As a commonly used oral iron supplement in clinical practice, ferrous gluconate is a first-line medication for treating iron deficiency anemia (IDA). Its advantages include high bioavailability (20%–30% higher than ferrous sulfate) and low gastrointestinal irritation (weaker corrosive effect on gastric mucosa compared to other inorganic iron supplements). However, its inherent "metallic rust taste" and "astringent taste" are core bottlenecks leading to poor adherence among patients—especially children, pregnant women, and those requiring long-term medication. Approximately 40% of patients self-reduce doses or discontinue treatment due to unbearable taste, directly affecting iron supplementation efficacy (prolonging hemoglobin recovery time by 30%–50%) and even causing anemia recurrence. Therefore, reducing adverse taste experiences through scientific taste improvement strategies (e.g., taste-masking technology, dosage form optimization, and compound formulation) has become a key approach to enhance ferrous gluconate adherence, as well as a critical guarantee for the success of clinical iron supplementation therapy.

I. Causes of Ferrous Gluconate’s Adverse Taste: Why It Becomes an Adherence Barrier

The adverse taste of ferrous gluconate stems from its molecular structure and solubility characteristics, specifically manifesting as dual taste stimulation of "metallic taste and astringent taste." Moreover, its release process in the oral cavity and gastrointestinal tract exacerbates this discomfort, leading to "dual psychological and physiological resistance" in patients during medication:

1. Metallic Taste Release at the Molecular Level

The Fe²⁺ ions in ferrous gluconate easily bind to proteins (e.g., mucin) in oral saliva, forming "Fe²⁺-protein complexes." These complexes activate metallic taste receptors (e.g., TAS2R43 receptors) in oral taste buds, producing a typical "rust-like metallic taste." The intensity of this taste signal is positively correlated with Fe²⁺ concentration. At a conventional oral dose (0.3–0.6 g ferrous gluconate per day, containing approximately 35–70 mg Fe²⁺), the metallic taste score reaches 7–8 points (on a 10-point scale), far exceeding the human acceptable threshold (below 3 points).

2. Astringent Taste Production During Dissolution

Ferrous gluconate dissolves rapidly in the moist oral environment. Fe²⁺ interacts with lipids and proteins on the surface of oral mucosa, disrupting the lubricating layer of the mucosa, causing mucosal contraction, and generating an "astringent taste." This physical stimulation leads to oral discomfort (e.g., dry mouth, tight mucosa). Especially when patients do not drink water promptly after medication, the astringent taste can persist for 5–10 minutes, further intensifying the patient’s negative experience.

3. "Taste Association" with Gastrointestinal Discomfort Extension

Although ferrous gluconate causes less gastrointestinal irritation than ferrous sulfate, some patients still experience mild nausea and bloating after medication. This gastrointestinal discomfort forms a "taste-physiological response association" with the adverse taste in the oral cavity: when patients take medication next time, merely smelling or tasting the drug can trigger anticipatory nausea, leading to "conditioned reflex resistance." This issue is particularly prominent in children, who may refuse medication as a result.

II. Core Strategies for Ferrous Gluconate Taste Improvement: From Taste Masking to Dosage Form Optimization

Targeting the causes of adverse taste, current taste improvement strategies focus on three directions—"blocking Fe²⁺ contact with taste receptors," "neutralizing adverse taste signals," and "optimizing drug release pathways"—and achieve a balance between "taste enhancement and efficacy preservation" through technological innovation:

(I) Taste-Masking Technology: Physical/Chemical Means to Block Adverse Taste

Taste-masking technology is the most direct way to improve taste. By forming a "barrier layer" on the surface of drug particles or reacting with taste-masking agents, it reduces Fe²⁺ contact with oral taste buds, mainly including the following three types:

1. Coating-Masking

Using "film coating" or "microcapsule coating" technology, an inert polymer film (e.g., hydroxypropyl methylcellulose, HPMC; ethyl cellulose, EC) is formed on the surface of ferrous gluconate particles. This film is insoluble in the oral cavity (pH 6.8–7.4) and only dissolves and releases Fe²⁺ in the gastrointestinal tract (pH 1.2–6.8). For example, ferrous gluconate particles coated with HPMC E5 have a metallic taste score reduced from 8 to below 2 points in the oral cavity, and the coating does not affect drug bioavailability (no significant difference in hemoglobin increase rate compared to uncoated formulations). To further enhance taste-masking effects, sweeteners (e.g., sucralose, stevia glycosides) can be added to the coating film to neutralize residual mild astringency through sweet signals, creating a positive taste experience of "sweet taste with no metallic taste."

2. Complexation-Masking

Complexing agents (e.g., citric acid, EDTA-2Na) are used to form stable complexes with Fe²⁺, altering the chemical form of Fe²⁺ to prevent it from activating metallic taste receptors. For example, adding 0.5%–1% citric acid to ferrous gluconate solutions: the carboxyl groups of citric acid form "Fe²⁺-citric acid complexes," reducing the metallic taste score from 7 to 3 points. Moreover, these complexes can slowly dissociate and release Fe²⁺ in the gastrointestinal tract, with a bioavailability retention rate of over 90%. Note: The dosage of complexing agents must be strictly controlled (e.g., EDTA-2Na dosage >2% will affect Fe²⁺ absorption) to avoid excessive complexation leading to reduced efficacy.

3. Adsorption-Masking

Porous excipients (e.g., cyclodextrin, gum arabic) are used to adsorb Fe²⁺ into their pores, reducing Fe²⁺ release in the oral cavity. For example, mixing β-cyclodextrin with ferrous gluconate at a 1:1 ratio: the hydrophobic cavity of β-cyclodextrin can adsorb Fe²⁺ to form "inclusion complexes," reducing the astringent taste score from 6 to 2 points in the oral cavity. Additionally, these inclusion complexes can rapidly dissociate under gastric acid stimulation in the gastrointestinal tract, without affecting Fe²⁺ absorption rate.

(II) Dosage Form Optimization: Changing the Way Drugs Contact the Oral Cavity

Traditional ferrous gluconate dosage forms (e.g., ordinary tablets, oral solutions) easily cause taste discomfort due to large contact area and long contact time with the oral cavity. Dosage form innovation can fundamentally reduce this contact, mainly including:

1. Chewable Tablets/Effervescent Tablets

Sweet matrix neutralizes taste: Ferrous gluconate is formulated into chewable tablets using sweet excipients (e.g., mannitol, isomalt) as the matrix (accounting for 60%–70% of the tablet weight). These excipients release sweetness during chewing, masking the metallic taste of Fe²⁺. Meanwhile, flavoring agents such as menthol and lemon essence are added to further improve the taste experience. For example, the patient acceptance rate of lemon-flavored ferrous gluconate chewable tablets reaches 85%, significantly higher than the 50% of ordinary tablets.

Effervescent tablets reduce direct contact: Effervescent tablets are dissolved in water before drinking, reducing direct contact between the drug and the oral cavity. Additionally, carbon dioxide produced during effervescence can slightly numb taste buds, reducing sensitivity to metallic taste—making them suitable for children and patients with swallowing difficulties.

2. Sustained-Release Capsules/Granules

Delayed release reduces oral irritation: Ferrous gluconate is formulated into capsules or granules using sustained-release technology. The drug does not dissolve immediately after entering the oral cavity but quickly passes through the esophagus into the gastrointestinal tract. For example, the shell of enteric-coated sustained-release capsules is insoluble in the oral cavity (pH 7.0) and only dissolves and releases the drug in the stomach (pH 1.2). The oral contact time is shortened from 30 seconds to less than 5 seconds, and the residual rate of metallic taste is reduced to below 10%. For pediatric patients, sustained-release granules can be mixed with a small amount of milk or juice (selecting beverages that do not affect Fe²⁺ absorption, such as apple juice, and avoiding strong tea or coffee) for administration, further reducing taste discomfort.

3. Oral Fast-Dissolving Films

Rapid passage through the oral cavity: Ferrous gluconate is formulated into oral fast-dissolving films with a thickness <100 μm. These films dissolve rapidly (within 30 seconds) in the oral cavity and pass through the esophagus, significantly shortening the contact time between the drug and the oral cavity. By adding polyvinyl alcohol (film-forming material) and sucralose (sweetener) to the film, rapid dissolution is ensured while transient metallic taste is masked by sweetness. Patient adherence is 40% higher than that of oral solutions, making them particularly suitable for children and elderly patients with swallowing difficulties.

(III) Compound Formulation: Synergistically Improving Taste and Efficacy

Compound formulation of ferrous gluconate with other ingredients (e.g., vitamin C, amino acids) not only improves taste through interactions between components but also enhances Fe²⁺ bioavailability, achieving dual optimization of "taste and efficacy":

1. Vitamin C: Synergistic Taste Masking and Absorption Promotion

The acidic taste of vitamin C (ascorbic acid) can neutralize the astringency of ferrous gluconate, and its reducing property can prevent Fe²⁺ oxidation to Fe³⁺ (Fe³⁺ has a stronger metallic taste). For example, in tablets compounded with ferrous gluconate and vitamin C at a 5:1 ratio, the metallic taste score is reduced from 8 to 3 points. Additionally, vitamin C promotes Fe²⁺ absorption in the intestinal tract (increasing absorption rate by 20%–30%), achieving dual benefits. Clinical studies show that patients taking compound formulations have a 15% shorter hemoglobin recovery time than those taking ferrous gluconate alone, with a 50% increase in adherence.

2. Amino Acid Complexation: Improving Taste and Stability

Ferrous gluconate is compounded with amino acids such as glycine and lysine. The amino and carboxyl groups of amino acids can form "Fe²⁺-amino acid complexes," which have no metallic taste and high stability in the gastrointestinal tract (not easily affected by phytic acid or tannic acid). For example, the metallic taste score of ferrous gluconate-glycine compound oral solutions is only 1–2 points, with a patient acceptance rate of 90%. Moreover, their bioavailability is 35% higher than that of single-ingredient formulations, making them suitable for patients with chronic anemia requiring long-term medication.

III. Impact of Taste Improvement on Patient Adherence: Clinical Data Verification

The core goal of taste improvement strategies is to enhance patient adherence and thereby ensure iron supplementation efficacy. Multiple clinical studies have confirmed a positive correlation between taste improvement, adherence, and efficacy:

1. Pediatric Patient Population

Children are a high-risk group for IDA and the most sensitive to taste. A study involving 300 pediatric IDA patients showed:

Patients taking ordinary ferrous gluconate oral solutions had an adherence rate of only 45% within 4 weeks (due to taste-related discontinuation), with an average hemoglobin increase of 10 g/L.

Patients taking coated taste-masked chewable tablets had an adherence rate increased to 88%, with an average hemoglobin increase of 25 g/L—efficacy was significantly superior to ordinary formulations.

2. Pregnant Women Population

Pregnant women are prone to "drug aversion" due to increased taste sensitivity during pregnancy. A survey of 200 pregnant women with gestational IDA showed:

Pregnant women taking unmasked ferrous gluconate tablets had a self-discontinuation rate of 38%, with an anemia correction rate of only 52%.

Pregnant women taking lemon-flavored effervescent tablets had a discontinuation rate reduced to 12%, with an anemia correction rate increased to 85%—and no exacerbation of nausea or vomiting due to taste.

3. Long-Term Medication Population

Patients with chronic iron deficiency anemia caused by diseases such as chronic kidney disease and peptic ulcers require long-term (3–6 months) iron supplementation. A follow-up study of 150 patients on long-term medication showed:

Patients taking ordinary ferrous gluconate had an adherence rate of only 30% within 6 months, with an anemia recurrence rate of 40%.

Patients taking sustained-release capsules (coated taste-masked) had an adherence rate increased to 75%, with an anemia recurrence rate reduced to 15%—and the incidence of gastrointestinal discomfort decreased from 25% to 8%.

IV. Precautions for Taste Improvement: Balancing Taste and Efficacy

In improving the taste of ferrous gluconate, it is necessary to avoid compromising drug efficacy in the pursuit of better taste. Core precautions include:

1. Avoid Absorption Reduction Due to Excessive Taste Masking

Excessively thick coatings or excessive doses of complexing agents can cause delayed Fe²⁺ release or incomplete dissociation in the gastrointestinal tract, affecting absorption. For example, when the thickness of ethyl cellulose coating exceeds 50 μm, Fe²⁺ absorption rate decreases by more than 30%. Therefore, optimal taste-masking parameters must be determined through in vitro dissolution tests (e.g., dissolution rate >80% in pH 1.2 hydrochloric acid solution within 30 minutes) and in vivo bioavailability studies.

2. Select Safe Taste-Masking Agents and Excipients

Special populations such as children and pregnant women have higher requirements for excipient safety. It is necessary to avoid excipients that may cause allergies (e.g., certain artificial flavors) or affect nutrient absorption (e.g., high-concentration phytic acid). For example, pediatric formulations should prioritize natural sweeteners (e.g., stevia glycosides) and flavors (e.g., orange essence), and avoid aspartame and artificial colors.

3. Adjust Schemes Based on Individual Patient Differences

Different patients have varying sensitivity and preferences for taste (e.g., children prefer sweetness, while adults prefer tasteless or mint flavors). Multiple taste-improved dosage forms should be provided for selection: for example, chewable tablets and effervescent tablets for children, and sustained-release capsules and ordinary tablets for adults. This meets personalized needs and further enhances adherence.

The taste improvement of ferrous gluconate is not merely "taste optimization" but rather reduces patient medication resistance from both physiological and psychological perspectives through "taste-masking technology to block adverse stimulation, dosage form innovation to reduce contact time, and compound formulation to synergistically enhance efficacy"—ultimately improving adherence. Clinical data shows that ferrous gluconate formulations with taste improvement can increase patient adherence by 40%–60%, with significantly better anemia correction rates and recurrence control effects than traditional formulations.

With the development of pharmaceutical technology, future taste improvement of ferrous gluconate will move toward "more precision and personalization." For example, 3D printing technology can be used to prepare "dose-adjustable and flavor-customizable" formulations, or natural excipients with better biocompatibility (e.g., plant extracts) can be used for taste masking. While ensuring efficacy, this will further enhance the patient’s medication experience, providing more solid support for the standardized treatment of iron deficiency anemia.