Venturi effect preparation method of terbinafine film-forming composition

Abstract

The invention relates to a venturi effect preparation method of a terbinafine film-forming composition, which comprises the following steps: 1) dissolving terbinafine or terbinafine hydrochloride in a solvent to obtain a medicine liquid; 2) mixing the medium chain triglyceride and the medicine liquid to obtain mixed liquid; 3) performing dry mixing with a film-forming agent to obtain a dry-mixed polymer; and 4) adding the dry-mixed polymer into the mixed liquid through a Venturi effect, and hydrating the obtained polymer. The preparation method has the advantages that the composition proportion, the preparation method and the mixing equipment are reasonable in design, the dry-mixed polymer is introduced into the liquid by utilizing the Venturi effect, lumps can be effectively crushed, the hydration effect is improved, the preparation method is efficient and economical, and the preparation time can be effectively saved and the energy consumption can be effectively reduced on the premise of ensuring the use effect.

Description

Technical Field

[0001] The invention relates to a method for preparing a terbinafine film-forming composition, in particular to a method for preparing a terbinafine film-forming composition through a Venturi effect. Background Art

[0002] The prior art terbinafine film-forming composition generally contains two polymers: acrylate / octylacrylamide copolymer (Dermacry 1 79) and hydroxypropylcellulose (Hypro l ose). These two polymers have the problem of agglomeration and are difficult to hydrate, requiring a long time, in most cases requiring more than 24 hours of hydration time.

[0003] The formation of lumps is generally caused by uneven mixing of polymers in the dispersion medium. The existing formulations or preparation methods have problems with insufficient rheology and viscosity.

[0004] The Venturi effect is a fluid mechanics phenomenon that occurs when a moving fluid passes through a tapered pipe section, narrowing in the middle and then widening again. As the fluid flows through the tapered pipe section, the velocity of the fluid increases in the area with a smaller pipe diameter. This is because the fluid flow must maintain its volume flow rate, i.e. the same amount of fluid must pass through any cross section of the pipe in a certain amount of time. Therefore, in order to speed up the flow rate, the cross-sectional area must be as small as possible. According to Bernoulli's principle, the acceleration of the fluid in the narrow area of ​​the pipe causes the pressure in that area to decrease. This decrease in pressure is the so-called Venturi low pressure. In contrast, in the wider part of the pipe, the fluid velocity is lower and the pressure is higher. Compared with the high-pressure area, the lower pressure formed in the narrow pipe part makes it easy for particles to enter and the mixing efficiency is higher.

[0005] The pressure of the liquid on the outer wall creates the Venturi effect. In chemical engineering, the Venturi effect is used in various devices and processes. For example, laboratory aspirators are used to create a vacuum in laboratory equipment to facilitate various chemical operations. The Venturi effect is also used in reagent mixers to achieve uniform mixing of reagents in chemical processes. In addition, air ejectors in reactors can also use the Venturi effect to increase the oxygen content and the efficiency of chemical reactions. Summary of the invention

[0006] The present invention provides a Venturi effect preparation method of a terbinafine film-forming composition, which aims to overcome the above-mentioned shortcomings of the prior art and shorten the hydration time under the premise of ensuring the hydration effect.

[0007] The technical solution of the present invention is a Venturi effect preparation method of a terbinafine film-forming composition, comprising:

[0008] 1) dissolving terbinafine or terbinafine hydrochloride in a solvent to obtain a drug liquid;

[0009] 2) mixing the medium chain triglyceride and the drug liquid to obtain a mixed liquid;

[0010] 3) dry-mixing the film-forming agent to obtain a dry-mixed polymer;

[0011] 4) Adding the dry-mixed polymer to the mixed liquid by the Venturi effect and hydrating the resulting polymer.

[0012] Preferably, the mixed liquid in step 4) and the dry mixed polymer added by the Venturi effect are both introduced into a homogenizer.

[0013] Preferably, the step 4) uses a preparation device to add a dry mixed polymer to the mixed liquid through the Venturi effect, and the preparation device includes a hopper, a Venturi effect contraction tube and a mixing container with an agitator and a homogenizer, wherein the Venturi effect contraction tubes are connected to both sides of the hopper outlet at the bottom of the hopper, one side of the Venturi effect contraction tube is connected to the mixing container inlet of the mixing container, and the other side of the Venturi effect contraction tube is connected to the mixing container outlet of the mixing container through a transmission pipeline.

[0014] Preferably, a hopper cover is provided on the top of the hopper, and a hopper bracket is supported on the bottom of the hopper.

[0015] Preferably, the content of terbinafine or terbinafine hydrochloride in the composition is 0.97%-1.125% by weight.

[0016] Preferably, the film-forming agent comprises a hydrophilic polymer and a hydrophobic polymer.

[0017] Further preferably, the film former comprises 4% to 6% by weight of octyl acrylamide acrylate copolymer and 2% to 3% by weight of hydroxypropyl cellulose in the composition.

[0018] Preferably, the solvent is a mixture of one or more of ethanol, isopropanol, acetone and ethyl acetate.

[0019] Preferably, the solvent is a mixture of ethanol and water.

[0020] The advantages of the present invention are as follows: the composition ratio, preparation method and mixing equipment are reasonably designed, and the dry mixed polymer is introduced into the liquid by using the Venturi effect, which can effectively break up the lumps and improve the hydration effect. It is efficient and economical, and can effectively save preparation time and reduce energy consumption while ensuring the use effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a schematic structural diagram of an embodiment of the preparation device adopted in the present invention.

[0022] Figure 2 yes Figure 1 Schematic diagram of the enlarged structure of the middle hopper and the Venturi effect contraction tube.

[0023] Figure 3 yes Figure 2 Schematic diagram of the reaction at the connection between the Chinese Turey effect shrink tube and the hopper outlet.

[0024] In the figure, 1 is the hopper cover, 2 is the hopper, 3 is the hopper outlet, 4 is the venturi effect contraction tube, 5 is the hopper bracket, 6 is the mixing container, 7 is the mixing container outlet, 8 is the transmission pipeline, and 9 is the mixing container inlet. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0026] A Venturi effect preparation method of a terbinafine film-forming composition comprises:

[0027] 1) dissolving terbinafine or terbinafine hydrochloride in a solvent to obtain a drug liquid;

[0028] 2) mixing the medium chain triglyceride and the drug liquid to obtain a mixed liquid;

[0029] 3) dry-mixing the film-forming agent to obtain a dry-mixed polymer;

[0030] 4) Adding the dry-mixed polymer to the mixed liquid by the Venturi effect and hydrating the resulting polymer.

[0031] As a preferred embodiment, the mixed liquid in step 4) and the dry mixed polymer added by the Venturi effect are both introduced into the homogenizer.

[0032] As a preferred embodiment, step 4) uses a preparation device made of metal material to mix the dry-mixed polymer and the mixed liquid.

[0033] As a further preferred embodiment, the preparation device is made of 316 stainless steel, 320 stainless steel or a combination of the two.

[0034] like Figure 1-3 As shown, the preparation device includes a hopper 2, a venturi effect contraction tube 4 and a mixing container 6, wherein a hopper cover 1 is provided on the top of the hopper 2, a hopper bracket 5 is supported at the bottom of the hopper 2, and Venturi effect contraction tubes 4 are connected to both sides of a hopper outlet 3 at the bottom of the hopper 2, one side of the Venturi effect contraction tube 4 is connected to a mixing container inlet 9 of the mixing container 6, and the other side of the Venturi effect contraction tube 4 is connected to a mixing container outlet 7 of the mixing container 6 through a transmission pipe 8.

[0035] The hopper cover 1 is used to protect the material from contamination; the hopper 2 is used to hold the dry mixed polymer; the hopper outlet 3 is used to connect with the venturi effect contraction tube 4 to transmit the dry mixed polymer into the solution or dispersion flow generated by the venturi effect in the venturi effect contraction tube 4; the mixing container 6 is the prior art, which is provided with an agitator and a homogenizer; the pipeline 8 is used to transport the solution or dispersion flow from the mixing container outlet 7 to the mixing container inlet 9.

[0036] As a preferred embodiment, the content of terbinafine or terbinafine hydrochloride in the composition is between 0.5%-30% by weight, preferably 0.75%-20% by weight, more preferably 0.9%-15% by weight, and most preferably 1%-10% by weight.

[0037] As a further preferred embodiment, the content of terbinafine or terbinafine hydrochloride in the composition is 0.9%-1.2% by weight, preferably 0.95%-1.15%, more preferably 0.97%-1.125%, most preferably 1%.

[0038] As a preferred embodiment, the film former suitable for the present invention includes hydrophilic and / or hydrophobic polymers. The hydrophobic polymer is selected from acrylate polymers, acrylate copolymers, alkyl olefin acids, alkyl olefin acid ester copolymers, amide / olefin acids, amide / olefin acid copolymers and polyvinyl acetate. It is preferably selected from acrylamide octyl ester, acrylamide octyl ester acrylate copolymers, acrylate octyl ester acrylamide copolymers, methacrylic acid aminoalkyl ester copolymers, methacrylic acid aminoester copolymers, polyvinyl acetate and alkyl acrylate methyl methacrylate copolymers. The hydrophilic polymer is selected from polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymers, hydroxyalkyl cellulose and alkyl cellulose. It is preferably selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. The hydrophilic polymer and the hydrophobic polymer preferably exist simultaneously.

[0039] As a further preferred embodiment, the content of the hydrophilic polymer in the composition is 0.05%-30% by weight, preferably 0.5%-10%, more preferably 1%-5%; the content of the hydrophobic polymer in the composition is 0.05%-30% by weight, preferably 1%-10%, more preferably 3%-7%.

[0040] As the most preferred embodiment, the composition contains 4%-6% by weight of octyl acrylamide acrylate copolymer and 2%-3% by weight of hydroxypropyl cellulose.

[0041] As a preferred embodiment, the solvent is selected from ethanol, isopropanol, acetone and ethyl acetate, and more preferably ethanol or a mixture of ethanol and water.

[0042] As a preferred embodiment, other ingredients may also be included. Such as plasticizers, film modifiers, surfactants, penetration enhancers, colorants, antioxidants, complexing agents and ultraviolet light absorbers. Plasticizers are preferably selected from dialkyl phthalates (such as dibutyl phthalate), hydroxy fatty acid oils (such as castor oil), triglycerides and silicone oils. Film modifiers are preferably selected from acrylates, aryl sulfonamide formaldehyde, cellulose derivatives or polyamides.

[0043] As a preferred embodiment, other pharmaceutically active agents may also be included, such as anti-inflammatory agents. The anti-inflammatory agent may be selected from steroids, such as hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone acetonide, medrysone, prednisolone, fludrocortisone lactone, prednisone, halocindone, methylprednisolone, fludrocortisone lactone, prednisone, halocindone, methylprednisolone, fludrocortisone, corticosterone, paramethasone and betamethasone; and non-steroidal anti-inflammatory drugs, such as ibuprofen, diclofenac, naproxen, fenobuprofen, fenbufen, flurbiprofen, indoibuprofen, ketoibuprofen, super ibuprofen, indomethacin, sulfasalazine, piroxicam and aspirin. Particularly suitable are hydrocortisone, diclofenac, indomethacin and their salts. Adding an anti-inflammatory agent can improve and heal symptoms associated with fungal illnesses, such as itching, redness, blisters, burning, or cracks, more quickly.

[0044] The composition of the present invention is applied to the skin area infected with fungi to treat the infection. The composition is very effective in treating fungal skin infections (including tinea pedis, tinea corporis, tinea cruris and tinea capitis). The composition is applied to the infected skin area and the solvent of the composition is allowed to evaporate. As the solvent evaporates, the composition forms a thin film on the skin, which comes into close contact with the skin and delivers the active agent directly to the infected area.

[0045] The composition can adhere to the skin for at least 48 hours, preferably at least 60 hours, and more preferably at least 72 hours, during which a small portion may be removed or worn away. Studies have shown that the therapeutic effect of using the composition of the present invention once can be equivalent to or better than the therapeutic effect of using the commercial over-the-counter antifungal drug product repeatedly for one to four weeks.

[0046] Example 1

[0047]

[0048]

[0049] Preparation steps:

[0050] (1) Dissolve terbinafine hydrochloride in ethanol and stir slowly until a transparent solution is formed.

[0051] (2) Add medium chain triglycerides to the solution obtained in step (1) under stirring and mix for 10 minutes.

[0052] (3) Dry-mixing the acrylate / octylacrylamide copolymer and hydroxypropylcellulose under stirring to obtain a polymer dry mixture.

[0053] (4) Add the polymer dry mixture obtained in step (3) into a hopper connected to a venturi effect shrink tube, and directly introduce it into a homogenizer, and homogenize it with the solution obtained in step (2) for 10 minutes under stirring.

[0054] (5) The polymer was hydrated for 60 minutes with stirring.

[0055] Example 2

[0056] The difference from Example 1 is that the preparation step (4) is: manually adding the polymer dry mixture obtained in step (3) to the solution obtained in step (2) under stirring, and homogenizing for 10 minutes under stirring.

[0057] Example 3

[0058] The difference from Example 3 is that the preparation step (5) is: hydrating the polymer for 24 hours under stirring.

[0059] Example 4: Comparison of solution appearance

[0060] The solutions prepared in Examples 1-3 were checked for appearance and the presence of lumps.

[0061] The samples were placed in clear glass tubes and observed under white light and against a dark background.

[0062]

[0063]

[0064] Example 5: Comparison of solution viscosity

[0065] Viscosity analysis was performed on the solutions prepared in Examples 1-3 to compare the hydration of the polymers. The hydration of the polymer directly affects the rheology and viscosity of the solution. Poor hydration will result in reduced viscosity and consistency of the formulation, and vice versa.

[0066]

[0067] Example 6: Uniformity Comparison

[0068] For analysis, 10 samples each of Examples 1-3 were collected from various locations on the main production vessel.

[0069] The difference between the highest and lowest values ​​indicates the distribution of terbinafine in the composition, which is related to the degree of hydration of the polymer. Smaller differences between volume uniformity values ​​indicate a higher degree of hydration, while larger differences indicate a lower degree of hydration.

[0070] The difference between the volume uniformity values ​​of Examples 1 and 3 is small, while the difference of Example 2 is large, which indicates that Examples 1 and 3 are fully hydrated, while the hydration of Example 2 is poor, so terbinafine is not mixed uniformly.

[0071]

[0072]

[0073] Example 7: In vitro release study

[0074] The tests were performed using a Franz diffusion cell, using a Logan Instrument SYSTEM 913A-12 modular, fully automated, 12-position transdermal diffusion system. A magnetic stirrer was placed in the receptor chamber of the diffusion cell. The receptor chamber was filled with receptor solution, i.e., 10x phosphate buffered saline: water, 10:90 v / v, containing 7% ascorbic acid w / v. The membrane was mounted on the receptor chamber until the membrane touched the interface between the receptor and donor chambers. The donor chamber was placed on top of the membrane, properly aligned with the diffusion cell assembly. The connection between the donor and receptor chambers was secured with a clamp. The temperature was set appropriately to maintain the membrane at approximately 32 ± 1 °C. The magnetic stirrer was kept on throughout the test (fixed speed of approximately 560 rpm). The membrane was allowed to equilibrate for 30 minutes. The temperature of the membrane surface was measured using a calibrated infrared thermometer. Before applying the formulation on the membrane surface, a pre-dose sample (300 μL) was collected from the center of the receptor chamber of each diffusion cell and transferred to a sample collection vial. The receptor chamber was replenished with receptor stock solution after each sampling. Analyze the drug release in solution. Compare with commercial formulation Once, calculate the release ratio of the example compared with the commercially available product.

[0075]

[0076]

[0077]

[0078] As shown in the table above, the 90% confidence interval index of the 8th and 29th test ratios of Examples 1, 2 and 3 to the reference are 96.4-106.2, 83.6-123.2 and 97.8-109.2, respectively. The release amounts of Examples 1 and 3 are similar, while the release amount of Example 2 using the ordinary hydration method varies greatly, which is far from the other two samples. Therefore, Example 1, which uses the Venturi effect to add the polymer and mixes it through a homogenizer, can avoid the long-term hydration of Example 3 and provide a product effect that meets the requirements.

[0079] Conclusion: The improved method for preparing the terbinafine film-forming composition helps to save time and energy, and its hydration degree is the same as that of the product without the venturi effect shrink tube and the commercial product.

[0080] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A Venturi effect preparation method of a terbinafine film-forming composition, characterized in that: include: 1) dissolving terbinafine or terbinafine hydrochloride in a solvent to obtain a drug liquid; 2) mixing the medium chain triglyceride and the drug liquid to obtain a mixed liquid; 3) dry-mixing the film-forming agent to obtain a dry-mixed polymer; 4) Adding the dry-mixed polymer to the mixed liquid by the Venturi effect and hydrating the resulting polymer.

2. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 1, characterized in that: The mixed liquid in step 4) and the dry mixed polymer added by the Venturi effect are both introduced into the homogenizer.

3. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 1, characterized in that: The step 4) uses a preparation device to add a dry mixed polymer to the mixed liquid through the Venturi effect, and the preparation device includes a hopper, a Venturi effect contraction tube and a mixing container with a homogenizer and an agitator, wherein the Venturi effect contraction tubes are connected to both sides of the hopper outlet at the bottom of the hopper, one side of the Venturi effect contraction tube is connected to the mixing container inlet of the mixing container, and the other side of the Venturi effect contraction tube is connected to the mixing container outlet of the mixing container through a transmission pipeline.

4. The Venturi effect preparation method of a terbinafine film-forming composition as claimed in claim 3, characterized in that: A hopper cover is arranged on the top of the hopper, and a hopper bracket is supported on the bottom of the hopper.

5. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 1, characterized in that: The content of the terbinafine or terbinafine hydrochloride in the composition is 0.97%-1.125% by weight.

6. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 1, characterized in that: The film-forming agent comprises a hydrophilic polymer and a hydrophobic polymer.

7. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 6, characterized in that: The film former in the composition contains 4%-6% by weight of octyl acrylamide acrylate copolymer and 2%-3% by weight of hydroxypropyl cellulose.

8. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 1, characterized in that: The solvent is a mixture of one or more of ethanol, isopropanol, acetone and ethyl acetate.

9. The Venturi effect preparation method of a terbinafine film-forming composition according to claim 8, characterized in that: The solvent is a mixture of ethanol and water.

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