Mesalamine pharmaceutical formulations and methods of use thereof

Abstract

The present invention provides a method and composition for local administration of a therapeutic agent to the rectum or colon (e.g., by enema). The method and composition are useful for the treatment of inflammatory bowel disease (including Crohn's disease and ulcerative colitis). The composition of the present invention comprises an active ingredient, at least one grade of thermogelling polymer (wherein, if present, each grade is present at a different concentration), lipid, and a solubilizer for the lipid. The present invention also provides a kit comprising a first container comprising a first composition comprising the active ingredient; and a second container comprising a second composition comprising at least one grade of thermogelling polymer, lipid, and a solubilizer for the lipid.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 306,942, filed February 4, 2022, the contents of which are incorporated by reference in their entirety herein.

[0002] FIELD OF THEINVENTION The present invention relates generally to pharmaceutical formulations of mesalamine, kits for providing the same to subjects, and methods of use by subjects. [Background technology]

[0003] background Inflammatory bowel disease (IBD) affects approximately 3 million Americans and over 11 million people worldwide. IBD is a group of inflammatory conditions of the digestive tract, including the mouth, esophagus, stomach, small intestine, and colon, with Crohn's disease and ulcerative colitis being the main forms. IBD causes debilitating symptoms (e.g. abdominal pain, diarrhea, rectal bleeding, cramps, weight loss, and anemia) and can be fatal if left untreated.

[0004] Anti-inflammatory agents (e.g., mesalamine (also called mesalazine or 5-aminosalicylic acid (5-ASA)) or corticosteroids (e.g., budesonide or hydrocortisone)) are often used to treat IBD. However, despite the existence of suitable pharmacological agents that combat many forms of IBD, treatment of IBD is hampered by the difficulty of administering such agents. For example, when drugs such as mesalamine or budesonide are administered orally, most of the active agent is metabolized as it passes through the gastrointestinal tract or is eliminated via bulk transit. As a result, oral formulations are generally unable to achieve therapeutic concentrations of the drug in the distal colon, which is the site of disease in many cases of ulcerative colitis and Crohn's disease. Formulations designed to overcome this obstacle by preventing release of the drug in the stomach are hampered by other problems (e.g., incomplete release, release in the proximal rather than distal colon, release of toxic metabolites, and high interpatient variability). Another concern is that oral or parenteral administration of immunosuppressants increases the risk of malignancies and infections.

[0005] Current local administration methods present their own set of problems. The GI tract (including the colon) is designed to continuously move consumed contents throughout the body while absorbing nutrients. As a result, therapeutic agents administered locally, i.e., directly to the surface of the colon, tend to be rapidly cleared from the target tissue as the ingested material passes through the intestine. Because treatment of inflamed or infected GI tissue requires continuous exposure of such tissue to therapeutic agents, frequent administration (e.g., once a day or multiple times per day) is often necessary to achieve the full therapeutic benefit of locally administered agents. As a result, many patients are unable to comply with the prescribed administration regimen.

[0006] Another barrier to effective localized treatment of IBD comes from the mode of administration. Enemas allow therapeutic agents to be delivered to the entire descending colon. However, enema-based treatments typically require patients to retain a significant volume of liquid (e.g., 60-100 ml) in the colon for extended periods of time with multiple daily doses, an unpleasant challenge that further impedes patient compliance. Suppositories and foams, while less inconvenient than enemas, generally cannot deliver drugs beyond the rectum and sigmoid colon, respectively. One of the major symptoms of IBD is urgency and diarrhea, which causes enema, foam, or suppository formulations to be purged with bowel movements, thereby limiting their effectiveness. In conclusion, existing methods for delivering therapeutic agents are inadequate for treating many forms of IBD, and millions of people continue to suffer from conditions such as Crohn's disease and ulcerative colitis. Summary of the Invention [Means for solving the problem]

[0007] Abstract The present invention includes improved thermogelling compositions and formulations, and methods of using them to treat inflammatory conditions of the gastrointestinal tract. The compositions of the present invention include an active ingredient, at least one grade of thermogelling polymer (wherein each grade, if present, is present at a different concentration), lipid, and a solubilizer for the lipid. The present invention also provides a kit comprising a first container comprising a first composition comprising the active ingredient; and a second container comprising a second composition comprising at least one grade of thermogelling polymer, lipid, and a solubilizer for the lipid. The present invention further provides a method of treating a condition in a subject, comprising receiving a kit comprising a first container comprising a first composition comprising the active ingredient; and a second container comprising a second composition comprising at least one grade of thermogelling polymer, lipid, and a solubilizer for the lipid, mixing the first and second compositions to form a final formulation, and administering the final formulation.

[0008] In certain embodiments, the composition is in a liquid state near room temperature (e.g., 20-25° C.) and transitions to a gel state near body temperature (e.g., 32-37° C.). This allows the invention to be stored as a liquid and provide the penetration / access advantages of a liquid enema. However, when introduced to body temperature, the composition gels, facilitating retention of the enema by the subject, thereby providing the retention advantages of a foam or suppository preparation. Retention of the enema is critical to the therapeutic efficacy of the enema. However, the invention also provides increased absorption of the active ingredient due to other agents included in the formulation.

[0009] The present invention provides an advantageous utility over currently used compositions since the stability of the active ingredient can be improved by adding some of the other drugs. The kit separates the active ingredient from other drugs until the subject is ready to administer the drug, eliminating stability problems associated with previous formulations and making the preparation more commercially viable due to its longer shelf life.

[0010] In an exemplary embodiment, the active ingredient is mesalamine. Mesalamine is degraded in an aqueous environment, and the stability and shelf life of mesalamine is reduced, especially in the formulation of the present invention. In addition, mesalamine may degrade polymers such as poloxamer 407 and 188 (also present in one embodiment of the present invention) in the formulation. Therefore, keeping the active ingredient (e.g., mesalamine) in a separate container and out of aqueous solution (e.g., dry) until combined on-site by the end-user patient or caregiver allows for dramatically improved storage stability and supply chain durability compared to formulations that are provided with mesalamine and poloxamer already present together. It also provides greater efficacy with reduced side effects, as the formulation is more likely to provide the desired dose to the patient and does not need to incorporate additional stabilizers or excipients that may cause adverse events.

[0011] Another problem solved by the present invention is the ability to ship and transport thermogelled products which may be subjected to high temperatures if not maintained under strict temperature control. By keeping the active ingredient separate, should gelling occur during shipping, the quality of the active ingredient is not affected as it would be if it were already mixed with other drugs.

[0012] The presence of the lipid and the lipid solubilizer helps to control the temperature at which the polymer transitions from liquid to gel. If the gelling temperature is too low, the composition may form a gel while remaining on the shelf, spoiling the product. If it is too high, body temperature may be insufficient to gel the product, eliminating the advantage that this composition has over liquid enemas.

[0013] An embodiment of the present invention may use mesalamine as the active ingredient, poloxamer 407, poloxamer 188 as grades of thermogelling polymer present in different concentrations, phosphatidylcholine as the lipid, and diethylene glycol monoethyl ether as the solubilizing agent.

[0014] In one embodiment of the invention, the concentration of mesalamine is between about 0.5-15% w / v of the composition; in another embodiment, the concentration of mesalamine is between about 6-8% w / v of the composition. In one embodiment of the invention, the concentration of poloxamer 407 is between about 10-16% w / v of the composition; in another embodiment, the concentration of poloxamer 407 is between about 12-13.5% w / v of the composition. In one embodiment of the invention, the concentration of poloxamer 188 is between about 0.001-1% w / v of the composition. In one embodiment of the invention, the concentration of phosphatidylcholine is between about 0.001-4% w / v of the composition; in another embodiment of the invention, the concentration of phosphatidylcholine is between 1.5-2.5% w / v of the composition. In one embodiment of the invention, the concentration of diethylene glycol monoethyl ether is between 5-15% w / v of the composition; in another embodiment of the invention, the concentration of diethylene glycol monoethyl ether is between about 8-10% w / v of the composition.

[0015] The present invention further discloses an embodiment as a kit comprising a first container containing a first composition comprising the active ingredient; and a second container containing a second composition comprising at least one grade of thermogelling polymer, where the grades, if present, are present in different concentrations, a lipid, and a solubilizer for the lipid.

[0016] A further embodiment of the present invention is a method for treating a condition in a subject, comprising receiving a kit comprising a first container comprising a first composition comprising the active ingredient; and a second container comprising a second composition comprising at least one grade of thermogelling polymer, where the grade, if present, is present in different concentrations, lipid, and a solubilizer for the lipid, mixing the first and second compositions to form a final formulation, and administering the final formulation.The composition can be irritable bowel disorder or ulcerative colitis.In one embodiment of the present invention, the subject administers the formulation topically, in one embodiment, as an enema.

[0017] According to the method of the present invention, the subject performs mixing and administering. Mixing can include adding the second composition to the first composition, and shaking for at least 30 seconds to suspend the formulation. Mixing can include adding the second composition to the first composition, and shaking for at least 15 seconds to suspend the formulation. Mixing can include adding the second composition to the first composition, and shaking for at least 10 seconds, leaving for 1 minute, and then shaking again for another 10 seconds to suspend the formulation. Mixing can include adding the first composition to the second composition, and shaking for at least 10 seconds, leaving for 1 minute, and then shaking again for another 10 seconds to suspend the formulation. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 illustrates the layout of the study described in the Examples. [Diagram 2] FIG. 2 shows the study period dosing and PK sample collection timeline for the study in FIG. [Figure 3A]Figure 3 shows the plasma PK of the test compound (INT-001) from the study of Figure 1 versus the reference compound (ROWASA). Figure 3A shows mesalamine, while Figure 3B shows n-acetyl-mesalamine. [Figure 3B] Figure 3 shows the plasma PK of the test compound (INT-001) from the study of Figure 1 versus the reference compound (ROWASA). Figure 3A shows mesalamine, while Figure 3B shows n-acetyl-mesalamine. [Figure 4] FIG. 4 shows the mesalamine reference data for the study in FIG. [Diagram 5] FIG. 5 shows the test compound data from the study of FIG. [Figure 6] FIG. 6 shows the mean 5-ASA in feces for the test and reference compounds in the study of FIG. [Figure 7] FIG. 7 shows the mean n-ac-5-ASA in feces for the test and reference compounds in the study of FIG. [Figure 8] FIG. 8 shows the time to first stool following administration of the reference compound and the test compound for six exemplary test subjects in the study of FIG. [Figure 9] FIG. 9 shows stability data for various exemplary compound formulations. [Figure 10] FIG. 10 shows poloxamer stability with respect to lipid S100. [Figure 11] FIG. 11 shows poloxamer stability with respect to p90G. [Figure 12] FIG. 12 shows the gelation temperatures for various compounds in the excipient compatibility study. [Figure 13] FIG. 13 shows the gelation temperatures for various lipid combinations. [Figure 14] FIG. 14 shows the gelation temperature for poloxamer 188. [Figure 15] FIG. 15 shows the gelation temperature for the Lipoid S 100 composition. [Figure 16] FIG. 16 shows the gelation temperatures for Phospholipon 90 G compositions. [Figure 17]FIG. 17 shows the rheology results for composition 278. [Figure 18] FIG. 18 shows the rheology results for composition 279. [Figure 19] FIG. 19 shows the rheology results for composition 280. [Figure 20] FIG. 20 shows the rheology results for composition 278 versus composition 291. [Figure 21] FIG. 21 shows the rheology results for composition 279 versus composition 292. [Figure 22] FIG. 22 shows the rheology results for composition 280 versus composition 293. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description The present invention includes a composition comprising an active ingredient, at least one grade of thermogelling polymer, lipid, and a solubilizer for said lipid.It further includes a kit comprising a first container comprising a first composition comprising said active ingredient; a second container comprising a second composition comprising at least one grade of thermogelling polymer, lipid, and a solubilizer for said lipid.The present invention further includes a method of treating a condition in a subject, comprising the steps of receiving a kit comprising a first container comprising a first composition comprising said active ingredient; a second container comprising a second composition comprising at least one grade of thermogelling polymer, lipid, and a solubilizer for said lipid; mixing said first and second compositions to form a final formulation, and administering said final formulation.

[0020] The active ingredient can be an aminosalicylate. The aminosalicylate can be 5-ASA, 4-ASA, azodisalicylate, balsalazide, ipsalazide, olsalazine, or sulfasalazine.

[0021] One embodiment of the present invention is encompassed by mesalamine as the active ingredient. Mesalamine is variously known as mesalazine, 5-aminosalicylic acid, 5-ASA. Mesalamine has the following structure: [ka] and has the chemical formula C7H7NO3. Mesalamine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalamine. Mesalamine is known as a disease-modifying antirheumatic drug (DMARD), but its exact mechanism of action is unknown. Mesalamine may reduce the activity of cyclooxygenase and lipoxygenase, thus reducing the presence of prostaglandins, which in turn has an anti-inflammatory effect. Current mesalamine treatments administer the drug locally into the gastrointestinal lumen, either via enteric-coated or other delayed release oral dosage forms, or rectally as an enema. In one embodiment of the invention, the concentration of mesalamine is between about 0.5-15% w / v of the composition; in another embodiment, the concentration of mesalamine is between about 6-8% w / v of the composition.

[0022] The present invention may include any one or more grades of thermogelling polymers, where each grade is present in a different concentration.

[0023] A preferred embodiment of the present invention may include Poloxamer 407 as one of the grades of thermogelling polymer. Poloxamer 407 is a copolymer used as a hydrophilic non-ionic surfactant. As a surfactant, it reduces surface tension, allowing for the suspension and emulsification of, for example, lipophilic solids in hydrophilic liquids (or vice versa). It has the chemical formula C 572 H 1146 O 259and has two hydrophilic blocks of polyethylene glycol with about 101 repeats, surrounded by a block of polypropylene glycol with 56 repeats. In one embodiment of the invention, the concentration of poloxamer 407 is between about 10-16% w / v of the composition; in another embodiment, the concentration of poloxamer 407 is between about 12-13.5% w / v of the composition.

[0024] Another embodiment of the present invention may include Poloxamer 188 as one of the grades of thermogelling polymers. Poloxamer 188 is also a copolymer and another surfactant molecule. It has the chemical formula CH 18 O3 and is a copolymer of ethylene oxide and propylene oxide. In one embodiment of the invention, the concentration of poloxamer 188 is between about 0.001-1% w / v of the composition.

[0025] An embodiment of the present invention may include lipids. Lipids are a major group of biomolecules that are typically carbohydrates. Lipids are not normally soluble in water. Phospholipids are a class of lipids that have a hydrophobic tail protruding from the hydrophilic head of the molecule. Phospholipids occur naturally and are found in cell membranes.

[0026] One embodiment of the present invention may include phosphatidylcholine as the lipid. Phosphatidylcholine is a type of phospholipid with choline as the head group; it is a common component of biological membranes and acts as a surfactant. Phosphatidylcholine may be commercially produced by purifying naturally occurring phosphatidylcholine. A commercially available phosphatidylcholine, in one embodiment of the present invention, is LIPOID S 100 (phosphatidylcholine derived from soybeans with aggregates, Lipoid GmbH). In one embodiment of the present invention, the concentration of phosphatidylcholine is between about 0.001-4% w / v of the composition; in another embodiment of the present invention, the concentration of phosphatidylcholine is 1.5-2.5% w / v of the composition.

[0027] One embodiment of the present invention can include the solubilizer of the lipid.Solubilizer acts as a surfactant and increases the solubility of one drug in the other drug.For example, lipophilic substances that may not dissolve in aqueous solution can be solubilized by solubilizer, which acts as a surfactant and reduces the surface tension between solute and solvent.

[0028] An embodiment of the present invention may include diethylene glycol monoethyl ether as a solubilizing agent. Diethylene glycol monoethyl ether has the chemical formula CH3CH2OCH2CH2OCH2CH2OH, has the IUPAC name 2-(2-ethoxyethoxy)ethan-1-ol, and exhibits apparent activity as a solvent. Diethylene glycol monoethyl ether is sold under a number of trade names, including Transcutol (Millipore Sigma KGaA). In one embodiment of the present invention, the concentration of diethylene glycol monoethyl ether is between 5-15% w / v of the composition; in another embodiment of the present invention, the concentration of diethylene glycol monoethyl ether is between about 8-10% w / v of the composition.

[0029] In another embodiment of the invention, the invention is provided as a kit comprising a first container containing a first composition comprising the active ingredient; and a second container containing a second composition comprising multiple grades of thermogelling polymer, the grades being present in different concentrations, a lipid, and a solubilizer for the lipid.

[0030] A further embodiment of the present invention is a method for treating a condition in a subject, comprising receiving a kit comprising a first container comprising a first composition comprising the active ingredient; and a second container comprising a second composition comprising a plurality of grades of thermogelling polymer, said grades being present at different concentrations, a lipid, and a solubilizer for said lipid, mixing said first and second compositions to form a final formulation, and administering said final formulation.The method may comprise providing said kit locally to the colon of the subject.The method is useful for treating digestive disorders (e.g., irritable bowel disorder, ulcerative colitis, or Crohn's disease).

[0031] In one embodiment of the invention, the composition is liquid at 20-25°C and transitions to a gel at 32-37°C. This allows the present invention to be presented to a subject in a stable form of liquid, which when administered to the subject is then presented to the rectum via an enema, and the temperature of the mixture rises to the subject's body temperature. In the context of the present invention, this causes the composition to gel when introduced to the colon, making enema retention easier for the subject. Enema retention is crucial to the absorption of mesalamine and therefore its effectiveness.

[0032] According to one method of the present invention, the subject performs mixing and administering. The mixing step can include adding the second composition to the first composition, and shaking for at least 30 seconds to suspend the formulation. The mixing step can include adding the second composition to the first composition, and shaking for at least 15 seconds to suspend the formulation. The mixing step can include adding the second composition to the first composition, and shaking for at least 10 seconds, leaving for 1 minute, and then shaking again for another 10 seconds to suspend the formulation. The mixing step can include adding the first composition to the second composition, and shaking for at least 10 seconds, leaving for 1 minute, and then shaking again for another 10 seconds to suspend the formulation.

[0033] Administration Those skilled in the art will determine the dosing interval for the above method.Dosing regimen may include one or more of dosage, dosing frequency, dosing mode, and duration.Multiple dose regimen may differ in dosage, dosing frequency, dosing mode, or any combination thereof.

[0034] The frequency of administration can be defined by the interval between doses. By way of example and not limitation, the interval between doses can be about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 5 days, about 6 days, about 7 days, about 8 days, about 10 days, about 12 days, about 14 days, about 3 weeks, about 4 weeks, at least 6 hours, at least 8 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 5 days, at least It can be at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 12 days, at least 14 days, at least 3 weeks, at least 4 weeks, more than 6 hours, more than 8 hours, more than 12 hours, more than 15 hours, more than 24 hours, more than 36 hours, more than 48 hours, more than 60 hours, more than 72 hours, more than 84 hours, more than 96 hours, more than 5 days, more than 6 days, more than 7 days, more than 8 days, more than 10 days, more than 12 days, more than 14 days, more than 3 weeks, or more than 4 weeks.

[0035] The administration regimen may include one or more modes of administration. The modes of administration may be suitable for local or systemic administration. By way of example and not limitation, modes of local administration include topical administration and rectal administration (e.g., via enema, suppository, foam), and other delivery methods via the anus. By way of example and not limitation, modes of systemic administration include oral, enteral, parenteral, by injection, and by infusion.

[0036] In methods involving multiple phases, for example two or more phases of treatment, the phases may differ by any relevant parameter. By way of example and not limitation, the phases may differ in one or more of duration, dosage, frequency, mode of administration, route of administration, or therapeutic composition. The first phase of treatment may have a longer or shorter duration than the second phase of treatment. The first phase of treatment may have a higher or lower dosage of the agent than the second phase of treatment. The first phase of treatment may have a shorter or longer interval between dose administrations than the second phase of treatment. The first and second phases of treatment may have the same mode of administration, or they may have different modes of administration. The first and second phases of treatment may have the same route of administration, or they may have different routes of administration. The first and second phases of treatment may use the same composition, or they may use different compositions. One phase of treatment may use a single therapeutic agent and another phase may use a combination of therapeutic agents. The first and second phases of treatment may use different combinations of therapeutic agents.

[0037] The subject can be an animal (e.g., a mammal). A mammalian subject can nonexclusively be a human, a mouse, or a rat.

[0038] Different dosing regimens may achieve separate therapeutic objectives, for example, a first dosing regimen may induce alleviation of a condition, and a second dosing regimen may maintain alleviation of the condition.

[0039] Induction therapy is typically used to treat the acute phase of a condition or to provide relief from symptoms associated with the acute phase. The acute phase of a condition may have one or more of the following characteristics: sudden onset, short duration, rapid progression, need for urgent treatment, elevated levels of diagnostic markers. The acute phase of certain conditions (e.g., IBD) is known as a "flare-up."

[0040] Maintenance therapy, on the other hand, generally prevents the condition or its symptoms from recurring. Maintenance therapy can be used to treat any non-acute phase of the condition, i.e., any phase of the condition that does not have one or more criteria of an acute phase. Thus, maintenance therapy is usually long-term and continues even if the patient does not experience symptoms.

[0041] The method of the present invention may include providing a drug locally as described herein without the use of another form of treatment. Alternatively, the method of the present invention may include administering a drug locally as described herein in combination with another form of treatment. By way of example and not limitation, the second form of treatment may differ in drug, dosing regimen, dosage, dosing interval, mode of administration, route of administration, or any combination of the aforementioned elements. For example, the second form of treatment may include administering a drug non-locally, for example, systemically or orally. The second form of treatment may be performed before, simultaneously, or after providing a drug locally as described herein. Each method of treatment may independently induce alleviation of a condition, maintain alleviation of a condition, or both.

[0042] Treatment of post-acute GI conditions The present invention also includes a method of treating a GI condition by providing a drug locally to the rectum or colon of a subject after the acute phase or exacerbation of the GI condition. The treatment can maintain the GI condition in a reduced state. For example, the treatment can maintain the alleviation of the condition. Additionally or alternatively, the method can include treating the GI condition by providing a drug locally to the upper GI tract (e.g., mouth, esophagus, or stomach) of a subject after the acute phase or exacerbation of the GI condition.

[0043] As noted above, the acute phase or exacerbation of a condition may have one or more of the following characteristics: sudden onset, short duration, rapid progression, need for urgent treatment, elevated levels of diagnostic markers. Thus, post-acute phase treatment may include any post-acute phase treatment of a condition that does not meet one or more criteria of an acute phase.

[0044] The method can include locally administering an agent according to a dosing regimen, which can include any of the elements described above in connection with dosing regimens (e.g., dosage, frequency of administration, mode of administration, and duration).

[0045] As indicated above, the frequency of administration can be defined by the interval between doses. By way of example and not limitation, the interval between doses can be about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 5 days, about 6 days, about 7 days, about 8 days, about 10 days, about 12 days, about 14 days, about 3 weeks, about 4 weeks, at least 6 hours, at least 8 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 5 days, at least 10 days, at least 12 days, at least 14 ... It can be at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 12 days, at least 14 days, at least 3 weeks, at least 4 weeks, more than 6 hours, more than 8 hours, more than 12 hours, more than 15 hours, more than 24 hours, more than 36 hours, more than 48 hours, more than 60 hours, more than 72 hours, more than 84 hours, more than 96 hours, more than 5 days, more than 6 days, more than 7 days, more than 8 days, more than 10 days, more than 12 days, more than 14 days, more than 3 weeks, or more than 4 weeks.

[0046] As described above, the administration regimen may include one or more administration modes. The administration modes may be suitable for local or systemic administration. By way of example and not limitation, local administration modes include topical administration and rectal administration (e.g., via enema, suppository, foam), and other methods of delivery via the anus. By way of example and not limitation, systemic administration modes include oral, enteral, parenteral, by injection, and by infusion.

[0047] The subject can be any type of subject, as described above. The subject can be a human.

[0048] The method may include providing the agent locally as described herein without the use of another form of treatment. Alternatively, the method of the present invention may include providing the agent locally as described herein in combination with another form of treatment. The second form of treatment may have any of the elements described above.

[0049] Treating GI conditions using extended intervals between doses Embodiments of the invention include treating a GI condition by repeatedly providing a drug locally to the rectum or colon of a subject, the doses being separated by long intervals. Additionally or alternatively, the method may include treating a GI condition by repeatedly providing a drug locally to the upper GI tract (e.g., mouth, esophagus, or stomach) of a subject, the doses being separated by long intervals.

[0050] A problem with previous methods of local administration of therapeutic agents to the colon is the poor retention of the agent in the colon after defecation, necessitating frequent re-administration of the agent via an enema. This inconvenience results in low rates of patient compliance with the prescribed administration regimen. See, for example, Boyle et al., Adherence to Rectal Mesalamine in Patients with Ulcerative Colitis, Inflamm. Bowel Dis. 2015 Dec;21(12):2873-8. doi: 10.1097 / MIB.0000000000000562, the contents of which are incorporated herein by reference. Due to the superior retention of therapeutic agents in the colon using the compositions and methods of the present invention, embodiments of the present invention allow subjects to extend the interval between administration of enemas, resulting in better patient compliance.

[0051] The interval between doses can be a specified period of time. By way of example and not limitation, the interval between doses can be about 6 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 5 days, about 6 days, about 7 days, at least 6 hours, at least 8 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 5 days, at least 6 days, at least 7 days, more than 6 hours, more than 8 hours, more than 12 hours, more than 24 hours, more than 36 hours, more than 48 hours, more than 60 hours, more than 72 hours, more than 84 hours, more than 96 hours, more than 5 days, more than 6 days, or more than 7 days.

[0052] The agent can be retained in the colon for a specified period of time. By way of example and not limitation, the agent can be retained in the colon for at least 6 hours, at least 8 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 5 days, at least 6 days, at least 7 days, more than 6 hours, more than 8 hours, more than 12 hours, more than 24 hours, more than 36 hours, more than 48 hours, more than 60 hours, more than 72 hours, more than 84 hours, more than 96 hours, more than 5 days, more than 6 days, or more than 7 days.

[0053] The agent may exert or maintain a therapeutic effect in the colon for a specified period of time. By way of example and not limitation, the agent may exert or maintain a therapeutic effect in the colon for at least 6 hours, at least 8 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 5 days, at least 6 days, at least 7 days, more than 6 hours, more than 8 hours, more than 12 hours, more than 24 hours, more than 36 hours, more than 48 hours, more than 60 hours, more than 72 hours, more than 84 hours, more than 96 hours, more than 5 days, more than 6 days, or more than 7 days.

[0054] The method can include locally administering an agent according to a dosing regimen, which can include any of the elements described above in connection with dosing regimens (e.g., dosage, frequency of administration, mode of administration, and duration).

[0055] The subject may be any type of subject described above. The subject may be a human.

[0056] The method may include providing the agent locally as described herein without the use of another form of treatment. Alternatively, the method of the present invention may include providing the agent locally as described herein in combination with another form of treatment. The second form of treatment may have any of the elements described above.

[0057] Treats GI conditions without repeating doses after bowel movements The embodiments of the present invention may include a method of locally providing a drug to the rectum or colon of a subject, the drug is not re-administered to the subject after defecation, but maintains its therapeutic effect after defecation. Clearance from the colon is a problem with previous methods of administering therapeutic agents. For example, when 5-ASA is orally administered to a subject, the level of 5-ASA in the colon is reduced by laxatives or colonic irrigation. De Vos et al., Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations, Gut, 1992 Oct;33(10):1338-42, the contents of which are incorporated herein by reference. When 5-ASA is locally applied by enema, 5-ASA in the colon is dramatically reduced after defecation. Campieri et al., Topical administration of 5-aminosalicylic acid enemas in patients with ulcerative colitis, Studies on rectal absorption and excretion, Gut, 1985, 26, 400-405, the contents of which are incorporated herein by reference.

[0058] The methods and compositions of the present invention provide stable delivery of a therapeutic agent that is retained in the colon even after bowel emptying. Thus, the present invention provides a method in which local administration of a therapeutic agent does not have to be repeated after the subject has mobilized his bowels.

[0059] For example, in certain methods of the present invention, the effectiveness of drug absorption is not hindered or only minimally hindered, i.e., is not hindered above a specified threshold after the subject has defecation.In certain methods of the present invention, the effectiveness, drug absorption, and / or drug level are maintained above a specified threshold after the subject has defecation.In conclusion, compared with previous methods, the method of the present invention is less burdensome.

[0060] A certain amount of the drug can be retained in the colon after defecation.For example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the drug can be retained in the colon after defecation by the subject.

[0061] The therapeutic effect of the agent can be maintained in the colon after defecation.For example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the therapeutic effect can be maintained in the colon after defecation by the subject.

[0062] In the method that does not require re-administration of drug after defecation, the drug can nevertheless be re-administered at an interval that is independently defined and does not depend on the defecation of the subject.For example, the drug can be re-administered after one of the intervals described above or according to the administration regimen described above.The administration regimen can include any of the elements (e.g., dosage, administration frequency, administration mode, and duration) described above in connection with administration regimen.

[0063] The subject may be any type of subject described above. The subject may be a human.

[0064] The method may include providing the agent locally as described herein without the use of another form of treatment. Alternatively, the method of the present invention may include providing the agent locally as described herein in combination with another form of treatment. The second form of treatment may have any of the elements described above.

[0065] Treats GI conditions without repeating doses after consumption of food or liquids As described below, the methods of the present invention are also useful for treating conditions of the upper GI tract (e.g., eosinophilic esophagitis, oral mucositis, and esophageal varices). In certain embodiments, the present invention provides methods and compositions that are retained in the upper GI tract (e.g., mouth, esophagus, or stomach) even after consumption of liquid or solid food. Thus, the present invention provides methods in which local administration of a therapeutic agent does not need to be repeated after the subject eats and / or drinks.

[0066] A specified amount of the drug can be retained in the upper GI tract after consumption of food, liquid, or both. For example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the drug can be retained in the upper GI tract after consumption of food, liquid, or both.

[0067] The prescribed therapeutic effect of the agent may be maintained in the upper GI tract after consumption of food, liquid, or both. For example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the therapeutic effect may be maintained in the upper GI tract after consumption of food, liquid, or both.

[0068] In the method that does not require re-administration of drug after consuming food, liquid, or both, the drug can nevertheless be re-administered at an interval that is independently defined and does not depend on the subject eating or drinking.For example, the drug can be re-administered after one of the intervals described above, or according to the administration regimen described above.The administration regimen can include any of the elements (e.g., dosage, administration frequency, administration mode, and duration) described above in connection with administration regimen.

[0069] The subject may be any type of subject described above. The subject may be a human.

[0070] The method may include providing the agent locally as described herein without the use of another form of treatment. Alternatively, the method of the present invention may include providing the agent locally as described herein in combination with another form of treatment. The second form of treatment may have any of the elements described above.

[0071] Liquid to gel transition The agent is provided in a formulation that exists as a liquid when the formulation is below a threshold condition and exists as a gel when the formulation is above a threshold condition, which can be any combination of physical, chemical, and temporal conditions.

[0072] The chemical condition may be acidity, alkalinity, or pH. The threshold condition may be a transition pH. The formulation may exist as a liquid when the formulation is below a transition pH and as a gel when the formulation is above a transition pH. The threshold condition may be a transition pH. The formulation may exist as a liquid when the formulation is above a transition pH and as a gel when the formulation is below a transition pH.

[0073] The temporal condition can be time. The threshold condition can be a transition time point. The formulation can exist as a liquid prior to the transition time point and as a gel after the transition time point.

[0074] The physical condition may be a temperature. The threshold condition may be a transition temperature. The formulation may exist as a liquid when the formulation is below the transition temperature and as a gel when the formulation is above the transition temperature. The formulation may exist as a liquid when the formulation is above the transition temperature and as a gel when the formulation is below the transition temperature.

[0075] The agent may be provided in a formulation that exists as a liquid at a first temperature and transitions to a gel at a second temperature. The transition from the first temperature to the second temperature may be accompanied by an increase in viscosity. For example, the formulation may exist as a liquid at or near room temperature (about 23°C) and as a gel at or near physiological temperature (about 37°C). When such formulations are stored and administered to a patient at room temperature, for example, via an enema, they may easily reach the rectum, sigmoid colon, and descending colon. Once inside the colon, such formulations transition to a gel phase and adhere to the lining of the colon, thereby allowing prolonged exposure of inflamed tissue to the agent. Formulations that undergo such phase transitions and their use for delivery of therapeutic agents to the colon are described, for example, in International Patent Publication No. WO 2016 / 179227; and Sidhartha R. Sinha et al., A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies, Gastroenterology, 2015 Jul;149(1):52-55.e2, doi: 10.1053 / j.gastro.2015.04.002, the contents of each of which are incorporated herein by reference.

[0076] By way of example and not limitation, the formulations may exist as a liquid at about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, or about 35°C.

[0077] By way of example and not limitation, the formulations may exist as liquids at about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, or about 40°C.

[0078] By way of example and not limitation, the above formulations may be used in a temperature range of about 16°C to about 40°C, about 18°C ​​to about 40°C, about 20°C to about 40°C, about 22°C to about 40°C, about 24°C to about 40°C, about 26°C to about 40°C, about 28°C to about 40°C, about 30°C to about 40°C, about 32°C to about 40°C, about 34°C to about 40°C, about 36°C to about 40°C, about 38°C to about 40°C, about 16°C to about 38°C, about 18°C ​​to about 38°C, about 20°C to about 38°C, about 22°C to about 38°C, about 24°C to about 38°C, about 26°C to about 38°C, about 28°C to about 38°C, about 30°C to about 38°C, about 32°C to about 38°C, about 34°C to about 38°C, about 36°C to about 38°C, from about 16°C to about 36°C, about 18°C ​​to about 36°C, about 20°C to about 36°C, about 22°C to about 36°C, about 24°C to about 36°C, about 26°C to about 36°C, about 28°C to about 36°C, about 30°C to about 36°C, about 32°C to about 36°C, about 34°C to about 36°C, about 16°C to about 34°C, about 18°C ​​to about 34°C, about 20°C to about 34°C, about 22°C to about 34°C, about 24°C to about 34°C, about 26°C to about 34°C, about 28°C to about 34°C, About 30°C to about 34°C, about 32°C to about 34°C, about 16°C to about 32°C, about 18°C ​​to about 32°C, about 20°C to about 32°C, about 22°C to about 32°C, about 24°C to about 32°C, about 26°C to about 32°C, about 28°C to about 32°C, about 30°C to about 32°C, about 16°C to about 30°C, about 18°C ​​to about 30°C, about 20°C to about 30°C, about 22°C to about 30°C, about 24°C to about 30°C, about 26°C to about 30°C, about 28°C to about 30°C,, It may transition to a gel at from about 16°C to about 28°C, about 18°C ​​to about 28°C, about 20°C to about 28°C, about 22°C to about 28°C, about 24°C to about 28°C, about 26°C to about 28°C, about 16°C to about 26°C, about 18°C ​​to about 26°C, about 20°C to about 26°C, about 22°C to about 26°C, about 24°C to about 26°C, about 16°C to about 24°C, about 18°C ​​to about 24°C, about 20°C to about 24°C, about 22°C to about 24°C, about 16°C to about 22°C, about 18°C ​​to about 22°C, about 20°C to about 22°C, about 16°C to about 20°C, or about 18°C ​​to about 20°C.

[0079] The agent may be provided in a formulation that transitions between liquid and gel phases in response to a stimulus other than or in addition to a temperature change. By way of example and not limitation, the stimulus may be or may include one or more of a change in pH, a solvent exchange, electromagnetic radiation (e.g., visible light, ultraviolet light, infrared light, X-rays, fluorescent light), sound waves (e.g., ultrasound), pressure, or the presence of certain ions or molecules. Examples of systems that exhibit an in situ sol-gel transition are known in the art and are described, for example, in Kouchak, M., In Situ Gelling Systems for Drug Delivery, Jundishapur J Nat Pharm Prod. 2014 Aug; 9(3): e20126, PMCID: PMC4165193; PMID: 25237648; and Jones and Steed, Gels with sense: supramolecular materials that respond to heat, light and sound, Chem. Soc. Rev., 2016, 45, 6546-6596, DOI 10.1039 / C6CS00435K, each of which is incorporated herein by reference.

[0080] GI state The methods of the present invention can be used to treat any GI condition. By way of example and not limitation, the GI condition may be achalasia, Barrett's esophagus, Boerhaave syndrome, celiac disease, constipation, Crohn's disease, diverticulitis, enteritis, enterocolitis, eosinophilic esophagitis, esophageal burn, esophageal candidiasis, esophageal spasm, esophageal stricture, esophageal webbing, esophageal varices, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal bleeding, indeterminate colitis, inflammatory bowel disease, intestinal graft-versus-host disease, irritable bowel syndrome, Mallory-Weiss tears, microscopic colitis, nutcracker esophagus, oral mucositis, pernicious anemia, pouchitis, radiation colitis, radiation esophagitis, radiation proctitis, ulcerative colitis, ulcer, or Zenker's diverticulum.

[0081] Certain methods of the present invention are useful for the treatment of IBD. IBD is a group of debilitating conditions that includes Crohn's disease, ulcerative colitis, and indeterminate colitis. IBD occurs when tissues in the GI tract become inflamed. Crohn's disease can affect tissues of the mouth, esophagus, stomach, small intestine, large intestine, or anus. Ulcerative colitis primarily affects the colon and rectum. Inflammation can be localized or concentrated in one or more specific parts of the colon (e.g., ascending colon, transverse colon, descending colon, sigmoid colon), or rectum. Indeterminate colitis includes colitis that is not considered to be either Crohn's disease or ulcerative colitis, and may have some characteristics of either or both. IBD may be accompanied by one or more symptoms (e.g., abdominal pain, anemia, arthritis, bronchiolitis obliterans with organizing pneumonia, cramps / muscle spasms, deep vein thrombosis (DVT), diarrhea, fatigue, fever, loss of appetite, non-thyroid disease syndrome (NTIS), primary sclerosing cholangitis, pyoderma gangrenosum, erythema nodosum, arthritis, and rectal bleeding.

[0082] Treatment of IBD typically includes two phases. In the first phase (induction), the goal of treatment is to induce abatement of inflammation and provide relief from symptoms. Induction treatment is used during the acute phase or flare-up of IBD. Once abatement is achieved, the second phase of treatment (maintenance) is directed to maintaining the abatement and preventing recurrence. Maintenance therapy is generally long-term and continues even if the patient is not experiencing symptoms. Thus, maintenance therapy is used to maintain IBD in a reduced state. The induction and maintenance phases may include the same or different medications, modes of administration, frequency of administration, and dosages.

[0083] The acute phase of IBD may have one or more of the following characteristics generally described above in relation to the acute phase of the condition. As indicated above, the acute phase of IBD is sometimes referred to as "flare-up". The following markers can be used to diagnose IBD, determine its severity level, and characterize the phase of the condition (e.g., determine whether it is acute or non-acute): albumin, antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), C-reactive protein (CRP), calprotectin, erythrocyte sedimentation rate (ESR), lactoferrin, white blood cell count, platelet count, and alpha 1 acid glycoprotein (orosomucoid). IBD can also be evaluated by analysis of proteome, transcriptome, genome, and post-translational modifications (e.g., phosphorylation, acetylation, glycosylation, disulfide bond formation, deamidation, and citrullination).Biomarkers for IBD and their diagnostic applications are described in more detail in, for example, Bennike T. et al., Biomarkers in inflammatory bowel diseases: Current status and proteomics identification strategies, World J Gastroenterol. 2014 Mar 28; 20(12): 3231-3244, doi: 10.3748 / wjg.v20.i12.3231; Mohsen Norouzinia et al., Biomarkers in inflammatory bowel diseases: insight into diagnosis, prognosis and treatment, Gastroenterol Hepatol Bed Bench, 2017 Summer; 10(3): 155-167; and Viennois E. et al., Biomarkers of IBD: from classical laboratory tools to personalized medicine, Inflamm Bowel Dis. 2015 Oct; 21(10): 2467-2474, doi: 10.1097 / MIB.0000000000000444, the contents of each of which are incorporated herein by reference.

[0084] The method of the present invention is also useful for treating irritable bowel syndrome (IBS).IBS includes GI symptoms (such as abdominal pain and changes in bowel patterns) without any evidence of underlying damage.Symptoms can occur over several years.IBS has been classified into four types based on whether diarrhea and constipation are common: IBS-D (where diarrhea is common); IBS-C (where constipation is common); IBS-M (where both diarrhea and constipation are common); and IBS-U (where neither diarrhea nor constipation are common).

[0085] The methods of the present invention may also be used to treat conditions of the upper GI tract. By way of example and not limitation, the methods may include the treatment of eosinophilic esophagitis, oral mucositis, or esophageal varices. EXAMPLES

[0086] Working Example Two compartments: During the stability of the single compartment formulations, most of the formulations showed an increase in gelling temperature (>40° C.). In addition to this, a change in appearance is also observed. The appearance changes from a light pink dispersion to a brownish dispersion. To address the challenge, a two-compartment formulation was assumed. One compartment contains the API and the other contains the diluent. The API needs to be reconstituted before use.

[0087] The goals of the two-compartment formulation are: Gelation temperature: 30~37℃ Gel time – less than 5 minutes Reconstitution time – less than 1 minute Viscosity at RT – <3000cps The reconstituted formulation should be stable for at least 3 hours. Based on the excipients used in the formulations, the formulations were classified into non-lipid and lipid-based formulations.

[0088] Non-lipid-based formulations: During the formulation development, we observed that one dilute formulation did not gel when heated to 50° C., but only began to gel after reconstitution with mesalamine. The composition is provided as follows: [Table 1]

[0089] observation The initial gel temperature is satisfactory.

[0090] Stability batch: Multiple batches were prepared and the stability was monitored to understand the reproducibility of the gelation temperature. In addition, the source of mesalamine was varied in one of the batches to understand its effect on various physical parameters.

[0091] The composition for the stability batch is provided below: [Table 2]

[0092] Manufacturing process: The manufacture of the non-lipid diluent involves a number of steps. A detailed manufacturing process is provided below:

[0093] Preparation of Tris solution: Tris was dissolved in a partial amount of water with stirring. Stirring was continued until a clear, colorless solution was observed.

[0094] Preparation of polycarbophil phase: Polycarbophil was dispersed in a partial amount of purified water with stirring. Stirring was continued until a lump-free dispersion was observed. The Tris solution prepared above was slowly added to the polycarbophil dispersion with stirring. Stirring was continued for 15 minutes.

[0095] Preparation of sodium chloride solution: A weighed amount of sodium chloride was dissolved in a partial amount of purified water.

[0096] Preparation of diluents: Purified water was placed in a stainless steel container and heated to 50±5°C. To it, Edetate Disodium and Vitamin E TPGS were added with stirring and dissolved. The solution was cooled to 2-5°C using an ice-water bath. Poloxamer 407 was added under vortex to ensure a uniform dispersion. Stirring was continued while maintaining the temperature (<5°C) until Poloxamer 407 was completely dissolved. To this, the required amount of Transcutol P was added under stirring. Stirring was continued for another 15 minutes to ensure uniform mixing. To this mixture, the previously prepared polycarbophil phase was added with stirring while maintaining the product temperature below 5°C. To this mixture, the previously prepared sodium chloride solution was added with stirring while maintaining the product temperature below 5°C. The mixture was removed from the ice-water bath and stirring was continued until the product temperature reached 25°C. To this, PVP (Kollidon 30) was added with stirring. Stirring was continued until the PVP was completely dissolved.

[0097] [Table A]

[0098] observation: No significant changes in gelation temperature and pH are observed in all batches. The formulations have been found to be stable for up to 12 months. Further changes in excipient concentration were made to understand the effect on gelation temperature. The compositions are shown below: [Table 3-1] [Table 3-2]

[0099] Manufacturing Process: POC-0718 / 285 / P, POC-0718 / 400 / P, POC-0718 / 401 / P Preparation of the poloxamer phase: Dissolve edetate disodium in a partial amount of purified water. Heated to 55°C. Dissolved Vitamin E TPGS with stirring at 200-400 RPM. Cooled to 5±3°C. Poloxamer 407 was added with stirring over 3 hours. Store overnight in a cooling cabinet maintained at 5±3°C. Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dispersed in partial volume of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of sodium chloride solution · Sodium chloride was dissolved in a partial amount of water. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Mixed for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Addition was carried out for 15 minutes at 750±200 RPM. Sodium chloride solution was added to the above mixture. Addition was performed for 15 minutes at 750±200 RPM. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 478 / P Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of sodium chloride solution · Sodium chloride dissolved in partial volume of water. Preparation of the poloxamer phase: Dissolve edetate disodium in a partial amount of purified water. Heated to 55° C. Vitamin E TPGS was dissolved with stirring at 200-400 RPM. Cooled to 5±3°C. Poloxamer 407 was added with stirring. Stirred for 3 hours. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Sodium chloride solution was added to the above mixture. Stirred at 750±200 RPM for 15 minutes. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kolliodon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 488 / P Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dispersed in a partial amount of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of the poloxamer phase: Heat a portion of the water to 55°C. Dissolve Vitamin E TPGS with stirring at 200-400 RPM. Cooled to 5±3°C. Poloxamer 407 was added with stirring. Stirring was continued for 3 hours. Preparation of sodium chloride solution · Sodium chloride dissolved in partial volume of water. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Sodium chloride solution was added to the above mixture. Stirred at 750±200 RPM for 15 minutes. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 489 / P Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dispersed in a partial amount of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of the poloxamer phase: Heat a portion of the water to 55°C. Dissolve Vitamin E TPGS while stirring at 200-400 RPM. Cooled to 5±3° C. Poloxamer 407 was added with stirring. Stirring was continued for 3 hours. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 490 / P Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dissolved in a partial amount of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of the poloxamer phase: A portion of the water was cooled to 5±3°C. Poloxamer 407 was added with stirring. Stirring was continued for 3 hours. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 499 / P Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dissolved in a partial amount of water while stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of the poloxamer phase: A portion of the water was cooled to 5±3°C. Poloxamer 407 was added with stirring. Stirring was continued for 3 hours. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. POC-0718 / 511 / P, POC-0718 / 512 / P Preparation of the poloxamer phase: Dissolve edetate disodium in a partial amount of purified water. Heat to 55°C. Dissolve Vitamin E TPGS while stirring at 200-400 RPM. Cool to 5±3°C. Add Poloxamer 407 with stirring. Stir for 3 hours until the poloxamer is completely dissolved. Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dissolved in a partial amount of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Preparation of sodium chloride solution · Sodium chloride dissolved in partial volume of water. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Sodium chloride solution was added to the above mixture. Stirred at 750±200 RPM for 15 minutes. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours. POC-0718 / 513 / P Preparation of the poloxamer phase: Dissolve edetate disodium in a partial amount of purified water. Heat to 55°C. Dissolve Vitamin E TPGS while stirring at 200-400 RPM. Cool to 5±3°C. Add Poloxamer 407 with stirring. Stir for 3 hours until the poloxamer is completely dissolved. Preparation of Tris solution · Tris was dissolved in partial volume of water. Preparation of polycarbophil phase Polycarbophil was dissolved in a partial amount of water with stirring at 500-600 RPM. · Tris solution was added to the above dispersion while stirring at 500±200 RPM. Processing in the main production vessel Transcutol P was added to the poloxamer phase. Stirred for 15 minutes at 750±200 RPM. Polycarbophil phase was added to the above mixture. Stirred for 15 minutes at 750±200 RPM. Stirring was continued without the ice bath to allow the product temperature to rise. It took about 1.5 hours to reach a temperature of 25°C. Kollidon 30 was added to it. Stirred at 75±200 RPM for 2 hours.

[0100] observation: Any small change in composition will result in a variation in the gelling temperature.

[0101] Effect of Mesalamine Concentration on Gelation Temperature: Various concentrations of mesalamine were dispersed in non-lipid diluents to understand their effect on the gelation temperature. [Table B]

[0102] observation: Mesalamine at 0.3 g and higher amounts exhibit the desired gelling temperature.

[0103] Lipid formulations The gelation phenomenon of poloxamers is reversible and is characterized by a sol-gel transition temperature. Thermal gelation is due to hydrophobic interactions between the poloxamer 407 copolymer chains. By increasing the temperature, the poloxamer 407 copolymer chains start to aggregate into micellar structures. The formation of the micellar structure is the result of the dehydration of the hydrophobic PPO repeating units and defines the first step of gelation. Phospholipids are widely used in the formation of micelles.

[0104] However, phospholipids are difficult to stabilize in an aqueous environment. The long-term stability or shelf life of lipid-containing drug products can be dramatically affected by the lipid species used in the formulation. The most common degradation pathways are oxidation and hydrolysis. 123 In general, the more unsaturated compounds, the more the product is oxidized, and therefore the shorter the shelf life of the product. Lipids derived from biological sources (e.g., egg, bovine, or soybean) typically contain significant levels of polyunsaturated fatty acids and are therefore inherently less stable than their synthetic counterparts. Saturated lipids offer the greatest stability with respect to oxidation, but they also present other difficulties in formulation, since they have much higher transition temperatures. Aqueous formulations of drug products tend to be less stable, because the presence of excess or bulk water leads to rapid hydrolysis in lipid preparations. This hydrolysis depends on several factors, including pH, temperature, type of buffer, ionic strength, acyl chain length and head group, and state of aggregation. 1Frrkjaer, S., Hjorth, EL, and Wrrts, O., Stability and storage of liposomes, in Optimization of Drug Delivery, Bundgaard, H., Bagger Hansen, A., and Kofod, H., Eds., Munksgaard, Copenhagen, 1982, 384. 2 Kensil, CR and Dennis, EA, Alkaline hydrolysis of phospholipids in model membranes and the dependence on their state of aggregation, Biochemistry, 20, 6079, 1981. 3 Grit, M., de Smidt, JH, Struijke, A., and Crommelin, DJA, Hydrolysis of phosphatidylcholine in aqueous liposome dispersions, Int. J. Pharm., 50, 1, 1989.

[0105] A variety of lipids of saturated and unsaturated nature were screened. Details of the lipids screened are as follows: saturated fat Phospholipon 90 H DSPC DPPC Lipoid SPC 3 unsaturated lipids Lipoid S 100 Phospholipon 90 g Formulation with Phospholipon 90 H Lipid 90 H is an unsaturated lipid and contains less than 90% hydrogenated phosphatidylcholine.

[0106] Various concentrations of Phospholipon 90H and Poloxamer 407 were screened, and the compositions are shown in Table 4.

[0107] [Table 4]

[0108] Manufacturing process: POC-0718 / 271 / P: Poloxamer phase Disodium edetate was dissolved in purified water. The solution was cooled to 5±3°C. The poloxamer was added to the cooled solution with stirring. Stir at 400-600 RPM for 2 hours. o Keep in cooling cabinet overnight for complete dissolution of poloxamer. · Lipid phase Phospholipon 90H was dissolved in transcutol at 45-50°C. · Emulsification The poloxamer phase was heated to 45°C. o The lipid phase was added to the poloxamer phase with stirring. Homogenize at 6000 RPM for 30 minutes. Cool to room temperature with stirring. POC-0718 / 282 / P, POC-0718 / 286 / P, POC-0718 / 287 / P: Poloxamer phase Disodium edetate was dissolved in purified water. The solution was cooled to 5±3°C. The poloxamer was added to the cooled solution with stirring. Stir at 400-600 RPM for 2 hours. o Keep in cooling cabinet overnight for complete dissolution of poloxamer. · Lipid phase Phospholipon 90H was dissolved in transcutol at 45-50°C. · Emulsification The poloxamer phase was heated to 45-50°C. o The lipid phase was added to the poloxamer phase with stirring. Homogenize at 7500 RPM for 15 minutes. Cool to room temperature with stirring.

[0109] Stress test: Among all batches, #286, #305 and #307 showed the desired gel temperature. A decrease in gel temperature was observed with increasing poloxamer concentration (13% and above). All these batches were subjected to stress testing at 60° C. and at the end of one week, all formulations showed gel temperatures above 40° C.

[0110] observation: Phospholipon 90H has a transition temperature of 55° C. Therefore, the emulsification temperature needs to be kept at 40-50° C. At higher temperatures, the poloxamer phase starts to thicken, which results in foam formation.

[0111] All of the above formulations exhibited non-gelling behavior at the end of one week at 60° C. In view of this, the strategy was discontinued.

[0112] Formulation with Lipoid SPC 3 Lipid SPC 3 is a saturated phospholipid that exhibits better aqueous stability when compared to unsaturated phospholipids. It is a saturated phospholipid with a low iodine value (3 or less). The lower the iodine value, the less unsaturated it is.

[0113] Lipidic SPC exhibits limited solubility at room temperature in Transcutol P and physical instability with the formulation made at room temperature. For improved physical stability, medium chain triglycerides were used in some experiments as a solvent to solubilize lipidic SPC 3.

[0114] The composition for the formulation with Lipoid SPC 3 is described as follows: [Table 5]

[0115] Manufacturing process for POC-0718 / 426: Poloxamer phase Disodium edetate was dissolved in purified water. The solution was cooled to 5±3°C. The poloxamer was added to the cooled solution with stirring. Stir at 400-600 RPM for 2 hours. o Keep in cooling cabinet overnight for complete dissolution of poloxamer. · Lipid phase Lipid SPC 3 was dissolved in transacetone at 40°C. · Emulsification The poloxamer phase was brought to RT with stirring. o The lipid phase was added to the poloxamer phase with stirring. Homogenize at 9000 RPM for 30 minutes. An emulsion with few lipid particles was observed on the surface of the formulation.

[0116] Manufacturing process of POC-0718 / 427: Poloxamer phase Disodium edetate was dissolved in purified water. The solution was cooled to 5±3°C. The poloxamer was added to the cooled solution with stirring. Stir at 400-600 RPM for 2 hours. o Keep in cooling cabinet overnight for complete dissolution of poloxamer. · Lipid phase Lipid SPC 3 was dissolved in transglycol and medium chain triglycerides at 55-60°C. · Emulsification The poloxamer phase was brought to RT with stirring. o The lipid phase was added to the poloxamer phase with stirring. Homogenize at 9000 RPM for 30 minutes.

[0117] Some formulations were made without edetate disodium to understand the impact on gelation temperature. The details of the above formulations are given in Table 6.

[0118] [Table 6]

[0119] Manufacturing process of POC-0718 / 437: Poloxamer phase ○ The purified water was cooled to 5±3°C. The poloxamer was added to the cooled solution with stirring. Stir at 400-600 RPM for 2 hours. o Keep in cooling cabinet overnight for complete dissolution of poloxamer. · Lipid phase Lipid SPC 3 was dissolved in transglycol and medium chain triglycerides at 55-60°C. · Emulsification The poloxamer phase was brought to RT with stirring. o The lipid phase was added to the poloxamer phase with stirring. Homogenize at 9000 RPM for 30 minutes.

[0120] These formulations were packed in both packaging materials (HDPE bottles and EVOh coated HDPE bottles) and subjected to stress testing (60°C) to obtain the stability at high temperature. During this testing, only the gelling temperature was monitored as the critical testing parameter. The results are shown below:

[0121] Stability testing: #426 and #427 showed promising gel temperatures. Reproducible batches were prepared for stability testing. The compositions for the stability batches are shown here: [Table C]

[0122] Manufacturing process of POC-0718 / 470: Manufacturing process of POC-0718 / 471: During the stability study, only the gelling temperature and pH of the reconstituted formulation were monitored.

[0123] [Table D]

[0124] Conclusion: Both formulations showed increased gel temperature at 6 months. Based on this, the strategy was discontinued.

[0125] Formulation with Lipoid S 100 Lipoid S 100 is an unsaturated phospholipid with a low transition temperature. Numerous experiments were performed to understand the effect of the formulation on the gelation temperature. The composition for the prototype formulation is shown below:

[0126] [Table 7]

[0127] Most of the above formulations showed gelation temperatures ranging from 25 to 36° C. To understand the effect of heat and time on the gelation temperature, all these formulations were kept at 60° C. for 4 weeks. The gelation temperature was monitored every week. The results are shown below:

[0128] [Table 8-1]

[0129] observation: #231 - Showed the desired gel temperature (30-36°C), but during stress testing, a decrease in gel temperature was observed. #236 and #243 – An increase in gel temperature is observed during stress testing. · #235 and #265 - Initial and stress tested samples showed low gel temperatures (<30°C).

[0130] Optimization of Lipoid S 100 concentration The Lipoid S 100 concentration in the formulation was optimized in the formulation by varying the Lipoid S 100 concentration. The composition is shown as follows: [Table 8-2]

[0131] Manufacturing process: Batch number POC-0718 / 231 / P Batch number POC-0718 / 263 / P Batch number POC-0718 / 264 / P

[0132] Stress test: The formulation with 1.5% Lipoid S 100 showed gelation whereas the formulation with 1% Lipoid S 100 did not gel when heated to 50°C.

[0133] A stress test (60°C) was performed on the above formulation (#264). The gelling temperature was monitored during the test. The results are shown as follows: [Table 9]

[0134] observation: At the initial time point, the desired gelation temperature (30-36°C) is observed. However, during the stress test, a decrease in the gelation temperature is observed. Based on the stress test, a minimum of 1.5% Lipoid S 100 is required to exhibit thermogelation behavior.

[0135] Stability batch: The formulation with 2% Lipoid S 100 was considered as the lead formulation. Reproducible batches with batch sizes (3-4 Kg) were manufactured and the stability was monitored. These batches were packed into different packaging materials MoC to understand its impact on the physical properties.

[0136] The composition of the batch is given as follows: [Table 10]

[0137] [Table 11]

[0138] [Table 12]

[0139] [Table 13]

[0140] [Table 14]

[0141] observation: The formulation is consistent in gelation temperature regardless of the source of API (diluent and reconstitution). No significant increases in impurity profile and other test parameters were observed.

[0142] During the formulation development, it was observed that additives such as PVP and poloxamer 188 increase the gelation temperature, whereas BHT decreases the gelation temperature. Further experiments were carried out to screen additives.

[0143] Effect of BHT on Lipoid S 100 formulation: In some formulations, BHT reduces the gelling temperature. This may further reduce the concentration of poloxamer 407 in the formulation. Experiments with different concentrations of BHT along with reducing the poloxamer were performed to understand its effect on the gelling temperature. The composition is shown below:

[0144] [Table 15]

[0145] Effect of Poloxamer 188 in Lipoid S 100 Formulations Based on compatibility studies (references: POC-0718 / 269 / P, POC-0718 / 270 / P and POC-0718 / 272 / P), Poloxamer 188 increases the gel temperature. The current lead formulation exhibits a gel temperature close to 30°C, and formulations with different concentrations of Poloxamer 188 were made to achieve the desired gel temperature of 32-36°C. The composition is shown below:

[0146] [Table 16]

[0147] observation: An increase in gelation temperature is observed with the addition of Poloxamer 188. To understand long-term storage, stability was monitored for two prototypes with 0.1% and 0.3% Poloxamer 188.

[0148] Stability batches with 0.1% Poloxamer 188: A formulation with 0.1% Poloxmer 188 was prepared. Stability was monitored with different grades and sources of mesalamine. The composition and stability details are as follows: [Table 17]

[0149] [Table 18]

[0150] [Table 19]

[0151] [Table 20]

[0152] [Table 21]

[0153] Stability batches with 0.3% Poloxamer 188: A formulation with 0.3% Poloxamer 188 was prepared. Stability was monitored with various grades and sources of mesalamine. The composition and stability details are as follows: [Table 22]

[0154] [Table 24]

[0155] The effect of polyvinylpyrrolidone (PVP) in Lipoid S 100 formulations. POC-0718 / 253-m Based on compatibility testing (reference: POC-0718 / 253-m), PVP K-30 increases the gel temperature. Experiments with different concentrations of PVP (Kollidon 30) were performed to understand its effect on the gel temperature. The composition is shown below:

[0156] [Table 25]

[0157] Observations: Among all the experiments, #432 and #444 showed the desired gelling temperature. These formulations were subjected to ICH stability studies to understand the impact.

[0158] [Table 26]

[0159] [Table 27]

[0160] observation: An increase in gelation temperature is observed during stability testing. Significant changes in gelation temperature are observed in formulations stored at accelerated conditions. The 6M 40 / 75 sample did not gel even at 40° C. Given the instability at accelerated conditions, the strategy was discontinued.

[0161] Effect of edetate disodium on Lipoid S 100 formulations Experiments involving the addition of disodium edetate were carried out to understand its effect on the gelation temperature. The composition is shown below: [Table 28]

[0162] Effect of phosphate buffer on Lipoid S 100 formulations. The pH for the reconstituted formulation is lower than the diluent. Mesalamine undergoes degradation at low pH. To control the pH for the diluent and reconstituted formulation, phosphate buffers of pH 7.4 and 8.0 were evaluated. The composition of the formulation is shown as follows:

[0163] [Table 29]

[0164] observation: A decrease in pH after reconstitution is observed despite the different buffers. An increase in the gelling temperature of the reconstituted formulation is also observed. Furthermore, the strategy was discontinued.

[0165] Reconstitution Test The lead prototype (#278 / P) was reconstituted with mesalamine (MSN). The gelation temperature was monitored periodically for up to 24 hours.

[0166] [Table 30]

[0167] Observations: No significant change in gelation temperature was observed up to 8 hours after reconstitution. After that, an increase in gelation temperature is observed.

[0168] Formulation with Phospholipon 90 G Phospholipon 90 G is an unsaturated phospholipid with a low transition temperature. Numerous experiments were performed to understand the effect of the formulation on the gelation temperature. The composition for the prototype formulation is shown below:

[0169] [Table 31]

[0170] [Table 32]

[0171] Stress test: To understand the effect of heat and time on the gelling temperature, all these formulations were kept at 60° C. for 4 weeks. The gelling temperature was monitored every week. The results are shown below:

[0172] [Table 33]

[0173] Formulation with 0.5% Phospholipon 90 G: [Table 34]

[0174] [Table 35]

[0175] [Table 36]

[0176] Stability at 0.75% Phospholipon 90 G: Multiple reproducible batches of #262 / P were manufactured and the stability was monitored with various sources / grades of mesalamine to understand their effect. The composition is provided below:

[0177] [Table 37]

[0178] [Table 38]

[0179] [Table 39]

[0180] [Table 40]

[0181] [Table 41]

[0182] observation: Heterogeneity of mesalamine is observed in Cambrex SH grades. Selected grades of mesalamine are aggregated and difficulty in achieving a uniform dispersion is observed during reconstitution. The formulation is found to be stable in HDPE bottles. Instability is observed in both batches packed in EVOH coated HDPE bottles.

[0183] Effect of Poloxamer 188 in Lipoid S 100 Formulations Based on compatibility studies (references: POC-0718 / 269 / P, POC-0718 / 270 / P and POC-0718 / 272 / P), Poloxamer 188 increases the gel temperature. The current lead formulation exhibited a gel temperature close to 30°C, and formulations with various concentrations of Poloxamer 188 were carried out to achieve the desired gel temperature of 32-36°C. The composition is shown below: [Table 42]

[0184] Effect of BHT on Phospholipon 90 G Preparation In some formulations, BHT reduces the gelling temperature. This may further reduce the concentration of poloxamer 407 in the formulation. Experiments with lowering poloxamer and different concentrations of BHT were performed to understand its effect on the gelling temperature. The composition is shown below: [Table 43]

[0185] Effect of edetate disodium on phospholipon 90 G formulations. Experiments involving the addition of disodium edetate were carried out to understand its effect on the gelation temperature. The composition is shown below: [Table 44]

[0186] [Table 45]

[0187] Conclusion: Phospholipon 90G formulations without edetate disodium show no change in gelation temperature during stability studies up to 12 months.

[0188] Effect of phosphate buffer on phospholipon 90 G formulations. The pH for the reconstituted formulation is lower than the diluent. Mesalamine undergoes degradation at low pH. To control the pH for the diluted and reconstituted formulation, phosphate buffers of pH 7.4 and 8.0 were evaluated. The composition of the formulation is shown as follows:

[0189] [Table 46]

[0190] Drugs suspended in transcutol To avoid spillage (of API into diluent) during reconstitution, the mesalamine was dispersed in transcutol containing lipids and the poloxamer phase in another container. The composition of the above formulation is provided as follows:

[0191] Lipid Compartment Trial 2 Stability Compartment-1: EDTA and Poloxamer P 407 in purified water Compartment-2: PG 90G, 5-ASA slurry in Transcutol [Table 47]

[0192] [Table 48]

[0193] Reconstitution Test Lead prototypes (#279 / P and #280 / P) were reconstituted with mesalamine (source - MSN). Gelling temperature was monitored periodically for up to 24 hours.

[0194] [Table 49]

[0195] Observations: No significant change in gelation temperature was observed up to 8 hours after reconstitution. After that, an increase in gelation temperature is observed.

[0196] Formulation with Lipoid S 100 and Phospholipon 90 G During stress testing, the formulation with Phospholipon 90 G shows an increase in gelation temperature, whereas a decrease in gelation temperature is observed for the formulation with Lipoid S100. Mixtures of both lipids were evaluated to have a consistent gelation temperature during stability testing. The composition is shown below:

[0197] [Table 50]

[0198] observation: #417, #419 and #424 exhibited the desired gelling temperature. Stability studies were initiated on selected prototypes.

[0199] Stability testing The composition for the stability batch is given as follows: [Table 51]

[0200] [Table 52]

[0201] [Table 53]

[0202] INT-CL-001 Phase 1 Pharmacokinetic (PK) Comparison Study Designed to Demonstrate Advantage Over Standard of Care Enema ROWASA® in Q1 2022: The endpoints of the study were to demonstrate better retention and improved absorption of 5-ASA versus standard of care; and the addition of fecal PK to provide prediction of mucosal tissue concentrations (which correlate with efficacy). The layout of the study is depicted diagrammatically in Figure 1.

[0203] Figure 2 shows the study period dosing and PK sample collection timeline. PK sample collection intervals included hourly for the first 12 hours, followed by PK blood draws at 18, 24, 36, 48, 60, and 72 hours (±10 min); urine was pooled at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours, and 48-72 hours; feces was pooled at 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours. Vital signs were measured 30 min prior to PK samples. Washout was 7 days in-house.

[0204] Table 54 shows the dosing overview and details for the INT-CL-001 Phase 1 PK study: [Table 54]

[0205] Table 55 shows single-dose PK in healthy volunteers for selected FDA-approved 5-ASA products: [Table 55-1] [Table 55-2] [Table 55-3]

[0206] Figure 3 shows the plasma PK of the test compound (INT-001) versus the reference compound (ROWASA). Figure 3A shows mesalamine, while Figure 3B shows n-acetyl-mesalamine.

[0207] FIG. 4 shows the mesalamine reference data, while FIG. 5 shows the data for the test compound.

[0208] Table 56 shows the bioequivalence calculations for the test and reference: [Table 56]

[0209] Table 57 shows the time to first stool versus MRT: [Table 57]

[0210] Table 58 shows the subgroup analysis by time to first stool, 0-4 hours and 4-8 hours: [Table 58]

[0211] Table 59 shows subgroup analysis by time to first stool, 8-12 hours and 12+ hours:

Table 59

[0212] Figure 6 shows the mean 5-ASA in feces and Figure 7 shows the mean n-ac-5-ASA in feces for the test and reference compounds. The reference compound appears on the left side of each pair of bars on the chart, while the test compound appears on the right side. Figure 8 shows the time to first feces after administration of the reference and test compounds for six test subjects plotted on the plasma PK curves (y-axis is plasma 5-ASA in ng / ml and x-axis is time after administration). For all but one (subject 9), the first feces occurred more quickly with the reference compound than with the test compound. In these examples, the plasma concentration of mesalamine falls to zero after defecation for subjects after receiving the reference compound. However, for subjects receiving the test compound, mesalamine levels remained elevated for 18-48 hours after defecation. This likely indicates that the subjects were retaining some of the gel in the colon despite having defecation. For reference, previous 5-ASA trials include the ROWASA mesalamine enema (4 g / 60 mL) in 1987, the CANASA mesalamine suppository (500 mg) in 2001, and the UCERIS budesonide rectal foam (2 mg rectal foam 505b2) in 2014.For further references, see Dilger K et al. A clinical trial on absorption and N-acetylation of oral and rectal Mesalazine. Eur J Clin Invest. 2007 Jul;377:558-65; Aumais G et al. Pharmacokinetics and Pilot Efficacy of a Mesalazine Rectal Gel in Distal Ulcerative Colitis. Drugs RD 2005;61:41-46; and Aumais G et al. Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients. Aliment Pharmacol Ther 2003;17:93-97, the contents of each of which are incorporated herein by reference in their entirety.Further data relating to 5-ASA dose response can be found, for example, in Hanauer SB. Dose-ranging study of mesalamine PENTASA enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The US PENTASA Enema Study Group. Inflamm Bowel Dis. 1998 May;42:79-83; Campieri M et al. Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis. Gut 1991, 32, 929-931; Frieri G. Mucosal 5-aminoslicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis. Gut 2000;47:410-414l; and Naganuma M. Measurement of colonic mucosal concentrations of 5-aminoslicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine. IBD 2001;7(3):221-225, the contents of each of which are incorporated herein by reference in their entireties.

[0213] Formulation Testing Stability data for various compound formulations is shown in Figure 9. Formulations I (P90G) and II (S100) were stored with and without lipid at 4°C, RT and 60°C. PH was used as an indicator to detect possible degradation. Formulation I (P90G) was found to perform better at 60°C compared to formulation II (S100). Figure 10 shows the poloxamer stability for lipid S100 and Figure 11 shows the poloxamer stability for p90G.

[0214] One-part and two-part formulations Data for two exemplary non-lipid-based one-part formulations are shown in Table 67: [Table 67]

[0215] Stability data for the above one-part formulations are shown in Table 68: [Table 68-1] [Table 68-2]

[0216] The formulations were stored at 60°C. Related substances were determined using HPLC. Changes in gelation temperature were observed in the active compound. However, no changes in gelation temperature were observed for the placebo. More impurities were observed during stability analysis. In this study, the one-part formulation containing mesalamine was not stable. Mesalamine was found to turn brown within 3 days after preparation of the one-part formulation due to oxidation in aqueous solution.

[0217] Excipients were tested for compatibility. Constant - 15% Poloxamer 407 was used. Compatibility studies were performed with the following excipients: Mesalamine - 6.67%; Transcutol - 10%; EDTA - 0.1%; Polocarbophil - 0.25% + Tris - 0.15%; TPGS - 0.2%; NaCl - 0.5%; Sodium pyrosulfite - 0.2%; PVA 30 CPS -1%; Kollidon 30 -1%. The following lipids were investigated: DSPC - 0.5% + DPCC - 0.5%; Phospholipon 90G - 1%; Lipoid S 100 - 1%; Phospholipon 90H - 1%; Lecithin - 1%. The following combinations of poloxamer grades were also tested (Poloxamer 188 - 1.5, 2.5 and 5%). The gelation temperatures for the various excipient combinations are shown in Figure 12. No or slight effect was found (1-2°C from initial) for the following excipients: Transcutol, EDTA, TPGS, NaCl, and PVA. A moderate effect (2-5°C from initial) was found for Mesalamine. Significant effects on gelation temperature were found for Polycarbophil + TRIS, Sodium Metabisulfite, Xanthan Gum, and Kollidon. Sodium Metabisulfite, a preservative used in Rowasa® (a drug listed as a reference) to prevent oxidation of Mesalamine (which is susceptible to degradation by oxidation), has a significant effect on gelation temperature. Figure 13 shows the gelation temperatures for the various lipid combinations. No or slight effects (1-2°C from initial) were found for combinations with DSPC + DPCC, Phospholipon 90 G, and Lipoid S 100. A moderate effect (2-5°C from initial) was found with lecithin, and a significant effect was shown by Phospholipon 90 H. Figure 14 shows the gelation temperature for Poloxamer 188. All poloxamer combinations were stable for 28 days.

[0218] In certain embodiments, a composition with Lipoid S 100 may be used. The composition consists of two parts: Part 1 - lipid (vehicle) emulsified in poloxamer dissolved in water and Part 2 - API. An exemplary formulation with Lipoid S 100 is shown in Table 69 below: [Table 69-1]

[0219] The batch sizes were 278 / 314 - 4 kg and 291 - 2 kg. Higher gelation temperatures were observed in the new batches at early time points as seen in Figure 15 which shows the gelation temperatures for the Lipoid S 100 composition. The Tg was stable up to 3 hours. MSN and Cambrex (as shown in Figure 15) are different mesalamine manufacturers and represent the source of the test material.

[0220] In certain embodiments, a composition with Phospholipon 90 G may be used. The composition consists of two parts: Part 1 - lipid emulsified with poloxamer dissolved in water (vehicle) and Part 2 - API. An exemplary formulation with Lipoid S 100 is shown below in Table 69: [Table 69-2]

[0221] Batch sizes were 278 / 315 - 4 kg and 280 / 316 - 4 kg. Higher gelation temperatures were observed in reproducible batches of #279 and #280 as seen in Figure 16 which shows the gelation temperatures for the Phospholipon 90 G compositions. The Tg was stable up to 3 hours.

[0222] Rheology results are shown for various compositions in Figures 17-22. Figure 17 shows the rheology results for composition 278. The reconstituted formulation showed lower gel strength than the vehicle. The 1M 40 / 75 sample showed lower Tg and higher gel strength. Figure 18 shows the rheology results for composition 279. The reconstituted formulation showed lower gel strength than the vehicle. Figure 19 shows the rheology results for composition 280. The reconstituted formulation showed lower gel strength than the vehicle (except cambrex - initial). Figure 20 shows the rheology results for composition 278 vs. composition 291. The 291 composition showed a higher Tg and no significant change with the addition of API. Figure 21 shows the rheology results for composition 279 vs. composition 292. The 292 composition showed a higher Tg and no significant change with the addition of API. Figure 22 shows the rheology results for composition 280 vs. composition 293. It showed a higher Tg than composition 293, and did not change significantly with the addition of API.

[0223] References References and citations to other documents (e.g., patents, patent applications, patent publications, journals, books, articles, web content) are made throughout this disclosure. All such documents are incorporated by reference herein in their entirety for all purposes.

[0224] Equivalent Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Active ingredient; A thermogelling polymer of at least one grade, wherein different grades are present in different concentrations; Lipids; and The aforementioned lipid solubilizer, A composition containing the following:

2. The composition according to claim 1, wherein the active ingredient is mesalamine.

3. The composition according to claim 2, wherein the concentration of the active ingredient is between approximately 0.5 and 15% w / v of the composition.

4. The composition according to claim 2, wherein the concentration of the active ingredient is between approximately 6% and 8% w / v of the composition.

5. The composition according to claim 1, wherein one grade of the thermogelling polymer is poloxamer 407.

6. The composition according to claim 5, wherein the concentration of poloxamer 407 is between approximately 10 and 16% w / v of the composition.

7. The composition according to claim 5, wherein the concentration of poloxamer 407 is between approximately 12 and 13.5% w / v of the composition.

8. The composition according to claim 1, wherein one grade of the thermogelling polymer is poloxamer 188.

9. The composition according to claim 8, wherein the concentration of poloxamer 188 is between approximately 0.001% and 1% w / v of the composition.

10. The composition according to claim 1, wherein the lipid is a phospholipid.

11. The composition according to claim 10, wherein the phospholipid is phosphatidylcholine.

12. The composition according to claim 10, wherein the phosphatidylcholine is phosphatidylcholine derived from soybeans having aggregates.

13. The composition according to claim 10, wherein the concentration of the lipid is between approximately 0.001% and 4% w / v of the composition.

14. The composition according to claim 10, wherein the concentration of the lipid is 1.5 to 2.5% w / v of the composition.

15. The composition according to claim 1, wherein the solubilizer for the lipid is diethylene glycol monoethyl ether.

16. The composition according to claim 15, wherein the concentration of the solubilizer for the lipid is between approximately 5% and 15% w / v of the composition.

17. The composition according to claim 15, wherein the concentration of the solubilizer for the lipid is between approximately 8 and 10% w / v of the composition.

18. The composition according to claim 1, wherein the composition is a liquid at 20 to 25°C and transitions to a gel at 29 to 37°C.

19. It's a kit, A first container containing a first composition containing an active ingredient; and A second container comprising a second composition comprising at least one grade of a thermogelling polymer, where each grade is present in different concentrations, a lipid, and a solubilizer for the lipid. A kit that includes this.

20. The kit according to claim 19, wherein the active ingredient is mesalamine.

21. The kit according to claim 20, wherein the concentration of the active ingredient is between approximately 0.5% and 15% w / v of the composition.

22. The kit according to claim 20, wherein the concentration of the active ingredient is between approximately 6% and 8% w / v of the composition.

23. The kit according to claim 19, wherein one grade of thermogelling polymer is poloxamer 407.

24. The kit according to claim 23, wherein the concentration of poloxamer 407 is between approximately 10 and 16% w / v of the composition.

25. The kit according to claim 23, wherein the concentration of poloxamer 407 is between approximately 12 and 13.5% w / v of the composition.

26. The kit according to claim 19, wherein one grade of thermogelling polymer is poloxamer 188.

27. The kit according to claim 26, wherein the concentration of poloxamer 188 is between approximately 0.001% and 1% w / v of the composition.

28. The kit according to claim 19, wherein the lipid is a phospholipid.

29. The kit according to claim 28, wherein the phospholipid is phosphatidylcholine.

30. The kit according to claim 28, wherein the phosphatidylcholine is phosphatidylcholine derived from soybeans having aggregates.

31. The kit according to claim 28, wherein the concentration of the lipid is between approximately 0.001% and 4% w / v of the composition.

32. The kit according to claim 28, wherein the concentration of the lipid is 1.5 to 2.5% w / v of the composition.

33. The kit according to claim 19, wherein the solubilizer for the lipid is diethylene glycol monoethyl ether.

34. The kit according to claim 33, wherein the concentration of the solubilizer for the lipid is between approximately 5% and 15% w / v of the composition.

35. The kit according to claim 33, wherein the concentration of the solubilizer for the lipid is between approximately 8 and 10% w / v of the composition.

36. The kit according to claim 19, wherein the composition is a liquid at 20 to 25°C and transitions to a gel at 29 to 37°C.

37. A kit for use in a method of treating a condition in a subject, The kit comprises a first container containing a first composition comprising an active ingredient; and a second container containing a second composition comprising at least one grade of a thermal gelling polymer, each grade present in different concentrations, the thermal gelling polymer, a lipid, and a solubilizer for the lipid; The aforementioned method, A step of mixing the first and second compositions to form the final formulation; and A step of administering the final formulation, A kit that includes everything.

38. The kit according to claim 37, wherein the condition is irritable bowel disorder.

39. The kit according to claim 37, wherein the condition is ulcerative colitis.

40. The kit according to claim 37, wherein the administration step is local administration.

41. The kit according to claim 37, wherein the administration step is the administration of the preparation as an enema.

42. The kit according to claim 37, wherein the subject performs the mixing step and the administration step.

43. The kit according to claim 37, wherein the mixing step comprises the step of adding the second composition to the first composition, and the step of shaking for at least 30 seconds to suspend the formulation.

44. The kit according to claim 37, wherein the mixing step comprises the step of adding the second composition to the first composition, and the step of shaking for at least 15 seconds to suspend the formulation.

45. The kit according to claim 37, wherein the mixing step comprises the steps of adding the second composition to the first composition, and shaking for at least 10 seconds, letting stand for 1 minute, and then shaking again for another 10 seconds to suspend the formulation.

46. The kit according to claim 37, wherein the mixing step comprises the steps of adding the first composition to the second composition, and shaking for at least 10 seconds, letting stand for 1 minute, and then shaking again for another 10 seconds to suspend the formulation.

47. The kit according to claim 37, wherein the active ingredient is mesalamine.

48. The kit according to claim 47, wherein the concentration of the active ingredient is between approximately 0.5 and 15% w / v of the composition.

49. The kit according to claim 47, wherein the concentration of the active ingredient is between approximately 6% and 8% w / v of the composition.

50. The kit according to claim 37, wherein one grade of thermogelling polymer is poloxamer 407.

51. The kit according to claim 50, wherein the concentration of poloxamer 407 is between approximately 10 and 16% w / v of the composition.

52. The kit according to claim 50, wherein the concentration of poloxamer 407 is between approximately 12 and 13.5% w / v of the composition.

53. The kit according to claim 37, wherein one grade of thermogelling polymer is poloxamer 188.

54. The kit according to claim 53, wherein the concentration of poloxamer 188 is between approximately 0.001% and 1% w / v of the composition.

55. The kit according to claim 37, wherein the lipid is a phospholipid.

56. The kit according to claim 55, wherein the phospholipid is phosphatidylcholine.

57. The kit according to claim 55, wherein the phosphatidylcholine is phosphatidylcholine derived from soybeans having aggregates.

58. The kit according to claim 55, wherein the concentration of the lipid is between approximately 0.001% and 4% w / v of the composition.

59. The kit according to claim 55, wherein the concentration of the lipid is 1.5 to 2.5% w / v of the composition.

60. The kit according to claim 37, wherein the solubilizer for the lipid is diethylene glycol monoethyl ether.

61. The kit according to claim 60, wherein the concentration of the solubilizer for the lipid is between approximately 5% and 15% w / v of the composition.

62. The kit according to claim 60, wherein the concentration of the solubilizer for the lipid is between approximately 8 and 10% w / v of the composition.

63. The kit according to claim 37, wherein the composition is a liquid at 20 to 25°C and transitions to a gel at 29 to 37°C.

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