Formulation and Evaluation of Enteric Coated Aspirin Capsules 1 Enteric polymer coatings create a protective gastro- resistant barrier that prevents oral medication from dissolving or disintegrating in the stomach before it reaches the small intestine. Although enteric polymer coatings long have been used in tablet formulations for controlled drug delivery systems, little research has been conducted to evaluate coatings for capsule drug formulations. Enteric coating may be necessary to either protect acid-sensitive Active Pharmaceutical Ingredient (API) from gastric conditions, or to create a controlled release drug delivery system. Some APIs degrade in low pH conditions, and typically would be destroyed in the harsh environment in the stomach. This creates a need to protect sensitive APIs used in oral dosage forms. Additionally, enteric coatings can be formulated specifically to dissolve at higher pH conditions than what exists in the stomach, which is key for targeted drug delivery. The stomach, small intestine and large intestine each have very constant and specific physiological pH conditions. As an oral solid dose drug moves through the digestive system, its solubility can change based upon pH conditions it is exposed to, and therefore its solubility changes based on location. 2 3 Optimizing release based on location allows scientists to design drugs targeted to release, for example, only at the large intestine. Often, however, the solubility of an API is not designed specifically for a desired location and the drug will release prior to reaching the optimal location for dosing. Thus, enteric coatings can allow formulators to control the characteristics of a drug beyond what the API itself allows. Additonally, some enteric coatings function only to protect acid- sensitive API molecules. The conditions of the stomach are harsh, with a very low pH of ~1.2, and many novel APIs can be destroyed in these conditions. This poses an issue for formulators when a novel drug exists with essential therapeutic qualities, but the drug cannot withstand the environmental conditions of the stomach, which prevents it from becoming an oral solid dose drug. Enteric coatings are not soluble in the low pH conditions of the stomach, so they serve as a barrier around API to prevent it from being destroyed before it can release and dose the patient. The coating can be selected and formulated to dissolve and release the API once conditions are suitable for the drug to dose, and may degrade acid sensitive molecules. Development of a capsule dosage form could provide a novel system for controlled drug delivery of new drug formulations. The ability to control the type of coating and the amount applied to the capsule would allow for greater precision in formulations. Additionally, polymer coatings are continuously evolving, and development of a consistent application methodology would allow for rapid adaptations for new formulations. 4 5 Objectives For this study, a preliminary batch of enteric-coated capsules was prepared After completing this preliminary testing, a more thorough investigation was and allowed to sit in dissolution vessels containing acidic media for more performed to assess the capability and efficency of the enteric-coating on than six hours. capsule formulations. After that period of time, no visible release of drug product into the media was Three formulations of aspirin capsules using two types of excipients were observed, but the capsules did display ballooning in the vessels. Ballooning would prepared. Evaluation of initial conditions would provide clear information for a typically indicate moisture uptake into the capsules, resulting in their expanded size. path forward as to what additional information would be required. An API only blend was prepared as a control in addition to two API and excipient blends. In this situation, however, no visible openings were observed in the capsules that had been exposed to acidic media. This suggested the possibility that the acidic The excipients utilized were chosen based on their propensity to absorb water. media was permeating the coating on the capsules, and was coming into contact This parameter was selected for its clear ability to demonstrate the permeability with the Active Pharmaceutical Ingredient (API) inside. Unfortunately, this would of the coating. If water managed to make it through the capsule coating, this indicate that the enteric coating was not functioning as a nonpermeable barrier to may demonstrate a failure of the coating to properly seal the capsule from acidic media. In vivo, this would result in exposure of API prior to the desired time acidic conditions. High-moisture excipients would provide a clear example of or location for targeted drug delivery. The presence of this moisture could affect water uptake due to their ability to readily absorb water. If water was able to bioavailability of enteric-coated hard gel capsules. make it through the coating, it would completely be absorbed by the excipient and could be recovered during Karl Fischer water content tesing. A low-moisture Therefore, it was critical to demonstrate the ability of the enteric coating to properly excipient would provide a contrast to the high-moisture excipient and would be seal and protect capsule contents through various analytical tests. a source of control of natural humidity conditions. Addionally, if a high uptake of moisture was observed in the low-moisture excipient, this would clearly indicate a high presence of water and a clear failure of the coating to seal the capsule. 6 7 Mannitol was chosen as the low-moisture excipient. Mannitol is a popular The three aspirin capsule exipient in pharmaceutical science because of its physicochemical formulations were: characteristics such as a low hygroscopicity; a strong inertness towards 1. Capsules containing asprin only, both the API and the patient’s body; its good compactibility; and the ability to produce extremely robust tablets. 2. Capsules containing 50:50 aspirin and mannitol, and The low hygroscopicity of the excipient prevents severe moisture uptake 3. Capsules containing 50:50 and keeps the tablets or capsules dry, preventing premature degradation aspirin and MCC. of active. Ideally, an excipient needs to be inert to both the patient’s body as well as other ingredients in the formulation. If the excipient is All were prepared and coated not inert, it may cause undesired reactions, preventing bioavailability for with the enteric coating. the patient or causing additional impurities to form. Mannitol’s ability to compact well allows it to be used in many tablet formulations as the oral dose is able to be pressed without becoming friable, which helps produce robust tablets. Microcrystalline cellulose (MCC) was chosen as a high-moisture excipient. Microcrystalline cellulose is a versatile and user-friendly excipient in its characteristics, grades and physical properties. It has a high compressibility to help produce robust tablets that resist breaking. MCC also is an excellent disintegrant, which ads in disintegration and dissolution of capsules and tablets which, in turn, allows for quick dispersion of the drug. 8 9 After preliminary testing of enteric-coated capsules, the ballooning observed by the team raised concerns about the ability of the coating to properly seal capsules and prevent moisture from coming into contact with the API. The following evaluation of both stressed and unstressed capsules was made to compare values and rule out the possibility of moisture permeating the capsules and degrading contents. The aim of this project was to demonstrate the suitability of an enteric polymer coating for capsule drug formulations. Preliminary testing was performed to evaluate and develop dissolution, assay, and water content methods to assess the impact of acidic conditions on drug recovery. These tests were chosen based on their ability to demonstrate preliminary functional characteristics required by an oral solid dosage. Typically, dissolution is performed to demonstrate the appropriate release of API from the capsule or tablet. For the purpose of this experiment, dissolution testing only needed to demonstrate the Methods ability of the formulation to not release into the media in order to demonstrate the suitability of the coating. Future experiments would be developed to formulate a release media into desired conditions. 10 11 Assay was chosen in order to assess Generation of an HPLC method for For each sequence performed on the UV, Coulometric titration was utilized for the the consistency of label claim between quantitation would require more intensive system suitability was calculated using formulation containing neat API, with stressed and unstressed capsules. method development and would not five replicate standards as well as regular titrations performed in Coulomat AG and Ideally, a consistent label claim provide any additional information at this reading of standards throughout the Coulomat CG. Formulations containing between stressed and unstressed phase of the project. Additionally, UV-Vis run. The percentage of relative standard excipient were tested via volumetric capsules would be determined, which allows for a quick turnaround time for data deviation for absorbance values was titration. Methanol was used as solvent and would indicate the consistent potency generation due to the ability to analyse verified to be below 1.0% for both replicate product was titrated using Composite 5. of API after exposure to media. several samples in only a few minutes. standards and all standards for each sequence. A blank reading of dissolution Capsule contents were assayed using a Finally, water content was chosen to Standards were made in a diluent media or diluent only was also performed composite of n=3 capsules. The unstressed provide an assessment to the permeability (acetonitrile: formic acid, 99:1) and scans to prove there was no interference with capsules were weighed and cut open. A of coating. A completely impermeable taken on the UV-Vis spectrophotometer quantitation of the main peak. homogeneous composite was prepared coating would demonstrate identical water from 200 to 400 nm to evaluate the from contents.