Structured lipid compositions

Abstract

The present invention relates to a composition for use in treating a lower gastrointestinal condition, such as ulcerative colitis, comprising: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) a carrier comprising a monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, the monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof; and b) a pharmaceutically active agent, wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. The composition is particularly suitable for rectal administration, e.g., as an enema. Also disclosed are compositions, methods for preparing the compositions, and kits for making the compositions.

Description

[Technical Field]

[0001] The present invention relates to a composition for use in treating a lower gastrointestinal condition, such as ulcerative colitis, comprising: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) a carrier comprising a monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, the monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof; and b) a pharmaceutically active agent, wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. The composition is particularly suitable for rectal administration, e.g., as an enema. Also disclosed are compositions, methods for preparing the compositions, and kits for making the compositions. [Background technology]

[0002] Background of the Invention Ulcerative colitis (UC) is a chronic, remitting, relapsing inflammatory disorder of the large intestine, involving the colonic and rectal mucosa. 1 Clinically, 75% of patients suffer from left-sided colitis or proctitis, but the inflammation may extend upward in a continuous manner and may involve the colon partially or entirely. 2

[0003] There is no known cure for ulcerative colitis and the chronic relapses and remitting periods that often leave patients disabled. 1、2 All treatments currently recommended by the European Crohn's and Colitis Council (ECCO) and the American Gastroenterological Association (AGA) strive to achieve the desired remission rate, and many patients must cycle through several different therapies to achieve remission. 3、4Following a step-up approach, the first-line treatment for mild to moderate left-sided UC or pancolitis is 5-ASA (topical and oral combination) for induction of remission. For refractory patients and in severe disease, systemic corticosteroids, azathioprine, 6-mercaptopurine, monoclonal antibodies (such as infliximab, anti-TNF-α; vedolizumab, anti-α4β7 integrin; and ustekinumab, IL-12 / IL-23 blockade), and ozanimod (a sphingosine 1-phosphate receptor modulator) are the treatments of choice for achieving remission. 4~8 Compared to conventional treatments, biologically based therapies have considerable side effects, including systemic toxicity, loss of sustained response to therapy over time resulting in symptomatic relapse, opportunistic infections, psoriasis, and lupus-like syndromes. 9~13

[0004] Recently, tofacitinib (TOFA), a small molecule inhibitor of the enzymes Janus kinase 1 and 3 (JAK3 and JAK1, respectively), 14 has been approved by European and US regulatory authorities for the oral treatment of UC in patients with intolerance to biologics, and its oral administration is superior to biologics in maintaining remission and endoscopic improvement. 15、16 In steroid-refractory UC, the use of tacrolimus (TAC), a macrolide that inhibits T lymphocyte activation, is recommended. 17 However, TOFA and TAC exhibit dose-dependent adverse effects when administered systemically in a significant proportion of patients (e.g., nephrotoxicity, thromboembolic complications, headache, metabolic disorders). 18~21 This may require discontinuing treatment in some cases. 21 Taken together, the side effects of these systemically administered drugs must weigh heavily in patient management against their potential benefits for the treatment of UC.

[0005] The specific localization of the disease to the colon encourages the use of local therapies. 22Indeed, delivery via the rectal route is a safer therapeutic approach that may maximize drug concentrations directly at the site of inflammation with minimal systemic exposure, and is routinely used as a first-line treatment for UC. 23、24 As seen with 5-ASA, rectal administration of this compound in UC patients is significantly more effective than oral administration. 25~30 In addition, resistant ulcerative proctitis can be treated with ointment 27、31 , suppositories 32 , and enemas 30 It is managed by TAC administered topically as a steroid.

[0006] Although clinical studies have shown that rectal preparations are more effective than oral preparations, these treatments are still prescribed very rarely. 33 This is because the effectiveness of traditional enema-based preparations is due to their poor retention in the colon. 34 and bowel urgency associated with large volume administration 35 The reason is that the .lambda. 35 Also, the required holding time—at least 20 minutes—along with frequent dosing negatively impacts patient compliance. 36

[0007] Another major difficulty with the use of topical preparations (e.g., enemas) in body cavities such as the GI tract is the fact that such cavities are typically covered with non-adhesive, rapidly turning over mucous membranes. Thick, viscous preparations can be difficult to effectively apply to the rectum relative to the lower GI tract, and are also difficult to manufacture due to their high viscosity, which prevents sterile filtration. Existing compositions typically have low viscosity and short shelf life, or long shelf life at the expense of high viscosity. Furthermore, existing topical compositions often contain only low levels of active agents due to poor compatibility between the base composition (e.g., carrier) and the active agent. This results in compositions that rapidly lose effectiveness as they begin to disappear from the site of action.

[0008] Lipid-based drug delivery systems are designed to address issues such as solubility and bioavailability of poorly water-soluble drugs. Lipid-based formulations can be adapted to meet a wide range of product requirements, dictated by disease indications, route of administration, cost considerations, product stability, toxicity, and efficacy. These formulations are also commercially viable strategies for formulating pharmaceuticals for topical, oral, pulmonary, or parenteral delivery.

[0009] The use of non-lamellar phase structures (such as liquid crystalline phases) in the delivery of bioactive agents is relatively well known. Such structures form when amphiphilic compounds are exposed to solvents because the amphiphile possesses both polar and non-polar groups that cluster to form polar and non-polar regions. These regions can effectively solubilize both polar and non-polar compounds. Such non-lamellar phase formulations can form liquid crystalline phase structures upon contact with aqueous fluids. However, given the characteristics of the rectal environment, which is characterized by low volume and has a composition that is highly influenced by age, biological sex, and pathology, aqueous fluids are not the most suitable trigger for in situ gelation. Furthermore, such non-lamellar systems can exhibit a burst release of the encapsulated active upon exposure to aqueous fluids.

[0010] Thus, there remains a need for improved or alternative delivery systems for use in treating UC. In particular, topical formulations that are bioadhesive (i.e., to mucosal surfaces) and can be formulated as low viscosity compositions will become adhesive upon exposure to a suitable trigger in situ.

[0011] Upon hydration, monoacylglycerol lipids (such as monolinolein - MLO, Generally Recognized As Safe for Human and / or Animal Use - GRAS, according to the FDA) can self-assemble into different arrangements. By increasing the water content, the low viscosity lamellar (L) phase transforms first into Ia3d and then Pn3m cubic phases (Q), which are similar in appearance and rheology to the highly viscous cross-linked hydrogels. 37To overcome the obstacles to administering highly viscous gels, temperature, as well as water, can be used as a trigger to adjust the viscosity of the system. Thus, as described herein, the inventors have developed a gel platform that uses rectal temperature as a trigger for the formation of a highly viscous adhesive depot system. It has been unexpectedly discovered that the compositions of the present invention can be used to effectively deliver high concentrations of drugs locally to the colonic mucosa, resulting in sustained drug release. Summary of the Invention [Means for solving the problem]

[0012] A brief summary of the disclosure In accordance with the present invention, a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents A composition comprising: the lipid is selected from monolinolein or monoolein; A composition is provided, wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0013] Preferably, the carrier comprises 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier. Thus, in an embodiment, the carrier consists of 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier.

[0014] Preferably, the lipid is monolinolein.

[0015] In embodiments, the composition comprises: a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) Monolinolein in an amount of 75% to 90% by weight of the carrier a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0016] In embodiments, the carrier comprises about 16% by weight water and about 84% by weight monolinolein, where the % is the % by weight of the carrier. In embodiments, the carrier comprises 16% by weight water and 84% by weight monolinolein, where the % is the % by weight of the carrier. In embodiments, the carrier consists of about 16% by weight water and about 84% by weight monolinolein, where the % is the % by weight of the carrier. In embodiments, the carrier consists of 16% by weight water and 84% by weight monolinolein, where the % is the % by weight of the carrier.

[0017] In embodiments, the compositions of the present invention have a lamellar phase structure at 25°C. Thus, in embodiments, the compositions are lamellar gels at 25°C. As shown in the examples herein, temperature can be used as a triggering factor for converting the lamellar phase structure to a lipid cubic phase. In particular, the inventors have discovered that rectal temperature can be used as a triggering factor for converting the lamellar phase structure to a lipid cubic phase, such that upon rectal administration, the compositions of the present invention convert to a lipid cubic phase and act as highly viscous bioadhesive controlled depot systems. Thus, in embodiments, the compositions of the present invention form a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, the compositions of the present invention form a lipid cubic phase at a temperature of 38°C.

[0018] In embodiments, the compositions of the present invention are substantially free of organic solvents.

[0019] Also provided are compositions of the invention for use as pharmaceuticals.

[0020] Also provided are compositions of the invention for use in treating lower gastrointestinal conditions.

[0021] Also provided is a method of treating a lower gastrointestinal tract condition in a subject, comprising administering to the subject an effective amount of a composition of the invention.

[0022] There is also provided a use of a composition of the invention for the manufacture of a medicament for the treatment of a lower gastrointestinal tract condition in a subject.

[0023] Also provided is a composition of the present invention for use in treating conditions affecting the colon, wherein the composition is topically applied to the colon and / or rectum of a subject.Preferably, the composition is administered to a subject via the rectum, and the composition coats the inner wall of the colon and / or rectum.Therefore, the composition is topically applied to the inner wall of the colon and / or rectum.

[0024] In any of the embodiments herein relating to compositions for use, methods of treatment, or use of compositions, the compositions of the present invention may be topically administered to a subject. Thus, the composition may be topically applied to the colon of a subject. The composition may be topically applied to the rectum of a subject. In some embodiments, the composition is administered to a subject via the rectum. The composition may be administered to a subject via the rectum in the form of a suppository; a rectal capsule; a semi-solid rectal preparation; a rectal foam; a rectal tampon; or an enema. The composition may be a semi-solid rectal preparation. The composition may be an enema composition.

[0025] In embodiments, the compositions of the present invention have a lamellar phase structure at 25° C. and are administered to a subject via the rectum (e.g., as an enema). When administered rectally (e.g., as an enema), the composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, when administered rectally (e.g., as an enema), the composition forms a lipid cubic phase at a temperature of 38° C.

[0026] In other embodiments herein relating to the use of compositions, methods of treatment, or compositions, the compositions of the present invention can be injectable formulations.Therefore, the injectable formulations can be subcutaneous, intramuscular, or intradermal injectable formulations.In some embodiments, the compositions are administered subcutaneously, intramuscularly, or intradermally to the subject.Preferably, the injectable formulations are subcutaneous injectable formulations, and therefore the compositions are administered subcutaneously to the subject.

[0027] Also provided is the use of a formulation comprising 10% to more than 30% w / w of water and 70% to 90% w / w of lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein. The formulation may comprise 10% to more than 25% w / w of water and 75% to 90% w / w of lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from monolinolein or monoolein.

[0028] In embodiments, the formulation comprises about 16% water by weight and about 84% monolinolein by weight. In embodiments, the formulation comprises 16% water by weight and 84% monolinolein by weight. In embodiments, the formulation consists of about 16% water by weight and about 84% monolinolein by weight. In embodiments, the formulation consists of 16% water by weight and 84% monolinolein by weight.

[0029] 1. Use of a preformulation composition comprising a lipid and a pharmaceutically active agent for the manufacture of a composition of the present invention, comprising: There is also provided a use wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0030] 1. A method of making a composition of the present invention, comprising: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition Including, Also provided is a method wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0031] 1. A method of making a composition of the present invention, comprising: a) dissolving a pharmaceutically active agent in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition Including, Also provided is a method wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein. Preferably, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0032] a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition of the present invention; A kit comprising: Also provided is a kit wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0033] a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide a composition of the present invention. A kit comprising: Also provided is a kit wherein the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein. Preferably, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0034] 1. A composition for use in the treatment of a lower gastrointestinal tract condition, the composition comprising: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36°C to 39°C, The composition is administered rectally; Also provided is a composition wherein preferably the monoacylglycerol lipid is monolinolein.

[0035] a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition A composition comprising: Also provided is a composition, wherein the composition forms a lipid cubic phase at a temperature between 36°C and 39°C.

[0036] 1. Use of a preformulation composition comprising a monoacylglycerol lipid and a pharmaceutically active agent for the manufacture of a composition as defined herein, comprising: Optionally, there is also provided a use wherein the preformulated composition is a lyophilized mixture. The pharmaceutically active agent can be any of the pharmaceutically active agents described herein.The monoacylglycerol lipid can comprise at least 50% by weight of monolinolein as described herein.The monoacylglycerol lipid can comprise monolinolein or monoolein, or a combination thereof as described herein.

[0037] A composition for use as defined herein or a method of making a composition as defined herein, comprising: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition Including, as needed, A1) the mixture in step a) is a freeze-dried mixture; and / or A2) The freeze-dried mixture is i) dissolving a lipid and a pharmaceutically active agent in an organic solvent; and ii) freeze-drying the mixture of i) to provide a freeze-dried mixture. obtained by; and / or A3) There is also provided a method, wherein in step i) the organic solvent is selected from ethanol or methanol, preferably the organic solvent is ethanol. The lipid may be a monoacylglycerol lipid containing at least 50% by weight of monolinolein, as described herein. The lipid may be a monoacylglycerol lipid containing monolinolein or monoolein, or a combination thereof, as described herein. The lipid may be selected from monolinolein or monoolein. The pharmaceutically active agent may be any of the pharmaceutically active agents described herein.

[0038] A composition for use as defined herein or a method of making a composition as defined herein, comprising: a) dissolving a pharmaceutically active agent in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition Including, Optionally, methods are also provided wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. The lipid may be a monoacylglycerol lipid containing at least 50% by weight of monolinolein, as described herein. The lipid may be a monoacylglycerol lipid containing monolinolein or monoolein, or a combination thereof, as described herein. The lipid may be selected from monolinolein or monoolein. The pharmaceutically active agent may be any of the pharmaceutically active agents described herein.

[0039] A composition for use as defined herein or a method of making a composition as defined herein, comprising: a) heating a lipid to provide a molten lipid; b) mixing the molten lipid with a pharmaceutically active agent to provide a lipid-drug mixture; c) mixing the lipid-drug mixture with water; and d) Equilibrating the lipid-drug mixture and water to provide the composition. Including, as needed, C1) the molten lipid and the pharmaceutically active agent in step b) are mixed at a temperature of about 30°C to 70°C, preferably about 40°C to 60°C; and / or C2) A method is also provided wherein the lipid-drug mixture in step c) is mixed with water in a dual syringe. The lipid may be a monoacylglycerol lipid containing at least 50% by weight of monolinolein, as described herein. The lipid may be a monoacylglycerol lipid containing monolinolein or monoolein, or a combination thereof, as described herein. The lipid may be selected from monolinolein or monoolein. The pharmaceutically active agent may be any of the pharmaceutically active agents described herein.

[0040] a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition for use as defined herein or a composition as defined herein; A kit comprising: Optionally, the kit further comprises a second container, the second container comprising water; Further optionally, kits are provided wherein the lipid and pharmaceutically active agent in the first container are provided as a lyophilized mixture. The lipid may be a monoacylglycerol lipid containing at least 50% by weight of monolinolein, as described herein. The lipid may be a monoacylglycerol lipid containing monolinolein or monoolein, or a combination thereof, as described herein. The lipid may be selected from monolinolein or monoolein. The pharmaceutically active agent may be any of the pharmaceutically active agents described herein.

[0041] a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide a composition for use as defined herein or a composition as defined herein. A kit comprising: Optionally, the kit further comprises a second container, the second container comprising a pharmaceutically active agent dissolved in water; Further optionally, kits are provided wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. The lipid may be a monoacylglycerol lipid containing at least 50% by weight of monolinolein, as described herein. The lipid may be a monoacylglycerol lipid containing monolinolein or monoolein, or a combination thereof, as described herein. The lipid may be selected from monolinolein or monoolein. The pharmaceutically active agent may be any of the pharmaceutically active agents described herein.

[0042] Further aspects and features of the present invention are set forth in the detailed description that follows. [Brief explanation of the drawings]

[0043] [Figure 1] SAXS spectra acquired at different temperatures on gels containing 10% w / w TOFA (Figure 1A) and 10% w / w TAC (Figure 1B).

[0044] [Figure 2-1]In vitro and ex vivo characterization of TIF gels: Figure 2A) Schematic of the in vitro characterization and mechanism of gel formation. Figure 2B) SAXS spectra acquired at different temperatures (25 °C, 30 °C, and 38 °C; bottom, middle, and top spectra, respectively) for gels containing increasing amounts of water (12%, 14%, 16%, and 18% w / w). Figure 2C) Resulting partial phase diagrams (gray circles: L; black circles: coexistence of Ia3d+L; gray squares: Ia3d). Figure 2D) SAXS spectra acquired at different times (5, 10, 20, and 30 min) after incubation at 38 °C. Figure 2E) Frequency sweeps at the end of the release experiment (gray circles) and at the beginning of the experiment (gray triangles). Figure 2F) SAXS before and after the release experiment (1: before; 2: after release in HEPES; 3: after release by lipase). Figure 2G) Pour and yield points obtained for the lamellar phase (light gray bars) and cubic gels (dark gray bars) from amplitude sweep experiments. Figure 2H) In vitro characterization of TIF gels: SAXS spectra acquired at different temperatures: 25 °C (bottom), after 30 min of equilibration at 38 °C (middle), and after 30 min of equilibration at 25 °C (top). SAXS was used to determine the reversibility of the lipid phase and, therefore, the transition. Figure 2I) Amplitude sweep experiments acquired at 25 °C (triangle symbols) and 38 °C (circle symbols) on empty gels. a) The storage modulus (G') and the decrease in modulus (G'') are plotted against shear stress. The yield point is the value of shear stress at the limit of the LVE region, while the pour point is the value of shear stress at the crossover point G' = G''. b) Shear strain is plotted against stress; the yield point is exceeded at the point where deformation begins and deviates from linearity. Figure 2J) SAXS spectra acquired at 38 °C at different time points (pre-administration, excretion with feces, and residual gel present in the colon). [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 2-5] Same as above.

[0045] [Figure 3-1]In vitro and ex vivo characterization of TIF gels: Figure 3A) SAXS spectra of TOFA-loaded gels (TIF gel-TOFA) acquired at different temperatures. Figure 3B) In vitro release of free drug (TOFA, gray squares) and TIF gel-TOFA in HEPES buffer (TIF gel-TOFA, black triangles) and in the presence of lipase (TIF gel-TOFA(lipase), gray triangles). Results are reported as mean ± standard deviation (n=3). Figure 3C) Ex vivo release of free drug (TOFA, gray squares) and TIF gel-TOFA (TIF gel-TOFA, black triangles). Results are reported as mean ± standard deviation (n=3). Figure 3D) SAXS spectra of TAC-loaded LMPS (TIF gel-TAC) acquired at different temperatures. Figure 3E) In vitro release of free drug (TAC, gray squares), TIF gel-TAC (TIF gel-TAC, black triangles), and in the presence of lipase (TIF gel-TAC(lipase), gray triangles). Results are reported as mean ± STDV (n=3). Figure 3F) Ex vivo release of free drug (TAC, gray squares) and TIF gel-TAC in HEPES buffer (TIF gel-TAC, black triangles). Results are reported as mean ± STDV (n=3). Figure 3G) Schematic representing the in vitro release experiment, where drug-loaded TIF gel formulations were placed in the donor chamber of a vertical diffusion cell. Figure 3H) Drug distribution into TIF gels. a) WAXS spectra obtained for an empty gel (bottom), a TOFA-loaded gel (middle), and a TAC-loaded gel (top). All WAXS spectra (acquired at 25°C for 30 min) show only broad shoulders (and no distinct peaks), indicating the amorphous state of the lipid chains and the absence of crystalline structure. b) Uniformity of drug in the gel. The amount of drug present in the three different gel layers (top, middle, and bottom) was assessed by HPLC. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Figure 3-4] Same as above.

[0046] [Figure 4-1]In vitro release of free drug in HEPES buffer and TIF gel-loaded drug over an 8 hour period. Figure 4A) In vitro release of clotrimazole in HEPES buffer ("free drug", square symbols) and TIF gel-loaded clotrimazole ("LC", circle symbols). Figure 4B) In vitro release of mesalamine in HEPES buffer ("free drug", circle symbols) and TIF gel-loaded mesalamine ("LC", square symbols). Figure 4C) In vitro release of budesonide in HEPES buffer ("free drug", square symbols) and TIF gel-loaded budesonide ("LC", circle symbols). [Figure 4-2] Same as above.

[0047] [Figure 5-1]TIF gel-TOFA effectively alleviates intestinal inflammation and disease induced by DSS treatment in mice. Mice were prophylactically treated rectally with either empty gel (TIF gel; n = 6), tofacitinib in vehicle (TOFA; n = 7), or TOFA-loaded gel (TIF gel-TOFA; n = 6), followed by challenge with 2% DSS in drinking water. Treatments were then administered every other day until the end of the experiment. Body weight (Figure 5A) and disease scores (Figure 5B) were recorded throughout the experiment. At the end of the experiment, spleens, mesenteric lymph nodes (mLNs), and colons were removed from the mice. Spleens were weighed (Figure 5C), and single splenocytes were counted (Figure 5D). Tissue concentrations of various cytokines were measured (Figure 5E). Mouse colon lengths were measured (Figure 5F), and the colons were opened obliquely, washed, and prepared for histological examination (Figure 5G). Colon histopathology scores were determined and summarized (Figure 5H). *: p<0.05, **: p<0.01, ***: p<0.001, and actual values ​​are provided for values ​​that did not meet the significance threshold but were less than 0.1, as determined by two-way ANOVA (Figure 5A), multiple Student's test with Holm-Sidak correction for multiple comparisons (Figures 5B and 5E), and one-way ANOVA with multiple comparisons and Tukey correction (Figures 5C, 5D, 5F, 5H). All tests were performed using Prism (GraphPad) with the default settings for the analyses listed above. All error bars are ±SEM. [Figure 5-2] Same as above. [Figure 5-3] Same as above. [Figure 5-4] Same as above.

[0048] [Figure 6-1]Evaluation of the effect of TAC-loaded gel on T cell-mediated colitis: 12-15 week-old Rag- / - mice developed colitis via transfer of 2.5 x 10 naive T cells. Starting on day 3 after T cell transfer, mice received daily rectal infusions of drug-free TIF gel (TIF gel), TAC-loaded TIF gel (TIF gel-TAC), or TAC in vehicle (TAC). Figure 6A) Schematic overview of the experimental setup. Figure 6B) Body weight change over the course of the experiment. Figure 6C) Cumulative disease activity score. Figures 6D and 6E) Representative photographs and individual scores from mouse colonoscopy on day 19 after T cell transfer and H&E-stained sections of the terminal colon collected on day 19 after T cell transfer. [Figure 6-2] Same as above. [Figure 6-3] Same as above.

[0049] [Figure 7] Immune cell populations in the colon from TAC-loaded TIF gel-treated mice: 12-15 week-old Rag- / - mice developed colitis via transfer of 2.5 x 10 naive T cells. Starting 3 days after T cell transfer, mice received daily rectal infusions of drug-free TIF gel (TIF gel), TAC-loaded TIF gel (TIF gel-TAC), or TAC in vehicle (TAC). Figure 7A shows the relative abundance of the indicated cell populations in the colonic lamina propria, mesenteric lymph nodes, and spleen at 19 days after T cell transfer, as well as (d) the levels of the indicated cytokines in colonic lysates. *p<0.05, **p<0.01, ***p<0.001 as determined by one-way ANOVA with multiple comparisons and Tukey's correction. All tests were performed using Prism (GraphPad) with the default settings for the analyses listed above. All error bars are ±SEM.

[0050] [Figure 8]Long-term stability of TOFA loaded onto TIF gels (FIG. 8A) and TAC loaded onto TIF gels (FIG. 8B) over a one-month period analyzed by HPLC. Samples were stored at 4° C. (black bars) and 25° C. (gray bars) over the course of the study. Data are expressed as percentages ± SD.

[0051] [Figure 9] Drug delivery via TIF gel results in low systemic drug exposure. (a) Experimental design for pharmacokinetic studies. Healthy mice (n = 5 / group) received a single enema of either drug-loaded TIF gel (TIF gel-TOFA or TIF gel-TAC) or free drug (TOFA or TAC). Plasma drug concentrations were measured at the indicated time points after administration. Plasma concentration versus time profiles of pharmacokinetic experiments for TOFA (b) and TAC-treated animals (c), as well as area under the curve (AUC) 0-48 h values ​​for TOFA- and TAC-treated mice (d and e, respectively). ***p<0.001 as determined by Student's t-test.

[0052] [Figure 10] The TIF gel adheres to healthy colon tissue for at least 6 hours. a) Experimental scheme illustrating the procedure: Healthy animals received an enema of 100 μL of DiR-TIF gel. The animals were sacrificed after 30 minutes, 2, and 6 hours, and the colons were harvested and imaged (b). c) The resulting signal was analyzed as radiant efficiency (RE), which was normalized to the radiant efficiency recorded at 30 minutes. DETAILED DESCRIPTION OF THE INVENTION

[0053] Detailed Description Throughout this description and the claims, the words "comprise" and "contain," as well as variations thereof, mean "including but not limited to," and they are not intended to exclude (or not exclude) other moieties, additives, components, integers, or steps. Throughout this description and the claims, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood as contemplating both plurality and singularity unless the context requires otherwise.

[0054] It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract, and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of the features disclosed in this specification (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of the steps of any method or process so disclosed.

[0055] For the avoidance of doubt, the information previously disclosed herein under the heading "Background" is relevant to the present invention and should be read as part of the disclosure of the present invention.

[0056] The reader's attention is directed to all articles and documents filed in conjunction with this application, contemporaneously with or prior to this application, and hereby opened to public inspection, and the contents of all such articles and documents are incorporated herein by reference. definition

[0057] Unless otherwise stated, the following terms used in the specification and claims have the following meanings indicated below.

[0058] The term "treatment" and therapies encompassed by the present invention include the following and combinations thereof: (1) reducing or inhibiting, e.g., delaying, the onset and / or progression of a condition, disorder, or condition; (2) preventing, e.g., reducing the risk of, or delaying the onset of clinical symptoms of a condition, disorder, or condition in a patient (e.g., a human or animal) who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition, but who may be afflicted with or susceptible to the condition, disorder, or condition; (3) inhibiting the condition, disorder, or condition (e.g., halting, reducing, or delaying the occurrence of a disease or its recurrence, in the case of maintenance treatment of at least one clinical symptom or subclinical symptom thereof); and / or (4) alleviating the condition (e.g., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof). When the compositions of the present invention are used in the treatment of a patient, treatment contemplates any one or more of the following: maintaining the patient's health; restoring or improving the patient's health; and delaying the progression of the disorder. The benefit to the treated patient can be statistically significant, or at least be perceived by the patient or doctor.It is understood that a medicine does not necessarily produce a clinical effect in every patient to which it is administered, and this paragraph should be interpreted accordingly.The compositions and methods described herein are useful for disease therapy and / or prevention.The compositions and methods described herein are useful for inhibiting or preventing disease progression.

[0059] Treatment can include maintenance therapy for patients who suffer from the disorder and whose condition subsequently improves, for example, due to treatment. Such patients may or may not suffer from symptomatic disorders. Maintenance therapy aims to stop, reduce, or delay the (re)occurrence or progression of the disorder.

[0060] References herein to a "therapeutically effective amount" refer to an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of a disorder; reverse, completely stop, or slow the progression of a disorder; or reduce the risk of the disorder worsening; for example, an amount sufficient to induce remission of ulcerative colitis or an amount sufficient to maintain remission of ulcerative colitis. It is within the skill of a person skilled in the art to determine the appropriate treatment period, appropriate dosage, and any possible concomitant treatments based on an evaluation of the therapeutic or prophylactic response.

[0061] Reference herein to "modified release" includes compositions, particularly compositions that alter the release of drug from the composition, for example, to provide controlled release, extended (or sustained) release or delayed release, or any combination thereof, e.g., delayed and controlled release of drug from the composition after administration, e.g., after rectal administration via an enema.

[0062] "C m ~C n The term " refers to a group having m to n carbon atoms.

[0063] The term "C1-C6-alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. 32"-Alkyl" similarly refers to such groups containing from 6 carbon atoms up to 32 carbon atoms. Alkyl groups can be unsubstituted or substituted with one or more substituents. Substituents on alkyl groups can be halogen, e.g., fluorine, chlorine, bromine, and iodine, OH, C1-C4 alkoxy.

[0064] The term "antibody", in the context of the present invention, refers to an "immunoglobulin" (Ig), which is defined as a protein belonging to the classes IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), and includes all conventional known antibodies and their functional fragments. In the context of the present invention, a "functional fragment" of an antibody / immunoglobulin is defined as an antigen-binding fragment of a parent antibody or other derivative that essentially maintains the properties of such parent antibody. An "antigen-binding fragment" of an antibody / immunoglobulin is defined as a fragment that retains the antigen-binding region (e.g., the variable region of IgG). The "antigen-binding region" of an antibody is typically found in one or more hypervariable regions of the antibody, i.e., the CDR-1, -2, and / or -3 regions. "Antigen-binding fragments" according to the present invention include the domains of the F(ab')2 fragment and the Fab fragment. "Functional fragments" of the present invention include Fab fragments, F(ab')2 fragments, Fab' fragments, scFv, dsFv, VHH, diabodies, triabodies, tetrabodies, Fc fusion proteins, and minibodies. The F(ab')2 or Fab domains may be engineered to minimize or completely eliminate intermolecular disulfide interactions that occur between the CH1 and CL domains. The antibodies or functional fragments used for the present invention may be part of bi- or multifunctional constructs.

[0065] The term "immunosuppressant" is intended to mean a pharmacologically acceptable compound which has the effect of suppressing the immune response in the human or animal body. The term "antineoplastic agent" is intended to mean a pharmacologically acceptable compound which is cytotoxic to neoplastic cells.

[0066] The term "gel" is used herein to refer to a semisolid, apparently homogeneous substance that can be elastic and jelly-like (as in gelatin). A gel comprises a three-dimensional polymeric or inorganic matrix dispersed within a liquid phase. The gel matrix comprises a physically or chemically crosslinked polymer or copolymer network that does not dissolve but swells in the presence of a solvent. The crosslinks within the gel matrix may be physical (e.g., by hydrogen bonds or ionic crosslinks) or covalently crosslinked. Gels are generally transparent in appearance; however, turbid gels are also contemplated. The USP defines a gel as a semisolid system consisting of a dispersion made of either small inorganic particles or large organic molecules encapsulated and incorporated in a liquid. The European Pharmacopoeia defines a gel as a semisolid preparation consisting of a single-phase liquid base gelled with a suitable gelling agent. The active substance is dissolved or dispersed in the base.

[0067] In embodiments, the carrier of the composition comprises: a1) water in an amount of 10% to greater than 30% by weight of the carrier; and a2) lipid in an amount of 70% to 90% by weight of the carrier. The lipid may be selected from monolinolein or monoolein. In embodiments, the carrier of the composition consists of: a1) water in an amount of 10% to greater than 30% by weight of the carrier; and a2) lipid in an amount of 70% to 90% by weight of the carrier, wherein the lipid is selected from monolinolein or monoolein. It should be understood that reference herein to an embodiment referring to a "carrier comprising" lipid and water also encompasses embodiments in which the carrier consists solely of lipid and water. Thus, by way of example, the carrier may consist solely of monolinolein and water in the amounts specified in any of the embodiments herein.

[0068] The composition also contains a pharmaceutically active agent, for example, 0.1%-10% of a pharmaceutically active agent, where % is % by weight based on the weight of the composition.Therefore, the carrier acts as a vehicle for the pharmaceutically active agent in the composition.It will be clear to those skilled in the art that the reference to the term "carrier" refers to the lipid and water components of the total composition.For example, the composition may contain: a) a1) water in an amount of 10% by weight of the carrier; and a2) a carrier containing lipid in an amount of 90% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 10% by weight of the composition.In this example, the total composition is a) 90% of a carrier (where % is % by weight of the composition), wherein the carrier is: a1) water in an amount of 10% by weight of the carrier; and a2) lipids in an amount of 90% by weight of the carrier a carrier comprising: b) 10% of a pharmaceutically active agent (where % is % by weight of the composition) Includes.

[0069] In each of the examples listed above, the ratio of the components in the carrier is fixed (i.e., 10% water and 90% lipid), but the amount of carrier in the total composition varies according to the amount of pharmaceutically active agent present in the composition.

[0070] The term "carrier" refers to a formulation that comprises, or preferably consists of, water and lipid (e.g., monolinolein or monoolein). A "composition" includes a carrier, a pharmaceutically active agent, and, if necessary, other components (e.g., additives). The term "by weight of the carrier" refers to the total weight of water and lipid (e.g., monolinolein or monoolein) present in the carrier. Thus, the compositions of the present invention are a) a1) 10% to more than 30% water by weight; a2) a carrier containing 70% to 90% lipid by weight; and b) 0.1% to 10% by weight of the composition of a pharmaceutically acceptable drug and Here, the total weight of a1)-a2) is 100%, and the term "by weight" in a1) and a2) refers to "% by weight of carrier." In this example, the % by weight of the pharmaceutically acceptable agent refers to the % by weight of the total weight of the composition containing all components of the composition.

[0071] References herein to "the pharmaceutically acceptable agent is present in an amount of about x% by weight of the carrier" refer to the weight percentage of the pharmaceutically acceptable agent compared to the total weight of the carrier, including water and lipid (e.g., monolinolein or monoolein).

[0072] Those skilled in the art will appreciate that a composition of the present invention comprising: a) 90-99.9% carrier (where % is % by weight of the composition), the carrier comprising: a1) water in an amount of 10-30% by weight of the carrier; and a2) lipid in an amount of 70-90% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 0.1-10% by weight of the composition, (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent; (ii) 63% w / w to 89.9% w / w lipids; and (iii) 9% w / w to 29.97% w / w of water A composition comprising: % is the % by weight of the composition; the lipid is selected from monolinolein or monoolein; It will be appreciated that the composition is equivalent to a composition that forms a lipid cubic phase at a temperature between 36°C and 39°C. Those skilled in the art will appreciate that a composition of the present invention comprising: a) 90-99.9% carrier (where % is by weight of the composition), the carrier comprising: a1) water in an amount of 10-25% by weight of the carrier; and a2) lipid in an amount of 75-90% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 0.1-10% by weight of the composition, (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent; (ii) 67.5% w / w to 89.9% w / w lipids; and (iii) 9% w / w to 24.9% w / w of water A composition comprising: % is the % by weight of the composition; the lipid is selected from monolinolein or monoolein; It will also be appreciated that the composition is equivalent to a composition that forms a lipid cubic phase at a temperature of 36° C. to 39° C. For example, the composition may include: a) a1) water in an amount of 10% by weight of the carrier; and a2) a carrier comprising lipid in an amount of 90% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 5% by weight of the composition. In this example, the total composition may include: (i) 5% w / w of a pharmaceutically active agent; (ii) 85.5% w / w lipids; and (iii) 9.5% w / w water Includes. In another example, the composition may include: a) a1) water in an amount of 10% by weight of the carrier; and a2) a carrier comprising a lipid in an amount of 90% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 1% by weight of the composition. In this example, the total composition may include: (i) 1% w / w of a pharmaceutically active agent; (ii) 89.1% w / w lipids; and (iii) 9.9% w / w water Includes.

[0073] For the avoidance of doubt, monolinolein (2,3-dihydroxypropyl(9Z,12Z)-9,12-octadecadienoate) has the following structure: [ka] It has.

[0074] For the avoidance of doubt, monoolein (2,3-dihydroxypropyl(9Z)-9-octadecanoate) has the following structure: [ka] It has.

[0075] The term "rectal temperature" refers to a temperature in the range of about 36°C to about 39°C. Thus, in embodiments described herein, the term rectal temperature can refer to a temperature of 36.0°C, 36.1°C, 36.2°C, 36.3°C, 36.4°C, 36.5°C, 36.6°C, 36.7°C, 36.8°C, 36.9°C, 37.0°C, 37.1°C, 37.2°C, 37.3°C, 37.4°C, 37.5°C, 37.6°C, 37.7°C, 37.8°C, 37.9°C, 38.0°C, 38.1°C, 38.2°C, 38.3°C, 38.4°C, 38.5°C, 38.6°C, 38.7°C, 38.8°C, 38.9°C, or 39.0°C. In particular, the term rectal temperature can refer to a temperature of about 38°C. Preferably, the term rectal temperature refers to a temperature of 38°C.

[0076] References to "rectal administration" or "rectally administered" include any route of administration (e.g., topical administration) of a composition of the invention via the rectum directly to tissues of the lower gastrointestinal (GI) tract. The lower GI tract is generally divided into three major parts: the colon, the rectum, and the anal canal. The colon is generally divided into five major segments. The right colon includes the cecum, ascending colon, hepatic flexure, and the right half of the transverse colon. The left colon includes the left half of the transverse colon, the descending colon, the splenic flexure, and the sigmoid colon. The rectum is the last anatomical segment before the anus. Therefore, "rectal administration" or "rectally administered" also encompasses any route of administration (e.g., topical administration) of a composition of the invention via the rectum directly to tissues of the colon (e.g., sigmoid colon, descending colon, transverse colon, ascending colon), rectum, and / or anus. Preferably, the compositions of the present invention are administered rectally to the rectum, sigmoid colon, and / or descending colon. More preferably, the compositions of the present invention are administered rectally to the rectum and / or sigmoid colon. "Rectal administration" or "administered rectally" also encompasses administration of the compositions of the present invention via an artificial anus (e.g., when the subject has a colostomy).

[0077] The compositions of the present invention (e.g., lamellar gel compositions) are also referred to as "TIF gel" compositions, meaning that the compositions are temperature-triggered, in situ-forming, bioadhesive lipid gels. The composition is triggered by a temperature of 36°C to 39°C, preferably 38°C. In a preferred embodiment, the composition is administered rectally (e.g., as an enema). As such, the composition is triggered by rectal temperature (as defined herein). The compositions of the present invention undergo a phase transition upon exposure to a temperature trigger, thus converting from a lamellar phase structure to a lipidic cubic phase at a temperature of 36°C to 39°C, preferably 38°C. The term "in situ" may be taken to mean that the composition undergoes this phase transition from a lamellar phase structure to a lipidic cubic phase when the composition is injected into the rectum of a subject and the composition reaches rectal temperature (as defined herein).

[0078] The compositions of the present invention are substantially free of organic solvents. Thus, the compositions disclosed herein contain less than 10%, less than 5%, less than 1%, or preferably less than 0.01%, or preferably less than 0.001% of organic solvents. Preferably, the compositions of the present invention do not contain detectable organic solvents.

[0079] In some embodiments, the compositions of the present invention are substantially free of surfactants. In some embodiments, the compositions of the present invention are substantially free of non-ionic surfactants, such as poloxamers. Thus, in some embodiments, the compositions disclosed herein contain less than 10%, less than 5%, less than 1%, or suitably less than 0.01%, or preferably less than 0.001% of surfactants (e.g., non-ionic surfactants such as poloxamers). References to surfactants in this paragraph do not include lipids present in the carrier of the compositions of the present invention.

[0080] A "topical formulation" is a formulation that is applied to a body surface, such as the skin or mucous membrane, for treatment. Topical formulations can also be applied rectally or vaginally to tissue surfaces other than the skin, such as dental surfaces. Topical formulations differ from many other types of drugs because their mishandling can lead to certain complications in patients or those administering the drug. Preferably, the compositions described herein are applied topically to the colon. Preferably, the topical formulations described herein are administered rectally, for example, as an enema.

[0081] The terms "lamella," "lamellar gel," "lamellar shape," "lamellar phase," "lamellar phase structure," and "L" refer to a two-dimensional stack of amphiphilic bilayers separated by a water layer. Each bilayer consists of two monolayers packed tail-to-tail to minimize contact between the hydrocarbon chains and water. In this configuration, water partitions almost exclusively into the lipid polar heads, forming water-lipid head slabs. Thus, the compositions of the present invention are in a lamellar phase at 25°C, as determined by small-angle X-ray scattering (SAXS).

[0082] The terms "cubic crystal," "lipidic cubic phase," "cubic shape," "lipidic cubic phase structure," "cubic phase," and "Q" refer to a bicontinuous cubic phase composed of two sets of aqueous channels separated by a curved bilayer in 3D space, such that every point on the central surface of the bilayer is a saddle point with zero mean curvature. The bilayer encompasses a system of aqueous channels, forming a nonbirefringent, optically transparent, structured yet flexible network. Specifically, lipid molecules in the bicontinuous cubic phase form a highly curved, continuous bilayer that separates two interpenetrating but nonintersecting aqueous channel networks. The structure may exhibit double gyroid (Ia3d, with threefold connectivity of aqueous channels), double diamond (Pn3m, with fourfold connectivity), and primitive (Im3m, with symmetric sixfold connectivity). Thus, the compositions of the present invention are in a cubic phase at about 36°C to about 39°C, as determined by small-angle X-ray scattering (SAXS). In embodiments, compositions of the present invention may be in a cubic-Ia3d phase at about 36°C to about 39°C. In embodiments, compositions of the present invention may be in a cubic-pn3m phase at about 36°C to about 39°C when present in an aqueous environment. For example, in some embodiments, compositions of the present invention absorb water at the site of administration to a subject (e.g., after rectal administration) and form a cubic-pn3m phase at a temperature of about 36°C to about 39°C. As discussed above, SAXS can be used to determine lipid phases and thus construct partial phase diagrams for different lipid-water systems (e.g., MLO-water systems). This method relies on constructive interference in reciprocal space from many ordered scattering planes belonging to mesophases. An X-ray beam is directed at a lipid sample, and the resulting scattering pattern exhibits a characteristic set of rings, or maxima, corresponding to Bragg reflections. Their position in reciprocal space depends on the Miller indices of the mesophase scattering plane, and the set of Bragg reflections (and their ratio) therefore identifies the symmetry of the mesophase being studied. SAXS makes it possible to determine the lattice constant - the size of the repeating unit cell. Once this constant is transformed, it is possible to reconstruct the entire mesophase in 3D. SAXS measurements were used to determine the phase identity and symmetry of the resulting LMPs.Measurements were performed on a Bruker AXS Micro using Cu Kα radiation at 1.5418 Å, as described in more detail in “Analytical Methods.” The following sequence of Bragg reflections was used to determine the symmetry of each of the mesophases studied: L:1:2:3:4; Ia3d:√6:√8:√14:√16:√20:√22; Pn3m:√2:√3:√4:√6:√8:√9; and H:√1:√3:√4. 37、38、39

[0083] Cross-polarized light microscopy was also used to determine the lipid phase. 40 Lyotropic liquid crystals organize themselves into networks with inherent symmetry, meaning that their basic motif repeats itself periodically. Liquid crystal cubic phases (Ia3d, pn3m, or Im3m) are isotropic, meaning they do not have any birefringence. Therefore, when a slide with a layer of lyotropic liquid crystal film is placed under a light source that allows polarized light to pass through, it appears black when observed through another polarizer tilted 90°. On the other hand, lamellar phases are anisotropic, meaning they have birefringence. Therefore, when a slide with a layer of lamellar gel is placed under a light source that allows polarized light to pass through, it appears colored when observed through another polarizer tilted 90°.

[0084] References to a "pharmaceutically acceptable salt" of a compound mean a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such a pharmaceutically acceptable salt can be, for example, an acid addition salt of the compound, such as an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, or maleic acid; or, for example, a salt of the compound that is sufficiently acidic, such as an alkali metal or alkaline earth metal salt, such as sodium, calcium, or magnesium, or ammonium salt, or a salt with an organic base, such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine.

[0085] The terms "hydrophobic pharmaceutically active agent," "hydrophobic pharmaceutically acceptable agent," or "hydrophobic agent," as used herein, refer to agents, e.g., long-chain alcohols, that have higher solubility in low-polarity organic solvents than in aqueous solutions. "Hydrophobic" means "water-averse" and is used herein to refer to agents that are poorly soluble or insoluble in water and soluble in non-polar solvents.

[0086] The terms "hydrophilic pharmaceutically active agent," "hydrophilic pharmaceutically acceptable agent," or "hydrophilic agent," as used herein, refer to an agent that has a higher solubility in aqueous media. "Hydrophilic" means "water-loving" and is used herein to refer to an agent that is water-soluble, i.e., has a strong affinity for water.

[0087] The ingredients and excipients of the described compositions are suitable for the intended purpose, e.g., a pharmaceutical composition includes ingredients that are pharmaceutically acceptable.

[0088] Unless otherwise stated, the ingredients, components, excipients, etc. of the compositions of the present invention are suitable for one or more of the intended purposes discussed elsewhere herein.

[0089] When the present invention is referred to as a formulation, this is taken to be the same as a composition of the present invention. Thus, the terms formulation and composition are used interchangeably.

[0090] When the composition of the present invention is referred to as a lamellar gel, this is taken to be the same as a composition of the present invention having a lamellar phase structure, and therefore these terms are used interchangeably.

[0091] Reference to "about" in the context of a numerical value is intended to encompass the value + / - 10%, for example, about 20% includes a range of 18% to 22%. composition

[0092] a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents A composition comprising: Provided herein are compositions, wherein the composition forms a lipid cubic phase at a temperature between 36°C and 39°C.

[0093] The composition comprises: a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0094] a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition A composition comprising: Also provided herein are compositions, wherein the composition forms a lipid cubic phase at a temperature between 36°C and 39°C.

[0095] Lipids are neutral lipid components that contain a polar "head" group and a non-polar "tail" group. Generally, the head and tail of a lipid are joined by an ester moiety, but this attachment can also be by an ether, amide, carbon-carbon bond, or other attachment. Preferred polar head groups are non-ionic, and include polyols such as glycerol, diglycerol, and sugar moieties (such as inositol and glucosyl-based moieties); and esters of polyols such as acetate or succinate. Preferred polar groups are glycerol and diglycerol, especially glycerol.

[0096] Preferably, the lipid is a monoacylglycerol lipid. The non-polar group may be saturated or unsaturated. Examples of non-polar groups include C6-C 32 Alkyl groups and C6-C 32Included are alkenyl groups, which are typically present as esters of long-chain carboxylic acids. They are often described with reference to the number of carbon atoms and unsaturations in the carbon chain. Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Specific examples include caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitolcoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0), and lignoceroyl (C24:9) groups. Therefore, typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, phytanic acid, palmitic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid or lignoceric acid, or corresponding alcohols.Preferred non-polar chains are oleic acid and linoleic acid, especially linoleic acid.Those skilled in the art will understand that lipids are naturally derived or semi-synthetic raw materials, and therefore, the origin of raw materials and therefore their composition may vary.Therefore, those skilled in the art will understand that any reference herein to monolinolein lipids includes both purified forms of monolinolein and commercially available forms of monolinolein (for example, food-grade forms of monolinolein). For example, a commercial grade form of monolinolein lipid may contain a mixture of monoacylglycerol lipids (such as monolinolein and monoolein), and, if desired, further additional lipids. Those skilled in the art will also understand that any reference herein to monoolein lipid encompasses both purified forms of monoolein and commercial grade forms of monoolein (e.g., food-grade forms of monoolein).For example, commercially available grade forms of monoolein lipids may contain a mixture of monoacylglycerol lipids (such as monoolein and monolinolein) and, optionally, further additional lipids.

[0097] Therefore, monolinolein lipids may contain more than about 90 wt% monoacylglycerol lipids. Monolinolein lipids may contain more than about 95 wt% monoacylglycerol lipids. Monolinolein lipids may contain more than about 98 wt% monoacylglycerol lipids. Monolinolein lipids may contain more than about 99.9 wt% monoacylglycerol lipids. For example, monolinolein lipids (e.g., commercially available grade forms of monolinolein lipids) may contain about 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, or 100 wt% monoacylglycerol lipids.

[0098] The monolinolein lipid may contain up to 100 wt% monolinolein. The monolinolein lipid may contain greater than or equal to about 99 wt% monolinolein. The monolinolein lipid may contain greater than about 90 wt% monolinolein. The monolinolein lipid may contain greater than about 80 wt% monolinolein. The monolinolein lipid may contain greater than about 70 wt% monolinolein. The monolinolein lipid may contain greater than about 60 wt% monolinolein. The monolinolein lipid may contain greater than about 50 wt% monolinolein. The monolinolein lipid may comprise greater than about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% monolinolein.

[0099] The monolinolein lipid may be free of monoolein. The monolinolein lipid may contain less than about 50 wt% monoolein. The monolinolein lipid may contain less than about 40 wt% monoolein. The monolinolein lipid may contain less than about 30 wt% monoolein. The monolinolein lipid may contain less than about 20 wt% monoolein. The monolinolein lipid may contain less than about 10 wt% monoolein. The monolinolein lipid may contain less than about 5 wt% monoolein. The monolinolein lipid may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt% monoolein.

[0100] Monoolein lipids may contain more than about 90 wt% monoacylglycerol lipids. Monoolein lipids may contain more than about 95 wt% monoacylglycerol lipids. Monoolein lipids may contain more than about 98 wt% monoacylglycerol lipids. Monoolein lipids may contain more than about 99.9 wt% monoacylglycerol lipids. For example, monoolein lipids (e.g., commercially available grade forms of monoolein lipids) may contain about 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, or 100 wt% monoacylglycerol lipids.

[0101] The monoolein lipids may contain up to 100 wt% monoolein. The monoolein lipids may contain greater than or equal to about 99 wt% monoolein. The monoolein lipids may contain greater than about 90 wt% monoolein. The monoolein lipids may contain greater than about 80 wt% monoolein. The monoolein lipids may contain greater than about 70 wt% monoolein. The monoolein lipids may contain greater than about 60 wt% monoolein. The monoolein lipids may contain greater than about 50 wt% monoolein. The monoolein lipid may comprise greater than about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% monoolein.

[0102] The monoolein lipid may be free of monolinolein. The monoolein lipid may contain less than about 50 wt% monolinolein. The monoolein lipid may contain less than about 40 wt% monolinolein. The monoolein lipid may contain less than about 30 wt% monolinolein. The monoolein lipid may contain less than about 20 wt% monolinolein. The monoolein lipid may contain less than about 10 wt% monolinolein. The monoolein lipid may contain less than about 5 wt% monolinolein. The monoolein lipid may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt% monolinolein.

[0103] In some embodiments, the monoacylglycerol lipid may contain up to 100 wt% monolinolein. The monoacylglycerol lipid may contain greater than or equal to about 99 wt% monolinolein. The monoacylglycerol lipid may contain greater than about 90 wt% monolinolein. The monoacylglycerol lipid may contain greater than about 80 wt% monolinolein. The monoacylglycerol lipid may contain greater than about 70 wt% monolinolein. The monoacylglycerol lipid may contain greater than about 60 wt% monolinolein. The monoacylglycerol lipid may contain greater than about 50 wt% monolinolein. The monoacylglycerol lipid may contain more than about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% monolinolein. The monoacylglycerol lipid may be free of monoolein. The monoacylglycerol lipid may contain less than about 50 wt% monoolein. The monoacylglycerol lipid may contain less than about 40 wt% monoolein. The monoacylglycerol lipids may contain less than about 30 wt% monoolein. The monoacylglycerol lipids may contain less than about 20 wt% monoolein. The monoacylglycerol lipids may contain less than about 10 wt% monoolein. The monoacylglycerol lipids may contain less than about 5 wt% monoolein. The monoacylglycerol lipids may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt% monoolein.

[0104] In other embodiments, the monoacylglycerol lipid may contain up to 100 wt% monoolein. The monoacylglycerol lipid may contain greater than or equal to about 99 wt% monoolein. The monoacylglycerol lipid may contain greater than about 90 wt% monoolein. The monoacylglycerol lipid may contain greater than about 80 wt% monoolein. The monoacylglycerol lipid may contain greater than about 70 wt% monoolein. The monoacylglycerol lipid may contain greater than about 60 wt% monoolein. The monoacylglycerol lipid may contain greater than about 50 wt% monoolein. The monoacylglycerol lipid may contain more than about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% monoolein. The monoacylglycerol lipid may be free of monolinolein. The monoacylglycerol lipid may contain less than about 50 wt% monolinolein. The monoacylglycerol lipid may contain less than about 40 wt% monolinolein. The monoacylglycerol lipid may contain less than about 30 wt% monolinolein. The monoacylglycerol lipid may contain less than about 20 wt% monolinolein. The monoacylglycerol lipid may contain less than about 10 wt% monolinolein. The monoacylglycerol lipid may contain less than about 5 wt% monolinolein. The monoacylglycerol lipids may contain about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt% monolinolein.

[0105] In embodiments, the lipid is a monoacylglycerol lipid. In preferred embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. Thus, the lipid may be monolinolein. The lipid may be monoolein.

[0106] In embodiments, the lipid is a monoacylglycerol lipid. The monoacylglycerol lipid may include monolinolein or monoolein, or a combination thereof. Thus, the monoacylglycerol lipid may include monolinolein and monoolein. The monoacylglycerol lipid may include monolinolein. The monoacylglycerol lipid may include monoolein. The monoacylglycerol lipid may further include other lipids. The monoacylglycerol lipid may further include up to about 10% other lipids. The monoacylglycerol lipid may further include up to about 8% other lipids. The monoacylglycerol lipid may further include up to about 5% other lipids. The monoacylglycerol lipid may further include about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% other lipids. The monoacylglycerol lipid may be substantially free of other lipids.

[0107] The monolinolein lipid may comprise a monoacylglycerol lipid. The monolinolein lipid may comprise a monoacylglycerol lipid and a diglyceride. The monolinolein lipid may comprise more than about 90 wt% of a monoacylglycerol lipid. The monolinolein lipid may comprise more than about 95 wt% of a monoacylglycerol lipid. The monolinolein lipid may comprise more than about 98 wt% of a monoacylglycerol lipid. The monoacylglycerol lipid may comprise a C18 lipid. The monoacylglycerol lipid may comprise more than about 80% of a C18 lipid. The monoacylglycerol lipid may comprise more than about 85% of a C18 lipid. The monoacylglycerol lipid may comprise more than about 90% of a C18 lipid, for example, 91% of a C18 lipid. The C18 lipids may comprise C18:2, C18:1, and / or C18:0 lipids. The C18 lipids may comprise greater than about 50% C18:2 lipids. The C18 lipids may comprise greater than about 55% C18:2 lipids. The C18 lipids may comprise greater than about 60% C18:2 lipids. The C18 lipids may comprise about 60% to about 65% C18:2 lipids, for example, about 60%, 60.5%, 61%, 61.5%, 61.6%, 61.7%, 61.8%, 61.9%, 62%, 62.1%, 62.2%, 62.3%, 62.4%, 62.5%, 63%, 63.5%, 64%, 64.5%, or 65% C18.2 lipids. The C18 lipids may contain about 61.9% C18:2 lipids. The C18 lipids may contain more than about 15% C18:1 lipids. The C18 lipids may contain more than about 20% C18:1 lipids. The C18 lipids may contain about 25% C18:1 lipids. The C18 lipids may contain less than about 30% C18:1 lipids.The C18 lipids may contain about 20% to about 30% C18:1 lipids, for example, about 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, or 30% C18.1 lipids. The C18 lipids may contain about 24.9% C18:1 lipids. The C18 lipids may contain more than about 1% C18:0 lipids. The C18 lipids may contain about 4% C18:0 lipids. The C18 lipids may contain about 5% C18:0 lipids. The C18 lipids may contain less than about 10% C18:0 lipids. The C18 lipids may contain about 1% to about 5% C18:0 lipids, for example, about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% C18.0 lipids. The C18 lipids may contain about 4.2% C18:1 lipids. The monoacylglycerol lipids may contain C16 lipids, for example, C16:0 lipids. The monoacylglycerol lipids may contain more than about 1% C16:0 lipids. The monoacylglycerol lipids may contain more than about 5% C16:0 lipids. The monoacylglycerol lipids may contain greater than about 7% C16:0 lipids. The monoacylglycerol lipids may contain less than about 10% C16:0 lipids. The monoacylglycerol lipids may contain about 5% to about 10% C16:0 lipids, for example, about 5%, 5.5%, 6%, 6.5%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8%, 8.5%, 9%, 9.5%, or 10% C16:0 lipids. The monoacylglycerol lipids may contain about 7.4% C16:0 lipids. The monolinolein lipids may contain less than about 5% diglycerides. The monolinolein lipids may contain less than about 3% diglycerides. The monolinolein lipids may contain more than about 1% diglycerides.For example, the monolinolein lipids may contain about 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 3.5%, 4%, 4.5%, or 5% diglycerides. Thus, the monolinolein lipids may contain greater than 98 wt% monoacylglycerol lipids (including 61.9% C18:2 lipids, 24.9% C18:1 lipids, 4.2% C18:0 lipids, and 7.4% C16:0 lipids) and 1.6% diglycerides.

[0108] Therefore, in the embodiment, a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents A composition comprising: the lipid is selected from monolinolein or monoolein; Provided herein are compositions, wherein the composition forms a lipid cubic phase at a temperature between 36°C and 39°C.

[0109] The composition comprises: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0110] The composition comprises: a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) may contain a pharmaceutically active agent; the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the lipid is monolinolein.

[0111] The lipid may be monolinolein. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) Monolinolein in an amount of 75% to 90% by weight of the carrier a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0112] The lipid may be monoolein. a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) Monoolein in an amount of 70% to 90% by weight of the carrier a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. In a preferred embodiment, the composition contains up to 10% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. Thus, the composition may contain: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0113] The composition comprises: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0114] Therefore, the composition a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0115] In embodiments, the composition comprises: (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent; (ii) 67.5% w / w to 89.9% w / w lipids; and (iii) 9% w / w to 24.9% w / w of water Including, the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0116] In a preferred embodiment, the composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition Including, The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0117] In embodiments, the compositions of the present invention have a lamellar phase structure at 25°C. The compositions of the present invention may have a lamellar phase structure at temperatures ranging from above 25°C to below rectal temperature. For example, the compositions of the present invention may have a lamellar phase structure at temperatures ranging from above 25°C to below 38°C. Thus, the compositions of the present invention may have a lamellar phase structure at 25°C to 37°C. The compositions of the present invention may have a lamellar phase structure at 25°C to 36°C. The compositions of the present invention may have a lamellar phase structure at 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C.

[0118] In embodiments, the composition may be a lamellar gel at 25°C. The composition of the present invention may be a lamellar gel at temperatures ranging from above 25°C to below rectal temperature. For example, the composition of the present invention may be a lamellar gel at temperatures ranging from above 25°C to below 38°C. Thus, the composition of the present invention may be a lamellar gel at 25°C to 37°C. The composition of the present invention may be a lamellar gel at 25°C to 36°C. The composition of the present invention may be a lamellar gel at 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C.

[0119] In embodiments, lamellar gels have lower structural strength relative to the lipidic cubic phase (as indicated by lower storage modulus values ​​and modulus reductions (G' and G'' respectively). As such, lamellar gels are less viscous when the composition transforms into the lipidic cubic phase. Lamellar gels are therefore easier to administer to a subject. Preferably, the lamellar composition or gel has a viscosity at ambient temperature (e.g., 25°C) suitable for injection through a standard gauge needle (e.g., for subcutaneous administration) or via a conventional enema or rectal administration device.

[0120] The lamellar phase (e.g., lamellar gel) of the composition at ambient temperature is more viscous than a simple aqueous solution of the pharmaceutically active agent. The higher viscosity of the lamellar composition of the present invention at ambient temperature improves the retention of the composition in the subject immediately after rectal administration, but the composition undergoes a transition to a higher viscosity phase as the temperature of the composition warms to rectal temperature. Initial composition retention is therefore improved compared to the use of conventional simple aqueous solutions or suspensions of the active agent.

[0121] In embodiments, when the composition is in a lipidic cubic phase, the composition has both G' and G'' higher than G' and G'' in the lamellar phase. A lamellar gel may have both G' and G'' lower than G' and G'' in the lipidic cubic phase. The composition may be less viscous in the lamellar phase. The composition may be more viscous in the lipidic cubic phase. As the composition phase transitions from the lamellar phase to the lipidic cubic phase, the viscosity of the composition may increase. Thus, the lipidic cubic phase structure forms a sustained release depot in situ.

[0122] In embodiments, the lipid cubic phase composition is retained in the rectum for about 10 minutes to about 24 hours. The lipid cubic phase composition may be retained in the rectum for about 20 minutes to about 12 hours. The lipid cubic phase composition may be retained in the rectum for about 30 minutes to about 6 hours. The lipid cubic phase composition may be retained in the rectum for about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. Preferably, the lipid cubic phase composition may be retained in the rectum for at least 30 minutes.

[0123] In an embodiment, the composition is subjected to a stress-controlled rheometer (Modular Compact Rheometer MCR 72, manufactured by Anton Paar, Graz, Austria) using a cone-plate geometry, an angle of 0.993°, and a diameter of 49.942 mm at 25°C and a shear rate of 0.01 s -1 ) measured at 1×10 6 ~1×10 7 The composition has a zero shear viscosity of 0.01 mPa·s. -1 Measured in 1 x 10 6 mPa·s, 2×10 6 mPa·s, 3×10 6 mPa·s, 4×10 6 mPa·s, 5×10 6 mPa·s, 6×10 6 mPa·s, 7×10 6 mPa·s, 8×10 6 mPa·s, 9×10 6 mPa·s, or 1×10 7 The composition may have a zero shear viscosity of 0.01 mPa·s at 25°C and 0.01 mPa·s. -1 Measured in 1 x 10 6 The composition may have a zero shear viscosity of 0.01 mPa·s at 25°C and 0.01 mPa·s. -1Measured in 1 x 10 7 It may have a zero shear viscosity of 0.015 mPa·s.

[0124] In an embodiment, the composition has a lamellar phase structure and is -1 Measured in 1 x 10 6 mPa·s~1×10 7 The composition may have a lamellar phase structure and has a zero shear viscosity of 25°C and 0.01 s. -1 Measured in 1 x 10 6 mPa·s, 2×10 6 mPa·s, 3×10 6 mPa·s, 4×10 6 mPa·s, 5×10 6 mPa·s, 6×10 6 mPa·s, 7×10 6 mPa·s, 8×10 6 mPa·s, 9×10 6 mPa·s, or 1×10 7 It may have a zero shear viscosity of 0.015 mPa·s.

[0125] In embodiments, the composition has a lipid cubic phase structure and has a lipid cubic phase structure of about 1 x 10 7 mPa·s ~ approx. 1×10 9 The composition may have a lipid cubic phase structure and a viscosity of about 1 x 10 mPa·s measured at 38°C. 7 mPa·s ~ approx. 1×10 8 The composition may have a lipid cubic phase structure and a viscosity of about 1×10 mPa·s measured at 38° C. 8 mPa·s ~ approx. 1×10 9 It may have a viscosity of mPa·s.

[0126] In some embodiments, the composition is an enema composition.Therefore, in some embodiments, the composition is administered rectally to the lower colon of the subject as an enema.The unit dose of the enema preparation can be administered from a pre-filled bag or a pre-filled syringe.The composition can be administered rectally to the sigmoid colon, descending colon and / or rectum of the subject as an enema.

[0127] The viscosity of the enema composition, measured at 25° C., is preferably 10,000 to 70,000 mPa·s, more preferably 10,000 to 70,000 mPa·s, and most preferably 10,000 to 40,000 mPa·s. The pH is preferably 5.5 to 7.5, and more preferably 6.5 to 7.5.

[0128] When administered to a subject (e.g., as an enema), the composition having a lamellar phase structure gradually absorbs heat (and available water) from the body and converts to a lipid cubic phase, thus forming a controlled-release depot in situ. The composition may adhere to the wall of the colon, thus forming a bioadhesive controlled-release depot in situ. The composition may adhere to the wall of the sigmoid colon, descending colon, and / or rectum, thus forming a bioadhesive controlled-release depot in situ.

[0129] In an embodiment, the composition forms a lipid cubic phase in situ. The term "in situ" can be considered to mean that the composition undergoes a phase transition from a lamellar phase structure to a lipid cubic phase when the composition is administered to a subject and reaches a temperature of 36°C to 39°C, preferably 38°C. The phase transition of the composition from a lamellar phase structure to a lipid cubic phase can be measured using SAXS and can be determined after equilibration at the required temperature.

[0130] Preferably, the composition is administered to a subject rectally (e.g., as an enema). Therefore, "in situ" may be considered to mean that the composition is injected into the subject's rectum and undergoes a phase transition from a lamellar phase structure to a lipidic cubic phase once the composition reaches a temperature of 36°C to 39°C, preferably 38°C (i.e., rectal temperature).

[0131] In embodiments, the composition forms a lipid cubic phase at a temperature of about 36° C. to about 39° C. The composition may also form a lipid cubic phase at a temperature of 36° C. to 39° C., 37° C. to 39° C., or 37.5° C. to 38.5° C.

[0132] The composition may form a lipid cubic phase at rectal temperature. Thus, the composition may form a lipid cubic phase at temperatures of 36.0°C, 36.1°C, 36.2°C, 36.3°C, 36.4°C, 36.5°C, 36.6°C, 36.7°C, 36.8°C, 36.9°C, 37.0°C, 37.1°C, 37.2°C, 37.3°C, 37.4°C, 37.5°C, 37.6°C, 37.7°C, 37.8°C, 37.9°C, 38.0°C, 38.1°C, 38.2°C, 38.3°C, 38.4°C, 38.5°C, 38.6°C, 38.7°C, 38.8°C, 38.9°C, or 39.0°C. Preferably, the composition may form a lipid cubic phase at a temperature of 38°C.

[0133] In embodiments, the composition forms a lipid cubic phase after about 1 minute at a temperature of about 36°C to about 39°C. The composition may form a lipid cubic phase after about 1 minute to 30 minutes at a temperature of about 36°C to about 39°C. The composition may form a lipid cubic phase after about 1 minute to 20 minutes at a temperature of about 36°C to about 39°C. The composition may form a lipid cubic phase after about 1 minute to 10 minutes at a temperature of about 36°C to about 39°C. Preferably, the composition may form a lipid cubic phase after about 5 minutes at a temperature of about 38°C.

[0134] In embodiments, the composition converts to a lipidic cubic phase upon contact with water, body fluids, and / or other aqueous media at a temperature of about 36° C. to about 39° C. The composition may convert to a lipidic cubic phase upon contact with water, body fluids, and / or other aqueous media at a temperature of 38° C. The body fluid may be fluid from a mucosal surface, digestive fluid, extravascular fluid, extracellular fluid, interstitial fluid, or plasma.

[0135] In embodiments, the composition converts in situ to a lipidic cubic phase upon contact with water, body fluids, and / or other aqueous media. Thus, the composition may be administered to a subject (e.g., rectally, e.g., as an enema), and the composition may convert from a lamellar phase structure to a lipidic cubic phase structure at a temperature of about 36°C to about 39°C upon contact with water, body fluids, and / or other aqueous media. The composition may be administered to a subject rectally (e.g., as an enema), and the composition may convert from a lamellar phase structure to a lipidic cubic phase structure at rectal temperatures upon contact with water, body fluids, and / or other aqueous media. The composition may be administered to a subject rectally (e.g., as an enema), and the composition may convert from a lamellar phase structure to a lipidic cubic phase structure at a temperature of 38°C upon contact with water, body fluids, and / or other aqueous media.

[0136] In embodiments, the composition forms a lipid cubic phase in the pH range of about 5 to about 9. The composition may form a lipid cubic phase in the pH range of about 6 to about 8. The composition may form a lipid cubic phase in the pH range of about 6.5 to about 7.5. Thus, the composition may form a lipid cubic phase at a pH of about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9.

[0137] In embodiments, the composition is substantially free of organic solvents. Thus, the composition may contain less than 10% organic solvent. The composition may mean that it contains less than 5% organic solvent. The composition may mean that it contains less than 1% organic solvent. The composition may mean that it contains less than 0.01% organic solvent. The composition may mean that it contains less than 0.001% organic solvent. The composition may mean that it contains no detectable organic solvent.

[0138] In embodiments, the composition is substantially free of other lipids. Thus, the composition may contain less than 10% other lipids. It may also mean that the composition contains less than 5% other lipids. It may also mean that the composition contains less than 1% other lipids. It may also mean that the composition contains less than 0.01% other lipids. It may also mean that the composition contains less than 0.001% other lipids. It may also mean that the composition contains no detectable other lipids.

[0139] In embodiments, the composition is substantially free of other lipid components. Thus, the composition may contain less than 10% other lipid components. The composition may also mean that it contains less than 5% other lipid components. The composition may also mean that it contains less than 1% other lipid components. The composition may also mean that it contains less than 0.01% other lipid components. The composition may also mean that it contains less than 0.001% other lipid components. The composition may also mean that it contains no detectable other lipid components.

[0140] In embodiments, the composition is substantially free of additives. Thus, the composition may contain less than 10% additives. The composition may mean that it contains less than 5% additives. The composition may mean that it contains less than 1% additives. The composition may mean that it contains less than 0.01% additives. The composition may mean that it contains less than 0.001% additives. The composition may mean that it contains no detectable other additives. Carrier

[0141] In embodiments, the composition comprises a carrier, the carrier comprising 10% to more than 30% water and 70% to 90% lipid, where the % are by weight based on the weight of the carrier. The carrier may consist of 10% to more than 30% water and 70% to 90% lipid, where the % are by weight based on the weight of the carrier.

[0142] In an embodiment, the composition comprises a carrier, the carrier comprising 10% to more than 25% water and 75% to 90% lipid, where the % is by weight based on the weight of the carrier. In a preferred embodiment, the carrier consists of 10% to more than 25% water and 75% to 90% lipid, where the % is by weight based on the weight of the carrier.

[0143] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from monolinolein or monoolein. Preferably, the lipid in the carrier is monolinolein. Thus, in an embodiment, the carrier comprises 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier, and the lipid is selected from monolinolein or monoolein. In a preferred embodiment, the carrier consists of 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier, and the lipid is selected from monolinolein or monoolein.

[0144] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. In embodiments, the monoacylglycerol lipid comprises monolinolein or monoolein, or a combination thereof. Preferably, the lipid in the carrier is monolinolein. Thus, in embodiments, the carrier comprises 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier, and the lipid is selected from monolinolein or monoolein. In embodiments, the carrier comprises 10% to more than 30% water and 70% to 90% lipid, where % is by weight based on the weight of the carrier, and the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In a preferred embodiment, the carrier is comprised of 10% to greater than 30% water and 70% to 90% lipid, where the % is by weight based on the weight of the carrier, and the lipid is selected from monolinolein or monoolein. The carrier may also be comprised of 10% to greater than 30% water and 70% to 90% lipid, where the % is by weight based on the weight of the carrier, and the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof.

[0145] In embodiments, the carrier contains 10% to more than 30% water, where % is by weight based on the weight of the carrier. For example, the carrier may contain 10% to 30% water, 20% to 30% water, 10% to 25% water, 11% to 20% water, or 14% to 18% water, where % is by weight based on the weight of the carrier. The carrier may contain 10%, 10.5%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% water. Preferably, the carrier may contain 16% water.

[0146] In embodiments, the water used in the carrier is deionized water. In certain embodiments, the water used for the carrier is ultrapure water (e.g., having a resistivity of greater than about 18 MΩ.cm at 25°C). In certain embodiments, the water used in the carrier is phosphate buffered saline. In embodiments, the water used in the carrier is water for injection (WFI).

[0147] In embodiments, the carrier comprises 70% to 90% lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 70% to 90% lipid, 75% to 90% lipid, 70% to 80% lipid, 80% to 90% lipid, or 84% to 88% lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% lipid. Preferably, the carrier may comprise 86% lipid.

[0148] In embodiments, the carrier comprises 70% to 90% lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 70% to 90% lipid, 75% to 90% lipid, 70% to 80% lipid, 80% to 90% lipid, or 84% to 88% lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 70% to 90% lipid, 75% to 90% lipid, 70% to 80% lipid, 80% to 90% lipid, 82% to 86% lipid, or 84% to 88% lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% lipid. The carrier may comprise 86% lipid. Preferably, the carrier may comprise 84% lipid.

[0149] In embodiments, the carrier may comprise 10% to greater than 20% water and 80% to 90% lipid. In a preferred embodiment, the carrier may comprise 16% water and 84% lipid.

[0150] In embodiments, the carrier may comprise 10% to over 20% water and 80% to 90% lipid. The carrier may comprise 14% to 18% water and 82% to 86% lipid. In a preferred embodiment, the carrier may comprise 16% water and 84% lipid.

[0151] In other embodiments, the carrier may contain 20% to 30% water and 70% to 80% lipid.

[0152] In embodiments, the carrier comprises 75% to 90% monoacylglycerol lipid, where % is by weight based on the weight of the carrier, and the monoacylglycerol lipid comprises monolinolein or monoolein, or a combination thereof. The carrier may comprise 75% to 90% monoacylglycerol lipid, 80% to 90% monoacylglycerol lipid, or 84% to 88% monoacylglycerol lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 75% to 90% monoacylglycerol lipid, 80% to 90% monoacylglycerol lipid, 82% to 86% monoacylglycerol lipid, or 84% to 88% monoacylglycerol lipid, where % is by weight based on the weight of the carrier. The carrier may comprise 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% monoacylglycerol lipid, wherein the monoacylglycerol lipid comprises monolinolein or monoolein, or a combination thereof. The carrier may comprise 86% monoacylglycerol lipid. Preferably, the carrier may comprise 84% monoacylglycerol lipid.

[0153] In embodiments, the carrier comprises 75% to 90% monolinolein, where % is by weight based on the weight of the carrier. The carrier may comprise 75% to 90% monolinolein, 80% to 90% monolinolein, or 84% to 88% monolinolein, where % is by weight based on the weight of the carrier. The carrier may comprise 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% monolinolein. Preferably, the carrier may comprise 86% monolinolein.

[0154] In embodiments, the carrier comprises 75% to 90% monolinolein, where % is by weight based on the weight of the carrier. The carrier may comprise 75% to 90% monolinolein, 80% to 90% monolinolein, or 84% to 88% monolinolein, where % is by weight based on the weight of the carrier. The carrier may comprise 75% to 90% monolinolein, 80% to 90% monolinolein, 82% to 86% monolinolein, or 84% to 88% monolinolein, where % is by weight based on the weight of the carrier. The carrier may comprise 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% monolinolein. The carrier may contain 86% monolinolein. Preferably, the carrier may contain 84% monolinolein.

[0155] In embodiments, the composition comprises: a) a1) water in an amount greater than 10% to 20% by weight of the carrier; and a2) Monolinolein in an amount of 80% to 90% by weight of the carrier a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0156] In embodiments, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the composition forms a lipid cubic phase at rectal temperature. a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 38°C.

[0157] In embodiments, the carrier comprises 70% to 90% monoolein, where % is by weight based on the weight of the carrier. The carrier may comprise 70% to 90% monoolein, 70% to 85% monoolein, or 70% to 80% monoolein, where % is by weight based on the weight of the carrier. The carrier may comprise 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% monoolein.

[0158] In embodiments, the composition comprises: a) a1) water in an amount greater than 20% to 30% by weight of the carrier; and a2) Monoolein in an amount of 70% to 80% by weight of the carrier a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. In an embodiment, the composition comprises: a) a1) water in an amount of 20% by weight of the carrier; and a2) Monoolein in an amount of 80% by weight of the carrier a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, the composition may form a lipid cubic phase at rectal temperature. Therefore, the composition may a) a1) water in an amount of 20% by weight of the carrier; and a2) Monoolein in an amount of 80% by weight of the carrier a carrier comprising: b) pharmaceutically active agents and The composition forms a lipid cubic phase at a temperature of 38°C.

[0159] In embodiments, the composition comprises: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may be monolinolein.

[0160] In embodiments, the composition comprises: a) a1) water in an amount greater than 10% to 20% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 80% to 90% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may be monolinolein.

[0161] In embodiments, the composition comprises: a) a1) water in an amount greater than 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 82% to 86% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may be monolinolein.

[0162] In embodiments, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monoacylglycerol lipids, comprising monolinolein or monoolein, or a combination thereof, in an amount of 84% by weight of the carrier; a carrier comprising: b) pharmaceutically active agents Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may be monolinolein.

[0163] In embodiments, the composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may comprise at least 55% by weight monolinolein.

[0164] In embodiments, the composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may comprise at least 55% by weight monolinolein.

[0165] In embodiments, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 84% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition Including, The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at rectal temperature. The composition may form a lipid cubic phase at 38° C. The monoacylglycerol lipid may comprise at least 55% by weight monolinolein, for example, at least about 60% by weight monolinolein. Pharmaceutically Active Agents

[0166] In embodiments, the composition comprises at least one pharmaceutically active agent. Thus, the composition may comprise one pharmaceutically active agent. The composition may comprise more than one pharmaceutically active agent. For example, the composition may comprise two pharmaceutically active agents. The composition may comprise two or more pharmaceutically active agents. For example, the composition may comprise three pharmaceutically active agents. The composition may comprise four pharmaceutically active agents.

[0167] In an embodiment, the composition comprises up to 20% w / w of a pharmaceutically active agent. Thus, the composition may comprise 0.1% to 20% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. In a preferred embodiment, the composition comprises up to 10% w / w of a pharmaceutically active agent. The composition may comprise 0.1% to 10% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. Thus, the composition comprises a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0168] The composition may contain 0.1% to 10% of a pharmaceutically active agent, 0.5% to 10% of a pharmaceutically active agent, 0.5% to 7.5% of a pharmaceutically active agent, or 1% to 5% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. Preferably, the composition may contain 0.1% to 10% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. More preferably, the composition may contain 1% to 5% of a pharmaceutically active agent, where % is by weight based on the weight of the composition. Thus, the composition may contain: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0169] The composition comprises: a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein, preferably monolinolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. In this example, the total composition is (i) 1% w / w to 5% w / w of a pharmaceutically active agent; (ii) 71.25% w / w to 89.1% w / w lipids; and (iii) 9.5% w / w to 24.75% w / w of water Includes.

[0170] For example, composition can comprise 1% pharmaceutically active agent, and % is % by weight based on the weight of composition.In a preferred embodiment, composition can comprise a) a1) water in the amount of 16% by weight of carrier; and a2) carrier comprising lipid in the amount of 84% by weight of carrier; and b) pharmaceutically active agent in the amount of 1% by weight of composition.Therefore, composition can comprise: a) 99% of a carrier (where % is % by weight of the composition), wherein the carrier is: a1) water in an amount of 16% by weight of the carrier; and a2) lipids in an amount of 84% by weight of the carrier a carrier comprising: b) 1% of a pharmaceutically active agent (where % is by weight of the composition) and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the lipid is monolinolein. In this example, the total composition is (i) 1% w / w of a pharmaceutically active agent; (ii) 83.16% w / w monolinolein; and (iii) 15.84% w / w water Includes.

[0171] In another example, the composition may comprise 5% pharmaceutically active agent, and % is % by weight based on the weight of the composition.In a preferred embodiment, the composition may comprise: a) a1) water in an amount of 16% by weight of the carrier; and a2) a carrier comprising lipid in an amount of 84% by weight of the carrier; and b) 5% pharmaceutically active agent by weight of the composition.Therefore, the composition may comprise: a) 95% of a carrier (where % is % by weight of the composition), wherein the carrier is: a1) water in an amount of 16% by weight of the carrier; and a2) lipids in an amount of 84% by weight of the carrier a carrier comprising: b) 5% of a pharmaceutically active agent (where % is by weight of the composition) and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the lipid is monolinolein. In this example, the total composition is (i) 5% w / w of a pharmaceutically active agent; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Includes.

[0172] In other embodiments, the composition may comprise: a) a1) water in an amount of 20% by weight of the carrier; and a2) a carrier comprising a lipid in an amount of 80% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 1% by weight of the composition. a) 99% of a carrier (where % is % by weight of the composition), wherein the carrier is: a1) water in an amount of 20% by weight of the carrier; and a2) lipids in an amount of 80% by weight of the carrier a carrier comprising: b) 1% of a pharmaceutically active agent (where % is by weight of the composition) and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the lipid is monoolein. In this example, the total composition is (i) 1% w / w of a pharmaceutically active agent; (ii) 79.2% w / w monoolein; and (iii) 19.8% w / w water Includes.

[0173] In another example, the composition may include: a) a1) water in an amount of 20% by weight of the carrier; and a2) a carrier comprising a lipid in an amount of 80% by weight of the carrier; and b) a pharmaceutically active agent in an amount of 5% by weight of the composition. a) 95% of a carrier (where % is % by weight of the composition), wherein the carrier is: a1) water in an amount of 20% by weight of the carrier; and a2) lipids in an amount of 80% by weight of the carrier a carrier comprising: b) 5% of a pharmaceutically active agent (where % is by weight of the composition) and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, the lipid is monoolein. In this example, the total composition is (i) 5% w / w of a pharmaceutically active agent; (ii) 76% w / w monolinolein; and (iii) 19% w / w water Includes.

[0174] In embodiments, the pharmaceutically active agent is selected from a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent. Therefore, the pharmaceutically active agent may be a hydrophilic pharmaceutically active agent. Therefore, the pharmaceutically active agent may be water-soluble. In other embodiments, the pharmaceutically active agent may be a hydrophobic pharmaceutically active agent. Therefore, the pharmaceutically active agent may be a lipophilic pharmaceutically active agent.

[0175] In embodiments, the pharmaceutically active agent is dissolved in the carrier, hi other embodiments, the pharmaceutically active agent is suspended in the carrier.

[0176] In embodiments, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent, which is dissolved in water to provide a drug mixture, as described in detail in the "Methods of Preparation" section herein.

[0177] In embodiments, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent, which is insoluble in water. The hydrophobic pharmaceutically active agent may be mixed with lipids and hydrated in water to provide a lipid-drug mixture, as described in detail in the "Methods of Preparation" section herein.

[0178] In some embodiments, the pharmaceutically active agent is water-soluble. "Soluble" means that 1 g of the pharmaceutically active agent requires less than 10,000 mL, preferably less than 1,000 mL, more preferably less than 100 mL, and even more preferably less than 30 mL or 10 mL of solvent to dissolve at a given pH (25.0±0.5°C). "Soluble" may also mean that the logP of the substance has a negative value. In embodiments, the pharmaceutically active agent is soluble in water at pH 7.0 and 25.0±0.5°C.

[0179] In other embodiments, the pharmaceutically active agent is water-insoluble. "Insoluble" means that 1 g of the pharmaceutically active agent requires more than 10,000 mL of solvent to dissolve at a given pH (e.g., pH 7.0 and 25.0±0.5° C.). "Insoluble" may also mean that the logP of the substance has a positive value.

[0180] The pharmaceutically active ingredient is not particularly limited and can be selected by those skilled in the art according to need.

[0181] In embodiments, the composition may be for use in the treatment or prevention of IBD (particularly ulcerative colitis). In embodiments, the composition may be for use in inhibiting IBD (particularly ulcerative colitis) or preventing disease progression. Thus, the composition may comprise at least one pharmaceutically active agent selected from the group consisting of anti-inflammatory agents (e.g., 5-ASA, 4-ASA, sulfasalazine, and balsalazide); non-steroidal anti-inflammatory agents (e.g., ibuprofen and diclofenac); steroids (e.g., prednisolone; budesonide, hydrocortisone, or fluticasone); immunosuppressants (e.g., azathioprine; cyclosporine; tacrolimus and methotrexate); antibiotics (e.g., metronidazole, ciprofloxacin, amoxicillin, tetracycline, and sulfamethoxazole); and biological agents, including peptides, proteins, antibodies, and antibody fragments. Suitable examples of biologic agents include alkaline phosphatase and anti-TNF antibodies, such as infliximab, adalimumab, certolizumab pegol, golimumab, and ustekinumab.

[0182] In embodiments, the pharmaceutically active agent is selected from the group consisting of a biologic agent, an anti-inflammatory agent, a corticosteroid, an immunosuppressant, an antifungal agent, an antibiotic, an antifibrotic agent, and an anti-cancer agent. In embodiments, the pharmaceutically active agent is selected from the group consisting of a biologic agent (e.g., an anti-TNF antibody, an IL-23 inhibitor, an IL-12 inhibitor, a TLR9 agonist, an anti-MAdCAM antibody, a human IL-22Fc fusion protein, an interleukin, an anti-β7 integrin antibody, a matrix metalloproteinase 9 (MMP9) inhibitor), a JAK inhibitor, a PDE4 inhibitor, a sphingosine-1-phosphate receptor modulator, an anti-inflammatory agent, a corticosteroid, an immunosuppressant, an antifungal agent, an antibiotic, an antifibrotic agent, and an anti-cancer agent.

[0183] In embodiments, the pharmaceutically active agent is a biological agent, such as a peptide, protein, antibody, or antibody fragment. In embodiments, the pharmaceutically active agent is an antibody or a functional fragment thereof. In embodiments, the pharmaceutically active agent is a peptide.

[0184] In embodiments, the pharmaceutically active agent is an antibody or functional fragment thereof, and is suitable for use in the treatment of a gastrointestinal disease, such as inflammatory bowel disease (IBD) (e.g., Crohn's disease or ulcerative colitis), cancer (e.g., colorectal cancer or small intestine cancer), celiac disease, or an infectious disease (e.g., Clostridium difficile infection), more preferably IBD.

[0185] The antibody or functional fragment thereof used in the composition is not particularly limited. In one embodiment, the antibody or functional fragment thereof is an antibody. In another embodiment, the antibody or functional fragment thereof is a functional fragment as defined herein. The antibody or functional fragment thereof may further comprise one or more modifications, for example, in the form of residue addition or substitution, which improves stability, specificity, or targeting. These may include any such modifications known in the art.

[0186] The antigen against which an antibody or functional fragment is directed, i.e., the immunogen, peptide, protein, or other molecular structure to which the antibody or functional fragment thereof can specifically bind, is not limited. In its most general form (and when no defined reference is given), "specific for" or "specifically binds" refers to the ability of an antibody or functional fragment thereof to distinguish between a target of interest and unrelated biomolecules (e.g., for an antibody specific for human TNFα to distinguish between human TNFα and unrelated biomolecules), for example, as determined according to specificity assays known in the art.

[0187] In embodiments, the antibody or functional fragment thereof is selected from antibodies and functional fragments thereof specific for tumor necrosis factor alpha (TNFα), antibodies and functional fragments thereof specific for a4137 integrin, antibodies and functional fragments thereof specific for CD3, CD4 or CD20, antibodies and functional fragments thereof specific for interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors, antibodies and functional fragments thereof specific for Janus kinase (JAK), antibodies and functional fragments thereof specific for CXCL10 / IP-10, and antibodies and functional fragments thereof specific for the p40 protein subunit. In embodiments, the antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, erdelumab, abrilumab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, tofacitinib, or vedolizumab, and functional fragments thereof.

[0188] In embodiments, the antibody or functional fragment thereof in the composition specifically binds to TNFα. The terms "anti-TNFα antibody," "TNFα antibody," and "antibody specific for TNFα" are interchangeable when used herein. In one embodiment, specific binding refers to the ability of the antibody or fragment to distinguish between human TNFα and human TNFβ. In a preferred embodiment of the present invention, the TNFα antibody or functional fragment thereof is a TNFα antibody. In an alternative preferred embodiment of the present invention, the TNFα antibody or functional fragment thereof is a functional fragment of a TNFα antibody.

[0189] Currently approved anti-TNFα biologics include: (i) infliximab, a chimeric IgG anti-human monoclonal antibody (Remicade®); (ii) etanercept, a TNFR2 dimeric fusion protein with IgG1 Fc (Enbrel®); (iii) adalimumab, a fully human monoclonal antibody (mAb) (Humira®), (iv) certolizumab, a PEGylated Fab fragment (Cimzia®), and (v) golimumab, a human IgG1K monoclonal antibody (Simponi®). Thus, in embodiments, the antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, and golimumab, or a functional fragment thereof.

[0190] In an embodiment, the pharmaceutically active agent is an anti-tumor necrosis factor-alpha inhibitor (TNF inhibitor). The TNF inhibitor may be selected from adalimumab, certolizumab, and infliximab. In an embodiment, the pharmaceutically active agent is an anti-integrin agent. The anti-integrin agent may be selected from natalizumab and vedolizumab. In an embodiment, the pharmaceutically active agent is an anti-interleukin-12 agent or an anti-interleukin-23 agent, for example, ustekinumab. In an embodiment, the pharmaceutically active agent is a JAK inhibitor, for example, tofacitinib. In a preferred embodiment, the pharmaceutically active agent is tofacitinib.

[0191] In embodiments, the pharmaceutically active agent is an anti-inflammatory agent. The anti-inflammatory agent may be a corticosteroid, such as prednisolone. Corticosteroids are steroids that help reduce both inflammation and immune response. The composition may include a corticosteroid. The composition may include a corticosteroid and a 5-ASA. Preferably, the corticosteroid is not used as a long-term treatment to maintain remission of UC. Therefore, the composition containing a corticosteroid may be used as a short-term treatment for UC.

[0192] In embodiments, the pharmaceutically active agent is a corticosteroid selected from the group consisting of beclomethasone dipropionate, budesonide, hydrocortisone, methylprednisolone, prednisone, and prednisolone.

[0193] In an embodiment, the pharmaceutically active agent is an anti-inflammatory agent, and the anti-inflammatory agent is aminosalicylic acid. It is understood that aminosalicylic acid reduces inflammation in the intestinal lining, thereby relieving the symptoms of IBD (e.g., ulcerative colitis) and / or Crohn's disease. Preferably, the composition may include aminosalicylic acid, and the composition is for use in treating mild to moderate episodes of Crohn's disease.

[0194] In embodiments, the pharmaceutically active agent is an aminosalicylate selected from the group consisting of balsalazide, mesalamine, olsalazine, and sulfasalazine.

[0195] Crohn's disease is understood to be caused by a problem with the immune system, where cells that normally protect the body attack the GI tract instead. Thus, pharmaceutically active agents that suppress or modulate the immune system (i.e., immunosuppressants) are commonly used in the treatment of Crohn's disease.

[0196] In embodiments, the pharmaceutically active agent is an immunosuppressant. The composition may be for use in treating a fistula, such as an IBD-related perianal fistula or a vaginal fistula, and the composition comprises an immunosuppressant.

[0197] The subject may be administered a composition comprising an immunosuppressant as an alternative treatment to an aminosalicylate and / or a corticosteroid.

[0198] In embodiments, the pharmaceutically active agent is an immunosuppressant selected from the group consisting of azathioprine, cyclosporine, mercaptopurine, methotrexate, mycophenolate mofetil, or tacrolimus. Preferably, the pharmaceutically active agent may be tacrolimus.

[0199] In embodiments, the pharmaceutically active agent may be an antifungal agent for use in the treatment of fungal infections. The antifungal agent may be: (i) polyenes (e.g., amphotericin B (e.g., amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex, or amphotericin B colloidal dispersion), candicidin, filipin, hamycin, natamycin, nystatin, or rimocidin); (ii) a triazole, preferably a triazole other than a compound of the invention (e.g., albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, or voriconazole); (iii) imidazoles (e.g., bifonazole, butoconazole, chlormidazole, clotrimazole, eberconazole, econazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, or tioconazole); (iv) thiazoles (e.g., abafungin); (v) echinocandins (e.g., anidulafungin, biafungin, caspofungin, or micafungin); (vi) an allylamine (e.g., amorolfine, butenafine, naftifine, or terbinafine); or (vii) amorolfine, ciclopirox olamine, griseofulvin, or flucytosine (5-fluorocytosine) It may be the case that

[0200] In certain embodiments, the pharmaceutically active agent is an antifungal agent selected from clotrimazole or fluconazole. Thus, the composition may include clotrimazole. The composition may include fluconazole.

[0201] In embodiments, the pharmaceutically active agent may be an antibiotic.The composition comprising the antibiotic may be used to treat bacterial infection, for example, bacterial infection caused by Crohn's disease.For example, the bacterial infection caused by Crohn's disease may be fistula and / or abscess.

[0202] In embodiments, the pharmaceutically active agent is an antibiotic selected from the group consisting of ampicillin, ceftizoxime, sulbenicillin, piperacillin, mezlocillin, bacampicillin, cefoxitin, cefazolin, latamoxef, cefotaxime, ceftazidime, gentamicin, tobramycin, erythromycin, metronidazole, tinidazole, fluconazole, mupirocin, demeclocycline, retapamulin, chlortetracycline, virginiamycin, chloramphenicol, oxytetracycline, bacitracin, tetracycline, gentamicin, ciprofloxacin, rifaximin, and vancomycin.

[0203] In embodiments, the pharmaceutically active agent may be an anti-fibrotic agent, and thus the composition may include an anti-fibrotic agent, wherein the anti-fibrotic agent is selected from pirfenidone or nintedanib.

[0204] In an embodiment, the composition of the present invention is for use in the treatment of cancer. Preferably, the composition of the present invention is for use in the treatment of cancer affecting the GI tract, particularly the lower GI tract, especially the colon. Thus, the composition may be for use in the treatment of colorectal cancer. Therefore, the pharmaceutically active agent in the composition may be an anti-cancer agent. Alternatively, the composition may further comprise an anti-cancer agent.

[0205] Anti-cancer agents that may be suitable for use with the compositions described herein include, but are not limited to, one or more agents selected from the following:

[0206] (i) antiproliferative / antineoplastic agents and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine, and antifolates, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, anti-inflammatory drugs such as cyclosporine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine and hydroxyurea; antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polokinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and camptothecin);bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (e.g., IFN-alpha), etoposide, teniposide, VP-16, DNA demethylating agents (e.g., azacitidine or decitabine); and histone deacetylase (HDAC) inhibitors (e.g., vorinostat, MS-275, panobinostat, romidepsin, valproic acid, mocetinostat (MGCD0103), and pracinostat SB939);

[0207] (ii) Cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and inhibitors of 5α-reductase, such as finasteride; and navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosfamide, and droloxafme;

[0208] (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase;

[0209] (iv) inhibitors of growth factor function: for example, inhibitors including growth factor antibodies and growth factor receptor antibodies, for example, the anti-erbB2 antibody trastuzumab [Herceptin®], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (for example, EGFR family tyrosine kinase inhibitors, for example, gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, such as lapatinib), and antibodies against costimulatory molecules, such as CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-10, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, for example, farnesyltransferase inhibitors, such as sorafenib, tipifarnib and lonafarnib), inhibitors of cell signaling by MEK and / or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; Aurora kinase inhibitors, and cyclin-dependent kinase inhibitors, for example, CDK2 and / or CDK4 inhibitors; and CCR2, CCR4 or CCR6 antagonists;

[0210] (v) Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™)]; thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

[0211] (vi) gene therapy approaches, including approaches to replace abnormal genes such as, for example, abnormal p53 or abnormal BRCA1 or BRCA2;

[0212] (vii) immunotherapeutic approaches, including, for example, antibody therapies, such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; prophylactic and therapeutic vaccines, such as cancer vaccines, including HPV vaccines, for example, Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (Ad.p53 DCs and the like; Toll-like receptor modulators, e.g., TLR-7 or TLR-9 agonists; PD-1, PD-L1, PD-L2 and CTL4-A modulators (e.g., nivolumab), antibodies and vaccines; other IDO inhibitors (e.g., indoximod); anti-PD-1 monoclonal antibodies (e.g., MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (e.g., MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (e.g., ipilumumab); and

[0213] (viii) Cytotoxic agents, such as fludarabine (fludara), cladribine, pentostatin (Nipent™).

[0214] In embodiments, the composition may be for use in preventing colon or colorectal cancer, primarily in patients suffering from colitis. Thus, the pharmaceutically active agent may be selected from the anti-inflammatory agents 5-ASA, sulindac, celecoxib, and / or eflornithine (DFMO).

[0215] In embodiments, the composition is administered to the subject as an enema, and thus, in embodiments, the pharmaceutically active agent may be selected from the group consisting of mesalamine, budesonide, prednisolone, hydrocortisone, cobitolimod, tacrolimus, cyclosporine, or tofacitinib.

[0216] Cytokine mediators of inflammation in IBD, such as IL-9, IL-12, IL-23, and interferon-gamma (IFN-γ), depend on signal transduction through the Janus kinase signal transduction and activator of transcription (JAK-STAT) pathway. Therefore, targeting JAK-STAT is an attractive therapeutic modality for IBD. JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) are all part of the JAK family of tyrosine kinase proteins. Therefore, in embodiments, the pharmaceutically active agent is a JAK inhibitor. In embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib, filgotinib, upadacitinib, TD-1473, brepositinib (PF-06700841), or PF-06651600. In embodiments, the pharmaceutically active agent is a TYK2 inhibitor. In embodiments, the TYK2 inhibitor is brepositinib (PF-06700841), or BMS-986165.

[0217] IL-23 is a regulator of helper T (Th)-17 cells, and the type 3 innate lymphoid cell (ILC3) pathway, which leads to inflammatory cytokine production and inflammation, and polymorphisms in the IL-23 receptor gene, may be associated with increased susceptibility to Crohn's disease. IL-23 prevents regulatory T cell responses in the intestine, thus increasing inflammation in the intestine. In embodiments, the pharmaceutically active agent is an IL-23 inhibitor. In embodiments, the IL-23 inhibitor is selected from risankizumab, brazikumab, mirikizumab, or guselkumab.

[0218] In embodiments, the pharmaceutically active agent is an IL-6 inhibitor. The IL-6 inhibitor may be PF-04236921.

[0219] In embodiments, the pharmaceutically active agent is a human IL-22Fc fusion protein. The human IL-22Fc fusion protein may be UTTR1147A.

[0220] The migration of pro-inflammatory T cells to the intestine promotes the inflammation characteristic of Crohn's disease and ulcerative colitis. The interaction between surface-expressed α4β1 and α4β7 integrins on lymphocytes and adhesion molecules present on endothelial cells allows activated effector T cells to target the intestine. Therefore, in embodiments, the pharmaceutically active agent may be an anti-adhesion molecule. The pharmaceutically active agent may be an α4β7 integrin inhibitor. The pharmaceutically active agent may be an α4β7 and αEβ7 integrin inhibitor. The pharmaceutically active agent may be an α4 integrin inhibitor. The pharmaceutically active agent may be selected from vedolizumab, etrolizumab, AJM300, abrilumab (AMG 181 or MEDI 7183), or PF-00547659 (SHP647).

[0221] In embodiments, the pharmaceutically active agent is an anti-TNF agent. The anti-TNF agent may be selected from AVX-470, or OPRX-106.

[0222] In embodiments, the pharmaceutically active agent is a sphingosine-1-phosphate receptor modulator (S1P1-S1P5). S1P1-S1P5 may be selected from ozanimod, etrasimod, or amiselimod (MT-1303).

[0223] In embodiments, the pharmaceutically active agent is a phosphodiesterase 4 (PDE4) inhibitor. The PDE4 inhibitor may be apremilast.

[0224] In embodiments, the pharmaceutically active agent is a Toll-like receptor 9 (TLR9) inhibitor. The TLR9 inhibitor may be cobitolimod.

[0225] In embodiments, the pharmaceutically active agent is selected from those listed in Table 1. [Table 1-1] [Table 1-2]

[0226] In embodiments, the pharmaceutically active agent is selected for use in the treatment of Crohn's disease and / or ulcerative colitis. Thus, the pharmaceutically active agent may be ZEPOSIA® (ozanimod), HUMIRA® (adalimumab), Hulio® (adalimumab-fkjp), Avsola™ (infliximab-axxq), Remicade® (infliximab), Abrilada™ (adalimumab-afzb), HADLIMA (adalimumab-bwwd), Hyrimoz (adalimumab-adaz), Xeljanz® (tofacitinib), IXIFI™ (infliximab-qbtx), CYLTEZO™ (adalimumab-adbm), RENFLEXIS® (infliximab-abda), STELARA® (ustekinumab), AMJEVITA™ (adalimumab-atto), mesalamine DR 800 mg, INFLECTRA™ (infliximab-dyyb), UCERIS® (budesonide), and ENTYVIO™ (vedolizumab).

[0227] In embodiments, the pharmaceutically active agent is selected from the group consisting of an antibody or functional fragment thereof, an anti-inflammatory agent, an anti-inflammatory drug, an immunosuppressant, an anti-fungal agent, an antibiotic, an anti-fibrotic agent, and an anti-cancer agent.

[0228] In embodiments, the pharmaceutically active agent is AbGn168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol, CP-690,550, corticosteroids (e.g., multimac cusbudesonide, methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC 1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tacrolimus, Janus kinase inhibitors (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressants (e.g., rapamycin), antifibrotic agents (e.g., pirfenidone, nintedanib), and antifungal agents (e.g., clotrimazole, fluconazole).

[0229] In a preferred embodiment, the pharmaceutically active agent is a Janus kinase inhibitor. In an embodiment, the pharmaceutically active agent is an inhibitor of the enzyme Janus kinase 1 (JAK1) and / or 3 (JAK3). Preferably, the Janus kinase inhibitor is tofacitinib (TOFA). The pharmaceutically active agent may be tofacitinib or a pharmaceutically acceptable salt thereof. Thus, the composition may contain tofacitinib or a pharmaceutically acceptable salt thereof. In an embodiment, the composition contains up to 20% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. In a preferred embodiment, the composition contains 0.1% to 10% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% tofacitinib or a pharmaceutically acceptable salt thereof, 0.5% to 10% tofacitinib or a pharmaceutically acceptable salt thereof, 0.5% to 5% tofacitinib or a pharmaceutically acceptable salt thereof, or 1% to 5% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. Thus, the composition may contain: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, in this embodiment, the lipid is monolinolein.

[0230] The composition comprises: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0231] The composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0232] Preferably, the composition may contain 1% to 5% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0233] More preferably, the composition may contain 5% tofacitinib or a pharmaceutically acceptable salt thereof, where % is by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 5% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at a temperature of 38° C. For the avoidance of doubt, in this embodiment, the total composition is (i) 5% w / w of tofacitinib or a pharmaceutically acceptable salt thereof; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Including, That is, the composition contains 5 mg of TOFA per 100 mg of carrier.

[0234] In another preferred embodiment, the pharmaceutically active agent is tacrolimus (TAC). Therefore, the composition may contain tacrolimus. In an embodiment, the composition contains up to 20% tacrolimus, where % is by weight based on the weight of the composition. In a preferred embodiment, the composition contains 0.1% to 10% tacrolimus, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% tacrolimus, 0.5% to 10%, 0.5% to 5%, or 1% to 5% tacrolimus, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% tacrolimus, where % is by weight based on the weight of the composition. Therefore, the composition a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) tacrolimus in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, in this embodiment, the lipid is monolinolein.

[0235] The composition comprises: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) tacrolimus in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0236] The composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) tacrolimus in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0237] Preferably, the composition may contain 1% to 5% tacrolimus, where % is by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) tacrolimus in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0238] More preferably, the composition may contain 1% tacrolimus, where % is by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) tacrolimus in an amount of 1% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at a temperature of 38° C. For the avoidance of doubt, in this embodiment, the total composition is (i) 1% w / w tacrolimus; (ii) 83.16% w / w monolinolein; and (iii) 15.84% w / w water Includes. That is, the composition contains 1 mg of TAC per 100 mg of carrier.

[0239] In other embodiments, the pharmaceutically active agent is clotrimazole. Thus, the composition may contain clotrimazole. In embodiments, the composition contains up to 20% clotrimazole, where % is by weight based on the weight of the composition. In preferred embodiments, the composition contains 0.1% to 10% clotrimazole, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% clotrimazole, 0.5% to 10% clotrimazole, 0.5% to 5% clotrimazole, or 1% to 5% clotrimazole, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% clotrimazole, where % is by weight based on the weight of the composition. Thus, the composition may contain: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) clotrimazole in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. Preferably, in this embodiment, the lipid is monolinolein.

[0240] The composition comprises: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) clotrimazole in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0241] The composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) clotrimazole in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0242] Preferably, the composition may contain 1% to 5% clotrimazole, the % being by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) Clotrimazole in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0243] More preferably, the composition may contain 5% clotrimazole, where % is by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) clotrimazole in an amount of 5% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at a temperature of 38° C. For the avoidance of doubt, in this embodiment, the total composition is (i) 5% w / w clotrimazole; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Includes. That is, the composition contains 5 mg of clotrimazole per 100 mg of carrier.

[0244] In embodiments, the pharmaceutically active agent is mesalamine. It will be understood that mesalamine is also known as 5-aminosalicylic acid (5-ASA). Thus, the pharmaceutically active agent may be 5-ASA.

[0245] In other embodiments, the pharmaceutically active agent is mesalamine. Thus, the composition may contain mesalamine. In embodiments, the composition contains up to 20% mesalamine, where % is by weight based on the weight of the composition. In preferred embodiments, the composition contains 0.1% to 10% mesalamine, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% mesalamine, 0.5% to 10% mesalamine, 0.5% to 5% mesalamine, or 1% to 5% mesalamine, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% mesalamine, where % is by weight based on the weight of the composition. Thus, the composition may contain: a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) mesalamine in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, in this embodiment, the lipid is monolinolein.

[0246] The composition comprises: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) mesalamine in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0247] The composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) mesalamine in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0248] Preferably, the composition may contain 1% to 5% mesalamine, where % is by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) mesalamine in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0249] More preferably, the composition may contain 5% mesalamine, where % is by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) mesalamine in an amount of 5% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at a temperature of 38° C. For the avoidance of doubt, in this embodiment, the total composition is (i) 5% w / w mesalamine; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Includes. That is, the composition contains 5 mg of mesalamine per 100 mg of carrier.

[0250] In other embodiments, the pharmaceutically active agent is budesonide. Thus, the composition may contain budesonide. In embodiments, the composition contains up to 20% budesonide, where % is by weight based on the weight of the composition. In preferred embodiments, the composition contains 0.1% to 10% budesonide, where % is by weight based on the weight of the composition. The composition may contain 0.1% to 10% budesonide, 0.5% to 10% budesonide, 0.5% to 5% budesonide, or 1% to 5% budesonide, where % is by weight based on the weight of the composition. For example, the composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% budesonide, where % is by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) budesonide in an amount of 0.1% to 10% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, in this embodiment, the lipid is monolinolein.

[0251] The composition comprises: a) a1) water in an amount of 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids containing monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) budesonide in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0252] The composition comprises: a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) budesonide in an amount of 0.1% to 10% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0253] Preferably, the composition may contain 1% to 5% budesonide, where % is by weight based on the weight of the composition. a) a1) water in an amount greater than 10% to 25% by weight of the carrier; and a2) 75% to 90% by weight of lipids in the carrier a carrier comprising: b) budesonide in an amount of 1% to 5% by weight of the composition and the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0254] More preferably, the composition may contain 5% budesonide, where % is by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition comprises: a) a1) water in an amount of 16% by weight of the carrier; and a2) monolinolein in an amount of 84% by weight of the carrier a carrier comprising: b) budesonide in an amount of 5% by weight of the composition and The composition forms a lipid cubic phase at a temperature of 36° C. to 39° C. The composition may form a lipid cubic phase at a temperature of 38° C. For the avoidance of doubt, in this embodiment, the total composition is (i) 5% w / w budesonide; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Includes. That is, the composition contains 5 mg of budesonide per 100 mg of carrier. Other additives

[0255] Additives can modify the structure of lipid mesophases. For example, the addition of increasing amounts of hexadecane or vitamin A can modify the phase of monoolein-water systems. The shape of the self-assembled mesophase is important in determining the release rate; therefore, the open or closed state of the aqueous channels affects the rate of drug release. Typical lipid mesophases with symmetric Pn3m, Im3m, or Ia3d structures are characterized by water channels with diameters of approximately 3–5 nm. This shape constraint prevents large hydrophilic molecules, such as hydrophilic proteins, hormones, and antibodies, from entering the mesophase. However, this structural limitation can be overcome by additives that increase the dimensions of the water channels, including hydration modulators, such as sucrose stearate, phospholipids, and cholesterol. Electrostatic swelling, for example, increases the size of the water channels by doping the lipid with charged lipids that can swell the mesophase.

[0256] Therefore, in embodiments, the composition further comprises an additive. The composition may include at least one additive. Therefore, the composition may include one additive. The composition may include more than one additive. For example, the composition may include two additives. The composition may include three additives. The composition may include four additives.

[0257] In embodiments, the composition further comprises up to 10% of an additive, where % is by weight based on the weight of the composition. Thus, the composition may comprise 0.1% to 10% of the additive, where % is by weight based on the weight of the composition. The composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the additive, where % is by weight based on the weight of the composition.

[0258] In embodiments, the additive is selected from the group consisting of vitamin A, sucrose stearate, phospholipids, cholesterol, and electrolytes (eg, sodium chloride, sodium sulfate, sodium iodide, and calcium cations).

[0259] In embodiments, the additive is a negatively or positively charged phospholipid. Therefore, the additive may be selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), and 2-dioleoyl-3 trimethylammonium propane (DOTAP). The composition may further include cholesterol and a negatively or positively charged phospholipid (e.g., DOPG, DOPS, and DOTAP).

[0260] In embodiments, the additive is a negatively or positively charged phospholipid (e.g., DOPG, DOPS, and DOTAP). Thus, the composition may further comprise up to 10% of a negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition. Thus, the composition may further comprise 0.1% to 10% of a negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition. The composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of a negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition.

[0261] In embodiments, the additive is cholesterol. Thus, the composition may further comprise up to 5% cholesterol, where % is by weight based on the weight of the composition. Thus, the composition may further comprise 0.1% to 5% cholesterol, where % is by weight based on the weight of the composition. The composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, or 5% cholesterol, where % is by weight based on the weight of the composition.

[0262] In embodiments, the composition further comprises cholesterol and a negatively or positively charged phospholipid (e.g., DOPG, DOPS, and DOTAP). The composition may further comprise up to 5% cholesterol and up to 10% negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition. Thus, the composition may further comprise 0.1% to 5% cholesterol and 0.1% to 10% negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition. The composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, or 5% cholesterol and 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% negatively or positively charged phospholipid (e.g., DOPG, DOPS, or DOTAP), where % is by weight based on the weight of the composition.

[0263] In embodiments, the composition may further comprise an additive selected from suspending agents, dispersing agents, antioxidants, buffering agents, pH adjusting agents, colorants, flavoring agents, preservatives, and foam enhancing agents.

[0264] In an embodiment, the composition does not include any further additives.

[0265] In an embodiment, the additive is an additional lipid. Thus, the composition may contain an additional lipid. The composition may contain one or more additional lipids. The composition may further contain up to 10% additional lipid, where % is by weight based on the weight of the composition. Thus, the composition may contain 0.1% to 10% additional lipid, where % is by weight based on the weight of the composition. The composition may contain 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% additional lipid, where % is by weight based on the weight of the composition. The composition may contain 10% or less additional lipid. The composition may not contain additional lipid, i.e., may be substantially free of additional lipid. use

[0266] Also provided herein is the use of a formulation comprising 10% w / w to more than 30% w / w of water and 70% w / w to 90% w / w of lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from monolinolein or monoolein. In an embodiment, the formulation comprises 10% w / w to more than 25% w / w of water and 75% w / w to 90% w / w of lipid as a carrier for the pharmaceutically active agent, wherein the lipid is selected from monolinolein or monoolein. In an embodiment, the pharmaceutically active agent may be dispersed or dissolved in the carrier.

[0267] Furthermore, the formulations provide sustained and controlled release of pharmaceutically active agents with adjustable time frames. The formulations are therefore highly suitable for forming depot compositions after non-parenteral (e.g., topical) administration to body cavities and / or body surfaces, and are formed from lipids that may themselves offer unique benefits in addition to forming highly effective carriers and topical depots for active agents.

[0268] Thus, in embodiments, the carrier provides controlled release of the pharmaceutically active agent at a temperature of 36° C. to 39° C. The carrier may also provide controlled release of the pharmaceutically active agent at a temperature of 36° C. to 39° C., 37° C. to 39° C., or 37.5° C. to 38.5° C. For example, the carrier may provide controlled release of the pharmaceutically active agent at a temperature of 36.0°C, 36.1°C, 36.2°C, 36.3°C, 36.4°C, 36.5°C, 36.6°C, 36.7°C, 36.8°C, 36.9°C, 37.0°C, 37.1°C, 37.2°C, 37.3°C, 37.4°C, 37.5°C, 37.6°C, 37.7°C, 37.8°C, 37.9°C, 38.0°C, 38.1°C, 38.2°C, 38.3°C, 38.4°C, 38.5°C, 38.6°C, 38.7°C, 38.8°C, 38.9°C, or 39.0°C. Preferably, the carrier may provide controlled release of the pharmaceutically active agent at a temperature of 38°C.

[0269] In embodiments, the carrier forms a controlled-release depot for the pharmaceutically active agent at a temperature of 36° C. to 39° C. The carrier may also form a controlled-release depot for the pharmaceutically active agent at a temperature of 36° C. to 39° C., 37° C. to 39° C., or 37.5° C. to 38.5° C. For example, the carrier may be capable of forming a controlled release depot for the pharmaceutically active agent at a temperature of 36.0° C., 36.1° C., 36.2° C., 36.3° C., 36.4° C., 36.5° C., 36.6° C., 36.7° C., 36.8° C., 36.9° C., 37.0° C., 37.1° C., 37.2° C., 37.3° C., 37.4° C., 37.5° C., 37.6° C., 37.7° C., 37.8° C., 37.9° C., 38.0° C., 38.1° C., 38.2° C., 38.3° C., 38.4° C., 38.5° C., 38.6° C., 38.7° C., 38.8° C., 38.9° C., or 39.0° C. Preferably, the carrier may be capable of forming a controlled release depot for the pharmaceutically active agent at a temperature of 38° C.

[0270] Therefore, an advantage of the controlled release depot of the present invention is that the pharmaceutically active agent is gradually released over an extended period of time without the need for repeated dosing.

[0271] The formulations of the present invention may form non-parenteral depots that slowly release the pharmaceutically active agent on a body surface. It is particularly important that the compositions prepared from the formulations be bioadhesive, as this allows for localized release of the pharmaceutically active agent over a sustained period. Therefore, the compositions must cover the surface to which they are applied and remain in place even when the surface is exposed to air or liquid flow and / or friction. For example, the compositions may be administered rectally, coating the walls of the colon, and the composition will remain in place for the desired retention period (as described herein). The compositions may be administered rectally, coating the walls of the sigmoid colon, descending colon, and / or rectum, and the composition will remain in place for the desired retention period (as described herein).

[0272] Preferably, the carrier is administered into a body cavity, for example, the formulation is a rectal formulation, and thus, in a preferred embodiment, the carrier is administered as an enema.

[0273] Also provided herein is the use of a preformulation composition comprising a lipid and a pharmaceutically active agent for the manufacture of a composition of the invention, wherein the lipid is selected from monolinolein or monoolein.

[0274] Also provided is the use of a preformulation composition comprising a monoacylglycerol lipid and a pharmaceutically active agent for the manufacture of a composition of the invention. The monoacylglycerol lipid may contain at least 50% by weight of monolinolein.

[0275] In embodiments, the pharmaceutically active agent in the pre-formulation is a hydrophilic pharmaceutically active agent, as described herein.

[0276] In embodiments, the preformulation composition is a lyophilized mixture, hi embodiments, the lyophilized mixture is hydrated with water to provide the composition of the present invention. Therapeutic Uses and Applications

[0277] The compositions of the present invention may advantageously be used for rectal delivery of pharmaceutically active agents by forming a sustained release depot in situ.

[0278] The compositions of the present invention include modified release compositions comprising a monoacylglycerol lipid (such as monolinolein (MLO)), water, and a pharmaceutically acceptable agent for targeting the release of the pharmaceutically acceptable agent to the lower GI tract (GIT), particularly the colon and / or rectum.

[0279] Therefore, compositions according to the present invention comprising a pharmaceutically acceptable agent for localized treatment of the lower GIT are expected to be useful for treating or preventing GIT conditions. In certain embodiments, the compositions of the present invention are for use in the treatment or prevention of conditions affecting the descending colon, sigmoid colon, and / or rectum. In certain embodiments, the compositions of the present invention are for use in the treatment or prevention of conditions affecting the rectum. In certain embodiments, the compositions of the present invention are for use in the treatment or prevention of conditions affecting the sigmoid colon. In certain embodiments, the compositions of the present invention are for use in the treatment or prevention of conditions affecting the descending colon. The pharmaceutically acceptable agent may be a hydrophilic pharmaceutically acceptable agent, such as tofacitinib (TOFA). The pharmaceutically acceptable agent may be a hydrophobic pharmaceutically acceptable agent, such as tacrolimus (TAC). The composition may comprise one or more pharmaceutically acceptable agents. Thus, the composition may comprise TOFA and an additional pharmaceutically acceptable agent. The composition may comprise TAC and an additional pharmaceutically acceptable agent. The composition may comprise mesalamine and an additional pharmaceutically acceptable agent. The composition may comprise budesonide and an additional pharmaceutically acceptable agent. For example, the composition of the present invention may comprise TOFA and / or an additional pharmaceutically acceptable agent and may be useful for preventing or treating inflammatory conditions affecting the lower GI tract, particularly conditions affecting the colon. The composition of the present invention may comprise TAC and / or an additional pharmaceutically acceptable agent and may be useful for preventing or treating inflammatory conditions affecting the lower GI tract, particularly conditions affecting the colon. The composition of the present invention may comprise mesalamine and / or an additional pharmaceutically acceptable agent and may be useful for preventing or treating inflammatory conditions affecting the lower GI tract, particularly conditions affecting the colon.The compositions of the present invention may contain budesonide and / or additional pharmaceutically acceptable agents and may be useful in the prevention or treatment of inflammatory conditions affecting the lower GI tract, particularly conditions affecting the colon.

[0280] In embodiments, the compositions of the present invention may be administered via injection, for example, as a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation.

[0281] In other embodiments, the compositions of the present invention may be used for vaginal delivery of pharmaceutically active agents by forming a sustained-release depot in situ. In embodiments, the compositions of the present invention may be applied topically, for example, via rectal or vaginal administration. Thus, the compositions may be applied topically to the colon, for example, as an enema. The required dosage will vary depending on the particular condition and stage of the condition being treated. In the case of compositions containing TAC, the compositions are generally administered to provide a dose of 0.1 mg to 5 mg of TAC, e.g., a dose of 0.1 mg to 3 mg, or particularly, a dose of 0.5 mg to 1.5 mg of TAC. In the case of compositions containing TOFA, the compositions are generally administered to provide a dose of 0.1 mg to 10 mg of TOFA, e.g., a dose of 2.5 mg to 10 mg, or particularly, a dose of 5 mg to 10 mg of TOFA. The compositions are suitably administered as a single daily dose or twice-daily doses, preferably twice-daily doses. Alternatively, the composition is administered as a once-weekly dose.

[0282] In one aspect of the present invention, the composition of the present invention is provided for use in the treatment or prevention of disease.In an embodiment, the composition of the present invention is used to inhibit or prevent disease progression.The disease may be selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (e.g., accompanied by constipation, diarrhea, and / or pain symptoms), diverticulosis, diverticulitis, proctitis, chemotherapy-related colitis, radiation-related colitis, colitis, colorectal cancer, adenocarcinoma, inflammatory disorders such as diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, ileocolitis, granulomatous colitis, familial adenomatous polyposis, or perianal Crohn's disease, including perianal fistula.

[0283] Thus, in embodiments, the compositions of the invention are for use in the treatment or prevention of inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (e.g., associated with constipation, diarrhea, and / or pain symptoms), diverticulosis, diverticulitis, proctitis, chemotherapy-associated colitis, radiation-associated colitis, colitis, colorectal cancer, adenocarcinoma, inflammatory disorders such as fecal diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, ileocolitis, granulomatous colitis, familial adenomatous polyposis, or perianal Crohn's disease, including perianal fistulas.

[0284] In one embodiment, the composition of the present invention is for use in the treatment of inflammatory bowel disease. In an embodiment, the composition of the present invention is for use in inhibiting or preventing the progression of inflammatory bowel disease. The main forms of inflammatory bowel disease are Crohn's disease and ulcerative colitis. Therefore, the composition of the present invention may be useful in treating both of these conditions.

[0285] The compositions of the present invention may be used to treat or prevent irritable bowel syndrome (e.g., associated with constipation, diarrhea, and / or pain symptoms), diverticulitis, proctitis, radiation-related enteritis, colitis, diverticulosis, colorectal cancer, adenocarcinoma, inflammatory disorders such as diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, ileocolitis, or granulomatous colitis. The compositions may also be used to treat or prevent Clostridium difficile colitis.

[0286] Crohn's disease can affect the entire GI tract, including the colon.However, ulcerative colitis is a condition that only affects the colon and rectum.Therefore, the release profile provided by the pharmaceutically acceptable drug-containing (for example, TAC-containing or TOFA-containing) composition of the present invention that targets the colon is expected to be particularly beneficial for the treatment of ulcerative colitis.

[0287] The colon-targeting composition of the present invention mainly releases pharmaceutically acceptable drug (such as TAC or TOFA) in the colon.However, pharmaceutically acceptable drug can also be released highly in the GI tract, and therefore the composition can also provide therapeutic benefits in the conditions that affect other parts of the lower GI tract, such as Crohn's disease, irritable bowel syndrome (for example, accompanied by constipation, diarrhea and / or pain symptoms), diverticulosis, collagen colitis, proctitis, radiation-related enteritis, diverticulosis, colorectal cancer or adenocarcinoma.

[0288] In a further embodiment, there is provided a composition of the invention for use in the treatment or prevention of ulcerative colitis. In an embodiment, the composition of the invention is for use in inhibiting or preventing the progression of ulcerative colitis.

[0289] A further aspect of the present invention provides a composition comprising a pharmaceutically active agent as defined herein for use in the treatment of cancers affecting the GI tract, particularly the lower GI tract, especially the colon.Thus, the composition comprising a pharmaceutically active agent may be for use in the treatment of colorectal cancer.The composition comprising a pharmaceutically active agent may be for use in providing a cytostatic effect on cancers affecting the GI tract, particularly colorectal cancer.

[0290] Also provided are compositions comprising a pharmaceutically active agent for use in preventing or delaying the onset of cancer in the GI tract, particularly in patients with chronic inflammatory conditions affecting the GI tract, particularly the lower GI tract, especially the colon. For example, the compositions comprising a pharmaceutically active agent may be for use in inhibiting tumor development in the GI tract, particularly the colon.

[0291] The composition comprising a pharmaceutically active agent can be used alone or together with another anti-cancer agent to treat or delay the onset of cancer affecting the GI tract.Therefore, in embodiments, the pharmaceutically active agent in the composition can be an anti-cancer agent.Alternatively, the composition comprising a pharmaceutically active agent can be administered to a subject as a fixed dose combination with one or more additional anti-cancer agents.Anti-cancer agents that may be suitable for use with the composition are described herein.

[0292] Also provided are compositions comprising a pharmaceutically active agent for use in the prevention or treatment of a fibrotic disease or disorder, which may be selected from the group consisting of intestinal fibrosis, intra-articular fibrosis, vaginal fibrosis, arthrofibrosis, endometrial fibrosis, endometriosis, epidural fibrosis, and dermal fibrosis.

[0293] Also provided are compositions comprising pharmaceutically active agents for use in the prevention or treatment of fungal infections, such as vaginal fungal infections, or fungal colonic infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis).

[0294] Also provided are compositions comprising a pharmaceutically active agent for use in the prevention or treatment of bacterial infections, such as bacterial infections caused by Crohn's disease, such as fistulas and / or abscesses. ulcerative colitis

[0295] Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffuse mucosal inflammation of the colon. This disease is characterized by bloody diarrhea, often accompanied by symptoms of fecal urgency and rectal tenesmus, among other features. As used herein, the term "ulcerative colitis" includes diverticulitis, pouchitis, proctitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis, radiation-associated colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, and granulomatous colitis. The present invention contemplates the use of the compositions described herein for the treatment of any of these conditions. Compositions for use in the treatment of colitis associated with inflammatory diseases of the gastrointestinal tract, particularly colitis associated with inflammatory diseases affecting the colon, are also contemplated.

[0296] When UC is suspected in a patient, initial diagnosis generally includes a complete blood count to check for anemia, urinalysis, stool culture, erythrocyte sedimentation rate (ESR) as an indicator of inflammation, liver and kidney function tests, and electrolyte tests. However, these markers alone may not be sufficient to conclusively diagnose ulcerative colitis. Therefore, preferably, endoscopy is generally the most accurate diagnostic tool for UC. Flexible sigmoidoscopy is usually sufficient to diagnose UC, however, total colonoscopy may be performed when the diagnosis is unclear. This procedure includes examination for the presence of superficial ulcers, mucosal erythema or easy bleeding, loss of colonic vascular appearance, and pseudopolyps.

[0297] Biopsies may also be performed to distinguish UC from Crohn's disease. Biopsy samples are generally obtained at the time of endoscopy and are examined for distortion of crypt architecture, crypt inflammation, crypt abscesses, and hemorrhage or inflammation in the lamina propria.

[0298] Ulcerative colitis can affect parts of the colon or substantially the entire colon. Ulcerative colitis can be ulcerative proctosigmoiditis. References herein to "ulcerative proctosigmoiditis" refer to ulcerative colitis that is limited to the rectum and sigmoid colon.

[0299] The ulcerative colitis may be left-sided ulcerative colitis. References herein to "left-sided colitis" mean ulcerative colitis that is limited to the portion of the colon distal to the splenic flexure, and more specifically, ulcerative colitis that extends beyond the rectum and as proximal as possible to the splenic flexure.

[0300] The ulcerative colitis may be extensive ulcerative colitis, in which substantially all of the colon is affected. References herein to "extensive ulcer" or "pancolitis" refer to ulcerative colitis that extends proximal to the splenic flexure (i.e., extending beyond the splenic flexure toward the ileocecal junction).

[0301] Thus, the compositions of the present invention comprise a pharmaceutically active agent for use in the treatment of ulcerative colitis affecting any part or substantially all of the colon, e.g., ulcerative colitis selected from ulcerative proctosigmoiditis, left-sided ulcerative colitis, and extensive ulcerative colitis.

[0302] Ulcerative colitis is generally further characterized by the severity of the disease, and may be mild, moderate, or severe ulcerative colitis. Thus, the compositions of the present invention comprise a pharmaceutically active agent for use in the treatment of mild, moderate, or severe ulcerative colitis. For example, the use of the compositions of the present invention may be for the treatment of mild ulcerative colitis. The use of the compositions of the present invention may be for the treatment of moderate ulcerative colitis. The use of the compositions of the present invention may be for the treatment of severe ulcerative colitis. The use of the compositions of the present invention may be for the treatment of patients with mild or moderate ulcerative colitis. The use of the compositions of the present invention may be for the treatment of patients with moderate or severe ulcerative colitis.

[0303] The severity of ulcerative colitis can be determined by known methods, which generally depend on a combination of patient characteristics.For example, mild, moderate or severe UC can be determined as described in Dignas et al., " Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis ", J. Crohns Colitis. 2012 December;6(10), which is incorporated herein by reference.Mild, moderate and severe ulcerative colitis can also be defined according to the criteria adopted by Truelove and Witts; Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041-8.

[0304] It should be understood that methods of treatment corresponding to any of the uses of the compositions in the treatment of ulcerative colitis described herein are intended to be encompassed within the present invention.Similarly, any of the uses described herein may be described in relation to the use of the compositions in the manufacture of a medicament for use in any of the treatments of ulcerative colitis described herein.The present invention encompasses all such corresponding uses in the manufacture of a medicament. Dosage and Dosage Regimen

[0305] The amount of pharmaceutically active agent that is formulated using the composition of the present invention depends on the functional dose and the duration that the depot composition that is formed when administered provides sustained release.Usually, the dosage that is formulated for a specific pharmaceutically active agent is approximately equivalent to the usual single dose multiplied by a factor that is greater than the expected duration of action that the formulation provides.Obviously, this amount needs to be adjusted to take into account any adverse effects of large doses at the beginning of treatment, and therefore this is generally the maximum dosage that is used.The exact amount that is suitable for any case can be easily determined by suitable experiment.

[0306] The compositions of the present invention may be administered topically, for example for a period of less than two weeks.

[0307] The duration of treatment depends on the nature of the infection being treated. Preferably, topical administration is continued until the condition is eradicated and / or the symptoms of the condition are reduced or eliminated. The upper limit of the duration of treatment can be readily determined by a physician. The composition may be topically administered for a period selected from, for example, 1 day, 2 days, more than 3 days, more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, more than 6 weeks, more than 12 weeks, more than 6 months, and more than 1 year. For example, the composition may be topically administered for a period of 2 weeks to more than about 1 year; for a period of 3 weeks to 1 year; for a period of 4 weeks to 1 year; for a period of 4 weeks to 6 months; or for a period of 4 weeks to 3 months.

[0308] The frequency of administration of the composition of the present invention depends on several factors that can be easily determined by a physician, such as the severity of the condition, the response to initial treatment, and the specific condition to be treated.Preferably, the composition of the present invention can be topically administered once a day, twice a day, three times a day, four times a day, once every other day, or once a week.Preferably, the composition of the present invention can be topically applied to the colon of the subject.Preferably, the composition can be administered as an enema.

[0309] The dosage of the pharmaceutically active agent administered using the compositions of the present invention will vary depending on several factors, including, for example, the age, weight, and sex of the animal or human suffering from the condition, the severity of the condition, and the selected frequency of administration.

[0310] Suitable dosages for topical application can be readily determined by a physician. The composition suitably contains about 0.1% to about 20%, preferably about 0.1% to about 10%, more preferably about 0.5% to about 6%, and even more preferably about 1% to about 5% of the pharmaceutically active agent, where % is by weight based on the weight of the composition.

[0311] The compositions of the present invention are suitably applied topically to the colon of a subject. Preferably, the compositions of the present invention are administered rectally, for example, the compositions of the present invention are administered as an enema. Route of administration

[0312] The composition of the present invention can be administered to a subject by any suitable route of administration that is suitable for the condition to be treated and the pharmaceutically active agent used.For example, it can be administered topically, rectally, vaginally or intravenously.The composition can be administered topically, rectally or vaginally.

[0313] Routes of administration include, but are not limited to, oral (e.g., by ingestion, tablet, spray, etc.); buccal; sublingual; transdermal (including, e.g., by patch, plaster, dressing, etc.); transmucosal (including, e.g., by patch, plaster, etc.); ocular (e.g., by eye drops); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implant.

[0314] The compositions of the present invention may be non-parenteral compositions (e.g., topical) and may be administered to the skin, mucous membranes and / or nail surfaces, ophthalmic, nasal, oral or internal surfaces, or cavities such as the nasal, rectal, vaginal or oral cavity, periodontal pockets, or cavities formed after extraction of a natural or implanted structure or prior to insertion of an implant (e.g., joint, stent, cosmetic implant, tooth, dental filling or other implant).

[0315] In a preferred embodiment, the composition of the present invention is administered rectally.Therefore, the composition of the present invention may be in the form of a suppository; a rectal capsule; a rectal solution, emulsion or suspension; a powder or tablet for rectal solution or suspension; a semi-solid rectal preparation; a rectal foam; a rectal tampon; or an enema.In a preferred embodiment, the composition may be administered to a subject via the rectum in the form of a suppository; a rectal capsule; a semi-solid rectal preparation; a rectal foam; a rectal tampon; or an enema.Preferably, the composition of the present invention may be administered rectally as an enema.Therefore, in a preferred embodiment, the composition of the present invention is directly administered as a flowable composition.For example, the composition of the present invention is administered rectally as a lamellar gel, for example, in the form of an enema.

[0316] As described herein, at room temperature (e.g., about 25°C), the compositions of the present invention have a lamellar phase structure (e.g., the compositions of the present invention are lamellar gels). Therefore, the compositions of the present invention are easily administered rectally to the lower gastrointestinal (GI) tract and rapidly convert to a highly viscous lipidic cubic phase at rectal temperatures (e.g., about 36°C to 39°C). This is particularly advantageous because thick, viscous preparations can be difficult to effectively rectally apply to the lower GI tract. Also, less viscous preparations (although easier to administer) are less likely to remain in place, which results in rapid loss of material. In contrast, the compositions of the present invention act as highly viscous, bioadhesive, controlled depot systems that remain in place for at least about 6 hours.

[0317] It is well understood that the lower GI tract begins with the cecum and also includes the appendix (in humans), colon (e.g., sigmoid colon, descending colon, transverse colon, ascending colon), splenic flexure, hepatic flexure, rectum, and anus. As described herein, the compositions of the present invention are administered to the lower GI tract of a subject. As such, the compositions of the present invention may be topically applied to the inner wall of the lower GI tract. For example, the compositions of the present invention may be topically applied to the inner wall of the colon and / or rectum. As such, the compositions of the present invention may be topically applied to the inner wall of the lower GI tract via the rectum, e.g., in the form of an enema. For example, the compositions of the present invention may be topically applied to the inner wall of the colon via the rectum, e.g., in the form of an enema. In certain embodiments, the compositions of the present invention are topically applied to the rectum, sigmoid colon, and / or descending colon. More preferably, the compositions of the present invention are topically applied to the rectum and / or sigmoid colon.

[0318] Enema devices and / or kits used for enema delivery are well known and include, for example, enema bags, tubes, nozzles, syringes (such as rectal bulb syringes), and the like. In embodiments, the compositions of the present invention are delivered locally via an endoscope to target the composition to specific areas of the lower GI tract, for example, sites of inflammation, injury, tumors, polyps, and the like. The compositions of the present invention may be delivered via an endoscope to tissues of the sigmoid colon, descending colon, transverse colon, ascending colon, and / or rectum. In embodiments, the compositions of the present invention are administered rectally via a rectal catheter.

[0319] The subject may have undergone a colostomy (a surgical procedure connecting to the colon through an opening in the abdominal wall (an artificial anatomy)). As such, the subject may have an artificial anatomy. Suitably, the compositions of the present invention may be administered to the subject's lower GI tract via the colostomy, for example, in the form of a suppository or enema. The compositions of the present invention may be administered to the subject's lower GI tract via the colostomy in the form of an enema. For example, the compositions of the present invention may be administered to the subject's colon via the colostomy in the form of an enema. As such, the compositions of the present invention may be topically applied to the inner wall of the lower GI tract via the colostomy in the form of an enema. For example, the compositions of the present invention may be topically applied to the inner wall of the colon via the colostomy in the form of an enema.

[0320] In an embodiment, the composition of the present invention is a parenteral composition. Therefore, the composition of the present invention may be an injection preparation and may be administered to a subject subcutaneously, intramuscularly, or intradermally. Preferably, the composition is administered to a subject subcutaneously.

[0321] In embodiments, the compositions of the present invention are administered vaginally. As such, the compositions of the present invention may be in the form of a vaginal tablet; a vaginal suppository or pessary; a vaginal foam, spray, gel, or cream. subject

[0322] The compositions of the present invention are suitable for use in the treatment of subjects affected by any of the diseases or conditions described herein. Preferably, the compositions of the present invention are suitable for use in the local treatment of subjects affected by any of the diseases or conditions described herein, where the compositions are applied locally to the colon of the subject, for example, the compositions are administered rectally to the subject, preferably as an enema.

[0323] In embodiments, the subject may be a warm-blooded mammal. In certain embodiments, the subject to be treated is a human. The subject may be a human adult (18 years of age or older). The subject may be a human child under the age of 18. The pediatric subject may be between 2 and 4 years of age. The pediatric subject may be between 5 and 10 years of age. The pediatric subject may be between 11 and 18 years of age.

[0324] In embodiments, the subject may be an animal. In certain embodiments, the compositions of the present invention are for use as veterinary products for the topical treatment of animals. In certain embodiments, the compositions of the present invention are for use in the topical treatment of diseases and conditions in commercial animals, such as livestock (e.g., cows, sheep, chickens, pigs, geese, ducks, goats, etc.). In other embodiments, the compositions of the present invention may be for use in the topical treatment of diseases or conditions in companion animals, such as cats, dogs, horses, etc. Method of preparation

[0325] The composition of the present invention comprises: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition It may be prepared by a method comprising:

[0326] In embodiments, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent. For example, the pharmaceutically active agent may be tacrolimus. Thus, the composition may comprise: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent (e.g., a hydrophobic pharmaceutically active agent) with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition It may also be prepared by a method comprising:

[0327] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. The lipid may be monolinolein. The lipid may be monoolein.

[0328] In embodiments, the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In embodiments, the lipid is a monoacylglycerol lipid comprising at least 50% by weight monolinolein.

[0329] Thus, in an embodiment, the composition of the present invention comprises: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent (e.g., a hydrophobic pharmaceutically active agent) with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition A method comprising: It may be prepared by a method in which the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0330] In an embodiment, in step a), the mixture is hydrated with deionized water. In an embodiment, in step a), the mixture is hydrated with phosphate buffered saline (PBS). In an embodiment, in step a), the mixture is hydrated with water for injection (WFI).

[0331] In embodiments, the lipid-drug mixture of step a) is vortexed at room temperature until a homogenous mixture is obtained.

[0332] In embodiments, in step b), the lipid-drug mixture is equilibrated for up to about 48 hours. The lipid-drug mixture may be equilibrated for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours.

[0333] In embodiments, the pharmaceutically active agent is light sensitive, so the lipid-drug mixture may be equilibrated in step b) under dark conditions.

[0334] In an embodiment, the mixture in step a) is a lyophilized mixture. The lyophilized mixture comprises: i) dissolving a lipid and a pharmaceutically active agent in an organic solvent; and ii) freeze-drying the mixture of i) to provide a freeze-dried mixture. It may also be obtained by

[0335] In an embodiment, in step i), the organic solvent may be an alcohol. Examples of suitable alcohols include ethanol, methanol, isopropanol, and glycerol formal. The organic solvent may be ethanol. The organic solvent may be methanol. Preferably, the organic solvent is ethanol.

[0336] In an embodiment, in step ii), the mixture is freeze-dried by removing the organic solvent. The organic solvent may be removed under reduced pressure. The organic solvent may be removed by freeze-drying the mixture of i). The mixture of i) may be freeze-dried for about 24 hours. Preferably, the mixture of i) is freeze-dried at 0.22 mbar for 24 hours to provide a freeze-dried mixture.

[0337] In other embodiments, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. The pharmaceutically active agent may be a Janus kinase inhibitor. Preferably, the pharmaceutically active agent may be tofacitinib or a pharmaceutically acceptable salt thereof. Therefore, the composition of the present invention also comprises: a) dissolving a pharmaceutically active agent (e.g., a hydrophilic pharmaceutically active agent) in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition It may be prepared by a method comprising:

[0338] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. The lipid may be monolinolein. The lipid may be monoolein.

[0339] In embodiments, the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In embodiments, the lipid is a monoacylglycerol lipid comprising at least 50% by weight monolinolein.

[0340] Therefore, in embodiments, the compositions of the present invention also comprise: a) dissolving a pharmaceutically active agent (e.g., a hydrophilic pharmaceutically active agent) in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition A method comprising: It may be prepared by a method in which the lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0341] In an embodiment, in step a), the pharmaceutically active agent is dissolved in deionized water.In an embodiment, in step a), the pharmaceutically active agent is dissolved in water for injection (WFI).

[0342] In embodiments, the lipid-drug mixture of step b) is vortexed at room temperature until a homogeneous mixture is obtained. The lipid-drug mixture of step b) may be vortexed at room temperature for 30 seconds to at least 10 minutes. The lipid-drug mixture of step b) may be vortexed at room temperature for at least 30 seconds, 40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes. Preferably, the lipid-drug mixture of step b) may be vortexed at room temperature for at least 5 minutes.

[0343] In embodiments, in step c), the lipid-drug mixture is equilibrated for up to about 48 hours. The lipid-drug mixture may be equilibrated for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours.

[0344] In embodiments, the pharmaceutically active agent is light sensitive, so the lipid-drug mixture in step c) may be equilibrated under dark conditions.

[0345] The composition of the present invention may also be prepared by the steps of: a) heating a lipid to provide a molten lipid; b) mixing the molten lipid with a pharmaceutically active agent to provide a lipid-drug mixture; c) mixing the lipid-drug mixture with water; and d) Equilibrating the lipid-drug mixture and water to provide the composition. It may be prepared by a method comprising:

[0346] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. The lipid may be monolinolein. The lipid may be monoolein.

[0347] In embodiments, the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In embodiments, the lipid is a monoacylglycerol lipid comprising at least 50% by weight monolinolein.

[0348] In an embodiment, in step a), the lipids are heated to a temperature of about 30°C to 70°C. The lipids may be heated to a temperature of about 40°C to 60°C. The lipids may be heated to a temperature of about 45°C to 55°C. Preferably, the lipids may be heated to a temperature of about 50°C.

[0349] In embodiments, in step b), the molten lipid and pharmaceutically active agent are heated to a temperature of about 30°C to 70°C. The molten lipid and pharmaceutically active agent may be heated to a temperature of about 40°C to 60°C. The molten lipid and pharmaceutically active agent may be heated to a temperature of about 45°C to 55°C. Preferably, the molten lipid and pharmaceutically active agent may be heated to a temperature of about 50°C.

[0350] In embodiments, in step b), the molten lipid and the pharmaceutically active agent are mixed until a homogeneous lipid-drug mixture is obtained. The molten lipid and the pharmaceutically active agent may be mixed for up to about 1 hour. The molten lipid and the pharmaceutically active agent may be mixed for up to about 30 minutes. The molten lipid and the pharmaceutically active agent may be mixed for up to about 15 minutes. The molten lipid and the pharmaceutically active agent may be mixed for up to about 5 minutes. The molten lipid and the pharmaceutically active agent may be mixed for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 1 hour.

[0351] In embodiments, in step c), the lipid-drug mixture is mixed with deionized water. In embodiments, in step c), the lipid-drug mixture is mixed with phosphate buffered saline (PBS). In embodiments, in step c), the lipid-drug mixture is mixed with water for injection (WFI).

[0352] The lipid-drug mixture in step c) can be mixed by any method known in the art. For example, the lipid-drug mixture can be mixed with water in a dual syringe. The dual syringe can include two separate chambers, a mixing nozzle, and a plunger. Thus, the lipid-drug mixture is inserted into the first chamber, and water is inserted into the second chamber. When force is applied to the plunger, the lipid-drug mixture and water are mixed in the mixing nozzle to obtain a homogeneous mixture. Alternatively, the dual syringe can include two syringes attached via a connector. Thus, the lipid-drug mixture is inserted into the first syringe, and water is inserted into the second syringe. The lipid-drug mixture in the first syringe is transferred to the second syringe containing water. Then, the lipid-drug mixture and water are returned to the first syringe. This process is repeated until a homogeneous mixture is obtained. Therefore, the lipid-drug mixture in step c) can be mixed using a dual syringe.

[0353] In embodiments, in step d), the lipid-drug mixture and water are equilibrated for up to about 1 hour. The lipid-drug mixture may be equilibrated for up to about 30 minutes. The lipid-drug mixture may be equilibrated for up to about 15 minutes. The lipid-drug mixture may be equilibrated for up to about 5 minutes. The lipid-drug mixture may be equilibrated for up to about 1 minute. The lipid-drug mixture may be equilibrated for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 1 hour. kit

[0354] a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition of the present invention; Provided herein is a kit comprising:

[0355] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. The lipid may be monolinolein. The lipid may be monoolein.

[0356] In embodiments, the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In embodiments, the lipid is a monoacylglycerol lipid comprising at least 50% by weight monolinolein.

[0357] Thus, in embodiments, the kit comprises: a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition of the present invention; Including, The lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0358] In embodiments, the pharmaceutically active agent is selected from any of the pharmaceutically active agents defined herein. Preferably, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent. The pharmaceutically active agent may be tacrolimus.

[0359] In embodiments, the kit further comprises a second container, the second container comprising water. The water may be deionized water. The water may be water for injection (WFI). Thus, the kit comprises: a) a first container containing a lipid and a pharmaceutically active agent; b) a second container containing water; and c) instructions for combining a) with b) to provide a composition of the present invention. and The lipid is selected from monolinolein or monoolein.

[0360] In some embodiments, the lipid and pharmaceutically active agent in the first container are provided as a lyophilized mixture.Lyophilized mixture can be obtained by the method described herein.Therefore, the kit can include instructions for hydrating the lyophilized mixture with a certain amount of water to obtain the composition of the present invention.For example, the kit can include: a) a first container containing a lyophilized mixture, the lyophilized mixture comprising a lipid and a pharmaceutically active agent; b) a second container containing water; and c) instructions for combining a) with b) to provide a composition of the present invention. and The lipid is selected from monolinolein or monoolein.

[0361] In a preferred embodiment, the kit comprises: a) a first container containing a lyophilized mixture, the lyophilized mixture comprising monolinolein and tacrolimus; b) a second container containing water; and c) instructions for combining a) with b) to provide a composition of the present invention. and The resulting composition is (i) 1% w / w tacrolimus; (ii) 83.16% w / w monolinolein; and (iii) 15.84% w / w water Includes.

[0362] In other embodiments, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. For example, the pharmaceutically active agent can be tofacitinib or a pharmaceutically acceptable salt thereof. a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent (e.g., a hydrophilic pharmaceutically active agent) dissolved in water to provide a composition of the invention; Also provided is a kit comprising:

[0363] In embodiments, the lipid is a monoacylglycerol lipid. In embodiments, the monoacylglycerol lipid is selected from monolinolein or monoolein. The lipid may be monolinolein. The lipid may be monoolein.

[0364] In embodiments, the lipid is a monoacylglycerol lipid comprising monolinolein or monoolein, or a combination thereof. In embodiments, the lipid is a monoacylglycerol lipid comprising at least 50% by weight monolinolein.

[0365] Thus, in embodiments, the kit comprises: a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent (e.g., a hydrophilic pharmaceutically active agent) dissolved in water to provide a composition of the invention; Including, The lipid is selected from monolinolein or monoolein. Preferably, the lipid is monolinolein.

[0366] In an embodiment, the kit further comprises a second container, the second container comprising a pharmaceutically active agent dissolved in water. The water may be deionized water. The water may be water for injection (WFI). Thus, the kit comprises: a) a first container containing lipid; b) a second container containing a solution comprising a pharmaceutically active agent dissolved in water; and c) instructions for combining a) with b) to provide a composition of the present invention. and The lipid is selected from monolinolein or monoolein.

[0367] The kit may include instructions for hydrating the lipid in the first container with a certain amount of solution in the second container to arrive at the composition of the invention. For example, the kit may include: a) a first container containing monolinolein; b) a second container containing a solution comprising tofacitinib or a pharmaceutically acceptable salt thereof dissolved in water; and c) instructions for combining a) with b) to provide a composition of the present invention. and The resulting composition is (i) 5% w / w of tofacitinib or a pharmaceutically acceptable salt thereof; (ii) 79.8% w / w monolinolein; and (iii) 15.2% w / w water Includes.

[0368] The following examples are intended to illustrate, rather than limit, either explicitly or implicitly, the invention in any manner, shape, or form. [Example]

[0369] Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were carried out at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to methods described herein or using literature procedures. Abbreviation DC: dendritic cell DSS: dextran sulfate sodium h: time H: Hexagonal phase H&E: hematoxylin and eosin HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC: High-performance liquid chromatography L: Lamellar phase LMP: lipid mesophase LVR: Linear viscoelastic region min:minutes MLO: Monolinolein PBS: phosphate buffered saline Q: Cubic phase SAXS: Small angle X-ray scattering TAC: tacrolimus TIF gels: temperature-triggered in situ forming adhesive lipid gels TOFA: Tofacitinib UC: Ulcerative colitis WAXS: Wide-angle X-ray scattering material

[0370] Monolinolein (MLO) was purchased from NU-Check Prep, Inc. (MN, USA). Ultrapure water with a resistivity of 18.2 MΩ·cm was generated using a Barnstead Smart2pure (Thermo Scientific) and used as the aqueous phase. Methanol, acetonitrile, and tetrahydrofuran were analytical grade supplied by Fisher Scientific (Schwerte, Germany). Absolute ethanol >99.5 wt% was obtained from VWR chemicals BDH (London, UK). Tofacitinib citrate (TOFA) was purchased from LC laboratories (Woburn, MA), and tacrolimus (TAC) was obtained from R&S Pharmchem Co., Ltd. (Shangai, China). Clotrimazole and mesalamine were purchased from Merck (Darmstadt, Germany). Budesonide (97% purity) was obtained from Thermo Scientific (Pittsburgh, USA). Porcine pancreatic lipase and methylcellulose (viscosity 25 cp) were obtained from Sigma Chemical Co. (St. Louis, USA). Caffeine (Ph.Eur. quality) was purchased from Hanseler Swiss Pharma. HEPES salt was obtained from Carl Roth (Karlsruhe, Germany). Analysis method Small-angle X-ray scattering (SAXS)

[0371] SAXS measurements were used to determine the phase identity and symmetry of the resulting LMPs. Measurements were performed on a Bruker AXS Micro using a microfocus X-ray source operating at a voltage and filament current of 50 kV and 1000 μA, respectively. Cu Kα radiation (λCu Kα=1.5418 Å) was collimated by a 2D Kratky collimator, and data were collected by a 2D Pilatus 100K detector. The scattering vector Q=(4π / λ)sin θ was calibrated using silver behenate, with 2θ being the scattering angle. Data were collected using Saxsgui software and averaged by azimuth angle to yield values ​​between 0.001 and 0.5 Å. -1 1D intensity versus scattering vector Q was obtained for Q in the range of 10 μL. For all measurements, samples with a sample volume of 10 μL and a thickness of approximately 1 mm were placed inside a stainless steel cell between two thin, interchangeable mica sheets and sealed with an O-ring. Measurements were performed at 25°C, 30°C, 34°C, 36°C, and 38°C. Samples were equilibrated for 10 min before measurement, but scattering intensity was collected over 30 and 60 min in the case of lamellar phases. On the other hand, for kinetic studies, samples were inserted into a sample holder pre-equilibrated at 25°C and maintained at 38°C, and scattering intensity was collected over 5 min. SAXS data information on the spatial lattice was combined with the sample composition to determine structural parameters such as the size of water channels (R. Mezzenga, et al., Shear rheology of lyotropic liquid crystals: a case study, Langmuir 21, 3322-3333 (2005)). SAXS spectra acquired at different temperatures on gels containing 10% w / w TOFA and 10% w / w TAC MLO was used as the lipid component of the mesophase and was mixed with a weighed amount of drug (10% w / w) in a sealed Pyrex tube and alternately centrifuged (10 min, 5000 g) several times at room temperature until a homogeneous mixture was obtained. The mesophase was then equilibrated at room temperature in the dark for 48 h (see Figures 1A and 1B). Rheology Experiments

[0372] A stress-controlled rheometer (Modular Compact Rheometer MCR 72, Anton Paar, Graz, Austria) was used with a cone-and-plate geometry, a 0.993° angle, and a diameter of 49.942 mm. Temperature control was set to either 25 °C or 38 °C. First, a strain sweep was performed at 1 Hz from 0.002 to 100% strain to determine the linear range, the linear viscoelastic region (LVR), the yield point, and the subpoint. Next, an oscillatory frequency sweep was performed at 0.1% strain from 0.1 to 100 rad / s. The frequency sweep measurements were performed at a constant strain in the linear viscoelastic region (LVR), as determined by oscillatory strain sweep (amplitude sweep) measurements performed on each sample. Within the linear viscoelastic region, the material response is virtually independent of the magnitude of deformation, and the material structure remains intact, a necessary condition for accurately determining the material's mechanical properties. Release experiments of TAC and TOFA: in vitro and ex vivo setups and HPLC drug quantification

[0373] The formulations and free drug enemas were tested in vitro and ex vivo using a vertical diffusion cell (PermeGear, Pennsylvania, USA) with a 3000 nm polycarbonate membrane (Sterlitech Corporation, USA). pH 7.4 HEPES buffer (8 mL) was used as the release medium, and the device was placed in a shaking incubator at 100 rpm and 37°C. To examine the effect of lipase on drug release, porcine pancreatic lipase (1000 U / mL) was added to the sample in the donor chamber. Ex vivo experiments were performed using rat intestinal tissue to evaluate the drug release of the TIF gel. Briefly, fresh intestinal tissue was obtained and cut into samples (2 mm × 1 mm × 1 mm) suitable for the Franz cell apparatus. The tissue was placed on a polycarbonate membrane for tensile loading. At the designated time points (0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, and 8 h), the release medium was completely replaced with 8 mL of fresh HEPES, and 1 mL aliquots were taken for lyophilization. Each sample was resuspended with an internal standard in the mobile phase, and the drug content was analyzed by HPLC. The same experimental design was used for both TOFA- and TAC-loaded TIF gels. Samples of the drug-containing TIF gels were also stored at room temperature and 4°C for 30 days. The drug stability was determined by HPLC analysis. The same experimental design was used for both TOFA- and TAC-loaded TIF gels. HPLC Method: Tofacitinib Citrate

[0374] Tofacitinib citrate was detected by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 × 250 mm; 5.0 μm particle size) column. The mobile phase consisted of acetonitrile / methanol / water (13:13:74 v / v) + 0.1% trifluoroacetic acid, with a flow rate of 1 mL / min, a temperature of 25°C, and UV detection at λ = 278 nm. An internal standard (caffeine, 20 μg / mL) was added to each sample to correct for injection-to-injection variations and UV detection at λ = 278 nm. Data were collected and analyzed using Chromeleon 7 software (Thermo Fisher). HPLC Method: Tacrolimus

[0375] Tacrolimus was detected by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 × 250 mm; 5.0 μm particle size) column. The mobile phase consisted of methanol / water (80:20 v / v) + 0.1% trifluoroacetic acid, with a flow rate of 1 mL / min, a temperature of 50°C, and UV detection at λ = 214 nm. An internal standard (ketoconazole, 20 μg / mL) was added to each sample to correct for injection-to-injection variations and UV detection at λ = 278 nm. Data were collected and analyzed using Chromeleon 7 software (Thermo Fisher). Release experiments of clotrimazole, budesonide and mesalamine: In vitro setup and HPLC drug quantification Release experiment: clotrimazole

[0376] A 5% w / w clotrimazole formulation was prepared according to the preparation method described in Example 1. Briefly, the TIF gel composition contained a) a1) water in an amount of 16% by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) clotrimazole in an amount of 5% by weight of the composition. A 0.5 mg / mL solution of free clotrimazole was also prepared using 2% w / v Tween® 80 as the solvent. The drug release profile was then tested in vitro using a vertical Franz cell (PermeGear, Pennsylvania, USA) and a 3000 nm polycarbonate membrane (Sterlitech Corporation, USA). The donor chamber contained 8 mL of 2% w / v Tween 80 release medium. The loaded Franz cell was placed in a shaking incubator at 100 rpm and 37°C. For free clotrimazole and 5% w / w TIF gel, 300 μL and approximately 40 mg, respectively, were directly placed in the donor chamber. At predetermined time points of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours, the release medium was completely replaced and aliquots were lyophilized. Each sample was resuspended in acetonitrile / water (70:30 v / v) and analyzed for clotrimazole content by HPLC. HPLC Method: Clotrimazole

[0377] Clotrimazole concentrations were determined by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 × 250 mm; 5.0 μm particle size) column with a mobile phase consisting of acetonitrile / water (70:30 v / v) + 0.1% trifluoroacetic acid, a flow rate of 0.5 mL / min, a temperature of 40°C, and UV detection at λ = 200 nm. Release experiment: Budesonide

[0378] A 5% w / w budesonide formulation was prepared according to the preparation method described in Example 1. Briefly, the TIF gel composition contained a) a1) water in an amount of 16% by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) budesonide in an amount of 5% by weight of the composition. A 0.5 mg / mL solution of free budesonide was also prepared using Tween 80 (2% w / v) as the solvent. The drug release profile was then tested in vitro using a vertical Franz cell (PermeGear, Pennsylvania, USA) and a 3000 nm polycarbonate membrane (Sterlitech Corporation, USA). The donor chamber contained 8 mL of 2% w / v Tween 80 release medium. The loaded Franz cell was placed in a shaking incubator at 100 rpm and 37°C. For free budesonide and 5% w / w TIF gel, 300 μL and approximately 40 mg, respectively, were placed directly into the donor chamber. At predetermined time points (0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours), the release medium was completely replaced and aliquots were lyophilized. Each sample was resuspended in acetonitrile / water (70:30 v / v) and analyzed for clotrimazole content by HPLC. HPLC Method: Budesonide

[0379] Budesonide concentrations were determined by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 × 250 mm; 5.0 μm particle size) column with a mobile phase consisting of acetonitrile / water (70:30 v / v) + 0.1% trifluoroacetic acid, a flow rate of 0.5 mL / min, a temperature of 40°C, and UV detection at λ = 260 nm. Release experiment: Mesalamine

[0380] A 5% w / v mesalamine formulation was prepared according to the method described in Example 1. Briefly, the TIF gel composition contained a) a1) water in an amount of 16% by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) mesalamine in an amount of 5% by weight of the composition. A 1 mg / mL solution of free mesalamine in HEPES (10 mM, pH 7.4) was also prepared. The drug release profile was tested in vitro using a vertical Franz cell (PermeGear, Pennsylvania, USA) and a 3000 nm polycarbonate membrane (Sterlitech Corporation, USA). The donor chamber contained 8 mL of HEPES (10 mM, pH 7.4) release medium. The loaded Franz cell was placed in a shaking incubator at 100 rpm and 37°C. For free mesalamine and 5% w / w TIF gel, 300 μL and approximately 40 mg, respectively, were placed directly into the donor chamber. At predetermined time points of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours, the release medium was completely replaced. 200 μL aliquots were directly analyzed by absorbance. HPLC Method: Mesalamine

[0381] Mesalamine concentrations were determined by absorbance using a microplate reader (Spark 10M, Tecan, Switzerland). The maximum absorption wavelength of mesalamine was 298 nm for mesalamine in HEPES (10 mM, pH 7.4) at 20°C. Drug uniformity in the gel structure

[0382] To determine whether TOFA and TAC were uniformly distributed in the gel matrix, gels (loaded with TAC or TOFA) were prepared as described herein and transferred to 2 mL Eppendorf tubes. The tubes were centrifuged and allowed to stand for 24 hours. The gels were then divided into three distinct layers (top, middle, and bottom), and the drug content was assessed by HPLC. LC-MS / MS analysis

[0383] Samples, standards, and QCs were extracted by protein precipitation and analyzed by LC-MS / MS using the following method: For plasma samples, 10 μL of plasma was mixed with 25 μL of precipitation solution (80:20 acetonitrile:methanol + 0.1 μM loperamide). Samples were centrifuged at 10,000 g for 10 minutes, and 20 μL of the supernatant was diluted with 40 μL of HO + 0.1% FA. Samples were centrifuged at 3,400 rpm for 10 minutes, and 50 μL of the supernatant was diluted with 100 μL of HO + 0.1% FA. All samples were analyzed by LC-MS / MS (Shimadzu prominence HPLC connected to an AB / SCIEX 4000 QTRAP) in positive MRM mode. Samples were separated on a Cortecs RP shielded column (3 x 50 mm, 2.6 u) using a fast gradient of ammonium formate (A) and methanol (B) in 10 mM water. The gradient started at 20% B, increased to 98% B in 2 min, held for 0.5 min, and equilibrated for 1.4 min. MRM parameters were optimized for each analyte. The MRM transition from 313 to 149.3 was selected for tofacitinib, the MRM transition from 822.3 to 770.1 was selected for tacrolimus, and the MRM transition from 477.1 to 266.0 was selected for loperamide (internal standard). Samples were quantified using a matrix-prepared calibration curve using the area ratio of the analyte to the internal standard. WAXS (wide-angle X-ray scattering)

[0384] WAXS measurements were performed on a Bruker AXS Micro using a microfocus X-ray source operating at a voltage and filament current of 50 kV and 1000 μA, respectively. Cu Kα radiation (λCu Kα = 1.5418 Å) was collimated by a 2D Kratky collimator, and data were collected by a 2D Pilatus 100K detector. The scattering vector Q = (4π / λ) sin θ was calibrated using silver behenate at the scattering angle 2θ. Data were collected and averaged azimuthally using Saxsgui software to obtain 1D intensity versus scattering vector Q with Q ranging from 13 to 18 nm. For all measurements, samples were placed inside a stainless steel cell between two thin, interchangeable mica sheets, with a sample volume of 10 μL and a thickness of approximately 1 mm, and sealed with an O-ring. Methods - In vivo study Chemical-induced colitis based on the application of DSS

[0385] Female 6-8 week-old C57B / 6J mice (e.g., Charles River, Germany) were maintained under specific and opportunistic germ-free (SOPF) microbiota conditions in the animal facility at the University of Bern. Mice were ear-marked and randomly assigned to different cages and treatment groups. To avoid potential cage effects on the microbiota, bedding was mixed between all cages. All methods used were approved by the Bernese Animal Welfare Authority (Permit Number BE 20 / 18). One day before the start of DSS supplementation, mice were intrarectally instilled with 100 μL of empty gel, TOFA in 1% methylcellulose, or TOFA-loaded gel (5 mg TOFA / 100 μL gel). The following day, mouse drinking water was supplemented with 2% w / v dextran sodium sulfate (DSS; MP Biomedicals, 160110). Different compounds were applied intrarectally every other day until the end of the experiment. Mice were monitored regularly throughout the experiment, and weight and disease scores were recorded, if appropriate. Disease scores were determined by grading the following criteria from 1 to 4 (grade 4 corresponds to the most unhealthy / abnormal): posture, mobility, fur appearance, weight, stool consistency, and stool color (LF Mager, et al., The ESRP1-GPR137 axis contributes to intestinal pathogenesis, Elife 6 (2017), doi:10.7554 / eLife.28366.). At the end of the experiment, mice were euthanized by carbon dioxide asphyxiation, and organs were collected and used as described in the Results section. Swiss rolls (C. Moolenbeek, et al., (1981) The "Swiss roll": A simple technique for histological studies of the rodent intestine, Lab. Anim. 15, 57-59) were prepared from colons, fixed overnight in 10% formalin in PBS, washed with PBS, embedded in paraffin, and sectioned for H&E staining.Histopathological scoring was performed by a qualified pathologist in a blinded manner using the following criteria: goblet cell loss, crypt abscesses, epithelial erosion, hyperemia, mucosal thickness, and cellular infiltration (maximum score per category: 3). Single cell flow cytometry and quantification

[0386] The gating strategy was adapted from our previous publication (S.E. Liyanage, et al., Flow cytometric analysis of inflammatory and resident myeloid populations in mouse ocular inflammatory models, Exp. Eye Res. 151, 160-170 (2016)). Briefly, mouse spleens (after weighing) and mesenteric lymph nodes were homogenized through a 70 μm cell strainer. After that, red blood cells were removed from the spleens by resuspending the cell pellet in ACK lysis buffer (150 mM NH4Cl, 10 mM KHCO3, 0.1 mM; pH: 7.4) at room temperature for 5 minutes. Splenocytes were quantified using a CASY cell counter (Omni Life Sciences), and the following populations were quantified according to single cell and live / dead selection (Thermofischer, L34961): T cells (defined as CD3ε+ cells; antibodies used: eBioscience, 25-0031-82); dendritic cells (CD11c+, CD11b+; Biolegend 117324 and 101241); neutrophils (CD11b+, Ly6G+; Biolegend, B156884), macrophages (CD11b+, CD11c-, Ly6G-, Ly6C-), and inflammatory monocytes (CD11b+, Ly6C+; Biolegend, 128024). Stained cells were analyzed on a BD Bioscience LSR II SORP flow cytometer. T cell transference colitis

[0387] To induce T cell-mediated colitis, CD4+ T cells were isolated from the spleens of C57 / BL6 mice (strain no.: 000664; RRID: IMSR_JAX: 000664, e.g., Jackson laboratories) using a CD4 T cell isolation kit from Stemcell Technologies (no. 19852; Cologne, Germany). Naive helper T cells (CD3+, CD4+, CD25low, CD6Lhigh, CD44low cells) were then isolated as previously described (DV Ostanin, et al., T cell transfer model of chronic colitis: Concepts, considerations, and tricks of the trade-offs between T cell transfer and T cell proliferation; Am. J. Physiol. - Gastrointest. Liver Physiol. 296, 135-146 (2009); MR Spalinger, et al., PTPN2 controls differentiation of CD4+ T cells and limits intestinal inflammation and intestinal inflammation). dysbiosis, Mucosal Immunol. 8, 918-929 (2015); M.R. Spalinger, et al., Loss of PTPN22 Promotes Intestinal Inflammation by Compromising Granulocyte-Mediated Antibacterial Defense, J. Crohn's Colitis 15, 2118-2130 (2021)). Male and female 12- to 15-week-old rabbits on a C57 / BL6 background were sorted on a FACS Aria III (Becton Dickinson; Eysins, Switzerland). - / - Mouse (model RAGN12 (B6.129S6-Rag2 tm1Fwa N12), e.g., Taconic), 2.5 x 10 5Naive helper T cells were injected intraperitoneally (all methods used were approved under license number ZH043 / 2021). Starting on day 2 after T cell injection, mice received a rectal injection (100 μL) of empty TIF gel, TAC-loaded TIF gel, or TAC in vehicle solution (1% nitrocellulose in distilled water) once daily. Body weight change and disease activity scores were measured daily. On the final day of the experiment (day 18), mice were anesthetized using a mixture of ketamine 90–120 mg / kg body weight (Vetoquinol, Bern, Switzerland) and xylazine 8 mg / kg body weight (Bayer, Lyssach, Switzerland) and subjected to murine endoscopy to assess the severity of endoscopic colitis (M.R. Spalinger, et al., Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner, J. Clin. Invest. 129, 2527–2541 (2019)) using the following parameters: 1) colon wall thickness, 2) vascularization / bleeding, 3) degree of fibrin deposition, 4) rough appearance of the colon wall, and 5) stool consistency. Each parameter was scored from 0 (normal) to 3 (most severe appearance), resulting in a maximum total score of 15. After colonoscopy, mice were sacrificed and colon tissue was collected for histological examination and isolation of lamina propria immune cells. Immune cells were isolated from the colon, mesenteric lymph nodes, and spleen and analyzed for immune cell subsets (M.R. Spalinger, et al., (2019) Loss of PTPN22 abrogates the beneficial effect of cohousing-mediated fecal microbiota transfer in murine colitis, Mucosal Immunol. 12, 1336-1347). H&E staining and histological analysis of colitis severity

[0388] To assess the microscopic extent of colitis, formalin-fixed, paraffin-embedded sections of the most distal 1.5 cm of the colon were subjected to hematoxylin and eosin (H&E) staining using standard protocols (M.R. Spalinger, et al. (2019)). Sections were analyzed by two blinded scientists for the degree of epithelial damage (score 0–4) and immune cell infiltration (score 0–4), resulting in a maximum possible score of 8. Images were acquired using a Zeiss Axio Imager.Z2 microscope (Zeiss) equipped with an AxioCam HRc (Zeiss, Jena, Germany) camera and ZEN imaging software (Zeiss, Germany). Identification of phase transitions after in vivo application

[0389] Healthy animals were administered 100 mL of TIF gel, and either the excreted gel (with the feces after 30 min) or the residual gel present in the colon after 6 h was collected and analyzed by SAXS (the animals were sacrificed, the colons were harvested, and the residual gel was washed three times with PBS before analysis). As shown in Figure 2J, Bragg reflections characteristic of the L phase were present at 25 °C before administration, but the gel excreted with the feces exhibited an L → Ia3d transition. Furthermore, the lamellar phase absorbed heat and water during the experiment, reaching a cubic (pn3m) phase, as previously observed in in vitro studies. Analysis of cytokine levels in the colon

[0390] To analyze cytokine levels in the colon, colonic pieces were lysed in PBS (1 ml PBS / 0.1 mg tissue) using a Miltenyi Biotec GentleMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany). Lysates were then analyzed for cytokines using Bio-Rad's Bio-Plex Pro Mouse Cytokine 23-plex assay (Hercules, CA) according to the manufacturer's instructions. Pharmacokinetics (PK)

[0391] PK studies in healthy animals were conducted by the Platform of Biopharmacy of the University of Montreal in accordance with the local animal welfare committee of the University of Montreal and in accordance with Canadian Council on Animal Care (CCAC) regulations. Healthy female C57BL / 6 mice (5 animals per group) received a single rectal administration (100 μL) of either drug-loaded TIF gel (TIF gel-TOFA or TIF gel-TAC) or free drug (TOFA or TAC in suspension) under anesthesia. All formulations contained 5 mg TOFA or 1 mg TAC and were applied once rectally at t = 0. Plasma levels were determined 0.25, 1, 2, 4, 6, 12, 24, and 48 hours after application. Animals were euthanized by CO2 after the final sampling point. Blood was collected and stored in K2-EDTA BD-Microtainer™ (Fisher Scientific AG, Switzerland). Drugs were extracted from plasma and their concentrations were determined using LC-MS / MS analysis (see above). AUC 0-48h was calculated according to the trapezoidal method. In vivo / ex vivo experiments to evaluate the adhesion of TIF gel to the colon wall For in vivo adhesion studies, healthy animals (n = 11) under anesthesia received an enema of 100 μl of DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide)-loaded gel (DiR-TIF gel) as described above. Animals were sacrificed after 30 min (n = 3), 2, and 6 h (n = 4). The distal 3 cm of the colon (including the rectum) was collected, gently washed with PBS, and then immediately imaged. Fluorescent signal intensity was measured using an IVIS SpectrumCT In Vivo Imaging System (PerkinElmer, MA, US). DiR fluorescent signal (excitation 754 nm, emission 778 nm) was detected in the distal portion of the dissected colon at three time points after gel injection. Untreated control mice (n = 3) were included in each measurement. Acquired images were analyzed using Living Image® software (PerkinElmer, MA, US). The background (untreated tissue sample) was measured for each time point. The resulting signal was analyzed as radiant efficiency (RE), a calibrated unit that compensates for device settings and non-uniform light excitation patterns. Example 1 TIF gel preparation

[0392] MLO was used as the lipid component of the mesophase and mixed with TOFA (5% w / w; 5 mg / 100 mg) or TAC (1% w / w; 1 mg / 100 mg). Lipid / drug mixtures were prepared by dissolving appropriate amounts of lipid and drug stock solutions together in ethanol. The solvent was then completely removed under reduced pressure (freeze-dried at 0.22 mbar for 24 hours), and the dried lipid mixture was hydrated by mixing with a measured amount of water (16% w / w) in a sealed Pyrex tube and centrifuged (10 min, 5000 g) several times at room temperature until a homogeneous mixture was obtained. The mesophase was then equilibrated in the dark at room temperature for 48 hours. The final TOFA-loaded TIF gel composition contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 5% TOFA by weight of the composition. The final TAC-loaded TIF gel composition contained a) a1) water in an amount of 16% by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) TAC in an amount of 1% by weight of the composition. The resulting TOFA concentration was 5 mg / 100 mg of composition. The resulting TAC concentration was 1 mg / 100 mg of composition. For in vivo studies, after 48 hours of equilibration (as described above), the formulation was drawn into a 1 mL syringe (Injekt-F, Braun), and the dead volume of an animal feeding needle (20G, L x 1.5 inches diameter x 1.9 mm) for rectal administration was calculated so that exactly 100 μL was applied. Example 2 Physicochemical characterization of TAC- and TOFA-loaded TIF gels

[0393] At 25 °C, in the presence of a low percentage of water, MLO forms a lamellar (L) phase with lower structural strength relative to the cubic (Q) phase, resulting in a formulation that is easier to administer and can treat remote tissue regions, as depicted in Figure 2 A. When applied rectally, the precursor L phase gradually absorbs heat (and available amounts of water) from the body and rapidly (<5 min) transforms into a cubic phase, contributing to the formation of an in situ depot that locally releases the incorporated drug in a sustained manner.

[0394] First, small-angle X-ray scattering (SAXS) measurements were used to determine the optimal amount of water required to obtain a lamellar phase that provides a cubic transition at 38 °C (Figures 2B and 2C). An X-ray beam directed at the gel results in a scattering pattern with a set of maxima, which correspond to sharp Bragg reflections characteristic of long-range positional order. The arrangement of the Bragg reflections (and their ratios; listed in Figure 2A) identifies the symmetry of the mesophase studied (see also Figures 1A and 1B).

[0395] As shown in Figures 2B and 2C, with 12% water, Bragg reflections characteristic of the L phase were present at 25 °C and 38 °C. Hydrating MLO with 14% water resulted in a lamellar structure at 25 °C and the coexistence of L and Q structures (with Ia3d morphology) at 38 °C, whereas increasing the amount of water up to 18% w / w induced the L → Q transition already at 30 °C. On the other hand, a mesophase composed of 16% w / w water and 84% w / w MLO gave Bragg reflections characteristic of a lamellar structure at 25 °C and a transition to the Q structure (with Ia3d morphology) at 38 °C, i.e., rectal temperature.

[0396] The reflection features of this L phase adopt those of the Q phase after only 5 min of incubation at 38 °C (Figure 2D), indicating a fast transformation of the lamellar precursor into an Ia3d cubic structure, particularly suitable for rectal administration. The transition is reversible when the temperature is returned to 25 °C (Figure 2H). While this information is not clear for rectal application itself, it is an important property for the storage conditions of the TIF gel.

[0397] The diverse topologies of the mesophase were confirmed by distinct viscoelastic regions identified by rheological (frequency sweep) measurements. Specifically, the precursor L phase, relative to the viscoelastic Q phase, had lower structural strength, as indicated by lower storage modulus values ​​and decreased modulus (G' and G'', respectively), resulting in a less viscous pseudoplastic gel characterized by a broad energy dissipation mechanism associated with parallel slip of lamellae. Under simulated administration conditions, increasing temperature and water availability resulted in structural swelling corresponding to the Q phase transition (when both G' and G'' are higher than those obtained in the L phase; Figure 2E). Furthermore, either the flow point or yield point (both representing the shear limit above which the material begins to behave like a fluid) clearly determined the differences between our low-viscosity lamellar precursor and the highly viscoelastic cubic gel, and they may identify the upper threshold above which the formulation becomes too elastic for rectal application (Figure 2G). Because lamellae sliding can occur along any possible direction, low shear must be applied to this gel so that it begins to behave like a fluid and can easily pass through an enema cannula, syringe, or colonic pipe. This results in a low-viscosity material with low structural strength that is easy to administer compared to fully hydrated cubic gels, thanks to its high flow and yield points (Figure 2I).

[0398] To verify the appearance of the expected transition, a series of SAXS experiments were performed after immersing the gel in 1 mL of HEPES (or, alternatively, a buffer containing lipase) and incubating it at 38 °C for 8 h. As shown in Figure 2F, the L phase was present at the beginning of the release experiment at 25 °C, which absorbed heat (and water) during the release experiment, and at its maximum hydration level, it had a lattice constant (a = 8.7 nm) and water channels (d) comparable to those obtained for the Pn3m phase. w = 4 nm) to reach a cubic (pn3m) phase (43). These transitions were also confirmed in vivo, where gels excreted and collected with the feces 30 min after rectal administration had the identity of the Ia3d phase, whereas the residual gel present in the colon 6 h later was determined to be the pn3m cubic phase (Figure 2J).

[0399] The presence of lipase (1000 U / mL) hydrolyzed the ester groups of MLO and induced a Q → hexagonal phase (H) transition, the latter not associated with any burst release phenomenon (Figure 3). Based on this initial pivotal characterization, we selected a formulation of 84% MLO and 16% water for subsequent in vitro and in vivo studies, which had suitable rheological properties to pass through a small-diameter animal feeding needle (size 20G), which further expanded into a sponge-like system upon rectal injection. Example 3 TOFA and TAC encapsulation and release from TIF gels

[0400] To evaluate the effect of guest drugs on phase identity, TOFA- or TAC-loaded mesophases were prepared and analyzed by SAXS. The TOFA-loaded mesophase compositions contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 5% TOFA by weight of the composition. The TAC-loaded mesophase compositions contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 1% TAC by weight of the composition. Notably, drug incorporation (5 mg TOFA and 1 mg TAC in 100 mg of gel—5 or 1% w / w, respectively) (Figures 3A and 3D) did not affect the phase identity or thermal behavior of the carrier gels; rectal temperature still induced an L→Q phase transition. Both drugs could be encapsulated in the TIF gels with 100% encapsulation efficiency. Furthermore, neither drug formed crystals once embedded in the 3D gel structure, as evidenced by the absence of reflections associated with drug crystals in the wide-angle X-ray scattering (WAXS) spectra at high q (Figure 3H). The drugs were also uniformly distributed throughout the gel matrix (Figure 3H).

[0401] Upon hydration with water, the lipid / drug mixture forms a lamellar structure of the drug, and the entire drug becomes embedded in the gel. For in vitro release experiments, the drug-loaded TIF gel formulation was placed in the donor chamber of a vertical diffusion cell (as depicted in Figure 3G) and kept separated from the acceptor chamber by a polycarbonate membrane with a 3 μm pore diameter that allowed only the free drug to pass through.

[0402] In contrast to the small intestine, where different in vitro models have been established, only animal models are available for the rectum, and most have been used in preclinical studies. Therefore, to circumvent this limitation, we used an ex vivo approach to study the diffusion time of drugs from gels across the rectal epithelium. Isolated tissue from healthy rat rectums was used as a natural membrane, and the amount of drug that diffused into the acceptor chamber was quantified. The 3D gel network reduced the release rate of TOFA (a hydrophilic drug) in either an in vitro or ex vivo setting (Figures 3B and 3C, respectively). The same set of experiments was also performed on TAC-loaded gels. Furthermore, in this case, the gels were able to retain the drug and slowly release it in both in vitro and ex vivo experiments (Figures 3E and 3F, respectively).

[0403] Notably, the presence of lipase in our experimental conditions was consistent with previous studies reported for IT-hydrogel, another lipid-based gel developed for the topical treatment of UC. 41The enzyme did not induce gel degradation, resulting in a burst release of the drug. While the enzyme induced a responsive release in the IT-hydrogel only after 24 h (+20% of the drug was released), TAC and TOFA were released from our TIF gels within only 8 h, a time frame more compatible with the retention time of rectally administered dosage forms. The structure-control effectiveness index (SCEI) provides an estimate of the kinetics of drug release for various phases. However, the phase identity of the gels described herein dynamically changes during release experiments. Therefore, the SCEI cannot be used to describe the release profile. In fact, hydrophobic drugs do not follow a Fickian diffusion profile, and therefore, the release profile cannot be modeled using the Higuchi equation. We did not observe any gel erosion (weight loss was not recorded in in vitro or ex vivo experiments), and therefore, we can reject the hypothesis that the release process is driven by gel dissolution. Interestingly, 10 mg of drug (10% w / w of both TOFA and TAC) did not affect the phase identity and transition temperature of the gel, which gave a lamellar phase at room temperature and a cubic (Ia3d) phase at 38°C (see Figures 1A and 1B). This demonstrates that administration of a low volume of TIF gel was able to deliver a high amount of drug while reducing the urgency associated with high application volumes. Example 4 Release of clotrimazole, budesonide, and mesalamine from TIF gels Drug-loaded TIF gel formulations and free drug formulations were prepared according to the method described above: "Release Experiments of Clotrimazole, Budesonide, and Mesalamine: In Vitro Setup and HPLC Drug Quantification." Upon hydration with water, the lipid / drug mixture formed a lamellar structure, embedding the entire drug within the gel. For in vitro release experiments, the drug-loaded TIF gel formulation was placed in the donor chamber of a vertical diffusion cell, separated from the acceptor chamber by a polycarbonate membrane with a 3 μm pore diameter, allowing only the free drug to pass through. The 3D gel network reduced the release rates of all free drugs used, as shown in Figures 4A, 4B, and 4C. Example 5 Effect of TOFA / TIF gel on dextran sulfate sodium (DSS)-induced acute colitis

[0404] To test the gel's potential effectiveness in treating acute UC flare-ups, we applied a TOFA-loaded TIF gel to a mouse model of acute colitis induced by dextran sulfate sodium (DSS). The TOFA-loaded TIF gel contained a) 16% water by weight of the carrier; and b) 84% MLO by weight of the carrier; and c) 5% TOFA by weight of the composition. DSS is toxic to epithelial cells, and its application compromises the integrity of the intestinal barrier, thereby leading to the activation of submucosal immune cells by gut microbes. Throughout the experiment, we demonstrated that twice-daily application of the gel resulted in robust relief of local and systemic inflammation.

[0405] Mice treated with this TIF gel-TOFA regimen showed reduced weight loss and disease severity compared to mice treated with empty TIF gel (Figures 5A and 5B). In contrast, drug (TOFA) in vehicle solution improved weight loss but not disease scores in these mice (Figure 5B). Notably, daily application of the compound did not produce robust results, and the difference between free TOFA and TIF gel-TOFA was less evident under this regimen.

[0406] Signs of systemic inflammation, as determined by spleen size and cellularity, were also alleviated in these mice treated twice daily with TIF gel-TOFA (Figures 5C and 5D). Furthermore, local pro-inflammatory cytokine levels were reduced in TOFA- and TIF gel-TOFA-treated mice, while anti-inflammatory IL-10 levels were increased only in the TIF gel-TOFA group (Figure 5E). Local inflammation was also alleviated by TIF gel-TOFA, as determined by reductions in colon shortening and pathology (Figures 5F, 5G, and 5H). TIF gel-TOFA was more effective than the drug in vehicle for colon shortening, but not for histopathology. No differences were detectable in immune cell populations in the spleen or mesenteric lymph nodes of the different treatment groups. Overall, these data indicate that locally applied, temperature-dependent, in situ-forming gels with TOFA represent a valuable tool for alleviating acute intestinal inflammation. Example 6 Effect of TAC / TIF gel on T cell transfer colitis

[0407] TIF gels act as platforms capable of accommodating and releasing molecules with different polarities. Therefore, hydrophobic TAC was loaded into TIF gels, and its ability to reduce the severity of colitis was also evaluated using a model of T cell-mediated colitis, i.e., T cell transfer colitis. The TAC-loaded TIF gels contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 1% TAC by weight of the composition. In this model, naive T cells were induced by B- and T cell-deficient Rag colonies. - / - Rag is transferred into recipient mice, which leads to the development of T cells that react to luminal antigens and subsequent intense colonic inflammation. - / -Three days after naive T cell transfer into the host, mice were treated daily via rectal infusion with 100 μL of i) TAC-loaded TIF gel (TIG-gel-TAC), ii) empty TIF gel (TIF-gel), or iii) TAC in vehicle solution (TAC) (Figure 6A). Monitoring of weight change and disease activity demonstrated that mice receiving empty TIF gel or TAC in vehicle solution began to develop the first signs of colitis approximately 10 days after T cell transfer, evidenced by progressive weight loss and signs of diarrhea (Figures 6B and 6C). Notably, mice treated with TAC-loaded TIF gel did not lose weight, and diarrhea scores were lower than those in the other two groups (Figures 6B and 6C). On day 19 after T cell administration, all mice underwent colonoscopy to assess macroscopic signs of colitis, were sacrificed, and colon tissues were collected for histological and molecular analysis of colitis severity. Interestingly, TAC administration via TIF gel and in vehicle reduced endoscopic signs of colitis. There was a clear trend toward a further reduction in endoscopic scores in mice receiving TAC in TIF gel, but this was not significant (Figure 6D). In contrast, however, consistent with disease activity scores, mice receiving TAC in TIF gel did not show a clear reduction in colitis severity compared to mice treated with empty TIF gel, nor compared to mice receiving TAC in vehicle solution (Figure 6D). Notably, all mice receiving TAC (administered in TIF gel or vehicle) showed longer colon and reduced spleen weights (Figure 6E), indicating reduced disease in these two groups compared to mice treated with empty TIF gel. Taken together, these data clearly demonstrate that administration of TAC via TIF gel is superior to administration of TAC in vehicle in reducing the severity of colitis.

[0408] Transfusion-induced colitis is primarily mediated by abnormally activated helper T cells, particularly IFN-γ (Th1) and IL-17 (Th17) CD4 T cells, which contribute to the disease. To test the effects of TAC administration either in vehicle or TIF gel, we analyzed the proportion of helper T cells in the colonic lamina propria (Figure 7A), mesenteric lymph nodes (Figure 7B), and spleen (Figure 7C). Notably, both TAC administrations reduced the relative abundance of T cells in the lamina propria, mesenteric lymph nodes, and spleen (Figures 7A-7C). Among helper T cells, Th1 and Th17 cells were reduced by TAC in vehicle and TAC-loaded TIF gel compared to mice receiving only empty TIF gel (Figure 7). Although there was no difference in Th1 cells between mice receiving TAC in vehicle and mice receiving TAC in TIF gel, the reduction in Th17 cells was significantly more pronounced in mice receiving TAC in TIF gel than in mice receiving TAC in vehicle (Figure 7). In general, there was no significant effect on the abundance of FOXP3+ (regulatory) T cells (Figure 7). These findings were also reflected in cytokine measurements in colonic tissue (Figure 7D), which found reduced levels of IFN-γ and IL-17 in mice treated with free drug. TIF gel-TAC further reduced the levels of these two cytokines and, in addition, significantly reduced TNF-α levels (Figure 7D), indicating that TIF gel-TAC was more effective at reducing the production of pro-inflammatory cytokines than free drug alone. In summary, these results indicate that administration of TAC in TIF gel is superior in reducing disease-promoting helper T cells in the setting of T cell-induced colitis. Example 7 Stability study of TAC and TOFA loaded TIF gels

[0409] TAC- and TOFA-loaded TIF gels were prepared according to Example 1. Briefly, the final TOFA-loaded TIF gel composition contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 5% TOFA by weight of the composition. The TAC-loaded TIF gel composition contained a) a1) 16% water by weight of the carrier; and a2) a carrier containing MLO in an amount of 84% by weight of the carrier; and b) 1% TAC by weight of the composition. The long-term stability of TOFA-loaded gels and TAC-loaded gels of the present invention was monitored over a period of one month at 4°C and 25°C. At specified time points, aliquots of the formulations were analyzed by HPLC, and the drug content was recorded. Data are expressed as a relative percentage to day 0.

[0410] As can be seen in Figure 8, both TOFA (Figure 8A) and TAC (Figure 8B) loaded gels appeared stable at both 4°C and 25°C over a period of one month. Example 8 Rectal drug delivery via TIF gel reduces systemic drug exposure

[0411] To demonstrate that rectal TIF gel application was indeed suitable for minimizing systemic drug release, drug release was analyzed in vivo by monitoring drug plasma levels in mice over time after colonic TIF gel enema. To this end, healthy mice received a single enema of either drug-loaded TIF gel (TIF gel-TOFA or TIF gel-TAC) or free drug (TOFA or TAC), and plasma drug concentrations were measured at different time points (Figure 9A). Mice receiving free TOFA had an early peak in plasma concentration at 0.25 h (Figure 9B); TOFA plasma levels subsequently declined rapidly, following first-order kinetics. In mice receiving TIF gel-TOFA, the peak concentration at 0.25 h was significantly lower. The area under the curve (AUC), a measure of cumulative systemic drug absorption, was also significantly reduced in mice treated with TIF gel-TOFA compared with the group treated with free TOFA (Figure 9D). Administration of TAC either as free drug or as drug-loaded gel resulted in low (and negligible) systemic drug circulation (FIG. 9C), and no difference was detected in their AUC (FIG. 9E). Example 9 Assessment of TIF gel adhesion to the colon wall At 25°C, in the presence of 16% w / w water, MLO forms an L phase with low structural strength, resulting in a formulation that is easy to apply and can reach more remote areas of the colon. On the other hand, the pseudoplastic precursor has a higher viscosity than commercially available enemas, such as Asacol® and Pentasa®, and 5-ASA and budesonide-containing foams. Therefore, once applied, the TIF gel remains for at least 6 hours, the time necessary to adhere to healthy colon tissue and avoid material loss (see Figure 10). Additional Embodiments

[0412] The present invention is further illustrated by the following numbered embodiments:

[0413] 1.a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents A composition comprising: the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C, Preferably, the composition wherein the lipid is monolinolein.

[0414] 2. The composition of embodiment 1, wherein the carrier comprises 14% to 18% water, where % is by weight of the carrier.

[0415] 3. The composition of embodiment 2, wherein the carrier comprises 16% water, the % being by weight of the carrier.

[0416] 4. The composition of any one of embodiments 1 to 3, wherein the carrier comprises 80% to 90% lipid, the % being the % by weight of the carrier.

[0417] 5. The composition of embodiment 4, wherein the carrier comprises 84% ​​monolinolein, where % is by weight of the carrier.

[0418] 6. The composition of any one of embodiments 1 to 5, comprising the pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition.

[0419] 7. The composition of embodiment 6, comprising 1% to 5% of the pharmaceutically active agent by weight of the composition.

[0420] 8. The composition of any one of embodiments 1-7, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent.

[0421] 9. The pharmaceutically active agent is selected from the group consisting of AbGn168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol, CP-690,550, corticosteroids (e.g., Multimax budesonide, methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC 1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tacrolimus, Janus kinase inhibitors (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressants (e.g., rapamycin), antifibrotic agents (e.g., pirfenidone, nintedanib), and antifungal agents (e.g., clotrimazole, fluconazole).

[0422] 10. The composition of embodiment 9, wherein the pharmaceutically active agent is tofacitinib or a pharmaceutically acceptable salt thereof.

[0423] 11. The composition of embodiment 9, wherein the pharmaceutically active agent is tacrolimus.

[0424] 12. The composition of any one of embodiments 1 to 11, having a lamellar phase structure at 25°C, preferably being a lamellar gel at 25°C.

[0425] 13. The composition of any one of embodiments 1 to 11, which forms a lipid cubic phase at a temperature of about 38°C.

[0426] 14. The composition of any one of embodiments 1 to 13, further comprising an additive.

[0427] 15. The composition of any one of embodiments 1-14, which is substantially free of organic solvents.

[0428] 16.25℃ and 0.01s -1 Measured in 1 x 10 6 ~1×10 7 16. The composition of any one of embodiments 1-15, having a zero shear viscosity of mPa·s.

[0429] 17. The composition of any one of embodiments 1 to 16, which is an injectable formulation.

[0430] 18. The composition according to embodiment 17, wherein the injectable formulation is a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation.

[0431] 19. The composition of any one of embodiments 1 to 16, which is a topical formulation.

[0432] 20. The composition of embodiment 19, wherein the topical formulation is an enema.

[0433] 21. The composition of any one of embodiments 17 to 20, wherein the formulation forms a bioadhesive controlled release depot at a temperature of 36°C to 39°C.

[0434] 22. The composition according to any one of embodiments 1 to 21, for use as a medicament.

[0435] 23. The composition of any one of embodiments 1-21, for use in treating a condition of the lower gastrointestinal tract.

[0436] 24. The composition for use of embodiment 23, wherein the condition is selected from the group consisting of inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colon polyps, proctitis, radiation-associated colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagen colitis, colorectal cancer and adenocarcinoma, IBD-associated perianal fistulas, vaginal fistulas, intestinal fibrosis, and fungal colon infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis).

[0437] 25. The composition for use according to embodiment 24, wherein the condition is ulcerative colitis.

[0438] 26. The composition for use according to embodiment 25, wherein the ulcerative colitis is mild ulcerative colitis, moderate ulcerative colitis, severe ulcerative colitis, active ulcerative colitis, left-sided colitis, extensive colitis or ulcerative proctitis.

[0439] 27. A composition according to any one of embodiments 1-16 or 19-21 for use in treating a condition affecting the colon, wherein the composition is applied topically to the colon of a subject.

[0440] 28. The composition for use according to embodiment 27, wherein the condition is selected from inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis and colorectal cancer, IBD-associated perianal fistulas, vaginal fistulas, intestinal fibrosis, and fungal colon infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis).

[0441] 29. The composition for use according to embodiment 28, wherein the condition is ulcerative colitis.

[0442] 30. The composition for use according to embodiment 29, wherein the ulcerative colitis is mild ulcerative colitis, moderate ulcerative colitis, severe ulcerative colitis, active ulcerative colitis, left-sided colitis, extensive colitis or ulcerative proctitis.

[0443] 31. The composition for use according to any one of embodiments 27 to 30, which is administered rectally, preferably as an enema.

[0444] 32. A composition for use according to any one of embodiments 27 to 31, which forms a controlled release depot in situ after administration to a subject.

[0445] 33. Use of a formulation comprising 10% w / w to more than 30% w / w of water and 70% w / w to 90% w / w of lipids as a carrier for a pharmaceutically active agent, The use wherein the lipid is selected from monolinolein or monoolein.

[0446] 34. The use according to embodiment 33, wherein the pharmaceutically active agent is dispersed or dissolved in a carrier.

[0447] 35. The use of embodiment 33 or embodiment 34, wherein the carrier provides a controlled release of the pharmaceutically active agent at a temperature of 36°C to 39°C.

[0448] 36. The use according to any one of embodiments 33 to 35, wherein the carrier forms a controlled release depot for the pharmaceutically active agent at a temperature of 36°C to 39°C.

[0449] 36. The use of any one of embodiments 33-36, wherein the carrier is administered as an enema.

[0450] 37. Use of a preformulation composition comprising a lipid and a pharmaceutically active agent for the manufacture of a composition according to any one of embodiments 1 to 21, The use wherein the lipid is selected from monolinolein or monoolein.

[0451] 38. The use according to embodiment 37, wherein the preformulation composition is a lyophilized mixture.

[0452] 39. A method of making a composition according to any one of embodiments 1 to 21, comprising: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition Including, The method wherein the lipid is selected from monolinolein or monoolein.

[0453] 40. The method of embodiment 39, wherein the mixture in step a) is a freeze-dried mixture.

[0454] 41. The freeze-dried mixture is i) dissolving a lipid and a pharmaceutically active agent in an organic solvent; and ii) freeze-drying the mixture of i) to provide a freeze-dried mixture. 41. The method of embodiment 40, wherein the method is obtained by

[0455] 42. The method of embodiment 41, wherein in step i) the organic solvent is selected from ethanol or methanol, preferably the organic solvent is ethanol.

[0456] 43. A method of making a composition according to any one of embodiments 1 to 21, comprising: a) dissolving a pharmaceutically active agent in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition Including, The method wherein the lipid is selected from monolinolein or monoolein.

[0457] 44. The method of embodiment 43, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0458] 45. a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition of any one of embodiments 1-21. A kit comprising: The kit, wherein the lipid is selected from monolinolein or monoolein.

[0459] 46. ​​The kit of embodiment 45, further comprising a second container, wherein the second container comprises water.

[0460] 47. The kit of embodiment 45 or embodiment 46, wherein the lipid and the pharmaceutically active agent in the first container are provided as a lyophilized mixture.

[0461] 48. a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide a composition according to any one of embodiments 1 to 21. A kit comprising: The kit, wherein the lipid is selected from monolinolein or monoolein.

[0462] 49. The kit of embodiment 48, further comprising a second container, the second container comprising a pharmaceutically active agent dissolved in water.

[0463] 50. The kit of embodiment 48 or embodiment 49, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0464] The present invention is further illustrated by the following numbered embodiments:

[0465] P1.a) a1) water in an amount greater than 10% to 30% by weight of the carrier; and a2) 70% to 90% by weight of lipids in the carrier a carrier comprising: b) pharmaceutically active agents A composition comprising: the lipid is selected from monolinolein or monoolein; The composition forms a lipid cubic phase at a temperature of 36°C to 39°C, Preferably, the lipid is monolinolein.

[0466] P2. The carrier contains 14% to 18% water, where % is the weight of the carrier; Optionally, the composition of embodiment P1, wherein the carrier comprises 16% water, wherein the % is by weight of the carrier.

[0467] P3. The carrier comprises 80% to 90% lipid, where % is the weight percent of the carrier; Optionally, the composition of embodiment P1 or embodiment P2, wherein the carrier comprises 84% ​​monolinolein, where % is by weight of the carrier.

[0468] P4. The composition comprises a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition; Optionally, the composition comprises 1% to 5% by weight of the composition of a pharmaceutically active agent; Further optionally, the composition of any one of embodiments P1 to P3, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent.

[0469] P5. The pharmaceutically active agent is selected from the group consisting of AbGn168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol, CP-690,550, corticosteroids (e.g., Multimax budesonide, methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC 1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tacrolimus, Janus kinase inhibitors (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressants (e.g., rapamycin), antifibrotic agents (e.g., pirfenidone, nintedanib), and antifungal agents (e.g., clotrimazole, fluconazole); Optionally, the pharmaceutically active agent is (i) tofacitinib or a pharmaceutically acceptable salt thereof; or (ii) tacrolimus The composition of any one of embodiments P1 to P4, wherein

[0470] P6.(i) the composition has a lamellar phase structure at 25°C, preferably the composition is a lamellar gel at 25°C; and / or (ii) the composition forms a lipid cubic phase at a temperature of about 38°C; and / or (iii) further comprising an additive; and / or (iv) substantially free of organic solvents; and / or (v) 25°C and 0.01 s -1 Measured in 1 x 10 6 ~1×10 7The composition of any one of embodiments P1-P5, having a zero shear viscosity of mPa·s.

[0471] P7. The composition is (i) an injectable formulation, Optionally, the injectable formulation is a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation; or (ii) a topical formulation; Optionally, the topical formulation is an enema; and / or (iii) The composition of any one of embodiments P1 to P6, which forms a bioadhesive controlled release depot at a temperature of 36°C to 39°C.

[0472] P8. The composition of any one of embodiments P1-P7 for use as a medicament.

[0473] P9. The composition of any one of embodiments P1-P7 for use in treating a lower gastrointestinal condition, Optionally, the condition is selected from the group consisting of inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colon polyps, proctitis, radiation-associated colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagen colitis, colorectal cancer and adenocarcinoma, IBD-associated perianal fistulas, vaginal fistulas, intestinal fibrosis, and fungal colon infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis); Further optionally, the condition is ulcerative colitis, for example, the ulcerative colitis is selected from mild ulcerative colitis, moderate ulcerative colitis, severe ulcerative colitis, active ulcerative colitis, left-sided colitis, extensive colitis, and ulcerative proctitis.

[0474] P10. The composition of any one of embodiments P1-P7 for use in treating a condition affecting the colon, wherein the composition is applied topically to the colon and / or rectum of a subject; Optionally, the condition is selected from inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis and colorectal cancer, IBD-related perianal fistulas, vaginal fistulas, intestinal fibrosis, and fungal colon infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis); Further optionally, the condition is ulcerative colitis, for example, the ulcerative colitis is selected from mild ulcerative colitis, moderate ulcerative colitis, severe ulcerative colitis, active ulcerative colitis, left-sided colitis, extensive colitis, and ulcerative proctitis.

[0475] P11. The composition is administered rectally, and optionally: (i) the composition is administered as an enema; and / or (ii) the composition forms a controlled-release depot in situ after administration to a subject; A composition for use according to embodiment P9 or embodiment P10.

[0476] P12. Use of a formulation comprising 10% w / w to more than 30% w / w of water and 70% w / w to 90% w / w of lipids as a carrier for a pharmaceutically active agent, the lipid is selected from monolinolein or monoolein; as needed, (i) the pharmaceutically active agent is dispersed or dissolved in a carrier; and / or (ii) the carrier provides controlled release of the pharmaceutically active agent at a temperature between 36°C and 39°C; and / or (iii) the carrier forms a controlled-release depot for the pharmaceutically active agent at a temperature of 36°C to 39°C; and / or (iv) The use wherein the carrier is administered as an enema.

[0477] P13. Use of a preformulation composition comprising a lipid and a pharmaceutically active agent for the manufacture of a composition according to any one of embodiments P1 to P7, the lipid is selected from monolinolein or monoolein; Optionally, the preformulation composition is a lyophilized mixture.

[0478] P14. Method A or Method B: Method A: A method of making a composition according to any one of embodiments P1 to P7, comprising: a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrating the lipid-drug mixture to provide a composition Including, the lipid is selected from monolinolein or monoolein; as needed, A1) the mixture in step a) is a freeze-dried mixture; and / or A2) The freeze-dried mixture is i) dissolving a lipid and a pharmaceutically active agent in an organic solvent; and ii) freeze-drying the mixture of i) to provide a freeze-dried mixture. obtained by; and / or A3) A process wherein in step i) the organic solvent is selected from ethanol or methanol, preferably the organic solvent is ethanol; or Method B: A method of making a composition according to any one of embodiments P1 to P7, comprising: a) dissolving a pharmaceutically active agent in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide a composition Including, the lipid is selected from monolinolein or monoolein; Optionally, the method wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0479] P15. Kit A or Kit B: Kit A: a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition according to any one of embodiments P1-P7. A kit comprising: the lipid is selected from monolinolein or monoolein; Optionally, the kit further comprises a second container, the second container comprising water; Further optionally, the kit wherein the lipid and the pharmaceutically active agent in the first container are provided as a lyophilized mixture; or Kit B: a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide a composition according to any one of embodiments P1 to P7. A kit comprising: the lipid is selected from monolinolein or monoolein; Optionally, the kit further comprises a second container, the second container comprising a pharmaceutically active agent dissolved in water; Further optionally, the kit, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. [ka] [ka] [ka]

Claims

1. 1. A composition for use in the treatment of a lower gastrointestinal tract condition, said composition comprising: a) a1) water in an amount of 10% to greater than 30% by weight of the carrier; and a2) monoacylglycerol lipids comprising monolinolein or monoolein, or a combination thereof, in an amount of 70% to 90% by weight of the carrier; a carrier comprising: b) Pharmaceutically Active Agents Including, the composition forms a lipid cubic phase at a temperature of 36°C to 39°C; the composition is administered rectally; Preferably, the composition wherein the monoacylglycerol lipid is monolinolein.

2. the carrier comprises 14% to 18% water, said % being by weight of the carrier; 2. A composition for use according to claim 1, wherein the carrier optionally comprises 16% water, said percentages being by weight of the carrier.

3. the carrier comprises 80% to 90% monoacylglycerol lipid, said % being by weight of the carrier; 3. A composition for use according to claim 1 or claim 2, wherein the carrier optionally comprises 84% ​​monolinolein, said percentage being the percentage by weight of the carrier.

4. the composition comprises the pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition; Optionally, the composition comprises 1% to 5% of the pharmaceutically active agent by weight of the composition; The composition for use according to any one of claims 1 to 3, further optionally wherein the pharmaceutically active agent is a hydrophilic or hydrophobic pharmaceutically active agent.

5. the pharmaceutically active agent is selected from the group consisting of a biological agent (e.g., an anti-TNF antibody, an IL-23 inhibitor, an IL-12 inhibitor, a TLR9 agonist, an anti-MAdCAM antibody, a human IL-22Fc fusion protein, an interleukin, an anti-β7 integrin antibody, a matrix metalloproteinase 9 (MMP9) inhibitor), a JAK inhibitor, a PDE4 inhibitor, a sphingosine-1-phosphate receptor modulator, an anti-inflammatory agent, a corticosteroid, an immunosuppressant, an antifungal agent, an antibiotic, an antifibrotic agent, and an anti-cancer agent; Optionally, the pharmaceutically active agent is (i) ABT-494, ABX464, apremilast, 6-mercaptopurine, azathioprine, CP-690,550, Multimax budesonide, methylprednisolone, cyclosporine, E6007, etrasimod, filgotinib, IMU-838, mesalamine, RPC 1063, sulfasalazine, TD-1473, TJ301, tacrolimus, tofacitinib, rapamycin, pirfenidone, nintedanib, clotrimazole, and fluconazole; and / or (ii) AbGn168H, PF-00547659, PF-06687234, adalimumab, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol, etrolizumab, guselkumab, golimumab, IL-2, infliximab, GS-5745, mirikizumab (LY3074828), risankizumab (BI 6555066), SHP647, tildrakizumab (MK 3222), ustekinumab, UTTR1147A, and vedolizumab is selected from the group consisting of Further optionally, the pharmaceutically active agent is (a) tofacitinib or a pharmaceutically acceptable salt thereof; or (b) tacrolimus The composition for use according to any one of claims 1 to 4, wherein

6. (i) the composition has a lamellar phase structure at 25°C, preferably the composition is a lamellar gel at 25°C; and / or (ii) the composition forms a lipid cubic phase at a temperature of about 38°C; and / or (iii) the composition further comprises an additive; and / or (iv) the composition is substantially free of organic solvents; and / or (v) the composition is heated at 25°C and 0.01 s －１ Measured at 1 x 10 ６ ~1 x 10 ７ 6. The composition for use according to any one of claims 1 to 5, having a zero shear viscosity of mPa·s.

7. The composition comprises: (i) administered as an enema; and / or (ii) A composition for use according to any one of claims 1 to 6, which forms a bioadhesive controlled release depot at a temperature of 36°C to 39°C.

8. the condition is selected from the group consisting of inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colonic polyps, proctitis, radiation-associated colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis, colorectal cancer and adenocarcinoma, IBD-associated perianal fistulas, vaginal fistulas, intestinal fibrosis, and fungal colon infections (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis); 8. The composition for use according to any one of claims 1 to 7, wherein optionally the condition is ulcerative colitis, for example the ulcerative colitis is selected from mild ulcerative colitis, moderate ulcerative colitis, severe ulcerative colitis, active ulcerative colitis, left-sided colitis, extensive colitis and ulcerative proctitis.

9. a) a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 82% to 86% by weight of the carrier, containing at least 50% by weight of monolinolein a carrier comprising: b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition A composition comprising: The composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

10. (i) the composition comprises 16% water, said % being by weight of the carrier; and / or (ii) The composition of claim 9, wherein the composition is substantially free of other lipids.

11. (i) the composition comprises 1% to 5% of the pharmaceutically active agent by weight of the composition; Optionally, the pharmaceutically active agent is a hydrophilic or hydrophobic pharmaceutically active agent; and / or (ii) the pharmaceutically active agent is selected from the group consisting of a biological agent (e.g., an anti-TNF antibody, an IL-23 inhibitor, an IL-12 inhibitor, a TLR9 agonist, an anti-MAdCAM antibody, a human IL-22Fc fusion protein, an interleukin, an anti-β7 integrin antibody, a matrix metalloproteinase 9 (MMP9) inhibitor), a JAK inhibitor, a PDE4 inhibitor, a sphingosine-1-phosphate receptor modulator, an anti-inflammatory agent, a corticosteroid, an immunosuppressant, an antifungal agent, an antibiotic, an antifibrotic agent, and an anti-cancer agent; Optionally, the pharmaceutically active agent is (I) ABT-494, ABX464, apremilast, 6-mercaptopurine, azathioprine, CP-690,550, Multimax budesonide, methylprednisolone, cyclosporine, E6007, etrasimod, filgotinib, IMU-838, mesalamine, RPC 1063, sulfasalazine, TD-1473, TJ301, tacrolimus, tofacitinib, rapamycin, pirfenidone, nintedanib, clotrimazole, and fluconazole; and / or (II) AbGn168H, PF-00547659, PF-06687234, adalimumab, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol, etrolizumab, guselkumab, golimumab, IL-2, infliximab, GS-5745, mirikizumab (LY3074828), risankizumab (BI 6555066), SHP647, tildrakizumab (MK 3222), ustekinumab, UTTR1147A, and vedolizumab. is selected from the group consisting of Further optionally, the pharmaceutically active agent is (a) tofacitinib or a pharmaceutically acceptable salt thereof; or (b) tacrolimus The composition according to claim 9 or claim 10, wherein

12. The composition comprises: (i) an injectable formulation; Optionally, the injectable formulation is a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation; or (ii) a topical formulation; Optionally, the topical formulation is an enema; and / or (iii) A composition according to any one of claims 9 to 11, which forms a bioadhesive controlled release depot at a temperature of 36°C to 39°C.

13. 13. Use of a preformulation composition comprising the monoacylglycerol lipid and the pharmaceutically active agent for the manufacture of a composition according to any one of claims 9 to 12, comprising: Optionally, the preformulation composition is a lyophilized mixture.

14. A method selected from Method A, Method B, or Method C: Method A: A method for making a composition for use according to any one of claims 1 to 8 or a composition according to any one of claims 9 to 12, comprising: a) hydrating a mixture comprising the lipid and the pharmaceutically active agent with water to provide a lipid-drug mixture; and b) equilibrating the lipid-drug mixture to provide the composition Including, as needed, A1) the mixture in step a) is a freeze-dried mixture; and / or A2) The freeze-dried mixture is i) dissolving the lipid and the pharmaceutically active agent in an organic solvent; and ii) freeze-drying the mixture of i) to provide the freeze-dried mixture. obtained by; and / or A3) a method wherein in step i) the organic solvent is selected from ethanol or methanol, preferably the organic solvent is ethanol; or Method B: A method for making a composition for use according to any one of claims 1 to 8 or a composition according to any one of claims 9 to 12, comprising the steps of: a) dissolving the pharmaceutically active agent in water to provide a drug mixture; b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrating the lipid-drug mixture to provide the composition Including, optionally, a method wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent; or Method C: A method for making a composition for use according to any one of claims 1 to 8 or a composition according to any one of claims 9 to 12, comprising the steps of: a) heating the lipid to provide molten lipid; b) mixing the molten lipid with the pharmaceutically active agent to provide a lipid-drug mixture; c) mixing the lipid-drug mixture with water; and d) equilibrating the lipid-drug mixture with water to provide the composition. Including, as needed, C1) the molten lipid and the pharmaceutically active agent in step b) are mixed at a temperature of about 30°C to 70°C, preferably about 40°C to 60°C; and / or C2) The method wherein the lipid-drug mixture in step c) is mixed with water in a dual syringe.

15. A kit selected from Kit A or Kit B: Kit A: a) a first container containing a lipid and a pharmaceutically active agent; and b) instructions for combining a) with water to provide a composition for use according to any one of claims 1 to 8 or a composition according to any one of claims 9 to 12 A kit comprising: Optionally, the kit further comprises a second container, the second container comprising water; Further optionally, the lipid and the pharmaceutically active agent in the first container are provided as a lyophilized mixture; or Kit B: a) a first container containing lipid; and b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide a composition for use according to any one of claims 1 to 8 or a composition according to any one of claims 9 to 12. A kit comprising: Optionally, the kit further comprises a second container, the second container containing the pharmaceutically active agent dissolved in water; Further optionally, the kit wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

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