External gel preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an external gel preparation and a preparation method thereof. The invention provides an external gel preparation containing substitutable carbomer as a gel matrix and a preparation method of the external gel preparation, specifically, a concentrated dispersion of an acrylamide / sodium dimethyl taurate acrylate copolymer in isohexadecane, such as Sepino P 600, is used for replacing carbomer, so that the problems that in an existing brimonidine gel preparation, due to the fact that carbomer is inconvenient to swell, the gel matrix can not be used as a gel matrix, and the gel matrix can not be used as a gel matrix are solved. The swelling time is long; the production efficiency is low; and the cost is increased. The product obtained by the preparation method is good in performance, and the preparation process is simple and quick to operate and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an external gel preparation and a preparation method thereof. Background Art

[0002] Brimonidine gel is an external medicine that acts on the dilated blood vessels on the face to make them contract, thereby reducing the appearance of facial erythema. This mechanism of action makes brimonidine gel an effective medicine for treating rosacea.

[0003] Currently, a brimonidine gel preparation without crystal particles is disclosed in Chinese Patent CN103298451B, which contains brimonidine tartrate, methylparaben and a second preservative, carbomer, polyol, titanium dioxide, sodium hydroxide pH regulator and purified water; Chinese Patent CN116159018B discloses a novel external brimonidine gel and its application in the treatment of mild and moderate erythematotelangiectatic and papulopustular rosacea. Its prescription contains brimonidine tartrate, volatile oil, carbomer gel matrix, polyol, titanium dioxide, sodium hydroxide pH regulator and purified water. The volatile oil is used instead of methylparaben as the preparation bacteriostatic agent, avoiding the related side effects of parabens preservatives and the risk of crystal precipitation during storage and use. However, in the prior art, the gel matrix used in brimonidine gel is all carbomer, and the swelling of carbomer requires high-speed stirring or overnight static swelling. In actual production, if carbomer is swollen by high-speed stirring, the two-pot method involves the transfer of the gel matrix, and there are risks of material transfer loss and material contamination during the transfer process, which requires an additional cleaning operation process for the equipment, increasing the production cost and time. If carbomer is swollen by static swelling, the preparation method mentioned in CN116159018B requires up to 12 hours to swell carbomer, which will greatly reduce the production efficiency. Not only the production cycle is prolonged, but also more equipment and manpower are required to maintain production, increasing the cost.

[0004] Therefore, it is necessary to study a substitute material for carbomer to simplify the preparation process of brimonidine gel preparation, reduce the production cost while meeting the performance requirements of the product. Summary of the Invention

[0005] To solve the problems of the above-mentioned swelling carbomer involving transfer operations and long time consumption, the object of the present invention is to provide an external gel preparation using a concentrated dispersion of acrylamide / sodium dimethyl taurate copolymer in isocetane as a gel matrix and its preparation method. Specifically, the present invention for the first time uses acrylamide / sodium acryloyldimethyltaurate copolymer & isocetane & polysorbate 80 & sorbitan oleate (Sepineo P 600) as a gel matrix for the preparation of brimonidine gel preparation. This gel matrix is simple and convenient to use, does not require high shear, homogenization or overnight swelling, and the gel can be prepared by a one-pot method, which is beneficial to reducing material loss, and the prepared gel preparation has stable quality, a smooth product surface, is easy to apply, and is convenient to use.

[0006] To achieve the above object, the present invention is realized through the following technical solutions:

[0007] The present invention provides an external gel preparation, which contains water, a drug and a gel matrix. The drug is brimonidine and its pharmaceutically acceptable salts, and the preferred drug is brimonidine tartrate; the gel matrix is a concentrated dispersion of acrylamide / sodium dimethyl taurate copolymer in isocetane.

[0008] In some embodiments, the gel matrix is specifically acrylamide / sodium acryloyldimethyltaurate copolymer & isocetane & polysorbate 80 & sorbitan oleate (i.e., Sepineo P 600). Specifically, Sepineo P600 is a multi-component excipient, in which acrylamide / sodium acryloyldimethyltaurate copolymer is dispersed in isocetane, and polysorbate 80 is used as a stabilizer. When a negatively charged polymer such as Sepineo P 600 undergoes a hydration process, the negative charges on its polymer chains are pushed apart by electrostatic repulsion, causing the polymer chains to rapidly unfold and swell, and finally forming a complex and stable three-dimensional network structure, which endows Sepineo P600 with various advantages in practical applications, such as easy operation and incorporation into formulations, compatibility with many solvents and oil phases, the ability to incorporate hydrophilic and hydrophobic drugs, and being patient-friendly.

[0009] In some embodiments, the content of the drug is 0.2% - 2% by mass percentage of the external gel preparation, and the mass ratio of the drug to the gel matrix is 1:0.25 - 1:50, preferably 1:1.25 - 1:30.

[0010] The external gel preparation of the present invention may further contain preservatives and polyhydric alcohols. In some embodiments, the preservative is methylparaben and one or more selected from sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea, and diazolidinyl urea. In some embodiments, the polyhydric alcohols include one or more of sorbitol, xylitol, pentaerythritol, ethylene glycol, liquid polyethylene glycol, polypropylene glycol, butanediol, dipropylene glycol, hexanetriol, hexylene glycol, neopentyl glycol, diethylene glycol, dipropylene glycol, trimethylolpropane, propylene glycol, and glycerol, preferably one or more of pentaerythritol, ethylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, diethylene glycol, dipropylene glycol, trimethylolpropane, propylene glycol, and glycerol.

[0011] The external gel preparation of the present invention may also contain other components commonly used in topical skin preparations, including but not limited to physical sunscreens (such as titanium dioxide, zinc oxide), pH regulators (such as sodium hydroxide, sodium citrate, sodium tartrate, triethanolamine, potassium hydroxide), antioxidants (such as α-tocopherol, dibutylhydroxytoluene, butylated hydroxyanisole), stabilizers, emollients, lubricants, moisturizers, pigments, fragrances, skin soothers, skin healers, and skin conditioners.

[0012] In some embodiments, the external gel preparation, by mass percentage, comprises: 0.2% - 2% of the drug, 0.5% - 10% of the gel matrix, 0.05% - 1% of the preservative, 6% - 25% of the polyhydric alcohol, 0% - 5% of the physical sunscreen, 0% - 10% of the pH regulator, 50% - 90% of water, and optionally 0% - 10% of other components for topical skin preparations.

[0013] Specifically, in some embodiments, the external gel preparation, by mass percentage, comprises: 0.2% - 2% of brimonidine tartrate, 0.5% - 10% of Sepineo P 600, 0.05 - 1% of methylparaben and phenoxyethanol, 6% - 25% of propylene glycol and glycerol, 0% - 5% of the physical sunscreen, 0% - 10% of the pH regulator, 50% - 90% of water, and optionally 0% - 10% of other components for topical skin preparations.

[0014] Specifically, in some embodiments, the external gel preparation, by mass percentage, comprises 0.2% - 2% of brimonidine tartrate, 2.5% - 6% of Sepineo P 600, 0.05% - 0.1% of methylparaben, 0.3% - 0.6% of phenoxyethanol, 4% - 6% of propylene glycol, 4% - 6% of glycerol, 0.01% - 1% of titanium dioxide, 0% - 10% of sodium hydroxide, and 70% - 90% of water.

[0015] The present invention also provides a method for preparing an external gel preparation, which comprises the following steps: mixing a drug, an optional preservative, an optional polyol, optional other components for topical skin preparations and a part of water, then adding a gel matrix to swell and mix to obtain a drug-containing mixture, and then adjusting the pH value of the drug-containing mixture with a pH regulator and making up to the prescribed amount with water and mixing to obtain the external gel preparation; the drug is brimonidine and its pharmaceutically acceptable salts, and the preferred drug is brimonidine tartrate; the gel matrix is a concentrated dispersion of acrylamide / sodium dimethyltaurate copolymer in isocetane.

[0016] In some specific embodiments, the amount of the part of water used in the preparation method is 50% - 99% of the total amount of water in the external gel preparation.

[0017] In some specific embodiments, the pH value of the drug-containing mixture is adjusted to 5.0 - 6.5 with a pH regulator in the preparation method.

[0018] In some specific embodiments, the external gel preparation obtained by the preparation method can be further filled into a polyethylene / aluminum / polyethylene composite medicinal ointment tube for storage.

[0019] In some specific embodiments, the method for preparing the external gel preparation comprises the following steps: 1) dissolving methylparaben and phenoxyethanol in propylene glycol to obtain a phase A liquid; 2) mixing brimonidine tartrate, glycerol, titanium dioxide, the phase A liquid and a part of purified water, and then adding the gel matrix Sepineo P 600 to swell and mix to obtain a drug-containing mixture; 3) adjusting the pH value of the drug-containing mixture to 5.0 - 6.5 with a sodium hydroxide solution, and then making up to the prescribed amount with purified water and mixing to obtain the external gel preparation.

[0020] In some specific embodiments, the addition of the gel matrix Sepineo P 600 in the preparation method can obtain a drug-containing mixture by homogeneous swelling and mixing or stirring swelling and mixing.

[0021] In some embodiments, more specifically, the method for preparing the external gel preparation comprises the following steps:

[0022] 1) Dissolving 0.05% - 0.1% methylparaben and 0.3% - 0.6% phenoxyethanol in 4% - 6% propylene glycol to obtain a phase A liquid;

[0023] 2) Add 0.2% - 2% of brimonidine tartrate to 50% - 60% of purified water based on the formulation prescription amount, add it to a homogenizing pot and stir until completely dissolved. Then add the phase A liquid, 4% - 6% of glycerol, and 0.01% - 1% of titanium dioxide, mix evenly. Then add 2.5% - 6% of Sepineo P 600, stir at 100 rpm - 200 rpm for 10 min - 60 min to fully swell and mix evenly to obtain a drug-containing mixture;

[0024] 3) Then adjust the pH value of the drug-containing mixture to 5.0 - 6.5 with 0.1 mol / L - 1 mol / L of sodium hydroxide solution, and make up to 100% of the prescription amount with purified water, mix evenly to obtain the external gel preparation.

[0025] The external gel preparation provided by the present invention has stable quality and performance. Compared with the prior art, the external gel preparation and its preparation method have the following advantages:

[0026] 1. For the first time, a brimonidine gel preparation is prepared with a gel matrix in liquid form such as Sepineo P 600, without the need for special equipment for high-shear and homogenization, the operation is convenient and fast, greatly simplifying the preparation process, and obtaining a brimonidine gel preparation with stable quality and qualified products;

[0027] 2. Adopt a one-pot preparation process, without the need to separately swell and transfer the gel matrix, avoiding the loss of viscous materials and being beneficial to reducing the risk of material contamination;

[0028] 3. Further improve the appearance and smooth spreading property of the brimonidine gel preparation. The gel matrix (such as Sepineo P 600) used in the present invention can not only be used as a thickening agent, helping to improve the properties of the gel preparation and making it have a smooth and soft surface; at the same time, the gel matrix (such as Sepineo P 600) has non-thixotropy, and when the preparation is applied to the skin, it is more likely to spread and penetrate with the increase of shear force, which is beneficial for patients to use. Description of the Drawings

[0029] Figure 1 It is a graph of the investigation of the amount of Sepineo P 600 - in vitro release results;

[0030] Figure 2 It is a graph of the investigation of the swelling method of Sepineo P 600 - gel matrix viscosity results;

[0031] Figure 3 The gel preparation obtained by the method of homogeneous swelling (1000 rpm, 10 min) of Sepineo P 600 in Example 3;

[0032] Figure 4The gel preparation obtained by stirring and swelling (50 rpm, 60 min) of Sepineo P 600 in Example 3;

[0033] Figure 5 The gel preparation obtained by stirring and swelling (100 rpm, 10 min) of Sepineo P 600 in Example 3;

[0034] Figure 6 The gel preparation obtained by stirring and swelling (200 rpm, 10 min) of Sepineo P 600 in Example 3. Detailed implementation mode

[0035] Combined with the following specific examples and drawings, the present invention will be further described in detail. The protection scope of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be conceived by those skilled in the art are included in the present invention, and the appended claims are used as the protection scope. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no special restrictive content.

[0036] In the present invention, unless otherwise specified, the percentages and ratios are weight percentages and weight ratios. The terms "comprising", "including", "containing" are open expressions, that is, including the content specified by the present invention, but not excluding other aspects. The term "part" is used to represent the quantity of a certain substance or component, and this quantity can be mass, volume or other appropriate units. "Part" is used as a relative unit to represent the proportional relationship between components.

[0037] In the present invention, "h" represents hour; "min" represents minute; "s" represents second; "g" represents gram; "ml" and "mL" both represent milliliter; "rpm" represents revolutions per minute; "M" represents moles per liter; "wt%" is the percentage of the weight of the component in the total weight of the preparation; "solution" means that the basic solvent is water, such as "sodium hydroxide solution" and "aqueous sodium hydroxide solution" both represent the aqueous solution of sodium hydroxide.

[0038] In the specific embodiments of the present invention, the gel matrix is represented by Sepineo P 600.

[0039] Investigation on the dosage of the gel matrix in Example 1

[0040] Prepare brimonidine gel preparations with different dosages of the gel matrix according to the following method:

[0041] (1) Dissolve 0.1 g of methylparaben and 0.4 g of phenoxyethanol in 6 g of propylene glycol under a water bath condition of 40°C to 60°C. After complete dissolution, cool to room temperature to obtain the Phase A liquid material;

[0042] (2) Dissolve 0.5 g of brimonidine tartrate in 50 ml of purified water, then add the Phase A liquid material, 6 g of glycerol and 0.1 g of titanium dioxide, and mix evenly. Then add different dosages of Sepineo P 600 (such as 4.0 g, 4.5 g, 5.0 g), and stir at a stirring speed of 200 rpm for 20 min to fully swell and mix evenly to obtain the drug-containing mixture;

[0043] (3) Use 1 mol / L sodium hydroxide solution to adjust the pH value of the drug-containing mixture to 5.0 - 6.5, and finally add purified water to make up to 100 g, and stir to make a uniform gel, thus obtaining the brimonidine gel preparation.

[0044] Table 1 Investigation on the dosage of Sepineo P 600 - Detection results of viscosity and viscoelasticity

[0045]

[0046] Conclusion: It is found that the storage modulus of the viscosity and viscoelasticity of the preparation increases with the increase in the dosage of Sepineo P 600; as Figure 1 shown, when performing the in vitro release test of the gel preparation, the amount of drug released per unit area on average at the same time point shows a tendency to decrease with the increase in the dosage of Sepineo P 600; The dosage of Sepineo P 600 being 4.0% - 5.0% all meets the product quality requirements.

[0047] Investigation on the pH value during the preparation process of Example 2

[0048] Prepare brimonidine gel preparations with different pH values of the drug-containing mixture according to the following method:

[0049] (1) Dissolve 0.1 g of methylparaben and 0.4 g of phenoxyethanol in 6 g of propylene glycol under a water bath condition of 40°C to 60°C. After complete dissolution, cool to room temperature to obtain the Phase A liquid material;

[0050] (2) Dissolve 0.5 g of brimonidine tartrate in 60 ml of purified water, then add the Phase A liquid material, 6 g of glycerol and 0.1 g of titanium dioxide, and mix evenly. Then add 4.5 g of Sepineo P 600, and stir at a stirring speed of 200 rpm for 20 min to fully swell and mix evenly to obtain the drug-containing mixture;

[0051] (3) Adjust the pH value of the drug-containing mixture to different values (such as 5.0, 5.5, 6.0, 6.5) using 1 mol / L sodium hydroxide solution, and finally add purified water to make up to 100 g, and stir to make a uniform gel, thus obtaining the brimonidine gel preparation.

[0052] Examine the results of the properties, content, related substances, in vitro release, viscosity and viscoelasticity of the brimonidine gel preparation for different pH values of the drug-containing mixture. It is found that the brimonidine gel preparation provided by the present invention meets the quality standards.

[0053] Table 2 Investigation of the pH value of the drug-containing mixture - Results of appearance properties

[0054]

[0055]

[0056] Table 3 Investigation of the pH value of the drug-containing mixture - Results of viscosity and viscoelasticity

[0057]

[0058] Example 3 Investigation of the swelling mode of the gel matrix Sepineo P 600

[0059] Prepare the brimonidine gel preparation with different swelling modes of the gel matrix according to the following method:

[0060] (1) Under the water bath condition of 40 °C to 60 °C, dissolve 0.1 g of methylparaben and 0.4 g of phenoxyethanol in 6 g of propylene glycol. After complete dissolution, cool to room temperature to obtain the phase A liquid material;

[0061] (2) Dissolve 0.5 g of brimonidine tartrate in 50 ml of purified water, then add the phase A liquid material, 6 g of glycerol and 0.1 g of titanium dioxide, and mix evenly; then add 4.5 g of Sepineo P 600, and fully swell and mix it with different swelling modes (such as homogenizing and swelling at 10000 rpm, stirring and swelling at 50 - 200 rpm) to obtain the drug-containing mixture;

[0062] (3) Use 1 mol / L sodium hydroxide solution to adjust the pH value of the drug-containing mixture to 5.0 - 6.5, and finally add purified water to make up to 100 g, and stir to make a uniform gel, thus obtaining the brimonidine gel preparation.

[0063] It is found that the gel matrix Sepineo P 600 can be swollen by homogenizing and stirring:

[0064] 1) Homogenizing and swelling: Homogenize at 1000 rpm for 10 min, Sepineo P 600 can be completely swollen to form a gel, and the homogenizing time has no obvious influence on the viscosity of the gel matrix;

[0065] 2) Stirring and swelling: When the stirring speed is 50 rpm, it is too low to easily form a gel; when stirring at 100 rpm - 200 rpm for 10 min, a gel can be formed, and the stirring speed and stirring time have no obvious effect on the viscosity of the gel matrix.

[0066] Such as Figure 2 shown, Sepineo P 600 can swell through both homogenization and stirring, and can swell rapidly. Within a certain range, the homogenization time, stirring speed, and stirring time have no obvious effect on the viscosity of the brimonidine gel preparation, and the viscosity is stable.

[0067] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the technical principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A gel preparation for external use, characterized in that: The topical gel preparation comprises water, a drug and a gel matrix, wherein the drug is brimonidine and a pharmaceutically acceptable salt thereof, and preferably the drug is brimonidine tartrate; and the gel matrix is ​​a concentrated dispersion of acrylamide / sodium dimethyl taurate copolymer in isohexadecane.

2. The external gel preparation according to claim 1, characterized in that: The gel base is Sepineo P 600.

3. The external gel preparation according to any one of claims 1 to 2, characterized in that: The content of the drug is 0.2% to 2% by mass of the external gel preparation, and the mass ratio of the drug to the gel matrix is ​​1:0.25 to 1:

50.

4. The external gel preparation according to any one of claims 1 to 3, characterized in that: The topical gel preparation further contains preservatives, polyols and optionally other components for topical preparations for external use on the skin, wherein the other components for topical preparations for external use on the skin include but are not limited to physical sunscreens, pH adjusters, antioxidants, stabilizers, softeners, lubricants, emollients, pigments, fragrances, skin soothing agents, skin healing agents and skin conditioning agents.

5. The external gel preparation according to any one of claims 1 to 4, characterized in that: The preservative is composed of methylparaben and one or more selected from sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea; the polyol includes one or more selected from sorbitol, xylitol, pentaerythritol, ethylene glycol, liquid polyethylene glycol, polypropylene glycol, butylene glycol, dipropylene glycol, hexanetriol, hexylene glycol, neopentyl glycol, diethylene glycol, dipropylene glycol, trimethylolpropane, propylene glycol and glycerol.

6. The external gel preparation according to any one of claims 1 to 5, characterized in that: The external gel preparation comprises, by mass percentage, 0.2% to 2% of a drug, 0.5% to 10% of a gel matrix, 0.05% to 1% of a preservative, 6% to 25% of a polyol, 0% to 5% of a physical sunscreen, 0% to 10% of a pH regulator, 50% to 90% of water, and 0% to 10% of other optional components for topical preparations for skin external use.

7. The external gel preparation according to any one of claims 1 to 6, characterized in that: The topical gel preparation comprises, by mass percentage, 0.2% to 2% of brimonidine tartrate, 0.5% to 10% of Sepineo P 600, 0.05% to 1% of methylparaben and phenoxyethanol, 6% to 25% of propylene glycol and glycerol, 0% to 5% of physical sunscreen, 0% to 10% of pH regulator, 50% to 90% of water and 0% to 10% of other optional components for topical preparations for skin application.

8. The external gel preparation according to any one of claims 1 to 7, characterized in that: The topical gel preparation comprises, by mass percentage, 0.2% to 2% brimonidine tartrate, 2.5% to 6% Sepineo P 600, 0.05% to 0.1% methylparaben, 0.3% to 0.6% phenoxyethanol, 4% to 6% propylene glycol, 4% to 6% glycerol, 0.01% to 1% titanium dioxide, 0% to 10% sodium hydroxide and 70% to 90% water.

9. A method for preparing the external gel preparation according to claims 4-8, comprising the following steps: The drug, preservative, polyol, other optional components for topical preparations for skin external use and part of water are mixed, and then a gel matrix is ​​added to swell and mix to obtain a drug-containing mixture, and then the pH value of the drug-containing mixture is adjusted with a pH regulator, and water is added to the prescribed amount and mixed to obtain the topical gel preparation; the drug is brimonidine and a pharmaceutically acceptable salt thereof, and preferably the drug is brimonidine tartrate; the gel matrix is ​​a concentrated dispersion of acrylamide / sodium dimethyl taurate copolymer in isohexadecane.

10. The preparation method according to claim 9, characterized in that: The amount of part of the water used in the preparation method is 50% to 99% of the total amount of water used in the external gel preparation; and the pH value of the drug-containing mixture is adjusted to 5.0 to 6.5 by a pH regulator in the preparation method.

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