Delayed release oral pharmaceutical composition

Abstract

This document discloses compositions and methods for treating inflammatory bowel disease. According to some embodiments, the compositions and methods involve the use of delayed-release capsule formulations containing a mesalazine layer, a hyaluronic acid layer, and at least one coating layer.

Description

Technical Field

[0001] This disclosure relates to delayed-release pharmaceutical compositions and methods for treating and / or preventing inflammatory bowel disease (IBD) in patients. Specifically, the delayed-release pharmaceutical compositions described herein contain mesalazine, and the methods involve using such delayed-release capsule formulations to treat and / or prevent IBD in patients. Prior Technology

[0002] Ulcerative colitis (UC) is a chronic inflammatory bowel disease that causes inflammation and ulceration in the digestive tract, particularly the colon and rectum. Ulcerative colitis primarily affects the innermost lining of the colon and rectum.

[0003] Mesalamine, also known as 5-aminosalicylate, is a medication used to treat inflammatory bowel diseases, including ulcerative colitis. Effective treatment of ulcerative colitis typically requires delivery of mesalamine to the lesion site in the colon or rectum. Traditionally, this is achieved through oral or rectal administration, the latter being via suppositories or enemas. However, rectal administration is generally less convenient and less well-tolerated by patients compared to oral administration. Furthermore, suppositories only act on the rectum, and enemas typically only cover the left side of the colon, limiting the effectiveness of these methods in treating the right side of the colon and the transverse colon.

[0004] On the other hand, oral administration also has its limitations, as mesalazine may be absorbed in the digestive tract before reaching the colon or rectum. To address this issue, several oral "delayed-release (DR)" or "extended-release" mesalazine formulations have been developed. Delayed-release mesalazine releases the drug at the most needed site in the colon and / or rectum, while extended-release mesalazine releases the drug gradually throughout the colon and rectum. Currently, there are five oral mesalazine products approved by the U.S. Food and Drug Administration (FDA): APRISO® (extended-release capsules), ASACOL HD® (delayed-release tablets), DELZICOL® (delayed-release capsules), LIALDA® (delayed-release tablets), and PENTASA® (extended-release capsules). However, these oral mesalazine products still have their drawbacks. For example, the capsule sizes of DELZICOL® and LIALDA® are approximately 25.3 mm and 23.4 mm, respectively, which may be difficult for some patients (such as children or those with dysphagia) to swallow. Furthermore, delayed-release products such as ASACOL HD®, DELZICOL®, and PENTASA® typically require at least three daily doses with a total daily dose of at least 2 grams, which may lead to poor patient adherence. Therefore, existing oral mesalazine formulations still suffer from unsatisfactory drug release profiles and bioavailability, thus limiting their efficacy in treating chronic diseases such as ulcerative colitis.

[0005] In view of this, there is an urgent need in the art to propose a delayed-release pharmaceutical composition that has ideal pharmacokinetic properties and can improve patient compliance. Summary of the Invention

[0006] This summary is intended to provide a simplified overview of the disclosure to enable the reader to gain a basic understanding. It is not a complete summary of the disclosure and is not intended to identify key / critical elements of the embodiments or define the scope of the invention. The main purpose of this summary is to present certain concepts disclosed herein in a simplified form as a prelude to the embodiments described below.

[0007] One aspect of this disclosure relates to a delayed-release capsule formulation. The advantages of the proposed delayed-release capsule formulation include providing desirable pharmacokinetic properties to improve the delivery efficiency and bioavailability of the active ingredient. Furthermore, the proposed delayed-release capsule formulation also has a more compact size, thereby improving patient adherence.

[0008] According to certain embodiments, the delayed-release capsule formulations described herein comprise a capsule shell and a plurality of particles contained therein, wherein each particle comprises: (a) an inert core comprising about 10–20 wt% of the total weight of the particles; (b) a mesalazine layer disposed on the surface of the inert core, wherein the mesalazine layer comprises about 40–65 wt% of the total weight of the particles and contains about 80–99 wt% mesalazine; (c) a hyaluronic acid layer disposed on the surface of the mesalazine layer, wherein the hyaluronic acid layer comprises about 3–15 wt% of the total weight of the particles and contains about 51–70 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof; and (d) at least one coating layer disposed on the surface of the hyaluronic acid layer, wherein the at least one coating layer comprises about 15–30 wt% of the total weight of the particles.

[0009] According to certain embodiments of this disclosure, the inert core includes a filler.

[0010] According to certain embodiments of this disclosure, the mesalazine layer also includes at least one adhesive, the amount of which accounts for about 0.5-15 wt% of the weight of the mesalazine layer.

[0011] According to certain embodiments of this disclosure, the hyaluronic acid layer further comprises at least one adhesive, the content of which accounts for about 30-49 wt% of the weight of the hyaluronic acid layer.

[0012] According to certain embodiments of this disclosure, the hyaluronic acid layer comprises a high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof and a low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof, in an amount of approximately 1:5 to 5:1. Specifically, the high molecular weight hyaluronic acid or its pharmaceutically acceptable salt has a viscosity-average molecular weight (Mv) of 2000 kDa to 2500 kDa, and the low molecular weight hyaluronic acid or its pharmaceutically acceptable salt has an Mv of 300 kDa to 500 kDa.

[0013] According to certain embodiments of this disclosure, at least one coating layer comprises an enteric coating layer, which includes one or more copolymers.

[0014] According to certain embodiments of this disclosure, the enteric coating layer further comprises at least one plasticizer.

[0015] According to certain embodiments of this disclosure, at least one coating layer further includes an isolation layer disposed between the hyaluronic acid layer and the enteric coating layer, and includes one or more copolymers.

[0016] According to certain embodiments of this disclosure, the isolation layer further comprises at least one plasticizer.

[0017] According to certain embodiments of this disclosure, when the delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide a mean peak plasma concentration (Cmax) of mesalazine of at least 400 ng / mL.

[0018] According to certain embodiments of this disclosure, when a delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide a mean plasma area under the curve (AUC6-12) of mesalazine of at least 600 ng·hr / mL over 6–12 hours.

[0019] According to certain embodiments of this disclosure, when a delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide an average AUC0–t of at least 1,800 ng·hr / mL for mesalazine.

[0020] According to certain embodiments of this disclosure, the inert core contains 60 mg to 100 mg per capsule, the mesalazine layer contains 100 mg to 450 mg per capsule, the hyaluronic acid layer contains 30 mg to 60 mg per capsule, and at least one enteric coating contains 80 mg to 100 mg per capsule.

[0021] Another aspect of this disclosure relates to a method of treating and / or preventing IBD in patients of need using the aforementioned delayed-release capsule formulation, wherein, after oral administration of the delayed-release capsule, the capsule provides the desired pharmacokinetic properties in the patient.

[0022] According to some embodiments of this disclosure, the method includes the step of administering the delayed-release capsule formulation presented herein to a patient at an effective dose.

[0023] Other aspects of this disclosure also include the following: the use of the delayed-release capsule formulations described herein in the manufacture of medicaments for the prevention and / or treatment of IBD, and delayed-release capsule formulations for the prevention and / or treatment of IBD.

[0024] After referring to the following embodiments and accompanying drawings, those skilled in the art will readily understand the many features and advantages of this disclosure. Simple Explanation of the Diagram

[0025] To make the above and other objects, features, advantages, embodiments, appended claims, and drawings of the present invention more apparent and understandable, the accompanying drawings are described below: Figures 1A and 1B show the mean plasma concentration of mesalazine versus time in 30 healthy human subjects under fasting conditions when treated with treatments A, B, and C. Figure 1A shows the linear scale, and Figure 1B shows the logarithmic scale. Implementation

[0026] The embodiments disclosed below, together with the accompanying drawings, are intended to illustrate the examples presented herein and should not be considered as the only form for constructing or implementing the embodiments disclosed herein. The embodiments cover the functionality of various specific embodiments and the method steps and their order for constructing and operating these specific embodiments. However, other specific embodiments may also be used to achieve the same or equivalent functionality and sequence of steps.

[0027] For ease of explanation, certain terms used in the specification, embodiments, and accompanying claims are summarized herein. Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meaning as understood and commonly used by one of ordinary skill in the art to which this invention pertains. Specifically, unless conflicting with the context, singular nouns used herein encompass their plural forms, and vice versa. Furthermore, in this specification and the claims, expressions such as "at least one" and "one or more" have the same meaning, both representing a total of one, two, three, or more.

[0028] While the numerical ranges and parameters used to define the broader scope of this invention are approximate, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual testing methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" means that the actual value falls within the acceptable standard error of the average value, as determined by those skilled in the art to which this invention pertains. It is understood that, except in experimental examples, or unless explicitly stated otherwise, all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and the like) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained by applying general rounding. Here, a range of values ​​is expressed as a range from one endpoint to the other or between the two endpoints; unless otherwise stated, the range of values ​​described herein includes the endpoints.

[0029] The term "treatment" or "treat" refers to preventative (e.g., preventative medication), curative, or palliative measures. Specifically, treatment here refers to the administration or delivery of the delayed-release capsule formulation of this invention to individuals who may have a medical condition or symptoms related to such condition, diseases or abnormalities arising from such condition, or who are susceptible to such condition, in order to partially or completely alleviate, improve, or reduce one or more symptoms or features of a specific abnormality and / or condition, such as inflammatory bowel disease, or to delay its onset, inhibit its progression, reduce its severity, and / or reduce its incidence. Treatment may also be given to individuals who have not yet shown signs of disease, abnormality, and / or condition, and / or individuals who show early signs, in order to reduce the risk of developing pathological changes associated with such disease, abnormality, and / or condition.

[0030] The terms "subject" or "patient" may be used interchangeably herein and refer to an animal (including humans) that is suitable for disposal with the delayed-release capsule formulation and / or methods disclosed herein. Unless otherwise specified, "subject" or "patient" generally includes both males and females.

[0031] The terms "application" and "administration" may be used interchangeably herein, referring to the provision of the delayed-release capsule formulation of the present invention to an individual in need of treatment.

[0032] Here, the term "effective amount" refers to an amount of the delayed-release capsule formulation of the present invention sufficient to elicit the desired therapeutic response. An effective amount of the agent does not necessarily cure the disease or symptom, but it can delay, inhibit, or prevent the occurrence of the disease or symptom, or alleviate symptoms associated with the disease or symptom. The effective therapeutic amount may be divided into one, two, or more doses and administered once, twice, or more times at an appropriate dose over a specified period. The specific effective therapeutic amount depends on various factors, such as the specific condition to be treated, the individual's physiological condition (e.g., individual weight, age, or sex), the mammal or animal type receiving treatment, the duration of treatment, the nature of concurrent treatment (if any), and the structure of the specific formulation and compound or its derivatives used. For example, the effective therapeutic amount may be expressed as the total weight (e.g., grams, milligrams, or micrograms) of the hyaluronic acid drug complex (or an equal amount of the drug) or as the concentration of the hyaluronic acid drug complex in the final formulation, such as milligrams per milliliter (mg / mL).

[0033] Here, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or coating material, which can be used to carry or transport a target ingredient from one organ or part of the body to another organ or part of the body. "Acceptable" excipient means that it is compatible with other components in the composition. A pharmaceutical formulation includes the hyaluronic acid drug complex described herein and one or more pharmaceutically acceptable excipients. Preferably, the excipient may be a liquid diluent. These pharmaceutical formulations are also within the scope of this invention. Generally, in pharmaceutical formulations, the active ingredient typically constitutes 0.1-95% of the total weight, preferably 0.2-20% for parenteral administration, and preferably 1-50% for oral administration. When the method of the present invention is used clinically, the pharmaceutical composition described herein can be formulated into a preparation suitable for the desired route of administration.

[0034] Here, "hyaluronic acid" (HA, also known as hyaluronate or hyaluronic acid) is an anionic, unsulfated glycosaminoglycan composed of at least one disaccharide unit, namely D-glucuronic acid and N-acetylglucosamine (-4GlcUAβ1-3GlcNAcβ1-). The molecular weight of HA ranges from 379 Daltons (Da) (single disaccharide unit) to millions of Daltons. Hyaluronic acid salts include sodium hyaluronate, methyl hyaluronate, and similar substances. The term "HA derivative" refers to any one of the hydroxyl, carboxyl, acetylglucosamine, or hydroxyl groups of one or more HA disaccharide units that has been modified.

[0035] According to this disclosure, Tmax refers to "time to peak concentration," which is the time required for a drug to reach its peak plasma concentration (Cmax) after oral administration; t1 / 2 refers to "biological half-life," which is the time required for the drug concentration to decrease to half of its original value; and Tlag refers to "lag time," which is the time from drug administration to the first measurable concentration. Furthermore, AUC refers to "area under the curve," which is the integral value of the concentration-time curve (either after a single dose or under steady-state conditions). Specifically, AUC0–t refers to the area under the curve from time zero to the last non-zero concentration, calculated using the linear trapezoidal method; AUCrefTmax refers to the area under the concentration-time curve from time zero to the time when the reference product reaches its maximum concentration (corresponding to the median Tmax of the reference product), calculated using the linear trapezoidal method; and AUC0–inf refers to the area under the curve from time zero to infinity (by extrapolation), calculated as AUC0–t + Ct / Kel, where Ct is the last observed non-zero concentration.

[0036] This disclosure is based, at least in part, on the discovery that the delayed-release capsule formulation described herein can improve the bioavailability of mesalazine to an unexpected and unintended degree. Specifically, the formulation comprises a hyaluronic acid layer, which plays a key role in regulating drug release characteristics and protecting mesalazine during its passage through the gastrointestinal tract (GI). The release characteristics can be further finely tuned by incorporating hyaluronic acid of different molecular weights. Therefore, the formulation can provide higher and more sustained mesalazine concentrations in the blood, a result confirmed by elevated Cmax (peak plasma concentration) and AUC (area under the curve) values, indicating improved absorption and prolonged therapeutic effect.

[0037] Furthermore, the delayed-release mechanism constructed through multi-layered particles ensures that mesalazine is primarily released in the intestines, rather than the stomach. This design not only reduces potential side effects such as gastric irritation but also maximizes the local therapeutic effect of mesalazine at the most needed site—the inflamed area of ​​the colon.

[0038] In summary, the formulation delivers mesalazine in a controlled and sustained manner, which can improve treatment outcomes for patients, particularly those with chronic intestinal diseases such as ulcerative colitis. This is achieved by maintaining effective drug concentrations over a longer period, thereby enhancing efficacy and improving patient outcomes.

[0039] In view of the foregoing, this disclosure also proposes a method for preventing and / or treating inflammatory bowel disease by oral administration of the delayed-release capsule formulation described herein. The use of the delayed-release capsule formulation for the prevention and / or treatment of inflammatory bowel disease, and its use in the manufacture of medicaments for the aforementioned therapeutic purposes, are also provided herein. Of course, the medicaments (i.e., pharmaceutical compositions) are also within the scope of this application.

[0040] One aspect of this disclosure relates to a delayed-release capsule formulation. The advantages of the proposed delayed-release capsule formulation include providing desirable pharmacokinetic properties to improve the delivery efficiency and bioavailability of the active ingredient. The proposed delayed-release capsule formulation also has a more compact size, thereby improving patient adherence.

[0041] According to certain embodiments, the delayed-release capsule formulations described herein comprise a capsule shell and a plurality of particles contained therein, wherein each particle comprises: (a) an inert core comprising about 10–20 wt% of the total weight of the particles; (b) a mesalazine layer disposed on the surface of the inert core, wherein the mesalazine layer comprises about 40–65 wt% of the total weight of the particles and contains about 80–99 wt% mesalazine; (c) a hyaluronic acid layer disposed on the surface of the mesalazine layer, wherein the hyaluronic acid layer comprises about 3–15 wt% of the total weight of the particles and contains about 51–70 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof; and (d) at least one coating layer disposed on the surface of the hyaluronic acid layer, wherein the at least one coating layer comprises about 15–30 wt% of the total weight of the particles.

[0042] It is understood that key ingredients such as mesalazine and hyaluronic acid or its pharmaceutically acceptable salts can be co-prepared with appropriate pharmaceutically acceptable excipients to form multilayer capsule formulations suitable for oral administration.

[0043] The term "inert core" as used herein refers to a pharmaceutically acceptable inert substrate commonly used in the field of formulation technology, in the form of, but not limited to, powders or multi-unit particles, such as granules, pellets, beads, spherical particles, microbeads, microspheres, nanospheres, microspheres, or mini tablets. According to certain embodiments of this disclosure, the inert core includes a filler. Examples of fillers include, but are not limited to, sugars, microcrystalline cellulose, plant gums, and waxes. In one embodiment, the filler of the inert core is microcrystalline cellulose. The inert core can be prepared using techniques well known to those skilled in the art, such as wet granulation, dry granulation, or extrusion-spheronization and similar methods.

[0044] The inert core contained in the particles may account for, for example, approximately 10 wt% to 20 wt%, 11 wt% to 19 wt%, 12 wt% to 18 wt%, 13 wt% to 17 wt%, 14 wt% to 16 wt%, 15 wt% to 18 wt%, or 17 wt% to 19 wt% of the total weight of the particles. More specifically, the inert core contained in the particles may account for approximately 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12% of the total weight of the particles. 1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14. 7, 14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 1 7.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9 or 20 wt%.

[0045] The mesalazine layer contained in the granules may, for example, comprise approximately 40 wt% to 65 wt%, 45 wt% to 60 wt%, or 50 wt% to 55 wt% of the total weight of the granules. More specifically, the mesalazine layer contained in the granules may comprise approximately 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65 wt% of the total weight of the granules.

[0046] Mesalazine is the main component of the mesalazine layer. Specifically, the content of mesalazine in the mesalazine layer can be, for example, approximately 80 wt% to 99 wt%, 82 wt% to 97 wt%, 84 wt% to 95 wt%, 86 wt% to 93 wt%, or 88 wt% to 91 wt% of the total weight of the mesalazine layer. More specifically, the content of mesalazine in the mesalazine layer can be 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% of the total weight of the mesalazine layer.

[0047] In addition to mesalazine, the mesalazine layer may further include excipients, such as at least one adhesive.

[0048] Examples of adhesives suitable for use in mesalazine layers include, but are not limited to, hydroxypropyl methylcellulose, sodium hydroxypropyl cellulose and carboxymethyl cellulose, povidone, magnesium copovidone stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitate, glyceryl oleate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, calcium trimethyl phosphate, and similar or mixtures thereof. In one embodiment, the adhesive used in the mesalazine layer comprises hydroxypropyl methylcellulose and talc.

[0049] The content of the binder in the mesalazine layer may be, for example, about 0.5 wt% to 15 wt%, 1 wt% to 14.5 wt%, 2 wt% to 14 wt%, 3 wt% to 13.5 wt%, 4 wt% to 13 wt%, 5 wt% to 12.5 wt%, 6 wt% to 12 wt%, or 6.5 wt% to 11.5 wt% of the total weight of the mesalazine layer. More specifically, the adhesive content in the mesalazine layer accounts for 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, and 3% of the total weight of the mesalazine layer. 8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11 7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9 or 15 wt%.

[0050] The hyaluronic acid layer in the particles may comprise, for example, approximately 3 wt% to 15 wt%, 4 wt% to 14 wt%, 5 wt% to 13 wt%, 6 wt% to 12 wt%, 7 wt% to 11 wt%, or 8 wt% to 10 wt% of the total particle weight. More specifically, the hyaluronic acid layer content in the particles accounts for approximately 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, and 5. 8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9 or 15 wt%.

[0051] The main component of the hyaluronic acid layer is hyaluronic acid or its pharmaceutically acceptable salts. Specifically, the content of hyaluronic acid or its pharmaceutically acceptable salts in the hyaluronic acid layer is between approximately 51 wt% and 70 wt%, 53 wt% and 68 wt%, 55 wt% and 66 wt%, or 57 wt% and 64 wt% of the total weight of the hyaluronic acid layer. More specifically, the content of hyaluronic acid or its pharmaceutically acceptable salts in the hyaluronic acid layer accounts for 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 wt% of the total weight of the hyaluronic acid layer.

[0052] According to certain embodiments of this disclosure, the hyaluronic acid layer comprises both high-molecular-weight hyaluronic acid (HMWHA) and low-molecular-weight hyaluronic acid (LMWHA), or pharmaceutically acceptable salts thereof. In some embodiments of this disclosure, the HMWHA has a viscosity-average molecular weight (Mv) of 2000 kDa to 2500 kDa, and the LMWHA has an Mv of 300 kDa to 500 kDa. More specifically, the Mv of HMWHA are 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, and 2.36. The hyaluronic acid concentrations are 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, or 2.5 million Daltons, while the Mv of the LMWHA is 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, or 0.5 million Daltons. In one embodiment, the hyaluronic acid layer comprises an HMWHA with an Mv of 2.18 million Daltons and an LMWHA with an Mv of 0.38 million Daltons.

[0053] According to certain embodiments of this disclosure, the content ratio of HMWHA to LMWHA in the hyaluronic acid layer is 1:5 to 5:1. For example, the content ratio of HMWHA to LMWHA can be 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1 or 5:1.

[0054] In addition to HMWHA and LMWHA, the hyaluronic acid layer may further include excipients, such as at least one adhesive. In one embodiment, the weight ratio of HMWHA to LMWHA in the hyaluronic acid layer is 4:1.

[0055] According to certain embodiments of this disclosure, the hyaluronic acid layer further comprises at least one adhesive, the content of which is 30 wt% to 49 wt% of the hyaluronic acid layer. The adhesive suitable for use in the hyaluronic acid layer can be any adhesive described above for the mesalazine layer. In several embodiments, the adhesive used in the hyaluronic acid layer may be the same as or different from the adhesive used in the mesalazine layer. In one embodiment, the adhesive used in the hyaluronic acid layer comprises low-substituted hydroxypropyl cellulose.

[0056] The amount of binder contained in the hyaluronic acid layer may be, for example, about 30 wt% to 49 wt%, 32 wt% to 45 wt%, or 34 wt% to 43 wt% of the total weight of the hyaluronic acid layer. More specifically, the binder content in the hyaluronic acid layer is about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 wt% of the total weight of the hyaluronic acid layer.

[0057] The coating layer is designed to ensure delayed release, allowing mesalazine to pass through the stomach and reach the more downstream parts of the gastrointestinal tract (GI) for more efficient absorption. The coating layer content of the granules is, for example, about 15 wt% to 30 wt%, 17 wt% to 28 wt%, 19 wt% to 26 wt%, or 21 wt% to 24 wt% of the total granule weight. More specifically, the coating layer content of the granules is approximately 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 wt% of the total granule weight.

[0058] According to certain embodiments of this disclosure, the at least one coating layer comprises an enteric coating layer, which is insoluble in gastric juice but soluble in intestinal juice with a pH greater than 5. The content of the enteric coating layer in the granules may be, for example, about 15 wt% to 20 wt%, 16 wt% to 19.5 wt%, or 17 wt% to 19 wt% of the total weight of the granules. More specifically, the content of the enteric coating layer in the granules is about 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1, or 17% of the total weight of the granules. 2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9 or 20 wt%.

[0059] The enteric coating layer preferably comprises one or more copolymers. Examples of copolymers suitable for use in enteric coating layers include, but are not limited to: methyl acrylate-methyl methacrylate-methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, and ethyl methacrylate copolymers. In one embodiment, the enteric coating layer comprises copolymers based on methyl acrylate, methyl methacrylate, and methacrylic acid, and copolymers based on methacrylic acid and ethyl acrylate.

[0060] The copolymer contained in the enteric coating layer may be, for example, about 75 wt% to 98 wt%, 80 wt% to 96 wt%, or 85 wt% to 94 wt% of the total weight of the enteric coating layer. More specifically, the copolymer content in the enteric coating layer is about 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, or 98 wt% of the total weight of the enteric coating layer.

[0061] According to certain optional embodiments of this disclosure, the enteric coating layer further comprises at least one plasticizer. Examples of plasticizers suitable for the enteric coating layer include, but are not limited to: tributyl acetate, triethyl acetate, benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerol, glyceryl monostearate, hydroxypropyl methylcellulose phthalate, mannitol, mineral oil lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, glyceryl triacetate, tributyl citrate, triethanolamine, and triethyl citrate. In one embodiment, the plasticizer used in the enteric coating layer comprises triethyl citrate, glyceryl monostearate, and sorbitol.

[0062] The content of plasticizer in the enteric coating layer can be, for example, about 2 wt% to 25 wt%, 5 wt% to 20 wt%, or 10 wt% to 15 wt% of the total weight of the enteric coating layer. More specifically, the content of plasticizer in the enteric coating layer is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 wt% of the total weight of the enteric coating layer.

[0063] According to certain embodiments of this disclosure, at least one coating layer further includes an isolation layer disposed between the hyaluronic acid layer and the enteric coating layer. The isolation layer preferably comprises one or more copolymers. Suitable copolymers for the isolation layer include, but are not limited to: methacrylate-methyl methacrylate copolymers, methacrylate-methyl acrylate copolymers, and methacrylate-ethyl acrylate copolymers. In one embodiment, the isolation layer comprises a copolymer based on methacrylic acid and methyl methacrylate.

[0064] The copolymer content in the separator layer can be, for example, about 51 wt% to 70 wt% or 55 wt% to 60 wt% of the total weight of the separator layer. More specifically, the copolymer content in the separator layer is about 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 wt% of the total weight of the separator layer.

[0065] According to certain embodiments of this disclosure, the isolation layer further comprises at least one plasticizer. The plasticizer suitable for the isolation layer can be any adhesive described above for the enteric coating layer. In several embodiments, the plasticizer used in the isolation layer may be the same as or different from the plasticizer used in the enteric coating layer. In one embodiment, the plasticizer used in the isolation layer comprises triethyl citrate.

[0066] The plasticizer content in the isolation layer can be, for example, about 30 wt% to 49 wt%, 32 wt% to 45 wt%, or 34 wt% to 40 wt% of the total weight of the isolation layer. More specifically, the plasticizer content in the isolation layer is about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 wt% of the total weight of the isolation layer.

[0067] According to various embodiments of this disclosure, a capsule encapsulation machine is used to encapsulate a desired amount of multilayered particles into a two-piece hard gelatin capsule. For example, coated multilayered particles are encapsulated in one capsule such that each capsule contains approximately 200 mg of mesalazine. According to some embodiments, the capsules used are size 0 capsules with a length of 21.6 mm.

[0068] According to certain embodiments of this disclosure, the inert core contains 60 to 100 mg per capsule, the mesalazine layer contains 100 to 450 mg per capsule, the hyaluronic acid layer contains 30 to 60 mg per capsule, and at least one enteric coating contains 80 to 100 mg per capsule.

[0069] Optionally, the content of sasalazine in each capsule can be 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 2 30, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 mg.

[0070] Optionally, the hyaluronic acid content in each capsule may be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45 mg.

[0071] According to certain embodiments of this disclosure, when the delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide a mean peak plasma concentration (Cmax) of mesalazine of at least 400 ng / mL.

[0072] According to certain optional embodiments, the delayed-release capsule formulation may provide an average Cmax of 400 to 600 ng / mL, 410 to 550 ng / mL, 420 to 500 ng / mL, or 430 to 450 ng / mL.

[0073] According to certain embodiments of this disclosure, when a delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide a mean plasma area under the curve (AUC6-12) of mesalazine of at least 600 ng·hr / mL over 6–12 hours.

[0074] According to certain optional embodiments, the delayed-release capsule formulation may provide an average AUC6-12 between 600 and 1,000 ng / mL, 650 and 950 ng / mL, 700 and 900 ng / mL, or 750 and 850 ng / mL.

[0075] According to certain embodiments of this disclosure, when a delayed-release capsule formulation is administered orally to a human subject as a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation can provide an average AUC0–t of at least 1,800 ng·hr / mL for mesalazine.

[0076] According to certain optional embodiments, the delayed-release capsule formulation may provide an average AUC0-t between 1,800 and 2,500 ng / mL, 1,900 and 2,400 ng / mL, or 2,000 and 2,300 ng / mL.

[0077] Another aspect of this disclosure relates to a method of treating and / or preventing IBD in patients of need using the aforementioned delayed-release capsule formulation, wherein, after oral administration of the delayed-release capsule, the capsule provides the desired pharmacokinetic properties in the patient.

[0078] According to some embodiments of this disclosure, the method includes the step of administering the delayed-release capsule formulation presented herein to a patient at an effective dose.

[0079] According to some embodiments, the delayed-release capsule formulation is administered twice daily, with each dose consisting of two capsules, each containing 200 mg of mesalazine.

[0080] Another aspect of this disclosure relates to the use of a delayed-release capsule formulation in the manufacture of a medicament for treating inflammatory bowel disease. Yet another aspect of this disclosure relates to a delayed-release capsule formulation for treating inflammatory bowel disease. Similarly, various dosing regimens (including dosage and dosing intervals) for the said delayed-release capsule formulation also apply to the above aspects.

[0081] The following description is intended to clarify some aspects of the present invention, so as to facilitate implementation of the invention by those skilled in the art. These descriptions should not be construed as limiting the scope of the invention in any way. It is believed that those skilled in the art, upon reading the description herein, can fully utilize and practice the invention without further explanation.

[0082] Clinical Trial Design Summary

[0083] A phase 1 clinical trial has been conducted to investigate the absorption rate and extent of absorption of three treatments: Treatment A: Mesalazine-Sodium Hyaluronate 200 mg–23 mg DR capsules, administered orally as a single dose of two capsules on an empty stomach; Treatment B: Mesalazine 200 mg DR capsules, administered orally as a single dose of two capsules on an empty stomach; and Treatment C: DELZICOL® 400 mg DR capsules, administered orally as a single dose of one capsule on an empty stomach. This trial is a single-center, randomized, single-dose, open-label, phase 3, six-sequence, crossover bioavailability (BA) study. A total of 30 healthy adult subjects were enrolled. Subjects were randomly assigned to their respective treatment groups using a randomization table prior to the start of the trial. Treatment periods were separated by a washout period of at least 14 days.

[0084] For mesalazine, blood was collected in EDTA K3-containing blood collection tubes (1 × 3 mL) at times before administration and at times 2, 4, 6, 7.5, 9, 10, 11, 12, 13, 14, 16, 18, 21, 24, 27, 30, 36, 48, 60, 72, and 96 hours after administration. For hyaluronic acid (treatment A only), blood was collected in plastic serum silica-sprayed blood collection tubes (1 × 3 mL) at times 1 hour, 0.5 hours, and 5 minutes before administration (0 hour), and at times 2, 4, 6, 7.5, 9, 10, 11, and 12 hours after administration. Where feasible, a margin of error of ±10 minutes relative to the nominal time was allowed for blood collection times at 1 hour and 0.5 hours before administration. The actual sampling time after administration was used for statistical analysis.

[0085] For mesalazine, blood samples were cooled in an ice-water bath and centrifuged at 3,000 rpm for at least 10 minutes at approximately 4°C (the time from blood collection to the start of centrifugation should not exceed 240 minutes). The plasma was then immediately aliquoted into two portions of at least 0.5 mL each (where feasible), placed in polypropylene tubes, and transferred to a freezer at -80°C (-65°C to -85°C) within 180 minutes of centrifugation for later analysis. For hyaluronic acid, blood samples were allowed to stand at room temperature for at least 30 minutes after collection to allow clotting to complete, and then centrifuged at 2,400 rpm for at least 10 minutes at room temperature (the time from blood collection to the start of centrifugation should not exceed 60 minutes). The serum was then immediately aliquoted into two portions of at least 0.5 mL each (where feasible), placed in polypropylene tubes, and transferred to a freezer at -80°C (-65°C to -85°C) within 120 minutes of centrifugation for later transport to the analytical laboratory.

[0086] The pharmacokinetic (PK) parameters assessed in this study were generally standard parameters, and the blood sampling time was determined based on preclinical PK data. In addition to commonly used PK parameters, this study also calculated partial AUCs for all treatment groups, including AUC8–48, AUC6–12, AUC12–24, and AUCrefTmax, to more comprehensively compare drug absorption at the colonic site of action (and thus drug availability). Data were analyzed using analysis of variance (ANOVA), and quantitative data are expressed as mean ± standard deviation (SD).

[0087] Capsule formulation

[0088] Multilayered particles are prepared using standard manufacturing procedures to obtain capsule formulations for treatment A and treatment B. Each capsule for treatment A contains: (1) Inert core: Approximately 80 mg of spherical starter pellets composed of microcrystalline cellulose (CELLETS® 500); (2) Mesalazine layer: approximately 200 mg mesalazine, approximately 15 mg hydroxypropyl methylcellulose (hypromellose 2910), and approximately 8 mg talc; (3) Hyaluronic acid layer: approximately 18.4 mg HMWHA (2180 kDa), approximately 4.6 mg LMWHA (380 kDa), and approximately 16.75 mg low-substituted hydroxypropyl cellulose; (4) Isolation layer: approximately 9 mg of methacrylate-methyl methacrylate copolymer (EUDRAGIT® L100), approximately 5 mg of talc, and approximately 1 mg of triethyl citrate; (5) Enteric coating: approximately 67 mg of methyl acrylate-methyl methacrylate-methacrylic acid copolymer (EUDRAGIT® FS 30 D), approximately 7.5 mg of methacrylic acid-ethyl acrylate copolymer (EUDRAGIT® L30D-55), and approximately 7.5 mg of lubricant / flow aid premix containing triethyl citrate, glyceryl monostearate, and sorbitol (PLASACRY® T20).

[0089] Each capsule of treatment B contains the same material as the capsule of treatment A, but without the hyaluronic acid layer.

[0090] result

[0091] The mean ± SD (coefficient of variation, CV%) of plasma mesalazine PK parameters are summarized in Table 1 below, while the curves of mean plasma mesalazine concentration versus time are shown on linear and logarithmic scales in Figures 1A and 1B, respectively.

[0092] Table 1 Mean ± SD (CV%) plasma mesalazine Process A Process B Processing Ce N 28e 29 28f AUC0-t (ng*hr / mL) 2010.47 ± 1220.12 (60.69) 1655.04 ± 1356.92 (81.99) 1394.61 ± 1205.00 (86.40) AUC0-inf (ng*hr / mL) 2179.02 ± 1235.63 (56.71)b 1930.74 ± 1431.25 (74.13)c 1670.74 ± 1206.73 (72.23)d Cmax (ng / mL) 448.81 ± 436.56 (97.27) 362.36 ± 408.30 (112.68) 111.88 ± 76.63 (68.49) AUC8-48 (ng*hr / mL) 827.25 ± 520.55 (62.93) 597.82 ± 324.72 (54.32) 1213.52 ± 1050.43 (86.56) AUC6-12 (ng*hr / mL) 800.57 ± 795.60 (99.38) 614.35 ± 494.05 (80.42) 179.39 ± 276.29 (154.02) AUC12-24 (ng*hr / mL) 233.66 ± 146.59 (62.73) 141.25 ± 74.68 (52.87) 388.28 ± 307.65 (79.23) AUCrefTmax (ng*hr / mL) 1575.17 ± 1237.90 (78.59) 1295.22 ± 1349.59 (104.20) 284.02 ± 343.60 (120.98) Residual area (%) 3.14 ± 3.56 (113.56)b 5.12 ± 5.40 (105.31)c 7.40 ± 9.34 (126.24)d Tlag a (hr) 2.00 (0.00 - 4.00) 2.01 (0.00 - 4.03) 7.50 (2.00 - 14.0) Tmax a (hr) 6.00 (3.99 - 59.7) 6.00 (4:00 - 9:00) 14.00 (7.50 - 59.9) a. Median (Minimum - Maximum) bn=25, subjects 1, 6, and 15 were not included in the aggregated statistical calculation. cn=23, subjects 1, 7, 17, 19, 23, and 27 were not included in the aggregated statistical calculation. dn=24, subjects 1, 11, 13, and 22 were not included in the aggregated statistical calculation. Data from subject 12 have been excluded. Data from subject 17 have been excluded.

[0093] The mean residual area of ​​mesalazine was less than 20% in all treatment groups, indicating that the 96-hour sampling period was sufficient for mesalazine. This result corresponds to a mean AUC0–t to AUC0–inf ratio greater than 80%.

[0094] The least squares ratios (A / C) of treatment A (mesalazine-sodium hyaluronate 200mg–23mg DR capsules) relative to treatment C (DELZICOL®) after natural log-transformation of AUC0–t, AUC0–inf, Cmax, AUC6–12, AUC12–24, AUC8–48, and AUCrefTmax were 169.76%, 141.73%, 313.27%, 4492.78%, 70.52%, 73.82%, and 1471.09%, respectively.

[0095] The least squares ratio (A / C) of AUC6–12 showed that treatment A provided more than 40 times the drug exposure during the 6–12 hour post-administration period compared to treatment C. The transit time of orally administered drugs in the colon is typically approximately 4–8 hours post-administration. Given the extremely high AUC6–12 (4492.78%) of treatment A compared to treatment C, this result indicates that a significant proportion of the drug was released during this critical time interval when the formulation was most likely located in the colon. By delivering high concentrations of mesalazine over a 6–12 hour timeframe, treatment A achieves a stronger local anti-inflammatory effect in the colon. This characteristic is particularly important for the treatment of inflammatory bowel diseases such as ulcerative colitis, as treatment relies on the local action of the drug in the inflamed area of ​​the colon.

[0096] Furthermore, compared to treatment C, treatment A achieved a significantly higher Cmax, more than three times higher (313.27%). This result, combined with treatment A's Tmax of 6 hours, indicates that treatment A delivers a more concentrated dose of mesalazine into the bloodstream upon reaching the colon, which is particularly advantageous for cases requiring rapid symptom relief. For patients experiencing acute exacerbations of ulcerative colitis, formulations with rapid onset of action are a key advantage, as they can reduce inflammation and alleviate discomfort more quickly than slower-release formulations (such as treatment C).

[0097] Furthermore, compared to treatment C, treatment A also showed higher AUC0–t (169.76%) and AUC0–inf (141.73%), indicating that it provided a higher overall drug absorption. This result suggests that treatment A ensures a higher systemic drug exposure, potentially leading to better overall therapeutic effects. Higher systemic absorption is particularly important in severe cases of ulcerative colitis, as deeper layers of the intestinal tissue are also affected, requiring higher concentrations of mesalazine to adequately control the inflammatory response.

[0098] In summary, treatment A demonstrated statistical advantages over treatment C in several pharmacokinetic parameters (including Cmax, AUC0–t, AUC0–inf, and AUC6–12), indicating that it delivers mesalazine more efficiently and at a higher dose than treatment C. Therefore, the delayed-release capsule formulation presented here (DR capsules of mesalazine-sodium hyaluronate 200 mg–23 mg) is more suitable for the control of ulcerative colitis, especially in situations requiring rapid drug availability and stable and adequate therapeutic coverage.

[0099] The least squares ratios (B / A) of treatment B (200 mg mesalazine DR capsules) relative to treatment A (200 mg–23 mg mesalazine-sodium hyaluronate DR capsules) after natural logarithmic transformation of AUC0–t, AUC0–inf, Cmax, AUC6–12, AUC12–24, AUC8–48, and AUCrefTmax were 72.64%, 81.95%, 81.21%, 73.52%, 63.97%, 75.00%, and 70.15%, respectively.

[0100] The results showed that treatment A outperformed treatment B in several pharmacokinetic parameters (including Cmax, AUC0–t, AUC0–inf, and AUC6–12), indicating better efficacy in treating inflammatory bowel disease. These parameters demonstrate superior drug delivery efficiency and therapeutic effect in the colon (the target site for inflammatory bowel disease treatment). The presence of a hyaluronic acid layer between the outer coating and the mesalazine layer allows for further fine-tuning of the mesalazine release characteristics, ensuring more controlled and sustained drug delivery in the colon. This hyaluronic acid layer also provides additional protection to the mesalazine layer, preventing premature release of the drug in the upper gastrointestinal tract (especially in the stomach), thus ensuring more mesalazine reaches the inflamed areas of the colon. Furthermore, hyaluronic acid itself has known anti-inflammatory effects, which can further benefit the treatment of colonic inflammation and may enhance the overall therapeutic effect of mesalazine.

[0101] It is understood that the embodiments described above are merely illustrative, and those skilled in the art can make various modifications. The description, experimental examples, and data above fully describe the structure and application of the exemplary embodiments of the present invention. Although the above embodiments have specifically or with reference to one or more individual embodiments have disclosed various embodiments of the present invention, those skilled in the art can make various modifications without departing from the principles and spirit of the present invention.

[0102] none

Claims

1. A delayed-release capsule formulation comprising a capsule shell and a plurality of particles contained therein, wherein each particle comprises: (a) an inert core comprising 10–20 wt% of the total weight of the particle; (b) a mesalazine layer disposed on the surface of the inert core, wherein the mesalazine layer comprises 40–65 wt% of the total weight of the particle and comprises 80–99 wt% mesalazine; (c) a hyaluronic acid layer disposed on the surface of the mesalazine layer, wherein the hyaluronic acid layer comprises 3–15 wt% of the total weight of the particle and comprises a high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof and a low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in a ratio of 1:5 to 5:1, and the hyaluronic acid or a pharmaceutically acceptable salt thereof comprises 51–70 wt% of the hyaluronic acid layer. (d) an isolation layer disposed on the surface of the hyaluronic acid layer, comprising one or more copolymers selected from the group consisting of: methacrylate-methyl methacrylate copolymer, methacrylate-methyl acrylate copolymer and methacrylate-ethyl acrylate copolymer; and (e) an enteric coating layer disposed on the surface of the isolation layer, comprising one or more copolymers selected from the group consisting of: methyl acrylate-methyl methacrylate-methacrylate copolymer, methacrylate-methyl methacrylate copolymer, methacrylate-ethyl acrylate copolymer and methacrylate copolymer, wherein the combined content of the isolation layer and the enteric coating layer accounts for 15–30 wt% of the total weight of the particles.

2. The delayed-release capsule formulation as claimed in claim 1, wherein the inert core comprises a filler selected from the group consisting of starch, sugars, microcrystalline cellulose, plant gums and waxes.

3. The delayed-release capsule formulation as claimed in claim 1, wherein the mesalazine layer further comprises at least one binder in an amount of 0.5-15 wt% of the weight of the mesalazine layer, and the binder is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitate, glyceryl oleate, polyethylene glycol, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, calcium trimethyl phosphate, and mixtures thereof.

4. The delayed-release capsule formulation as claimed in claim 1, wherein the high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof has a viscosity-average molecular weight of 2000 kDa to 2500 kDa, and the low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof has a viscosity-average molecular weight of 300 kDa to 500 kDa.

5. The delayed-release capsule formulation as claimed in claim 1, wherein the hyaluronic acid layer further comprises at least one binder having an amount of 30-49 wt% of the hyaluronic acid layer and being selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitate, glyceryl oleate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, calcium trimethyl phosphate, and mixtures thereof.

6. The delayed-release capsule formulation as claimed in claim 1, wherein the enteric coating further comprises at least one plasticizer selected from the group consisting of: tributyl acetate, triethyl acetate, benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerol, glyceryl monostearate, hydroxypropyl methylcellulose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, glyceryl triacetate, tributyl citrate, triethanolamine, and triethyl citrate.

7. The delayed-release capsule formulation as claimed in claim 1, wherein the insulating layer further comprises at least one plasticizer selected from the group consisting of: tributyl acetate, triethyl acetate, benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerol, glyceryl monostearate, hydroxypropyl methylcellulose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, glyceryl triacetate, tributyl citrate, triethanolamine, and triethyl citrate.

8. The delayed-release capsule formulation as claimed in claim 1, wherein the inert core is present in a content of 60 mg to 100 mg per capsule, the mesalazine layer is present in a content of 100 mg to 450 mg per capsule, the hyaluronic acid layer is present in a content of 30 mg to 60 mg per capsule, and the at least one enteric coating is present in a content of 80 mg to 100 mg per capsule.

9. The use of a delayed-release capsule formulation as claimed in claim 1 in the manufacture of a medicament for treating inflammatory bowel disease.

10. The use as claimed in claim 9, wherein the hyaluronic acid layer comprises a high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof and a low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof, in a ratio of 1:5 to 5:

1.

11. The use as claimed in claim 9, wherein the inert core is present in a content of 60 mg to 100 mg per capsule, the mesalazine layer is present in a content of 100 mg to 450 mg per capsule, the hyaluronic acid layer is present in a content of 30 mg to 60 mg per capsule, and the at least one enteric coating is present in a content of 80 mg to 100 mg per capsule.

12. The use as claimed in claim 9, wherein when the delayed-release capsule formulation is administered orally to a human subject in a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation provides a mean peak plasma concentration (Cmax) of mesalazine of at least 400 ng / mL.

13. The use as claimed in claim 9, wherein when the delayed-release capsule formulation is administered orally to a human subject in a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation provides a mean plasma area under the curve (AUC6-12) of mesalazine of at least 600 ng·hr / mL over 6–12 hours.

14. The use as claimed in claim 9, wherein when the delayed-release capsule formulation is administered orally to a human subject in a single dose of two capsules each containing 200 mg of mesalazine, the delayed-release capsule formulation provides an average AUC0–t of at least 1,800 ng·hr / mL for mesalazine.

15. A delayed-release granule formulation comprising a plurality of granules, wherein each granule comprises: (a) an inert core comprising 10–20 wt% of the total weight of the granules; (b) a mesalazine layer disposed on the surface of the inert core, wherein the mesalazine layer comprises 40–65 wt% of the total weight of the granules and comprises 80–99 wt% mesalazine; and (c) a hyaluronic acid layer disposed on the surface of the mesalazine layer, wherein the hyaluronic acid layer comprises 3–15 wt% of the total weight of the granules and comprises a high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof and a low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in a ratio of 1:5 to 5:1, and the hyaluronic acid or a pharmaceutically acceptable salt thereof comprises 51–70 wt% of the hyaluronic acid layer. (d) an isolation layer disposed on the surface of the hyaluronic acid layer, comprising one or more copolymers selected from the group consisting of: methacrylate-methyl methacrylate copolymer, methacrylate-methyl acrylate copolymer and methacrylate-ethyl acrylate copolymer; and (e) an enteric coating layer disposed on the surface of the isolation layer, comprising one or more copolymers selected from the group consisting of: methyl acrylate-methyl methacrylate-methacrylate copolymer, methacrylate-methyl methacrylate copolymer, methacrylate-ethyl acrylate copolymer and methacrylate copolymer, wherein the combined content of the isolation layer and the enteric coating layer accounts for 15–30 wt% of the total weight of the particles.

16. The delayed-release particulate formulation as claimed in claim 15, wherein the inert core comprises a filler selected from the group consisting of starch, sugars, microcrystalline cellulose, plant gums and waxes.

17. The delayed-release particulate formulation as claimed in claim 15, wherein the mesalazine layer further comprises at least one binder in an amount of 0.5-15 wt% of the weight of the mesalazine layer, and the binder is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitate, glyceryl oleate, polyethylene glycol, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, calcium trimethyl phosphate, and mixtures thereof.

18. The delayed-release particulate formulation as claimed in claim 15, wherein the high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof has a viscosity-average molecular weight of 2000 kDa to 2500 kDa, and the low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof has a viscosity-average molecular weight of 300 kDa to 500 kDa.

19. The delayed-release particulate formulation as claimed in claim 15, wherein the hyaluronic acid layer further comprises at least one binder in an amount of 30-49 wt% of the hyaluronic acid layer and is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitate, glyceryl oleate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, calcium trimethyl phosphate, and mixtures thereof.

20. The delayed-release particulate formulation as claimed in claim 15, wherein the enteric coating further comprises at least one plasticizer selected from the group consisting of: tributyl acetate, triethyl acetate, benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerol, glyceryl monostearate, hydroxypropyl methylcellulose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, glyceryl triacetate, tributyl citrate, triethanolamine, and triethyl citrate.

21. The delayed-release particulate formulation as claimed in claim 15, wherein the isolation layer further comprises at least one plasticizer selected from the group consisting of: tributyl acetate, triethyl acetate, benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerol, glyceryl monostearate, hydroxypropyl methylcellulose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, glyceryl triacetate, tributyl citrate, triethanolamine, and triethyl citrate.

22. The delayed-release particulate formulation as claimed in claim 15, wherein the inert core is present in a concentration of 60 mg to 100 mg per unit, the mesalazine layer is present in a concentration of 100 mg to 450 mg per unit, the hyaluronic acid layer is present in a concentration of 30 mg to 60 mg per unit, and the at least one enteric coating is present in a concentration of 80 mg to 100 mg per unit.

23. Use of a delayed-release particulate formulation as described in claim 15 in the manufacture of a medicament for treating inflammatory bowel disease.

24. The use as claimed in claim 23, wherein the hyaluronic acid layer comprises a high molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof and a low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof, in a ratio of 1:5 to 5:

1.

25. The use as claimed in claim 23, wherein the inert core is present in a concentration of 60 mg to 100 mg per unit, the mesalazine layer is present in a concentration of 100 mg to 450 mg per unit, the hyaluronic acid layer is present in a concentration of 30 mg to 60 mg per unit, and the at least one enteric coating is present in a concentration of 80 mg to 100 mg per unit.

26. The use as described in claim 23, wherein when the delayed-release granule formulation is administered orally to a human subject in a single dose of two units of granules each containing 200 mg of mesalazine, the delayed-release granule formulation provides a mean peak plasma concentration (Cmax) of mesalazine of at least 400 ng / mL.

27. The use as described in claim 23, wherein, after a single oral administration of the delayed-release granule formulation to a human subject in the form of two units of granules each containing 200 mg of mesalazine, the delayed-release granule formulation provides a mean plasma area under the curve (AUC6-12) of mesalazine of at least 600 ng·hr / mL over 6–12 hours.

28. The use as described in claim 23, wherein, after a single oral administration of the delayed-release granule formulation to a human subject in the form of two units of granules each containing 200 mg of mesalazine, the delayed-release granule formulation provides an average AUC0–t of at least 1,800 ng·hr / mL for mesalazine.

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