Hydrogel-Based Materials for Delivery of Herbal Medicines - ACS

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Hydrogel-based Materials for Delivery of Herbal Medicines Wing-Fu Lai, and Andrey L. Rogach ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b16120 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on March 1, 2017

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ACS Applied Materials & Interfaces

Hydrogel-based Materials for Delivery of Herbal Medicines

Wing-Fu Lai1,2,*, Andrey L. Rogach3

1.

Department of Pharmacy, Health Science Center, Shenzhen University, Shenzhen

2.

Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong

3.

Department of Physics and Materials Science and Centre for Functional Photonics, City University of Hong Kong, Hong Kong

*To whom correspondence should be addressed: Department of Pharmacy, Health Science

Center,

Shenzhen

University,

Shenzhen

518060,

[email protected]

ACS Paragon Plus Environment

China.

E-mail:


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Abstract Herbal medicine, as an integral component of oriental medicine, has assimilated into the lives of Asian people for millennia. The therapeutic efficiency of herbal extracts and ingredients has, however, been limited by various factors, including the lack of targeting capacity and poor bioavailability. Hydrogels are hydrophilic polymer networks that can imbibe a substantial amount of fluids. Their high water content and low surface tension are some of the factors leading to good biocompatibility. Some hydrogels have also exhibited high drug loading efficiency, and have attracted widespread studies in pharmaceutical formulation. This article first examines the latest progress in the development of hydrogel-based materials as carriers of herbal medicines, followed by a discussion on the design of hydrogel properties for enhancing the carrier performance. Finally, the promising potential of using hydrogels to combine herbal medicines with synthetic drugs in one single treatment will be highlighted as an avenue for future research.

Keywords Hydrogels; oriental medicine; drug delivery; herb; sustained release


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1. Introduction Herbal medicine is an integral component of oriental medicine. Attributed to the prospect of drug discovery from medicinal herbs, the therapeutic potential of herbal medicine has begun to be recognized globally. One example of drugs discovered from herbal medicines is Kanglaite, which is an investigational anti-cancer drug extracted from Semen coicis. The injectable form of Kanglaite has been approved in China for treating cancers.1 Another example is ephedrine. It is a sympathomimetic amine isolated from Ephedra vulgaris. This drug has been commonly used as a cardiac stimulant, bronchodilator, and hyperglycaemic agent.2 From vision enhancement with Lycium barbarum fruits to cancer treatments,3-6 herbal medicine has assimilated into the lives of Asian people for millennia. Despite this, the therapeutic efficiency of herbal medicines has been hindered by various factors, including the lack of targeting capacity and poor bioavailability. Furthermore, due to the variations in structures and properties (such as the surface charge and molecular weight) of different bioactives in herbal medicines, the efficiency of absorption and cellular internalization of those bioactives, which are integral parts of the herbal treatment, may vary greatly, reducing the treatment efficacy.

To solve these problems, one possible strategy is to adopt a carrier to facilitate the delivery of herbal bioactives. As a matter of fact, various materials (including lipids and hydrogels) have already been developed over the years for drug delivery purposes.7-10 While there is an upsurge of reviews summarizing the applications of these materials in delivery of synthetic drugs, the possible use of these materials in formulating herbal medicines has rarely been put to formal discussions in the literature. This article attempts to fill this gap by highlighting the possible



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incorporation of current drug delivery technologies, with a special focus on hydrogels, into herbal treatment, and examining how the properties of hydrogels can be tailored to enhance the delivery efficiency of herbal medicines.

2. Strengths of Hydrogels for Delivery of Herbal Medicines Hydrogels are swellable networks that can absorb a substantial amount of fluids. Their major constituents are polymers, which can be natural or synthetic in origin. One important natural polymer for hydrogel synthesis is alginate (Alg). It is an anionic polysaccharide consisting of (1–4)-linked β-D-mannuronic acid and α-L-guluronic acid.11-17 Upon gelation with simple divalent ions (e.g. Ca2+), Alg can form matrices for beads, gels, microparticles and nanospheres.18, 19 Another example of natural polymers is collagen, which is a major constituent of the extracellular matrix of the connective tissue. Collagen has high mechanical strength.20 It has been used to fabricate hydrogels for tissue engineering21 and corneal applications.22 Other common examples of natural polymers for hydrogel synthesis include chitosan (CS),23 gelatin,24 agarose,25 and hyaluronic acids.26 Apart from natural polymers, advances in materials science have led to the development of diverse synthetic polymers for hydrogel

formation,

poly(2-hydroxyethyl

including

methacrylate)

poly(N-vinylpyrrolidone)

(PHEMA),28-30

(PVP),27

poly(N-isopropylacrylamide)

(PNIPAM),31, 32 and poly(ethylene glycol) (PEG).33, 34 Compared to natural polymers, synthetic polymers and their derivatives usually have higher mechanical strength; however, they in general have raised more concerns on toxicity and biodegradability. Current research is seeking to generate a hybrid polymer by combining the advantages of both natural and synthetic materials for hydrogel fabrication. In an earlier study, dextran has been copolymerized with lactic acid oligomers.35 By using this approach,


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the hydrogel obtained is fully degradable under physiological conditions. This is because degradation can occur via either random hydrolysis of the ester bonds in the lactate grafts, or cleavage of the lactate grafts from the dextran backbone by the attack of OH−.35 Many of the related efforts have been reviewed elsewhere.36-41 Readers are directed to those reviews for details.

Compared to other systems developed for delivery of herbal medicines (Table 1),42-46 a unique strength possessed by hydrogels is the high water absorption capacity.47 This capacity has favored the loading of herbal formulations, which are in general aqueous in nature, into hydrogels. With advances in materials design, some hydrogels have also been reported to allow for prolonged and stimuli-controlled drug release.8, 48 An overview of the important properties of hydrogels for delivery of herbal medicines has been provided in Fig. 1. The possibility of using hydrogels as carriers of herbal medicines has been demonstrated by Lim et al.,49 who have prepared a hydrogel patch containing two herbal extracts for treatment of atopic dermatitis (AD). The first extract is from Ulmus davidiana var. japonica (UD), which is a deciduous broad-leaved tree commonly found in oriental countries. Its root barks and stem have been found to be therapeutic to mastitis, cancers, inflammation, edema, and rheumatoid arthritis.50 The second one is from Houttuynia cordata Thunb. The extract has been used to treat herpes simplex,51 chronic sinusitis,52 and nasal polyps.52 It has also been reported to have anticancer,53 antioxidant,54 and adjuvant activities.55 A hydrogel patch containing the two extracts has been fabricated by “freezing and thawing” and 60Co γ-ray irradiation.49 Due to the moisturizing effects and the activity of the extracts on atopic wounds, mice treated with the patch have effectively recovered from edema upon induction of contact dermatitis (Fig. 2),49 and have



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suffered from less itchiness caused by AD.49 In addition, the patch can be attached to or detached from the skin easily.49 This makes clinical applications of the patch more viable.

The promising potential of using hydrogels to deliver herbal medicines has been further supported by a recent study,56 in which a solid lipid nanoparticle (SLN)-enriched hydrogel has been reported for topical delivery of astragaloside IV, which is a major constituent of Astragalus membranaceus. Results have shown that the hydrogel has enabled sustained release of astragaloside IV, and has enhanced the migration and proliferation of keratinocytes in vitro.56 In a full-skin excision rat model, the hydrogel has been demonstrated to increase the wound closure rate, and has facilitated angiogenesis and collagen deposition (Fig. 3).56 These have rendered the hydrogel-based system viable for use as a wound management product. As a matter of fact, over the years the possible use of hydrogels loaded with herbal medicines has already been exploited in diverse areas, from product development to disease treatment (Table 2).46,

57-69

For the latter, the clinical potential has been

evidenced in clinical trials. A good example has been provided by a randomized, double-blind, placebo-controlled clinical trial conducted with ambulatory patients.70 In the study, the extract of the Mimosa tenuiflora cortex, which is a popular remedy utilized in Mexico to treat skin lesions, has been incorporated into a hydrogel (which has been prepared with Carbopol® 940, PEG 200, and triethanol amine) for the treatment of venous leg ulceration (VLU) disease. The size of the ulcer in patients treated with the extract-loaded hydrogel has been significantly reduced (Fig. 4), while those treated with the hydrogel alone have exhibited no significant improvement.


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Based on the evidence above, it is clear that delivery of herbal medicines using hydrogels holds promise for facilitating the future development of oriental medicine.

3. Preparation of Hydrogels for Delivery of Herbal Medicines Many first-generation hydrogels are principally chemical hydrogels.71 Some of them have been fabricated by cross-linking hydrophilic polymers such as poly(vinyl alcohol) (PVA) and PEG. Others have been formed via polymerization of water-soluble monomers in the presence of a cross-linker. A representative example of the latter case is the poly(acrylamide) hydrogel, which has been exploited initially for physical entrapment of cells and enzymes72, 73 and later for use as soft tissue fillers.74 Notwithstanding the track record of chemical hydrogels in drug delivery, using chemical hydrogels as carriers of herbal medicines might not be favorable. This is because loading of the herbal medicines is usually performed by simply mixing the medicines with hydrogel constituents before cross-linking occurs. Herbal medicines usually contain multiple components and hence a variety of functional groups. Side reactions between the cross-linker and any of these components may jeopardize the integrity and efficacy of the treatment.

Compared to chemical hydrogels, physical hydrogels may have lower long-term stability and mechanical strength; however, covalent cross-linkers are not required for their formation. Side reactions with the herbal components can be minimized.75 This has been demonstrated using the crude leaf extract of Hemigraphis alternata. The extract has previously been reported to have anti-inflammatory effects, and has facilitated wound contraction and epithelialisation in the carrageenan-induced paw edema mouse model.76 Upon loading into a hydrogel, the extract has maintained its



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haemostatic and antibacterial activities.77 This, together with the effects of the extract-loaded hydrogel in facilitating platelet activation, dermal fibroblast attachment and blood clotting, has made the hydrogel-based system potentially useful for future wound care.77

To obtain physical hydrogels, various methods have been reported. One method is ionic gelation, which is based on electrostatic interactions between polymer chains and oppositely charged ions. Some examples of hydrogels generated from this method are Ca2+-crosslinked Alg hydrogels and CS-tripolyphosphate (TPP) hydrogels. Another method to fabricate physical hydrogels is stereocomplexation. This has been adopted by an earlier report in which two complementing stereoregular polymers have interacted to display physical properties different from either of the two polymers.78 By using this method, self-assembled hydrogels have been generated from enantiomeric lactic acid oligomer-grafted dextran (dex-lactate).35 More recently, the sol-gel properties of polymers have been exploited for generation of physical hydrogels to enhance the performance of herbal medicines. This is demonstrated in a report on a thermosensitive injectable hydrogel fabricated from an amphiphilic triblock copolymer of poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)– PEG–poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)

(PECT).

The

hydrogel has facilitated the delivery of an active herbal ingredient, namely embelin, whose in vivo applications have been limited by its poor aqueous solubility. The hydrogel has enabled sustained release of embelin.69 Upon a single local peritumoral injection of the embelin-loaded hydrogel into a liver at a low dosage of 0.5 mg per hepatocarcinoma-bearing mouse, the antitumor effect attained has been found to be comparable to a total dose of 6 mg of free embelin per mouse.69 This promising result


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has corroborated the possible role of physical hydrogels in boosting the efficacy of oriental herbal medicine.

4. Modulation of Hydrogel Properties for Delivery of Herbal Medicines When carriers of herbal medicines are developed, one of the factors to be considered is the loading efficiency, which is largely affected by the affinity of the herbal components to the hydrogel matrix. In oriental medicine, one regimen is generally consisted of multiple herbs. Multiple components, therefore, have to be delivered simultaneously in order for the treatment to be effective. This is technically challenging because most of the delivery systems reported in the literature are mainly designed for use in single drug therapies. Settling this problem necessitates a hydrogel-based system that can carry herbal components with different degrees of hydrophilicity. Hydrogels, however, are hydrophilic in nature. If the loaded components are hydrophobic, the affinity of the components to the hydrogel matrix will be low in general. The components may simply diffuse out of the matrix before the loading process is complete, limiting the final loading yield.

One strategy to solve this problem is to first encapsulate the hydrophobic components into a system that shows a higher affinity to the hydrogel matrix, before the components are loaded into a hydrogel. This approach has been adopted in an in situ gel-forming system, which composes of curcumin-loaded micelles and a thermosensitive hydrogel. Curcumin is an active component of turmeric (the powdered rhizome of Curcuma longa L.). In China and some Asian countries, it has been used as a spice, and as a remedy to treat diverse inflammatory and chronic diseases.79 It has also been reported to be effective in wound repair upon oral and



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topical administration.80, 81 Despite this, the clinical efficacy of curcumin has been limited partly by extensive first pass metabolism.82 This problem might be alleviated by loading curcumin into hydrogels for more sustained release. Curcumin, however, has low aqueous solubility.83 Its affinity to the hydrogel matrix is low. To address this problem, curcumin has first been encapsulated in polymeric micelles.84 The encapsulated curcumin (Cur-M) has subsequently been loaded into a thermosensitive PEG–poly(ɛ-caprolactone)–PEG (PEG–PCL–PEG) hydrogel to form a system (viz. Cur-M-H) for use as a wound dressing.84 The system is a free-flowing sol at ambient conditions, but can be converted into a non-flowing gel at body temperature (Fig. 5A). Compared to those treated with normal saline, wounds treated with Cur-M-H have exhibited negligible signs of inflammation and infection, and have not had any pathological fluid oozing out (Fig. 5B).84 Histopathologic analysis has revealed that wounds treated with Cur–M–H have shown a higher degree of re-epithelialization, well-organized granulation tissues, and significant fibroblastic deposition, compared to those treated with Cur–M, normal saline, and the hydrogel containing blank micelles (Fig. 5C).84 This study has demonstrated the feasibility of enhancing the efficiency of the loading process by first encapsulating a herbal ingredient in another system before hydrogel encapsulation.

To improve the loading efficiency, another method is to modulate hydrogel properties to increase the affinity of the hydrogel matrix to hydrophobic components. This has been hinted at in a previous study, in which an Alg-based hydrogel has been adopted to encapsulate a herbal extract of Piper sarmentosum.85 Hydrogels fabricated from Alg with a higher mannuronate/guluronate (M/G) ratio have been shown to have higher encapsulation efficiency.85 This suggests that engineering the chemical


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composition of polymers can be a strategy to facilitate the loading of herbal medicines into hydrogels. Although related efforts are still incipient, the theoretical plausibility of this strategy has already been demonstrated by Byrne and co-workers,86 who have used different functional monomers and template molecules to generate a hydrogel for loading molecules with varying degrees of hydrophilicity. A more recent study has also modified CS with hypromellose to generate hypromellose-graft-chitosan (HC) (Fig. 6A).8 The copolymer has higher aqueous solubility than native CS,8 and can form a hydrogel upon complexation with carboxymethylcellulose (CMC) to physically entrap drug molecules (Fig. 6B-C). In total four drug models (viz. mometasone furoate, methylene blue, tetracycline hydrochloride, and metronidazole) with different degrees of hydrophilicity have been tested. The drug encapsulation efficiency of the HC/CMC hydrogel has been found to be 1-2 folds higher than that attainable by the hydrogel formed using CS (Fig. 6D). This has pointed to the prospects of improving the loading of components with varying properties by optimizing the molecular design of a hydrogel-based system.

In addition to the loading efficiency, when a carrier is developed, another factor to be considered is the release sustainability. It can be controlled by changing the polymer composition to modulate the tortuosity and mesh size of the polymer network,87 the hindrance of polymer chains to drug diffusion,87 and the swelling of a hydrogel. This has been illustrated by Patenaude and Hoare,88 who have functionalized natural polymers (such as CMC, dextran, and hyaluronic acid) and PNIPAM-based synthetic oligomers with hydrazide or aldehyde functional groups to generate a series of in situ gelation, hydrazone-cross-linked hydrogels (Fig. 7). By changing the number and ratio of different reactive oligomers or polymer precursors, hydrogels with different



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swelling properties and degradation kinetic profiles have been generated. More recently, a composite hydrogel comprising both poloxamer 407 (P407) and CMC has been reported as a carrier of the Cortex Moutan (CM) extract for the treatment of AD.57 The high moisture content of P407-based hydrogels has helped moisturizing the skin of AD patients. Upon the addition of CMC, the porous structure, gelation transition temperature and rheological property of the hydrogel have been further optimized. Changes in the concentrations of P407 and CMC have been shown to lead to changes in the bulk viscosity of the hydrogel-based system and hence the release of the extract.57 This has revealed the close relationship between the release sustainability and composition of a hydrogel.

Last but not the least, high biodegradability and low toxicity are important prerequisites to be met if a carrier is to be applied to a biological body, but this is particularly a problem in chemical hydrogels. This problem can be tackled by incorporating biodegradable chemical groups or polymer segments into the backbone of the polymer constituent, as demonstrated in an earlier study in which dextran has been copolymerized with lactic acid oligomers.35 As degradation can occur via either random hydrolysis of the ester bond in the lactate graft, or via cleavage of the lactate graft by attack of OH−, the hydrogel has been reported to be fully degradable under physiological conditions.35 A similar strategy has also been adopted in a recent study,89 in which the toxicity of poly(ethylenimine) (PEI) has been lowered by graft polymerization with polysorbate 20, generating hydrogel nanoparticles with a higher safety profile for biological applications.89 Over the years, substantial efforts have been devoted in the literature to generate polymers with low toxicity and high


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biodegradability. Many of these efforts have already been reviewed elsewhere.36-41 Readers are referred to those reviews for details.

5. Prospects and Limitations Oriental medicine and Western medicine are two important systems in medicine science. Oriental medicine views a human body as a microcosm consisting of both internal and external conditions, emphasizing the equipoise of “energies” in the five zang-viscera.90 It has the merit of being attentive to the root of the medical condition, but is perceived to be slower in action.91 On the other hand, Western medicine confronts the symptoms directly and hence has quicker effects, but the restoration of the internal balance has not been emphasized as much as that in oriental medicine.91 In the light of this, integrating herbal medicines with synthetic drugs from Western medicine may become a future approach in disease treatment. This potential has been presented in an earlier study on patients with idiopathic nephrotic syndrome.92 Compared to those treated with synthetic drugs (viz. prednisone and Cytoxan) alone, those treated with both synthetic drugs and herbal soups have been reported to have a higher remission rate, a lower adverse reaction rate and a longer remission period. Similar promising effects have also been documented by Yao et al.,93 who have integrated herbal remedies (comprising herbs such as dandelion, giant knotweed, and barbed stullcap) with synthetic drugs (e.g. cyclosporine A, mycophenolate, prednisone, rapamycin, azathioprine, and tacrolimus) in the treatment of severe post-kidney-transplant lung infection. Among the 18 patients participated in the study, 15 of them have shown positive outcomes. This has been attributed to the effect of the herbal remedies in increasing the blood neutrophilic granulocyte phagocytic index and



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blood plasma total complementary level in patients, thereby enhancing patients’ immune functions to fight against the infection.93

Despite the potential as depicted above, some herbal medicines and synthetic drugs may be incompatible with each other. Their combined use may jeopardize the efficacy of the treatment. This is exemplified by the herb Hypericum perforatum, which induces the expression of cytochrome P450 enzymes and P-glycoprotein, ultimately lowering the serum concentration of synthetic drugs such as cyclosporine, indinavir, irinotecan, and nevirapine.94 Another study on pulmonary fibrosis rat models has also found that the health conditions of animals treated with a combined therapy consisting of azathioprine and Tripterygium wilfordii were worse than those treated with azathioprine alone.95 Herb-drug interactions, therefore, have to be taken into consideration when a combined therapy is administered. Solutions to this incompatibility problem have lately been illuminated by advances in microfabrication technologies such as microfluidic electrospray, which has been adopted to generate multicompartment hdyrogel beads for co-delivery of incompatible agents.7 By using cadmium–telluride (CdTe) quantum dots (QDs) and PEI as a model pair, the beads have separated the incompatible agents in different compartments during the delivery process.7 Moreover, the composition of the compartments can be tuned using the polymer blending technique to attain different release profiles of the co-delivered agents.7 The versatility provided by the beads is expected to bring new opportunities to the development of therapies that integrate both herbal medicines and synthetic drugs into one single system.


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Finally, it is worth noting that the success of delivering herbal medicines using hydrogels may be more complicated than expected. Much more optimization may be required before success can be achieved. This is demonstrated in a clinical trial in which a hydrogel containing tepescohuite, which is the extract of the bark of Mimosa tenuiflora, has been studied for the treatment of venous leg ulcers (VLUs).96 The study has recruited 41 patients, who have been instructed to first cleanse the ulcer daily, followed by topical application of the hydrogel and compression. Histologic evaluation, however, has shown that the therapeutic effect of the extract-loaded hydrogel is not significantly different from that of the blank hydrogel. This reveals that successful incorporation of herbal medicines into hydrogels for clinical use may necessitate prior optimization and careful execution.

6. Concluding Remarks Herbal medicine is an important part of oriental medicine which has been gaining recognition and popularity around the world. In this article, we have reviewed the latest advances in the development of hydrogel-based materials as carriers of herbal medicines, and have discussed the clinical challenges and potential for future research. As shown by the evidence presented, hydrogels are biocompatible materials that can be used as carriers to improve the efficacy of herbal treatments in both clinical and pre-clinical studies. This encouraging potential has been augmented by advances in microfabrication technologies, which enable hydrogel manipulation and make future integration of herbal medicines with synthetic drugs technically feasible. In the forthcoming decade, rejuvenation and advancement of herbal medicine are expected to be facilitated continuously by advances in drug delivery technologies and



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materials science. What we are looking forward to is the emergence of more effective herbal treatments in the foreseeable future.

Acknowledgments The authors would like to thank Marie C. Lin, Cheng-Shen Hu and Yau-Foon Tsui for their help and support during the preparation of this manuscript.


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Figure Captions

Fig. 1 Properties of hydrogels for delivery of herbal medicines

Fig. 2 Photos taken at different stages of the contact dermatitis treatment, in which the hydrogel patch containing extracts of UD and Houttuynia cordata Thunb has been adopted (Reproduced with permission from reference 49. Copyright 2009 Elsevier)

Fig. 3 The effects of the SLN-enriched hydrogel loaded with astragaloside IV in inducing wound healing. In this figure, I represents the blank control group. I, II and IV have been treated with the blank SLN-enriched hydrogel, astragaloside IV solution, and astragaloside IV-loaded SLN-enriched hydrogel, respectively. V represents the normal skin. (A) Masson's trichrome staining at 1, 3, and 7 weeks post-wounding. (B) Collagen deposition in the regenerated skin as examined by scanning electron microscopy at 3 weeks post-wounding at different magnifications. (C) Sirius red staining at 3 weeks post-wounding. (Reproduced with permission from reference 56. Copyright 2013 Elsevier)

Fig. 4 Photos of skin lesions in two VLU patents (viz. G.M.M. and S.Z.E.) treated with the hydrogel containing the extract of Mimosa tenuiflora. (Reproduced with permission from reference 70. Copyright 2007 Elsevier)

Fig. 5 (A) The structural formula of PEG–PCL–PEG, which is used to form Cur-M-H. (B) Preparation and characterization of the Cur–M–H composite. (i) Cur–M–H at 10 °C (left) and 37 °C (right); (ii) dermal adhesiveness of the Cur–M–H composite. (C)



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Images of skin wounds treated with (i) normal saline, (ii) the hydrogel containing blank micelles, (iii) Cur–M, and (iv) Cur–M–H, on the 14th day of wound healing. (D) The hematoxylin and eosin stained sections of the granulation tissue in groups treated with (i) normal saline, (ii) the hydrogel containing blank micelles, (iii) Cur–M, and (iv) Cur–M–H, on the 14th day of wound healing. (Reproduced with permission from reference 84. Copyright 2013 Elsevier)

Fig. 6 (A) A schematic diagram showing the synthesis of HC. (B) A schematic diagram illustrating the complexation of HC with CMC. (C) The efficiency of HC/CMC and CS/CMC hydrogels in encapsulating drug molecules with varying degrees of hydrophilicity. Abbreviations: CDI, 1,1’-carbonyldiimidazole; CMC, carboxymethylcellulose; CS, chitosan; HC, hypromellose-graft-chitosan; MB, methylene blue; MF, mometasone furoate; MT, metronidazole; TH, tetracycline hydrochloride (Reproduced with permission from reference 8. Copyright 2015 American Chemical Society)

Fig. 7 A schematic diagram showing the synthesis of aldehyde-functionalized carbohydrates and hydrazide-functionalized poly(NIPAM-co-ADH), as well as the use of a double-barrel syringe for the formation of an in situ hydrazone cross-linked hydrogel. Abbreviations: AA, acrylic acid; ADH, adipic acid dihydrazide; AIBME, 2,2-azobisisobutyric acid dimethyl ester; CMC, carboxymethylcellulose; EDC, N’-ethyl-N-(3-dimethylaminopropyl)-carbodiimide, MAA, thioglycolic acid; NIPAM, N-isopropylacrylamide (Reproduced with permission from reference 88. Copyright 2012 American Chemical Society)


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Table 1 Some of the delivery systems exploited in the literature for delivery of herbal medicines Delivery system

Description

Phytosomes

Phytosomes are usually prepared by complexation between phosphatidylcholine and polyphenolic phytoconstituents

•

Liposomes are constructed of phospholipids. They can encapsulate both hydrophilic and hydrophobic molecules.

• Co-delivery of both hydrophilic

Liposomes

Strengths

•

•

Polymeric nanoand microparticles

Emulsions

Hydrogels

Polymeric nano- and microparticles generally have spherical morphologies, though generation of non-spherical particles has been reported. During the loading process, the agent to be delivered can either be encapsulated inside, or can adsorb on the particle surface Emulsions, in general, are biphasic systems in which one phase is dispersed in the other phase in the form of minute droplets. Some emulsions may have more than two phases

•

Hydrogels are hydrophilic polymer networks that can imbibe a substantial amount of fluids

•

•

• •

•

•

Limitations

Comparatively safe and biocompatible Can be produced in different sizes, thereby enabling encapsulation of molecules with diverse size ranges and hydrophobic molecules has been made possible using multi-layered liposomes Can be produced in different sizes, thereby enabling encapsulation of molecules with diverse size ranges Can offer controlled and sustained release of the encapsulated molecules Techniques in polymer engineering have been well-established, making functionalization of the particles (and hence modulation of the particle properties) feasible Comparatively easy in production The physics of emulsion production has been well-studied, making engineering of the emulsion production process feasible Biocompatible, and comparatively low in toxicity Possible to offer controlled and sustained release of the encapsulated molecules Sophisticated techniques in polymer engineering, making functionization of polymer constituents (and hence modulation of hydrogel properties) feasible

• Poor storage stability • Laborious production procedures •

Poor encapsulation efficiency

• Poor storage stability • Laborious production procedures • Poor encapsulation efficiency

Application Example Phytosomes have been fabricated with silybin, which is the most potent flavonoid in the fruit of the milk thistle plant (Silybum marianum, Family Asteraceae). Compared to conventional silymarin, the phytosomes have exhibited enhanced bioavailability and liver protection effects. Liposomes have been adopted to enhance the inhibitory effect of diospyrin, a bisnaphthoquinonoid plant product, on tumor growth. Compared to those treated with the free drug, the tumor-bearing mice treated with liposomal diospyrin have been reported to have enhanced longevity.

Ref. 42

43

Particle-particle aggregation may occur, limiting the storage stability Difficult to encapsulate molecules with different degrees of hydrophilicity at the same time Precise control the polydispersity of the particles is technically challenging. This hampers the efficiency of drug delivery

PLA nanoparticles have been reported to improve the solubility, permeability and stability of quercitrin, which is an antioxidant isolated from Albizia chinensis.

44

• •

Poor storage stability Droplets in emulsions, in general, are highly polydispersed. This hampers the efficiency of drug delivery

Quercetin has been formulated as a water-in-oil microemulsion to enhance its skin penetration.

45

•

Difficult to encapsulate hydrophobic molecules, or to be simultaneously loaded with molecules with varying degrees of hydrophilicity Possible to inactivate herbal components when chemical cross-linking is involved during hydrogel fabrication

The Sanqi bone paste, which is a formulation containing herbal medicines such as Notoginseng Radix et Rhizoma (Sanqi) and Dipsaci Radix, has been incorporated into a hydrogel. Compared to the conventional bone paste, the generated hydrogel patch has exhibited enhanced transdermal properties and release sustainability of the herbal bioactives.

46

• •

•

•

Abbreviation: PLA, poly-D,L-lactide



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Table 2 Some of the applications of hydrogels loaded with herbal medicines Area of application

Principle of application

Treatment of cutaneous anomalies

Be applied topically to skin to deliver herbal medicines to the site of interest

Tissue engineering

Wound healing

Development of cosmeceutical products

Food production

Cancer treatment

Examples Polymer constituent(s) Poloxamer 407, CMC Carbopol 940

Bulk

Be loaded with herbal medicines that are thought to facilitate tissue regeneration, and applied to the affected area Be adopted to deliver herbal medicines to the wounded area to facilitate the wound healing process

Alg CS

Bulk Bulk

CS, PVP, PNIPAm

Film

Pluronic F-127

Bulk

Be adopted to develop skin care products containing herbal extracts or ingredients

Carbopol 934, Carbopol 940, Carbopol 941, xanthan gum Carbomer

Bulk

The polymers have been dispersed in water, followed by neutralization with NaOH. The hydrogel has been incorporated with nanospheres before use

Active ingredient

Bulk

The polymer has been dispersed in water, followed by neutralization with triethanolamine The polymers have been dispersed in water, followed by neutralization with NaOH. The hydrogel has been incorporated with a nanoemulsion before use Alg has undergone ionic gelation with Ca2+

Be utilized to encapsulate herbal components to improve the stability and functionality of those components in food products Be adopted to release the herbal ingredient to the tumor site in a sustained manner

Form of the hydrogel Bulk

Bulk

Alg

Particulate

Bulk

Poloxamer 407 has been added into a CMC solution in an ice bath under constant magnetic stirring Carbopol 940 has been dispersed in water at room temperature, followed by neutralization with triethanolamine Alg has undergone ionic gelation with Ca2+ The CS solution has been mixed with a solution of ammonium hydrogen phosphate salt at 4 oC Solutions of CS and PVP have been mixed, followed by addition of the PNIPAm solution. The mixed solution has then been dried to form a film. Gel formation has been induced by elevation of temperature

Carbopol Ultrez 20

PECT

Method of fabrication

PECT has been used to form a powder, in which the herbal active ingredient has been incorporated, via nanoprecipitation. The powder has subsequently been dispersed in saline to form a solution, which can form a gel by elevation of temperature The polymers have been used to form different phases by being dissolved in their corresponding solvents. The phases have then been mixed at different time points to form the hydrogel patch

Agent to be delivered Herbal extract

Herb(s) involved

Ref 57

Herbal extract

Paeonia suffruticosa Andrews Ipomea pes-tigridis

58

Active ingredient Herbal extract

Liver-softening herbs Cissus quadrangularis

59 60

Herbal extract

Salix alba leaves

61

Herbal extract Active ingredient

Terminalia arjuna bark Terminalia arjuna bark for tannins Rhodiola rosea for salidroside, and peonies for paeonol

62

Herbal extract

Imperata cylindrical

64

Herbal extract

Achyrocline satureioides

65

Herbal extract

Pterospartum tridentatum Ilex paraguariensis

66 67

Thymus serpyllum L.

68

Embelia ribes Burm for embelin

69

Panax notoginseng, Carthamus tinctorius L., and other herbs used in the Sanqi bone paste

46

Active ingredient

Be used to release the herbal Bulk Herbal ViscomateTM bioactives to the affected site in NP700, formulation a sustained manner to facilitate Carbopol 940, alleviation of the musculoskeletal PVP, gelatin injury Abbreviations: Alg, alginate; CMC, carboxymethylcellulose; CS, chitosan; PECT, poly (ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone); PNIPAm, poly(N-isopropyl acrylamide); PVP, poly(vinyl pyrolidone) Bone setting


63

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Table of Content


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Fig. 1 Properties of hydrogels for delivery of herbal medicines Fig. 1 160x90mm (300 x 300 DPI)



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Fig. 2 Photos taken at different stages of the contact dermatitis treatment, in which the hydrogel patch containing extracts of UD and Houttuynia cordata Thunb has been adopted (Reproduced with permission from reference 49. Copyright 2009 Elsevier) Fig. 2 136x108mm (300 x 300 DPI)


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Fig. 3 The effects of the SLN-enriched hydrogel loaded with astragaloside IV in inducing wound healing. In this figure, I represents the blank control group. I, II and IV have been treated with the blank SLN-enriched hydrogel, astragaloside IV solution, and astragaloside IV-loaded SLN-enriched hydrogel, respectively. V represents the normal skin. (A) Masson's trichrome staining at 1, 3, and 7 weeks post-wounding. (B) Collagen deposition in the regenerated skin as examined by scanning electron microscopy at 3 weeks postwounding at different magnifications. (C) Sirius red staining at 3 weeks post-wounding. (Reproduced with permission from reference 56. Copyright 2013 Elsevier) Fig. 3 127x156mm (300 x 300 DPI)



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Fig. 4 Photos of skin lesions in two VLU patents (viz. G.M.M. and S.Z.E.) treated with the hydrogel containing the extract of Mimosa tenuiflora. (Reproduced with permission from reference 70. Copyright 2007 Elsevier) Fig. 4 143x125mm (300 x 300 DPI)


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Fig. 5 (A) The structural formula of PEG–PCL–PEG, which is used to form Cur-M-H. (B) Preparation and characterization of the Cur–M–H composite. (i) Cur–M–H at 10 °C (left) and 37 °C (right); (ii) dermal adhesiveness of the Cur–M–H composite. (C) Images of skin wounds treated with (i) normal saline, (ii) the hydrogel containing blank micelles, (iii) Cur–M, and (iv) Cur–M–H, on the 14th day of wound healing. (D) The hematoxylin and eosin stained sections of the granulation tissue in groups treated with (i) normal saline, (ii) the hydrogel containing blank micelles, (iii) Cur–M, and (iv) Cur–M–H, on the 14th day of wound healing. (Reproduced with permission from reference 84. Copyright 2013 Elsevier) Fig. 5 141x209mm (300 x 300 DPI)



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Fig. 6 (A) A schematic diagram showing the synthesis of HC. (B) A schematic diagram illustrating the complexation of HC with CMC. (C) The efficiency of HC/CMC and CS/CMC hydrogels in encapsulating drug molecules with varying degrees of hydrophilicity. Abbreviations: CDI, 1,1’-carbonyldiimidazole; CMC, carboxymethylcellulose; CS, chitosan; HC, hypromellose-graft-chitosan; MB, methylene blue; MF, mometasone furoate; MT, metronidazole; TH, tetracycline hydrochloride (Reproduced with permission from reference 8. Copyright 2015 American Chemical Society) Fig. 6 189x185mm (300 x 300 DPI)


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Fig. 7 A schematic diagram showing the synthesis of aldehyde-functionalized carbohydrates and hydrazidefunctionalized poly(NIPAM-co-ADH), as well as the use of a double-barrel syringe for the formation of an in situ hydrazone cross-linked hydrogel. Abbreviations: AA, acrylic acid; ADH, adipic acid dihydrazide; AIBME, 2,2-azobisisobutyric acid dimethyl ester; CMC, carboxymethylcellulose; EDC, N’-ethyl-N-(3dimethylaminopropyl)-carbodiimide, MAA, thioglycolic acid; NIPAM, N-isopropylacrylamide (Reproduced with permission from reference 88. Copyright 2012 American Chemical Society) Fig. 7 189x119mm (300 x 300 DPI)


Hydrogel-Based Materials for Delivery of Herbal Medicines - ACS

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