafenib, and continue to stir for 10 minutes.

[0046] (3) After standing and cooling, fill it into a pre-prepared composite hose and seal it. Then the dabrafenib cream is obtained.

[0047] Test results:

[0048] The permeation rate was detected using a transdermal absorption diffusion cell, and the test results are shown in Table 4.

[0049] Table 4 Permeation rate test results

[0050]

[0051] Conclusion: Without adding lecithin, the permeation rate of the drug decreased significantly.

[0052] Example 3

[0053] Conduct tests using either azone or lecithin respectively.

[0054] Table 5 Formulation

[0055]

[0056] Preparation process:

[0057] (1) Dissolve 10 g of dabrafenib in 40 g of isopropyl alcohol.

[0058] (2) Heat 10 g of glycerol, 17 g of azone or lecithin, 10 g of oleic acid, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high-speed homogenizer for 10 minutes, add the isopropyl alcohol solution containing dabrafenib, and continue to stir for 10 minutes.

[0059] (3) After standing and cooling, fill it into a pre-prepared composite hose and seal it. Then the dabrafenib cream is obtained.

[0060] Test results:

[0061] The permeation rate was detected using a transdermal absorption diffusion cell, and the test results are shown in Table 6.

[0062] Table 6 Permeation rate test results

[0063]

[0064] Conclusion: When using azone lecithin alone, the permeation rate of dabrafenib is also significantly lower.

[0065] Example 4

[0066] Table 7 Prescription

[0067] Name Dosage (g) Dabrafenib 10 Isopropyl Alcohol 40 Glycerol 10 Azone 7 Lecithin 10 Sodium Cholate 3 Sodium Benzoate 1 Stearic Acid 20

[0068] Preparation process:

[0069] (1) Dissolve 10 g of dabrafenib in 40 g of isopropanol.

[0070] (2) Heat 10 g of glycerol, 7 g of azone, 10 g of lecithin, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high-speed homogenizer for 10 minutes, add the isopropanol solution containing dabrafenib, and continue to stir for 10 minutes.

[0071] (3) After standing and cooling, fill it into a pre-prepared composite hose and seal it. The dabrafenib cream is obtained.

[0072] Test results:

[0073] The permeation rate was detected using a transdermal absorption diffusion cell, and the test results are shown in Table 8.

[0074] Table 8 Test results of permeation rate

[0075] Time Dabrafenib Concentration (mg / mL) 3 0.017 6 0.036 12 0.049

[0076] Example 5

[0077] Table 9 Prescription

[0078] Name Dosage (g) Dabrafenib 10 Isopropyl Alcohol 40 Glycerol 10 Azone 10 Lecithin 10 Sodium Cholate 3 Sodium Benzoate 1 Stearic Acid 20

[0079] Preparation process:

[0080] (1) Dissolve 10 g of dabrafenib in 40 g of isopropanol.

[0081] (2) Heat 10 g of glycerol, 10 g of azone, 10 g of lecithin, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high-speed homogenizer for 10 minutes, add the isopropanol solution containing dabrafenib, and continue to stir for 10 minutes.

[0082] (3) After standing and cooling, fill it into a pre-prepared composite hose and seal it. The dabrafenib cream is obtained.

[0083] Test results:

[0084] The transmittance was detected using a transdermal absorption diffusion cell, and the detection results are shown in Table 10.

[0085] Table 10 Transmittance Detection Results

[0086] Time Dabrafenib Concentration (mg / mL) 3 0.017 6 0.037 12 0.050

[0087] Example 6

[0088] Dabrafenib was dissolved using different solvents, and after dissolution, it was mixed with the matrix to prepare samples.

[0089] Table 11 Formulation

[0090]

[0091] Preparation process:

[0092] (1) Dissolve 10 g of dabrafenib in 40 g of the solvent.

[0093] (2) Heat 10 g of glycerol, 10 g of azone, 10 g of lecithin, 3 g of sodium cholate, 1 g of sodium benzoate, and 20 g of stearin into a solution state, stir with a high-speed homogenizer for 10 minutes, add the solvent solution containing dabrafenib, and continue to stir for 10 minutes.

[0094] (3) After standing and cooling, it was filled into a pre-prepared composite hose and sealed. Thus, the dabrafenib cream was obtained.

[0095] Detection results:

[0096] The transmittance was detected using a transdermal absorption diffusion cell, and the detection results are shown in Table 12.

[0097] Table 12 Transmittance Detection Results

[0098]

[0099] Conclusion: It can be seen from the above results that different solvents have basically no effect on the transmittance of dabrafenib.

[0100] In summary, the transdermal preparation of dabrafenib prepared by the present invention has a certain transdermal effect. In particular, the combination of azone and lecithin can significantly improve the transmittance of dabrafenib.

[0101] The above-described embodiments have detailed the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the present invention. Any modifications, supplements, equivalent replacements, etc. made within the principle scope of the present invention should be included within the protection scope of the present invention.

Claims

1. A trametinib transdermal preparation composition, characterized in that: It contains dabrafenib, a penetration enhancer, a solvent, and a solubilizer; The penetration enhancer is azone; The solubilizer is lecithin; The formulation also contains a gelling agent and a preservative; The transdermal preparation is a cream.

2. The trametinib transdermal preparation composition according to claim 1, wherein: The solvent is one or more of isopropyl alcohol, methanol, acetone, ethyl acetate, tert-butanol, or dimethyl sulfoxide.

3. The dabrafenib transdermal preparation composition according to claim 1, wherein: The mass content of the penetration enhancer is 0.5 - 30%, and the mass content of the solubilizer is 0.5 - 30%.

4. The dabrafenib transdermal preparation composition according to claim 1, characterized in that: The gelling agent is carbomer, hydroxypropyl cellulose, ethyl cellulose, hard fat, glycerol, or polyethylene glycol.

5. The dabrafenib transdermal preparation composition according to claim 1, characterized in that: The preservative is sodium benzoate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, or benzoic acid.

6. A preparation method of the dabrafenib transdermal preparation according to any one of claims 1-5, characterized in that: It includes the following steps: (1) Add dabrafenib to the solvent and dissolve it to prepare a dabrafenib solution; (2) Add the gelling agent, penetration enhancer, solubilizer, and preservative, heat and stir to obtain a matrix solution; (3) Add the dabrafenib solution prepared in step (1) to the matrix solution under stirring, stir, and cool to obtain a cream; (4) Add the cooled cream to a composite hose, seal it, and obtain the dabrafenib transdermal preparation.

7. The preparation method of the dabrafenib transdermal preparation according to claim 6, characterized in that: In step (1), the mass concentration of dabrafenib in the solution is 5 - 50%.

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