Which of the following instructions should an MA give to a patient when administering an enteric coated tablet?

14.4.1 Drug Release Test Methods for Enteric Coated Products

Enteric coating is a special case of a mechanism using erosion or dissolution of a coating to control release. An enteric coating resists dissolution under acidic conditions, but is freely soluble at the more basic conditions of the intestinal tract. Enteric coating may be used to protect acid-labile drugs or to avoid gastric distress induced by high concentrations of some drugs, such as aspirin. When a dosage form design includes an enteric coat, the dissolution test will include two stages: an acid stage of pH 1 to demonstrate the integrity of the enteric coat, and a drug release phase at a higher pH (USP <711>). The amount released in the acid stage is commonly limited to 10% or less of the labeled content. The release in the buffer stage will be determined by the design of the dosage form, with typical release criteria for an IR or extended-release as appropriate. The dual stage testing can be conducted using two vessels, one at acidic conditions, and the other basic. In this case, the dosage form will be transferred between the two vessels. This can be impractical for multiparticulate dosage forms (for which Apparatus III may be more appropriate), and adds a time-consuming step that is not conducive to the workflow of a quality control laboratory. When a single vessel is used, the acid stage can be conducted, for example, in 500 mL of medium, and then the initiation of the buffer stage begins with the addition of a prewarmed buffer concentrate that will result in the final desired pH.

Enteric-coated capsules

Enteric coating is a useful strategy for the oral delivery of drugs like insulin which rapidly degrade in the stomach, as it prevents the drug being released in the acidic conditions of the stomach before reaching the intestine.

Wu et al. synthesized insulin-loaded PLGA/Eudragit® RS enteric capsules coated with pH-sensitive hydroxypropyl methylcellulose phthalate (HP55), which could selectively release insulin from nanoparticles in the intestinal tract, instead of the stomach. This nanoparticle system induced a prolonged hypoglycaemic effect and the pharmacological availability was found to be approximately 9.2% [232].

The relative bioavailability of insulin in the enteric-coated capsule filled with chitosan/poly(gamma-glutamic acid) was found to be approximately 20% [233]. From this observation, it is clear that enteric coating protected insulin from the acidic environment of the stomach, thereby enhancing the intestinal absorption of insulin and providing a prolonged hypoglycaemic effect. Eudragit S100-coated Witepsol W35 with sodium salicylate as an absorption enhancer exhibited a blood glucose reduction of 25–30% and relative hypoglycaemia (RH) of about 12.5% relative to subcutaneous injection of insulin.

34.2.4.1 Delayed-release (enteric) coatings

Enteric coatings are primarily used for the purpose of:

Maintaining the stability of APIs that are unstable when exposed to the acidic conditions of the gastric milieu. Such API’s include erythromycin, pancreatin, and the class of proton pump inhibitors, such as omeprazole.

Minimizing the side effects (eg, nausea, and gastric irritation and bleeding) that can occur with APIs such aspirin and certain nonsteroidal inflammatory compounds.

Creating opportunities for “night-time dosing” strategies, where the intent is to allow the dosage form to be consumed at bed-time, and permit effective blood levels of the API to be attained just prior to waking.

Facilitating colonic drug delivery.

The functionality of enteric coatings is, for the most part, mediated by a change in pH of the environment to which the enteric-coated product is exposed. Enteric polymers remain unionized (and thus, insoluble) at low pH values, and begin to dissolve at a pH value of approximately 5.0–5.5. In addition, the functionality of enteric coatings can be greatly affected by many other factors, such as:

The nature of the API contained in the dosage form; this is especially true when that API is ionic in nature.

The quantity of coating applied; insufficient coating can result in ineffective gastric resistance, while too much applied coating can seriously delay drug release when the dosage form passes into the small intestine.

The presence of imperfections in the coating (eg, cracks, “pick marks,” etc.) that can also lead to reduced gastric resistance.

The chemistry of the polymer used (especially dissolution pH and dissolution rate at a given pH).

The influence of the in-vitro test conditions used (such as pH and ionic strength of the test medium; as well as the agitation rate used in the test).

Enteric film-coating polymers are essentially polyacids (see Fig. 34.16), and typically only dissolve in water above pH=5.0–6.0; these polymers are selected for their ability not only to form robust coatings that adhere strongly to tablet surfaces, but also to permit rapid drug release from dosage form once it passes from the stomach into the small intestine (see Fig. 34.17).

A list of commonly used enteric-coating polymers is given in Table 34.13, and these form the basis of enteric coating formulations used in either organic-solvent-based or aqueous-coating formulations. A breakdown of coating systems specially designed for aqueous-coating applications is shown in Table 34.14.

Table 34.13. Examples of Common Polymers Used in Enteric Coating Formulations

MA, Methacrylic acid; EA, Ethyl acrylate; MMA, Methyl methacrylate.

Table 34.14. Examples of Aqueous Enteric Coating Systems

MA, Methacrylic acid; EA, Ethyl acrylate.

While enteric-coated products have conventionally taken the form of tablets, recently a preference has been shown for coating multiparticulates because of their more consistent gastrointestinal transit characteristics. Enteric-coated capsules (especially one-piece softgels, containing garlic or fish oils used in nutraceutical applications) have also become quite commonplace.

Delayed-release (Enteric) Coatings

Enteric coatings are primarily used for the purpose of:

Maintaining the stability of APIs that are unstable when exposed to the acidic conditions of the gastric milieu. Such APIs include erythromycin, pancreatin, and the class of proton pump inhibitors, such as omeprazole.

Minimizing the side-effects (e.g., nausea, gastric irritation and bleeding) that can occur with certain APIs, such as aspirin and certain non-steroidal inflammatory compounds.

Creating opportunities for “night-time dosing” strategies, where the intent is to allow the dosage form to be consumed at bed-time, to permit effective blood levels of the API to be attained just prior to waking.

Facilitating colonic drug delivery.

The functionality of enteric coatings is, for the most part, mediated by a change in pH of the environment to which the enteric-coated product is exposed. That said, such functionality can be greatly affected by many factors, such as:

the nature of the API contained in the dosage form; this is especially true when that API possesses distinct pH effects of its own;

the quantity of coating applied; insufficient coating can result in ineffective gastric resistance, while too much applied coating can seriously delay drug release when the dosage form passes into the small intestine;

the presence of imperfections in the coating (e.g., cracks, “pick marks,” etc.) that can also lead to reduced gastric resistance;

the chemistry of the polymer used (especially dissolution pH, and dissolution rate at a given pH);

the influence of the in vitro test conditions used (such as pH and ionic strength of the test medium, as well as the agitation rate used in the test).

Enteric film-coating polymers are essentially polyacids (see Figure 33.16), and typically only dissolve in water above pH=5.0 to 6.0. These polymers are selected for their ability to:

form tough films;

adhere strongly to tablet surfaces;

facilitate ease of processing (pumping, spraying, atomization, and lack of tackiness);

permit rapid drug release from the dosage form once it passes from the stomach into the small intestine (see Figure 33.17).

A list of commonly-used enteric-coating polymers is given in Table 33.13, and these form the basis of enteric-coating formulations used in either organic solvent-based or aqueous coating formulations. A breakdown of coating systems especially designed for aqueous coating applications is shown in Table 33.14.

Table 33.13. Examples of common polymers used in enteric coating formulations

Table 33.14. Examples of aqueous enteric coating systems

While enteric-coated products have conventionally taken the form of tablets, more recently a preference has been shown for coating multiparticulates, because of the more consistent GI transit characteristics of this type of dosage presentation. Enteric-coated capsules (especially one-piece softgels containing garlic or fish oils used in nutraceutical applications) have also become quite commonplace.

14.1.4.4 Polymers for enteric coating

Polymers for enteric coatings are mainly used to resist the release of the API in the acidic gastric fluid in the stomach but allows for release above pH 5.0. They remain unionized at low pH and therefore remain insoluble. As the pH enhances in the GI tract on reaching the small intestine, the functional acidic groups of the enteric polymer are capable of ionization within the intestinal fluid and the polymer becomes soluble and swells (Tadmor and Gogos, 2013). Compatibility should exist between the polymer, coating solution, and the drug granule or tablet surface substrates. Enteric polymer stability should be managed and maintained alone and in coating solutions in such a way that the continuous film undergoes very minimal degradation over time. These polymers should have compatibility with the selected type of coating solution and the API, and the enteric polymer coating solutions should not require special equipment for film coating.

10.2.5 Pharmacology and the kinetics of aspirin

The normal aspirin tablet (without enteric coating), once orally taken, goes into dissolution in the stomach, releasing ASA. In the acidic medium of the stomach, the active ingredient ASA remains ASA (not a salt form) and is absorbed (as it is in the form of ASA) in the stomach and small intestine. Once the ASA is in the blood, it forms acetylsalicylate at the blood pH of 7.4; then its concentration slowly decreases as it starts to convert to salicylate and acetic acid (Figure 10.33). The metabolism of ASA to salicylate is achieved by the enzyme esterases, and the concentration of salicylate slowly increases until within less than an hour it reaches the peak concentration. The salicylate stays in the body for almost 24 hours afterwards.

Before excretion in urine, most salicylates are further converted to different polar water soluble products. About 75% of salicylates are conjugated with the amino acid glycine, forming salicyluric acid, and are then excreted via the kidney. About 10% of salicylates are conjugated with glucuronic acid as salicyl acyl glucuronide and salicyl phenolic glucuronide. A very small portion (1%) is hydroxylated to gentisic acid. The rest is eliminated as free salicylic acid.

Aspirin has been on the market for almost 110 years. Hundreds of scientists have discussed this drug, and research on it continues. Low dose aspirin (baby aspirin, 75 mg or 81 mg) has been developed for antiplatelet action, which is caused by the acetyl group of ASA.

4.1.2 Polymers based on cellulose derivatives

Cellulose derivatives are commonly used as enteric coatings due to their non-animal origin, cost-effectiveness, and swellable and hydrophilic character. They are commonly used in solid formulations on capsules, pills and tablets, but several nanoparticulated systems have also incorporated those materials in their formulation to achieve gastric protection. Hydrogel nanoparticles prepared by emulsion solvent evaporation have been prepared by combining HPMC and polyvinyl pyrrolidone (PVP) and applied in anti-malarial therapy in a Plasmodium berghei infected murine model [82]. Curcumin was loaded in the nanoparticles during the emulsification process and the resulting nanoparticles were administered to the infected animals by oral gavage. The results conclude that the formulation is biologically safe, non-genotoxic, and could be potentially used as an adjuvant therapy for malaria management.

HPMC is commonly used to control drug crystal growth and aggregation, and to achieve stable amorphous drug nanoparticles. HPMC is also capable of increasing the bioavailability of poorly-water soluble drugs due to the introduction of a large number of hydroxyl groups available for intermolecular hydrogen bond formation. HPMC is included in the synthesis of amorphous nanocrystals following the co-solvent precipitation technique, also called anti-solvent precipitation. Considering the crystalline equilibrium solubility of the parent drugs, amorphous crystals can be formed thanks to HPMC allow high supersaturation of the metastable state, acting as a crystallization inhibitor [83]. HPMC is also applied as dispersing phase in micronized drug formulations to increase the solubility of poorly soluble drugs (e.g., lercanidipine [83], lumefantrine [84], felodipine [85], etc.)

Yu et al. [86] showed an enhanced oral bioavailability and diminished food effect of lurasidone hydrochloride nanosuspensions using HPMC as stabilizer. Compared to the administration of the free drug as a suspension, the authors showed that the formulation containing HPMC exhibited a rapid and superior absorption irrespective of food intake. This nanoformulation had higher maximum plasma drug concentration (2.08- and 1.37-fold increase) in fasted and fed states, respectively. Using the liquid Anti-Solvent (LAS) precipitation technique and HPMC, Deshpande et al. [87] synthesized nanoparticles containing a BCS class-II anti-diabetic drug (Fig. 1). The nanoparticles were orally administered to rats to study the bioavailability of the hydrophobic nanoformulated drug compared to the administration of the free drug. The rate and extent of drug absorption in the gastrointestinal tract were improved when using the nanoparticulated system.

Nanofibers have also been prepared using cellulose derivatives to provide different drugs with gastroprotection. In this regard, cellulose acetate phthalate and HPMC phthalate have been electrospun together with magnetic nanoparticles, and indomethacin and aspirin as model drugs with the goal of achieving magnetically responsive drug loaded nanocomposites [88]. This pH-sensitive cellulose derivative can be dissolved at pH ≥ 5.5 thanks to reversible hydration or coacervate formation (hydrophobic aggregation) of the phthalyl substituents of the polymer, depending on the pH of the medium [88]. Zero-order kinetics were obtained for the model drugs in simulated intestinal fluid after degradation of the cellulose derivative at pH > 5.5.

Hydrophobically modified hydroxyethyl cellulose has been used to functionalize PLGA nanoparticles to provide them with neutral charge and to evaluate their fate in mice after oral administration [89]. The study revealed that the smaller the nanoparticles, the greater the uptake by the Peyer's patches. Also, the authors showed by confocal microscopy that the uptake of rhodamine-6G labeled nanoparticles by the Peyer's patches was superior when using hydroxyethyl cellulose functionalized nanoparticles compared to positively charged-modified nanoparticles.

Hydroxypropyl cellulose and hydroxyethyl cellulose have also been conjugated to fluoroquinolone-derived antibiotics for the delayed oral administration of these broad-spectrum antibiotics. In this regard, Amin et al. [90] showed that the oral administration of the nanoconjugates, and comparing to the effect of the free drug (i.e., ofloxacin) and to physical mixtures of the cellulose derivatives and the drug, resulted in a superior bioavailability for the preclinical model used. In the pharmacokinetic evaluation of concentration versus time, the areas under the curve from time zero to time infinity of the nanoconjugates were 2.1 and 2.3 times greater than those obtained for the free drug and for the corresponding physical mixture of ofloxacin with the cellulose derivative, respectively.

Interestingly, a comparative study of the biodistribution profiles of a highly lipophilic drug (i.e., RR01) using poly(methacrylic acid-co-ethyl acrylate) nanoparticles and a standard formulation of the drug and hydroxypropyl cellulose (reference formulation) after oral administration in dogs revealed a superior interindividual variability for the reference formulation [91]. Maximized bioavailability of the highly hydrophobic drug was reached when using the nanoformulation.

2.2 Delayed release formulations

Delayed drug release is commonly achieved via enteric coating of dosage forms such as tablets, capsules and multiparticulates [6, 7]. Typically, enteric coatings are pH activated, wherein they are insoluble at low pH but dissolved readily at higher pH (e.g., pH 5–7) [8]. The main function of an enteric coating is to protect the underlying dosage form and drug substance, enabling it to remain intact the gastric environment and instead dissolve and undergo drug release in the small intestine [9, 10]. Such strategies are used to prevent gastric mucosa irritation caused by certain drugs (e.g., non-steroidal anti-inflammatory drugs; NSAIDs), or to avoid the degradation of acid-labile drugs in GI fluid, such as enzymes or peptides [11]. Protection can be easily and readily provided with the application of polymeric coatings that are inherently insoluble at acidic pH values.

Enteric coatings can also be applied for the local treatment of intestinal diseases. For example, duodenal peptic ulcers are commonly treated locally against Helicobacter pylori with antibiotics like clarithromycin and amoxicillin in combination with acid blockers such as cimetidine or ranitidine. Medicines used to treat inflammatory bowel diseases (e.g., budesonide) also use delayed-release coatings using polymers to enable targeted in specific regions in the GI tract.

However, several studies have shown that enteric-coated products designed to release in the proximal small intestine do not disintegrate rapidly after emptying from the stomach [12]. Indeed, it was shown in vivo that such products can take up to 2 h to disintegrate in the human small intestine [13–15]. Drug release will then occur in the distal small intestine and cause a delayed response to medication, and potentially reduce the bioavailability of those drugs with an absorption window in the upper small intestine. To overcome this challenge, and to ensure drug release at the upper small intestine, a novel double-layer technology marketed under the brand name DuoCoat was developed (Fig. 7).

The outer layer of the DuoCoat technology is composed of a regular EUDRAGIT L 30 D-55 enteric coating that protects the dosage form during upper gastric transit and starts to dissolve at the pH of the upper small intestine (pH 5.5). The inner layer is a modified EUDRAGIT L 30 D-55 coating which has been neutralized by the addition of sodium hydroxide [16]. When the DuoCoat formulation enters the duodenum, the environmental pH value increases and at pH 5.5 the outer EUDRAGIT coating starts to swell and dissolve [17]. Intestinal fluid then penetrates into the system and reaches the neutralized inner coating layer, causing rapid dissolution of the coating and hence drug release [7]. Results from both in vitro biorelevant dissolution tests and in vivo human gamma scintigraphy studies showed that the the DuoCoat formulations released over twice as fast compared with a standard enteric polymer and demonstrated less variable results (Fig. 8) [7, 18].

2.3.3 Methacrylic acid copolymers for enteric drug release

Methacrylic acid copolymers are extensively used for enteric coatings. Eudragit L 30 D 55 is a latex dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate (Fig. 3.4), with free carboxyl groups in a ratio of 1:1 with the ester groups [39]. The carboxylic groups begin to ionize in aqueous media at pH 5.5 and above, being the polymer resistant to acidic media but soluble in intestinal fluid. Eudragit L 30 D 55 has an MFT of 25°C and with the addition of 10% TEC it is reduced to 0°C [80]. Curing temperature and time were found to have an effect on adhesion of Eudragit L 30 D 55 coating to a tablet substrate [93]. The adhesion increased after curing at 40°C and 60°C, and was equilibrated within 4 h. This was attributed to an increase of interaction between the polymer and substrate resulting from a more complete film formation. Upon thermal curing, the solvent evaporates and coalescence leads to an increase of contact areas for binding sites to occur between the polymer and the substrate. Storage of coated dosage forms at elevated temperatures and humidity can have an impact on adhesion of the polymer to the substrate due to increased internal stress [20, 25]. Decreased adhesion between the Eudragit L 30 D 55 coating and tablet substrate was observed, irrespective of the storage conditions [20]. At elevated humidity and despite the fact that water plasticizes the polymer [21], the decrease of adhesion was a result of swelling of the film and tablet core leading to internal stress in the polymer. In the absence of humidity, adhesion also decreased due to internal stress in the coating resulting from moisture loss that causes the film to be more brittle. At high temperatures, water evaporates, leading to a decrease in elongation at adhesive failures and adhesive toughness.

Oral and Transdermal Breast Cancer Vaccine

Whole cell vaccine was formulated into microparticles using enteric coating polymers. The microparticle formulation is optimized by using a different combination and concentration of polymers. These microparticles were administered both orally and transdermally. In vitro and in vivo studies were carried out to evaluate the humoral and cellular response against the vaccine loaded microparticles.

In vitro experiments showed that spray-dried microparticles provided protection against gastric conditions and controlled the release for about six hours. Vaccine-loaded particles were nontoxic to normal cells. The majority of the particles were in the size range of 1 to 5 μm. In vivo studies proved that both oral and transdermal groups were able to prevent and delay tumor growth compared to the control groups receiving blank microparticles. Flow cytometry results for the immune organs revealed that animals receiving the vaccine showed higher CD4+ T cells, CD4+, CD161+, and CD8+ levels than the control groups. A higher expression of these markers shows that the vaccine particles were able to induce a better immune response to fight against the cancer cells. Efficacy of vaccine microparticles could be seen with the tumor volume data (Figure 5.7).109 Therapeutic applications of vaccine microparticles are currently being evaluated. The therapeutic efficacy of these vaccine microparticles is reportedly enhanced when given in combination with cytotoxic drug and adjuvants.