A quality detection method for spray film agent

Abstract

The present invention belongs to the technical field of preparation quality detection, and specifically relates to a quality detection method for a film spray. The present invention uses the microscopic shape, volatility, content uniformity, viscosity, moisture retention, irritation, fluidity, sterility and pH value of the film as detection indicators to evaluate the quality of the film spray. The method of the present invention has the advantages of comprehensive evaluation, strong objectivity of index detection and strong operability, and is very suitable as a standard quality detection system for film sprays.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation quality detection, and in particular relates to a quality detection method for a film spraying agent. Background Art

[0002] External preparations refer to preparations that are directly applied to the skin and mucous membranes to treat systemic and local diseases through the skin and mucous membranes. External preparations of traditional Chinese medicine are one of the common dosage forms of traditional Chinese medicine used in clinical practice. They can better avoid the first-pass effect of the liver, protect the skin and mucous membranes, and improve the bioavailability of drugs, thereby reducing irritation to the gastrointestinal tract and adverse reactions.

[0003] Chinese medicine external preparations are generally divided into solid external preparations, liquid external preparations, semi-solid external preparations and other external preparations (suppositories, patches, suspensions), etc. Modern external preparations are divided into rubber patches, gel patches, creams, etc. Chinese medicine external preparations have the advantages of simple administration, convenient carrying, high bioavailability, and high patient compliance, but at the same time, they also have shortcomings such as less promotion, low technology, general guidance, and lagging theory.

[0004] Traditional ointments and gels have a noticeable sticky feeling after use and are easily stuck to clothes, resulting in a poor experience of use. They also have poor air permeability and are prone to cause skin allergies or necrosis after long-term use. With the advancement of technology, transdermal preparations have gradually been developed, and film spray is one of them. It is administered transdermally and is usually composed of drugs, solvents, matrices, etc. It is sprayed on the injured area, and the solvent evaporates to form a complete thin film, which can not only protect the wound, but also play a role in sustained release. It is often used for medication for infants and young children, chronic diseases, and wounds such as burns.

[0005] Spray film is different from traditional ointment which is heavy and spray film which lacks protection. It can protect the wound surface and reduce the secondary damage to the wound surface. It is generally stored in solution state and can be sprayed in mist form. Once sprayed into film, it quickly forms a soluble biofilm with good air permeability, which can protect the wound surface, inhibit bacteria and resist inflammation. It is known as liquid bandage.

[12] It can not only be used to protect and treat skin trauma, but also to treat diseases such as arthritis. Different medicinal materials have different effects, and most Chinese medicines have the effects of enhancing immunity and regulating the body.

[0006] In recent years, this dosage form has been widely used in medical devices or disinfection products, such as Changsha Ruitai Medical Technology Co., Ltd.'s biological wound protection spray film (Xiang Xie No. 20162140334), Hunan Kangerjia Fuquan Medical Technology Co., Ltd.'s chitosan biological wound protection spray film functional dressing (Xiang Xie No. 20162640212) and Hunan Kangerjia Biomedical Technology Co., Ltd.'s chitosan biological wound protection spray film functional dressing (Xiang Xie No. 20172140235). It is also gradually emerging in drug research, but because this dosage form has not yet been included in the "Chinese Pharmacopoeia"

[19] There is no "General Rules for Preparations" to evaluate the quality of its dosage form, and the research levels vary. When testing the quality of drugs, how to set indicators to comprehensively and accurately reflect the quality of the drugs, and how to accurately test various indicators with highly operable means is a complex issue. Therefore, for film-spraying agents, it is urgent to establish a comprehensive, accurate and highly operable quality standard system. Summary of the invention

[0007] In view of the problems of the prior art, the present invention provides a quality detection method for a film spraying agent, the purpose of which is to establish a suitable quality detection method according to the characteristics of the film spraying agent dosage form, so as to achieve comprehensive and accurate detection of the quality of the film spraying agent.

[0008] The invention discloses a method for detecting the quality of a film spraying agent, which uses the microscopic shape, volatility, content uniformity, viscosity, moisture retention, irritation, fluidity, sterility and pH value of the film as detection indicators to evaluate the quality of the film spraying agent.

[0009] Preferably, the microscopic shape of the film is quantitatively scored according to the following method:

[0010] Step 1.1, observing the film obtained after the film-forming agent is sprayed with an electron microscope;

[0011] Step 1.2, the film is scored by a weighted scoring method, wherein: if the surface is smooth, there are no small bubbles, the film is thin and uniform, and the integrity is the best, 100 points are given. If there are protrusions or depressions on the surface, 4 points are reduced for each additional protrusion or depression; 1 point is reduced for each additional small bubble; 4 points are reduced for each additional uneven area of ​​the film; and 4 points are reduced for each notch on the edge.

[0012] Preferably, the volatilization amount is detected according to the following method:

[0013] Step 2.1, spray a spray film into the culture dish and dry it at 32±0.5℃ for 5min;

[0014] Step 2.2, weigh and calculate the volatilization amount in 5 minutes.

[0015] Preferably, the content uniformity is detected according to the following method:

[0016] Step 3.1, the spray liquid of the spray agent is fixed to a certain volume, and the content of the effective substance in the spray liquid is determined, and multiple groups are measured in parallel;

[0017] Step 3.2, calculate the RSD values ​​of multiple groups of test results.

[0018] Preferably, the viscosity is detected according to the following method:

[0019] Step 4.1, spray a spray film agent into the culture dish, dry at 37±0.5°C, take out one experimental group after film formation, and take out another experimental group before film formation. The specific operation of the experimental group before film formation is to take out after drying for 2.5 minutes;

[0020] Step 4.2, cover the samples taken out in step 4.1 on 2.5×3.5 cm cotton dyed with 0.6% phenol red, weighing 0.2 g; press a 300 g weight on it for 20 seconds;

[0021] Step 4.3, transfer the sample treated in step 4.2 into a centrifuge tube with 5 ml of sample solvent, centrifuge, and take the supernatant for UV scanning;

[0022] Step 4.4, establish a standard curve to calculate the ultraviolet absorption concentration during and after film formation to obtain the absorbance that characterizes the viscosity.

[0023] Preferably, the moisture retention is detected according to the following method:

[0024] Step 5.1, take a weighing bottle and accurately weigh the weight M0;

[0025] Step 5.2, accurately transfer 0.5 mL of the film into a weighing bottle, spread it evenly, put it into a 32±0.5℃ oven to form a film, and weigh the weight M1;

[0026] Step 5.3, place in a desiccator filled with saturated ammonium chloride solution or sodium chloride solution to absorb moisture for 24 hours, wipe off the surface moisture, and weigh the weight M2;

[0027] Step 5.4, calculate the moisturizing rate according to the following formula:

[0028] Moisture retention rate = (M2-M1) / (M1-M0)*100%.

[0029] Preferably, the irritation evaluation method is a Draize test or a human patch test.

[0030] Preferably, the method for detecting the fluidity is:

[0031] Step 6.1, add the spray liquid of the film spray agent into the capillary viscometer, use an ear bulb to suck the liquid above the first scale line, and adjust the viscometer to a vertical state;

[0032] Step 6.2, when the spray liquid flows to the first scale line under gravity, start timing, and stop timing when it reaches the second scale line, to obtain the flow time;

[0033] In step 6.3, calculate the kinematic viscosity using the capillary constant and the flow time obtained in step 6.2.

[0034] Preferably, the sterility detection method is detected by the method under Item 1101 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0035] Preferably, the pH value detection method is detected by the method under General Rules 0631 of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.

[0036] The present invention establishes a quality standard system for film spraying agents, which can comprehensively and accurately reflect the quality of film spraying agents. At the same time, the detection method of various indicators of the present invention avoids subjective influence to the greatest extent, has strong operability, and can more accurately reflect the quality of the medicine.

[0037] Specifically, in the preferred embodiment, the microscopic properties of the film are observed using a microscope, and a scoring method is provided, which is simple and easy to implement, and can be quantitatively controlled and objective. The volatilization amount is used to replace the film-forming time of the prior art, avoiding the subjectivity of judging the film-forming phenomenon, and is highly feasible and objective.

[0038] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0039] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0040] Example 1 Quality testing method for film-spraying agent dosage form

[0041] The quality inspection method of this embodiment includes inspecting the following indicators: microscopic shape, volatility, content uniformity, viscosity, moisture retention, irritation, fluidity, sterility and pH value of the film.

[0042] The specific detection methods for each indicator are as follows:

[0043] 1. Microscopic properties of membrane

[0044] The integrity of the film of the spray film directly affects the protective performance of the drug on wounds, etc. The smoothness of the film surface and the number of bubbles directly affect the patient's subjective feelings and compliance. Therefore, it is very necessary to evaluate the quality of the film properties of the spray film after film formation. The microscopic properties of the film of the spray film refer to the complete film that appears at the wound or disease site after the drug evaporates with the solvent. Its appearance, thickness, integrity, uniformity, etc. are observed under a microscope. The evaluation method is as follows:

[0045] Take 3 clean glass slides of the same size, place them in a petri dish, place them 10 cm away from the sample spray bottle, spray the sample once, and dry them at 37±0.5℃. Observe the prepared film under a 40× electron microscope. The scoring method can use the weighted scoring method, such as 100 points for a smooth surface, no small bubbles, thin and uniform film, and the best integrity. If there are protrusions or depressions on the surface, 4 points will be reduced for each additional protrusion; 1 point will be reduced for each additional small bubble; 4 points will be reduced for each additional uneven area of ​​the film; 4 points will be reduced for each notch on the edge. Make three groups of each sample in parallel, and take the average score of the three groups as the score of the sample in terms of film properties, and finally as the weighted score.

[0046] 2. Volatility

[0047] The volatilization amount of the drug is closely related to the speed of film formation, which has a certain impact on the patient's compliance. The solvent of the spray film is generally selected as a low-toxic, volatile reagent such as ethanol. The volatilization amount of the spray film is closely related to the patient's skin feel, so it is of great significance to evaluate the volatilization amount of the spray film. The volatilization amount refers to the use of heating or other methods to make the volatile solvent in the sample escape. According to the weight reduction of the sample, the weight of the solvent in the sample is calculated to evaluate the volatilization amount of the sample. The evaluation method is as follows:

[0048] Take 3 clean culture dishes of the same specifications, spray one spray of the film-spraying agent sample into them (discard the first spray), and weigh them accurately; dry them with air at 32±0.5℃ for 5 minutes, then take them out and weigh them; calculate the percentage of volatility in 5 minutes, and take the maximum percentage of volatility as the best state.

[0049] 3. Content uniformity

[0050] The safety of drugs has always been a concern for doctors and patients. From the perspective of the drugs themselves, the uniformity of drug quality directly affects the occurrence of drug overdose or underdose during drug use; according to the 2020 edition of the Chinese Pharmacopoeia, under Item 0941 of the General Rules of Part Four, transdermal patches, etc. should be checked for content uniformity. Therefore, content uniformity should be used as an evaluation indicator in the quality standard system of film sprays. Content uniformity refers to the degree to which the content of each tablet (piece) of small-dose or single-dose solid preparations, semi-solid preparations, and heterogeneous liquid preparations meets the labeled amount. The evaluation method is as follows:

[0051] Take 6 dry and clean volumetric bottles of the same size, weigh them accurately, take 1 bottle of the spray film test sample, discard one spray, spray once in the volumetric bottle, stopper it, weigh it, and calculate the spray volume of each spray; determine the content of the collected spray liquid after volume adjustment, and calculate the percentage content (%) and RSD value (%) of the effective substance in each spray according to the spray volume of each spray. The smaller the RSD value, the more uniform the content, and the better the effect of adhering to the skin to release the drug.

[0052] 4. Viscosity

[0053] In a narrow sense, viscosity refers to the adhesion of the drug to the skin or mucous membrane. The film formation of the spray film is divided into three stages: before film formation, during film formation, and after film formation; based on the properties of the spray film, the viscosity of the spray film refers to the degree to which the drug adheres to the injured area after the drug solution is sprayed on the corresponding part of the patient and the solvent evaporates. The spray film must have a certain viscosity before film formation so that it can adhere to the skin surface and facilitate drug release. After forming, the viscosity to clothes should be weak to avoid contaminating clothes and damaging the surface of the drug film. There is currently no specific method to measure the viscosity of the spray film. This example establishes a model for measuring the adhesion performance of drugs to phenol red cotton balls, and the evaluation method is as follows:

[0054] Take 3 clean and dry culture dishes of the same specifications, discard the first spray, spray the sample once in the culture dish, place it in a blast drying oven at 37±0.5℃, one as a blank control, one taken out after film formation, and one taken out for 2.5min; cover them with 2.5×3.5cm cotton dyed with about 0.2g 0.6% phenol red; press 300g weights on it for 20s, remove it, and transfer the above samples to a centrifuge tube with 5mL sample solvent; centrifuge in a centrifuge, and take the supernatant for ultraviolet scanning. By establishing a standard curve to calculate the ultraviolet absorption concentration during and after film formation, the absorbance range of its viscosity is determined according to the properties of the actual drug, and finally the viscosity can be scored by a weighted scoring method. The inventor found through testing that the absorbance during film formation is not less than 0.25, and the absorbance after film formation is not higher than 0.03 for the best viscosity state.

[0055] 5. Moisturizing

[0056] A certain degree of moisturizing property is beneficial to keep the skin moist, thus achieving a release of the drug; it is also beneficial to moisturize the wound and promote wound healing; therefore, it is necessary to ensure the moisturizing property of the spray film. Moisturizing property is one of the key properties of drugs. It mainly moisturizes the sebum and mucous membrane on the skin surface, making the skin and mucous membrane soft, controlling the evaporation of water, and making them fuller and rounder. The evaluation method is as follows:

[0057] Take three dry and clean weighing bottles of the same specifications, accurately weigh M0, accurately transfer 0.5mL of film agent into the weighing bottle, spread it evenly, put it in a 32±0.5℃ oven to form a film, weigh M1, put it in a desiccator filled with saturated ammonium chloride solution or sodium chloride solution to absorb moisture for 24h, wipe off the surface moisture, weigh M2, and repeat 3 times for each sample.

[0058] Moisturizing rate = (M2-M1) / (M1-M0)*100%; Score = Moisturizing rate / maximum moisturizing rate*100.

[0059] 6. Irritation

[0060] Burns, scalds, wounds, etc. are the main diseases treated by spray film. If the irritation of the drug is not controlled, it may aggravate the patient's condition and cause further serious injuries. Therefore, it is necessary to investigate the irritation of external preparations such as spray film. Irritation refers to the reversible inflammatory changes caused by non-oral drug preparations to the administration site after administration. The evaluation method is as follows:

[0061] Regarding the irritation experiments on Chinese herbal preparations, the commonly used evaluation methods are the Draize test and the human patch test. The main subjects selected in the Draize test include pigs, rabbits, rats, etc.

[0062] Specific experimental method: Use scissors and depilatory cream to remove the long hair and fluff on the spine of the animal's back, then wash it with clean water and wait for 24 hours. Use a sterilized scalpel to draw a "+" on the skin on one side of the spine, with the standard of injuring the epidermis but not cutting the fat tissue and slight bleeding as the standard, as a damaged skin model, and the other side as normal skin as a control.

[0063] The skin on both sides was divided into 3 parts, and physiological saline, spray film sample, and blank matrix were administered respectively for one week, three times a day in the morning, noon, and evening, with a fixed administration time. Observe and record the appearance of erythema or edema 30 minutes after each administration. After the last administration, observe the skin state at 30 minutes, 1 hour, 12 hours, 24 hours, and 48 hours, and record the erythema and edema state for scoring. No erythema and edema, score 100 points; mild erythema and edema (barely visible), minus 10 points; moderate erythema and edema (obviously visible), minus 20 points; severe erythema and edema (bulges visible to the naked eye), minus 40 points; skin shows obvious edema and purple erythema, then 0 points.

[0064] 7. Liquidity

[0065] Fluidity refers to the ability of an object to continuously deform under the action of a small force. The lower the fluidity of the spray before it forms a film on the skin surface, the stronger the patient's compliance. Viscosity is a measure of the viscosity of a fluid and an expression of the fluid's flow force on its internal friction. The greater the viscosity, the greater the internal friction and the lower the fluidity. The evaluation method is as follows:

[0066] Accurately pipette the liquid and place it in a capillary viscometer (the viscometer constant is 1.264 mm 2 / s 2 ), use the ear bulb to suck the liquid above the first scale line, and adjust the viscometer to a vertical position

[29] When the liquid flows to the first scale line under gravity, the timing starts, and when it reaches the second scale line, the timing stops. Each batch of spray film sample is measured 5 times in parallel. The product of the capillary constant of the viscometer and the flow time is the kinematic viscosity.

[0067] Since the viscosity of the drug solution is related to the spraying effect, the lower the viscosity, the easier it is to spray into a mist and form a uniform film. However, it will also contaminate clothing and flow at the drug administration site on the body surface, making it difficult to form a film, resulting in poor patient compliance. Therefore, a comprehensive consideration should be made between spray formation and patient compliance to determine the fluidity of the drug solution.

[0068] 8. Sterility

[0069] Spray films used for traumatic wounds should be tested for sterility. The specific testing methods refer to the inspection under Item 1101 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0070] 9. pH value

[0071] The pH value of a drug will affect its stability, solubility, efficacy, irritation and other aspects. As a topical preparation that can be used for traumatic events, the pH value of the spray film needs to be examined. The specific method can be found in the inspection under Item 0631 of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.

[0072] From the above examples, it can be seen that the present application constructs a quality detection method for film sprays by detecting 9 indicators, namely, the microscopic shape of the film, volatility, content uniformity, viscosity, moisture retention, irritation, fluidity, sterility and pH value. The method of the present invention has the advantages of comprehensive evaluation, strong objectivity in indicator detection and strong operability, and is very suitable as a standard quality detection system for film sprays.

Claims

1. A method for detecting the quality of a film spraying agent, characterized in that: It uses the film's microscopic shape, volatility, content uniformity, viscosity, moisture retention, irritation, fluidity, sterility and pH value as detection indicators to evaluate the quality of the film spraying agent; The volatilization amount is detected according to the following method: Step 2.1, spray a spray film into the culture dish and dry it at 32±0.5℃ for 5min; Step 2.2, weigh and calculate the volatilization amount in 5 minutes; The content uniformity is tested according to the following method: Step 3.1, the spray liquid of the spray agent is fixed to a certain volume, and the content of the effective substance in the spray liquid is determined, and multiple groups are measured in parallel; Step 3.2, calculating the RSD values ​​of multiple groups of test results; The viscosity is tested as follows: Step 4.1, spray a spray film agent into the culture dish, dry at 37±0.5°C, take out one experimental group after film formation, and take out another experimental group before film formation. The specific operation of the experimental group before film formation is to take out after drying for 2.5 minutes; Step 4.2, cover the samples taken out in step 4.1 on 2.5×3.5 cm cotton dyed with 0.6% phenol red, weighing 0.2 g; press a 300 g weight on it for 20 seconds; Step 4.3, transfer the two groups of samples treated in step 4.2 into a centrifuge tube with 5 ml of sample solvent, centrifuge, and take the supernatant for UV scanning; Step 4.4, establish a standard curve to calculate the ultraviolet absorption concentration during and after film formation to obtain the absorbance representing the viscosity; The fluidity detection method is: Step 6.1, add the spray liquid of the film spray agent into the capillary viscometer, use an ear bulb to suck the liquid above the first scale line, and adjust the viscometer to a vertical state; Step 6.2, when the spray liquid flows to the first scale line under gravity, start timing, and stop timing when it reaches the second scale line, to obtain the flow time; Step 6.3, calculating the kinematic viscosity using the capillary constant and the flow time obtained in step 6.2; The viscosity test result satisfies: the absorbance during film formation is not less than 0.25, and the absorbance after film formation is not more than 0.

03.

2. The quality inspection method according to claim 1, characterized in that: The microscopic morphology of the membrane was quantitatively scored as follows: Step 1.1, observing the film obtained after the film-forming agent is sprayed with an electron microscope; Step 1.2, the film is scored using a weighted scoring method, wherein the scoring method is: if the surface is smooth, there are no small bubbles, the film is thin and uniform, and the integrity is the best, it is 100 points; if there are protrusions or depressions on the surface, 4 points will be reduced for each additional protrusion or depression; 1 point will be reduced for each additional small bubble; 4 points will be reduced for each additional uneven area of ​​the film; and 4 points will be reduced for each notch on the edge.

3. The quality inspection method according to claim 1, characterized in that: The moisture retention is tested as follows: Step 5.1, take a weighing bottle and accurately weigh the weight M0; Step 5.2, accurately transfer 0.5 mL of the film into a weighing bottle, spread it evenly, put it into a 32±0.5℃ oven to form a film, and weigh the weight M1; Step 5.3, place in a desiccator filled with saturated ammonium chloride solution or sodium chloride solution to absorb moisture for 24 hours, wipe off the surface moisture, and weigh the weight M2; Step 5.4, calculate the moisturizing rate according to the following formula: Moisture retention rate = (M2-M1) / (M1-M0)*100%.

4. The quality inspection method according to claim 1, characterized in that: The irritation evaluation method is to use the Draize test or the human patch test.

5. The quality inspection method according to claim 1, characterized in that: The sterility detection method is tested using the method under Item 1101 of the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

6. The quality inspection method according to claim 1, characterized in that: The pH value detection method is detected by method under General Rules 0631 of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.