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Advances in the pharmaceutical research of curcumin for oral administration

  • Cheng Li , Abid Naeem , Jiangwen Shen , Weiwei Zha , Qingyun Zeng , Peng Zhang , Lin Li , Zhenggen Liao and Xulong Chen EMAIL logo
Published/Copyright: December 20, 2023
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Open Chemistry
From the journal Open Chemistry Volume 21 Issue 1

Abstract

Curcumin is an isolated phytopolyphenol pigment found in the Curcuma longa, commonly known as turmeric, with various pharmacological properties. It has many effects, including anti-tumour, anti-inflammatory, anti-bacterial, anti-oxidation, and hypoglycemic properties. However, due to its oral bioavailability, the use of the drug in the clinical environment is limited. Moreover, curcumin’s low bioavailability is attributed to its insoluble nature, poor permeability, and inhibition of P-glycoprotein efflux and enzyme metabolism. Several new dosage forms of curcumin have been developed based on its physical properties to improve oral administration. However, the curcumin oral administration system still needs to be improved from the perspective of both research and clinical applications.

Keywords: curcumin; pharmaceuticals; bioavailability; oral administration

1 Introduction

Curcumin, a hydrophobic bioactive ingredient derived from turmeric, is considered a natural anti-inflammatory, antioxidant, and antitumor agent. It has been used by Indian and Chinese practitioners for a long time [1,2]. Unfortunately, because of the low bioavailability of oral curcumin, its application is restricted. In order to overcome the problem of poor solubility, many formulation methods have been explored and utilised over the years, and great progress has been made. Over the past decade, there has been a growing recognition that simply increasing the dissolution rate of APIs or making them dissolve is often not sufficient to achieve the desired bioavailability. In particular, BCS III and IV TCM components have poor permeability and cannot meet the requirements of improving their oral bioavailability through solubilization technology alone. Therefore, the oral administration of insoluble and low-permeability active ingredients in traditional Chinese medicine is a key scientific problem to be solved urgently in traditional Chinese medicine preparations [3].

This review will focus on the following aspects: (ⅰ) the intestinal barrier that affects the intestinal absorption of drugs; (ⅱ) the absorption mechanism of curcumin given orally; and (ⅲ) research on metabolic processes and formulation development. Finally, according to the characteristics of curcumin, a feasible oral administration improvement strategy was proposed, which provided a reference for dosage form design and clinical application.

2 Intestinal barrier

2.1 Mucous layer

The mucus forms the main barrier separating the contents of the intestinal tract from the intestinal epithelium, and if that barrier is absent, intestinal drugs will have direct contact with the epithelium. Generally, it is composed of water (95%), glycoproteins (1–10%), antibodies, electrolytes, and nucleic acids [4,5]. The mucous layer consists of a firmly adhered, non-agitated viscous inner layer tightly attached to the epithelium and a loosely adhered, less adhered outer layer derived from the epithelium. The mucous layer is a mesh gel with a biological layer thickness of about 50–200 µm and an average pore size of several hundred nanometers (about 10–200 nm) [6,7,8]. Mucin (a highly glycosylated protein) is several hundred nanometers (about 100–200 nm) in size and is the main structural component of mucus, providing good water solubility and preventing protease degradation [9,10]. In addition, mucins also contain oligosaccharide side chains, terminal sialic acid, and sulphate, which provide the mucus with a negative charge [11]. Most hydrophilic small molecules can be freely diffused through this barrier. At the same time, many foreign substances (including foreign bodies) are trapped by the intestinal mucous layer due to their large size or steric hindrance or as a result of interactions with mucus through electrostatic interactions, van der Waals forces, hydrophobic, hydrogen bonds, and entanglement [12]. The mucus in the intestinal wall is periodically renewed as a defence mechanism against foreign particles contacting epithelial cells. In this way, nanocarriers may be rapidly eliminated from the gut, reducing their chances of reaching the epithelium [13]. In addition, studies have shown that nanocarriers can be quickly removed by microflows in the viscous layer [14]. Bao et al. developed alpha-lactalbumin nanotubes that were able to overcome intestinal mucus and intestinal cell barriers and effectively increased curcumin bioavailability and anti-inflammatory effects in the colon [2]. Curcumin-loaded PLGA nanoparticles have also been evaluated in several studies, showing an increase in aqueous solubility, increase release rates in intestinal fluids, enhanced absorption due to improved permeability, and increased intestinal residence time, which may be related to curcumin’s improved oral bioavailability [15,16]. In a study, Sol-CUR improved micellar curcumin’s permeability by 3.8 times over its native form, resulting in a Papp value of 2.11 × 10−6 cm/s. Several human pharmacokinetic studies indicate that micellar curcumin formulations have significantly improved oral bioavailability compared to native curcumin, resulting in a 185-fold increase in AUC over native curcumin. This may be caused by an increase in absorption via small intestinal epithelial cells and increased transport through them [17].

Therefore, current research is devoted to developing nanocarriers that can quickly penetrate the mucus layer to escape being cleared by mucus, ensuring that the released drug is close to the maximum absorption limit of the epithelial surface and improving the bioavailability of the drug. So far, effective strategies are mainly to simulate virus nano-carriers and nano-carriers that allow the controlled release of mucous solubilizers. Because of their small size, the nano-carrier system effectively diffuses through the mucus barrier covering the entire intestinal tract and reaches the epithelium before the drug is released. The nano-carriers are in close contact with the mucous membrane surface so that they can maintain stable drug release over a period of time [18,19].

2.2 Epithelial cells

Cells within the intestinal epithelium function to block the passage of pathogens, microorganisms, and toxins from the lumen, while simultaneously allowing nutritional substances, electrolytes, and water to enter the circulation. Two main mechanisms contribute to this selectivity of transport: transepithelial/transcellular and paracellular mechanisms. Amino acids [20], electrolytes [21], short-chain fatty acids, and sugars [22] are generally transported across epithelial cells by a cross-cellular pathway controlled by specific transporters. In paracellular transport, molecules are moved through the space between epithelial cells and are regulated by complexes located at the lateral membrane junctions and the parietal membrane junctions as well as by intercellular complexes along the lateral membrane [23,24]. Contact between adjacent epithelial cells is established by desmosomes, adhesion, and tight junctions. Transmembrane proteins form adhesion junction complexes that facilitate the attachment of neighbouring cells to the actin cytoskeleton through cytoplasmic scaffold proteins. Additionally, desmosomes play an important role in the mechanical connection between adjacent cells [25]. On the other hand, tight junctions keep the intercellular space sealed and regulate selective transport between cells [26]. Consequently, interventions that affect the expression or organization of these closely linked proteins may have an adverse effect on the paracellular delivery of drugs into the systemic circulation from the intestine. Researchers have found that curcumin increases the expression of ZO-1 and Claudin-1 in Caco-2 cells of the human intestinal epithelium, resulting in the improvement of intestinal barrier function and a reduction of paracellular permeability [27].

3 Absorption

There are many ways of administering traditional Chinese medicine, and oral administration has become the most common mode of administration because of its safety, convenience, and strong patient compliance. However, many traditional Chinese medicine ingredients have problems such as poor absorption and low bioavailability after entering the human body after oral administration [28]. Through a literature review, it was found that curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione), also known as diferoylmethane, cannot exert its biological activity due to its extremely poor water solubility, permeability, rapid metabolism, and rapid clearance, resulting in poor bioavailability. By exploring the path of curcumin in the body, it is found that when curcumin enters human intestinal cells and liver cells, most of the curcumin will interact with glucoglycic acid and sulphides in the organs to form curcumin metabolites which are quickly excreted from the body [29]. In addition, the literature shows that the gastrointestinal tract is the leading site of curcumin absorption in the body, and the current models for studying the intestinal absorption of curcumin mainly include in vitro and in vivo absorption models, as shown in Table 1. All these models can effectively evaluate the intestinal absorption of curcumin. It was found that passive transport was the main absorption mechanism of curcumin. P-glycoprotein (P-gp)-mediated active transport was also present, and the duodenum was the best site for absorption. Although the specific mechanism of the intestinal metabolism of curcumin is unknown, the main factors affecting curcumin absorption can be inferred to be poor water solubility and competitive protein inhibition.

Table 1

Intestinal absorption models and absorption mechanism of curcumin

Intestinal absorption model Evaluation index Intestinal absorption characteristics of curcumin References
Caco-2 cell model P app The osmosis was poor, and the energy-dependent pathway was mainly composed of grid protein, fossa protein, and micropinocytosis, with an efflux pump P-gp effect [35,36]
In situ unidirectional intestinal perfusion (SPIP) K a, P eff Duodenum is the main site of absorption and active transport, and there is a transporter saturation phenomenon; the absorption conforms to the first-order kinetic process [37,38]
Franz diffusion cell method P app Time-dependent absorption, near zero-order kinetic process [39]
Ectropion intestinal sac model in vitro P app With poor permeability, the duodenum is the main site of absorption, which is easier to be absorbed by intestinal epithelial cells [40,41]
MDCK cell model P app Passive transport [42]
Using chamber system P app Passive transport [43]
In vivo intestinal circulation model K a Concentration-dependent absorption, passive diffusion [44]

Note: P app is the apparent permeability coefficient, P eff is the effective permeability coefficient, and K a is the absorption rate constant.

Few studies have been reported on the inhibition of P-gp efflux and enzyme metabolism by curcumin through a certain signaling pathway or specific molecules. We conducted an extensive literature review and found that Zhang et al. [30] investigated the reversion effect of curcumin on the SW620/Ad 30 resistance in cancer-overexpressing human colon cancer cells with P-gp. The results showed that the concentration of doxorubicin and the level of the typical P-gp substrate Rho123 were significantly increased in the cells treated with curcumin compared with the control group, suggesting that curcumin could reduce the efflux activity of P-gp. Moreover, curcumin decreased intracellular glutathione and ATP levels, reducing the cellular ability to resist oxidative stress and reducing drug efflux. Zhang et al. [31] observed the downregulation of intestinal P-gp levels after curcumin use. Meanwhile, curcumin could also reduce the levels of CYP3A in the small intestine and induce the expression of CYP3A in the liver and kidney. Lee et al. [32] investigated the effects of oral curcumin on the pharmacokinetics of oral etoposide in rats. The results suggest that the enhanced oral bioavailability of etoposide in the presence of curcumin may be mainly due to the inhibition of the small intestinal P-gp efflux pump or due to the inhibition of rat CYP3A activity, which reduces the first-pass metabolism of etoposide in the small intestine. Cho et al. [33] studied the effects of curcumin on the bioavailability and pharmacokinetics of tamoxifen. The results suggest that curcumin improved the bioavailability of tamoxifen mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver and inhibition of P-gp efflux transporters in the small intestine rather than reducing the elimination of tamoxifen in the kidneys, suggesting that curcumin may reduce first-pass metabolism in the small intestine and/or liver by inhibiting P-gp or CYP3A4 subfamilies. Yang et al. [34] showed that curcumin inhibited the expression and efflux function of P-gp in a concentration- and time-dependent manner, which subsequently increased the accumulation of doxorubicin in K562/DOX. In conclusion, curcumin can exert various effects on in vivo pharmacokinetics by inhibiting P-gp expression, P-gp transport, inhibiting CYP3A enzyme activity, and reducing intracellular glutathione and ATP levels, which has a promising application prospect. In conclusion, active transport is the absorption mechanism of curcumin, and the gastrointestinal tract is the main absorption site. Therefore, the gastrointestinal tract is an important site for the absorption intensity of curcumin in the body. Exploring the absorption mechanism of curcumin is only the first step, and further studies on the mechanism of its action in the body are needed. The study on the absorption mechanism of curcumin laid a good foundation for improving the absorption of curcumin in the body and also laid a foundation for exploring the improvement of new dosage forms of curcumin in the future.

4 Metabolism and excretion

The metabolism of curcumin occurs mainly in the liver, as well as in the intestinal tract and intestinal microbiota [45]. Human intestinal microflora can transform curcumin through various metabolic pathways, such as acetylation, reduction, demethylation, and hydroxylation, to produce more bioactive curcumin metabolites, which can play a local and systemic role. Moreover, an alternative metabolism of curcumin occurs by the intestinal microflora, especially by Escherichia coli and Blautia sp. [46]. Ireson et al. [47] conducted in vitro research experiments on curcumin, using human intestines, liver cells, and liver tissues as mediators and preparing them into microsomal suspensions. The experimental results found that the metabolic process of curcumin in vitro is very rapid and can be metabolised entirely within minutes. Liu et al. [48] found that curcumin was first transformed into curcumin-like compounds in the body and then combined with glucuronic acid in the body. In addition, the team found eight metabolites of curcumin, including flavin, in the urine of rats (see Figure 1 for the structure). The eight components and their half-lives are summarised in Table 2.

Figure 1 Molecular structure and metabolites of curcumin.
Figure 1

Molecular structure and metabolites of curcumin.

Table 2

Summary of curcumin and its metabolites in rat urine

Compound t R (min)
Dihydrocurcumin 2.83
Hexahydrocurcumin-Glu 4.30
Tetrahydrocurcumin 5.65, 17.39
Hexahydrocurcumin 10.88
Hexahydroturmeric 14.54
Curcumin 19.56
Curcumin-Glu 4.62
Tetrahydrocurcumin-Glu 4.27

To explore the pathway of curcumin in the body, curcumin can be labelled with markers. Anand et al. [49] explored the path of curcumin excretion in the body experiments using the 3H2 radiolabeling method to label curcumin. Based on the results, curcumin is rapidly metabolized in the body and excreted through human excretion, and about 30% of curcumin is detected in feces, the form of existence of which is curcumin protoform. Vareed et al. [50] also explored the metabolic path of curcumin in the body and found that the metabolic path of curcumin in the body is as follows: a very small amount of curcumin first passes through the portal vein, enters the blood circulation of peripheral tissues, is then transported to bile and kidney, and finally excreted through bile and kidney. In addition, curcumin is present in very small amounts in urine and large amounts in feces. Combined with the above results, the metabolic path map of curcumin was drawn (Figure 2), from which it can be seen that the main metabolites of absorbed curcumin were excreted through urine and feces.

Figure 2 Metabolism and the excretion pathway of curcumin.
Figure 2

Metabolism and the excretion pathway of curcumin.

5 Pharmacokinetic parameters

To study the metabolism of curcumin in vivo, it is necessary to combine the pharmacokinetic parameters of curcumin, and the author consulted the literature on many pharmacokinetic parameters of curcumin and summarized the following pharmacokinetic parameters, which are shown in Table 3. Interestingly, the significant differences in pharmacokinetic parameters of different curcumin formulations can be attributed to administration, analytical techniques, dosage and sampling time after oral administration. However, meaningful comparisons between different formulations can only be achieved when the pharmacokinetic data are standardized based on the results of AUC (mg) and C max (mg) ingested curcumin, or by comparing different formulations using the same analytical and administration methods [51].

Table 3

Summary of pharmacokinetic parameters of curcumin

Drug Dose (mg/kg) C max (µg/L) T max (h) t 1/2 (h) AUC(0-t) (µg·min/L) References
0.5% CMC–Na suspension 250 64.47 ± 6.57 0.50 ± 0.04 4.10 ± 2.12 4.10 ± 2.12 [52]
0.5% SDS–Na suspension 100 30.23 0.6 7.56 2.26 [53]
Curcumin monomer 200 10,400 ± 1.90 3.00 ± 1.70 2.90 ± 0.30 935.00 ± 21.83 [54]
0.5% CMC–Na suspension 200 8980 ± 4410 1.16 ± 0.22 0.68 ± 0.25 21.00 ± 5.50 [55]
0.5% CMC–Na suspension 100 1.512 ± 0.401 0.73 ± 0.06 0.859 ± 0.214 0.025 ± 0.007 [56]
Curcumin suspension with Tween 20 (1%, v/v) 100 500.00 0.75 1.45 22.00 [57]
Curcumin aqueous suspension 50 4.066 ± 0.564 0.5 1.109 ± 0.124 0.145 ± 0.031 [58]
Free curcumin 35 21.76 0.5 0.48 0.73 [59]
1% CMC–Na suspension 3300 0.46 0.61 0.54 46600.0 [60]
0.5% CMC–Na suspension 100 1550.0 ± 210.0 1.7 ± 0.27 1.24 ± 0.10 367000 ± 21000.0 [61]
5% Dimethylsulfoxide–corn oil suspension 1000 15 ± 12 0.83 ± 0.53 1.58 ± 0.58 1480 ± 1290 [62]

6 Pharmaceutical research

Pharmaceutical research on curcumin is to innovate new dosage forms of curcumin, which is strongly fat-soluble and poorly water-soluble, so improving its absorption in the gastrointestinal tract is the key. Following the study of curcumin absorption, distribution, excretion, and metabolism, it was determined that curcumin is present in the body for a relatively short period of time following oral administration as well as having low bioavailability, suggesting that curcumin is not readily absorbed orally in its normal dosage form. The development of new dosage forms has become a very necessary work. A variety of drug delivery systems have been developed to solve this problem, including nanoparticles, liposomes, micelles, self-microemulsions, solid dispersions, phospholipids, etc. [63] By the preparation of a new drug delivery system and the addition of excipients, the serum level, tissue distribution, metabolism, and half-life of curcumin were changed, thereby improving the bioavailability of curcumin [64]. It was found via literature studies [65,66,67,68] that researchers improved curcumin’s oral absorption and availability based on modern pharmaceutical methods, such as physical parameters and structural modification, as shown in Figure 3.

Figure 3 Improvement strategies for oral curcumin delivery.
Figure 3

Improvement strategies for oral curcumin delivery.

6.1 Methods of early preparation

There are various ways to increase curcumin bioavailability. Due to curcumin’s fat-soluble nature, the consumption of curcumin in conjunction with fat powder enhances its absorption. Early methods took advantage of the synergy of these multiple components to increase curcumin bioavailability. Antony et al. added turmeric butter [69,70,71,72] and a small amount of piperine [51] in an attempt to stimulate the gastrointestinal tract and reduce curcumin efflux or turmeric resinous resin spillage, resulting in a gradual increase in the absorption of curcumin.

6.2 Modern pharmaceutical methods

6.2.1 Based on physical parameters

Various classical techniques based on physical parameters (e.g., heat, pH, and complexation with metal ions, polymers, or serums) have been used to prepare more soluble curcumin preparations. Kurien et al. demonstrated that curcumin and turmeric’s solubility can be increased by factors of 12 and 3, respectively, by heating without causing any disintegration of curcumin [73]. The most convenient and safest means for delivering drugs in vivo is water, which is why hot-dissolved curcumin is being investigated as a possible candidate for future in vitro and in vivo trials. Zebib et al. prepared complexes of curcumin with metal ions (Zn2+, Cu2+, Mg2+, and Se2+) and found that they were easily soluble in glycerol water and very stable to light and heat [74]. Additionally, the curcumin–serum albumin complex increased curcumin solubility while reducing amphotericin B’s toxic effects by delaying erythrocyte membrane damage [75].

6.2.2 Chemical modification

Curcumin has been chemically modified to increase its bioavailability by the preparation of derivatives and analogues. At present, a series of compounds with significantly improved solubility has been synthesised by modifying different active sites such as curcumin phenyl ring substituents and 1,6 heptadiene-3,5 diketone linkage chains. Qiu et al. reported that a chemically modified 4-arylcurcumin derivative showed improved solubility and effectiveness against cancer analogues over its original formulation [76]. A number of attempts have also been made to chemically modify curcumin in order to increase its anti-cancer activity and NF-kB inhibitory action [77–79].

6.2.3 Liposomes

Due to their unique membrane structure, liposomes have been used to improve the dissolution and bioavailability of various insoluble drugs. In addition, the preparation method, lipid composition, and surface modification can significantly improve the properties of liposomes, including stability, targeting, bioavailability, and slow and controlled release [80,81]. In recent years, the fat-soluble drug curcumin has been prepared in liposomes by many researchers to improve its oral bioavailability. You et al. [82] prepared curcumin liposomes and the study found that curcumin long-cycle liposomes significantly increased AUC compared with APIs, which may be due to the reduction of curcumin clearance in vivo, and the half-life of the drug was effectively extended, which improved the duration of action of the drug in vivo. Xie et al. [61] prepared a curcumin nano-lipid carrier (Cur-NLC), and the experimental results showed that the dosage form played an excellent protective role, effectively avoiding leakage when taking the drug, and found that the absorption rate of curcumin in the gastrointestinal tract was significantly increased. Curcumin oral administration significantly improved its bioavailability, thereby preventing drug leakage by improving its bioavailability. The specific preparation method of Cur-NLC is as follows: the mixture of 0.12 g of glyceryl trilaurate, 0.48 g of octyl/capric triglyceride, and 0.04 g of Cur was heated to 80°C and melted to produce an oil phase, and 10 mL of aqueous solution containing Tween 80 (0.2 g) and SDS (0.001 g) was heated to 80°C to prepare an aqueous phase. Under magnetic stirring, the water phase at the same temperature was rapidly injected into the oil phase, and the stirring was continued for 5 min to prepare the mixture. After ultrasonication for 3 min (400 W), the obtained nanoemulsion droplets were quickly solidified in an ice bath for 30 min, and then filtered through a 0.45 μm microporous membrane to obtain Cur-NLC.

Xu et al. [60] compared the pharmacokinetic parameters of curcumin liposome and free curcumin solution, and the results showed that the half-life t 1/2, C max, and V/F (c) in three aspects were far greater than that in free curcumin solution. In conclusion, the bioavailability of curcumin can be significantly improved by making curcumin into liposomes. This formulation can significantly increase the duration of curcumin in the body.

6.2.4 Inclusion complex of hydroxypropyl β-cyclodextrin

Hydroxypropyl-β-cyclodextrin has many advantages in improving the bioavailability of poorly soluble drugs, such as enhancing the stability of easily oxidized and hydrolyzed drugs and prolonging drug efficacy and shelf life. Moreover, the clathrate is easily soluble in water [83], which can coat a variety of drugs, increase the solubility of the drug, and reduce toxicity and irritation of the drug. Compared with β-cyclodextrin, hydroxypropyl-β-cyclodextrin forms a complex with the drug to have a sustained release effect on the drug in vivo.

The curcumin hydroxypropyl-β-cyclodextrin complexes prepared by Gao et al. [84] under optimal process conditions had good reproducibility effects, and solubility and stability were improved. The specific preparation method of curcumin hydroxypropyl-β-cyclodextrin inclusion complex is as follows: A certain amount of CUR was weighed, a small amount of anhydrous ethanol was added to wet it, and then a dilute ethanol solution was added to dissolve it. Then, a certain amount of HP-β-CD (molar ratio 1:1) was weighed and dissolved in 50 mL, and the CUR solution was dropped into HP-β-CD under electromagnetic stirring (medium speed). The solution was continuously stirred for several hours. Then, it was freeze-dried and the dry powder was collected. Furthermore, the stirring method was selected to optimise the preparation process. The key parameters were inclusion temperature, stirring time, and mass ratio of CUR to HP-β-CD.

Li et al. [85] administered oral gavage of curcumin to rats and detected the C max, T max, and t 1/2 values in rats, and the results showed that the C max, T max and t 1/2 values in rats were 95. 05 mg/L, 10, and 21.67 min, respectively. By comparison, it was found that the content of curcumin wrapped by this dosage form increased significantly in the body, which directly indicated that this dosage form prolonged its residence time in the body. Khalil et al. [58] used a one-way perfusion model to explore the intestinal absorption of curcumin–hydroxypropyl–β-cyclodextrin complex, and the experimental results showed that compared with curcumin, the three aspects of curcumin–hydroxypropyl–β-cyclodextrin clathrate (absorption rate constant K a, effective permeability P app, and effective penetration efficiency in the colon) were significantly improved, and the absorption of each intestinal segment of rats was also significantly improved. It was proved that this formulation could significantly improve the absorption of curcumin in rat intestines compared with the curcumin raw material. The above experimental results show that the curcumin–hydroxypropyl–β-cyclodextrin complex can improve the shortcomings of low solubility and poor stability of curcumin in water. Studies show that hydroxypropyl–β-cyclodextrin has many advantages in improving the bioavailability of poorly soluble drugs. Li et al. [86] found that the mechanism by which 50 mM α-cyclodextrin can enhance the bioavailability of curcumin is to reduce the transepithelial resistance of the cell monolayer via the paracellular pathway and increase the permeability of 5(6)-carboxyfluorescein (a poorly absorbable drug). In addition, α-cyclodextrin can also reduce the expression of tight junction-related protein claudin-4 in brush border membrane vesicles via the transcellular pathway to increase the membrane fluidity of the lipid bilayer in the brush border membrane vesicles and enhance the penetration of drug molecules. In addition, the safety of this dosage form can also stand for consideration. Starch and cyclodextrin were labelled with isotope labelling, and after 24 h, the total metabolism of the two was found to be similar. Experiments showed that the body could also absorb cyclodextrin as carbohydrates, and there is no accumulation effect in the human body.

6.2.5 Self-microemulsifying drug delivery system

The self-microemulsifying drug delivery system (SMEDDS) is a thermodynamically stable mixture of the isotropic oil phase, surfactant, and cosurfactant to spontaneously form the micro milk under gastrointestinal peristalsis (Figure 4). SMEDDS form supersaturated solutions higher than the equilibrium solubility of drugs in the gastrointestinal tract, improve the activity of water-insoluble drugs in the body and thus promote drug absorption, which is a good preparation for improving the bioavailability of water-insoluble drugs [87,88].

Figure 4 Schematic of supersaturated self-microemulsion composition and its mechanisms for improving oral bioavailability.
Figure 4

Schematic of supersaturated self-microemulsion composition and its mechanisms for improving oral bioavailability.

In the conventional state, the drug loading of SMEDDS is low, which is easy to produce crystallization during the process of dispersion and digestion, thus affecting the drug absorption. In recent studies, hydrophilic polymers were introduced to construct the curcumin-saturated and stabilized SMEDDS (CUR-S-SMEDDS) to further improve drug bioavailability (Figure 4) [89].

Cui et al. [90] studied the absorption rate of curcumin self-microemulsifying concentrate by small intestinal reflux test, and the results showed that the main absorption intestinal segments of the drug were duodenum and jejunum. The apparent absorption permeability coefficient P app of the curcumin self-microemulsification concentrate was 2.5 times that of curcumin API, reflecting the superiority of this dosage form. SMEDDS can promote the synthesis of intestinal chylomere, bring the drug to systemic circulation through the lymphatic system [91], and reduce the first-pass effect of the liver on the drug [92]. In SMEDDS prescription, surfactants such as polyoxyethylene castor oil (EL) and polyoxyethylene hydrogenated castor oil (RH40) can inhibit drug efflux leakage by regulating P-gp [93]. The drug in SMEDDS is always in a dissolved state, which shortens the time of drug dissolution and release [94], and after emulsification, the drug is still stable in the milk drop in a completely dispersed state [95,96]. Therefore, the curcumin self-microemulsion delivery system is a dosage form that can better solve or improve the problems of poor solubility, low absorption, and low bioavailability of curcumin compared to other dosage forms, which provides theoretical guidance and experience for the practical clinical application of curcumin in the future.

6.2.6 Nanoparticles

In recent years, nano-preparations have become one of the hot spots in pharmaceutical research due to their advantages of enhancing drug-controlled release performance, targeting, improving bioavailability, and patient compliance [97,98]. Nanoparticles are solid colloidal particles of 10–1,000 nm with simple preparation, high physical stability, and stable drug release. Compared with other preparations, nanoparticles use fewer drug carriers and have the advantages of good biocompatibility, high solubility, slow controlled release, and targeted delivery [99]. Zhong et al. [100] studied the absorption experiment of curcumin–polylactic acid–glycolic acid nanoparticles in vivo. The results showed that curcumin nanoparticles could effectively reduce the proliferation ability of PC-3 cells while improving the sustained and controlled release of drugs in vivo. Sun et al. [101] investigated the effect of the dosage form of curcumin on the absorption of curcumin in vivo by preparing curcumin PLGA-TPGS nanoparticles, and the conclusion of this experiment proved that curcumin PLGA-TPGS nanoparticles have a targeted effect on the liver. Yu et al. [102] explored the distribution of curcumin nanoparticles in the body, and the test results showed that in addition to the distribution of brain tissue, the rest of the tissues in the plasma have distribution. The distribution in the body is very rapid; for example, curcumin can be detected in the liver, spleen, and kidneys: 125.72 µg g−1 in the liver, 33.60 µg g−1 in the spleen, and 16.81 µg g−1 in the kidney, but the presence of curcumin is not detected in plasma, lungs, and brain. The bioavailability of curcumin, a polyphenol found in turmeric, is restricted by poor absorption and rapid metabolism in the body. Studies showed that new dosage form like liposomes can improve curcumin’s oral bioavailability. Li et al. [103] developed silica-coated flexible liposomes (CUR-SLs) containing curcumin as a model drug using a thin-film method with homogenization, followed by a sol–gel procedure to form the silica shell. Accordingly, CUR-SLs and CUR-FLs demonstrated a greater bioavailability than curcumin suspensions, which is 7.76- and 2.35-fold higher, respectively. In summary, nanoparticle preparation has the characteristics of slow release and controlled release, as well as reducing the dose and frequency of administration, thus greatly prolonging the action duration of curcumin in vivo and also achieving the purpose of targeted administration. This dosage form provides a new idea for developing new dosage forms of curcumin.

6.2.7 Solid dispersion

Solid dispersion has achieved great success in improving the solubility, dissolution behaviour, and bioavailability of insoluble drugs. However, drugs dispersed in solid dispersions have a high energy relative to their crystalline form and a tendency to convert into stable crystallized states, resulting in a decrease in solubility and dissolution rate, eliminating the advantages of solid dispersions. In recent years, research on solid dispersible curcumin preparations has increased yearly.

Dong et al. [104] found that curcumin solid dispersions have very obvious lipid-lowering and antioxidant effects on diseased rats and observed and studied various indicators in the serum of rats in the experimental and control groups. From the relevant values of detecting diseased rats, curcumin solid dispersions have more obvious effects than curcumin APIs. Chen et al. [105] studied the absorption of curcumin solid dispersions in the gastrointestinal tract and found that curcumin solid dispersions were 6.75 times that of APIs. In addition, curcumin is easy to decompose in the case of strong acids and alkalis, which also shows that solid dispersions can significantly improve the stability of curcumin in the gastrointestinal tract. Guan et al. [106] also found that solid dispersions can significantly improve the bioavailability of curcumin. In summary, solid dispersion technology contributes significantly to curcumin’s bioavailability and stability. There are two specific preparation methods for curcumin solid dispersions. The first is to use the solvent method to dissolve the turmeric extract powder and excipients with anhydrous ethanol by ultrasonication, stir it on a magnetic stirrer for 3 h, transfer it to a rotary evaporator to evaporate the solvent, and the precipitate is placed in a vacuum drying box, removed, ground, and passed through an 80-mesh sieve, and the second approach is to use the melting method to mix the turmeric extract powder with the auxiliary material and heat it to 60–65°C. The melt is stirred vigorously and the melt is dumped on the glass plate into a thin layer to quickly cool it into a solid, and then the solid is placed in the dryer. Then, it is removed from the dryer, grounded, and passed through an 80-mesh sieve.

6.2.8 Phospholipid complex

The phospholipid delivery system is a new type of drug delivery system that combines insoluble drug molecules with phospholipids by freeze-drying technology. Phospholipids contain phosphatidylcholine, which has been found to have pharmacological effects in addition to drug molecules. Phosphatidylcholine can bind closely with drug molecules, positively affecting insoluble drugs’ oral utilization.

Hashemzehi et al. [107] found that the phytosome of curcumin has a more significant inhibitory effect on breast cancer cells than the traditional dosage form of curcumin. Safari et al. [108] studied the effect of curcumin phosphosomes in rats, and the results showed that compared with APIs, curcumin phosphosomes can significantly protect the cardiovascular system. Curcumin formulated with phospholipids in the form of phytosomes enhances the ability of curcumin to enter the bloodstream and be absorbed by the intestinal tract [109]. Phospholipids and crystalline drugs are combined under certain conditions through hydrogen bonding, van der Waals force, and other forces so that drugs exist in an amorphous state, adjust the oil–water partition coefficient, and promote oral absorption of drugs [110,111]. Many naturally active phospholipids, such as soy lecithin, brain lecithin, and egg yolk lecithin, are effective nutrients and antioxidants in their own right. Curcumin is made of lipid complex, and phospholipids can not only promote the metabolism of curcumin in animals but also play a synergistic role in antioxidants. In summary, preparing curcumin into curcumin phospholiposomes can significantly improve the bioavailability and stability of drugs.

6.2.9 Polymeric micelles (PM)

PM, which are commonly used to deliver insoluble drugs, have a core–shell micellar structure, and are made of amphiphilic copolymers, with hydrophobic blocks as the inner nucleus and hydrophilic blocks as the surrounding shell. Insoluble drugs can be dissolved in the hydrophobic core of the micelle and the hydrophilic shell interface of the biological medium [112]. PM can significantly improve the solubility of drugs, improve the gastrointestinal stability of drugs, and prolong the circulation time of drugs in vivo [113]. Furthermore, mixed polymer micelles (MPM) have higher micelle stability and drug-loading efficiency than ordinary PM [112].

Ni et al. prepared curcumin-carboxymethyl chitosan (CNC)/low molecular weight heparin-all-trans-retinoid acid MPM. The chemical bonding method was used to improve the stability and oral bioavailability of curcumin under physiological pH. A major efflux protein of the intestinal epithelium is P-gp, which is capable of decreasing the oral bioavailability of many types of substrate molecules. In addition, CNC conjugates are potential inhibitors of P-gp-mediated efflux and gastrointestinal absorption enhancers [113]. Wang et al. designed curcumin self-assembled polymer micelles (Cur-PMS). After intragastric administration, Cur-PMS enhanced the absorption of duodenum, jejunum, and ileum in rats. The AUC (0-t) of Cur-PMS is 2.87 times higher than that of curcumin solution. At the same time, Cur-PMS enhances cell uptake via energy-dependent macrophagocyte transcellular and lymphatic transport pathways [40]. Schiborr et al. found that the bioavailability of micellar curcumin was 185 times higher than that of natural curcumin, and the T max of micellar curcumin was significantly shortened and the absorption efficiency was faster [114]. From the above results, it can be concluded that polymer micelle is one of the promising strategies for delivering curcumin.

6.3 Others

Kim et al. [115] prepared a curcumin oral microcapsule delivery system, and in vitro release experiments showed that the release curve of drug-loaded microcapsules had clear pH dependence, and microcapsules could effectively improve the stability of curcumin. Zeng et al. [116] studied the pharmacokinetics of curcumin microcapsules, and the results showed that the AUC value of curcumin microcapsules was significantly higher than that of original curcumin drugs. In summary, microcapsule preparations can improve the stability of drugs in vivo and significantly extend the validity of drugs. In addition, due to the different microcapsule materials, some dosage forms are affected by the in vivo environment, thereby changing their drug release. This characteristic of curcumin microcapsules guides R&D personnel according to the therapeutic purpose and the environment of the site of action, selecting the appropriate microcapsule material so that the drug can be accurately and effectively released, improving its efficacy.

7 Conclusion

Overall, despite the extensive pharmacological effects of curcumin, there are still numerous areas that need further study regarding its effects on the human body and pharmacokinetics. According to the extensive literature review, curcumin’s physical and chemical properties, such as low solubility, poor water solubility, and strong fat solubility, restrict its application, as well as its easy decomposition in vitro, poor absorption in vivo and fast metabolism, resulting in its low bioavailability for oral administration, which restricts its application in the treatment of diseases.

In recent years, more and more new formulations have achieved success in improving the bioavailability of curcumin, such as liposome preparations, nanoparticles, phospholipid system agents, microcapsules, new self-microemulsion preparations, PM, etc., mainly by improving or modifying the present state of curcumin (crystalline or amorphous), reducing particle size, and dispersing in carrier materials. However, these new formulations have increased curcumin bioavailability to a certain extent but still, they may not reach the minimum effective plasma concentration in vivo because of the chemical and physical properties of the vehicle, which may induce side effects, including organ toxicity or immune response. They also may exhibit uneven particle size distribution, particle agglomeration, non-specific absorption, and rapid removal from the blood circulation. Targeted preparations have been a hot spot in formulation research in recent years, and targeted preparations can be phagocytosed by designated cells or aggregate in specific organs, thereby avoiding first-pass effects and improving drug bioavailability. In addition, the self-defense of the intestinal mucus layer is one of the obstacles to the absorption of oral administration, so improving the mucus permeability of nano-carriers is of great significance in improving the efficacy of drug delivery and enhancing the oral bioavailability of curcumin. Pereira de Sousa et al. confirmed that the mucus permeability of simulated virus nanoparticles with high-density charged surfaces increased, which increased the possibility of continuous drug release and directional delivery of drug-coated nanoparticles to epithelial cells, among which the negatively charged nanoparticles had the highest permeability, which may provide hints for the follow-up study of curcumin oral drug delivery system [117].

BCS III and IV drugs are poorly permeable, and simply increasing the apparent dissolution rate of the drug substance or making it dissolve is often insufficient to achieve the desired bioavailability. Recent studies have found that the thermodynamic activity of drugs in solution is positively correlated with absorption, while supersaturation is positively correlated with thermodynamic activity [118]. Therefore, the study of supersaturated drug delivery systems has attracted much attention. Currently, no curcumin has been marketed as a clinical oral dosage form. However, studies of curcumin in nanoemulsion delivery systems have been shown to exhibit significant anti-tumor [119], anti-Alzheimer’s [120], antioxidant, and anti-inflammatory effects in animals or cells [121].

SMEDDS can significantly improve the bioavailability of insoluble Chinese medicine active ingredients, but low drug loading limits its wide application. Some studies have introduced hydrophilic polymers to construct the CUR-S-SMEDDS to improve drug bioavailability [89]. In the supersaturated state of the polymer, S-SMEDDS drugs mainly exist in the form of molecules, micelles, or nanoemulsion during the dissolution process, thus promoting drug transmembrane transport, which is a promising preparation to improve the bioavailability of water-insoluble and low-permeability drugs, and will also actively promote the application of curcumin oral dosage forms in clinical disease treatment. Overall, the study of the curcumin oral drug delivery system is still in its infancy, and further in vitro and in vivo tests are required in order to continue to develop and improve the delivery system.

  1. Funding information: This study was supported by the Educational Department in Jiangxi Province [grant nos. GJJ201819 and GJJ211805], Health Commission of Jiangxi Provincial [grant no. 202212007], Jiangxi Provincial Administration of Traditional Chinese Medicine [grant nos. 2022A137 and 2023B1287], Beijing Medical and Health Foundation [grant no. TYU046B], and Beijing Medical Award Foundation [grant no. YXJL-2022-0734-0294].

  2. Author contributions: Cheng Li and Lin Li: writing-original draft. Peng Zhang, Jiangwen Shen, and Weiwei Zha: project administration. Abid Naeem and Qingyun Zeng: data/evidence collection; visualization. Xulong Chen: funding acquisition; resources; writing-review and editing. Zhenggen Liao: conceptualization; supervision.

  3. Conflict of interest: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

  4. Informed consent: Informed consent has been obtained from all individuals included in this study.

  5. Ethical approval: The research related to humans complied with all the relevant national regulations and institutional policies, and in accordance with the tenets of the Helsinki Declaration, and has been approved by the author’s institutional review board or equivalent committee.

  6. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request

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Received: 2023-07-08
Revised: 2023-10-02
Accepted: 2023-11-17
Published Online: 2023-12-20

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/chem-2023-0171
Keywords for this article
curcumin; pharmaceuticals; bioavailability; oral administration
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