A venturi method of preparing a terbinafine film forming composition

Abstract

The application is a venturi effect preparation method of terbinafine film forming composition, comprising the following steps: 1) dissolving terbinafine or hydrochloric acid terbinafine in a solvent to obtain a drug liquid; 2) mixing medium-chain glycerol tristearate with the drug liquid to obtain a mixed liquid; 3) dry mixing a film forming agent to obtain a dry mixed polymer; and 4) adding the dry mixed polymer into the mixed liquid through the venturi effect and hydrating the obtained polymer. The application has the advantages that the composition ratio, the preparation method and the mixing equipment design are reasonable, the dry mixed polymer is introduced into the liquid by the venturi effect, the blocky material can be effectively broken, the hydration effect is improved, the preparation is efficient and economical, the preparation time can be effectively saved and the energy consumption can be reduced under the premise of ensuring the use effect.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of terbinafine film-forming composition, in particular to a Venturi effect preparation method of terbinafine film-forming composition. BACKGROUND

[0002] The prior art terbinafine film-forming composition generally contains two polymers: acrylate / octyl acrylamide copolymer (Dermacryl 79) and hydroxypropyl cellulose (Hyprolose). The two polymers have the problems of caking and difficult hydration, and need a long time, usually more than 24 hours of hydration time.

[0003] The formation of caking is generally caused by uneven mixing of the polymer in the dispersion medium, and the prior art formula or preparation method has the problems of insufficient rheological property and viscosity.

[0004] Venturi effect is a fluid mechanics phenomenon that occurs when a moving fluid passes through a conical pipe section, the middle of which narrows and then widens again. When the fluid flows through the gradually narrowing pipe section, the velocity of the fluid increases in the area with smaller pipe diameter. This is because the fluid flow must maintain its volumetric flow rate, i.e. the same amount of fluid must pass through any cross-section of the pipe in a certain time. Therefore, the cross-sectional area must be as small as possible to increase the flow rate. According to Bernoulli's principle, the acceleration of the fluid in the narrow area of the pipe results in a decrease in pressure in that area. This decrease in pressure is called the Venturi low pressure. In contrast, in the wider part of the pipe, the fluid velocity is lower and the pressure is higher. The lower pressure formed at the narrow part of the pipe makes it easier for particles to enter and the mixing efficiency is higher compared to the high pressure area.

[0005] The liquid pressure of the outer wall forms 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 injectors in reactors can also use the Venturi effect to increase the oxygen content and efficiency of chemical reactions. SUMMARY

[0006] The present application proposes a Venturi effect preparation method of terbinafine film-forming composition, which aims to overcome the above-mentioned deficiencies in the prior art and shorten the hydration time while ensuring the hydration effect.

[0007] The technical solution of the present application: a Venturi effect preparation method of 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 with 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 into the mixed liquid by the Venturi effect and hydrating the obtained polymer.

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

[0013] Preferably, step 4) uses a preparation device to add the dry mixed polymer into the mixed liquid by the Venturi effect, and the preparation device comprises a hopper, a Venturi effect contraction pipe and a mixing container with a stirrer and a homogenizer, wherein the bottom of the hopper is connected with the Venturi effect contraction pipe on both sides of the hopper outlet, one side of the Venturi effect contraction pipe is communicated with the mixing container inlet of the mixing container, and the other side of the Venturi effect contraction pipe is communicated with the mixing container outlet of the mixing container through a transmission pipeline.

[0014] Preferably, the top of the hopper is provided with a hopper cover, and the bottom of the hopper is supported by a hopper support.

[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 content of the film forming agent in the composition is 4%-6% of octyl acrylamide acrylate copolymer and 2%-3% of hydroxypropyl cellulose by weight.

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

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

[0020] The advantages of the present application are that the composition ratio, preparation method and mixing equipment design are reasonable, the dry mixed polymer is introduced into the liquid by the Venturi effect, which can effectively break the blocky material and improve the hydration effect, and the preparation time and energy consumption can be effectively saved under the premise of ensuring the use effect. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is a schematic structural view of one embodiment of the preparation device used in the present application.

[0022] Figure 2 isFigure 1 A magnified schematic diagram of the middle hopper and the Venturi effect shrink tube.

[0023] Figure 3 yes Figure 2 A schematic diagram of the reaction at the connection between the Tubular contraction tube and the hopper outlet in Chinese.

[0024] In the diagram, 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 support, 6 is the mixing container, 7 is the mixing container outlet, 8 is the transfer pipe, and 9 is the mixing container inlet. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to embodiments and specific implementation methods.

[0026] A method for preparing a terbinafine film-forming composition using the Venturi effect, comprising:

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

[0028] 2) Mix the medium-chain triglycerides with the drug liquid to obtain a mixed liquid;

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

[0030] 4) Add the dry polymer to the mixed liquid through the Venturi effect and hydrate the resulting polymer.

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

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

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

[0034] like Figures 1-3 As shown, the preparation device includes a hopper 2, a Venturi effect shrinkage tube 4, and a mixing container 6. The top of the hopper 2 is provided with a hopper cover 1, and the bottom of the hopper 2 is supported by a hopper bracket 5. The two sides of the hopper outlet 3 at the bottom of the hopper 2 are connected to the Venturi effect shrinkage tubes 4. One side of the Venturi effect shrinkage tube 4 is connected to the mixing container inlet 9 of the mixing container 6, and the other side of the Venturi effect shrinkage tube 4 is connected to the mixing container outlet 7 of the mixing container 6 through a transmission pipe 8.

[0035] The hopper lid 1 is used to protect the material from contamination; the hopper 2 is used to hold the dry polymer blend; the hopper outlet 3 is used to connect to the venturi constriction 4 to deliver the dry polymer blend to the solution or dispersion stream created under the venturi effect within the venturi constriction 4; the mixing vessel 6 is of the prior art and contains an agitator and homogeniser; the conduit 8 is used to deliver the solution or dispersion stream from the mixing vessel outlet 7 to the mixing vessel inlet 9.

[0036] As a preferred embodiment, terbinafine or terbinafine hydrochloride is present in the composition at a level of 0.5% to 30%, preferably 0.75% to 20%, more preferably 0.9% to 15%, most preferably 1% to 10% by weight.

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

[0038] As a preferred embodiment, film forming agents suitable for use in the present application include hydrophilic and / or hydrophobic polymers. The hydrophobic polymer is selected from the group consisting of acrylate polymers, acrylate copolymers, alkyl olefinic acids, alkyl olefinic acid ester copolymers, amide / olefinic acid, amide / olefinic acid copolymers and polyvinyl acetate. Preferably, it is selected from the group consisting of octyl acrylamide, octyl acrylamide acrylate copolymer, octyl acrylate acrylamide copolymer, aminoalkyl methacrylate copolymer, amino methacrylate copolymer, polyvinyl acetate and alkyl acrylate methyl methacrylate copolymer. The hydrophilic polymer is selected from the group consisting of polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, hydroxyalkyl cellulose and alkyl cellulose. Preferably, it is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone. Preferably, both a hydrophilic and a hydrophobic polymer are present.

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

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

[0041] As a preferred embodiment, the solvent is selected from the group consisting of ethanol, isopropyl alcohol, acetone and ethyl acetate. Further preferably, it is ethanol or a mixture of ethanol and water.

[0042] As preferred embodiments, other ingredients can also be included. For example, plasticizers, film modifiers, surfactants, penetration enhancers, colorants, antioxidants, complexing agents, and ultraviolet absorbers. Plasticizers are preferably selected from the group consisting of dialkyl phthalates (e.g., dibutyl phthalate), hydroxy fatty acid oils (e.g., castor oil), triglycerides, and silicone oils. Film modifiers are preferably selected from the group consisting of acrylates, aryl sulfonamide formaldehydes, cellulose derivatives, or polyamides.

[0043] As preferred embodiments, other pharmaceutically active agents can also be included, such as anti-inflammatory agents. Anti-inflammatory agents can be selected from the group consisting of steroids, such as hydrocortisone, cortisone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, flurandrenolide, corticosterone, paramethasone, and betamethasone; and non-steroidal anti-inflammatory drugs, such as ibuprofen, diclofenac, naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen, ketoprofen, suprofen, indomethacin, sulfasalazine, piroxicam, and aspirin. Particularly useful are hydrocortisone, diclofenac, indomethacin, and salts thereof. The addition of anti-inflammatory agents can more rapidly improve and cure symptoms associated with the fungal infection, such as itching, erythema, vesicles, burning, or cracking.

[0044] The composition of the present application is applied to the area of the skin infected with the fungus to treat the infection. The composition is very effective in treating fungal infections of the skin, including athlete's foot, body ringworm, jock itch, and ringworm of the scalp. The composition is applied to the area of the skin infected and the solvent of the composition is allowed to evaporate. As the solvent evaporates, the composition forms a thin film on the skin that intimately contacts the skin and delivers the active agents directly to the infected area.

[0045] The composition adheres to the skin for at least 48 hours, preferably at least 60 hours, and further preferably at least 72 hours, during which time a small amount can be removed or abraded. Studies have shown that the therapeutic effect of a single application of the composition of the present application is equivalent to or better than the therapeutic effect of a regimen of strict adherence to the repeated use of a commercially available non-prescription antifungal product for one to four weeks.

[0046] Example 1

[0047]

[0048]

[0049] Preparation Procedure:

[0050] (1) Dissolve terbinafine hydrochloride in ethanol with slow stirring until a clear solution is formed.

[0051] (2) To the solution from step (1), add medium chain triglyceride under agitation and mix for 10 minutes.

[0052] (3) Dry blend the acrylates / octylacrylamide copolymer and hydroxypropyl cellulose under agitation to obtain a polymer dry blend.

[0053] (4) Add the polymer dry blend from step (3) to a hopper connected to a venturi-inlet and direct into a homogenizer, and homogenize under agitation with the solution from step (2) for 10 minutes.

[0054] (5) Hydrate the polymer under agitation for 60 minutes.

[0055] Example 2

[0056] The difference from Example 1 is that the preparation step (4) is to manually add the polymer dry blend from step (3) to the solution from step (2) under agitation and homogenize for 10 minutes under agitation.

[0057] Example 3

[0058] The difference from Example 3 is that the preparation step (5) is to hydrate the polymer under agitation for 24 hours.

[0059] Example 4: Solution Appearance Comparison

[0060] The appearance of the formulated solutions of Examples 1-3 was examined, as well as the presence of lumps.

[0061] The samples were loaded into clear glass tubes and observed under white light and a dark background.

[0062]

[0063]

[0064] Example 5: Solution Viscosity Comparison

[0065] The formulated solutions of Examples 1-3 were analyzed for viscosity to compare the hydration of the polymers. The hydration of the polymers directly affects the rheology and viscosity of the solution. Poor hydration can result in a decrease in the viscosity and consistency of the formulation, and vice versa.

[0066]

[0067] Example 6: Uniformity Comparison

[0068] For analysis, 10 samples of each of Examples 1-3 were collected from multiple locations in 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. The smaller the difference between the volume uniformity values, the higher the degree of hydration, and the greater the difference, the lower the degree of hydration.

[0070] The difference between the volume uniformity values of Examples 1, 3 is small, while the difference of Example 2 is greater, which indicates that Examples 1, 3 are completely hydrated, while Example 2 has a poor degree of hydration, and therefore the terbinafine is not mixed uniformly.

[0071]

[0072]

[0073] Example 7: In vitro release study

[0074] Franz diffusion cells were used, using a Logan Instrument SYSTEM 913A-12 modular fully automated 12-place transdermal diffusion system. A magnetic stirrer was placed inside the receptor chamber of the diffusion cell. The receptor chamber was filled with a 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 contacted the junction 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 fixed with a clamp. The temperature was set appropriately so that the membrane remained at around 32 ± 1 °C. The magnetic stirrer was left on throughout the test (at a fixed speed of approximately 560 rpm). The membrane was left to equilibrate for 30 minutes. A calibrated infrared thermometer was used to measure the temperature of the membrane surface. A pre-dose sample (300 μL) was collected from the center of the receptor chamber of each diffusion cell before the formulation was applied to the membrane surface and transferred to a sample collection vial. The receptor chamber was replenished with receptor stock solution after each sampling. The amount of drug released in the solution was analyzed. A commercial formulation was used as a control Once, the release ratio of the example compared to the commercial product was calculated.

[0075]

[0076]

[0077]

[0078] As shown in the above table, the 90% confidence interval index of the ratio of the 8th and 29th test of Example 1, 2 and 3 to the reference is 96.4-106.2, 83.6-123.2 and 97.8-109.2 respectively. The release amount of Example 1 and 3 is similar, while the release amount of Example 2 using the common hydration method varies greatly, which is far from the other two samples. Therefore, Example 1 using the Venturi effect to add polymer and mix by homogenizer can avoid the long hydration of Example 3 and provide the required product effect.

[0079] Conclusion: The improved preparation method of terbinafine film-forming composition helps to save time and energy, and the hydration degree is the same as that of the product hydrated for 24 hours without the configuration of Venturi effect contraction pipe and the commercially available product.

[0080] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the inventive concept, a number of modifications and improvements can be made, which are within the scope of the present application.

Claims

1. A method for the production of a film forming terbinafine composition by Venturi effect, characterized in that, The application relates to a preparation method of a terbinafine hydrochloride film-coated tablet, which comprises the following steps: 1) dissolving terbinafine or terbinafine hydrochloride in a solvent to obtain a drug liquid; 2) mixing medium-chain glyceride with the drug liquid to obtain a mixed liquid; 3) dry mixing a film former to obtain a dry-mixed polymer; 4) adding the dry-mixed polymer into the mixed liquid through a Venturi effect and hydrating the obtained polymer; and 5) introducing the mixed liquid and the dry-mixed polymer added through the Venturi effect into a homogenizer. The application further relates to a terbinafine hydrochloride film-coated tablet prepared by the above method. The application further relates to a preparation device for adding the dry-mixed polymer into the mixed liquid through the Venturi effect, which comprises a hopper, a Venturi effect contraction pipe and a mixing container with a homogenizer and a stirrer, wherein the bottom of the hopper is connected with the Venturi effect contraction pipe on both sides of a hopper outlet, one side of the Venturi effect contraction pipe is communicated with a mixing container inlet of the mixing container, and the other side of the Venturi effect contraction pipe is communicated with a mixing container outlet of the mixing container through a transmission pipeline. The top of the hopper is provided with a hopper cover, and the bottom of the hopper is supported by a hopper support. The content of terbinafine or terbinafine hydrochloride in the composition is 0.97%-1.125% by weight. The film former is octyl acrylamide acrylate copolymer with a content of 4%-6% by weight and hydroxypropyl cellulose with a content of 2%-3% by weight. The solvent is a mixture of ethanol and water. ​ ​ ​ 2. A method of preparing a terbinafine film forming composition by the Venturi effect as claimed in claim 1, wherein, ​

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