Dispersion process of adapalene in a gel preparation

Abstract

A dispersion process of adapalene gel preparation, including the following steps: pulverizing adapalene raw material to D50 not more than 10 m and D90 not more than 30 m by dry detection; adding methyl p-hydroxybenzoate, 1,2-propanediol, carbomer 980 and disodium edetate in water, heating and stirring consistently to obtain a matrix in a uniform jelly; adding poloxamer 188, propylene glycol and ethylene glycol phenyl ether in water, stirring and heating to prepare a mixed solution; adding adapalene in the mixed solution prepared, emulsifying at a high speed, then adding to the matrix for thorough stirring; and then adding a triethanolamine aqueous solution for homogenization and stirring. The preparation prepared has good emulsifying and dispersing effect of adapalene, can be expanded on a large scale, and the industrial promotion prospect is good.

Claims

1. A method for preparing a dispersed adapalene gel formulation, comprising the following steps: step 1: pulverizing adapalene raw material to D50 not more than 10 um and D90 not more than 30 um by dry detection, wherein a jet mill is used to pulverize adapalene starting material and the pulverization parameters include a venturi-tube pressure of 8.0-11.0 bar, an annular pressure of 8.0-10.0 bar, and a feed rate of 50-150 rpm; step 2: adding methyl p-hydroxybenzoate, 1,2-propanediol, carbomer 980 and disodium edetate in water, heating and stirring consistently to obtain a matrix in a uniform jelly; step 3: adding poloxamer 188, propylene glycol and ethylene glycol phenyl ether in water, stirring and heating to prepare a mixed solution, wherein, a mass ratio of water and poloxamer 188, propylene glycol, and ethylene glycol phenyl ether is 1:30-40:1; step 4: adding adapalene in the mixed solution prepared in step 3, emulsifying at a high speed, then adding to the matrix obtained in step 2 for thorough stirring; and then adding a triethanolamine aqueous solution for homogenization and stirring.

2. The method according to claim 1, wherein, the heating in steps 2 and 3 is performed up to 50-60 C.

3. The method according to claim 1, wherein, a mass ratio of the water, methyl p-hydroxybenzoate, 1,2-propanediol, carbomer 980, and disodium edetate in step 2 is 480:2-4:80-100:5-7:1-2.

4. The method according to claim 1, wherein, in step 4 a mass ratio of adapalene to the mixed solution obtained in step 2 is 1:20-200.

5. The method according to claim 1, wherein, the emulsification in step 4 is performed at a speed of 12-20 meters per second for 20-40 minutes.

6. The method according to claim 1, further comprising a sterilization step.

7. The method according to claim 6, wherein, the sterilization is a moist heat sterilization at 121 C.

Description

DETAILED DESCRIPTION

(1) The present invention discloses a dispersion process of adapalene in a gel preparation, and those skilled in the art can learn from the contents herein and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are apparent to those skilled in the art and are considered to be included in the present invention. The processes of the present invention have been described in terms of the preferred embodiments, and it is apparent that those skilled in the art can change and adapt and combine the methods and applications described herein to implement and apply the present invention without departing from the contents, spirits and scope of the invention.

(2) In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to specific embodiments.

Example 1: Dispersion Process of Adapalene

(3) 1. Pulverization and Particle Size Control of Adapalene Raw Material

(4) (1) Pulverization of Adapalene Raw Materials

(5) Method: The adapalene was pulverized using a jet mill to achieve the target particle size.

(6) Pulverization parameters: venturi-tube pressure 8.0 bar, annular pressure 8.0 bar, feed rate 50 rpm

(7) (2) Particle Size Control:

(8) Method: Taking the appropriate amount of this product, using Malvern MS3000 laser particle size analyzer, dry detection, D50 should not greater than 10 m, D90 should not greater than 30 um.

(9) 2. Dispersing Process of Adapalene

(10) (1) Matrix Preparation

(11) 60 Kg purified water was added to the emulsifying tank and heated to 555 C. Homogenization and stirring was started, then 250 g methyl parahydroxybenzoate and 10 kg 1, 2-propanediol were added and stirred homogeneously for 10 min, then 700 g carbomer 980, 125 g ethylenediamine tetraacetic acid disodium were added and stirred homogeneously for 20 minutes. A uniform gelatinized matrix was obtained.

(12) (2) Solution Preparation

(13) 1) 5 Kg purified water was added into the mixing tank, stirring was started and 1.125 Kg triethanolamine was added;

(14) 2) 5 Kg purified water was added to the tank, stirring was started, and 200 g Poloxamer 188 was added to the tank, heating to 555 C. was started, stirred for 15 minutes, and 6 kg 1,2 propanediol and 200 g ethylene glycol phenyl ether were added and stirred for 5 min.
(3) Sterilization
The matrix, triethanolamine aqueous solution, Poloxamol 188 aqueous solution, 1,2-propanediol and ethylene glycol phenyl ether mixture were sterilized under moisture heating at 121 C. for 20 minutes.
(4) Preparation Process
1) Clindamycin hydrochloride was dissolved in 7 Kg purified water to prepare clindamycin hydrochloride solution, after aseptic filtration, the solution was added directly to the matrix and mixed well.
2) 125 g adapalene was added to a sterilized mixture solution of 2.5 Kg 1, 2-propanediol, ethylene glycol phenyl ether and Poloxamer 188 mixture, high speed emulsification (speed 15 m/s) and dispersion was carried out for 30 mins in the emulsifying tank, then added into the matrix to stir, then triethanolamine aqueous solution was added slowly to the emulsifying tank, and was stirred homogeneously for 20 minutes.
3) Bubbles were removed in vacuum. Samples were taken and the viscosity, pH, the content of clindamycin hydrochloride, and the content and uniformity of adapalene were measured.

Example 2

(15) 1. Pulverization and Particle Size Control of Adapalene Raw Material

(16) (1) Pulverization of Adapalene Raw Materials

(17) Method: The adapalene was pulverized using a jet mill to achieve the target particle size.

(18) Pulverization parameters: venturi-tube pressure 9.0 bar, annular pressure 9.0 bar, feed rate 100 rpm

(19) (2) Particle Size Control:

(20) Method: Taking the appropriate amount of this product, using Malvern MS3000 laser particle size analyzer, dry detection, D50 should not greater than 10 m, D90 should not greater than 30 um.

(21) 2. Dispersing Process of Adapalene

(22) (1) Matrix Preparation

(23) 60 Kg purified water was added to the emulsifying tank and heated to 555 C. Homogenization and stirring was started, then 500 g methyl parahydroxybenzoate and 12 kg 1,2-propanediol were added and stirred homogeneously for 10 min, then 750 g carbomer 980, 200 g ethylenediamine tetraacetic acid disodium were added and stirred homogeneously for 20 minutes. A uniform gelatinized matrix was obtained.
(2) Solution Preparation
1) 5.5 Kg purified water was added into the mixing tank, stirring was started and 1.125 Kg triethanolamine was added;
2) 5 Kg purified water was added to the tank, stirring was started, and 500 g Poloxamer 188 was added to the tank, heating to 555 C. was started, stirred for 15 minutes, and 15 kg 1,2 propanediol and 500 g ethylene glycol phenyl ether were added and stirred for 5 min.
(3) Sterilization
The matrix, triethanolamine aqueous solution, Poloxamol 188 aqueous solution, 1,2-propanediol and ethylene glycol phenyl ether mixture were sterilized under moisture heating at 121 C. for 20 minutes.
(4) Preparation Process
1) Clindamycin hydrochloride was dissolved in 7 Kg purified water to prepare clindamycin hydrochloride solution, after aseptic filtration, the solution was added directly to the matrix and mixed well.
2) 125 g adapalene was added to a sterilized mixture solution of 5 Kg 1,2-propanediol, ethylene glycol phenyl ether and Poloxamer 188 mixture, high speed emulsification (speed 15 m/s) and dispersion was carried out for 30 mins in the emulsifying tank, then added into the matrix to stir, then triethanolamine aqueous solution was added slowly to the emulsifying tank, and was stirred homogeneously for 20 minutes.
3) Bubbles were removed in vacuum. Samples were taken and the viscosity, pH, the content of clindamycin hydrochloride, and the content and uniformity of adapalene were measured.

Example 3

(24) (1) The Pulverization:

(25) After pulverization the raw materials of adapalene was subjected to dry method detection and D50 was found not more than 10 um, D90 was found not more than 30 um. Adapalene was pulverized using a jet mill to achieve the target particle size.

(26) Pulverization parameters: Venturi-tube pressure 10.0 bar, annular pressure 9.0 bar, feed speed 100 rpm.

(27) (2) Matrix Preparation:

(28) Methyl parahydroxybenzoate and 1,2-propanediol were added into purified water, stirred evenly and heated continuously. Carbomer 980 and disodium ethylenediamine tetraacetic acid were added and stirred to form a uniform gelatinized matrix;

(29) Specifically, 60 Kg purified water was added to the emulsifying tank and heated to 555 C. After homogenization and stirring were started, 250 g methyl parahydroxybenzoate and 10 kg 1,2-propanediol were added, then 750 g carbomer 980 and 125 g ethylenediamine tetraacetic acid disodium was added, stirred homogeneously for 20 minutes, to form a uniform gelatinized matrix.
(3) Solution Preparation:

(30) Poloxamer 188, propanediol and ethylene glycol phenyl ether were added into purified water, stirred and heated for 5 min. 5 Kg purified water was added to the tank, stirring was started, and 500 g Poloxamer 188 was added, heating was started to 555 C., stirred for 15 minutes, 15 kg 1,2-propanediol and 500 g ethylene glycol phenyl ether were added and stirred.

(31) (4) Dispersion Steps:

(32) Adapalene was added to a mixture solution of 1,2-propanediol, ethylene glycol phenyl ether and Poloxamer 188, after high speed emulsification, added the matrix to stir fully; then triethanolamine aqueous solution was added and stirred homogeneously. In the emulsifying tank, high speed emulsification (15 m/s) (1220 m/s) was performed to disperse for 30 min (2040 min), then added the matrix and stirred evenly, triethanolamine aqueous solution was slowly added into the emulsifying tank, and stirred homogeneously for 20 minutes.
Clindamycin hydrochloride solution can be optionally added to prepare clindamycin hydrochloride adapalene compound gel.
5) Bubbles were removed in vacuum. Samples were taken and the viscosity, pH, the content of clindamycin hydrochloride, and the content and uniformity of adapalene were measured.

Example 4

(33) The results of adapalene hydrochloride clindamycin compound gel prepared from examples 1-3 are as follows:

(34) 1. Uniformity of the Preparation

(35) TABLE-US-00001 clindamycin viscosity particle size hydrochloride adapalene content Batch number pH (mP .Math. s) (D90) content (%) uniformity (%) 20150511 6.82 5680 17.5 um 99.79 101.20% A + 2.2S = 2.11 20150513 6.84 5570 16.7 um 98.76 103.91% A + 2.2S = 7.69 20150515 6.88 5870 17.0 um 102.86 102.73% A + 2.2S = 6.11 Note: particle size requirements: D90 50 um; Content uniformity requirement: According to China Pharmacopoeia 2015, A + 2.2S < 15 is in accordance with the provisions. detection method of particle size of the preparation: 5-10 g of the product was taken and mixed with 25 ml water. The saturated solution of adalalene in Tween-80 was used as the dispersing medium, the rotational speed was 1500 rpm, and the ultrasonic intensity was 20%.
2. Stability of the Preparation

(36) TABLE-US-00002 total impurity total impurity in time viscosity in adapalene clindamycin adalalene clindamycin batch no. (months) appearance pH value (mP .Math. s) (%) (%) content (%) content (%) 20150511 0 milky white gel 6.82 5680 0.34 1.18 101.20 99.79 3 milky white gel 6.84 5650 0.40 1.36 99.83 99.22 6 milky white gel 6.98 5612 0.43 1.60 99.35 98.78 9 milky white gel 6.82 5633 0.35 1.80 99.68 98.58 12 milky white gel 6.74 5590 0.38 2.02 99.70 98.41 18 milky white gel 6.80 5566 0.40 2.21 99.47 98.18 24 milky white gel 6.88 5525 0.44 2.46 99.23 98.30 20150513 0 milky white gel 6.84 5570 0.32 1.28 103.91 98.76 3 milky white gel 6.84 5618 0.38 1.38 103.22 98.65 6 milky white gel 6.80 5590 0.40 1.64 102.98 98.50 9 milky white gel 6.78 5532 0.38 1.82 102.90 98.54 12 milky white gel 6.79 5450 0.44 2.10 102.98 98.32 18 milky white gel 6.83 5440 0.42 2.21 102.87 98.04 24 milky white gel 6.88 5323 0.42 2.40 102.89 97.77 20150515 0 milky white gel 6.88 5870 0.35 1.22 102.73 102.86 3 milky white gel 6.80 5830 0.40 1.34 102.44 102.54 6 milky white gel 6.83 5805 0.41 1.55 102.56 102.20 9 milky white gel 6.80 5780 0.38 1.75 102.54 101.90 12 milky white gel 6.84 5800 0.44 1.98 102.21 101.56 18 milky white gel 6.80 5735 0.41 2.22 102.45 101.53 24 milky white gel 6.85 5700 0.40 2.39 102.2 101.22
According to the above data, it can be known that the uniformity and stability of the prepared preparations 20150511, 20150513 and 20150515 are good. Compared with 0-month sample, no significant change was found for the long-term 24-month sample with respect to all test indicators.
3. Pharmacokinetics and Clinical Study of the Preparation
Efficacy and safety assessments were performed through human pharmacokinetics studies and clinical studies. The results of clinical trials show that the safety of the product is good, and it has remarkable curative effect on acne vulgaris.
The above description only shows preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make a number of improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should be considered falling within the scope of protection of the present invention.