Essential oils, also known as volatile oils, are volatile oily liquids that exist in plants and can be distilled with steam. They are usually stored in the epidermis of medicinal plants in the form of oil droplets or coexist with resins in resin canals. Most volatile oils are colorless or light yellow at room temperature, while a few have other colors. Medicinal plants containing volatile oils are mainly distributed in the Asteraceae, Rutaceae, Apiaceae, Lamiaceae, and Zingiberaceae families, most of which have the effects of promoting qi (vital energy), activating consciousness, relieving exterior symptoms, resolving dampness, relieving pain, and promoting lung function. The main components of volatile oils in traditional Chinese medicine include monoterpenes, sesquiterpenes, aromatic compounds, aliphatic compounds, etc., most of which have antibacterial, antiviral, anti-inflammatory, analgesic, antipruritic, sedative, antitussive, and antiasthmatic effects.
Essential oils are one of the main active ingredients in most traditional Chinese medicinal materials and an important material basis for their clinical efficacy. However, due to the unstable physicochemical properties of essential oils in traditional Chinese medicine, the difficulty of quality control for related formulations has increased, which has limited their further development and promotion. With the improvement of the extraction, separation, and product development of aromatic essential oils in traditional Chinese medicine, the application of new technologies and methods has provided technical support for the research and development of essential oil-related formulations in traditional Chinese medicine. Chinese medicinal materials containing essential oils have been developed into various new formulations such as dripping pills, soft gel capsules, microemulsions, gel ointments, microcapsules, microspheres, liposomes, and polymer micelles. Meanwhile, multiple new drug delivery systems have been established, including nasal administration, transdermal administration, and colon-specific drug delivery.
1. Dripping Pills
Dripping pills are representative new formulations of traditional Chinese medicine that are widely used in clinical applications. This formulation is characterized by rapid absorption and high bioavailability, which helps improve patients' medication compliance. Some scholars have adopted supercritical CO2 fluid extraction to extract volatile oils from four main medicinal materials in Bawei Chenxiang Pills, and then used β-cyclodextrin inclusion technology to obtain volatile oil inclusion complexes. The resulting dripping pills have good appearance, low dissolution time limit, and small weight variation. Through the optimization of the preparation process conditions of Houttuynia cordata volatile oil dripping pills using star point design-response surface methodology, the optimal process was determined, and the appearance and quality of the resulting dripping pills meet relevant requirements.
2.Soft Gel Capsules
Soft gel capsules refer to a type of capsule formulation that seals a certain amount of liquid active ingredients directly, or prepares solutions, suspensions, emulsions, or semi-solids by dissolving or dispersing solid active ingredients in suitable excipients, and then sealing them in soft capsule materials. Compared to tablets and pills, soft gel capsules have the following advantages. First, they do not require binders and have a faster disintegration speed. Second, due to their relatively enclosed structure, soft gel capsules can effectively prevent drugs from being affected by humidity, oxygen, and light in the air, thereby improving the stability of the drugs. Finally, soft gel capsules are convenient to carry and easy to swallow, resulting in better medication compliance for patients. Some studies have pointed out that soft gel capsules can achieve timed and quantitative drug release by incorporating special materials. For example, if the drug needs to be effective in the intestine, it can be formulated as an enteric-soluble soft gel capsule for rectal administration. If the drug effect needs to be prolonged, a sustained-release soft gel capsule can be made for sustained-release administration. Some scholars have optimized the formulation process of Aifu Nuangong soft gel capsules, and the weight difference of the prepared soft gel capsules meets relevant regulations. Compared to the original pill form, the dosage of the improved soft gel capsule is significantly reduced.
3.Microemulsion and Microemulsion Gel Paste
Microemulsion is a thermodynamically stable system composed of oil, water, emulsifier, and co-emulsifier. Preparing volatile oils into emulsions can solve issues such as their insolubility in water and the uneven quality of liquid formulations. The optimal formulation of Forsythia suspensa volatile oil microemulsion was determined through solubility experiments, single-factor experiments, and pseudo-ternary phase diagrams, and its antipyretic effect was evaluated using a yeast-induced hyperthermia rat model. The results showed that formulating Forsythia suspensa volatile oil into a microemulsion not only improved the stability of the drug but also enhanced its antipyretic activity. The submicron emulsion formulation of Ligusticum wallichii volatile oil was optimized using single-factor and orthogonal experiments and formulated into a nasal spray, which can improve the bioavailability of the drug, the stability of the formulation, and patients' medication compliance.
Gel paste is a patch formulation made by mixing the active pharmaceutical ingredient with a suitable hydrophilic matrix and then applying it to a backing material. Compared to traditional ointments, gel paste is more comfortable to wear and has less irritation to the skin. Furthermore, due to the hydrophilic nature of the gel paste's matrix, which contains a certain amount of water, the skin's stratum corneum softens easily after application, enhancing hydration and facilitating the transdermal absorption of drugs. This makes it a novel transdermal drug delivery system. The microemulsion of Renshu (Amomum villosum, Atractylodes lancea, Cinnamomum cassia, and Caryophyllus aromaticus) volatile oil has been formulated into a gel paste, and its preparation process has been optimized through orthogonal experiments. The resulting Renshu microemulsion gel paste combines the dual advantages of microemulsion and gel paste, boasting fast transdermal absorption rate and high cumulative permeation rate, enabling repeated application and removal.
4.Microcapsules and Microcapsule Gel Paste
Microcapsules are miniature drug reservoirs made by encapsulating solid or liquid drugs with capsule materials, which can mask the unpleasant odor of drugs. The complex coacervation method was used to prepare microcapsules of Chuju chrysanthemum volatile oil, and the optimal preparation conditions for the microcapsules were selected through orthogonal experimental design. The resulting microcapsules have a round and smooth appearance with high drug loading and encapsulation efficiency. Some studies have pointed out that combining microcapsules with gel paste can harness the dual advantages of both. For example, the D-optimal mixture design was employed to optimize the formulation process of Chuanxiong oil microcapsule analgesic gel paste, improving the instability of Chuanxiong oil. The application of volatile oil microcapsule intermediates and gel paste not only compensates for the impact of adding different drugs on the gel paste matrix, enhancing the bioavailability of Chuanxiong oil, but also leverages the advantages of gel paste, such as good skin biocompatibility, non-allergenic, non-irritating properties, and improved hydration of the skin stratum corneum, which facilitates the transdermal absorption of drugs.
5.Microspheres
Microspheres are particle dispersion systems formed by swelling or adsorptive polymerization based on polymers. The complex emulsion-emulsification cross-linking method was used to prepare Fructus Magnoliae volatile oil chitosan microspheres. By taking particle size as an evaluation index, a suitable emulsification temperature was selected, and it was found that the prepared microspheres had a good stabilizing effect on Fructus Magnoliae volatile oil. Microspheres can also be used as targeted drug delivery systems. Some scholars have prepared Angelica sinensis volatile oil colon-targeted micro-pills, achieving localized targeted drug delivery and avoiding various shortcomings of oral drugs such as the first-pass effect.
6.Liposomes
Liposomes are tiny vesicles made by encapsulating drugs within a lipid bilayer. They offer advantages such as targeted drug delivery, prolonged efficacy, reduced adverse reactions, and altered routes of administration. Nanostructured liposomes loaded with mugwort volatile oil were prepared using the heating fusion-ultrasonic dispersion method. The formulation was optimized through orthogonal experiments, and the content of volatile oil was determined using gas chromatography-mass spectrometry. The results showed that the prepared nanostructured liposomes loaded with mugwort volatile oil were clear and transparent, had a high encapsulation efficiency, stable physicochemical properties, and exhibited a sustained-release effect.
7.Polymer Micelles
Polymer micelles, also known as macromolecular micelles, are colloidal solutions with a particle size of less than 500 nm formed by the self-assembly and encapsulation of hydrophobic drugs using amphiphilic block copolymer carrier excipients in water. They belong to thermodynamically stable systems. As a carrier for volatile oils, polymer micelles possess advantages such as good stability, high solubility, and high bioavailability, enabling the passive targeting of volatile oils to specific sites. The film dispersion method was used to prepare polymer micelles loaded with Houttuynia cordata volatile oil. This formulation can passively target the volatile oil to tumor sites, and the optimized process is stable and reliable, resulting in a formulation with a certain sustained-release effect.
8.Inclusion Complexes
The preparation of inclusion complexes from volatile oils is a current research hotspot. Some researchers have found that the grinding method for preparing inclusion complexes is simple and feasible, effectively improving the instability of volatile oils in traditional Chinese medicine. Through stability testing, it was discovered that the stability of the volatile oil from Jiuweipushuo Capsules was enhanced after being encapsulated with β-cyclodextrin. Using the saturated aqueous solution method, a mixture of volatile oils from Inula helenium and Kaempferia galanga in Siweitutumuxiang Powder was encapsulated with β-cyclodextrin to form an inclusion complex. This preparation process not only reduces the workload of individual encapsulation but also improves the stability of the formulation.
Volatile oils are the characteristic expression and pharmacological material basis of aromatic traditional Chinese medicines, possessing strong and widespread pharmacological activities. Although domestic research on novel formulations of volatile oils from traditional Chinese medicines has made certain progress, the research, development, and promotion of novel carrier technologies for volatile oils from traditional Chinese medicines are still in their infancy. Novel formulations of volatile oils from traditional Chinese medicines using supramolecular gels as carriers are rare, and the application of nano-scale polymer micelles in the pharmaceutical field of volatile oils from traditional Chinese medicines is still in the theoretical design stage. Furthermore, the sustained-release and controlled-release formulations of volatile oils from traditional Chinese medicines require further development.
Currently, research on targeted formulations of volatile oils from traditional Chinese medicines based on novel carrier technologies has become the leading direction in the development of new formulations. Compared with conventional formulations, targeted volatile oil formulations using novel carriers require less frequent dosing, exhibit better sustained-release and controlled-release effects, provide more stable therapeutic effects, and have fewer adverse reactions. This can significantly improve patient compliance and holds broad development prospects. Quality control for formulations of volatile oils from traditional Chinese medicines is a challenging aspect of new formulation development. This is related to the complex and unstable chemical composition of volatile oils, as well as various links such as harvesting, storage, and processing of Chinese herbal materials. Related companies need to strictly control all aspects of Chinese herbal medicine production, decoction piece processing, volatile oil extraction, and formulation processes to ensure traceability and consistency in the quality of medicinal material varieties, decoction piece specifications, and finished formulations, thereby reducing differences in formulation quality.
References
[1] Yu Zhaohai, Li Wanzhong. Overview of Extraction, Separation, and Formulation Research of Volatile Oil from Traditional Chinese Medicine [J]. Global Journal of Traditional Chinese Medicine, 2009,2 (03): 232-234
[2] Wang Xiaoyu, Wu Guotai, Du Lidong, Wang Ruiqiong, He Yilong. Research status of new formulations of traditional Chinese medicine volatile oils and their quality control [J]. China Pharmacy, 2021, 32 (20): 2551-2555
About the Author:
Xiaomichong, a researcher in pharmaceutical quality, has been dedicated to pharmaceutical quality research and verification of drug analysis methods for a long time. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection analysis and verification of analytical methods.
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