Design of berberine hydrochloride sustained-release cold sol using hydroxypropyl methyl cellulose K100M to achieve superior drug dissolution and transdermal absorption

In this study, berberine hydrochloride (Ber) was used as model drug to prepare a sustained-release cold sol using hydroxypropyl methyl cellulose (HPMC) to achieve superior drug dissolution and transdermal absorption effects. For comparison, a Ber cold sol without HPMC was also prepared using the same method. The preparation process was optimized based on the in vitro release and transdermal permeability of the drug. The results indicated that 1.67 wt% Carbomer 940 and 1.33 wt% HPMC K100M were selected as matrix components with the best sustained-release effect, and drug dissolution of cold sol prepared by combination of these two matrices was significantly slower than the cold sol without HPMC. In addition, transdermal absorption result demonstrated that 0.67 wt% glycerin and 1.33 wt% peppermint oil were the best osmotic enhancers for the optimization of Ber sustained-release cold sol. Herein, HPMC K100M performed important functions in the external application of Ber.

Introduction

Eczema belongs to a general term for a special type of inflammatory skin disease that is mainly characterized by severe pruritus, various forms of skin damage, exudation and recurrence. Eczema in children, also known as eczema dermatitis or atopic dermatitis, is a common skin disease caused by a variety of internal and external factors [1], including genetic factors, environmental factors, infant feeding and birth season, and mother’s diet during pregnancy [2]. Eczema is a common skin disease in infants and young children, especially in infants aged 1 to 3 months after birth. Infant eczema mostly occurs in the cheek, forehead, eyebrow and head, as well as in the trunk and limbs [3]. Due to the characteristics of a long course and difficulty to cure, repeated skin damage, itching and secondary infection seriously reduce the quality of life of infants and cause adverse effects on their health [4]. At present, the treatments of eczema in Western medicine are oral antihistamines, topical corticosteroids and antibiotic compound preparation. Internal administration of antihistamines can reduce the release of histamines telangiectasia, erythema and edema [5]. However, these treatments only relieve symptoms, and the recurrence rate remains high. In addition, long-term application of hormone drugs easily leads to dependence and significant side effects [6].

Berberine hydrochloride (Ber), one of the main active ingredients of several important varieties in traditional Chinese medicine treasures [35], is a quinoline alkaloid extracted from Ranunculaceae plants such as Coptis chinensis [7]. Ber has a broad spectrum of inhibitory effects on pathogenic microorganisms, bacteria, fungi and protozoa, and it is also effective in treating intestinal inflammation and infection [[31], [32], [33]]. The antibacterial effects of Ber are mainly achieved by inhibiting sugar metabolism process of bacterial, including bacterial DNA, RNA, protein and lipid synthesis. Furthermore, Ber inhibits fungal growth and activity by destroying the integrity of fungal cell wall. As an insulin secrete-promoting agent and sensitizer, Ber can also reduce blood sugar [8]. Relevant studies have proved that Ber promotes the apoptosis of tumor cells by hindering tumor cell growth [9], proliferation and metastasis [10]. Ber improves antioxidant capacity of the body and accelerated ester metabolism to reduce blood lipid. In summary, Ber can be used to treat anti-arrhythmia, anti-atherosclerosis, anti-platelet aggregation, cardiovascular diseases [11], inflammation, dermatitis, eczema and other skin diseases. Phellodendron chinense liquid and rhubarb ointment, containing the main active ingredient of Ber, are effective in treating eczema, indicating that Ber has a significant effect on the treatment of eczema [12].

At present, most commercially available Ber products are orally administered and cannot effectively treat eczema. In addition, the current reported external formulation of Ber failed to exhibit sustained-release with good transdermal drug ability [34]. To address this scientific problem, Ber sustained-release cold sol with a high amount of transdermal drug was developed for external use. Cold sol refers to a drug release system, which is improved based on traditional cold methods such as ice water, cold water, ethanol, etc. The as-synthesized Ber sustained-release cold sol is a cold sol obtained by applying ethanol. The local exudates produced by eczema (especially for acute eczema) can be treated by cold formulation, and therefore, the Ber sustained-release in the cold sol has significant application values. Carbomer 940, which has several advantages (good biocompatibility [14], easy coating, easy absorption after local administration [15], no contamination of clothing, good stability and high bioavailability [16]), served as a hydrophilic gel matrix [13]. Hydroxypropyl methylcellulose (HPMC), a hydrophilic gel skeleton material, is used to prepare hydrophilic sustained-release gel block [17,18,36]. By adhering to the biological mucosa, it increases the continuity and tightness with biological mucosa, further slowing drug release [19]. At the same time, HPMC can be used as a suspension agent to promote a more uniform and stable system [20], thereby increasing biological adhesion [21]. The physical and chemical properties of HPMC vary with their types, resulting in differences in their formability and drug release behaviors. Therefore, it is necessary to investigate the influence of different types and dosages of HPMC on the gel or sol. A number of studies [22] have shown that glycerol [23] and peppermint oil [24], which are permeability enhancers, have good transdermal permeability enhancement effects [25].

In this study, the influence of the amount of permeability enhancers on the transdermal absorption of Ber was studied through in vitro penetration experiment. Moreover, ethanol was added to make a sustained-release sol with cold effect, which was used to treat eczema and dermatitis. A constant temperature oscillation chamber and a transdermal diffusion apparatus were employed to investigate in vitro application abilities of these materials. Based on in vitro drug dissolution and transdermal absorption results, the main active ingredient in the formulation were screened, and the optimized Ber sustained-release cold sol was confirmed to achieve superior drug effects with the assistant of HPMC K100M. The cumulative permeability of optimized Ber sustained-release cold sol achieved 609.139 μg/cm2 at 24 h, which was significantly greater than that of the reported Ber formulation (about 70 μg/cm2 at 24 h) [34], reflecting the superiority of Ber sustained-release cold sol in this study.

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Drugs and reagents

Ber was purchased from Northeast Pharmaceutical Group Co., Ltd. (China). Carbomer 940 was bought from Roche Reagent Company (China), and hydroxypropyl methyl cellulose (HPMC) was provided by Ashland (America). Hydroxy ethyl benzene, sodium hydroxide, potassium dihydrogen phosphate, glycerin, hydrochloric acid, anhydrous ethanol, tween-80, triethanolamine and peppermint oil were bought from local companies in China. All chemical reagents with analytically pure were bought from China.

Xin Zhang, Xianbao Shi, Lei Tian, Design of berberine hydrochloride sustained-release cold sol using hydroxypropyl methyl cellulose K100M to achieve superior drug dissolution and transdermal absorption, International Journal of Biological Macromolecules, Volume 275, Part 2, 2024, 133611, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2024.133611.

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