The transdermal therapeutic system (transdermal therapeutic system, TTS) refers to a controlled-release preparation that delivers medication through the skin for local or systemic therapeutic effects. TTS has prominent advantages, such as avoiding the first-pass effect in the liver and degradation of drugs in the gastrointestinal tract, reducing gastrointestinal irritation; maintaining stable blood drug concentrations, avoiding the peak and trough phenomenon caused by oral administration, and reducing toxic side effects; providing long-lasting effects, extending dosing intervals, and reducing the frequency of administration, thus facilitating patient use.[1-2].
Traditional Chinese Medicine gel patches (original gel patches or plaster patches) refer to patches made by mixing traditional Chinese medicinal raw materials with suitable hydrophilic matrices and applying them to backing materials.[3] As an important component of TTS, Traditional Chinese Medicine gel patches not only possess the advantages of TTS but also, compared to traditional black plasters and rubber patches, utilize water-soluble polymer materials as matrices, which have good moisturizing properties, compatibility with the skin, breathability, and can be reapplied, thus gaining increasing attention from researchers.[4].
Guided by Traditional Chinese Medicine theory, Traditional Chinese Medicine gel patches inherit the foundation of traditional Chinese medicinal plasters while fully integrating modern gel patch preparation techniques and quality requirements, providing new directions for theoretical research in external treatment in Traditional Chinese Medicine and the secondary development of Chinese medicinal resources. This article reviews the current development status, matrix excipients, preparation processes, and quality control of Traditional Chinese Medicine gel patches.
1 Current Development Status of Traditional Chinese Medicine Gel Patches
Since the 1980s, Traditional Chinese Medicine gel patches have developed rapidly, first included in the 2000 edition of the Chinese Pharmacopoeia and named plaster patches, with corresponding quality specifications. The 2010 edition of the Chinese Pharmacopoeia renamed plaster patches to gel patches and established relevant production and storage conditions, as well as inspection indicators, such as checking the content of the gel, its formability, adhesion, and microbial limits, providing a legal basis for quality control of gel patches. The 2015 edition of the Chinese Pharmacopoeia redefined it as gel patches, categorizing it under patch preparations. The former State Food and Drug Administration (CFDA) has listed 9 Traditional Chinese Medicine products currently on the market, including anti-inflammatory and analgesic plaster patches, wind-dispelling and bone-pain plaster patches, compound Zijing pain-relieving plaster patches, bone-friend plaster patches, toad venom analgesic gel patches, toad venom gel patches, joint pain plaster patches, Jisheng pain-relieving patches, and Shaolin rheumatism and trauma gel patches, primarily used externally for soft tissue injuries, rheumatic pain, arthritis, and other conditions. The number of patent applications and new drug research related to Traditional Chinese Medicine gel patches is continuously increasing, involving drugs for cardiovascular, skin, respiratory, and circulatory diseases. A summary of research literature on Traditional Chinese Medicine gel patches from the past five years is provided in Table 1. While Traditional Chinese Medicine gel patches are rapidly developing, several issues remain: firstly, the complexity of Traditional Chinese Medicine components, which are often in compound form, leads to large dosages, and the drug loading capacity of the gel is limited; unreasonable matrix ratios result in unstable product quality, prone to peeling and leaking, and poor skin adherence; the quality evaluation system is incomplete, with low technical levels and a lack of unified quality standards; and relatively backward production equipment and technology greatly limit the industrialization and large-scale development of Traditional Chinese Medicine gel patches.[5-7].
2 Composition of the Matrix in Traditional Chinese Medicine Gel Patches
Traditional Chinese Medicine gel patches consist of a backing layer, a gel layer, and a protective layer, with the gel layer being the key component, serving as the drug reservoir that determines the quality of the gel patch. The matrix of the gel layer can be divided into non-crosslinked and crosslinked matrices, with crosslinked matrices becoming the focus of research.[24] The composition of crosslinked matrices is complex, and the formulation design of the matrix plays a crucial role in the overall adhesion, flowability, transdermal absorption, and moisturizing properties of the gel.
2.1 Crosslinked Framework
The framework materials in the matrix provide viscosity, allowing the gel to adhere to the skin surface, while also supporting the internal molecules of the gel to form a network structure, providing sufficient cohesion, elasticity, and strength. Common hydrophilic gel frameworks include synthetic, semi-synthetic, and natural polymer materials. Synthetic and semi-synthetic polymers include sodium polyacrylate, polyvinylpyrrolidone, polyvinyl alcohol, carbomer, sodium carboxymethyl cellulose, and methylcellulose; common natural polymer materials include gelatin, gum arabic, astragalus gum, white peony gum, alginates, and agar.[5,25].
During the preparation of the matrix, polymers such as sodium polyacrylate, carbomer, and gelatin undergo crosslinking reactions by adding crosslinking agents and crosslinking regulators, where divalent metal ions chelate with the crosslinked framework, resulting in crosslinking solidification reactions. Crosslinking regulators can adjust the reaction time and degree of crosslinking solidification, allowing the linear polymer chains to bond with each other, forming a crosslinked network structure. Common crosslinking agents are typically divalent metal ions, with aluminum salts being the most common, including aluminum glycine, aluminum hydroxide, aluminum chloride, and aluminum hydroxide; common crosslinking regulators include citric acid, tartaric acid, lactic acid, malic acid, and ethylenediaminetetraacetic acid (EDTA).[26].
2.2 Fillers
Fillers play an important role in the shaping of the gel, while also affecting the adhesion and cohesion of the gel, improving the excessive stickiness caused by the swelling of water-soluble polymer materials. Common fillers include kaolin, micro-silica, soapstone, white clay, titanium dioxide, calcium carbonate, zinc oxide, and drug fine powders.[27-28].
2.3 Moisturizers
The hydrophilic gel framework has a high water content, and the addition of moisturizers can delay the loss of water from the matrix, promote skin hydration, and also affect the formability, adhesion, and drug release of the matrix. Common moisturizers include glycerin, propylene glycol, polyethylene glycol, and sorbitol; a composite system of two moisturizers has better moisturizing effects.[28-29].
2.4 Pentration Enhancers
Due to the barrier effect of the stratum corneum, the transdermal rate of most drugs is slow, and the amount absorbed is low. By adding appropriate penetration enhancers, the skin structure can be reversibly altered, reducing the resistance encountered by drugs as they pass through the skin, allowing for local treatment or systemic absorption. Penetration enhancers can be divided into natural and synthetic categories, with natural enhancers primarily being volatile oils from Traditional Chinese Medicine, including terpenes and lactones, such as menthol, camphor, eucalyptus oil, and other volatile extracts; synthetic enhancers include lauryl dimethyl amine (azone), dimethyl sulfoxide (DMSO), propylene glycol, borneol, dimethylacetamide, organic acids, and esters.[30] DMSO is now used less frequently due to its strong toxicity and skin irritation, while lauryl dimethyl amine is recognized as a good penetration enhancer.[4].
Currently, multi-component systems are often used, employing two or more penetration enhancers, which can reduce the amount of enhancers used while achieving better transdermal absorption effects. For instance, Lou Buqing et al. conducted in vitro transdermal experiments, using the enhancement ratio (enhancement ratio, ER) as an indicator to investigate the promoting effects of lauryl dimethyl amine, oleic acid, and propylene glycol, either alone or in combination, on the transdermal permeation of berberine hydrochloride in the double yellow plaster, determining that the optimal ratio of lauryl dimethyl amine to propylene glycol to oleic acid was 3:5:1, indicating that using a ternary system can overcome the insufficiency of single-component systems and adverse effects on the gel.
3 Preparation Process
The appearance of Traditional Chinese Medicine gel patches should be uniform in color, free of bubbles and granules, and should not exhibit peeling, leaking, or skin residue. They should possess good adhesion, moisturizing properties, and excellent transdermal absorption effects. The preparation process of gel patches is closely related to these properties, and in-depth exploration of the matrix process of Traditional Chinese Medicine gel patches and the establishment of reasonable process routes have become key research focuses.[32].
3.1 Matrix Ratio Research
The research on the matrix of Traditional Chinese Medicine gel patches revolves around the ratios of crosslinked frameworks, moisturizers, fillers, and crosslinking agents, employing reasonable experimental design methods and evaluation indicators for comprehensive evaluation of the matrix. Currently, orthogonal experimental design, uniform experimental design, or response surface optimization methods are commonly used to optimize matrix formulations. Evaluation indicators include initial adhesion, holding power, peel strength, and overall sensory evaluation. For example, Xue Caihong et al. used an L9(34) orthogonal experimental design, focusing on appearance, peel strength, matrix residue, skin adhesion, and reusability, to investigate the amounts of sodium polyacrylate-pressure-sensitive adhesive, sodium carboxymethyl cellulose-gelatin, aluminum hydroxide, and glycerin, ultimately determining the optimal formulation ratio to be 0.5:1.0:0.4:0.1:0.3:3.0, resulting in a robust plaster with good formability and no skin residue. Zhang Hongbing et al. employed star-point design-response surface optimization methods, using initial adhesion and appearance (gel characteristics, residue, skin adherence) as comprehensive evaluation indicators, normalizing experimental data and performing multiple linear and nonlinear regression analyses, ultimately determining the optimal preparation process to be a drug loading of 8.7%, stirring speed of 500 r/min, and kneading temperature of 45 °C for 15 minutes, resulting in a smooth, moderately adhesive plaster.
3.2 Shaping Process Research
3.2.1 Drug Factors Most Traditional Chinese Medicines are added to the matrix formulation in the form of extracts or pastes, with complex and diverse components. For instance, the acidity and alkalinity of the drugs can affect the pH of the matrix, thereby influencing the adhesion of the patches; the dissociation of the drugs also impacts the shaping process. When free ions are present in the Traditional Chinese Medicine extracts, they can enter the network structure of the polymer, altering the time and degree of crosslinking solidification, ultimately affecting the properties of the gel.[35] Therefore, it is necessary to investigate the chemical properties of Traditional Chinese Medicine extracts and reduce their impact on the formulation by reasonably adding excipients.
3.2.2 Gel Factors The gel’s influence on the formulation primarily manifests in two aspects: first, the water content of the gel, which, as a hydrophilic gel framework, is significant, typically ranging from 40% to 60%; the polymer materials generate viscosity through water swelling and dissolution, but excessively high or low water content can have adverse effects. Second, the drug loading capacity of the gel; if the drug content is too high, it complicates the formulation, while too low a dosage fails to achieve clinical efficacy. Li Lin et al. studied the effects of different drug loading capacities of ligustrazine plaster on transdermal absorption, employing microdialysis technology to investigate its transdermal permeation in vivo, revealing that drug loading capacities of 1.5%, 1.0%, and 0.5% resulted in cumulative transdermal amounts of 8.32, 6.53, and 6.38 μg/cm2, respectively, further determining the optimal drug loading capacity for the plaster.
3.2.3 Process Factors During the preparation of the gel, the conditions of the preparation process significantly affect the shaping, focusing on: ① the order of material addition; the matrix composition involves crosslinked frameworks, fillers, crosslinking agents, etc., including synthetic or semi-synthetic polymers, as well as various inorganic materials and other substances, whose physicochemical properties require a reasonable addition order; otherwise, it directly affects the solidification of the gel. Bai Caitang et al. examined three different material addition methods, ultimately determining that the polymer gel phase should be mixed uniformly with the drug and moisturizing agent in the aqueous phase before slowly adding the aqueous phase containing the crosslinking agent to the mixed phase, resulting in a gel with elasticity and gloss. ② The degree of mixing and stirring; the time and speed of stirring during the mixing process significantly impact the gel; if the time is too short, the materials will not mix evenly; if the time is too long or the speed is too fast, it can create numerous bubbles, and the molecular chains of the polymer matrix may break, reducing the viscosity of the gel. ③ The kneading and drying temperature; excessive kneading and temperature can reduce the viscosity of the gel, necessitating the selection of the most suitable kneading temperature based on the specific matrix composition. Liu Lin et al. conducted orthogonal experimental designs, focusing on holding power, appearance, and other comprehensive scores, to investigate the effects of kneading temperature, kneading time, and stirring speed on the preparation process of β-asarone plaster, ultimately determining the optimal preparation process to be a drug loading of 8.7%, stirring speed of 500 r/min, kneading temperature of 45 °C, and kneading time of 15 minutes, resulting in a plaster with a glossy appearance and suitable viscosity.
3.3 Application of New Technologies in Shaping Processes
Due to the complexity of Traditional Chinese Medicine components, to further adapt to the formulation requirements of gel patches and address practical issues in the preparation process, an increasing number of new technologies and processes are being applied in the preparation of Traditional Chinese Medicine gel patches.
3.3.1 Solid Dispersion Technology Solid dispersion technology applied in the preparation of Traditional Chinese Medicine gel patches can improve the dispersion of drugs, facilitating their dissolution and absorption, thereby increasing the transdermal penetration of the drugs. Lin Yining et al. utilized carrier combination technology to prepare baicalin into solid dispersions, phospholipid complexes, and solid dispersions of phospholipid complexes, employing a modified Franz diffusion apparatus to measure the transdermal absorption characteristics of these three types of patches, revealing that the transdermal rates of the solid dispersion of phospholipid complexes, solid dispersions, phospholipid complexes, and the prototype drug of baicalin were 135.26, 100.22, 76.10, and 49.31 μg/(cm2·h), respectively, indicating that the solid dispersion of phospholipid complexes had the highest transdermal rate, effectively enhancing the transdermal absorption of baicalin.
3.3.2 Microemulsion Technology Microemulsion technology prepares a colloidal dispersion system by emulsifying the aqueous and oily phases, facilitating better mixing of lipophilic drugs with hydrophilic matrices, while also improving skin permeability. Zhang Guangchang et al. prepared a water-in-oil microemulsion plaster of evodia extract to enhance the permeability of lipophilic components, determining the microemulsion formulation to be evodia extract – isopropyl myristate – propylene glycol – polysorbate 80 – hydrogenated castor oil – water in a ratio of 0.3:0.6:3.6:3.6:3.6:18, resulting in the in vitro cumulative transdermal permeation amounts of evodiamine and rutaecarpine being 1.86 and 1.40 times that of ordinary plasters.
3.3.3 Inclusion Technology The volatile oil components of Traditional Chinese Medicine play a pharmacological role and can promote drug transdermal absorption to some extent, but the presence of large amounts of volatile oils can complicate the preparation of gel patches. Inclusion technology applied in the preparation of Traditional Chinese Medicine gel patches can improve the stability of volatile oils in the formulation.[45] Chen Hongmei et al. utilized β-cyclodextrin inclusion technology to encapsulate the volatile oil components in the cooling and activating plaster, facilitating the dispersion of volatile components in the hydrophilic matrix and enhancing the stability of the formulation.
3.3.4 Ultrafine Grinding Technology Some Traditional Chinese Medicines are incorporated into the gel in the form of powdered drugs, and after cell-level grinding, smaller particle sizes and larger specific surface areas can be obtained, allowing for the rapid release of effective drug components. Additionally, using ultrafine powders improves the compatibility of the drugs with the matrix. Li Yuehui et al. employed ultrafine grinding technology to grind pollen to a particle size of 37 μm (D90) and 11 μm (D50), preparing an ultrafine plaster of pain-relieving herbs, using a Franz diffusion cell to measure the transdermal rates of isorhamnetin-3-O-neohesperidoside, comparing it with ordinary pain-relieving plasters, revealing that the transdermal rates were 3.0382 and 2.7967 μg/(cm2·h), respectively, with cumulative permeation amounts and transdermal rates superior to those of ordinary pain-relieving plasters, indicating that ultrafine grinding technology can effectively enhance drug dissolution and transdermal absorption. Zhang Wei et al. compared the release rates of ferulic acid in ultrafine powdered ligusticum and ordinary powdered ligusticum in isolated rabbit skin, finding that the cumulative transdermal release rate of the ultrafine powdered plaster reached 42.57% within 4 hours and 58.26% within 20 hours, exceeding that of ordinary powdered samples by nearly 15%.
4 Quality Control Research
The 2015 edition of the Chinese Pharmacopoeia specifies conventional items for gel patches, including appearance, drug content, formability, adhesion, and heat resistance. The complexity of Traditional Chinese Medicine components significantly affects the properties of the gel, particularly its adhesion. At the same time, the release and transdermal absorption of Traditional Chinese Medicine components, as well as the irritation of toxic Traditional Chinese Medicines on the skin, require in-depth exploration and research. Therefore, establishing objective, scientific, comprehensive, and unified quality standards, and improving quality specifications that reflect the formulation requirements of Traditional Chinese Medicine gel patches is of great significance.
4.1 Adhesion Research
The pharmacopoeia evaluates adhesion quality based on three aspects: initial adhesion, holding power, and peel strength, without specifying the types of instrument parameters, backing materials, or quality standards. Many researchers have evaluated the properties of gels through a combination of instrumental and sensory evaluations; however, conventional instrumental evaluations cannot reflect the intrinsic rheological parameters of the gel, while sensory evaluations, although having practical significance, also face issues of subjectivity and variability among individuals, failing to comprehensively and accurately reflect the intrinsic quality of gel patches.
For crosslinked hydrogels, measuring their rheological parameters can objectively and accurately reflect the intrinsic crosslinking situation of the gel, providing reference for evaluating the adhesion of the matrix. Wang Jian et al. screened filler formulations by measuring the rheological properties of different filler matrix formulations using a rotational rheometer, including measuring complex modulus (G*), elastic modulus (G′), and viscous modulus (G″); results indicated that different fillers increased both G′ and G″ with increasing mass fraction, with micro-silica having the most significant effect, where increasing its mass fraction from 1% to 5% resulted in increases of 99% and 130% in G′ and G″, respectively, indicating that changes in G′ and G″ affect the elasticity and viscosity of the matrix. Gu Shengying et al. established a correlation between the rheological parameters of the plaster and the viscosity of the matrix, concluding that the initial adhesion of the plaster is negatively correlated with the phase angle δ (ω=0.1 rad/s), peel strength is negatively correlated with G′100/G′0.1 value, and the cohesion of the gel is negatively correlated with the creep compliance (Jc); when the δ0.1 value is between 24° and 26°, and the G′100/G′0.1 value is between 5 and 7, and the Jc value is around 0.1, the viscosity of the gel is suitable. Wu Wei et al. discussed the impact of the glass transition temperature (Tg) of polymers on the crosslinking solidification of the matrix, noting that phenomena such as overly hard or overly soft gels are closely related to the Tg of polymer materials, emphasizing the need to monitor the overall Tg of the gel in relation to the Tg of various excipients and the relative molecular weight distribution index, as well as production processes, providing new insights for researching matrix properties and preparation processes.
4.2 Transdermal Absorption Research
The release of active substances from the matrix and their transdermal absorption are key to the local or systemic therapeutic effects of the drugs, and are also critical aspects of ensuring product quality. In vitro transdermal experiments indicate that the physicochemical properties of the drugs, the type of receiving liquid, and the choice of animal skin can all influence the results of transdermal experiments.
When Traditional Chinese Medicine components are administered as monomers or as extracts, the release process and transdermal absorption behavior differ. Deng Yali et al. compared the drug release and transdermal behavior of compound plasters composed of the monomers of qingpeng alkaloid and tripterygium glycosides with those of their extract pastes, demonstrating that the in vitro release of qingpeng alkaloid and tripterygium glycosides conforms to the Higuchi equation, and that the release rates of the monomer and extract formulations in the same matrix were essentially the same; using the Franz diffusion cell method to measure in vitro transdermal absorption, the parameters were subjected to linear regression according to zero-order, first-order, and Higuchi kinetic equations, with the results indicating that the transdermal rates of the monomer formulations were slightly higher than those of the extract formulations.
The formulation of Traditional Chinese Medicine gel patches is often large and complex, with numerous indicator components, making the selection of appropriate in vitro transdermal evaluation indicators significant for quality control. Wu Xiaoru et al. employed a vertical Franz diffusion cell, using acid dye colorimetric methods and HPLC to measure the cumulative transdermal amounts of total alkaloids, atropine, and sulfasalazine in the pain-relieving plaster, regressing the cumulative amounts (Q) against time (t), with results indicating that both total alkaloids and the individual indicators of atropine and sulfasalazine conformed to zero-order kinetics, effectively reflecting the transdermal absorption process of the patches.
In vitro transdermal experiments indicate that the type of receiving liquid (penetration medium) and the choice of isolated animal skin can significantly affect the experimental results. Sun Yuan et al. employed a modified Franz diffusion cell method, using 65% ethanol solution, physiological saline, 2% sodium dodecyl sulfate solution, 2% polysorbate 80 solution, and 30% ethanol solution as receiving liquids, investigating the isolated skin of Kunming female and male mice, as well as SD rats, to determine the optimal penetration medium and skin type for the transdermal experiments of the pain-relieving plaster, with thin-layer chromatography indicating that using a 30% ethanol solution as the receiving liquid and male mouse skin yielded the best response.
4.3 Skin Irritation Research
The application site of gel patches is the skin, and the irritation and toxicity of the drugs applied to the skin require further validation and control. Evaluating the safety of toxic drugs and the special considerations for pediatric use is crucial for the quality control of Traditional Chinese Medicine gel patches and the safety of clinical use. Feng Wei et al. investigated the skin irritation of the toxic drug strychnine in plaster patches, conducting skin irritation experiments with single and multiple doses using New Zealand white rabbits as models, with results indicating that single doses did not produce irritation, erythema, or edema on either intact or damaged skin, while multiple doses on damaged skin resulted in mild erythema, suggesting avoidance of use on damaged skin; guinea pigs were used to observe skin sensitization, with results indicating that the strychnine plaster did not produce allergic reactions. Wang Jingxia et al. conducted skin irritation experiments with multiple doses on New Zealand rabbits, verifying that the pediatric diarrhea plaster had no irritation on intact skin but mild irritation on damaged skin, providing reference for the clinical safety of the pediatric diarrhea plaster.
5 Outlook
Compared to traditional black plasters and rubber patches, Traditional Chinese Medicine gel patches have significant advantages in dosage form, with hydrophilic gel framework materials exhibiting better compatibility with the skin, larger drug loading capacities, and the ability to be reapplied. With the development of modern pharmaceutical industry and the widespread application and continuous improvement of polymer materials, the preparation technology of Traditional Chinese Medicine gel patches is also continuously advancing and developing, gradually incorporating supercritical extraction technology, inclusion technology, solid dispersion, and microemulsion technology to address issues such as drug loading capacity, stability, and transdermal absorption in Traditional Chinese Medicine gel formulations. At the same time, new quality control technologies are also being applied in the quality evaluation of Traditional Chinese Medicine gel patches, such as near-infrared chemical imaging technology for evaluating the uniformity of the gel; 60Co-γ radiation sterilization for sterilizing heat-sensitive substances in gel patches; and microdialysis in transdermal absorption research, providing technical support for ensuring the quality and safety of Traditional Chinese Medicine gel patches. With the rapid development of transdermal drug delivery systems and the secondary development of Traditional Chinese Medicine varieties, Traditional Chinese Medicine gel patches are bound to encounter new development opportunities and achieve new technological breakthroughs and advancements.
References (omitted)
Source: Han Shuang, Feng Songhao, Ma Xuwei, Xu Jun, Chen Changqing. Research Progress of Traditional Chinese Medicine Gel Patches and Their Application in Product Development [J]. Chinese Herbal Medicine, 2018, 49(21):5197-5204.
