Pharmaceutical composition of minocycline and benzoyl peroxide as well as preparation method and application of pharmaceutical composition

Abstract

The invention discloses a minocycline and benzoyl peroxide pharmaceutical composition as well as a preparation method and application thereof, and relates to the technical field of medicines. The invention relates to a pharmaceutical composition of minocycline and benzoyl peroxide. The pharmaceutical composition comprises minocycline hydrochloride silicon dioxide sustained-release microcapsules, benzoyl peroxide silicon dioxide sustained-release microcapsules and pharmaceutic adjuvants. According to the invention, minocycline and benzoyl peroxide are combined for use and are prepared into a sustained-release microcapsule structure, so that the treatment effect after medicine combination is obviously superior to that of single use of antibiotics or benzoyl peroxide, and an obvious synergistic effect is achieved; minocycline and benzoyl peroxide are respectively prepared into silicon dioxide sustained-release microcapsule structures and then are combined, so that the stability of the medicine can be improved, the direct contact between the medicine and the skin can be avoided, and the irritation of the medicine to the skin is reduced; active ingredients are prepared into a sustained-release microcapsule structure, so that the medicine can be slowly released when being in contact with skin, and different sustained-release requirements can be met.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a pharmaceutical composition of minocycline and benzoyl peroxide, a preparation method thereof, and an application thereof. Background Art

[0002] Acne vulgaris, also known as "teenage acne", is a common skin disease that mainly occurs in areas with active sebaceous glands such as the face, back, and chest. It is an inflammatory reaction caused by the blockage of hair follicles and sebaceous glands by sebum, dead skin cells, and bacteria.

[0003] Acne vulgaris is prone to occur in adolescent men and women, and has a relatively high incidence rate among teenagers. It has become the eighth most common chronic disease globally, and is prone to post-inflammatory erythema and pigmentation. According to statistics, about one-third of acne vulgaris can be secondary to sensitive skin, and even a small number of patients may have scars left, seriously affecting the appearance, physical and mental health of patients.

[0004] There are various methods for treating acne vulgaris. However, due to the complex etiology and large individual differences in treatment responses, single therapies often cannot completely cure or effectively control the occurrence and development of acne. Especially during traditional drug treatment, due to the problems of drug resistance and side effects, finding a safer and more effective treatment plan is the key to treating acne vulgaris.

[0005] Minocycline is a broad-spectrum tetracycline antibiotic used to treat bacterial infections and acne vulgaris, and has shown significant efficacy in the treatment of bacterial infections and acne vulgaris. Its mechanism of action is to inhibit the growth of Propionibacterium acnes and other related bacteria, and reduce the inflammatory reaction of sebaceous glands. Minocycline has a significant antibacterial effect on skin bacteria and has an anti-inflammatory effect, which can reduce inflammatory damage.

[0006] Currently, minocycline is mostly an oral drug. The treatment with oral minocycline has certain risks of side effects, especially the impact on organs such as the gastrointestinal tract, skin, liver, and kidneys. Its toxic and side effects have a greater impact on the treatment of patients. Moreover, minocycline is rapidly absorbed orally. After a single oral administration on an empty stomach, the highest blood drug concentration of 1.20 μg / mL is reached 2 hours later, and the average blood drug concentration 8 hours after administration is 0.47 μg / mL. Administering the drug once a day easily leads to a relatively high peak blood drug concentration, which in turn causes central nervous side reactions, and there are large differences between batches, and the product stability is poor. This instability of blood drug concentration after oral administration may also lead to various side reactions of the central nervous system.

[0007] Recently, relevant researchers have also been developing topical dosage forms of minocycline. Relevant experimental data show that the topical administration of minocycline has good tolerance. In addition, the systemic exposure of topical minocycline is low, with few side effects, low drug resistance, and high patient compliance; however, the topical preparations of minocycline also have the problem of unstable drug activity.

[0008] Benzoyl peroxide is also a commonly used first-line drug in dermatology for the treatment of acne. It has significant antibacterial, keratolytic, and comedolytic activities, with strong bactericidal effects and stable efficacy. It is also known as the "killer" of acne and is one of the most powerful acne treatment methods currently. Benzoyl peroxide has extremely strong oxidizing properties. After topical application, it will slowly release nascent oxygen and benzoic acid, rapidly destroy microorganisms, and reduce inflammation. The number of Propionibacterium acnes significantly decreases within 48 hours after medication, and the symptoms of red and swollen acne are significantly improved.

[0009] Since benzoyl peroxide is neither a hormone nor an antibiotic, there is no drug resistance, and it can be used for a long time. Clinically, benzoyl peroxide is usually combined with antibiotics to reduce the drug resistance of antibiotics used alone and help exfoliate horny plugs and accelerate drug penetration. However, benzoyl peroxide belongs to strong oxidants, which are highly irritating to the skin and can also cause the instability of the properties of the combined drugs.

[0010] Based on the above background research, the applicant intends to combine minocycline and benzoyl peroxide to develop a new compound drug for the treatment of acne vulgaris. However, there are the following technical problems in the process of combining minocycline and benzoyl peroxide:

[0011] (1) In the process of combining minocycline and benzoyl peroxide as active drugs, how to improve the addition form of the active drugs to enhance the efficacy of the compound preparation and improve the synergistic effect of the drugs;

[0012] (2) Benzoyl peroxide belongs to strong oxidants. When combined with minocycline, it will affect the drug activity of minocycline and lead to a decrease in the overall drug stability of the compound preparation;

[0013] (3) There will be certain skin irritation when minocycline and benzoyl peroxide are used for topical administration, and benzoyl peroxide belongs to strong oxidants, which is highly irritating to the skin;

[0014] (4) The release rate of the active ingredients after combining minocycline and benzoyl peroxide drugs is unstable.

[0015] Therefore, how to solve the above technical problems is an urgent technical problem that those of ordinary skill in the art need to solve currently.

[0016] The information disclosed in this background art section is only intended to enhance the understanding of the overall background of the present invention and should not be regarded as an admission or any form of implication that this information constitutes the prior art already known to those of ordinary skill in the art. Summary of the Invention

[0017] In view of the above technical problems, the embodiments of the present invention provide a pharmaceutical composition of minocycline and benzoyl peroxide, and its preparation method and application, so as to solve the problems presented in the above background technology.

[0018] A pharmaceutical composition of minocycline and benzoyl peroxide, comprising minocycline hydrochloride silica sustained-release microcapsules, benzoyl peroxide silica sustained-release microcapsules and pharmaceutical excipients.

[0019] Preferably, the mass ratio of minocycline hydrochloride silica sustained-release microcapsules to benzoyl peroxide silica sustained-release microcapsules is 0.1-1:0.8-8.

[0020] Preferably, the dosage form of the pharmaceutical composition includes: gel, cream, patch, tincture, ointment, film, cataplasm, lotion, liniment, aerosol, spray, ointment, transdermal preparation, foam, solution, or suspension, rubber plaster or film-forming agent.

[0021] A preparation method of the pharmaceutical composition of minocycline and benzoyl peroxide as described above, comprising the following steps:

[0022] Prepare minocycline hydrochloride silica sustained-release microcapsules and benzoyl peroxide silica sustained-release microcapsules respectively;

[0023] Using minocycline hydrochloride silica sustained-release microcapsules and benzoyl peroxide silica sustained-release microcapsules as active ingredients, add pharmaceutical excipients to prepare the pharmaceutical composition.

[0024] Preferably, the preparation method of minocycline hydrochloride silica sustained-release microcapsules comprises the following steps:

[0025] Prepare a first aqueous solution of a cationic surfactant;

[0026] Add minocycline hydrochloride to the first aqueous solution and stir evenly to make the surface of minocycline hydrochloride carry a positive charge;

[0027] Continue to add sodium silicate to the first aqueous solution and stir evenly;

[0028] Add a pH regulator to the first aqueous solution to adjust the first aqueous solution to acidic; sodium silicate hydrolyzes to form orthosilicic acid under acidic conditions and condenses to form silica sol particles wrapped on the surface of minocycline hydrochloride; specifically, the pH value is adjusted to 2.5 < pH < 7;

[0029] Continue to add a cationic polymer and stir evenly to make the cationic polymer encapsulate on the surface of silica, obtaining an aqueous phase containing minocycline hydrochloride silica sustained-release microcapsules;

[0030] Freeze-dry the aqueous phase containing minocycline hydrochloride silica sustained-release microcapsules to obtain minocycline hydrochloride silica sustained-release microcapsules.

[0031] Preferably, the preparation method of the benzoyl peroxide silica sustained-release microcapsule comprises the following steps:

[0032] Prepare a second aqueous solution of a cationic surfactant;

[0033] Add benzoyl peroxide to the second aqueous solution and stir evenly to make the surface of benzoyl peroxide carry a positive charge;

[0034] Continue to add sodium silicate to the second aqueous solution and stir evenly;

[0035] Add a pH regulator to the second aqueous solution to adjust the second aqueous solution to acidic; sodium silicate hydrolyzes to form orthosilicic acid under acidic conditions and condenses to form silica sol particles wrapped on the surface of benzoyl peroxide; specifically, the pH value is adjusted to 2.5 < pH < 7;

[0036] Continue to add a cationic polymer and stir evenly to make the cationic polymer encapsulate on the surface of silica, obtaining an aqueous phase containing benzoyl peroxide silica sustained-release microcapsules;

[0037] Freeze-dry the aqueous phase containing benzoyl peroxide silica sustained-release microcapsules to obtain benzoyl peroxide silica sustained-release microcapsules.

[0038] It should be noted that the cationic polymer can be encapsulated on the surface of silica through electrostatic interaction to form complete minocycline hydrochloride silica sustained-release microcapsules, improving the encapsulation effect.

[0039] Preferably, the cationic surfactant is selected from one or more of: amine salt type cationic surfactants, quaternary ammonium salt type cationic surfactants, and heterocyclic type cationic surfactants; for example, one of cetyltrimethylammonium chloride (CTAC), octadecyltrimethylammonium chloride, cationic guar gum, cationic panthenol, cationic silicone oil, and dodecyldimethylamine oxide.

[0040] Preferably, the cationic polymer is selected from one or more of: polyquaternary ammonium polymers, polyacrylamine, polyamine, and polyvinylamine (PEI) cationic polymers; for example, one of polyquaternary ammonium-7, polyquaternary ammonium-6, polyquaternary ammonium-5, and polyquaternary ammonium-39.

[0041] Application of a pharmaceutical composition of minocycline and benzoyl peroxide as described above in the preparation of a medicament for treating acne.

[0042] Preferably, the pharmaceutical composition of minocycline and benzoyl peroxide is an external medicament.

[0043] The pharmaceutical composition of minocycline and benzoyl peroxide provided by the embodiments of the present invention, its preparation method and application have the following beneficial effects:

[0044] 1. Minocycline and benzoyl peroxide are used in combination. The therapeutic effect after the combination of the drugs is significantly better than that of using antibiotics or benzoyl peroxide alone, with an obvious synergistic effect. After the combination of minocycline and benzoyl peroxide, it can quickly and strongly kill bacteria and reduce drug resistance.

[0045] 2. Minocycline and benzoyl peroxide are respectively prepared into silica sustained-release microcapsule structures and then combined. An innovative physical barrier is formed between the two drugs of minocycline and benzoyl peroxide to block the contact between the two drugs, thereby improving the stability of the drugs.

[0046] 3. Minocycline and benzoyl peroxide are respectively prepared into silica sustained-release microcapsule structures. An innovative physical barrier is respectively formed between minocycline and benzoyl peroxide and the skin, which can reduce the direct contact between the drugs and the skin, reduce the irritation of the drugs to the skin, reduce adverse reactions, and improve compliance.

[0047] 4. Minocycline and benzoyl peroxide are respectively encapsulated in silica sustained-release capsule shells. By controlling the thickness of the capsule shells, a specific sustained-release effect can be achieved, enabling the drugs to be slowly released when contacting the skin, which can meet different sustained-release requirements; at the same time, it also avoids the rapid release of a large amount of drugs, direct contact with the facial skin, reduces irritation, and can reduce the frequency of drug use and improve the tolerance of patients.

[0048] 5. The silica sustained-release microcapsules of minocycline hydrochloride and the silica sustained-release microcapsules of benzoyl peroxide do not interfere with each other, and the transdermal absorption effects of the two drugs are excellent. Description of the Drawings

[0049] Figure 1 It is the release rate result of minocycline hydrochloride;

[0050] Figure 2 It is the release rate result of benzoyl peroxide;

[0051] Figure 3 It is the absorption rate result of minocycline hydrochloride;

[0052] Figure 4 It is the absorption rate result of benzoyl peroxide;

[0053] Figure 5 It is the stability result of minocycline hydrochloride;

[0054] Figure 6 It is the stability result of benzoyl peroxide. Detailed Embodiments

[0055] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0056] In view of the above technical problems, the embodiments of the present invention provide a pharmaceutical composition of minocycline and benzoyl peroxide, its preparation method and application, so as to solve the problems raised in the above background technology.

[0057] I. Drug Preparation

[0058] It should be noted that in this embodiment, the preparation of gel and cream is taken as an example to explain in detail the preparation process of the pharmaceutical composition of minocycline and benzoyl peroxide.

[0059] Example 1, Gel

[0060] The raw material components of the pharmaceutical composition of minocycline and benzoyl peroxide, by mass, are shown in Table 1;

[0061] Table 1

[0062] Function Ingredient Percentage by weight % Active ingredient 1 Minocycline hydrochloride silica sustained-release microcapsule 0.3 Active ingredient 2 Benzoyl peroxide silica sustained-release microcapsule 2.5 Gel matrix, thickening agent Carbomer 980 4 Solubilizer Poloxamer 182 0.2 Water-miscible organic solvent Propylene glycol 4 Chelating agent Disodium edetate 0.1 Preservative Methylparaben 0.3 Preservative Phenoxyethanol 0.75 pH regulator Hydrochloric acid / sodium hydroxide Adjusted to pH = 5 Solvent Purified water qs100%

[0063] Preparation Method

[0064] ① Gel phase: Add disodium edetate, propylene glycol, methylparaben, and phenoxyethanol to water, stir to dissolve, and add carbomer 980, and prepare the gel phase by high-shear.

[0065] ② Active phase 1: Add poloxamer 182 to the minocycline hydrochloride silica sustained-release microcapsule solution and stir evenly.

[0066] ③ Active phase 2: Add poloxamer 182 to the benzoyl peroxide silica sustained-release microcapsule solution and stir evenly.

[0067] ④ Main mixing phase: Transfer the active phase 1 and active phase 2 to the gel phase, and perform high-shear and evacuate to remove air.

[0068] ⑤ Final mixing phase: Adjust the pH value by adding dilute hydrochloric acid or sodium hydroxide solution, and add the remaining water and mix evenly.

[0069] Example 2, Cream

[0070] The raw material components of the pharmaceutical composition of minocycline and benzoyl peroxide, by mass, are shown in Table 2;

[0071] Table 2

[0072]

[0073]

[0074] Preparation method

[0075] ① Oil-phase base liquid: Heat stearyl alcohol, stearic acid, isopropyl myristate, and polyoxyl 40 stearate to 70 - 80 °C until melted.

[0076] ② Oil-phase 1: Dissolve sorbic acid and minocycline hydrochloride silica sustained-release microcapsules completely in the oil-phase base liquid.

[0077] ③ Oil-phase 2: Dissolve sorbic acid and benzoyl peroxide silica sustained-release microcapsules completely in the oil-phase base liquid.

[0078] ④ Aqueous phase: Heat water to 70 - 80 °C and add xanthan gum while stirring at 200 - 400 rpm to dissolve.

[0079] ⑤ Mixed phase: Add the aqueous phase to the oil phase, stir at 700 - 1000 rpm for 7 - 15 min, and homogenize at 6000 - 8500 rpm for 1.5 - 4 min.

[0080] ⑥ Phase inversion: Stir at 200 - 400 rpm and cool down to the phase inversion point.

[0081] Comparative Example 1

[0082] The difference from Example 1 is only that the active ingredient is only minocycline hydrochloride silica sustained-release microcapsules and there is no benzoyl peroxide silica sustained-release microcapsules; the components of each raw material, by mass fraction, are shown in Table 3;

[0083] Table 3

[0084] Function Ingredient Percentage by weight % Active ingredient Minocycline hydrochloride silica sustained-release microcapsule 0.3 Gel matrix, thickening agent Carbomer 980 4 Solubilizer Poloxamer 182 0.2 Water-miscible organic solvent Propylene glycol 4 Chelating agent Disodium edetate 0.1 Preservative Methylparaben 0.3 Preservative Phenoxyethanol 0.75 pH regulator Hydrochloric acid / sodium hydroxide Adjusted to pH = 5 Solvent Purified water qs100%

[0085] Preparation method

[0086] ① Gel phase: Add disodium edetate, propylene glycol, methylparaben, and phenoxyethanol to water, stir to dissolve, and add Carbopol 980, and prepare the gel phase by high-shear mixing.

[0087] ② Active phase: Add poloxamer 182 to the minocycline hydrochloride silica sustained-release microcapsule solution and stir evenly.

[0088] ③ Main mixed phase: Transfer the active phase to the gel phase, and perform high-shear mixing and evacuate to remove air.

[0089] ④ Final mixed phase: Adjust the pH value by adding dilute hydrochloric acid or sodium hydroxide solution, add the remaining water, and mix evenly.

[0090] Comparative Example 2

[0091] The difference from Example 1 is only that the active ingredient is only one kind of benzoyl peroxide silica sustained-release microcapsule, benzoyl peroxide silica sustained-release microcapsule; by mass fraction, see Table 4;

[0092] Table 4

[0093] Function Ingredient Percentage by weight % Active ingredient Benzoyl peroxide silica sustained-release microcapsule 2.5 Gel matrix, thickening agent Carbomer 980 4 Solubilizer Poloxamer 182 0.2 Water-miscible organic solvent Propylene glycol 4 Chelating agent Disodium edetate 0.1 Preservative Methylparaben 0.3 Preservative Phenoxyethanol 0.75 pH regulator Hydrochloric acid / sodium hydroxide Adjusted to pH = 5 Solvent Purified water qs100%

[0094] Preparation method

[0095] ① Gel phase: Add disodium edetate, propylene glycol, methylparaben, and phenoxyethanol to water, stir to dissolve, add Carbopol 980, and prepare the gel phase by high-shear.

[0096] ② Active phase: Add poloxamer 182 to the benzoyl peroxide silica sustained-release microcapsule solution and stir evenly.

[0097] ③ Main mixing phase: Transfer the active phase to the gel phase, perform high-shear and evacuate to remove air.

[0098] ④ Final mixing phase: Adjust the pH value by adding dilute hydrochloric acid or sodium hydroxide solution, add the remaining water, and mix evenly.

[0099] Comparative Example 3

[0100] The difference from Example 1 is that the active ingredients are minocycline hydrochloride and benzoyl peroxide, and the two active ingredients are not prepared into silica microcapsules; the raw material components of the drug composition of minocycline hydrochloride and benzoyl peroxide, by mass fraction, see Table 5;

[0101] Table 5

[0102] Function Ingredient Percentage by weight % Active ingredient 1 Minocycline hydrochloride 0.3 Active ingredient 2 Benzoyl peroxide 2.5 Gel matrix, thickening agent Carbomer 980 4 Solubilizer Poloxamer 182 0.2 Water-miscible organic solvent Propylene glycol 4 Chelating agent Disodium edetate 0.1 Preservative Methylparaben 0.3 Preservative Phenoxyethanol 0.75 pH regulator Hydrochloric acid / sodium hydroxide Adjusted to pH = 5 Solvent Purified water qs100%

[0103] Preparation method

[0104] ① Gel phase: Add disodium edetate, propylene glycol, methylparaben, and phenoxyethanol to water, stir to dissolve, add Carbopol 980, and prepare the gel phase by high-shear.

[0105] ② Active phase 1: Add minocycline hydrochloride and poloxamer 182 to water and stir evenly.

[0106] ③ Active phase 2: Add benzoyl peroxide and poloxamer 182 to water and stir evenly.

[0107] ④ Main mixing phase: Transfer Active phase 1 and Active phase 2 to the gel phase, perform high-shear and evacuate to remove air.

[0108] ⑤ Final mixing phase: Adjust the pH value by adding dilute hydrochloric acid or sodium hydroxide solution, add the remaining water, and mix evenly.

[0109] II. Investigation of drug properties

[0110] 1. Sensory evaluation

[0111] The samples of Examples 1-2 and Comparative Examples 1-3 were respectively applied to the wrists of volunteers. There were 30 people in each group. The sensory evaluations such as use comfort, skin irritation, and skin allergy were carried out. The results are shown in Table 6.

[0112] Table 6 Sensory evaluation

[0113]

[0114] It can be seen from the results in Table 6 that the samples prepared by formulating minocycline hydrochloride and benzoyl peroxide into sustained-release microcapsules (Examples 1-2, Comparative Examples 1-2) had good sensory evaluations. They were evenly and finely applied, without a gritty feeling, and had excellent evaluation effects in terms of use comfort, skin irritation, skin allergy, etc., and the patient compliance was high. Especially for skin irritation, after being formulated into sustained-release microcapsules, the irritation of the drug to the skin was significantly reduced. The sample that was not formulated into a sustained-release microcapsule (Comparative Example 3) had a poor sensory evaluation.

[0115] 2. Release rate test

[0116] The modified Franz diffusion cell method was adopted, with a polytetrafluoroethylene (PTFE) membrane as the barrier, and the samples of Examples 1-2 and Comparative Examples 1-3 were used for in vitro release tests.

[0117] Test method: Isopropanol-water (50:50) was used as the release medium. The radius of the cut polytetrafluoroethylene (PTFE) membrane was 0.7 cm, and the area was 1.54 cm 2 . The water bath temperature was adjusted to be constant at (32 ± 0.5) °C, and the stirring speed was 500 rpm. 4 ml of the release medium was aspirated at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h respectively, and an equal amount of (32 ± 0.5) °C release medium was added at the same time. The cumulative release percentage was calculated (that is, the percentage of the cumulative permeated minocycline hydrochloride or benzoyl peroxide in the total amount of minocycline hydrochloride or benzoyl peroxide in the drug). The results are shown in Tables 7-8 and Figure 1-2 .

[0118] Table 7 Minocycline hydrochloride release rate

[0119] Release rate % / time h 0h 1h 2h 3h 4h 6h 8h 12h 24h Example 1 0 23 38 50 61 73 89 96 100 Example 2 0 26 37 46 59 68 83 92 98 Comparative example 1 0 25 36 52 63 75 89 97 99 Comparative example 2 0 0 0 0 0 0 0 0 0 Comparative example 3 0 84 88 92 92 92 92 92 92

[0120] Table 8 Benzoyl peroxide release rate

[0121] Release rate % / time h 0h 1h 2h 3h 4h 6h 8h 12h 24h Example 1 0 18 32 43 55 67 79 89 98 Example 2 0 16 28 41 52 68 78 91 99 Comparative example 1 0 0 0 0 0 0 0 0 0 Comparative example 2 0 19 33 45 54 69 82 93 100 Comparative example 3 0 72 87 88 87 88 88 88 88

[0122] From Tables 7-8 and Figure 1-2As can be seen from the results, for the samples prepared by formulating minocycline hydrochloride or benzoyl peroxide into sustained-release microcapsules (Examples 1-2, Comparative Examples 1-2), the release of minocycline hydrochloride or benzoyl peroxide is slowed down, the sustained-release effect is obvious, and the contents of minocycline hydrochloride and benzoyl peroxide are both qualified, and the stability is good. For the sample not prepared into a sustained-release microcapsule (Comparative Example 3), minocycline hydrochloride or benzoyl peroxide is rapidly released, and the release degrees of minocycline hydrochloride and benzoyl peroxide are reduced, and the stability becomes poor.

[0123] 3. In vitro transdermal test

[0124] The modified Franz diffusion cell method was used, with the abdominal skin of pigs as the barrier, and the samples of Examples 1-2 and Comparative Examples 1-3 were used for in vitro transdermal tests.

[0125] Test method: The washed pig skins were respectively fixed at the release port of the Franz diffusion cell, and isopropanol-water (50:50) was added to the receiving chamber as the release medium to keep the inner cortex in close contact with the solution. The samples were evenly applied to the skin, the water bath was adjusted to keep the temperature of the outer jacket layer constant at (32 ± 0.5) °C, the stirring speed was 600 rpm, and 4 ml of the release medium was aspirated at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h respectively, and an equal amount of the release medium was added at the same time. Calculate the cumulative absorption percentage, and the results are shown in Tables 9-10 and Figure 3-4 .

[0126] Table 9 Absorbance of minocycline hydrochloride

[0127] Absorbance % / time h 0h 1h 2h 3h 4h 6h 8h 12h 24h Example 1 0 10.61 21.72 35.75 49.77 63.26 89.97 96.98 97.54 Example 2 0 10.23 21.44 34.67 48.65 63.02 90.31 98.95 99.52 Comparative example 1 0 10.54 21.69 35.66 49.54 64.00 91.34 97.23 99.02 Comparative example 2 0 0 0 0 0 0 0 0 0 Comparative example 3 0 18.99 37.23 56.65 68.20 68.87 68.86 68.87 68.88

[0128] Table 10 Absorbance of benzoyl peroxide

[0129] Absorbance % / time h 0h 1h 2h 3h 4h 6h 8h 12h 24h Example 1 0 0.66 1.54 4.90 9.23 12.22 17.42 24.76 35.98 Example 2 0 0.47 1.43 4.67 9.03 12.63 17.98 25.71 36.48 Comparative example 1 0 0 0 0 0 0 0 0 0 Comparative example 2 0 0.67 1.72 5.00 10.41 12.90 18.52 25.99 37.35 Comparative example 3 0 3.14 10.21 18.53 24.42 24.11 24.11 24.12 24.11

[0130] As can be seen from Tables 9-10 and Figure 3-4 the results, for the samples prepared by formulating minocycline hydrochloride or benzoyl peroxide into sustained-release microcapsules (Examples 1-2, Comparative Examples 1-2), the transdermal absorption of minocycline hydrochloride or benzoyl peroxide is slowed down, and the sustained-release effect is obvious. For the sample not prepared into a sustained-release microcapsule (Comparative Example 3), minocycline hydrochloride or benzoyl peroxide is rapidly released, and the transdermal absorption amounts of minocycline hydrochloride and benzoyl peroxide are reduced, and the stability becomes poor.

[0131] 12. Stability test

[0132] In order to confirm the formation of minocycline hydrochloride silica sustained-release microcapsules and benzoyl peroxide silica sustained-release microcapsules and their improvement effects on the stability of minocycline hydrochloride and benzoyl peroxide, the following stability tests were carried out.

[0133] Test method: Samples of Examples 1-2 and Comparative Examples 1-3 were placed under accelerated conditions (40°C / 75% RH), and samples were taken regularly for testing. The results are shown in Table 11 and Figure 5-6 .

[0134] Table 11 Stability

[0135]

[0136] From Table 11 and Figure 5-6 the data, it can be seen that for the samples prepared by formulating minocycline hydrochloride or benzoyl peroxide into sustained-release microcapsules (Examples 1-2, Comparative Examples 1-2), after being placed under accelerated conditions, the contents of minocycline hydrochloride and benzoyl peroxide remained basically unchanged, indicating good stability. For the sample not prepared into sustained-release microcapsules (Comparative Example 3), the contents of minocycline hydrochloride and benzoyl peroxide decreased significantly, indicating poor stability.

[0137] 13. Skin irritation test

[0138] In order to confirm that the formation of minocycline hydrochloride-silica sustained-release microcapsules and benzoyl peroxide-silica sustained-release microcapsules can reduce the skin irritation of the drugs, the following tests were carried out.

[0139] Test samples: Example 1, Example 2, Comparative Example 3

[0140] Test animals: Adult, healthy white rabbits with no skin damage, half male and half female were selected.

[0141] Test method: The rabbits were divided into multiple groups, with 4 rabbits in each group, half male and half female. They were divided into a blank group, an Example 1 group, an Example 2 group, and a Comparative Example 1 group. 24 hours before administration, the hair on both sides of the spine on the back of each group of rabbits was cut off, and the hair removal area was about 3 cm × 3 cm on the left and right sides.

[0142] The blank group was not given any drug, and the comparative example group and the example group were given 0.5 g. The test substance was applied to one side of the skin, then covered with two layers of gauze (2.5 cm × 2.5 cm) and one layer of cellophane, and then fixed with non-irritating adhesive tape and bandage. The other side of the skin was used as a control and smeared with physiological saline. After 24 hours, the test substance was removed with warm water, and the skin reaction at the application site was observed. The hair was cut before the next application, and this was continuously carried out for 14 days. The skin irritation degree of the hair removal area was observed 1 hour after the last removal of the test substance. The scoring was carried out according to Table 12:

[0143] Table 12

[0144]

[0145] A comprehensive evaluation was carried out based on the average integral per animal per day, and the calculation formula was:

[0146] Average score per animal per day = ∑ erythema and edema scores / number of test animals / 14

[0147] Determine the skin irritation intensity according to Table 13:

[0148] Table 13

[0149]

[0150] The test results are shown in Table 14:

[0151] Table 14

[0152] Group Average integral value observed after removing the drug Blank 0 Example 1 group 0.43 Example 2 group 0.25 Comparative example 1 group 3.83

[0153] It can be seen from the above results that compared with the comparative examples under the same active ingredient concentration, the skin irritation score of the examples is significantly reduced. When minocycline hydrochloride or benzoyl peroxide is prepared into sustained-release microcapsules, the skin irritation is significantly reduced.

[0154] 14. Therapeutic effect on the coal tar-induced rabbit ear acne model

[0155] In order to confirm that the combined use of minocycline hydrochloride and benzoyl peroxide has a significantly better curative effect than the use of minocycline hydrochloride or benzoyl peroxide alone, and to confirm that the topical preparations of the minocycline hydrochloride silica sustained-release microcapsules and benzoyl peroxide silica sustained-release microcapsules of the present invention have a significant therapeutic effect on acne, the following tests are carried out.

[0156] (1) Test drugs: Examples 1-2, Comparative Examples 1-2

[0157] Test animals: Adult, healthy male rabbits with intact skin, randomly divided into 6 groups, 8 in each group, including an acne model control group, a normal control group, an Example 1 group, an Example 2 group, a Comparative Example 1 group, and a Comparative Example 2 group.

[0158] (2) Test method:

[0159] Except for the normal control group, in the range of 2 cm × 2 cm at the opening of the ear canal on the inner side of both ears of the rabbits in the other groups, coal tar was applied daily, 0.5 mL each time, for 14 consecutive days to establish a rabbit ear acne model.

[0160] After establishing the rabbit ear acne model, the normal control group and the model control group were not applied with any drugs, and the corresponding drugs were externally applied to both ears of the example groups and the comparative example groups once a day for 14 consecutive days.

[0161] Before each drug administration and after the last drug administration, observe the drug administration site. After the observation of the last drug administration, inject 20 ml of air embolism into the marginal ear vein to sacrifice the animals, take local tissues, fix them with 10% formalin, embed them in paraffin, stain with HE, prepare pathological sections and observe the histological changes under an optical microscope.

[0162] (3) Test results:

[0163] Results of macroscopic and microscopic observations:

[0164] Blank control group: The ears of the rabbits were pink in color, thin, soft, with clear capillary structures on them. There were no horny plugs in the hair follicles in the ear canal opening area and they were arranged in an orderly manner. The epidermis was thin, with a small amount of keratinized substances visible on the surface. The boundary between the epidermis and the dermis was clear and hair follicles were visible.

[0165] Model control group: 14 days after modeling in rabbits, the ears at the sites coated with coal tar showed swelling and redness, the hair follicle openings bulged, and a large area of black comedone-like horny plugs were visible. Acne-like changes were obvious; the epidermis and hair follicle epithelium were irregularly thickened, the granular layer was significantly thickened, hyperkeratosis occurred, the hair follicles were dilated, and adjacent hair follicles fused, filled with a large amount of keratinized substances. 14 days after the administration period (the model control group was given normal saline), only a small amount of horny plugs fell off, and there were still papules but the degree of bulging decreased.

[0166] Example group: The phenomenon 14 days after modeling was the same as that of the model control group. 14 days after administration, the degree of epidermal keratinization in the rabbit ears was significantly alleviated, the hair follicle horny plugs were significantly reduced, the papules became flat and fewer, and the obvious hyperplasia and keratinization of the epidermis were improved to varying degrees. The local hair follicles were slightly dilated, containing a small amount of keratinized substances, and there was a small amount of inflammatory cell infiltration in the superficial dermis.

[0167] Comparative example group: The phenomenon 14 days after modeling was the same as that of the model control group. 14 days after administration, the degree of epidermal keratinization in the rabbit ears was somewhat alleviated, the hair follicle horny plugs were reduced, the papules became flat and fewer, and the hyperplasia and keratinization of the epidermis were improved. The local hair follicles were moderately dilated, containing keratinized substances, and there was inflammatory cell infiltration in the superficial dermis. The improvement degree of each symptom was significantly worse than that of the example group.

[0168] According to the degree of hair follicle dilation, the amount of keratinized substances, and their pathological changes, it was divided into 4 grades:

[0169] "-" grade, no comedones formed, and no obvious pathological changes were seen in the skin surface layer, sebaceous glands, hair follicles, and dermis;

[0170] "+" grade, the stratified squamous epithelium of the skin surface layer was thickened, blood vessels were dilated, a small amount of inflammatory cells infiltrated, and a small amount of dense keratinized substances were visible in the infundibulum of the hair follicle;

[0171] "++" grade, the stratified squamous epithelium of the skin surface layer was significantly thickened, abscesses formed in the dermis, blood vessels were dilated, collagen fibers around them proliferated, there was a moderate amount of inflammatory cell infiltration, and a moderate amount of keratinized substances were visible in the infundibulum of the hair follicle and extended to the sebaceous glands;

[0172] "+++" grade: The stratified squamous epithelium on the surface of the skin is significantly thickened, abscesses are formed in the dermis, blood vessels are dilated, the surrounding collagen fibers proliferate, there is a large amount of inflammatory cell infiltration, and there is extensive keratinized material in the dilated hair follicles, which is similar to human open acne.

[0173] The pathological tissue grading results of each group are shown in Table 15:

[0174] Table 15

[0175]

[0176] It can be seen from the above results that the combined use of minocycline hydrochloride and benzoyl peroxide (Example 1, Example) has a significantly better therapeutic effect than the use of minocycline hydrochloride (Comparative Example 1) or benzoyl peroxide (Comparative Example 2) alone. The external preparation of minocycline hydrochloride silica sustained-release microcapsules and benzoyl peroxide silica sustained-release microcapsules of the present invention has a significant therapeutic effect on acne.

[0177] The embodiments described above are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the claims of the present invention.

Claims

1. A pharmaceutical composition of minocycline and benzoyl peroxide, characterized in that: The invention comprises minocycline hydrochloride silicon dioxide sustained-release microcapsules, benzoyl peroxide silicon dioxide sustained-release microcapsules and pharmaceutical excipients.

2. The pharmaceutical composition of minocycline and benzoyl peroxide according to claim 1, characterized in that: The mass ratio of minocycline hydrochloride silicon dioxide sustained-release microcapsules to benzoyl peroxide silicon dioxide sustained-release microcapsules is 0.1-1:0.8-8.

3. The pharmaceutical composition of minocycline and benzoyl peroxide according to claim 1, characterized in that: The dosage form of the pharmaceutical composition includes: a gel, a cream, a patch, a tincture, an ointment, a film, a papule, a lotion, a liniment, an aerosol, a spray, an ointment, a transdermal preparation, a foam, a solution, or a suspension, a rubber plaster or a film coating.

4. A method for preparing the pharmaceutical composition of minocycline and benzoyl peroxide as claimed in claim 1, characterized in that: The following steps are involved: Minocycline hydrochloride silicon dioxide sustained-release microcapsules and benzoyl peroxide silicon dioxide sustained-release microcapsules were prepared respectively; The invention adopts minocycline hydrochloride silicon dioxide sustained-release microcapsules and benzoyl peroxide silicon dioxide sustained-release microcapsules as active ingredients and adds pharmaceutical excipients to prepare a pharmaceutical composition.

5. The method for preparing the pharmaceutical composition of minocycline and benzoyl peroxide according to claim 4, characterized in that: The preparation method of minocycline hydrochloride silicon dioxide sustained-release microcapsules comprises the following steps: preparing a first aqueous solution of a cationic surfactant; Adding minocycline hydrochloride to the first aqueous solution and stirring evenly to make the surface of minocycline hydrochloride carry positive charge; Continue to add sodium silicate to the first aqueous solution and stir evenly; A pH regulator is added to the first aqueous solution to adjust the first aqueous solution to acidity; sodium silicate is hydrolyzed under acidic conditions to generate orthosilicic acid, which is condensed to form silica sol particles that are wrapped around the surface of minocycline hydrochloride; Continue to add the cationic polymer and stir evenly to allow the cationic polymer to be encapsulated on the surface of the silica to obtain an aqueous phase containing minocycline hydrochloride silica sustained-release microcapsules; The aqueous phase containing the minocycline hydrochloride silica sustained-release microcapsules is freeze-dried to obtain the minocycline hydrochloride silica sustained-release microcapsules.

6. The method for preparing the pharmaceutical composition of minocycline and benzoyl peroxide according to claim 4, characterized in that: The preparation method of benzoyl peroxide silicon dioxide sustained-release microcapsules comprises the following steps: preparing a second aqueous solution of a cationic surfactant; Adding oxybenzoyl to the second aqueous solution and stirring evenly to make the surface of the oxybenzoyl carry a positive charge; Continue to add sodium silicate to the second aqueous solution and stir evenly; A pH regulator is added to the second aqueous solution to adjust the second aqueous solution to acidity; sodium silicate is hydrolyzed under acidic conditions to generate orthosilicic acid, which is condensed to form silica sol particles that are wrapped around the surface of oxybenzoyl; Continue to add the cationic polymer and stir evenly to allow the cationic polymer to be encapsulated on the surface of the silicon dioxide to obtain an aqueous phase containing benzoyl peroxide silicon dioxide sustained-release microcapsules; The aqueous phase containing the benzoyl peroxide silicon dioxide sustained-release microcapsules is freeze-dried to obtain the benzoyl peroxide silicon dioxide sustained-release microcapsules.

7. The method for preparing the pharmaceutical composition of minocycline and benzoyl peroxide according to claim 4 or 5, characterized in that: The cationic surfactant is selected from one or more of an amine salt type cationic surfactant, a quaternary ammonium salt type cationic surfactant, and a heterocyclic type cationic surfactant.

8. The method for preparing the pharmaceutical composition of minocycline and benzoyl peroxide according to claim 4 or 5, characterized in that: The cationic polymer is selected from one or more of: polyquaternary ammonium salt polymers, polyacrylamine, polyamine, and polyvinylamine.

9. Use of the pharmaceutical composition of minocycline and benzoyl peroxide as claimed in claim 1 in the preparation of a drug for treating acne.

10. Use of the pharmaceutical composition of minocycline and benzoyl peroxide according to claim 9 in the preparation of a drug for treating acne, characterized in that: The pharmaceutical composition is a medicine for external use.

Images