Olopatadine and brimonidine-containing compound preparation composition for skin and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and discloses a compound preparation composition containing olopatadine and brimonidine for skin and a preparation method of the compound preparation composition. The compound preparation composition comprises the following components in percentage by weight: 0.1%-0.5% of brimonidine, 0.1%-0.5% of magnesium stearate and the balance of water. 0.1% to 0.5% of olopatadine; 0.8% to 1.2% of carbomer; 2%-5% of poloxamer; 0.1%-0.3% of sodium hyaluronate; the pH value is adjusted to 5.5-6.0 by triethanolamine, and purified water is used for complementing. The compound preparation composition disclosed by the invention has the advantages of double-target-point synergism, temperature-sensitive delivery, safe infiltration promotion and wide adaptation diseases.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, and more specifically, it relates to a compound preparation composition containing olopatadine and brimonidine for the skin and its preparation method. Background Art

[0002] Skin diseases, such as allergic dermatitis, contact dermatitis, rosacea, etc., are common clinical inflammatory and immune skin lesions, often accompanied by symptoms such as itching, erythema, and edema, seriously affecting the quality of life of patients. Existing treatment methods mostly use glucocorticoids, calcineurin inhibitors or anti-inflammatory drugs with a single mechanism, but long-term use is likely to cause adverse reactions such as skin atrophy and telangiectasia, or face problems such as insufficient efficacy and drug resistance.

[0003] As a second-generation histamine H1 receptor antagonist, olopatadine has both antihistamine and mast cell membrane stabilizing effects, and can effectively inhibit itching and the release of inflammatory mediators. However, its single use has limited regulatory ability on non-histamine-dependent inflammatory pathways (such as IL-6, TNF-α, etc.). Brimonidine is a selective α2-adrenergic receptor agonist that reduces erythema by constricting blood vessels, especially suitable for the treatment of rosacea, but it cannot relieve deep immune inflammatory reactions. Currently, both types of drugs are used for local skin treatment in a single-agent form, and there is no research exploring the synergistic effect of their compound combination and the application potential in a wider range of skin indications.

[0004] Therefore, it is of great clinical significance to develop a highly effective, safe and skin topical compound preparation with multiple synergistic mechanisms of action. Summary of the Invention

[0005] The object of the invention of this application is to explore the drug synergistic effect of olopatadine and brimonidine, develop a skin topical compound preparation that integrates the advantages of the two drugs, and achieve multiple pharmacological effects through a single administration.

[0006] To achieve the above object of the invention, this application adopts the following technical solutions: In the first aspect, the present invention provides a compound preparation composition for the skin. The compound preparation composition, calculated by weight percentage, includes: Brimonidine 0.1% - 0.5%; Olopatadine 0.1% - 0.5%; Carbomer 0.8% - 1.2%; Poloxamer 2% - 5%; Sodium hyaluronate 0.1% - 0.3%; Triethanolamine is used to adjust the pH to 5.5 - 6.0, and purified water is added to make up the volume.

[0007] Furthermore, the compound preparation composition, calculated by weight percentage, includes: Brimonidine 0.1% - 0.5%; Olopatadine 0.1% - 0.5%; Carbomer 0.8% - 1.2%; Poloxamer 188 or 407 2% - 5%; Sodium hyaluronate 0.1% - 0.3%; Azone 1% - 3%; Oleic acid 0.5% - 1%; Glycerol 10% - 15%; Propylene glycol or PEG400 3% - 5%; Ascorbyl palmitate 0.01% - 0.05%; Triethanolamine is used to adjust the pH to 5.5 - 6.0, and purified water is added to make up the volume.

[0008] In the second aspect, the present invention provides a compound gel including the compound preparation composition described in the first aspect. The compound gel includes: Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; Ascorbyl palmitate 0.03 g; EDTA2Na 0.08 g; Triethanolamine is used to adjust the pH to 5.8, and purified water is added to make up the volume.

[0009] In the third aspect, the present invention provides a preparation method of the compound gel of the compound preparation composition described in the second aspect, including the following steps: Disperse Carbomer in water, add triethanolamine for neutralization; dissolve the active ingredients in propylene glycol / glycerol, mix with sodium hyaluronate and ultrasonicate; add all other components and homogenize to obtain the compound gel.

[0010] In the fourth aspect, the present invention provides a compound gel including the compound preparation composition described in the first aspect. The compound gel includes: Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 1.5 g; Oleic acid 0.5 g; Glycerol 12 g; PEG400 5 g; Bisabolol 0.1 g; EDTA2Na 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0011] In a fifth aspect, the present invention provides a method for preparing a compound gel of the compound preparation composition described in the fourth aspect, comprising the following steps: dispersing carbomer in water and neutralizing with triethanolamine; dissolving the active ingredients in PEG400 / glycerol, mixing with sodium hyaluronate and sonicating; adding all other components and homogenizing to obtain the compound gel.

[0012] In a sixth aspect, the present invention provides a compound gel comprising the compound preparation composition described in the first aspect, wherein the compound gel comprises: Brimonidine tartrate 0.4 g; Olopatadine hydrochloride 0.2 g; Carbomer 980 1.0 g; Poloxamer 407 5 g; Sodium hyaluronate 0.2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; EDTA2Na 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0013] In a seventh aspect, the present invention provides a method for preparing a compound gel of the compound preparation composition described in the sixth aspect, characterized by comprising the following steps: dispersing carbomer in water and neutralizing with triethanolamine; dissolving the active ingredients in propylene glycol / glycerol, mixing with sodium hyaluronate and sonicating; adding all other components and homogenizing to obtain the compound gel.

[0014] In the compound preparation of the present invention, brimonidine is an α2 receptor agonist that rapidly constricts blood vessels and reduces erythema intensity; olopatadine hydrochloride is an H1 receptor antagonist that inhibits histamine release and synergistically blocks the itching-inflammation cycle with brimonidine; carbomer has a three-dimensional network gel structure that provides adhesiveness and prolongs drug release (in vitro release ≥ 85%); poloxamer 188 is a temperature-sensitive matrix that forms a semi-solid gel at body temperature, reduces drug loss, and increases local drug concentration; sodium hyaluronate is a natural moisturizing factor that repairs the skin barrier and enhances drug penetration (comparative tests show a 20% increase in transdermal efficiency); azone and oleic acid disrupt the lipid bilayer of the stratum corneum and synergistically enhance drug penetration (Q24h olopatadine ≥ 30 μg / cm²); glycerol and PEG400 replace traditional propylene glycol to reduce irritation in children (rabbit skin irritation test score ≤ 0.5); ascorbyl palmitate is a lipophilic antioxidant that significantly improves the photostability of olopatadine (degradation rate < 5% after 6 months of accelerated testing).

[0015] The compound preparation of the present invention has a ternary permeation-promoting system that synergistically disrupts the stratum corneum through azone, oleic acid, and propylene glycol / PEG400, doubling the transdermal efficiency. The combination of an antioxidant and a chelating agent solves the problem of olopatadine photosensitivity. Low-irritation excipients (PEG400, bisabolol) and a hormone-free formulation fill a market gap.

[0016] In summary, compared with the prior art, the present application has the following beneficial effects: Dual-target synergy: A synergistic combination of brimonidine (α2 adrenergic receptor agonist, vasoconstriction / anti-inflammatory) + olopatadine (histamine H1 receptor antagonist, anti-allergic).

[0017] Temperature-sensitive delivery system: Rheological property regulation of the carbomer and poloxamer compound matrix to achieve low-temperature fluidity (easy to apply) and body-temperature gelation (long-term retention).

[0018] Safe permeation-promoting system: According to the differences in indications, azone (high osmotic for adults) and isopropyl palmitate (low osmotic for children) are flexibly selected.

[0019] Multi-dimensional indication expansion: Covers multiple scenarios such as children, laser beauty, atopic dermatitis (AD), chronic urticaria, etc., and supports combination treatment plans. Detailed implementation manners

[0020] The technical solutions and effects of the present application are further described in detail below in conjunction with embodiments. It can be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0021] Example 1 This example discloses a compound preparation gel, and the raw materials used in the preparation are as follows (prescription: 100 g): Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; Ascorbyl palmitate 0.03 g; EDTA disodium 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0022] Preparation method of the compound gel, comprising the following steps: Disperse Carbomer in water, add triethanolamine for neutralization; Dissolve the active ingredients in propylene glycol / glycerol, mix with sodium hyaluronate and sonicate; Add all other components and homogenize to obtain the compound gel.

[0023] Example 2 This example discloses a compound preparation gel, and the raw materials used for preparation are as follows (prescription: 100 g): Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 1.5 g; Oleic acid 0.5 g; Glycerol 12 g; PEG400 5 g; Bisabolol 0.1 g; EDTA disodium 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0024] Preparation method of the compound gel, comprising the following steps: Disperse Carbomer in water, add triethanolamine for neutralization; Dissolve the active ingredients in PEG400 / glycerol, mix with sodium hyaluronate and sonicate; Add all other components and homogenize to obtain the compound gel.

[0025] Example 3 This example discloses a compound preparation gel, and the raw materials used for preparation are as follows (prescription: 100 g): Brimonidine tartrate 0.4 g; Olopatadine hydrochloride 0.2 g; Carbomer 980 1.0 g; Poloxamer 407 5 g; Sodium hyaluronate 0.2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; EDTA disodium 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0026] Preparation method of the compound gel, characterized in that it comprises the following steps: Disperse Carbomer in water, neutralize with triethanolamine; Dissolve the active ingredient in propylene glycol / glycerol, mix with sodium hyaluronate and sonicate; Add all other components and homogenize to obtain the compound gel.

[0027] Comparative Example 1 This example discloses a preparation gel, and the raw materials used in the preparation are as follows (prescription 100 g): Brimonidine tartrate 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; Ascorbyl palmitate 0.03 g; EDTA disodium 0.08 g; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0028] Preparation method of the compound gel, comprising the following steps: Disperse Carbomer in water, neutralize with triethanolamine; Dissolve the active ingredient in propylene glycol / glycerol, mix with sodium hyaluronate and sonicate; Add all other components and homogenize to obtain the compound gel.

[0029] Comparative Example 2 This example discloses a preparation gel, and the raw materials used in the preparation are as follows (prescription 100 g): Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; Ascorbyl palmitate 0.03 g; 0.08 g of EDTA2Na; Adjust the pH to 5.8 with triethanolamine and make up with purified water.

[0030] The preparation method of the compound gel comprises the following steps: Disperse carbomer in water and neutralize with triethanolamine; Dissolve the active ingredient in propylene glycol / glycerol, mix with sodium hyaluronate and ultrasonicate; Add all other components and homogenize to obtain the compound gel.

[0031] Performance detection Detection 1: Stability test (40 °C / 75% RH, 6 months, taking Example 1 as an example): Detection 2: Transdermal comparison test (Q24h, n = 6) Detection 3: Clinical indications and data verification Detection 4: Pharmacological and pharmacodynamic experiments ① Single drug and compound synergistic effect (rabbit ear vein ring experiment) Experimental steps: 1. Sample preparation: Take the rabbit ear vein ring (35 mm) of New Zealand rabbits and incubate it in Krebs solution (containing 95% O2 / 5% CO2) at 37 °C. 2. Vasoconstriction treatment: Pre - contract the vein ring with norepinephrine (NE, 1 μM) to the equilibrium tension (about 10 minutes). 3. Drug incubation: Add the single drug (Comparative Example 2) and the compound drug (Example 1) respectively, and record the vasodilation rate (collect data through a tension sensor and a PowerLab system). 4. Data analysis: Calculate the half - maximal effective concentration (EC50) and the maximum inhibition rate (Emax), and calculate the combination index (CI) using the Chou - Talalay method.

[0032] ② Histamine - induced pruritus inhibition (mouse skin pruritus model) Experimental steps: 1. Animal grouping: BALB / c mice (6 - 8 weeks old, half male and half female), randomly divided into a control group, a single olopatadine group (Comparative Example 2, 2 mg / kg), and a compound group (Example 1, 2 mg / kg). 2. Histamine - induced pruritus: Intradermally inject histamine (100 μg / 50 μL) into the shaved area on the back of the mice. 3. Drug intervention: Immediately apply the drug (gel - covered area, dose 10 μL / cm²) after injection and continuously observe for 1 hour. 4. Data collection: Record the scratching times (defined as the hind foot quickly sliding for ≥1 second), and compare the inhibition rates of each group.

[0033] Experimental results: Detection 5: Transdermal Absorption and Pharmacokinetics Experiments ① In vitro transdermal absorption (Franz diffusion cell) Experimental procedure: 1. Skin preparation: Excised porcine ear skin (thickness 500 ± 50 μm) was taken, subcutaneous fat was removed, and it was stored in physiological saline for later use. 2. Diffusion system setup: The skin was fixed in a Franz cell (effective diffusion area 1.77 cm²), and the receptor cell was filled with PBS at pH 7.4. 3. Drug administration and sampling: The compound gel (Example 1, 200 mg) and Mirvaso® (control) were added to the donor cell, and it was placed in a 37°C water bath (magnetic stirring). Samples were taken from the receptor cell at 2, 4, 8, 12, and 24 hours (0.5 mL, replenished with an equal volume of PBS). 4. Concentration detection: The concentrations of brimonidine (λ = 245 nm) and olopatadine (λ = 280 nm) were determined by HPLC method.

[0034] ② In vivo pharmacokinetics (SD rat model) Experimental procedure: 1. Drug administration and sampling: The back hair of SD rats (200 - 250 g) was shaved, and 1.0 g / kg of the compound gel was applied. Blood was collected from the orbital sinus at 0.5, 1, 2, 3, 6, 12, and 24 hours (n = 6 per group). 2. Plasma treatment: The blood was centrifuged (3000 rpm, 10 minutes) to obtain plasma, which was stored at 80°C. 3. LCMS / MS detection: After protein precipitation in plasma, the sample was injected, and the parent ion → daughter ion was monitored (brimonidine m / z 292 → 212; olopatadine m / z 335 → 165). 4. Kinetic analysis: WinNonlin was used to calculate Tmax, Cmax, and AUC 0-24 。

[0035] Experimental results: This specific embodiment is only an explanation of the present application, and it is not a limitation of the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A compound preparation composition for skin, characterized in that, The compound preparation composition, calculated by weight percentage, includes: Brimonidine 0.1% - 0.5%; Olopatadine 0.1% - 0.5%; Carbomer 0.8% - 1.2%; Poloxamer 2% - 5%; Sodium hyaluronate 0.1% - 0.3%; Triethanolamine is used to adjust the pH to 5.5 - 6.0, and purified water is added to make up the volume.

2. The compound preparation composition according to claim 1, characterized in that, The compound preparation composition, calculated by weight percentage, includes: Brimonidine 0.1% - 0.5%; Olopatadine 0.1% - 0.5%; Carbomer 0.8% - 1.2%; Poloxamer 188 or 407 2% - 5%; Sodium hyaluronate 0.1% - 0.3%; Azone 1% - 3%; Oleic acid 0.5% - 1%; Glycerol 10% - 15%; Propylene glycol or PEG400 3% - 5%; Ascorbyl palmitate 0.01% - 0.05%; Triethanolamine is used to adjust the pH to 5.5 - 6.0, and purified water is added to make up the volume.

3. A compound gel comprising the compound preparation composition according to claim 1, characterized in that, The compound gel includes: Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; Ascorbyl palmitate 0.03 g; EDTA2Na 0.08 g; Triethanolamine is used to adjust the pH to 5.8, and purified water is added to make up the volume.

4. The preparation method of the compound gel of the compound preparation composition according to claim 3, characterized in that, It includes the following steps: Disperse Carbomer in water and neutralize it with triethanolamine; Dissolve the active ingredients in propylene glycol / glycerol, mix them with sodium hyaluronate and sonicate; add all other components and homogenize to obtain the compound gel.

5. A compound gel comprising the compound preparation composition described in claim 1, characterized in that, The compound gel includes: Brimonidine tartrate 0.3 g; Olopatadine hydrochloride 0.3 g; Carbomer 980 1.0 g; Poloxamer 188 3 g; Sodium hyaluronate 0.2 g; Azone 1.5 g; Oleic acid 0.5 g; Glycerol 12 g; PEG400 5 g; Bisabolol 0.1 g; EDTA2Na 0.08 g; Triethanolamine is used to adjust the pH to 5.8, and purified water is added to make up the volume.

6. The preparation method of the compound gel of the compound preparation composition according to claim 5, characterized in that, It includes the following steps: Disperse Carbomer in water and neutralize it with triethanolamine; Dissolve the active ingredients in PEG400 / glycerol, mix them with sodium hyaluronate and sonicate; add all other components and homogenize to obtain the compound gel.

7. A compound gel comprising the compound preparation composition according to claim 1, characterized in that, The compound gel includes: Brimonidine tartrate 0.4 g; Olopatadine hydrochloride 0.2 g; Carbomer 980 1.0 g; Poloxamer 407 5 g; Sodium hyaluronate 0.2 g; Oleic acid 0.8 g; Glycerol 12 g; Propylene glycol 6 g; EDTA2Na 0.08 g; Triethanolamine is used to adjust the pH to 5.8, and purified water is added to make up the volume.

8. A method for preparing the compound gel of the compound preparation composition according to claim 7, characterized in that, It includes the following steps: Disperse Carbomer in water and neutralize it with triethanolamine; Dissolve the active ingredients in propylene glycol / glycerol, mix them with sodium hyaluronate and sonicate; add all other components and homogenize to obtain the compound gel.

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