Low shear mixing method for improving stability of topical pharmaceutical formulation compositions

Abstract

The application is a low shear mixing method for improving the stability of external drug preparation composition, which refers to external liquid or semi-solid drug preparation composition, and the method comprises drug phase preparation and drug phase addition, the drug phase preparation is carried out by homogenization and / or stirring, the drug phase addition is carried out by homogenization and / or constant temperature stirring, the homogenization head speed is 0.55-1 m / s, and the stirring head speed is 0.55-1 m / s.The application has the advantages that the method is reasonably designed, the low shear process is optimized, a long-time low shear mixing process is designed, the caking of drug substances can be effectively controlled, and the stability of the composition can be improved without phase separation.

Description

Technical Field

[0001] This invention relates to a mixing method for preparing topical pharmaceutical formulations, specifically a low-shear mixing method for improving the stability of topical pharmaceutical formulations and solving the problem of drug clumping. Background Technology

[0002] For many topical pharmaceutical formulations, the drug exists in a dispersed form within the finished product. Agglomeration is a very common problem in these liquid or semi-solid formulations. The production of topical pharmaceutical formulations requires extensive agitation and homogenization under high shear conditions to improve the quality of the final product. However, high shear leads to increased collisions between drug particles, resulting in the formation of static charges on the particles. These static charges cause the particles to aggregate and form clumps, which alter the drug release pattern, thus affecting the safety and efficacy of the final product.

[0003] If production is carried out by reducing shear force, it will cause instability in the composition of the finished formulation. This is because the oily and watery components will not mix well, affecting the addition and mixing of the drug phase.

[0004] Based on the above problems, it is necessary to develop a process that enables drug particles to be better dispersed in topical pharmaceutical formulations while maintaining better stability. Summary of the Invention

[0005] The present invention proposes a low-shear mixing method for improving the stability of topical pharmaceutical formulations. Its purpose is to overcome the above-mentioned shortcomings of the prior art. Through an improved low-shear process, the dispersibility of drug particles in topical pharmaceutical formulations can be effectively improved while ensuring good stability.

[0006] The technical solution of this invention is a low-shear mixing method for improving the stability of topical pharmaceutical formulations. The topical pharmaceutical formulation refers to a topical liquid or semi-solid pharmaceutical formulation. The method includes drug phase preparation and drug phase addition. Drug phase preparation is carried out by homogenization and / or stirring. Drug phase addition is carried out by homogenization and / or isothermal stirring. The homogenizing head speed is 0.55-1.00 m / s, and the stirring head speed is 0.55-1.00 m / s.

[0007] Preferably, the drug is one of the following: corticosteroids, retinoids, non-retinoic acid, antibacterial agents, antifungal agents, immunosuppressants, PDE inhibitors, and antibodies.

[0008] Preferably, the drug is one of the following: low- to high-efficiency corticosteroids, first- to fourth-generation retinoic acid derivatives, non-retinoic acid derivatives, tetracyclic antibacterial agents, azole rings containing antifungal drugs, macrolides containing immunosuppressants, PDE4 inhibitors, and low molecular weight antibodies.

[0009] Preferably, the drug is desonide, clobetasol propionate, halobetasol propionate, difluralasone diacetate, betamethasone dipropionate, fluocinolone, halcinonide, ampicillin, dexamethasone, mometasone furoate, fluticasone propionate, betamethasone dipropionate, triamcinolone, fluocinolone acetoketone, fluocinolone acetoketone, triamcinolone acetoketone, mometasone furoate, hydrocortisone valerate, prednisone ester, hydrocortisone propionate, fluocinolone acetoketone. One of the following: hydrocortisone butyrate, hydrocortisone acetate, retinoic acid, retinaldehyde, isotretinoin, retinoic acid, retinoic acid, acitretin, acitretin, adapalene, aroten, tazarotene, acitretin, trafarotine, adapalene, fusidic acid, efconazole, voriconazole, ruliconazole, posaconazole, tacrolimus, pimecrolimus, aprexa, roflumilast, and ruxotinib phosphate.

[0010] Preferably, the drug is fusidic acid, which is dispersed in a cream matrix composed of cetyl alcohol, 85% glycerin, liquid paraffin, nephrite, polysorbate 60, hydrochloric acid, potassium sorbate, all-rac-α-tocopherol, butylated hydroxyanisole, and purified water.

[0011] Preferably, the production process further includes an emulsification step before the preparation of the pharmaceutical phase, wherein the emulsification is carried out by homogenization and / or constant temperature stirring.

[0012] Preferably, emulsification is performed at a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 70±5℃ for 10 minutes; the drug phase is prepared at a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 50±5℃ for 30 minutes; and the drug phase is added at a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 50±5℃ for 10 minutes.

[0013] Alternatively, preferably, the drug is desonide, which is dispersed in an emulsion base composed of cetyl alcohol, sodium EDTA, glyceryl stearate SE, light liquid paraffin, methylparaben, propylene glycol, propylparaben, purified water, sodium lauryl sulfate, sorbitan monostearate, stearyl alcohol, citric acid, sodium hydroxide, and purified water.

[0014] Preferably, the production process further includes an emulsification step before the preparation of the pharmaceutical phase, wherein the emulsification is carried out by homogenization and / or constant temperature stirring.

[0015] Preferably, emulsification is performed with a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 70±5℃ for 10 min; the drug phase is prepared with a homogenizing head speed of 0.55-1 m / s and a stirring head speed of 0.55-1 m / s for 30 min; and the drug phase is added with a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55 m / s, and a volumetric temperature of 50±5℃ for 10 min.

[0016] Alternatively, preferably, the drug is benzoyl peroxide, which is dispersed in a polymer matrix composed of purified water, glycerol, propylene glycol, carbomer and sodium hydroxide.

[0017] Preferably, the drug phase is prepared by stirring at a homogenizing head speed of 0.55-1 m / s for 60 min at a temperature of 10-20℃ and a stirring head speed of 0.55-1 m / s; the drug phase is added for 10 min at a homogenizing head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 10-20℃.

[0018] Alternatively, preferably, the drug is adapalene, which is dispersed in a gel matrix composed of carbomer 940, disodium EDTA, methylparaben, poloxamer, propylene glycol, purified water and sodium hydroxide.

[0019] Preferably, the homogenizer head speed is 0.55-1 m / s, and the stirring head speed is 0.55-1 m / s at a temperature of 25-30°C, and the drug phase is prepared for 30 min; the homogenizer head speed is 0.55-1 m / s, the stirring head speed is 0.55-1 m / s, and the drug phase is added after stirring for 10 min at 25-30°C.

[0020] Advantages of this invention: The method is rationally designed, the low-shear force process is optimized, and a long-term low-shear force mixing process is designed, which can effectively control the agglomeration of drug substances and improve the stability of the composition without phase separation. Attached Figure Description

[0021] Figure 1 This is an electron microscope image of the low shear force process in Example 1, A.

[0022] Figure 2 This is an electron microscope image of the low shear force delay process in Example 1 (B).

[0023] Figure 3 This is an electron microscope image of the high shear force process C in Example 1.

[0024] Figure 4 This is an electron microscope image of the low shear force process in Example 2A.

[0025] Figure 5 This is an electron microscope image of the low shear force delay process in Example 2 (B).

[0026] Figure 6 This is an electron microscope image of the particle size distribution of the high shear force process in Example 2.

[0027] Figure 7 This is an electron microscope image of the high shear force process spheres in Example 2.

[0028] Figure 8 This is an electron microscope image of the low shear force process in Example 3A.

[0029] Figure 9 This is an electron microscope image of the low shear force delay process in Example 3 (B).

[0030] Figure 10 This is an electron microscope image of the high shear force process in Example 3.

[0031] Figure 11 This is an electron microscope image of the low shear force process in Example 4, A.

[0032] Figure 12 This is an electron microscope image of the low shear force delay process in Example 4 (B).

[0033] Figure 13 This is an electron microscope image of the high shear force process in Example 4. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to embodiments and specific implementation methods.

[0035] A low-shear mixing method for improving the stability of topical pharmaceutical formulations, wherein the topical pharmaceutical formulation refers to a topical liquid or semi-solid pharmaceutical formulation, wherein the drug is selected from one of corticosteroids, retinoids, non-retinoic acid, antibacterial agents, antifungal agents, immunosuppressants, PDE inhibitors, and antibodies.

[0036] As a preferred embodiment, the drug is selected from one of the following: low- to high-efficiency corticosteroids, first- to fourth-generation retinoic acid derivatives, non-retinoic acid derivatives, tetracyclic antibacterial agents, azole rings containing antifungal drugs, macrolides containing immunosuppressants, PDE4 inhibitors, and low molecular weight antibodies.

[0037] As a further preferred embodiment, the drug is selected from desonide, clobetasol propionate, halobetasol propionate, difluralasone diacetate, betamethasone dipropionate, fluocinolone acetonide, halcinonide, aminoxinonide, dexamethasone, mometasone furoate, fluticasone propionate, betamethasone dipropionate, triamcinolone acetonide, fluocinolone acetonide, triamcinolone acetonide, mometasone furoate, hydrocortisone valerate, prednisone ester, hydrocortisone propionate, and fluocinolone acetonide. One of the following: acetophenone, hydrocortisone butyrate, hydrocortisone acetate, retinoic acid, retinaldehyde, isotretinoin, retinoic acid, retinoic acid, acitretin, acitretin, adapalene, aroten, tazarotene, alitretin, trafarotine, adapalene, fusidic acid, efconazole, voriconazole, ruliconazole, posaconazole, tacrolimus, pimecrolimus, aprolast, roflumilast, and ruxotinib phosphate.

[0038] As a further preferred embodiment, the drug is selected from fusidic acid.

[0039] Based on the drug being selected from fusidic acid, as a further preferred embodiment, fusidic acid is dispersed in a cream matrix composed of cetyl alcohol, 85% glycerin, liquid paraffin, nephrite, polysorbate 60, hydrochloric acid, potassium sorbate, all-rac-α-tocopherol, butylated hydroxyanisole, and purified water.

[0040] Alternatively, as a further preferred embodiment, the drug is selected from desonide.

[0041] Based on the drug selection of desonide, as a further preferred embodiment, Desonide is dispersed in an emulsion matrix consisting of cetyl alcohol, sodium EDTA, glyceryl stearate SE, light liquid paraffin, methylparaben, propylene glycol, propylparaben, purified water, sodium lauryl sulfate, sorbitan monostearate, stearyl alcohol, citric acid, sodium hydroxide, and purified water.

[0042] Alternatively, as a further preferred embodiment, the drug is selected from benzoyl peroxide.

[0043] Based on the drug being selected from benzoyl peroxide, as a further preferred embodiment, benzoyl peroxide is dispersed in a polymer matrix composed of purified water, glycerol, propylene glycol, carbomer, and sodium hydroxide.

[0044] Alternatively, as a further preferred embodiment, the drug is selected from adapalene.

[0045] Based on the drug selection of adapalene, as a further preferred embodiment, adapalene is dispersed in a gel matrix composed of carbomer 940, disodium EDTA, methylparaben, poloxamer, propylene glycol, purified water and sodium hydroxide.

[0046] The low-shear mixing method improves the dispersibility of drugs in pharmaceutical formulations and does not cause agglomeration of active pharmaceutical ingredients, thus ensuring stability.

[0047] As a further preferred embodiment, a modified low-shear force mixing production process is used.

[0048] As a further preferred embodiment, the drug is also uniformly dispersed in the finished product by slow stirring.

[0049] As a further preferred embodiment, the drug is uniformly dispersed in the finished product by stirring, homogenizing, or a combination of both.

[0050] As a further preferred embodiment, the production process for preparing fusidic acid cream includes three unit steps: emulsification, drug phase preparation, and drug phase addition.

[0051] As a further preferred embodiment, emulsification is performed by homogenization and / or isothermal stirring, drug phase preparation is performed by homogenization and / or stirring, and drug phase addition is performed by homogenization and / or isothermal stirring.

[0052] As a further preferred embodiment, emulsification was performed by using a homogenization tip speed of 0.55-1 m / s, a stirring tip speed of 0.55-1 m / s, and a bulk temperature of 70 ± 5 °C for 10 minutes; the drug phase was prepared using a homogenization tip speed of 0.55-1 m / s, a stirring tip speed of 0.55-1 m / s, and a bulk temperature of 50 ± 5 °C for 30 minutes; and the drug phase was added using a homogenization tip speed of 0.55-1 m / s, a stirring tip speed of 0.55-1 m / s, and a bulk temperature of 50 ± 5 °C for 10 minutes.

[0053] As a further preferred embodiment, the production process for preparing desonide emulsion includes three unit steps: emulsification, drug phase preparation, and drug phase addition.

[0054] As a further preferred embodiment, emulsification is performed by homogenization and / or isothermal stirring, drug phase preparation is performed by homogenization and / or stirring, and drug phase addition is performed by homogenization and / or isothermal stirring.

[0055] As a further preferred embodiment, emulsification was performed with a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 70±5℃ for 10 min; the drug phase was prepared at a homogenizer head speed of 0.55-1 m / s and a stirring head speed of 0.55-1 m / s for 30 min at a temperature of 50±5℃; the drug phase was added with a homogenizer head speed of 0.55-1 m / s and a stirring head speed of 0.55-1 m / s at a volumetric temperature of 50±5℃ for 10 min.

[0056] As a further preferred embodiment, the preparation of benzoyl peroxide gel includes two unit steps: drug phase preparation and drug phase addition.

[0057] As a further preferred embodiment, the drug phase is prepared by homogenization and / or stirring, and the drug phase is added using homogenization and / or stirring.

[0058] As a further preferred embodiment, the drug phase is prepared by stirring at 10-20°C for 60 min using a homogenizer head speed of 0.55-1 m / s; the drug phase is then added for 10 min using a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 10-20°C.

[0059] As a further preferred embodiment, the preparation of adapalene gel includes two unit steps: drug phase preparation and drug phase addition.

[0060] As a further preferred embodiment, the drug phase is prepared by homogenization and / or stirring, and the drug phase is added using homogenization and / or stirring.

[0061] As a further preferred embodiment, the drug phase is prepared for 10 minutes at a temperature of 25-30°C using a homogenizer head speed of 0.55-1 m / s and a stirring head speed of 0.55-1 m / s at a temperature of 25-30°C; the drug phase is then added after stirring for 10 minutes at a temperature of 25-30°C using both the homogenizer head speed and the stirring head speed.

[0062] In topical liquid or semi-solid pharmaceutical formulations, tip speed is crucial for process optimization during the transition from small-scale to large-scale production. Furthermore, increases in batch size inevitably lead to variations in process parameters, such as homogenization speed, due to changes in batch size and equipment. Homogenization head speed calculations help determine predicted process parameters during the scaling-up from laboratory-scale to large-scale manufacturing. During the manufacturing process transition, tip speeds should be matched between lower-scale and higher-scale manufacturing for better results.

[0063] Tip velocity calculation is performed using a simple formula:

[0064] Where π is a constant. R = radius (meters) S = speed in RPM.

[0065] Example 1: 2% Fusidic Acid Cream The product contains 2% fusidic acid, dispersed in a cream matrix composed of all-rac-α-tocopherol, butylated hydroxyanisole, cetyl alcohol, glycerin, hydrochloric acid, nephrite, liquid paraffin, polysorbate 60, potassium sorbate, and purified water. Dispersing fusidic acid in a cream matrix is ​​difficult and cannot be achieved without a low-shear manufacturing process as shown in the table.

[0066]

[0067] Example 2: 0.05% Desonide Emulsion Desonide, containing 0.05%, is dispersed in an emulsion matrix composed of hexadecyl alcohol, sodium EDTA, glyceryl stearate SE, light liquid paraffin, methylparaben, propylene glycol, propylparaben, purified water, sodium lauryl sulfate, sorbitan monostearate, stearyl alcohol, citric acid, sodium hydroxide, and purified water. Dispersing desonide in an emulsion matrix is ​​difficult and cannot be achieved without a low-shear manufacturing process as shown in the table below. Even when a stable emulsion is obtained under high shear forces, the particle size is too small, leading to instability and agglomeration of desonide in the finished product. Similar low-shear mixing has been used for the uniform dispersion of desonide in emulsions.

[0068]

[0069] Example 3: 5% Benzoyl Peroxide Gel It contains 5% benzoyl peroxide, dispersed in a polymer matrix composed of purified water, glycerol, propylene glycol, carbomer, and sodium hydroxide. Benzoyl peroxide requires prolonged homogenization to break down the slurry into actual drug particles.

[0070]

[0071] Example 4: 0.1% Adapalene Gel It contains 0.1% adapalene, dispersed in a gel matrix composed of carbomer 940, disodium EDTA, methylparaben, poloxamer, propylene glycol, purified water, and sodium hydroxide.

[0072]

[0073] Example 5: Sample Evaluation The test samples were evaluated using digital microscopy and automated methods. The results of particle size distribution, spherical particle size distribution, and agglomeration rate are shown in the table below.

[0074]

[0075] Based on the particle size distribution, spherical particle size distribution, and agglomeration rate results shown in the table above, the low-shear-force delay process is more effective for both emulsion-based and polymer-based products. Compared to both low-shear-force and high-shear-force processes, the low-shear-force delay process significantly reduces agglomeration. Overall, the results indicate that the low-shear-force delay process is superior to other processes.

[0076] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A low-shear mixing method for improving the stability of topical pharmaceutical formulations, characterized in that, The aforementioned topical pharmaceutical formulation composition refers to a topical liquid or semi-solid pharmaceutical formulation composition. The method includes drug phase preparation and drug phase addition. Drug phase preparation is carried out by homogenization and / or stirring, and drug phase addition is carried out by homogenization and / or constant temperature stirring. The homogenizing head speed is 0.55-1 m / s, and the stirring head speed is 0.55-1 m / s.

2. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 1, characterized in that, The drugs mentioned are desonide, clobetasol propionate, halobetasol propionate, difluralasone diacetate, betamethasone dipropionate, fluocinolone acetonide, halcinonide, ampicillinide, dexamethasone, mometasone furoate, fluticasone propionate, betamethasone dipropionate, triamcinolone acetonide, fluocinolone acetonide, triamcinolone acetonide, mometasone furoate, hydrocortisone valerate, prednisone ester, hydrocortisone propionate, fluocinolone acetonide, and butyl... One of the following: hydrocortisone acetate, hydrocortisone diacetate, hydrocortisone acetate, retinoic acid, retinaldehyde, isotretinoin, retinoic acid, retinoic acid, retinoic acid, acitretin, acitretin, adapalene, aroten, tazarotene, acitretin, trafarotine, adapalene, fusidic acid, efconazole, voriconazole, ruliconazole, posaconazole, tacrolimus, pimecrolimus, aprolast, roflumilast, and ruxotinib phosphate.

3. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 2, characterized in that, The drug in question is fusidic acid, which is dispersed in a cream matrix composed of cetyl alcohol, 85% glycerin, liquid paraffin, nephrite, polysorbate 60, hydrochloric acid, potassium sorbate, all-rac-α-tocopherol, butylated hydroxyanisole, and purified water.

4. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 3, characterized in that, The production process includes an emulsification step before the preparation of the drug phase. Emulsification is carried out by homogenization and / or isothermal stirring. Specifically, emulsification is carried out for 10 minutes with a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 70±5℃. The drug phase is then prepared for 30 minutes with a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 50±5℃. The drug phase is then added for 10 minutes with a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 50±5℃.

5. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 2, characterized in that, The drug in question is desonide, which is dispersed in an emulsion base composed of cetyl alcohol, sodium EDTA, glyceryl stearate SE, light liquid paraffin, methylparaben, propylene glycol, propylparaben, purified water, sodium lauryl sulfate, sorbitan monostearate, stearyl alcohol, citric acid, sodium hydroxide, and purified water.

6. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 5, characterized in that, The production process includes an emulsification step before the preparation of the drug phase. Emulsification is carried out by homogenization and / or constant-temperature stirring. Specifically, emulsification is carried out with a homogenizer speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 70±5℃ for 10 min. The drug phase is prepared with a homogenizer speed of 0.55-1 m / s and a stirring head speed of 0.55-1 m / s for 30 min. The drug phase is added with a homogenizer speed of 0.55-1 m / s, a stirring head speed of 0.55 m / s, and a volumetric temperature of 50±5℃ for 10 min.

7. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 2, characterized in that, The drug is benzoyl peroxide, which is dispersed in a polymer matrix composed of purified water, glycerol, propylene glycol, carbomer and sodium hydroxide.

8. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 7, characterized in that, The drug phase was prepared by stirring at a homogenizer head speed of 0.55-1 m / s for 60 min at a temperature of 10-20℃ and a stirring head speed of 0.55-1 m / s. The drug phase was then added for 10 min using a homogenizer head speed of 0.55-1 m / s, a stirring head speed of 0.55-1 m / s, and a volumetric temperature of 10-20℃.

9. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 2, characterized in that, The drug in question is adapalene, which is dispersed in a gel matrix composed of carbomer 940, disodium EDTA, methylparaben, poloxamer, propylene glycol, purified water, and sodium hydroxide.

10. The low-shear mixing method for improving the stability of topical pharmaceutical formulations as described in claim 9, characterized in that, The drug phase was prepared for 30 min using a homogenizer head with a speed of 0.55-1 m / s and a stirring head with a speed of 0.55-1 m / s at a temperature of 25-30℃. The drug phase was then added after stirring for 10 min at a temperature of 25-30℃ using both a homogenizer head and a stirring head with a speed of 0.55-1 m / s.

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