Structured lipid compositions

Abstract

The present invention relates to a composition for treating a lower gastrointestinal tract condition, such as ulcerative colitis, where the composition comprises: a) a carrier comprising: a1) water in an amount of more than 10% to 30% by weight of the carrier; and a2) a monoacylglycerol glyceride in an amount of from 70% to 90% by weight of the carrier wherein the monoacylglycerol glyceride comprises glyceryl monolinoleate or glyceryl monooleate or a combination thereof; and b) a pharmaceutically active agent, wherein the composition forms a cubic lipid phase at a temperature of 36 DEG C to 39 DEG C. The composition is particularly suitable for rectal administration, for example as an enema. A composition, a method for preparing the composition, and a kit for making the composition are also disclosed.

Description

[0001] The present invention relates to a composition for treating lower gastrointestinal disorders (such as ulcerative colitis), wherein the composition comprises: a) a carrier, which comprises: a1) water in an amount of more than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipids comprise glyceryl mono-linoleate or glyceryl mono-oleate 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, for example as an enema. Also disclosed is a composition, a method for preparing the composition, and a kit for manufacturing the composition. Background of the Invention

[0003] Ulcerative colitis (UC) is a chronic relapsing-remitting inflammatory disorder of the large intestine, involving the colonic and rectal mucosa. 1 Clinically, 75% of patients have left-sided colitis or proctitis, but the inflammation can spread continuously upwards and involve the colon partially or completely. 2

[0004] There is no known cure for ulcerative colitis, and chronic relapses and remissions often lead to disability in patients. 1,2 All currently recommended treatment methods by the European Crohn’s and Colitis Organisation (ECCO) and the American Gastroenterological Association (AGA) are difficult to achieve the expected remission rate, and many patients have to cycle through several different therapies to achieve remission. 3,4 According to the step-up regimen, the first-line treatment for mild to moderate left-sided UC or pancolitis is the use of 5-ASA (combined topical and oral administration) to induce remission. For refractory patients and severe disease cases, systemic corticosteroids, azathioprine, 6-mercaptopurine, monoclonal antibodies (such as infliximab, an anti-TNF-α; vedolizumab, an anti-α4β7 integrin; and ustekinumab, an IL-12 / IL-23 blocker) and ozanimod (a sphingosine 1-phosphate receptor modulator) are the preferred treatment methods to achieve remission. 4-8 Compared with conventional treatments, biologic-based therapies have considerable side effects, including systemic toxicity, loss of sustained response to treatment over time and symptom recurrence, opportunistic infections, psoriasis, and lupus-like syndromes. 9-13

[0005] In recent years, tofacitinib (TOFA) (a small molecule inhibitor of Janus kinases 1 and 3 (JAK3 and JAK1, respectively)) 14 ) has been approved by European and US regulatory agencies for oral treatment of UC in patients intolerant to biologic drugs. Its oral administration is superior to biologic drugs in maintaining remission and endoscopic improvement. 15,16 For steroid-refractory UC, tacrolimus (TAC) - a macrolide drug that inhibits T-lymphocyte activation - is recommended. 17 However, TOFA and TAC exhibit dose-dependent adverse effects (such as nephrotoxicity, thromboembolic complications, headache, metabolic disorders) when administered systemically in a substantial proportion of patients 18-21 , which may require treatment discontinuation in some cases. 21 In summary, the side effects of these systemically administered drugs must be weighed against the potential benefits of UC treatment in patient management.

[0006] Due to the disease being specifically located in the colon, local therapies are encouraged. 22 In fact, delivery via the rectal route is a safer treatment option, which can maximize drug concentration directly at the site of inflammation and minimize systemic exposure, and it is commonly used as first-line treatment for UC, 23,24 as seen with 5-ASA: rectal administration of this compound is significantly more effective than oral administration in UC patients. 25-30 In addition, refractory ulcerative proctitis has been treated with topically administered TAC (as an ointment 27、31 , suppository 32 and enema 30 ).

[0007] Although clinical studies have confirmed that rectal formulations are more effective than oral formulations, these treatment methods are still rarely adopted. 33 This is because the efficacy of conventional enema-based formulations is inherently limited by their insufficient retention in the colon 34 and fecal urgency associated with large-volume administration. 35 In addition, the required retention time (at least 20 minutes), together with frequent dosing, has a negative impact on patient compliance. 36

[0008] Another major difficulty in using topical formulations (such as enemas) in body cavities (such as the gastrointestinal tract) is the fact that such cavities are typically lined with non-adherent and rapidly renewing mucosa. Concentrated viscous formulations are difficult to effectively apply rectally to the lower gastrointestinal tract and are also difficult to manufacture due to the high viscosities that impede sterile filtration. Existing compositions are typically either low in viscosity and short-lived or long-lived but high in viscosity. In addition, due to poor compatibility between the base composition (such as the carrier) and the active agent, existing topical compositions can typically only contain low levels of the active agent. This results in the composition rapidly losing effectiveness as it dissipates from the site of action.

[0009] Lipid-based drug delivery systems are designed to address challenges such as solubility and bioavailability of poorly water-soluble drugs. Lipid-based formulations can be customized to meet a wide range of product requirements based on disease indication, route of administration, cost considerations, product stability, toxicity, and potency, among others. These formulations are also a commercially viable drug formulation strategy and can be used for topical, oral, pulmonary, or parenteral delivery.

[0010] The application 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 a solvent because amphiphiles have polar and non-polar groups that aggregate together to form polar and non-polar regions. These regions can effectively solubilize polar and non-polar compounds. Such non-lamellar phase formulations are capable of forming liquid crystalline phase structures upon contact with an aqueous fluid. However, considering the characteristics of the rectal environment, which is characterized by a small volume and a composition that is greatly affected by age, biological sex, and pathology, an aqueous liquid is not the most suitable in-situ gelling trigger. In addition, such non-lamellar systems can exhibit a burst release of the encapsulated active ingredient upon exposure to an aqueous fluid.

[0011] Therefore, there remains a need for an improved or alternative delivery system for treating UC. Specifically, a topical formulation that is bioadhesive (i.e., adheres to the mucosal surface) and can be formulated as a low-viscosity composition that becomes adhesive upon in-situ exposure to a suitable trigger.

[0012] Upon hydration, monoacylglycerol lipids (such as glyceryl monooleate - MLO, which is generally recognized as safe - GRAS by the FDA for human and / or animal use) can self-assemble in different arrangements. By increasing the water content, the less viscous lamellar (L) phase first transforms into the Ia3d and then into the Pn3m cubic phase (Q), which has an appearance and rheology similar to a highly viscous cross-linked hydrogel. 37To overcome the barriers to the administration of highly viscous gels, water as well as temperature can be used as trigger factors to modulate the viscosity of the system. Thus, as described herein, the inventors have developed a gel platform that utilizes rectal temperature as a trigger factor to form a highly viscous depot system. It has unexpectedly been found 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.

[0013] Brief summary of the disclosure

[0014] According to the present invention, there is provided a composition comprising:

[0015] a) a carrier comprising:

[0016] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0017] a2) lipid in an amount of 70% to 90% by weight of the carrier; and

[0018] b) a pharmaceutically active agent,

[0019] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate, and

[0020] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0021] Suitably, the carrier comprises more than 10% to 30% water and 70% to 90% lipid, wherein the % is by weight based on the weight of the carrier. Thus, in an embodiment, the carrier consists of more than 10% to 30% water and 70% to 90% lipid, wherein the % is by weight based on the weight of the carrier.

[0022] Suitably, the lipid is glyceryl mono-linoleate.

[0023] In an embodiment, the composition comprises:

[0024] a) a carrier comprising:

[0025] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0026] a2) glyceryl mono-linoleate in an amount of 75% to 90% by weight of the carrier; and

[0027] b) a pharmaceutically active agent,

[0028] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0029] In an embodiment, the carrier comprises about 16% by weight of water and about 84% by weight of glyceryl mono-oleate, wherein the % is based on the weight of the carrier. In an embodiment, the carrier comprises 16% by weight of water and 84% by weight of glyceryl mono-oleate, wherein the % is based on the weight of the carrier. In an embodiment, the carrier consists of about 16% by weight of water and about 84% by weight of glyceryl mono-oleate, wherein the % is based on the weight of the carrier. In an embodiment, the carrier consists of 16% by weight of water and 84% by weight of glyceryl mono-oleate, wherein the % is based on the weight of the carrier.

[0030] In an embodiment, the composition of the present invention has a lamellar phase structure at 25 °C. Thus, in an embodiment, the composition is a lamellar gel at 25 °C. As shown in the examples herein, temperature can be used as a trigger to convert the lamellar phase structure into a lipid cubic phase. Specifically, the inventors have found that rectal temperature can be used as a trigger to convert the lamellar phase structure into a lipid cubic phase, such that when administered rectally, the composition of the present invention converts into a lipid cubic phase and acts as a reservoir system with high viscosity for bioadhesion control. Thus, in an embodiment, the composition of the present invention forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Preferably, the composition of the present invention forms a lipid cubic phase at a temperature of 38 °C.

[0031] In an embodiment, the composition of the present invention is substantially free of organic solvents.

[0032] There is also provided a composition of the present invention for use as a medicament.

[0033] There is also provided a composition of the present invention for treating lower gastrointestinal disorders.

[0034] There is also provided a method of treating a lower gastrointestinal disorder in a subject, the method comprising administering to the subject an effective amount of a composition of the present invention.

[0035] There is also provided the use of a composition of the present invention for the preparation of a medicament for treating a lower gastrointestinal disorder in a subject.

[0036] There is also provided a composition of the present invention for treating a disorder affecting the colon, wherein the composition is topically applied to the colon and / or rectum of a subject. Suitably, the composition is administered rectally to the subject, wherein the composition coats the inner wall of the colon and / or rectum. Thus, the composition is topically applied to the inner wall of the colon and / or rectum.

[0037] In any embodiment of the compositions, methods of treatment, or uses of the compositions involved herein, the compositions of the invention can be administered topically to a subject. Thus, the compositions can be applied topically to the colon of the subject. The compositions can be applied topically to the rectum of the subject. In certain embodiments, the compositions are administered rectally to the subject. The compositions can be administered rectally to the subject in the following forms: suppositories; rectal capsules; semi-solid rectal preparations; rectal foams; rectal hygiene suppositories; or enemas. The compositions can be semi-solid rectal preparations. The compositions can be enema compositions.

[0038] In an embodiment, the composition of the invention has a lamellar phase structure at 25°C and is administered rectally to a subject (e.g., as an enema). Once administered rectally (e.g., as an enema), the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, once administered rectally (e.g., as an enema), the composition forms a lipid cubic phase at a temperature of 38°C.

[0039] In other embodiments of the compositions, methods of treatment, or uses of the compositions involved herein, the compositions of the invention can be injectable formulations. Thus, the injectable formulations can be subcutaneous, intramuscular, or intradermal injectable formulations. In certain embodiments, the compositions are administered subcutaneously, intramuscularly, or intradermally to the subject. Preferably, the injectable formulation is a subcutaneous injectable formulation, and thus the composition is administered subcutaneously to the subject.

[0040] There is also provided the use of a formulation comprising more than 10% w / w to 30% w / w water and 70% w / w to 90% w / w lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid is glyceryl mono-linoleate. The formulation can comprise more than 10% w / w to 25% w / w water and 75% w / w to 90% w / w lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[0041] In an embodiment, the formulation comprises about 16% by weight of water and about 84% by weight of glyceryl mono-linoleate. In an embodiment, the formulation comprises 16% by weight of water and 84% by weight of glyceryl mono-linoleate. In an embodiment, the formulation consists of about 16% by weight of water and about 84% by weight of glyceryl mono-linoleate. In an embodiment, the formulation consists of 16% by weight of water and 84% by weight of glyceryl mono-linoleate.

[0042] Also provided is the use of a pre-formulated composition comprising a lipid and a pharmaceutically active agent for the preparation of the composition of the present invention, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid is glyceryl mono-linoleate.

[0043] Also provided is a method for preparing the composition of the present invention, the method comprising:

[0044] a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and

[0045] b) equilibrating the lipid-drug mixture to provide the composition,

[0046] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid is glyceryl mono-linoleate.

[0047] Also provided is a method for preparing the composition of the present invention, the method comprising:

[0048] a) dissolving a pharmaceutically active agent in water to provide a drug mixture;

[0049] b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and

[0050] c) equilibrating the lipid-drug mixture to provide the composition,

[0051] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid is glyceryl mono-linoleate. Preferably, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0052] Also provided is a kit comprising:

[0053] a) a first container comprising a lipid and a pharmaceutically active agent; and

[0054] b) instructions for combining a) with water to provide the composition of the present invention,

[0055] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid is glyceryl mono-linoleate.

[0056] Also provided is a kit comprising:

[0057] a) a first container comprising a lipid; and

[0058] b) instructions for combining a) with a solution comprising a pharmaceutically active agent dissolved in water to provide the composition of the present invention,

[0059] Wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate. Suitably, the lipid is glyceryl mono - linoleate. Preferably, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0060] There is also provided a composition for treating lower gastrointestinal disorders, wherein the composition comprises:

[0061] a) a carrier, which comprises:

[0062] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0063] a2) a monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0064] b) a pharmaceutically active agent,

[0065] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C, and

[0066] wherein the composition is administered rectally;

[0067] Preferably, the monoacylglycerol lipid is glyceryl mono - linoleate.

[0068] There is also provided a composition, which comprises:

[0069] a) a carrier, which comprises:

[0070] a1) water in an amount of 14% to 18% by weight of the carrier; and

[0071] a2) a monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono - linoleate; and

[0072] b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0073] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C.

[0074] There is also provided the use of a pre - formulated composition comprising a monoacylglycerol lipid and a pharmaceutically active agent for preparing the composition as defined herein,

[0075] Optionally, the pre - formulated composition is a lyophilized mixture.

[0076] The pharmaceutical active agent can be any pharmaceutical active agent described herein. The monoacylglycerol lipid can comprise at least 50% by weight of the glyceryl mono-linoleate described herein. The monoacylglycerol lipid can comprise the glyceryl mono-linoleate or glyceryl mono-oleate described herein or a combination thereof.

[0077] There is also provided a method for preparing a composition for use as defined herein or a composition as defined herein, the method comprising:

[0078] a) hydrating a mixture comprising a lipid and a pharmaceutical active agent with water to provide a lipid-drug mixture; and

[0079] b) equilibrating the lipid-drug mixture to provide the composition,

[0080] Optionally wherein:

[0081] A1) the mixture in step a) is a lyophilized mixture; and / or

[0082] A2) the lyophilized mixture is obtained by:

[0083] i) dissolving the lipid and the pharmaceutical active agent in an organic solvent; and

[0084] ii) lyophilizing the mixture of i) to provide the lyophilized mixture; and / or

[0085] A3) in step i), the organic solvent is selected from ethanol or methanol, preferably wherein the organic solvent is ethanol.

[0086] The lipid can be a monoacylglycerol lipid comprising at least 50% by weight of the glyceryl mono-linoleate described herein. The lipid can be a monoacylglycerol lipid comprising the glyceryl mono-linoleate or glyceryl mono-oleate described herein or a combination thereof. The lipid can be selected from glyceryl mono-linoleate or glyceryl mono-oleate. The pharmaceutical active agent can be any pharmaceutical active agent described herein.

[0087] There is also provided a method for preparing a composition for use as defined herein or a composition as defined herein, the method comprising:

[0088] a) dissolving the pharmaceutical active agent in water to provide a drug mixture;

[0089] b) hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and

[0090] c) equilibrating the lipid-drug mixture to provide the composition,

[0091] Optionally wherein the pharmaceutical active agent is a hydrophilic pharmaceutical active agent.

[0092] The lipid may be a monoacylglycerol lipid, which comprises at least 50% by weight of the glyceryl monolinoleate described herein. The lipid may be a monoacylglycerol lipid, which comprises the glyceryl monolinoleate or glyceryl monooleate or a combination thereof described herein. The lipid may be selected from glyceryl monolinoleate or glyceryl monooleate. The pharmaceutically active agent may be any pharmaceutically active agent described herein.

[0093] There is also provided a method for preparing a composition for the use defined herein or a composition defined herein, the method comprising:

[0094] a) heating the lipid to provide a molten lipid;

[0095] b) mixing the molten lipid with the pharmaceutically active agent to provide a lipid-drug mixture;

[0096] c) mixing the lipid-drug mixture with water; and

[0097] d) equilibrating the lipid-drug mixture and water to provide the composition,

[0098] Optionally wherein:

[0099] C1) mixing the molten lipid and the pharmaceutically active agent in step b) at a temperature of about 30 °C to 70 °C, preferably about 40 °C to 60 °C; and / or

[0100] C2) mixing the lipid-drug mixture in step c) with water in a dual syringe.

[0101] The lipid may be a monoacylglycerol lipid, which comprises at least 50% by weight of the glyceryl monolinoleate described herein. The lipid may be a monoacylglycerol lipid, which comprises the glyceryl monolinoleate or glyceryl monooleate or a combination thereof described herein. The lipid may be selected from glyceryl monolinoleate or glyceryl monooleate. The pharmaceutically active agent may be any pharmaceutically active agent described herein.

[0102] There is also provided a kit, which comprises:

[0103] a) a first container, which contains a lipid and a pharmaceutically active agent; and

[0104] b) instructions for combining a) with water to provide a composition for the use defined herein or a composition defined herein,

[0105] Optionally wherein the kit further comprises a second container, wherein the second container contains water,

[0106] Further optionally wherein the lipid and the pharmaceutically active agent in the first container are provided as a lyophilized mixture.

[0107] The lipid may be a monoacylglycerol lipid, which comprises at least 50% by weight of the glyceryl mono-γ-linolenate described herein. The lipid may be a monoacylglycerol lipid, which comprises the glyceryl mono-γ-linolenate or glyceryl monooleate or a combination thereof described herein. The lipid may be selected from glyceryl mono-γ-linolenate or glyceryl monooleate. The pharmaceutically active agent may be any pharmaceutically active agent described herein.

[0108] There is also provided a kit, which comprises:

[0109] a) a first container, which contains a lipid; and

[0110] b) instructions for combining a) with a solution containing a pharmaceutically active agent dissolved in water to provide a composition for the use defined herein or a composition defined herein.

[0111] Optionally, the kit further comprises a second container, wherein the second container contains a pharmaceutically active agent dissolved in water.

[0112] Further optionally, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[0113] The lipid may be a monoacylglycerol lipid, which comprises at least 50% by weight of the glyceryl mono-γ-linolenate described herein. The lipid may be a monoacylglycerol lipid, which comprises the glyceryl mono-γ-linolenate or glyceryl monooleate or a combination thereof described herein. The lipid may be selected from glyceryl mono-γ-linolenate or glyceryl monooleate. The pharmaceutically active agent may be any pharmaceutically active agent described herein.

[0114] Other aspects and features of the present invention are set forth in the following detailed description. Brief Description of the Drawings

[0116] Figure 1 - SAXS spectra obtained on gels containing 10% w / w of TOFA ( Figure 1A ) and 10% w / w of TAC ( Figure 1B ) at different temperatures.

[0117] Figure 2 - In vitro and ex vivo characterization of the TIF-gel: Figure 2A ) Schematic depiction of the in vitro characterization and gel formation mechanism. Figure 2B ) SAXS spectra obtained on gels containing increasing amounts of water (12%, 14%, 16% and 18% w / w) at different temperatures (25 °C, 30 °C and 38 °C; bottom, middle and top spectra respectively). Figure 2C ) Resulting partial phase diagram (grey circles: L; black circles: Ia3d + L coexistence; grey squares: Ia3d). Figure 2D) SAXS spectra obtained at different times (5, 10, 20, and 30 min) after incubation at 38 °C. Figure 2E ) Frequency scans at the end of the release experiment (grey circles) and at the start of the experiment (grey triangles). Figure 2F ) SAXS before and after the release experiment (1: before; 2: after release in HEPES; 3: after release with lipase). Figure 2G ) Flow points and yield points of the lamellar phase (light grey bars) and cubic gels (dark grey bars) obtained from amplitude sweep experiments. Figure 2H ) In vitro characterization of TIF-gel: SAXS spectra obtained at different temperatures: at 25 °C (bottom), after equilibration at 38 °C for 30 min (middle), and after equilibration at 25 °C for 30 min (top). SAXS was used to determine the lipid phase and thus the reversibility of the transition. Figure 2I ) Amplitude sweep experiments obtained on empty gels at 25 °C (triangular symbols) and 38 °C (circular symbols). a) Storage modulus (G’) and loss modulus (G”) are plotted against shear stress. The yield point is the shear stress value at the limit of the LVE region, while the flow point is the shear stress value at the crossover point G' = G”. b) Shear strain is plotted against stress, and the yield point is exceeded at the point where the deformation begins to deviate from linearity. Figure 2J ) SAXS spectra obtained at 38 °C at different time points (before administration, excreted with feces, and residual gel present in the colon).

[0118] Figure 3 - In vitro and ex vivo characterization of TIF-gel: Figure 3A ) SAXS spectra of TOFA-loaded gels (TIF-gel-TOFA) obtained at different temperatures. Figure 3B ) In vitro release of free drug (TOFA, grey squares) and TIF-gel-TOFA in HEPES buffer (TIF-gel-TOFA, black triangles) and in the presence of lipase (TIF-gel-TOFA (lipase), grey triangles) (results are reported as mean ± STDV (n = 3)). Figure 3C ) Ex vivo release of free drug (TOFA, grey squares) and TIF-gel-TOFA (TIF-gel-TOFA, black triangles) (results are reported as mean ± STDV (n = 3)). Figure 3D ) SAXS spectra of TAC-loaded LMPS (TIF-gel-TAC) obtained at different temperatures. Figure 3E) In vitro release of free drug (TAC, grey squares), TIF-gel-TAC (TIF-gel-TAC, black triangles) and in the presence of lipase (TIF-gel-TAC (lipase), grey triangles) (results are reported as mean ± STDV (n = 3)). Figure 3F ) Ex vivo release of free drug (TAC, grey squares) and TIF-gel-TAC (TIF-gel-TAC, black triangles) in HEPES buffer (results are reported as mean ± STDV (n = 3)). Figure 3G ) Schematic diagram depicting the in vitro release experiment, where the drug-loaded TIF-gel formulation was placed in the donor chamber of a vertical diffusion cell. Figure 3H ) Drug distribution in TIF-gel. a) WAXS spectra obtained for empty gel (bottom), TOFA-loaded gel (middle) and TAC-loaded gel (top). All WAXS spectra (acquired at 25 °C for 30 min) showed only broad shoulders (and no distinct peaks), indicating an amorphous state of the lipid chains and the absence of a crystalline structure. b) Homogeneity of the drug in the gel. The amount of drug present in three different gel layers (top, middle and bottom) was evaluated by HPLC.

[0119] Figure 4 - In vitro release of free drug and TIF-gel-loaded drug in HEPES buffer over 8 h. Figure 4A ) In vitro release of clotrimazole (‘free drug’, square symbol) and TIF-gel-loaded clotrimazole (‘LC’, circular symbol) in HEPES buffer. Figure 4B ) In vitro release of mesalazine (‘free drug’, circular symbol) and TIF-gel-loaded mesalazine (‘LC’, square symbol) in HEPES buffer. Figure 4C ) In vitro release of budesonide (‘free drug’, square symbol) and TIF-gel-loaded budesonide (‘LC’, circular symbol) in HEPES buffer.

[0120] Figure 5 - TIF-gel-TOFA effectively alleviates intestinal inflammation and disease induced by DSS treatment in mice. Mice were given prophylactic rectal treatment with empty gel (TIF-gel; n = 6), tofacitinib in vehicle (TOFA; n = 7) or TOFA-loaded gel (TIF-gel-TOFA; n = 6), and then challenged with 2% DSS in drinking water. Treatments were then given every other day until the end of the experiment. Weight ( Figure 5A ) and disease score ( Figure 5B ) were recorded throughout the experiment. At the end of the experiment, spleens, mesenteric lymph nodes (mLN) and colons were removed from the mice. Spleens were weighed ( Figure 5C) and count individual splenocytes ( Figure 5D ) Measure the tissue concentrations of various cytokines ( Figure 5E ) Measure the length of the mouse colon ( Figure 5F ) The colon was opened transversely, washed and prepared for histological examination ( Figure 5G ) Determine and summarize the colon histopathology score ( Figure 5H ) *: p < 0.05, **: p < 0.01, ***: p < 0.001, and actual values are provided for values less than 0.1 but not reaching the significance threshold, determined by two-way ANOVA ( Figure 5A ) multiple Student's tests with multiple comparisons using Holm-Sidak correction ( Figure 5B and 5E ), and one-way ANOVA combined with multiple comparisons and Tukey correction ( Figure 5C , 5D , 5F, 5H). All experiments were performed using Prism (GraphPad) with the default settings for the above analyses; all error bars are ±SEM.

[0121] Figure 6 - Evaluation of the effect of TAC-loaded gels on T cell-mediated colitis: 12 - 15-week-old Rag - / - mice developed colitis by transfer of 2.5x10 5 naive T cells. Starting on day 3 after T cell transfer, mice were treated daily by rectal instillation with drug-free TIF-gel (TIF-gel), TAC-loaded TIF-gel (TIF-gel-TAC), or TAC in vehicle (TAC). Figure 6A ) Schematic of the experimental setup. Figure 6B ) Body weight development during the experiment. Figure 6C ) Cumulative disease activity score. Figure 6D and 6E ) Representative pictures and respective scores from mouse colonoscopy on day 19 after T cell transfer and representative pictures and respective scores of hematoxylin and eosin-stained sections of the terminal colon collected on day 19 after T cell transfer.

[0122] Figure 7 - Immune cell populations in the colon of mice treated with TAC-loaded TIC-gel: 12 - 15-week-old Rag - / - mice developed colitis by transfer of 2.5x10 5Colitis occurred following the transfer of naïve T cells. Starting from day 3 after T cell transfer, mice were administered daily by rectal instillation with drug-free TIF-gel (TIF-gel), TIF-gel loaded with TAC (TIF-gel-TAC), or TAC in vehicle (TAC). The relative abundances of the designated cell populations at the following locations were depicted: Figure 7 A) Colonic lamina propria, Figure 7 B) Mesenteric lymph nodes; and Figure 7 C) Spleen at day 19 after T cell transfer, and (d) the levels of indicated cytokines in colonic lysates. *p < 0.05, **p < 0.01, ***p < 0.001, determined by one-way ANOVA combined with multiple comparisons and Tukey correction. All experiments were performed using Prism (GraphPad) with the default settings for the above analysis; all error bars are ±SEM.

[0123] Figure 8 - Long-term stability of TOFA ( Figure 8A ) loaded into TIF-gel and TAC ( Figure 8B ) loaded into TIF-gel over one month, analyzed by HPLC. Samples were stored at 4 °C (black bars) and 25 °C (grey bars) during the study. Data are represented as percentage ± SD.

[0124] Figure 9 - Drug delivery via TIF-gel results in low systemic drug exposure. (a) Experimental design of the pharmacokinetic study. Healthy mice (n = 5 / group) received a single enema of 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 curves for the pharmacokinetic experiments of TOFA-(b) and TAC-treated animals (c), and area under the curve (AUC) values for TOFA- and TAC-treated mice (d and e, respectively) 0-48h ***p < 0.001, determined by Student's t-test.

[0125] Figure 10 - TIF-gel adheres to healthy colonic tissue for at least 6 h. a) Experimental protocol depicting the process: Healthy animals received an enema of 100 μL of DiR-TIF-gel. Animals were sacrificed at 30 min, 2, and 6 h later, and the colon was harvested and imaged (b). c) The signal obtained was analyzed as radiation efficiency (RE) and normalized to the radiation potency recorded at 30 min.

[0126] Detailed description

[0127] Throughout the description and claims of this specification, the words "comprise" and "comprising" and their variants mean "include, but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps. Throughout the description and claims of this specification, the singular includes the plural, unless the context otherwise requires. Specifically, in the case of using an indefinite article, the specification should be understood to cover both the plural and the singular, unless the context otherwise requires.

[0128] Features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention should be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except 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 foregoing embodiments. The invention extends to any novel individual or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel individual or any novel combination of steps of any method or process so disclosed.

[0129] For the avoidance of doubt, information disclosed in this specification previously under the "Background" heading is relevant to the invention and should be read as part of the disclosure of the invention.

[0130] The reader's attention is directed to all such papers and documents: which are filed concurrently with or earlier than the relevant specification of this application and which are open to public inspection together with this specification, and the content of all such papers and documents is incorporated herein by reference.

[0131] Definitions

[0132] Unless otherwise stated, the following terms used in this specification and claims have the following meanings set out below.

[0133] The terms "treatment" and therapy as encompassed by the present invention include the following and combinations thereof: (1) reducing the risk of a condition, disorder or disease, or inhibiting (e.g., delaying) the onset and / or progression of a condition, disorder or disease; (2) preventing the clinical symptoms of a condition, disorder or disease that occurs in a patient (e.g., a human or an animal), e.g., reducing the risk of said clinical symptoms, or delaying the appearance of said clinical symptoms, in a patient who may have or be susceptible to said condition, disorder or disease but has not yet experienced or shown the clinical or subclinical symptoms of said condition, disorder or disease; (3) inhibiting said condition, disorder or disease (e.g., preventing, reducing or delaying the development of a disease, or recurrence of at least one of its clinical or subclinical symptoms in maintenance therapy); and / or (4) alleviating said disease (e.g., causing regression of at least one of said condition, disorder or disease or its clinical or subclinical symptoms). Where the compositions of the present invention are used to treat a patient, treatment encompasses any one or more of the following: maintaining the health of the patient; restoring or improving the health of the patient; and delaying the progression of a disorder. The benefit to the patient to be treated may be statistically significant or at least perceptible to the patient or the physician. It should be understood that a drug may not produce a clinical effect in every patient to whom it is administered, and this paragraph should be construed accordingly. The compositions and methods described herein can be used to treat and / or prevent diseases. The compositions and methods described herein can be used to inhibit or prevent disease progression.

[0134] Treatment may include maintenance therapy of a patient who has a disorder and whose condition is subsequently improved (e.g., due to treatment). Such a patient may or may not have a symptomatic disorder. Maintenance therapy is intended to prevent, reduce or delay the (re)occurrence or progression of a disorder.

[0135] As used herein, "therapeutically effective amount" is an amount sufficient to achieve any of the following effects: alleviating or completely relieving the symptoms or other adverse effects of a disorder; reversing, completely halting or slowing the progression of a disorder; or reducing the risk of disorder exacerbation; e.g., an amount sufficient to induce remission of ulcerative colitis, or an amount sufficient to maintain remission of ulcerative colitis. Further within the skill of the ordinary artisan in the art is to determine an appropriate duration of treatment, an appropriate dosage, and any potential combination therapy based on an evaluation of the therapeutic or prophylactic response.

[0136] As used herein, "modified release" includes compositions that alter the release of a drug from a composition, particularly compositions that provide, for example, controlled release, extended (or sustained) release, or delayed release, or any combination thereof, e.g., delayed and controlled release of a drug from a composition following administration (e.g., following rectal administration by enema).

[0137] The term "C m -C n"represents a group having from m to n carbon atoms."

[0138] The term "C1-C6-alkyl" represents a straight-chain or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. "C6-C 32 -alkyl" similarly represents such a group containing from 6 to 32 carbon atoms. The alkyl group may be unsubstituted or substituted by one or more substituents. The substituents of the alkyl group may be halogen (such as fluorine, chlorine, bromine and iodine), OH, C1-C4 alkoxy.

[0139] In the context of the present invention, the term "antibody" represents "immunoglobulin" (Ig), which is defined as a protein belonging to the IgG, IgM, IgE, IgA or IgD class (or any subclass thereof), and includes all conventionally 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 or other derivative of the parental antibody that substantially maintains the properties of such a parental 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 generally located in one or more hypervariable regions of the antibody, i.e., the CDR-1, -2 and / or -3 regions. The "antigen-binding fragments" according to the present invention include the domains of F(ab′)2 fragments and Fab fragments. The "functional fragments" of the present invention include Fab fragments, F(ab′)2 fragments, Fab′ fragments, scFv, dsFv, VHH, diabodies, triabodies, tetra-bodies, Fc fusion proteins and minibodies. The F(ab′)2 or Fab domains can be engineered to minimize or completely eliminate intermolecular disulfide bond interactions that occur between the CH1 and CL domains. The antibodies or functional fragments used in the present invention may be part of a bifunctional or multifunctional construct.

[0140] The term "immunosuppressant" means a pharmacologically acceptable compound having the effect of suppressing the immune response in a human or animal body. The term "antineoplastic agent" means a pharmacologically acceptable compound that is cytotoxic to neoplastic cells.

[0141] The term "gel" is used herein to denote a semi-solid, apparently homogeneous substance, which can be elastic and jelly-like (as in gelatin). The gel contains a three-dimensional polymer or inorganic matrix in which a liquid phase is dispersed. The matrix of the gel contains a network of physically or chemically cross-linked polymers or copolymers, which swells but does not dissolve in the presence of a solvent. The cross-linking within the gel matrix can be physical cross-linking (e.g., by hydrogen bonding or ionic cross-linking) or can be covalent cross-linking. Gels are usually transparent in appearance, however, turbid gels are also encompassed. The United States Pharmacopeia defines a gel as a semi-solid system consisting of a dispersion composed of small inorganic particles or large organic molecules that enclose and are penetrated by a liquid. The European Pharmacopeia defines a gel as a semi-solid preparation consisting of a single-phase liquid base gelled by a suitable gelling agent. The active substance is dissolved or dispersed in the base.

[0142] In an embodiment, the carrier of the composition comprises: a1) water in an amount of more than 10% to 30% by weight of the carrier; and a2) lipid in an amount of 70% to 90% by weight of the carrier. The lipid can be selected from glyceryl mono-linoleate or glyceryl mono-oleate. In an embodiment, the carrier of the composition consists of: a1) water in an amount of more than 10% to 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 glyceryl mono-linoleate or glyceryl mono-oleate. It should be understood that embodiments herein where the "carrier comprises" lipid and water also encompass embodiments where the carrier consists only of lipid and water. Thus, for example, the carrier can consist only of glyceryl mono-linoleate and water in the amounts specified in any of the embodiments herein.

[0143] The composition further comprises a pharmaceutically active agent, for example 0.1% to 10% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. Thus, the carrier serves as a vehicle for the pharmaceutically active agent within the composition. It will be apparent to those skilled in the art that the reference to the term "carrier" relates to the lipid and water components of the total composition. For example, the composition can comprise: a) a carrier which comprises: a1) water in an amount of 10% by weight of the carrier; and a2) 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 case, the total composition comprises:

[0144] a) 90% of the carrier (wherein the % is % of the weight of the composition), wherein the carrier comprises:

[0145] a1) water in an amount of 10% by weight of the carrier; and

[0146] a2) lipid in an amount of 90% by weight of the carrier; and

[0147] b) 10% of a pharmaceutically active agent (wherein said % is % of the weight of the composition).

[0148] In each of the embodiments listed above, the proportion of the components in the carrier is fixed (i.e., 10% water and 90% lipid), while the amount of the carrier in the total composition varies according to the amount of the pharmaceutically active agent present in the composition.

[0149] The term "carrier" refers to a formulation comprising water and a lipid (such as glyceryl mono-linoleate or glyceryl mono-oleate) or preferably consisting of water and a lipid (such as glyceryl mono-linoleate or glyceryl mono-oleate). The "composition" comprises a carrier, a pharmaceutically active agent, and optionally other components (such as additives). The term "by weight of the carrier" refers to the total weight of the water and the lipid (such as glyceryl mono-linoleate or glyceryl mono-oleate) present in the carrier. Thus, the compositions of the present invention may comprise:

[0150] a) A carrier, which comprises:

[0151] a1) More than 10% to 30% by weight of water;

[0152] a2) 70% to 90% by weight of a lipid; and

[0153] b) 0.1% to 10% by weight of the composition of a pharmaceutically acceptable agent,

[0154] wherein the total weight of a1) to a2) is 100%, and the "by weight" of a1) and a2) means "% of the weight of the carrier". In this embodiment, the weight % of the pharmaceutically acceptable agent represents the weight % of the total weight of the composition containing all the components of the composition.

[0155] The phrase "a pharmaceutically acceptable agent is present in an amount of about x% by weight of the carrier" as used herein means the weight percentage of the pharmaceutically acceptable agent relative to the total weight of the carrier comprising water and a lipid (such as glyceryl mono-linoleate or glyceryl mono-oleate).

[0156] Those skilled in the art will recognize that a composition of the present invention comprising: a) 90 - 99.9% of a carrier (wherein said % is % of the weight of the composition), wherein the carrier comprises: a1) water in an amount of 10 - 30% of the weight of the carrier; and a2) a lipid in an amount of 70 - 90% of the weight of the carrier; and b) a pharmaceutically active agent in an amount of 0.1 - 10% of the weight of the composition, is equivalent to a composition comprising:

[0157] (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent;

[0158] (ii) 63% w / w to 89.9% w / w lipid; and

[0159] (iii) 9% w / w to 29.97% w / w water,

[0160] wherein said % is % of the weight of the composition,

[0161] wherein said lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0162] wherein said composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0163] Those skilled in the art will also realize that a composition of the present invention comprising: a) 90 - 99.9% of a carrier (wherein said % is % of the weight of the composition), wherein said carrier comprises: a1) water in an amount of 10 - 25% of the weight of the carrier; and a2) lipid in an amount of 75 - 90% of the weight of the carrier; and b) a pharmaceutically active agent in an amount of 0.1 - 10% of the weight of the composition is equivalent to a composition comprising:

[0164] (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent;

[0165] (ii) 67.5% w / w to 89.9% w / w lipid; and

[0166] (iii) 9% w / w to 24.9% w / w water,

[0167] wherein said % is % of the weight of the composition,

[0168] wherein said lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0169] wherein said composition forms a lipid cubic phase at a temperature of 36°C to 39°C. For example, the composition may comprise: a) a carrier, which comprises: a1) water in an amount of 10% of the weight of the carrier; and a2) lipid in an amount of 90% of the weight of the carrier; and b) a pharmaceutically active agent in an amount of 5% of the weight of the composition. In this case, the total composition comprises:

[0170] (i) 5% w / w of a pharmaceutically active agent;

[0171] (ii) 85.5% w / w lipid; and

[0172] (iii) 9.5% w / w water.

[0173] In another embodiment, the composition may comprise: a) a carrier, which comprises: a1) water in an amount of 10% by weight of the carrier; and a2) 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 case, the total composition comprises:

[0174] (i) 1% w / w of the pharmaceutically active agent;

[0175] (ii) 89.1% w / w lipid; and

[0176] (iii) 9.9% w / w water.

[0177] For the avoidance of doubt, glyceryl monolinoleate ((9Z,12Z)-9,12-octadecadienoic acid 2,3-dihydroxypropyl ester) has the following structure:

[0178]

[0179] For the avoidance of doubt, glyceryl monooleate ((9Z)-9-octadecenoic acid 2,3-dihydroxypropyl ester) has the following structure:

[0180]

[0181] The term "rectal temperature" refers to a temperature range of about 36°C to about 39°C. Thus, in the embodiments described herein, the term rectal temperature may 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. Specifically, the term rectal temperature may refer to a temperature of about 38°C. Preferably, the term rectal temperature refers to a temperature of 38°C.

[0182] As used herein, "rectal administration" or "administered rectally" encompasses any route of administration (e.g., topical administration) by which the compositions of the present invention are directly administered rectally to the tissues of the lower gastrointestinal (GI) tract. The lower GI tract is generally divided into three main parts: the colon, the rectum, and the anal canal. The colon is typically divided into 5 main 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, descending colon, splenic flexure, and sigmoid colon. The rectum is the last anatomical segment before the anus. Thus, "rectal administration" or "administered rectally" also encompasses any route of administration (e.g., topical administration) by which the compositions of the present invention are directly administered rectally to the 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 through a stoma (e.g., in the case where a subject has undergone a colostomy).

[0183] The compositions of the present invention (e.g., the layered gel compositions) are also referred to as "TIF-gel" compositions, which means that the compositions are temperature-triggered in-situ-forming bioadhesive lipid gels. The compositions are triggered at a temperature of 36°C to 39°C, preferably 38°C. In a preferred embodiment, the compositions are administered to the rectum (e.g., as an enema). Thus, the compositions are triggered by rectal temperature (as defined herein). The compositions of the present invention undergo a phase change upon exposure to the temperature trigger and thus transform from a lamellar phase structure to a lipid cubic phase at a temperature of 36°C to 39°C, preferably 38°C. The term "in-situ" can be understood to mean that once the compositions are injected into the rectum of a subject and the compositions reach rectal temperature (as defined herein), the compositions undergo this phase change from a lamellar phase structure to a lipid cubic phase.

[0184] 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 suitably less than 0.01% or preferably less than 0.001% organic solvent. Preferably, the compositions of the present invention are free of detectable organic solvents.

[0185] In certain embodiments, the compositions of the present invention are substantially free of surfactants. In certain embodiments, the compositions of the present invention are substantially free of nonionic surfactants, such as poloxamers. Thus, in certain 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% surfactant (e.g., nonionic surfactant such as poloxamer). The surfactants mentioned in this paragraph do not encompass lipids present in the carriers of the compositions of the present invention.

[0186] A "topical formulation" is a formulation that is applied to a body surface, such as the skin or mucosa, for treatment. Topical formulations can also be applied to tissue surfaces other than the skin, such as the tooth surface, rectum, or vagina. Topical formulations differ from many other types of drugs because improper handling of them can lead to certain complications in the patient or the person to whom the drug is administered. Suitably, the compositions described herein are applied topically to the colon. Preferably, the topical formulations described herein are administered rectally, such as as an enema.

[0187] The terms "lamellar", "lamellar gel", "lamellar geometry", "lamellar phase", "lamellar phase structure", "L" denote a two-dimensional stacking of amphiphilic bilayers separated by water layers. Each bilayer consists of two monolayers arranged tail-to-tail to minimize the contact between the hydrocarbon chains and water. In this arrangement, water is distributed almost entirely at the lipid polar heads and forms water-lipid head plates. Thus, as determined by small-angle X-ray scattering (SAXS), the compositions of the present invention are in the lamellar phase at 25 °C.

[0188] The terms "cubosome", "lipid cubic phase", "cubosome geometry", "lipid cubic phase structure", "cubic phase", "Q" denote a bicontinuous cubic phase consisting of two sets of water channels separated by curved bilayers in 3D space such that every point on the midplane surface of the bilayer is a saddle point with zero mean curvature. The bilayer contains a water channel system and forms a structured but flexible network that is non-birefringent and optically transparent. Specifically, the lipid molecules in the bicontinuous cubic phase form highly curved continuous bilayers that separate two interpenetrating but non-intersecting water channel networks. The structure can assume a double helical shape (Ia3d, with triple water channel connectivity), a double diamond shape (Pn3m, with quadruple connectivity), and a primitive shape (Im3m, with six-fold connectivity symmetry). Thus, as determined by small angle X-ray scattering (SAXS), the compositions of the present invention are in the cubic phase at about 36°C to about 39°C. In an embodiment, the compositions of the present invention can be in the Cubosome-Ia3d phase at about 36°C to about 39°C. In an embodiment, the compositions of the present invention can be in the Cubosome-pn3m phase at about 36°C to about 39°C when present in an aqueous environment. For example, in certain embodiments, the compositions of the present invention absorb water at the site of administration to a subject (e.g., after rectal administration) and form the Cubosome-pn3m phase at a temperature of about 36°C to about 39°C. As discussed above, SAXS can be used to determine the lipid phase and thereby construct a partial phase diagram of different lipid-water systems (e.g., MLO-water systems). The method relies on the constructive interference in reciprocal space of many ordered scattering planes belonging to the mesophase. An X-ray beam is incident on the lipid sample, and the resulting scattering pattern yields a set of characteristic rings or maxima corresponding to Bragg reflections. Their position in reciprocal space depends on the Miller indices of the mesophase scattering planes, and the sequence (and their ratios) of the Bragg reflections thus identifies the symmetry of the mesophase under study. SAXS allows determination of the lattice parameters, i.e., the size of the repeating unit cell. When the parameters are transformed, it is possible to reconstruct the entire mesophase in 3D. The SAXS measurements are used to determine the phase consistency and symmetry of the resulting LMP. Measurements were carried out on a Bruker AXS Micro using Cu Kα radiation as further described in detail in "Analytical Methods". The following sequences of Bragg reflections were used to determine the symmetry of each mesophase under study: 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

[0189] Cross-polarized optical microscopy can also be used to determine the lipid phase. 40Lyotropic liquid crystals self-assemble into networks with unique symmetries, meaning that their fundamental motifs repeat themselves periodically. Liquid crystal cubic phases (Ia3d, pn3m, or Im3m) are isotropic, meaning that they do not have any birefringence properties. Thus, if a glass slide with a layer of lyotropic liquid crystal film is placed under a light source that allows polarized light to pass through, it will appear black when viewed through another polarizer tilted 90°. On the other hand, the lamellar phase is anisotropic (non-isotropic), meaning that it has birefringence properties. Thus, if a glass slide with a lamellar gel layer is placed under a light source that allows polarized light to pass through, it will appear colored when viewed through another polarizer tilted 90°.

[0190] A "pharmaceutically acceptable salt" of a compound mentioned refers to a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such pharmaceutically acceptable salts can be, for example, acid addition salts of the compound, such as acid addition salts with inorganic acids or organic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, or maleic acid); or salts of compounds with sufficient acidity, such as alkali metal or alkaline earth metal salts (such as sodium, calcium, or magnesium salts) or ammonium salts, or salts with organic bases (such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine).

[0191] The terms "hydrophobic pharmaceutical active agent", "hydrophobic pharmaceutically acceptable agent", or "hydrophobic agent" as used herein refer to agents that have a greater solubility in low-polarity organic solvents (such as long-chain alcohols) than in aqueous solutions. "Hydrophobic" means "water-hating" and is used herein to denote agents that are poorly soluble or insoluble in water but soluble in non-polar solvents.

[0192] The terms "hydrophilic pharmaceutical active agent", "hydrophilic pharmaceutically acceptable agent", or "hydrophilic agent" as used herein refer to agents that have a higher solubility in aqueous media. "Hydrophilic" means "water-loving" and is used herein to denote water-soluble (i.e., having a strong affinity for water) agents.

[0193] The components and excipients of the described compositions are suitable for the intended purposes. For example, pharmaceutical compositions contain pharmaceutically acceptable components.

[0194] Unless otherwise stated, the components, ingredients, excipients, etc. of the compositions of the present invention are suitable for one or more of the intended purposes discussed elsewhere herein.

[0195] When the present invention is referred to as a formulation, it has the same meaning as the compositions of the present invention. Thus, the terms formulation and composition are used interchangeably.

[0196] When the composition of the present invention is referred to as a lamellar gel, it has the same meaning as the composition of the present invention having a lamellar phase structure. Thus, these terms are used interchangeably.

[0197] "About" in the context of a number is intended to cover values ±10%. For example, about 20% includes the range from 18% to 22%.

[0198] Composition

[0199] Provided herein is a composition comprising:

[0200] a) a carrier comprising:

[0201] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0202] a2) lipid in an amount of 70% to 90% by weight of the carrier; and

[0203] b) a pharmaceutically active agent,

[0204] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0205] The composition may comprise:

[0206] a) a carrier comprising:

[0207] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0208] a2) lipid in an amount of 75% to 90% by weight of the carrier; and

[0209] b) a pharmaceutically active agent,

[0210] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0211] Also provided herein is a composition comprising:

[0212] a) a carrier comprising:

[0213] a1) water in an amount of 14% to 18% by weight of the carrier; and

[0214] a2) a monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono-γ-linolenate; and

[0215] b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0216] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0217] The lipid is a neutral lipid component comprising a polar "head" group and a non-polar "tail" group. Generally, the head and tail portions of the lipid will be linked by an ester moiety, but this linkage can be by means of an ether, amide, carbon-carbon bond or other linkage. 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 esters. Preferred polar groups are glycerol and diglycerol, especially glycerol.

[0218] Suitably, the lipid is a monoacylglycerol lipid. The non-polar group can be saturated or unsaturated. Examples of non-polar groups include C6-C 32 alkyl and C6-C 32 alkenyl groups, which are usually present as esters of long-chain carboxylic acids. These are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Specific examples include hexanoyl (C6:0), octanoyl (C8:0), decanoyl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups. Thus, typical non-polar chains are fatty acids based on natural ester lipids, including caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, phytanic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid or lignoceric acid, or the corresponding alcohols. Preferred non-polar chains are oleic acid and linoleic acid, especially linoleic acid. One skilled in the art will know that lipids are raw materials of natural origin or semi-synthetic, and thus the source of the raw material and its composition can vary. Thus, one skilled in the art will understand that any reference herein to a mono-linolein lipid encompasses both the pure form of mono-linolein and the commercial grade form of mono-linolein (e.g., the food grade form of mono-linolein). For example, the commercial grade form of a mono-linolein lipid can contain a mixture of monoacylglycerol lipids (such as mono-linolein and mono-olein) and optionally other additional lipids. One skilled in the art will also understand that any reference herein to a mono-olein lipid encompasses both the pure form of mono-olein and the commercial grade form of mono-olein (e.g., the food grade form of mono-olein). For example, the commercial grade form of a mono-olein lipid can contain a mixture of monoacylglycerol lipids (such as mono-olein and mono-linolein) and optionally other additional lipids.

[0219] Thus, the glyceryl mono-linoleate lipid can comprise more than about 90 wt% of monoacylglycerol lipid. The glyceryl mono-linoleate lipid can comprise more than about 95 wt% of monoacylglycerol lipid. The glyceryl mono-linoleate lipid can comprise more than about 98 wt% of monoacylglycerol lipid. The glyceryl mono-linoleate lipid can comprise more than about 99.9 wt% of monoacylglycerol lipid. For example, the glyceryl mono-linoleate lipid (e.g., the commercial grade form of the glyceryl mono-linoleate lipid) can comprise about 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt% or 100 wt% of monoacylglycerol lipid.

[0220] The glyceryl mono-linoleate lipid can comprise up to 100 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than or equal to about 99 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than about 90 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than about 80 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than about 70 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than about 60 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise more than about 50 wt% of glyceryl mono-linoleate. The glyceryl mono-linoleate lipid can comprise 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% of glyceryl mono-linoleate.

[0221] The mono-linolein glyceride lipid may not contain mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 50 wt% of mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 40 wt% of mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 30 wt% of mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 20 wt% of mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 10 wt% of mono-olein glyceride. The mono-linolein glyceride lipid may contain less than about 5 wt% of mono-olein glyceride. The mono-linolein glyceride lipid 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% of mono-olein glyceride.

[0222] The mono-olein glyceride lipid may contain more than about 90 wt% of monoacylglycerol lipid. The mono-olein glyceride lipid may contain more than about 95 wt% of monoacylglycerol lipid. The mono-olein glyceride lipid may contain more than about 98 wt% of monoacylglycerol lipid. The mono-olein glyceride lipid may contain more than about 99.9 wt% of monoacylglycerol lipid. For example, the mono-olein glyceride lipid (e.g., the commercial grade form of mono-olein glyceride lipid) 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% of monoacylglycerol lipid.

[0223] The glyceryl monooleate lipid may contain up to 100% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than or equal to about 99% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than about 90% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than about 80% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than about 70% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than about 60% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain greater than about 50% by weight of glyceryl monooleate. The glyceryl monooleate lipid may contain 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% by weight of glyceryl monooleate.

[0224] The glyceryl monooleate lipid may not contain glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 50% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 40% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 30% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 20% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 10% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid may contain less than about 5% by weight of glyceryl monolinoleate. The glyceryl monooleate lipid 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% by weight of glyceryl monolinoleate.

[0225] In certain embodiments, the monoacylglycerol lipid may comprise up to 100 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than or equal to about 99 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than about 90 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than about 80 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than about 70 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than about 60 wt% of glyceryl mono-linoleate. The monoacylglycerol lipid may comprise greater than about 50 wt% of glyceryl mono-linoleate. The monoacylglycerol 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% of glyceryl mono-linoleate. The monoacylglycerol lipid may not comprise glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 50 wt% of glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 40 wt% of glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 30 wt% of glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 20 wt% of glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 10 wt% of glyceryl mono-oleate. The monoacylglycerol lipid may comprise less than about 5 wt% of glyceryl mono-oleate. The monoacylglycerol 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% glyceryl mono-oleate.

[0226] In other embodiments, the monoacylglycerol lipid can comprise up to 100% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than or equal to about 99% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than about 90% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than about 80% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than about 70% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than about 60% by weight of glyceryl monooleate. The monoacylglycerol lipid can comprise greater than about 50% by weight of glyceryl monooleate. The monoacylglycerol lipid can 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% by weight of glyceryl monooleate. The monoacylglycerol lipid can be free of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 50% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 40% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 30% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 20% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 10% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can comprise less than about 5% by weight of glyceryl monolinoleate. The monoacylglycerol lipid can 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% by weight of glyceryl monolinoleate.

[0227] In an embodiment, the lipid is a monoacylglycerol lipid. In a preferred embodiment, the monoacylglycerol lipid is selected from glyceryl monolinoleate or glyceryl monooleate. Thus, the lipid can be glyceryl monolinoleate. The lipid can be glyceryl monooleate.

[0228] In an embodiment, the lipid is a monoacylglycerol lipid. The monoacylglycerol lipid may comprise glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. Thus, the monoacylglycerol lipid may comprise glyceryl mono-linoleate and glyceryl mono-oleate. The monoacylglycerol lipid may comprise glyceryl mono-linoleate. The monoacylglycerol lipid may comprise glyceryl mono-oleate. The monoacylglycerol lipid may further comprise other lipids. The monoacylglycerol lipid may further comprise up to about 10% of other lipids. The monoacylglycerol lipid may further comprise up to about 8% of other lipids. The monoacylglycerol lipid may further comprise up to about 5% of other lipids. The monoacylglycerol lipid may further comprise about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of other lipids. The monoacylglycerol lipid may be substantially free of other lipids.

[0229] The mono-linolein lipid may comprise a monoacylglycerol lipid. The mono-linolein lipid may comprise a monoacylglycerol lipid and a diglyceride. The mono-linolein lipid may comprise more than about 90 wt% of a monoacylglycerol lipid. The mono-linolein lipid may comprise more than about 95 wt% of a monoacylglycerol lipid. The mono-linolein 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, such as 91% of a C18 lipid. The C18 lipid may comprise a C18:2, C18:1, and / or C18:0 lipid. The C18 lipid may comprise more than about 50% of a C18:2 lipid. The C18 lipid may comprise more than about 55% of a C18:2 lipid. The C18 lipid may comprise more than about 60% of a C18:2 lipid. The C18 lipid may comprise from about 60% to about 65% of a C18:2 lipid, such as, 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% of a C18:2 lipid. The C18 lipid may comprise about 61.9% of a C18:2 lipid. The C18 lipid may comprise more than about 15% of a C18:1 lipid. The C18 lipid may comprise more than about 20% of a C18:1 lipid. The C18 lipid may comprise about 25% of a C18:1 lipid. The C18 lipid may comprise less than about 30% of a C18:1 lipid. The C18 lipid may comprise from about 20% to about 30% of a C18:1 lipid, such as, 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% of a C18:1 lipid. The C18 lipid may comprise about 24.9% of a C18:1 lipid. The C18 lipid may comprise more than about 1% of a C18:0 lipid. The C18 lipid may comprise about 4% of a C18:0 lipid. The C18 lipid may comprise about 5% of a C18:0 lipid. The C18 lipid may comprise less than about 10% of a C18:0 lipid.The C18 lipid may comprise from about 1% to about 5% of C18:0 lipid, e.g., about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% of C18.0 lipid. The C18 lipid may comprise about 4.2% of C18:1 lipid. The monoacylglycerol lipid may comprise C16 lipid, e.g., C16:0 lipid. The monoacylglycerol lipid may comprise more than about 1% of C16:0 lipid. The monoacylglycerol lipid may comprise more than about 5% of C16:0 lipid. The monoacylglycerol lipid may comprise more than about 7% of C16:0 lipid. The monoacylglycerol lipid may comprise less than about 10% of C16:0 lipid. The monoacylglycerol lipid may comprise from about 5% to about 10% of C16:0 lipid, e.g., 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% of C16.0 lipid. The monoacylglycerol lipid may comprise about 7.4% of C16:0 lipid. The monolinolein lipid may comprise less than about 5% of diglyceride. The monolinolein lipid may comprise less than about 3% of diglyceride. The monolinolein lipid may comprise more than about 1% of diglyceride. For example, the monolinolein lipid may comprise 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% of diglyceride. Thus, the monolinolein lipid may comprise more than 98% by weight of monoacylglycerol lipid (comprising 61.9% of C18:2 lipid, 24.9% of C18:1 lipid, 4.2% of C18:0 lipid and 7.4% of C16:0 lipid) and 1.6% of diglyceride.

[0230] Thus, in an embodiment, there is provided herein a composition comprising:

[0231] a) a carrier comprising:

[0232] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0233] a2) a lipid in an amount of 70% to 90% by weight of the carrier; and

[0234] b) a pharmaceutically active agent,

[0235] wherein the lipid is selected from monolinolein or monoolein,

[0236] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0237] The composition may comprise:

[0238] a) a carrier, which comprises:

[0239] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0240] a2) a monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof; and

[0241] b) a pharmaceutically active agent,

[0242] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0243] The composition may comprise:

[0244] a) a carrier, which comprises:

[0245] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0246] a2) a lipid in an amount of 75% to 90% by weight of the carrier; and

[0247] b) a pharmaceutically active agent,

[0248] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0249] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. Preferably, the lipid is glyceryl mono-linoleate.

[0250] The lipid may be glyceryl mono-linoleate. Thus, the composition may comprise:

[0251] a) a carrier, which comprises:

[0252] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0253] a2) glyceryl mono-linoleate in an amount of 75% to 90% by weight of the carrier;

[0254] and

[0255] b) a pharmaceutically active agent,

[0256] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0257] The lipid may be glyceryl mono-oleate. Thus, the composition may comprise:

[0258] a) A carrier, comprising:

[0259] a1) Water in an amount of more than 10% to 30% by weight of the carrier; and

[0260] a2) Glyceryl monooleate in an amount of 70% to 90% by weight of the carrier; and

[0261] b) A pharmaceutically active agent,

[0262] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. In a preferred embodiment, the composition comprises at most 10% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. The composition may comprise 0.1% to 10% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise:

[0263] a) A carrier, comprising:

[0264] a1) Water in an amount of more than 10% to 30% by weight of the carrier; and

[0265] a2) A lipid in an amount of 70% to 90% by weight of the carrier; and

[0266] b) A pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0267] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl monooleate,

[0268] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0269] The composition may comprise:

[0270] a) A carrier, comprising:

[0271] a1) Water in an amount of more than 10% to 30% by weight of the carrier; and

[0272] a2) A monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl monooleate or a combination thereof; and

[0273] b) A pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0274] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0275] Thus, the composition may comprise:

[0276] a) A carrier, comprising:

[0277] a1) Water in an amount of more than 10% to 25% by weight of the carrier; and

[0278] a2) Lipid in an amount of 75% to 90% by weight of the carrier; and

[0279] b) A pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0280] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0281] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0282] In an embodiment, the composition comprises:

[0283] (i) 0.1% w / w to 10% w / w of a pharmaceutically active agent;

[0284] (ii) 67.5% w / w to 89.9% w / w lipid; and

[0285] (iii) 9% w / w to 24.9% w / w water,

[0286] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0287] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0288] In a preferred embodiment, the composition comprises:

[0289] a) A carrier, which comprises:

[0290] a1) Water in an amount of 14% to 18% by weight of the carrier; and

[0291] a2) Monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono - linoleate; and

[0292] b) A pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition,

[0293] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0294] In an embodiment, the composition of the present invention has a lamellar phase structure at 25°C. The composition of the present invention may have a lamellar phase structure at a temperature in the range from greater than 25°C to less than rectal temperature. For example, the composition of the present invention may have a lamellar phase structure at a temperature in the range from greater than 25°C to less than 38°C. Thus, the composition of the present invention may have a lamellar phase structure from 25°C to 37°C. The composition of the present invention may have a lamellar phase structure from 25°C to 36°C. The composition 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.

[0295] In an embodiment, the composition may be a lamellar gel at 25°C. The composition of the present invention may be a lamellar gel at a temperature in the range from greater than 25°C to less than rectal temperature. For example, the composition of the present invention may be a lamellar gel at a temperature in the range from greater than 25°C to less than 38°C. Thus, the composition of the present invention may be a lamellar gel from 25°C to 37°C. The composition of the present invention may be a lamellar gel from 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.

[0296] In an embodiment, the lamellar gel has a low structural strength relative to the lipid cubic phase (represented by lower storage modulus and loss modulus values (G' and G", respectively)). Thus, the viscosity of the lamellar gel is less than the viscosity when the composition transforms into the lipid cubic phase. Thus, the lamellar gel is more easily administered to a subject. Suitably, 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 through a conventional enema or rectal administration device.

[0297] The lamellar phase (e.g., lamellar gel) of the composition at ambient temperature is more viscous than a simple aqueous solution of a 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, and as the temperature of the composition rises to rectal temperature, the composition transforms into a higher viscosity phase. Thus, the initial retention of the composition is improved compared to using a conventional simple aqueous solution or suspension of the active agent.

[0298] In an embodiment, when the composition is in the lipid cubic phase, both G’ and G” of the composition are greater than G’ and G” in the lamellar phase. G’ and G” of the lamellar gel can both be lower than G’ and G” of the lipid cubic phase. This may be because the viscosity of the composition in the lamellar phase is lower. This may be because the composition in the lipid cubic phase is more viscous. This may be because as the phase of the composition changes from the lamellar phase to the lipid cubic phase, the viscosity of the composition increases. Thus, a sustained release depot is formed in situ with the lipid cubic phase structure.

[0299] In an embodiment, the composition in the lipid cubic phase is retained in the rectum for about 10 min to about 24 h. The composition in the lipid cubic phase can be retained in the rectum for about 20 min to about 12 h. The composition in the lipid cubic phase can be retained in the rectum for about 30 min to about 6 h. The composition in the lipid cubic phase can be retained in the rectum for about 10 min, 20 min, 30 min, 40 min, 50 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h or 24 h. Preferably, the composition in the lipid cubic phase can be retained in the rectum for at least 30 min

[0300] In an embodiment, the composition has a zero-shear viscosity of 1 x 10 -1 to 1 x 10 6 measured at 25 °C and at a shear rate of 0.01 s 7 using a stress-controlled rheometer (Modular Compact Rheometer MCR 72, from Anton Paar, Graz, Austria) with a cone-plate geometry, an angle of 0.993° and a diameter of 49.942 mm. The composition can have a zero-shear viscosity of 1 x 10 -1 mPa·s, 2 x 10 6 mPa·s, 3 x 10 6 mPa·s, 4 x 10 6 mPa·s, 5 x 10 6 mPa·s, 6 x 10 6 mPa·s, 7 x 10 6 mPa·s, 8 x 10 6 mPa·s, 9 x 10 6 mPa·s or 1 x 10 6 mPa·s measured at 25 °C and 0.01 s 7 . The composition can have a zero-shear viscosity of 1 x 10 -1 measured at 25 °C and 0.01 s 6The zero-shear viscosity of mPa·s. The composition may have a zero-shear viscosity of 1 x 10 -1 measured at 25 °C and 0.01 s 7 mPa·s.

[0301] In an embodiment, the composition has a lamellar phase structure and has a zero-shear viscosity of 1 x 10 -1 measured at 25 °C and 0.01 s 6 mPa·s to 1 x 10 7 mPa·s. The composition may have a lamellar phase structure and have a zero-shear viscosity of 1 x 10 -1 measured at 25 °C and 0.01 s 6 mPa·s, 2 x 10 6 mPa·s, 3 x 10 6 mPa·s, 4 x 10 6 mPa·s, 5 x 10 6 mPa·s, 6 x 10 6 mPa·s, 7 x 10 6 mPa·s, 8 x 10 6 mPa·s, 9 x 10 6 mPa·s or 1 x 10 7 mPa·s.

[0302] In an embodiment, the composition has a lipid cubic phase structure and has a viscosity of about 1 x 10 7 mPa·s to about 1 x 10 9 mPa·s measured at 38 °C. The composition may have a lipid cubic phase structure and have a viscosity of about 1 x 10 7 mPa·s to about 1 x 10 8 mPa·s measured at 38 °C. The composition may have a lipid cubic phase structure and have a viscosity of about 1 x 10 8 mPa·s to about 1 x 10 9 mPa·s.

[0303] In an embodiment, the composition is an enema composition. Thus, in an embodiment, the composition is administered rectally as an enema to the lower colon of a subject. A unit dose of the enema preparation can be administered from a pre-filled bag or syringe. The composition can be administered rectally as an enema to the sigmoid colon, descending colon, and / or rectum of a subject.

[0304] When measured at 25 °C, the viscosity of the enema composition is preferably from 10,000 to 70,000 mPa·s, more preferably from 10,000 to 70,000 mPa·s, and most preferably from 10,000 to 40,000 mPa·s. The pH is preferably from 5.5 to 7.5, more preferably from 6.5 to 7.5.

[0305] Once administered to a subject (e.g., as an enema), the composition having a lamellar phase structure will gradually absorb heat (and an available amount of water) from the body and transform into a lipid cubic phase, thereby forming a controlled release depot in situ. The composition can adhere to the colon wall and thereby form a bioadhesive controlled release depot in situ. The composition can adhere to the walls of the sigmoid colon, descending colon, and / or rectum and thereby form a bioadhesive controlled release depot in situ.

[0306] In an embodiment, the composition forms a lipid cubic phase in situ. The term "in situ" can be considered to mean that once the composition is administered to a subject, the composition undergoes a phase transition from a lamellar phase structure to a lipid cubic phase, and the composition 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 by SAXS and determined after equilibration at the desired temperature.

[0307] Preferably, the composition is administered to a subject rectally (e.g., as an enema). Thus, "in situ" can be considered to mean that once the composition is injected into the rectum of a subject, the composition undergoes a phase transition from a lamellar phase structure to a lipid cubic phase, and the composition reaches a temperature of 36 °C to 39 °C, preferably 38 °C (i.e., rectal temperature).

[0308] In an embodiment, the composition forms a lipid cubic phase at a temperature of about 36 °C to about 39 °C. The composition can 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.

[0309] The composition can form a lipid cubic phase at rectal temperature. Thus, the composition can form a lipid cubic phase 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 composition can form a lipid cubic phase at a temperature of 38 °C.

[0310] In an embodiment, the composition forms a lipid cubic phase after about 1 min at a temperature of about 36 °C to about 39 °C. The composition may form a lipid cubic phase after about 1 min to 30 min at a temperature of about 36 °C to about 39 °C. The composition may form a lipid cubic phase after about 1 min to 20 min at a temperature of about 36 °C to about 39 °C. The composition may form a lipid cubic phase after about 1 min to 10 min at a temperature of about 36 °C to about 39 °C. Suitably, the composition may form a lipid cubic phase after about 5 min at a temperature of about 38 °C.

[0311] In an embodiment, the composition is transformed into a lipid cubic phase by contacting with water, body fluid, and / or other aqueous media at a temperature of about 36 °C to about 39 °C. The composition may be transformed into a lipid cubic phase by contacting with water, body fluid, and / or other aqueous media at a temperature of 38 °C. The body fluid may be fluid from a mucosal surface, gastrointestinal fluid, extravascular fluid, extracellular fluid, interstitial fluid, or plasma.

[0312] In an embodiment, the composition is transformed in situ into a lipid cubic phase by contacting with water, body fluid, and / or other aqueous media. Thus, the composition can be administered to a subject (e.g., rectally to a subject, e.g., as an enema), and the composition is transformed from a lamellar phase structure into a lipid cubic phase structure by contacting with water, body fluid, and / or other aqueous media at a temperature of about 36 °C to about 39 °C. The composition can be administered to a subject rectally (e.g., as an enema), and the composition is transformed from a lamellar phase structure into a lipid cubic phase structure by contacting with water, body fluid, and / or other aqueous media at rectal temperature. The composition can be administered to a subject rectally (e.g., as an enema), and the composition is transformed from a lamellar phase structure into a lipid cubic phase structure by contacting with water, body fluid, and / or other aqueous media at a temperature of 38 °C.

[0313] In an embodiment, the composition forms a lipid cubic phase in a pH range of about 5 to about 9. The composition may form a lipid cubic phase in a pH range of about 6 to about 8. The composition may form a lipid cubic phase in a 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.

[0314] In an embodiment, the composition is substantially free of organic solvents. Thus, the composition may contain less than 10% organic solvent. It may mean that the composition contains less than 5% organic solvent. It may mean that the composition contains less than 1% organic solvent. It may mean that the composition contains less than 0.01% organic solvent. It may mean that the composition contains less than 0.001% organic solvent. It may mean that the composition contains no detectable organic solvent.

[0315] In an embodiment, the composition is substantially free of other lipids. Thus, the composition may contain less than 10% other lipids. It may mean that the composition contains less than 5% other lipids. It may mean that the composition contains less than 1% other lipids. It may mean that the composition contains less than 0.01% other lipids. It may mean that the composition contains less than 0.001% other lipids. It may mean that the composition contains no detectable other lipids.

[0316] In an embodiment, the composition is substantially free of other lipid components. Thus, the composition may contain less than 10% other lipid components. It may mean that the composition contains less than 5% other lipid components. It may mean that the composition contains less than 1% other lipid components. It may mean that the composition contains less than 0.01% other lipid components. It may mean that the composition contains less than 0.001% other lipid components. It may mean that the composition contains no detectable other lipid components.

[0317] In an embodiment, the composition is substantially free of additives. Thus, the composition may contain less than 10% additives. It may mean that the composition contains less than 5% additives. It may mean that the composition contains less than 1% additives. It may mean that the composition contains less than 0.01% additives. It may mean that the composition contains less than 0.001% additives. It may mean that the composition contains no detectable other additives.

[0318] carrier

[0319] In an embodiment, the composition comprises a carrier, wherein the carrier comprises more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier. The carrier may consist of more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier.

[0320] In an embodiment, the composition comprises a carrier, wherein the carrier comprises more than 10% to 25% water and 75% to 90% lipid, wherein the % is weight % based on the weight of the carrier. In a preferred embodiment, the carrier consists of more than 10% to 25% water and 75% to 90% lipid, wherein the % is weight % based on the weight of the carrier.

[0321] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Suitably, the lipid in the carrier is glyceryl mono-linoleate. Thus, in an embodiment, the carrier comprises more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. In a preferred embodiment, the carrier consists of more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[0322] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. In an embodiment, the monoacylglycerol lipid comprises glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. Suitably, the lipid in the carrier is glyceryl mono-linoleate. Thus, in an embodiment, the carrier comprises more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. In an embodiment, the carrier comprises more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In a preferred embodiment, the carrier consists of more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The carrier may consist of more than 10% to 30% water and 70% to 90% lipid, wherein the % is weight % based on the weight of the carrier, and wherein the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof.

[0323] In an embodiment, the carrier comprises from more than 10% to 30% water, where the % is weight % based on the weight of the carrier. For example, the carrier may comprise 10% to 30% water, 20% to 30% water, 10% to 25% water, 11% to 20% water, or 14% to 18% water, where the % is weight % based on the weight of the carrier. The carrier may comprise 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 comprise 16% water.

[0324] In an embodiment, 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 greater than about 18 MΩ·cm at 25 °C). In certain embodiments, the water used in the carrier is phosphate buffered saline. In an embodiment, the water used in the carrier is water for injection (WFI).

[0325] In an embodiment, the carrier comprises 70% to 90% lipid, where the % is 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 the % is 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.

[0326] In an embodiment, the carrier comprises 70% to 90% lipid, where the % is 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 the % is 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 the % is 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.

[0327] In an embodiment, the carrier may comprise more than 10% to 20% water and 80% to 90% lipid. In a preferred embodiment, the carrier may comprise 16% water and 84% lipid.

[0328] In an embodiment, the carrier may comprise more than 10% to 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.

[0329] In other embodiments, the carrier may comprise 20% to 30% water and 70% to 80% lipid.

[0330] In an embodiment, the carrier comprises 75% to 90% monoacylglycerol lipid, wherein the % is weight % based on the weight of the carrier, and wherein the monoacylglycerol lipid comprises glyceryl monolinoleate or glyceryl monooleate or a combination thereof. The carrier may comprise 75% to 90% monoacylglycerol lipid, 80% to 90% monoacylglycerol lipid or 84% to 88% monoacylglycerol lipid, wherein the % is 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, wherein the % is 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 glyceryl monolinoleate or glyceryl monooleate or a combination thereof. The carrier may comprise 86% monoacylglycerol lipid. Preferably, the carrier may comprise 84% monoacylglycerol lipid.

[0331] In an embodiment, the carrier comprises 75% to 90% glyceryl monolinoleate, wherein the % is weight % based on the weight of the carrier. The carrier may comprise 75% to 90% glyceryl monolinoleate, 80% to 90% glyceryl monolinoleate or 84% to 88% glyceryl monolinoleate, wherein the % is 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% glyceryl monolinoleate. Preferably, the carrier may comprise 86% glyceryl monolinoleate.

[0332] In an embodiment, the carrier comprises 75% to 90% glyceryl mono - linoleate, wherein the % is weight % based on the weight of the carrier. The carrier may comprise 75% to 90% glyceryl mono - linoleate, 80% to 90% glyceryl mono - linoleate or 84% to 88% glyceryl mono - linoleate, wherein the % is weight % based on the weight of the carrier. The carrier may comprise 75% to 90% glyceryl mono - linoleate, 80% to 90% glyceryl mono - linoleate, 82% to 86% glyceryl mono - linoleate or 84% to 88% glyceryl mono - linoleate, wherein the % is 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% glyceryl mono - linoleate. The carrier may comprise 86% glyceryl mono - linoleate. Preferably, the carrier may comprise 84% glyceryl mono - linoleate.

[0333] In an embodiment, the composition comprises:

[0334] a) a carrier, which comprises:

[0335] a1) water in an amount of more than 10% to 20% of the weight of the carrier; and

[0336] a2) glyceryl mono - linoleate in an amount of 80% to 90% of the weight of the carrier; and

[0337] b) a pharmaceutically active agent,

[0338] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C.

[0339] In an embodiment, the composition comprises:

[0340] a) a carrier, which comprises:

[0341] a1) water in an amount of 16% of the weight of the carrier; and

[0342] a2) glyceryl mono - linoleate in an amount of 84% of the weight of the carrier; and

[0343] b) a pharmaceutically active agent,

[0344] wherein 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. Thus, the composition may comprise:

[0345] a) a carrier, which comprises:

[0346] a1) water in an amount of 16% of the weight of the carrier; and

[0347] a2) glyceryl mono - linoleate, in an amount of 84% of the weight of the carrier; and

[0348] b) a pharmaceutically active agent,

[0349] wherein the composition forms a lipid cubic phase at a temperature of 38 °C.

[0350] In an embodiment, the carrier comprises 70% to 90% glyceryl mono - oleate, wherein the % is by weight based on the weight of the carrier. The carrier may comprise 70% to 90% glyceryl mono - oleate, 70% to 85% glyceryl mono - oleate, or 70% to 80% glyceryl mono - oleate, wherein the % 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% glyceryl mono - oleate.

[0351] In an embodiment, the composition comprises:

[0352] a) a carrier, which comprises:

[0353] a1) water, in an amount of more than 20% to 30% of the weight of the carrier; and

[0354] a2) glyceryl mono - oleate, in an amount of 70% to 80% of the weight of the carrier; and

[0355] b) a pharmaceutically active agent,

[0356] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. In an embodiment, the composition comprises:

[0357] a) a carrier, which comprises:

[0358] a1) water, in an amount of 20% of the weight of the carrier; and

[0359] a2) glyceryl mono - oleate, in an amount of 80% of the weight of the carrier; and

[0360] b) a pharmaceutically active agent,

[0361] wherein 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. Thus, the composition may comprise:

[0362] a) a carrier, which comprises:

[0363] a1) water, in an amount of 20% of the weight of the carrier; and

[0364] a2) glyceryl mono - oleate, in an amount of 80% of the weight of the carrier; and

[0365] b) a pharmaceutically active agent,

[0366] wherein the composition forms a lipid cubic phase at a temperature of 38 °C.

[0367] In an embodiment, the composition comprises:

[0368] a) a carrier, which comprises:

[0369] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[0370] a2) a monoacylglycerol lipid in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0371] b) a pharmaceutically active agent,

[0372] wherein 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 glyceryl mono - linoleate.

[0373] In an embodiment, the composition comprises:

[0374] a) a carrier, which comprises:

[0375] a1) water in an amount of more than 10% to 20% by weight of the carrier; and

[0376] a2) a monoacylglycerol lipid in an amount of 80% to 90% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0377] b) a pharmaceutically active agent,

[0378] wherein 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 glyceryl mono - linoleate.

[0379] In an embodiment, the composition comprises:

[0380] a) a carrier, which comprises:

[0381] a1) water in an amount of more than 14% to 18% by weight of the carrier; and

[0382] a2) A monoacylglycerol lipid, in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof; and

[0383] b) A pharmaceutically active agent,

[0384] wherein 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 glyceryl mono-linoleate.

[0385] In an embodiment, the composition comprises:

[0386] a) A carrier, which comprises:

[0387] a1) Water, in an amount of 16% by weight of the carrier; and

[0388] a2) A monoacylglycerol lipid, in an amount of 84% by weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof; and

[0389] b) A pharmaceutically active agent,

[0390] wherein 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 glyceryl mono-linoleate.

[0391] In an embodiment, the composition comprises:

[0392] a) A carrier, which comprises:

[0393] a1) Water, in an amount of 14% to 18% by weight of the carrier; and

[0394] a2) A monoacylglycerol lipid, in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono-linoleate; and

[0395] b) A pharmaceutically active agent, in an amount of 0.1% to 10% by weight of the composition,

[0396] wherein 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 of glyceryl mono-linoleate.

[0397] In an embodiment, the composition comprises:

[0398] a) A carrier, comprising:

[0399] a1) Water, in an amount of 14% to 18% by weight of the carrier; and

[0400] a2) Monoacylglycerol lipids, in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipids comprise at least 50% by weight of glyceryl mono - linoleate; and

[0401] b) A pharmaceutically active agent, in an amount of 1% to 5% by weight of the composition,

[0402] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. The composition can form a lipid cubic phase at rectal temperature. The composition can form a lipid cubic phase at 38°C. The monoacylglycerol lipids can comprise at least 55% by weight of glyceryl mono - linoleate.

[0403] In an embodiment, the composition comprises:

[0404] a) A carrier, comprising:

[0405] a1) Water, in an amount of 16% by weight of the carrier; and

[0406] a2) Monoacylglycerol lipids, in an amount of 84% by weight of the carrier, wherein the monoacylglycerol lipids comprise at least 50% by weight of glyceryl mono - linoleate; and

[0407] b) A pharmaceutically active agent, in an amount of 1% to 5% by weight of the composition,

[0408] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. The composition can form a lipid cubic phase at rectal temperature. The composition can form a lipid cubic phase at 38°C. The monoacylglycerol lipids can comprise at least 55% by weight of glyceryl mono - linoleate, for example, at least about 60% by weight of glyceryl mono - linoleate.

[0409] pharmaceutically active agent

[0410] In an embodiment, the composition comprises at least one pharmaceutically active agent. Thus, the composition can comprise one pharmaceutically active agent. The composition can comprise more than one pharmaceutically active agent. For example, the composition can comprise two pharmaceutically active agents. The composition can comprise two or more pharmaceutically active agents. For example, the composition can comprise three pharmaceutically active agents. The composition can comprise four pharmaceutically active agents.

[0411] In an embodiment, the composition comprises up to 20% w / w of a pharmaceutically active agent. Thus, the composition may comprise from 0.1% to 20% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition comprises up to 10% w / w of the pharmaceutically active agent. The composition may comprise from 0.1% to 10% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise:

[0412] a) a carrier, which comprises:

[0413] a1) water in an amount of more than 10% to 30% of the weight of the carrier; and

[0414] a2) a lipid in an amount of 70% to 90% of the weight of the carrier; and

[0415] b) a pharmaceutically active agent in an amount of 0.1% to 10% of the weight of the composition,

[0416] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0417] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0418] The composition may comprise from 0.1% to 10% of the pharmaceutically active agent, from 0.5% to 10% of the pharmaceutically active agent, from 0.5% to 7.5% of the pharmaceutically active agent or from 1% to 5% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. For example, 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 pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. Preferably, the composition may comprise from 0.1% to 10% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. More preferably, the composition may comprise from 1% to 5% of the pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise:

[0419] a) a carrier, which comprises:

[0420] a1) water in an amount of more than 10% to 30% of the weight of the carrier; and

[0421] a2) a lipid in an amount of 70% to 90% of the weight of the carrier; and

[0422] b) a pharmaceutically active agent in an amount of 1% to 5% of the weight of the composition,

[0423] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0424] Wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C.

[0425] The composition may comprise:

[0426] a) a carrier, which comprises:

[0427] a1) water, in an amount of more than 10% to 25% by weight of the carrier; and

[0428] a2) a lipid, in an amount of 75% to 90% by weight of the carrier; and

[0429] b) a pharmaceutically active agent, in an amount of 1% to 5% by weight of the composition,

[0430] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate, preferably glyceryl mono-linoleate,

[0431] Wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. In this case, the total composition comprises:

[0432] (i) 1% w / w to 5% w / w of a pharmaceutically active agent;

[0433] (ii) 71.25% w / w to 89.1% w / w lipid; and

[0434] (iii) 9.5% w / w to 24.75% w / w water.

[0435] For example, the composition may comprise 1% of a pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition may comprise: a) a carrier, which comprises: a1) water, in an amount of 16% by weight of the carrier; and a2) a lipid, in an amount of 84% by weight of the carrier; and b) a pharmaceutically active agent, in an amount of 1% by weight of the composition. Thus, the composition may comprise:

[0436] a) 99% of a carrier (wherein the % is % by weight of the composition), wherein the carrier comprises:

[0437] a1) water, in an amount of 16% by weight of the carrier; and

[0438] a2) a lipid, in an amount of 84% by weight of the carrier; and

[0439] b) 1% of a pharmaceutically active agent (wherein the % is % by weight of the composition),

[0440] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0441] Wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Preferably, the lipid is glyceryl mono-linoleate. In this case, the total composition comprises:

[0442] (i) 1% w / w of a pharmaceutically active agent;

[0443] (ii) 83.16% w / w of glyceryl mono-linoleate; and

[0444] (iii) 15.84% w / w of water.

[0445] In another embodiment, the composition may comprise 5% of a pharmaceutically active agent, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition may comprise: a) a carrier, which comprises: a1) water in an amount of 16% of the weight of the carrier; and a2) a lipid in an amount of 84% of the weight of the carrier; and b) a pharmaceutically active agent in an amount of 5% of the weight of the composition. Thus, the composition may comprise:

[0446] a) 95% of a carrier (wherein the % is % of the weight of the composition), wherein the carrier comprises:

[0447] a1) water in an amount of 16% of the weight of the carrier; and

[0448] a2) a lipid in an amount of 84% of the weight of the carrier; and

[0449] b) 5% of a pharmaceutically active agent (wherein the % is % of the weight of the composition),

[0450] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0451] Wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Preferably, the lipid is glyceryl mono-linoleate. In this case, the total composition comprises:

[0452] (i) 5% w / w of a pharmaceutically active agent;

[0453] (ii) 79.8% w / w of glyceryl mono-linoleate; and

[0454] (iii) 15.2% w / w of water.

[0455] In other embodiments, the composition may comprise: a) a carrier, which comprises: a1) water in an amount of 20% of the weight of the carrier; and a2) a lipid in an amount of 80% of the weight of the carrier; and b) a pharmaceutically active agent in an amount of 1% of the weight of the composition. Thus, the composition may comprise:

[0456] a) 99% of a carrier (wherein said % is % by weight of the composition), wherein said carrier comprises:

[0457] a1) water in an amount of 20% by weight of the carrier; and

[0458] a2) lipid in an amount of 80% by weight of the carrier; and

[0459] b) 1% of a pharmaceutically active agent (wherein said % is % by weight of the composition),

[0460] wherein said lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0461] wherein said composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Preferably, said lipid is glyceryl mono - oleate. In this case, the total composition comprises:

[0462] (i) 1% w / w of a pharmaceutically active agent;

[0463] (ii) 79.2% w / w of glyceryl mono - oleate; and

[0464] (iii) 19.8% w / w of water.

[0465] In another embodiment, the composition may comprise: a) a carrier which comprises: a1) water in an amount of 20% by weight of the carrier; and a2) 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. Thus, the composition may comprise:

[0466] a) 95% of a carrier (wherein said % is % by weight of the composition), wherein said carrier comprises:

[0467] a1) water in an amount of 20% by weight of the carrier; and

[0468] a2) lipid in an amount of 80% by weight of the carrier; and

[0469] b) 5% of a pharmaceutically active agent (wherein said % is % by weight of the composition),

[0470] wherein said lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0471] wherein said composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Preferably, said lipid is glyceryl mono - oleate. In this case, the total composition comprises:

[0472] (i) 5% w / w of a pharmaceutically active agent;

[0473] (ii) 76% w / w glyceryl mono - linoleate; and

[0474] (iii) 19% w / w water.

[0475] In embodiments, the pharmaceutically active agent is selected from hydrophilic pharmaceutically active agents or hydrophobic pharmaceutically active agents. Thus, the pharmaceutically active agent can be a hydrophilic pharmaceutically active agent. Thus, the pharmaceutically active agent can be water - soluble. In other embodiments, the pharmaceutically active agent can be a hydrophobic pharmaceutically active agent. Thus, the pharmaceutically active agent can be a lipophilic pharmaceutically active agent.

[0476] In embodiments, the pharmaceutically active agent is dissolved in the carrier. In other embodiments, the pharmaceutically active agent is suspended in the carrier.

[0477] In embodiments, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent, which is dissolved in water to provide a drug mixture, as detailed in the "Preparation Method" section herein.

[0478] In embodiments, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent, which is not dissolved in water. The hydrophobic pharmaceutically active agent can be mixed with lipids and hydrated in water to provide a lipid - drug mixture, as detailed in the "Preparation Method" section herein.

[0479] In certain 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, even more preferably less than 30 mL or 10 mL of solvent to dissolve at a given pH (at 25.0 ± 0.5 °C). "Soluble" can mean that the substance has a negative logP. In embodiments, the pharmaceutically active agent is soluble in water at pH 7.0 and 25.0 ± 0.5 °C.

[0480] In other embodiments, the pharmaceutically active agent is insoluble in water. "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., at pH 7.0 and 25.0 ± 0.5 °C). "Insoluble" can mean that the substance has a positive logP.

[0481] The pharmaceutically active ingredient is not particularly limited and can be selected by those skilled in the art according to needs.

[0482] In an embodiment, the composition can be used for treating or preventing IBD (specifically, ulcerative colitis). In an embodiment, the composition can be used for inhibiting IBD (specifically, ulcerative colitis) or preventing the progression of the disease. Thus, the composition can comprise at least one pharmaceutically active agent selected from the following: anti-inflammatory agents (such as 5-ASA, 4-ASA, sulfasalazine, and balsalazide); non-steroidal anti-inflammatory agents (such as ibuprofen and diclofenac); steroids (such as prednisolone; budesonide, hydrocortisone, or fluticasone); immunosuppressants (such as azathioprine; cyclosporine; tacrolimus, and methotrexate); antibiotics (such as metronidazole, ciprofloxacin, amoxicillin, tetracycline, and sulfamethoxazole); and biopharmaceuticals, including peptides, proteins, antibodies, and antibody fragments. Suitable examples of biopharmaceuticals include alkaline phosphatase and anti-TNF antibodies such as infliximab, adalimumab, certolizumab pegol, golimumab, and ustekinumab.

[0483] In an embodiment, the pharmaceutically active agent is selected from biopharmaceuticals, anti-inflammatory agents, corticosteroids, immunosuppressants, antifungal agents, antibiotics, antifibrotic agents, and anticancer agents. In an embodiment, the pharmaceutically active agent is selected from biopharmaceuticals (such as anti-TNF antibodies, IL-23 inhibitors, IL-12 inhibitors, TLR9 agonists, anti-MAdCAM antibodies, human IL-22Fc fusion proteins, interleukins, anti-β7 integrin antibodies, matrix metalloproteinase 9 (MMP9) inhibitors), JAK inhibitors, PDE4 inhibitors, sphingosine-1-phosphate receptor modulators, anti-inflammatory agents, corticosteroids, immunosuppressants, antifungal agents, antibiotics, antifibrotic agents, and anticancer agents.

[0484] In an embodiment, the pharmaceutically active agent is a biopharmaceutical, for example, a peptide, a protein, an antibody, or an antibody fragment. In an embodiment, the pharmaceutically active agent is an antibody or a functional fragment thereof. In an embodiment, the pharmaceutically active agent is a peptide.

[0485] In an embodiment, the pharmaceutically active agent is an antibody or a functional fragment thereof and is suitable for treating gastrointestinal diseases such as inflammatory bowel disease (IBD) (such as Crohn's disease or ulcerative colitis), cancer (such as colorectal cancer or small intestine cancer), celiac disease, or infection (such as Clostridium difficile infection), more preferably IBD.

[0486] There is no particular limitation on the antibody or its functional fragment used in the composition. In one embodiment, the antibody or its functional fragment is an antibody. In another embodiment, the antibody or its functional fragment is a functional fragment as defined herein. The antibody or its functional fragment may further comprise one or more modifications, such as in the form of added or replaced residues, which enhance stability, specificity or targeting. These may include any such modifications known in the art.

[0487] There is no limitation on the antigen to which the antibody or functional fragment is directed, i.e., the immunogen, peptide, protein or other molecular structure to which the antibody or its functional fragment can specifically bind. In its most general form (and when no explicit reference is made), "specific for" or "specifically binds to" means that the antibody or its functional fragment is able to distinguish the target of interest from unrelated biomolecules (e.g., an antibody specific for human TNFα can distinguish human TNFα from unrelated biomolecules), e.g., as determined by specific assays known in the art.

[0488] In an embodiment, the antibody or its functional fragment is selected from: an antibody specific for tumor necrosis factor α (TNFα) and its functional fragment, an antibody specific for α4β7 integrin and its functional fragment, an antibody specific for CD3, CD4 or CD20 and their functional fragments, an antibody specific for interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors and their functional fragments, an antibody specific for Janus kinase (JAK) and its functional fragment, an antibody specific for CXCL10 / IP-10 and its functional fragment, and an antibody specific for the p40 protein subunit and its functional fragment. In an embodiment, the antibody or its functional fragment is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, vedolizumab, edrucizumab, alirocumab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, tofacitinib or vedolizumab, and their functional fragments.

[0489] In an embodiment, the antibody or its functional fragment in the composition specifically binds to TNFα. The terms "anti-TNFα antibody", "TNFα antibody" and "antibody specific for TNFα" used herein are interchangeable. In one embodiment, specific binding means the ability of the antibody or fragment to distinguish human TNFα from human TNFβ. In a preferred embodiment of the present invention, the TNFα antibody or its functional fragment is a TNFα antibody. In another preferred embodiment of the present invention, the TNFα antibody or its functional fragment is a functional fragment of a TNFα antibody.

[0490] Currently approved anti-TNFα biotherapeutics include: (i) infliximab, a chimeric IgG anti-human monoclonal antibody (ii) etanercept, a TNFR2 dimer fusion protein with IgG1 Fc (iii) adalimumab, a fully human monoclonal antibody (mAb) (iv) certolizumab, a pegylated Fab fragment and (v) golimumab, a human IgG1κ monoclonal antibody Thus, in an embodiment, the antibody or its functional fragment is selected from infliximab, adalimumab, etanercept, certolizumab pegol, and golimumab or its functional fragment.

[0491] In an embodiment, the pharmaceutically active agent is an anti-tumor necrosis factor-α inhibitor (TNF inhibitor). The TNF inhibitor can be selected from adalimumab, certolizumab, and infliximab. In an embodiment, the pharmaceutically active agent is an anti-integrin agent. The anti-integrin agent can 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 such as ustekinumab. In an embodiment, the pharmaceutically active agent is a JAK inhibitor such as tofacitinib. In a preferred embodiment, the pharmaceutically active agent is tofacitinib.

[0492] In an embodiment, the pharmaceutically active agent is an anti-inflammatory agent. The anti-inflammatory agent can be a corticosteroid such as prednisolone. Corticosteroids are steroids that help reduce inflammation and the immune response. The composition can contain a corticosteroid. The composition can contain a corticosteroid and 5-ASA. Appropriately, corticosteroids are not used for long-term treatment to maintain remission in UC. Thus, a composition containing a corticosteroid can be used for short-term treatment of UC.

[0493] In an embodiment, the pharmaceutically active agent is a corticosteroid selected from beclomethasone dipropionate, budesonide, hydrocortisone, methylprednisolone, prednisone, and prednisolone.

[0494] In an embodiment, the pharmaceutically active agent is an anti-inflammatory agent, wherein the anti-inflammatory agent is an aminosalicylate. It should be understood that aminosalicylates reduce inflammation of the intestinal wall lining, thereby alleviating symptoms of IBD (such as ulcerative colitis) and / or Crohn's disease. Appropriately, the composition can contain an aminosalicylate, wherein the composition is used for the treatment of mild to moderate flares of Crohn's disease.

[0495] In an embodiment, the pharmaceutically active agent is an aminosalicylate selected from balsalazide, mesalazine, olsalazine, and sulfasalazine.

[0496] It should be understood that Crohn's disease is caused by problems with the immune system, where cells that normally protect the body instead attack the gastrointestinal tract. Thus, pharmaceutical active agents that inhibit or regulate the immune system (i.e., immunosuppressants) are commonly used to treat Crohn's disease.

[0497] In an embodiment, the pharmaceutical active agent is an immunosuppressant. The composition can be used to treat fistulas, such as perianal fistulas associated with IBD, or vaginal fistulas, wherein the composition comprises an immunosuppressant.

[0498] A composition comprising an immunosuppressant can be administered to a subject as an alternative treatment to aminosalicylates and / or corticosteroids.

[0499] In an embodiment, the pharmaceutical active agent is an immunosuppressant selected from the group consisting of azathioprine, cyclosporine, mercaptopurine, methotrexate, mycophenolate mofetil, or tacrolimus. Preferably, the pharmaceutical active agent can be tacrolimus.

[0500] In an embodiment, the pharmaceutical active agent can be an antifungal agent for treating fungal infections. The antifungal agent can be:

[0501] (i) polyenes (such as amphotericin B (such as amphotericin B deoxycholate, amphotericin B liposome, amphotericin B lipid complex, or amphotericin B colloidal dispersion), candicidin, filipin, hamycin, natamycin, nystatin, or rimocidin);

[0502] (ii) triazoles, preferably triazoles other than the compounds of the present invention (such as abaconazole, isavuconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, or voriconazole);

[0503] (iii) imidazoles (such as bifonazole, butoconazole, clotrimazole, econazole, eberconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, or tioconazole);

[0504] (iv) thiazoles (such as abafungin);

[0505] (v) echinocandins (such as anidulafungin, biafungin, caspofungin, or micafungin);

[0506] (vi) allylamines (such as amorolfine, butenafine, naftifine, or terbinafine); or

[0507] (vii) amorolfine, ciclopirox, griseofulvin, or flucytosine (5 - fluorocytosine).

[0508] In certain embodiments, the pharmaceutically active agent is an antifungal agent selected from clotrimazole or fluconazole. Accordingly, the composition may comprise clotrimazole. The composition may comprise fluconazole.

[0509] In an embodiment, the pharmaceutically active agent may be an antibiotic. A composition comprising an antibiotic is used to treat bacterial infections, such as those caused by Crohn's disease. For example, the bacterial infections caused by Crohn's disease may be fistulas and / or abscesses.

[0510] In an embodiment, the pharmaceutically active agent is an antibiotic selected from the following: ampicillin, cefotaxime, sulbenicillin, piperacillin, mezlocillin, bacampicillin, cefoxitin, cefazolin, latamoxef, cefotaxime, ceftazidime, gentamicin, tobramycin, erythromycin, metronidazole, tinidazole, fluconazole, mupirocin, demethylchlortetracycline, retapamulin, chlortetracycline, virginiamycin, chloramphenicol, oxytetracycline, bacitracin, tetracycline, gentamicin, ciprofloxacin, rifaximin, and vancomycin.

[0511] In an embodiment, the pharmaceutically active agent may be an anti-fibrotic agent. Accordingly, the composition may comprise an anti-fibrotic agent, wherein the anti-fibrotic agent is selected from pirfenidone or nintedanib.

[0512] In an embodiment, the composition of the present invention is used to treat cancer. Suitably, the composition of the present invention is used to treat cancers affecting the gastrointestinal tract, particularly the lower gastrointestinal tract, and especially the colon. Accordingly, the composition may be used to treat colorectal cancer. Accordingly, the pharmaceutically active agent in the composition may be an anti-cancer agent. Alternatively, the composition may further comprise an anti-cancer agent.

[0513] 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:

[0514] (i) Anti-proliferative / anti-neoplastic drugs and their combinations, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, nitrogen mustard, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylenemelamine, thiotepa (triethylenethiophoporamine), carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytarabine, floxuridine, arabinosylcytosine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine and hydroxyurea); antibiotics (e.g., anthracycline antibiotics such as doxorubicin, bleomycin, adriamycin, daunomycin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mithramycin); anti-mitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine and taxanes such as Taxol and Taxotere and polo kinase inhibitors); proteasome inhibitors, e.g., carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and camptothecin); bleomycin, actinomycin D, daunorubicin, adriamycin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol TM ), albumin-bound paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), 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);

[0515] (ii) Cell growth inhibitors such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and inhibitors of 5α-reductase such as finasteride; and navelbine, CPT-ll, anastrozole, letrozole, capecitabine, reloxafme, cyclophosphamide, ifosfamide, and droloxafine;

[0516] (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;

[0517] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM , the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as 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 co-stimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of apoptosis protein regulators (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 such as farnesyltransferase inhibitors, e.g., sorafenib, tipifarnib and lonafarnib), inhibitors of cell signaling through MEK and / or AKT kinases, 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 such as CDK2 and / or CDK4 inhibitors; and CCR2, CCR4 or CCR6 antagonists;

[0518] (v) Anti-angiogenic agents such as those that inhibit the action of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM )]; thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

[0519] (vi) Gene therapy regimens, including, for example, regimens for replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2;

[0520] (vii) Immunotherapy regimens, including, for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab Ofatumumab; interferons such as interferon α; interleukins such as IL-2 (aldesleukin); interleukin inhibitors such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, e.g., Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); toll-like receptor modulators such as 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 (such as dostarlimab); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab; and

[0521] (viii) cytotoxic agents such as fludarabine (Fludara), cladribine, pentostatin (NipentTM).

[0522] In an embodiment, the composition can be used for preventing colon cancer or colorectal cancer, mainly in patients with colitis. Thus, the pharmaceutically active agent can be selected from the anti-inflammatory agents 5-ASA, sulindac, celecoxib, and / or difluoromethylornithine (DFMO).

[0523] In an embodiment, the composition is administered to the subject as an enema. Thus, in an embodiment, the pharmaceutically active agent can be selected from mesalazine, budesonide, prednisolone, hydrocortisone, cobitolimod, tacrolimus, cyclosporine, or tofacitinib.

[0524] Cytokine mediators of inflammation in IBD such as IL-9, IL-12, IL-23, and interferon-gamma (IFN-γ) rely on Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway signaling. Thus, targeting JAK-STAT is an attractive therapeutic approach for IBD. JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) are all part of the JAK tyrosine kinase protein family. Thus, in an embodiment, the pharmaceutically active agent is a JAK inhibitor. In an embodiment, the JAK inhibitor is selected from tofacitinib, filgotinib, upadacitinib, TD-1473, Brepocitinib (PF-06700841), or PF-06651600. In an embodiment, the pharmaceutically active agent is a TYK2 inhibitor. In an embodiment, the TYK2 inhibitor is Brepocitinib (PF-06700841) or BMS-986165.

[0525] IL-23 is a regulator of the T-helper (Th)-17 cell and type 3 innate lymphoid cell (ILC3) pathways, which leads to inflammatory cytokine production and inflammation, and polymorphisms in the IL-23 receptor gene may be associated with an increased susceptibility to Crohn's disease. IL-23 blocks regulatory T-cell responses in the gut and thus increases gut inflammation. In an embodiment, the pharmaceutically active agent is an IL-23 inhibitor. In an embodiment, the IL-23 inhibitor is selected from risankizumab, brazikumab, mirikizumab, or guselkumab.

[0526] In an embodiment, the pharmaceutically active agent is an IL-6 inhibitor. The IL-6 inhibitor can be PF-04236921.

[0527] In an embodiment, the pharmaceutically active agent is a human IL-22Fc fusion protein. The human IL-22Fc fusion protein can be UTTR1147A.

[0528] The migration of pro-inflammatory T cells into the gut promotes the inflammation that is characteristic of Crohn's disease and ulcerative colitis. The interaction between the surface-expressed α4β1 and α4β7 integrins on lymphocytes and the adhesion molecules present on endothelial cells allows activated effector T cells to target the gut. Thus, in embodiments, the pharmaceutically active agent can be an anti-adhesion molecule. The pharmaceutically active agent can be an α4β7 integrin inhibitor. The pharmaceutically active agent can be an α4β7 and αEβ7 integrin inhibitor. The pharmaceutically active agent can be an α4 integrin inhibitor. The pharmaceutically active agent can be selected from vedolizumab, etrolizumab, AJM300, alirocumab (AMG 181 or MEDI 7183), or PF-00547659 (SHP647).

[0529] In embodiments, the pharmaceutically active agent is an anti-TNF agent. The anti-TNF agent can be selected from AVX-470 or OPRX-106.

[0530] In embodiments, the pharmaceutically active agent is a sphingosine-1-phosphate receptor modulator (S1P1-S1P5). The S1P1-S1P5 can be selected from ozanimod, itolimod, or amiselimod (MT-1303).

[0531] In embodiments, the pharmaceutically active agent is a phosphodiesterase 4 (PDE4) inhibitor. The PDE4 inhibitor can be apremilast.

[0532] In embodiments, the pharmaceutically active agent is a Toll-like receptor 9 (TLR9) inhibitor. The TLR9 inhibitor can be cobtiolimod.

[0533] In embodiments, the pharmaceutically active agent is selected from the agents listed in Table 1.

[0534]

[0535]

[0536] Table 1 - Janus kinase (JAK), tyrosine kinase 2 (TYK2), sphingosine 1-phosphate (S1P), sphingosine 1-phosphate receptor (S1PR), phosphodiesterase 4 (PDE4), toll-like receptor 9 (TLR9), α4-β7 (α4β7), α4 (α4), αE-β7 (αEβ7), mucosal addressin cell adhesion molecule-1 (MAdCAM), interleukin 23 (IL-23).

[0537] In embodiments, the pharmaceutically active agent is selected for the treatment of Crohn's disease and / or ulcerative colitis. Thus, the pharmaceutically active agent can be selected from: (Ozanimod), (Adalimumab), (Adalimumab-fkjp), AvsolaTM (Infliximab-axxq), (Infliximab), Abrilada TM (Adalimumab-afzb), HADLIMA (Adalimumab-bwwd), Hyrimoz (Adalimumab-adaz), (Toficitinib), IXIFI TM (Infliximab-qbtx), CYLTEZO TM (Adalimumab-adbm), (Infliximab-abda), (Ustekinumab), AMJEVITA TM (Adalimumab-atto), Mesalazine DR 800mg, INFLECTRATM (Infliximab-dyyb), (Budesonide) and ENTYVIO TM (Vedolizumab).

[0538] In embodiments, the pharmaceutically active agent is selected from: antibodies or functional fragments thereof, anti-inflammatory agents, anti-inflammatory agents, immunosuppressive agents, antifungal agents, antibiotics, anti-fibrotic agents, and anti-cancer agents.

[0539] In an embodiment, the pharmaceutically active agent is selected from: AbGn168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bavituximab, brepocitinib (MEDI2070), cobitolimod, certolizumab pegol, CP-690,550, corticosteroids (e.g., multimax budesonide, methylprednisolone), cyclosporine, E6007, itolimod, etrolizumab, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitor (e.g., GS-5745), mesalazine, mirikizumab (LY3074828), RPC 1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tezepelumab (MK 3222), tacrolimus, Janus kinase inhibitor (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressant (e.g., rapamycin), antifibrotic agent (e.g., pirfenidone, nintedanib) and antifungal agent (e.g., clotrimazole, fluconazole).

[0540] 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 (JAK 1) and / or 3 (JAK 3). Suitably, the Janus kinase inhibitor is tofacitinib (TOFA). The pharmaceutically active agent may be tofacitinib or a pharmaceutically acceptable salt thereof. Thus, the composition may comprise tofacitinib or a pharmaceutically acceptable salt thereof. In an embodiment, the composition comprises up to 20% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition comprises 0.1% to 10% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is weight % based on the weight of the composition. The composition may comprise 0.1% to 10% of tofacitinib or a pharmaceutically acceptable salt thereof, 0.5% to 10% of tofacitinib or a pharmaceutically acceptable salt thereof, 0.5% to 5% of tofacitinib or a pharmaceutically acceptable salt thereof or 1% to 5% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is weight % based on the weight of the composition. For example, the composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise:

[0541] a) A carrier, comprising:

[0542] a1) Water, in an amount of 10% to 30% of the weight of the carrier; and

[0543] a2) Lipid, in an amount of 70% to 90% of the weight of the carrier; and

[0544] b) Tofacitinib or a pharmaceutically acceptable salt thereof, in an amount of 0.1% to 10% of the weight of the composition,

[0545] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0546] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0547] Suitably, in this embodiment, the lipid is glyceryl mono - linoleate.

[0548] The composition may comprise:

[0549] a) A carrier, comprising:

[0550] a1) Water, in an amount of 10% to 30% of the weight of the carrier; and

[0551] a2) Monoacylglycerol lipid, in an amount of 70% to 90% of the weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0552] b) Tofacitinib or a pharmaceutically acceptable salt thereof, in an amount of 0.1% to 10% of the weight of the composition,

[0553] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0554] The composition may comprise:

[0555] a) A carrier, comprising:

[0556] a1) Water, in an amount of 14% to 18% of the weight of the carrier; and

[0557] a2) Monoacylglycerol lipid, in an amount of 82% to 86% of the weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono - linoleate; and

[0558] b) Tofacitinib or a pharmaceutically acceptable salt thereof, in an amount of 0.1% to 10% of the weight of the composition,

[0559] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0560] Preferably, the composition may comprise 1% to 5% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is % by weight based on the weight of the composition. Thus, the composition may comprise:

[0561] a) a carrier, which comprises:

[0562] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0563] a2) a lipid in an amount of 75% to 90% by weight of the carrier; and

[0564] b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 1% to 5% by weight of the composition,

[0565] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0566] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0567] More preferably, the composition may comprise 5% of tofacitinib or a pharmaceutically acceptable salt thereof, wherein the % is % by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition may comprise:

[0568] a) a carrier, which comprises:

[0569] a1) water in an amount of 16% by weight of the carrier; and

[0570] a2) glyceryl mono-linoleate in an amount of 84% by weight of the carrier; and

[0571] b) tofacitinib or a pharmaceutically acceptable salt thereof in an amount of 5% by weight of the composition,

[0572] wherein 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 comprises:

[0573] (i) 5% w / w of tofacitinib or a pharmaceutically acceptable salt thereof;

[0574] (ii) 79.8% w / w glyceryl mono-linoleate; and

[0575] (iii) 15.2% w / w water,

[0576] i.e., the composition comprises 5 mg of TOFA / 100 mg of carrier.

[0577] In other preferred embodiments, the pharmaceutically active agent is tacrolimus (TAC). Accordingly, the composition may comprise tacrolimus. In an embodiment, the composition comprises up to 20% of tacrolimus, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition comprises 0.1% to 10% of tacrolimus, wherein the % is weight % based on the weight of the composition. The composition may comprise 0.1% to 10% of tacrolimus, 0.5% to 10% of tacrolimus, 0.5% to 5% of tacrolimus or 1% to 5% of tacrolimus, wherein the % is weight % based on the weight of the composition. For example, the composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of tacrolimus, wherein the % is weight % based on the weight of the composition. Accordingly, the composition may comprise:

[0578] a) a carrier, comprising:

[0579] a1) water in an amount of more than 10% to 30% of the weight of the carrier; and

[0580] a2) a lipid in an amount of 70% to 90% of the weight of the carrier; and

[0581] b) tacrolimus in an amount of 0.1% to 10% of the weight of the composition,

[0582] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0583] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0584] Preferably, in this embodiment, the lipid is glyceryl mono - linoleate.

[0585] The composition may comprise:

[0586] a) a carrier, comprising:

[0587] a1) water in an amount of 10% to 30% of the weight of the carrier; and

[0588] a2) a monoacylglycerol lipid in an amount of 70% to 90% of the weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0589] b) tacrolimus in an amount of 0.1% to 10% of the weight of the composition,

[0590] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0591] The composition may comprise:

[0592] a) a carrier, which comprises:

[0593] a1) water in an amount of 14% to 18% by weight of the carrier; and

[0594] a2) a monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono - linoleate; and

[0595] b) tacrolimus in an amount of 0.1% to 10% by weight of the composition,

[0596] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0597] Preferably, the composition may comprise 1% to 5% of tacrolimus, wherein the % is % by weight based on the weight of the composition. Thus, the composition may comprise:

[0598] a) a carrier, which comprises:

[0599] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0600] a2) a lipid in an amount of 75% to 90% by weight of the carrier; and

[0601] b) tacrolimus in an amount of 1% to 5% by weight of the composition,

[0602] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0603] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0604] More preferably, the composition may comprise 1% of tacrolimus, wherein the % is % by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition may comprise:

[0605] a) a carrier, which comprises:

[0606] a1) water in an amount of 16% by weight of the carrier; and

[0607] a2) glyceryl mono - linoleate in an amount of 84% by weight of the carrier; and

[0608] b) tacrolimus in an amount of 1% by weight of the composition,

[0609] Wherein 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 comprises:

[0610] (i) 1% w / w tacrolimus;

[0611] (ii) 83.16% w / w glyceryl mono-oleate; and

[0612] (iii) 15.84% w / w water.

[0613] That is, the composition comprises 1 mg of TAC / 100 mg of carrier.

[0614] In other embodiments, the pharmaceutically active agent is clotrimazole. Accordingly, the composition may comprise clotrimazole. In an embodiment, the composition comprises up to 20% of clotrimazole, wherein the % is % by weight based on the weight of the composition. In a preferred embodiment, the composition comprises 0.1% to 10% of clotrimazole, wherein the % is % by weight based on the weight of the composition. The composition may comprise 0.1% to 10% of clotrimazole, 0.5% to 10% of clotrimazole, 0.5% to 5% of clotrimazole or 1% to 5% of clotrimazole, wherein the % is % by weight based on the weight of the composition. For example, the composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of clotrimazole, wherein the % is % by weight based on the weight of the composition. Accordingly, the composition may comprise:

[0615] a) a carrier, which comprises:

[0616] a1) water in an amount of more than 10% to 30% of the weight of the carrier; and

[0617] a2) lipid in an amount of 70% to 90% of the weight of the carrier; and

[0618] b) clotrimazole in an amount of 0.1% to 10% of the weight of the composition,

[0619] wherein the lipid is selected from glyceryl mono-oleate or glyceryl mono-linoleate,

[0620] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. Suitably, in this embodiment, the lipid is glyceryl mono-linoleate.

[0621] The composition may comprise:

[0622] a) a carrier, which comprises:

[0623] a1) Water, in an amount of 10% to 30% by weight of the carrier; and

[0624] a2) Monoacylglycerol lipids, in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipids comprise glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0625] b) Clotrimazole, in an amount of 0.1% to 10% by weight of the composition,

[0626] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0627] The composition may comprise:

[0628] a) A carrier, which comprises:

[0629] a1) Water, in an amount of 14% to 18% by weight of the carrier; and

[0630] a2) Monoacylglycerol lipids, in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipids comprise at least 50% by weight of glyceryl mono - linoleate; and

[0631] b) Clotrimazole, in an amount of 0.1% to 10% by weight of the composition,

[0632] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0633] Preferably, the composition may comprise 1% to 5% of clotrimazole, wherein the % is % by weight based on the weight of the composition. Thus, the composition may comprise:

[0634] a) A carrier, which comprises:

[0635] a1) Water, in an amount of more than 10% to 25% by weight of the carrier; and

[0636] a2) Lipids, in an amount of 75% to 90% by weight of the carrier; and

[0637] b) Clotrimazole, in an amount of 1% to 5% by weight of the composition,

[0638] wherein the lipids are selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0639] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0640] More preferably, the composition may comprise 5% of clotrimazole, wherein the % is % by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition may comprise:

[0641] a) A carrier, comprising:

[0642] a1) Water, in an amount of 16% of the weight of the carrier; and

[0643] a2) Monolinolein, in an amount of 84% of the weight of the carrier; and

[0644] b) Clotrimazole, in an amount of 5% of the weight of the composition,

[0645] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C. The composition can form a lipid cubic phase at a temperature of 38 °C. For the avoidance of doubt, in this embodiment, the total composition comprises:

[0646] (i) 5% w / w clotrimazole;

[0647] (ii) 79.8% w / w monolinolein; and

[0648] (iii) 15.2% w / w water.

[0649] That is, the composition comprises 5 mg of clotrimazole / 100 mg of carrier.

[0650] In an embodiment, the pharmaceutically active agent is mesalazine. It should be understood that mesalazine is also known as 5-aminosalicylic acid (5-ASA). Thus, the pharmaceutically active agent can be 5-ASA.

[0651] In other embodiments, the pharmaceutically active agent is mesalazine. Thus, the composition can comprise mesalazine. In an embodiment, the composition comprises up to 20% of mesalazine, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition comprises 0.1% to 10% of mesalazine, wherein the % is weight % based on the weight of the composition. The composition can comprise 0.1% to 10% of mesalazine, 0.5% to 10% of mesalazine, 0.5% to 5% of mesalazine or 1% to 5% of mesalazine, wherein the % is weight % based on the weight of the composition. For example, the composition can comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of mesalazine, wherein the % is weight % based on the weight of the composition. Thus, the composition can comprise:

[0652] a) A carrier, comprising:

[0653] a1) Water, in an amount of more than 10% to 30% of the weight of the carrier; and

[0654] a2) Lipids, in an amount of 70% to 90% by weight of the carrier; and

[0655] b) Mesalazine, in an amount of 0.1% to 10% by weight of the composition,

[0656] wherein the lipids are selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0657] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0658] Preferably, in this embodiment, the lipid is glyceryl mono - linoleate.

[0659] The composition may comprise:

[0660] a) A carrier, which comprises:

[0661] a1) Water, in an amount of 10% to 30% by weight of the carrier; and

[0662] a2) Monoacylglycerol lipids, in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipids comprise glyceryl mono - linoleate or glyceryl mono - oleate or a combination thereof; and

[0663] b) Mesalazine, in an amount of 0.1% to 10% by weight of the composition,

[0664] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0665] The composition may comprise:

[0666] a) A carrier, which comprises:

[0667] a1) Water, in an amount of 14% to 18% by weight of the carrier; and

[0668] a2) Monoacylglycerol lipids, in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipids comprise at least 50% by weight of glyceryl mono - linoleate; and

[0669] b) Mesalazine, in an amount of 0.1% to 10% by weight of the composition,

[0670] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0671] Preferably, the composition may comprise 1% to 5% of mesalazine, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise:

[0672] a) A carrier, which comprises:

[0673] a1) Water, in an amount of more than 10% to 25% of the weight of the carrier; and

[0674] a2) Lipid, in an amount of 75% to 90% of the weight of the carrier; and

[0675] b) Mesalazine, in an amount of 1% to 5% of the weight of the composition,

[0676] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0677] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0678] More preferably, the composition may comprise 5% of mesalazine, wherein the % is weight % based on the weight of the composition. Thus, in a preferred embodiment, the composition may comprise:

[0679] a) A carrier, which comprises:

[0680] a1) Water, in an amount of 16% of the weight of the carrier; and

[0681] a2) Glyceryl mono - linoleate, in an amount of 84% of the weight of the carrier; and

[0682] b) Mesalazine, in an amount of 5% of the weight of the composition,

[0683] wherein 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 comprises:

[0684] (i) 5% w / w of mesalazine;

[0685] (ii) 79.8% w / w of glyceryl mono - linoleate; and

[0686] (iii) 15.2% w / w of water.

[0687] That is, the composition comprises 5 mg of mesalazine / 100 mg of carrier.

[0688] In other embodiments, the pharmaceutical active agent is budesonide. Accordingly, the composition may comprise budesonide. In an embodiment, the composition comprises up to 20% of budesonide, wherein the % is weight % based on the weight of the composition. In a preferred embodiment, the composition comprises 0.1% to 10% of budesonide, wherein the % is weight % based on the weight of the composition. The composition may comprise 0.1% to 10% of budesonide, 0.5% to 10% of budesonide, 0.5% to 5% of budesonide, or 1% to 5% of budesonide, wherein the % is weight % based on the weight of the composition. For example, the composition may comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of budesonide, wherein the % is weight % based on the weight of the composition. Accordingly, the composition may comprise:

[0689] a) a carrier, comprising:

[0690] a1) water in an amount of more than 10% to 30% of the weight of the carrier; and

[0691] a2) a lipid in an amount of 70% to 90% of the weight of the carrier; and

[0692] b) budesonide in an amount of 0.1% to 10% of the weight of the composition,

[0693] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[0694] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0695] Preferably, in this embodiment, the lipid is glyceryl mono-linoleate.

[0696] The composition may comprise:

[0697] a) a carrier, comprising:

[0698] a1) water in an amount of 10% to 30% of the weight of the carrier; and

[0699] a2) a monoacylglycerol lipid in an amount of 70% to 90% of the weight of the carrier, wherein the monoacylglycerol lipid comprises glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof; and

[0700] b) budesonide in an amount of 0.1% to 10% of the weight of the composition,

[0701] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0702] The composition may comprise:

[0703] a) a carrier, which comprises:

[0704] a1) water in an amount of 14% to 18% by weight of the carrier; and

[0705] a2) a monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl mono - linoleate; and

[0706] b) budesonide in an amount of 0.1% to 10% by weight of the composition,

[0707] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0708] Preferably, the composition may comprise 1% to 5% of budesonide, wherein the % is % by weight based on the weight of the composition. Thus, the composition may comprise:

[0709] a) a carrier, which comprises:

[0710] a1) water in an amount of more than 10% to 25% by weight of the carrier; and

[0711] a2) a lipid in an amount of 75% to 90% by weight of the carrier; and

[0712] b) budesonide in an amount of 1% to 5% by weight of the composition,

[0713] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[0714] wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C.

[0715] More preferably, the composition may comprise 5% of budesonide, wherein the % is % by weight based on the weight of the composition. Thus, in a preferred embodiment, the composition may comprise:

[0716] a) a carrier, which comprises:

[0717] a1) water in an amount of 16% by weight of the carrier; and

[0718] a2) glyceryl mono - linoleate in an amount of 84% by weight of the carrier; and

[0719] b) budesonide in an amount of 5% by weight of the composition,

[0720] Wherein the composition forms a lipid cubic phase at a temperature of 36°C to 39°C. The composition can form a lipid cubic phase at a temperature of 38°C. For the avoidance of doubt, in this embodiment, the total composition comprises:

[0721] (i) 5% w / w of budesonide;

[0722] (ii) 79.8% w / w of glyceryl mono-linoleate; and

[0723] (iii) 15.2% w / w of water.

[0724] That is, the composition comprises 5 mg of budesonide / 100 mg of carrier.

[0725] other additives

[0726] Additives can alter the structure of the lipid mesophase. For example, the addition of incremental amounts of hexadecane or vitamin A can modulate the phase of the glyceryl monooleate-water system. The geometry of the self-assembled mesophase is important in determining the release rate, and thus, the open or closed state of the water channels affects the rate of drug release. Typical lipid mesophases with Pn3m, Im3m or Ia3d symmetry are characterized by having water channels with a diameter of about 3 to 5 nm. This geometric constraint prevents larger hydrophilic molecules (such as hydrophilic proteins, hormones and antibodies) from being included in the mesophase. However, this structural constraint can be overcome by additives that increase the size of the water channels (including hydration regulators such as sucrose stearate, phospholipids and cholesterol). Electrostatic swelling increases the size of the water channels, for example, by doping the lipid with charged lipids that can cause the mesophase to swell.

[0727] Thus, in an embodiment, the composition further comprises an additive. The composition can comprise at least one additive. Thus, the composition can comprise one additive. The composition can comprise more than one additive. For example, the composition can comprise two additives. The composition can comprise three additives. The composition can comprise four additives.

[0728] In an embodiment, the composition further comprises up to 10% of an additive, wherein the % is weight % based on the weight of the composition. Thus, the composition can comprise 0.1% to 10% of an additive, wherein the % is weight % based on the weight of the composition. The composition can comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of an additive, wherein the % is weight % based on the weight of the composition.

[0729] In an embodiment, the additive is selected from vitamin A, sucrose stearate, phospholipids, cholesterol, and electrolytes (such as sodium chloride, sodium sulfate, sodium iodide, and calcium cations).

[0730] In an embodiment, the additive is a negatively charged or positively charged phospholipid. Thus, the additive can be selected from: 1,2-dioleoyl-sn-glycero-3-phosphate-(1'-rac-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS), and 2-dioleoyl-3-trimethylammonium propane (DOTAP). The composition can further comprise cholesterol and a negatively charged or positively charged phospholipid (such as DOPG, DOPS, and DOTAP).

[0731] In an embodiment, the additive is a negatively charged or positively charged phospholipid (such as DOPG, DOPS, and DOTAP). Thus, the composition can further comprise up to 10% of a negatively charged or positively charged phospholipid (such as DOPG, DOPS, or DOTAP), wherein the % is weight % based on the weight of the composition. Thus, the composition can further comprise 0.1% to 10% of a negatively charged or positively charged phospholipid (such as DOPG, DOPS, or DOTAP), wherein the % is weight % based on the weight of the composition. The composition can comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of a negatively charged or positively charged phospholipid (such as DOPG, DOPS, or DOTAP), wherein the % is weight % based on the weight of the composition.

[0732] In an embodiment, the additive is cholesterol. Thus, the composition can further comprise up to 5% of cholesterol, wherein the % is weight % based on the weight of the composition. Thus, the composition can further comprise 0.1% to 5% of cholesterol, wherein the % is weight % based on the weight of the composition. The composition can comprise 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, or 5% of cholesterol, wherein the % is weight % based on the weight of the composition.

[0733] In an embodiment, the composition further comprises cholesterol and negatively or positively charged phospholipids (such as DOPG, DOPS, and DOTAP). The composition may further comprise up to 5% cholesterol and up to 10% negatively or positively charged phospholipids (such as DOPG, DOPS, or DOTAP), wherein the % is 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 phospholipids (such as DOPG, DOPS, or DOTAP), wherein the % is 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 and 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% negatively or positively charged phospholipids (such as DOPG, DOPS, or DOTAP), wherein the % is weight % based on the weight of the composition.

[0734] In an embodiment, the composition may further comprise additives selected from suspending agents, dispersing agents, antioxidants, buffers, pH regulators, colorants, flavorants, preservatives, and foam hardeners.

[0735] In an embodiment, the composition does not further comprise additives.

[0736] In an embodiment, the additive is an additional lipid. Thus, the composition may comprise an additional lipid. The composition may comprise one or more additional lipids. The composition may further comprise up to 10% additional lipid, wherein the % is weight % based on the weight of the composition. Thus, the composition may comprise 0.1% to 10% additional lipid, wherein the % is 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% additional lipid, wherein the % is weight % based on the weight of the composition. The composition may comprise no more than 10% additional lipid. The composition may not comprise an additional lipid, i.e., be substantially free of additional lipid.

[0737] Use

[0738] The present invention also provides the use of a formulation comprising more than 10% w / w to 30% w / w water and 70% w / w to 90% w / w lipid as a carrier for a pharmaceutically active agent, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. In an embodiment, the formulation comprises more than 10% w / w to 25% w / w water and 75% w / w to 90% w / w lipid, as a carrier for a pharmaceutically active agent, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. In an embodiment, the pharmaceutically active agent can be dispersed or dissolved in the carrier.

[0739] The formulation further provides sustained and controlled release of the pharmaceutically active agent and has an adjustable duration window. The formulation is thus well-suited for forming a depot composition after parenteral (e.g., topical) administration to a body cavity and / or body surface and is formed of a lipid which, in addition to forming an efficient carrier for the active agent and a topical depot, can itself provide inherent benefits.

[0740] Thus, in an embodiment, the carrier provides controlled release of the pharmaceutically active agent at a temperature of 36°C to 39°C. The carrier can 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 can 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 can provide controlled release of the pharmaceutically active agent at a temperature of 38°C.

[0741] In an embodiment, the carrier forms a controlled-release depot for a pharmaceutically active agent at a temperature of from 36°C to 39°C. The carrier can form a controlled-release depot for a pharmaceutically active agent at a temperature of from 36°C to 39°C, from 37°C to 39°C, or from 37.5°C to 38.5°C. For example, the carrier can form a controlled-release depot for a 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 can form a controlled-release depot for a pharmaceutically active agent at a temperature of 38°C.

[0742] Thus, one advantage of the controlled-release depot of the present invention is that the pharmaceutically active agent is gradually released over a long period of time without repeated administration.

[0743] The formulations of the present invention can form a parenteral depot in which the pharmaceutically active agent is slowly released at the body surface. Of particular importance is that the composition produced by the formulation is bioadhesive, as this allows for local release of the pharmaceutically active agent over a sustained period of time. Thus, the composition should cover the surface to which it is applied and should remain in place even when the surface is subject to gas or liquid flow and / or friction. For example, the composition can be administered rectally and cover the wall of the colon, where the composition remains in place for a desired retention time (as described herein). The composition can be administered rectally and cover the walls of the sigmoid colon, descending colon, and / or rectum, where the composition remains in place for a desired retention time (as described herein).

[0744] Suitably, the carrier is administered to a body cavity. For example, the formulation is a rectal formulation. Thus, in a preferred embodiment, the carrier is administered as an enema.

[0745] Also provided is the use of a pre-formulated composition comprising a lipid and a pharmaceutically active agent for the preparation of a composition of the present invention, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[0746] Also provided is the use of a pre-formulated composition comprising a monoacylglycerol lipid and a pharmaceutically active agent for the preparation of a composition of the present invention. The monoacylglycerol lipid can comprise at least 50% by weight of glyceryl mono-linoleate.

[0747] In an embodiment, the pharmaceutically active agent in the pre-formulated composition is the hydrophilic pharmaceutically active agent described herein.

[0748] In an embodiment, the pre-formulated composition is a lyophilized mixture. In an embodiment, the lyophilized mixture is hydrated with water to provide the composition of the present invention.

[0749] Therapeutic uses and applications

[0750] The composition of the present invention can be advantageously used for rectal delivery of a pharmaceutically active agent by in-situ formation of a sustained release depot.

[0751] The composition of the present invention comprises a modified release composition comprising a monoacylglycerol lipid (such as glyceryl mono-linoleate (MLO)), water, and a pharmaceutically acceptable agent to target release of the pharmaceutically acceptable agent to the lower gastrointestinal tract (GIT), particularly in the colon and / or rectum.

[0752] Accordingly, the composition of the present invention comprising a pharmaceutically acceptable agent for topical treatment of the lower GIT is expected to be useful for treating or preventing disorders of the GIT. In certain embodiments, the composition of the present invention is used for treating or preventing disorders affecting the descending colon, sigmoid colon, and / or rectum. In certain embodiments, the composition of the present invention is used for treating or preventing disorders affecting the rectum. In certain embodiments, the composition of the present invention is used for treating or preventing disorders affecting the sigmoid colon. In certain embodiments, the composition of the present invention is used for treating or preventing disorders affecting the descending colon. The pharmaceutically acceptable agent can be a hydrophilic pharmaceutically acceptable agent such as tofacitinib (TOFA). The pharmaceutically acceptable agent can be a hydrophobic pharmaceutically acceptable agent such as tacrolimus (TAC). The composition can comprise one or more pharmaceutically acceptable agents. Accordingly, the composition can comprise TOFA and another pharmaceutically acceptable agent. The composition can comprise TAC and another pharmaceutically acceptable agent. The composition can comprise mesalazine and another pharmaceutically acceptable agent. The composition can comprise budesonide and another pharmaceutically acceptable agent. For example, the composition of the present invention can comprise TOFA and / or another pharmaceutically acceptable agent and can be used for preventing or treating inflammatory disorders affecting the lower gastrointestinal tract, particularly disorders affecting the colon. The composition of the present invention can comprise TAC and / or another pharmaceutically acceptable agent and can be used for preventing or treating inflammatory disorders affecting the lower gastrointestinal tract, particularly disorders affecting the colon. The composition of the present invention can comprise mesalazine and / or another pharmaceutically acceptable agent and can be used for preventing or treating inflammatory disorders affecting the lower gastrointestinal tract, particularly disorders affecting the colon. The composition of the present invention can comprise budesonide and / or another pharmaceutically acceptable agent and can be used for preventing or treating inflammatory disorders affecting the lower gastrointestinal tract, particularly disorders affecting the colon.

[0753] In an embodiment, the composition of the present invention can be administered by injection, for example, as a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation.

[0754] In other embodiments, the composition of the present invention can be used for vaginal delivery of a pharmaceutically active agent by in-situ formation of a sustained release depot. In an embodiment, the composition of the present invention can be applied topically, for example, by rectal administration or vaginal administration. Thus, the composition can be applied topically to the colon, for example, as an enema. The required dose will vary depending on the specific condition being treated and the stage of the condition. For a composition containing TAC, the composition will generally be administered to provide a dose of TAC of 0.1 mg to 5 mg, for example, a dose of 0.1 mg to 3 mg, or particularly a dose of 0.5 mg to 1.5 mg of TAC. For a composition containing TOFA, the composition will generally be administered to provide a dose of TOFA of 0.1 mg to 10 mg, for example, a dose of 2.5 mg to 10 mg, or particularly a dose of 5 mg to 10 mg of TOFA. The composition is suitably administered as a single-day dose or a two-day dose, preferably a two-day dose. Alternatively, the composition is administered as a once-weekly dose.

[0755] In one aspect of the present invention, there is provided the composition of the present invention for treating or preventing a disease. In an embodiment, the composition of the present invention is used to inhibit or prevent disease progression. The disease can be selected from: inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (e.g., with symptoms of constipation, diarrhea, and / or pain), diverticulosis, diverticulitis, proctitis, chemotherapy-related enteritis, radiation-related enteritis, 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 fistulas).

[0756] Thus, in embodiments, the compositions of the invention are used for treating or preventing inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (e.g., with constipation, diarrhea, and / or pain symptoms), diverticulosis, diverticulitis, proctitis, chemotherapy-related enteritis, radiation-related enteritis, 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 fistulas).

[0757] In one embodiment, the compositions of the invention are used for treating inflammatory bowel disease. In embodiments, the compositions of the invention are used for inhibiting or preventing the progression of inflammatory bowel disease. The major forms of inflammatory bowel disease are Crohn's disease and ulcerative colitis. Thus, the compositions of the invention can be used for treating these two conditions.

[0758] The compositions of the invention can be used for treating or preventing irritable bowel syndrome (e.g., 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 can also be used for treating or preventing Clostridium difficile colitis.

[0759] Crohn's disease can affect the entire gastrointestinal tract, including the colon. However, ulcerative colitis is a condition that affects only the colon and rectum. Thus, the release characteristics provided by a colon-targeted composition according to the invention that contains a pharmaceutically acceptable agent (e.g., containing TAC or containing TOFA) are expected to be particularly beneficial in treating ulcerative colitis.

[0760] The colon-targeted compositions of the invention release a pharmaceutically acceptable agent (e.g., TAC or TOFA) primarily in the colon. However, the pharmaceutically acceptable agent may also be released higher up in the gastrointestinal tract, and thus the compositions may also provide therapeutic benefit in conditions that affect other parts of the lower gastrointestinal tract (e.g., Crohn's disease, irritable bowel syndrome (e.g., with constipation, diarrhea, and / or pain symptoms), diverticulitis, collagenous colitis, proctitis, radiation-related enteritis, diverticulosis, colorectal cancer, or adenocarcinoma).

[0761] In a further embodiment, there is provided a composition of the invention for the treatment or prevention of ulcerative colitis. In an embodiment, the composition of the invention is for inhibiting or preventing the progression of ulcerative colitis.

[0762] Another aspect of the invention provides a composition comprising a pharmaceutically active agent as defined herein for the treatment of cancers affecting the gastrointestinal tract, particularly the lower gastrointestinal tract, especially the colon. Thus, the composition comprising the pharmaceutically active agent can be used for the treatment of colorectal cancer. The composition comprising the pharmaceutically active agent can be used to provide a cell growth inhibitory effect against cancers affecting the gastrointestinal tract, particularly colorectal cancer.

[0763] There is also provided a composition comprising a pharmaceutically active agent for preventing or delaying the onset of gastrointestinal cancer in a patient suffering from a chronic inflammatory disorder affecting the gastrointestinal tract, particularly the lower gastrointestinal tract, especially the colon. For example, the composition comprising the pharmaceutically active agent can be used to inhibit tumorigenesis in the gastrointestinal tract, particularly the colon.

[0764] The composition comprising the pharmaceutically active agent can be used alone or in combination with another anti-cancer agent to treat or delay the onset of cancers affecting the gastrointestinal tract. Thus, in an embodiment, the pharmaceutically active agent in the composition can be an anti-cancer agent. Alternatively, the composition comprising the 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.

[0765] There is also provided a composition comprising a pharmaceutically active agent for the prevention or treatment of a fibrotic disease or disorder. The fibrotic disease or disorder can be selected from intestinal fibrosis, intra-articular fibrosis, vaginal fibrosis, joint fibrosis, endometriotic fibrosis, endometriosis, epidural fibrosis, and dermal fibrosis.

[0766] There is also provided a composition comprising a pharmaceutically active agent for the prevention or treatment of a fungal infection, e.g., a vaginal fungal infection or a fungal colonic infection (e.g., paracoccidioidomycosis, histoplasmosis, and candidiasis).

[0767] There is also provided a composition comprising a pharmaceutically active agent for the prevention or treatment of a bacterial infection, e.g., a bacterial infection caused by Crohn's disease, e.g., a fistula and / or an abscess.

[0768] ulcerative colitis

[0769] Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffuse mucosal inflammation of the colon. Features of the disease include other features such as bloody diarrhea, often accompanied by symptoms of rectal urgency and tenesmus. The term "ulcerative colitis" as used herein includes diverticulitis, cryptitis, proctitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis, radiation-induced 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 to treat any such conditions. Also contemplated are compositions for treating colitis associated with inflammatory diseases of the gastrointestinal tract, particularly colitis associated with inflammatory diseases affecting the colon.

[0770] When a patient is suspected of having UC, the initial diagnosis typically 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 studies. However, these markers alone may not be sufficient to definitively diagnose ulcerative colitis. Accordingly, appropriately, endoscopy is generally the most accurate diagnostic tool for UC. Flexible sigmoidoscopy is usually sufficient to diagnose UC, but if the diagnosis is unclear, colonoscopy may be performed. The procedure involves examining the presence of epidermal ulcers, erythema or friability of the mucosa, loss of the appearance of the colonic blood vessels, and pseudopolyps.

[0771] Biopsies may also be performed to distinguish UC from Crohn's disease. Biopsy samples are typically taken during endoscopy and examined for whether the crypt structure is distorted, whether the crypts are inflamed, whether the crypts are abscessed, and whether the lamina propria is hemorrhagic or inflamed.

[0772] Ulcerative colitis can affect part of the colon or almost the entire colon. Ulcerative colitis can be ulcerative proctosigmoiditis. As used herein, "ulcerative proctosigmoiditis" refers to ulcerative colitis confined to the rectum and sigmoid colon.

[0773] Ulcerative colitis can be left-sided ulcerative colitis. As used herein, "left-sided colitis" refers to ulcerative colitis confined to the portion of the colon distal to the splenic flexure, more specifically ulcerative colitis that extends beyond the rectum and proximally to the splenic flexure.

[0774] Ulcerative colitis can be extensive ulcerative colitis, in which substantially the entire colon is affected. As used herein, "extensive ulcerative" or "pancolitis" refers to ulcerative colitis that extends proximally to the splenic flexure (i.e., extends beyond the splenic flexure to the ileocecal junction).

[0775] Accordingly, the composition of the present invention comprises a pharmaceutically active agent for treating ulcerative colitis affecting any part or substantially the whole of the colon, such as ulcerative colitis selected from ulcerative proctosigmoiditis, left-sided ulcerative colitis, and extensive ulcerative colitis.

[0776] Ulcerative colitis is typically further characterized by the severity of the disease and can be mild, moderate, or severe ulcerative colitis. Accordingly, the composition of the present invention comprises a pharmaceutically active agent for treating mild, moderate, or severe ulcerative colitis. For example, the use of the composition according to the present invention can be for treating mild ulcerative colitis. The use of the composition according to the present invention can be for treating moderate ulcerative colitis. The use of the composition according to the present invention can be for treating severe ulcerative colitis. The use of the composition according to the present invention can be for treating a patient with mild or moderate ulcerative colitis. The use of the composition according to the present invention can be for treating a patient with moderate or severe ulcerative colitis.

[0777] The severity of ulcerative colitis can be determined by known methods, which typically rely on a combination of patient characteristics. For example, 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. December 2012; 6(10) (which is incorporated herein by reference), mild, moderate, or severe UC can be determined. Mild, moderate, and severe ulcerative colitis can also be defined according to the criteria employed by Truelove and Witts; Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955; 2:1041-8.

[0778] It should be understood that a method of treatment corresponding to any use of the composition described herein in the treatment of ulcerative colitis is intended to be encompassed by the present invention. Similarly, any use described herein can be described with respect to the use of the composition in the preparation of a medicament for any of the treatments of ulcerative colitis described herein. The present invention encompasses all such corresponding uses in the preparation of a medicament.

[0779] Dosage and dosage regimen

[0780] The amount of the pharmaceutical active agent to be formulated with the compositions of the present invention will depend on the functional dose and the period of time over which the depot composition formed after administration provides sustained release. Generally, the dose formulated for a particular pharmaceutical active agent will be approximately equivalent to the normal single dose multiplied by a factor greater than the expected duration of action to be provided by the formulation. Clearly, this amount will need to be adjusted to take into account any adverse effects of the large dose at the start of treatment and thus this will generally be the maximum dose used. In any case the exact amount appropriate will be readily determined by suitable experimentation.

[0781] The compositions of the present invention may be administered topically, for example, for a period of less than 2 weeks.

[0782] The duration of treatment will depend on the nature of the infection being treated. Suitably, topical administration is continued until the condition is eradicated and / or the symptoms of the condition are alleviated or eliminated. The upper limit of the treatment period can be readily determined by the physician. For example, the compositions may be topically administered for a period selected from 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 compositions may be topically administered for a period of more than 2 weeks to about 1 year; 3 weeks to 1 year; 4 weeks to 1 year; 4 weeks to 6 months; or 4 weeks to 3 months.

[0783] The frequency of administration of the compositions of the present invention will depend on a variety of factors that can be readily determined by the physician, such as the severity of the condition, the responsiveness to the initial treatment and the particular condition being treated. Suitably, the compositions of the present invention may be administered topically once a day, twice a day, three times a day, four times a day, once every other day or once a week. Preferably, the compositions of the present invention may be topically applied to the colon of the subject. Suitably, the compositions may be administered as an enema.

[0784] The dose of the pharmaceutical active agent administered with the compositions of the present invention will vary according to a number of factors including, for example, the age, weight and sex of the animal or person suffering from the condition, the severity of the condition and the selected frequency of administration.

[0785] The physician can readily determine the appropriate dose for topical application. The compositions suitably comprise the pharmaceutical active agent in an amount of from about 0.1% to about 20%, preferably from about 0.1% to about 10%, more preferably from about 0.5% to about 6%, and even more preferably from about 1% to about 5%, wherein the % is % by weight based on the weight of the composition.

[0786] The compositions of the present invention are suitably topically applied to the colon of the subject. Preferably, the compositions of the present invention are administered rectally, for example, the compositions of the present invention are administered as an enema.

[0787] Route of administration

[0788] The compositions of the present invention can be administered to a subject by any suitable route of administration adapted to the condition to be treated and the pharmaceutically active agent to be used. For example, topical administration, rectal administration, vaginal administration, or intravenous administration. The compositions can be administered topically, rectally, or vaginally.

[0789] Routes of administration include, but are not limited to, oral (e.g., by ingestion, tablets, sprays, etc.); buccal; sublingual; transdermal (including, e.g., by patches, plasters, dressings, etc.); transmucosal (including, e.g., by patches, plasters, etc.); ocular (e.g., by eye drops); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; or by implantation.

[0790] The compositions of the present invention can be parenteral compositions (e.g., topical) and are administered to the surfaces of the skin, mucosa, and / or nails, to the eye, nasal cavity, oral cavity, or inner surfaces, or to cavities such as the nasal, rectal, vaginal, or oral cavities, periodontal pockets, or cavities formed after removal of natural or implanted structures or before insertion of implants (e.g., joints, stents, cosmetic implants, teeth, dental fillings, or other implants).

[0791] In a preferred embodiment, the compositions of the present invention are administered rectally. Thus, the compositions of the present invention can be in the form of: suppositories; rectal capsules; rectal solutions, emulsions, or suspensions; powders or tablets for rectal solutions or suspensions; semi-solid rectal preparations; rectal foams; rectal hygiene suppositories; or enemas. In a preferred embodiment, the compositions can be administered to a subject rectally in the following forms: suppositories; rectal capsules; semi-solid rectal preparations; rectal foams; rectal hygiene suppositories; or enemas. Preferably, the compositions of the present invention are administered rectally as an enema. Thus, in a preferred embodiment, the compositions of the present invention are administered directly as a flowable composition. For example, the compositions of the present invention are administered rectally as a layered gel (e.g., in the form of an enema).

[0792] As described herein, at room temperature (e.g., at 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). Thus, the compositions of the present invention are readily administered rectally to the lower gastrointestinal (GI) tract and rapidly transform to a highly viscous lipid cubic phase at rectal temperature (e.g., a temperature of about 36 °C to 39 °C). This is particularly advantageous because thick and viscous formulations may be difficult to effectively apply rectally to the lower GI tract. In addition, less viscous formulations (while easy to administer) have poor retention in situ, which results in rapid loss of the material. In contrast, the compositions of the present invention act as a highly viscous bioadhesive controlled reservoir system and remain in situ for at least about 6 hours.

[0793] It is well known that the lower GI tract begins at the cecum and also includes the appendix (in humans), the colon (e.g., the sigmoid colon, descending colon, transverse colon, ascending colon), the splenic flexure, the hepatic flexure, the rectum, and the anus. As described herein, the compositions of the present invention are administered to the lower GI tract of a subject. Thus, the compositions of the present invention can be topically applied to the inner wall of the lower GI tract. For example, the compositions of the present invention can be topically applied to the inner wall of the colon and / or rectum. Thus, the compositions of the present invention can be topically applied rectally to the inner wall of the lower GI tract, e.g., in the form of an enema. For example, the compositions of the present invention can be topically applied rectally to the inner wall of the colon, 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.

[0794] Enema devices and / or kits for enema delivery are well known and include, for example, an enema bag, tubing, a nozzle, a syringe (e.g., a rectal bulb syringe), etc. In an embodiment, the compositions of the present invention are delivered topically via an endoscope for targeting the compositions to a specific area of the lower GI tract, e.g., the site of inflammation, injury, tumor, polyp, etc. The compositions of the present invention can be delivered via an endoscope to the tissues of the sigmoid colon, descending colon, transverse colon, ascending colon, and / or rectum. In an embodiment, the compositions of the present invention are administered rectally via a rectal catheter.

[0795] The subject may have undergone a colostomy (a surgical procedure that connects the colon through an opening in the abdominal wall (stoma)). Thus, the subject may have a stoma. Suitably, the compositions of the invention may be administered via the stoma to the lower gastrointestinal tract of the subject, for example in the form of a suppository or an enema. The compositions of the invention may be administered via the stoma to the lower gastrointestinal tract of the subject in the form of an enema. For example, the compositions of the invention may be administered via the stoma to the colon of the subject in the form of an enema. Thus, the compositions of the invention may be topically applied via the stoma in the form of an enema to the inner wall of the lower gastrointestinal tract. For example, the compositions of the invention may be topically applied via the stoma in the form of an enema to the inner wall of the colon.

[0796] In an embodiment, the composition of the invention is a parenteral composition. Thus, the composition of the invention may be an injectable formulation and administered subcutaneously, intramuscularly or intradermally to the subject. Preferably, the composition is administered subcutaneously to the subject.

[0797] In an embodiment, the composition of the invention is administered vaginally. Thus, the composition of the invention may be in the form of: vaginal tablets; vaginal suppositories or pessaries; vaginal foams, sprays, gels or creams.

[0798] Subject

[0799] The compositions of the invention are suitable for treating a subject affected by any disease or disorder described herein. Preferably, the compositions of the invention are suitable for topical treatment of a subject affected by any disease or disorder described herein, wherein the composition is topically applied to the colon of the subject, for example wherein the composition is administered rectally to the subject, preferably as an enema.

[0800] In an embodiment, the subject may be a warm-blooded mammal. In a particular embodiment, the subject being treated is a human. The subject may be an adult (18 years of age or older). The subject may be a child under 18 years of age. The pediatric subject may be 2 to 4 years of age. The pediatric subject may be 5 to 10 years of age. The pediatric subject may be 11 to 18 years of age.

[0801] In an embodiment, the subject may be an animal. In certain embodiments, the compositions of the invention are used as veterinary products for topical treatment of animals. In certain embodiments, the compositions of the invention are used for topical treatment of diseases and disorders in commercial animals such as livestock (e.g., cows, sheep, chickens, pigs, geese, ducks, goats, etc.). In other embodiments, the compositions of the invention may be used for topical treatment of diseases or disorders in companion animals (such as cats, dogs, horses, etc.).

[0802] Preparation method

[0803] The composition of the present invention can be prepared by a method comprising the following steps:

[0804] a) Hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and

[0805] b) Equilibrating the lipid-drug mixture to provide the composition.

[0806] In an embodiment, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent. For example, the pharmaceutically active agent can be tacrolimus. Thus, the composition can be prepared by a method comprising the following steps:

[0807] a) Hydrating a mixture comprising a lipid and a pharmaceutically active agent (such as a hydrophobic pharmaceutically active agent) with water to provide a lipid-drug mixture; and

[0808] b) Equilibrating the lipid-drug mixture to provide the composition.

[0809] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The lipid can be glyceryl mono-linoleate. The lipid can be glyceryl mono-oleate.

[0810] In an embodiment, the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In an embodiment, the lipid is a monoacylglycerol lipid comprising at least 50% by weight of glyceryl mono-linoleate.

[0811] Thus, in an embodiment, the composition of the present invention can be prepared by a method comprising the following steps:

[0812] a) Hydrating a mixture comprising a lipid and a pharmaceutically active agent (such as a hydrophobic pharmaceutically active agent) with water to provide a lipid-drug mixture; and

[0813] b) Equilibrating the lipid-drug mixture to provide the composition,

[0814] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Preferably, the lipid is glyceryl mono-linoleate.

[0815] 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).

[0816] In an embodiment, the lipid-drug mixture of step a) is vortexed at room temperature until a homogeneous mixture is obtained.

[0817] In an embodiment, in step b), the lipid-drug mixture is equilibrated for up to about 48 h. The lipid-drug mixture can be equilibrated for about 1 min, 2 min, 3 min, 4 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h or 48 h.

[0818] In an embodiment, the pharmaceutically active agent is photosensitive. Accordingly, the lipid-drug mixture in step b) can be equilibrated under dark conditions.

[0819] In an embodiment, the mixture in step a) is a lyophilized mixture. The lyophilized mixture can be obtained as follows:

[0820] i) Dissolve the lipid and the pharmaceutically active agent in an organic solvent; and

[0821] ii) Lyophilize the mixture of i) to provide the lyophilized mixture.

[0822] In an embodiment, in step i), the organic solvent can be an alcohol. Examples of suitable alcohols include ethanol, methanol, isopropanol and glycerol formal. The organic solvent can be ethanol. The organic solvent can be methanol. Preferably, the organic solvent is ethanol.

[0823] In an embodiment, in step ii), the mixture is lyophilized by removing the organic solvent. The organic solvent can be removed under reduced pressure. The organic solvent can be removed by freeze-drying the mixture of i). The mixture of i) can be freeze-dried for about 24 h. Suitably, the mixture of i) is freeze-dried at 0.22 mbar for 24 h to provide the lyophilized mixture.

[0824] In other embodiments, the pharmaceutically active agent is a hydrophilic pharmaceutically active agent. The pharmaceutically active agent can be a Janus kinase inhibitor. Preferably, the pharmaceutically active agent can be tofacitinib or a pharmaceutically acceptable salt thereof. Accordingly, the composition of the present invention can also be prepared by a method comprising the following steps:

[0825] a) Dissolve a pharmaceutically active agent (such as a hydrophilic pharmaceutically active agent) in water to provide a drug mixture;

[0826] b) Hydrate the lipid with the drug mixture to provide a lipid-drug mixture; and

[0827] c) Equilibrate the lipid-drug mixture to provide the composition.

[0828] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The lipid may be glyceryl mono-linoleate. The lipid may be glyceryl mono-oleate.

[0829] In an embodiment, the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In an embodiment, the lipid is a monoacylglycerol lipid comprising at least 50 wt% glyceryl mono-linoleate.

[0830] Thus, in an embodiment, the composition of the present invention can also be prepared by a method comprising the following steps:

[0831] a) Dissolving a pharmaceutical active ingredient (e.g., a hydrophilic pharmaceutical active ingredient) in water to provide a drug mixture;

[0832] b) Hydrating the lipid with the drug mixture to provide a lipid-drug mixture; and

[0833] c) Equilibrating the lipid-drug mixture to provide the composition,

[0834] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Preferably, the lipid is glyceryl mono-linoleate.

[0835] In an embodiment, in step a), the pharmaceutical active ingredient is dissolved in deionized water. In an embodiment, in step a), the pharmaceutical active ingredient is dissolved in water for injection (WFI).

[0836] In an embodiment, 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) can be vortexed at room temperature for more than 30 s to at least 10 min. The lipid-drug mixture of step b) can be vortexed at room temperature for at least 30 s, 40 s, 50 s, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min or 10 min. Appropriately, the lipid-drug mixture of step b) can be vortexed at room temperature for at least 5 min

[0837] In an embodiment, in step c), the lipid-drug mixture is equilibrated for up to about 48 h. The lipid-drug mixture can be equilibrated for about 1 min, 2 min, 3 min, 4 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h or 48 h.

[0838] In an embodiment, the pharmaceutical active agent is photosensitive. Thus, the lipid-drug mixture in step c) can be equilibrated under dark conditions.

[0839] The compositions of the present invention can also be prepared by a method comprising the following steps:

[0840] a) Heating the lipid to provide a molten lipid;

[0841] b) Mixing the molten lipid with the pharmaceutical active agent to provide a lipid-drug mixture;

[0842] c) Mixing the lipid-drug mixture with water; and

[0843] d) Equilibrating the lipid-drug mixture and water to provide the composition.

[0844] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The lipid can be glyceryl mono-linoleate. The lipid can be glyceryl mono-oleate.

[0845] In an embodiment, the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In an embodiment, the lipid is a monoacylglycerol lipid comprising at least 50% by weight of glyceryl mono-linoleate.

[0846] In an embodiment, in step a), the lipid is heated to a temperature of about 30°C to 70°C. The lipid can be heated to a temperature of about 40°C to 60°C. The lipid can be heated to a temperature of about 45°C to 55°C. Preferably, the lipid can be heated to a temperature of about 50°C.

[0847] In an embodiment, in step b), the molten lipid and the pharmaceutical active agent are heated to a temperature of about 30°C to 70°C. The molten lipid and the pharmaceutical active agent can be heated to a temperature of about 40°C to 60°C. The molten lipid and the pharmaceutical active agent can be heated to a temperature of about 45°C to 55°C. Preferably, the molten lipid and the pharmaceutical active agent can be heated to a temperature of about 50°C.

[0848] In an embodiment, in step b), the melted lipid and the pharmaceutical active agent are mixed until a homogeneous lipid-drug mixture is obtained. The melted lipid and the pharmaceutical active agent can be mixed for up to about 1 h. The melted lipid and the pharmaceutical active agent can be mixed for up to about 30 min. The melted lipid and the pharmaceutical active agent can be mixed for up to about 15 min. The melted lipid and the pharmaceutical active agent can be mixed for up to about 5 min. The melted lipid and the pharmaceutical active agent can be mixed for about 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min or 1 h.

[0849] In an embodiment, in step c), the lipid-drug mixture is mixed with deionized water. In an embodiment, in step c), the lipid-drug mixture is mixed with phosphate buffered saline (PBS). In an embodiment, in step c), the lipid-drug mixture is mixed with water for injection (WFI).

[0850] By any method known in the art, the lipid-drug mixture in step c) can be mixed. For example, the lipid-drug mixture can be mixed with water in a dual syringe. The dual syringe can comprise 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 a 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 comprise two syringes connected by 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 into the second syringe containing water. Then the lipid-drug mixture and water are transferred back into the first syringe. This process is repeated until a homogeneous mixture is obtained. Thus, the lipid-drug mixture in step c) can be mixed with a dual syringe.

[0851] In an embodiment, in step d), the lipid-drug mixture and water are equilibrated for up to about 1 h. The lipid-drug mixture can be equilibrated for up to about 30 min, for up to about 15 min, for up to about 5 min, for up to about 1 min, or for about 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, or 1 h.

[0852] Kit

[0853] Provided herein is a kit that comprises:

[0854] a) a first container that contains a lipid and a pharmaceutically active agent; and

[0855] b) instructions for combining a) with water to provide the composition of the invention.

[0856] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The lipid can be glyceryl mono-linoleate. The lipid can be glyceryl mono-oleate.

[0857] In an embodiment, the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In an embodiment, the lipid is a monoacylglycerol lipid comprising at least 50 wt% glyceryl mono-linoleate.

[0858] Thus, in an embodiment, the kit comprises:

[0859] a) a first container that contains a lipid and a pharmaceutically active agent; and

[0860] b) instructions for combining a) with water to provide the composition of the invention,

[0861] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Preferably, the lipid is glyceryl mono-linoleate.

[0862] In an embodiment, the pharmaceutically active agent is selected from any of the pharmaceutically active agents defined herein. Suitably, the pharmaceutically active agent is a hydrophobic pharmaceutically active agent. The pharmaceutically active agent can be tacrolimus.

[0863] In an embodiment, the kit further comprises a second container, wherein the second container contains water. The water can be deionized water. The water can be water for injection (WFI).

[0864] Thus, the kit can comprise:

[0865] a) A first container that contains a lipid and a pharmaceutically active agent;

[0866] b) A second container that contains water; and

[0867] c) Instructions for combining a) and b) to provide the composition of the present invention,

[0868] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate.

[0869] In an embodiment, the lipid and the pharmaceutically active agent in the first container are provided as a lyophilized mixture. The lyophilized mixture can be obtained by the methods described herein. Thus, the kit can comprise instructions for hydrating the lyophilized mixture with a specific amount of water to obtain the composition of the present invention. For example, the kit can comprise:

[0870] a) A first container that contains a lyophilized mixture, wherein the lyophilized mixture contains a lipid and a pharmaceutically active agent;

[0871] b) A second container that contains water; and

[0872] c) Instructions for combining a) and b) to provide the composition of the present invention,

[0873] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate.

[0874] In a preferred embodiment, the kit can comprise:

[0875] a) A first container that contains a lyophilized mixture, wherein the lyophilized mixture contains glyceryl mono - linoleate and tacrolimus;

[0876] b) A second container that contains water; and

[0877] c) Instructions for combining a) and b) to provide the composition of the present invention,

[0878] wherein the resulting composition comprises:

[0879] (i) 1% w / w tacrolimus;

[0880] (ii) 83.16% w / w glyceryl mono - linoleate; and

[0881] (iii) 15.84% w / w water.

[0882] 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. Accordingly, there is also provided a kit comprising:

[0883] a) a first container containing a lipid; and

[0884] b) instructions for combining a) with a solution comprising a pharmaceutically active agent (such as a hydrophilic pharmaceutically active agent) dissolved in water to provide the composition of the present invention.

[0885] In an embodiment, the lipid is a monoacylglycerol lipid. In an embodiment, the monoacylglycerol lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. The lipid can be glyceryl mono-linoleate. The lipid can be glyceryl mono-oleate.

[0886] In an embodiment, the lipid is a monoacylglycerol lipid comprising glyceryl mono-linoleate or glyceryl mono-oleate or a combination thereof. In an embodiment, the lipid is a monoacylglycerol lipid comprising at least 50% by weight of glyceryl mono-linoleate.

[0887] Accordingly, in an embodiment, the kit comprises:

[0888] a) a first container containing a lipid; and

[0889] b) instructions for combining a) with a solution comprising a pharmaceutically active agent (such as a hydrophilic pharmaceutically active agent) dissolved in water to provide the composition of the present invention,

[0890] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate. Preferably, the lipid is glyceryl mono-linoleate.

[0891] In an embodiment, the kit further comprises a second container, wherein the second container contains a pharmaceutically active agent dissolved in water. The water can be deionized water. The water can be water for injection (WFI). Accordingly, the kit can comprise:

[0892] a) a first container containing a lipid;

[0893] b) a second container containing a solution comprising a pharmaceutically active agent dissolved in water; and

[0894] c) instructions for combining a) and b) to provide the composition of the present invention, wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[0895] The kit may include instructions for hydrating the lipids in the first container with a specific amount of solution in the second container to obtain the composition of the present invention. For example, the kit may include:

[0896] a) A first container containing glyceryl monolinoleate;

[0897] b) A second container containing a solution of tofacitinib or a pharmaceutically acceptable salt thereof dissolved in water; and

[0898] c) Instructions for combining a) and b) to provide the composition of the present invention,

[0899] wherein the resulting composition comprises:

[0900] (i) 5% w / w tofacitinib or a pharmaceutically acceptable salt thereof;

[0901] (ii) 79.8% w / w glyceryl monolinoleate; and

[0902] (iii) 15.2% w / w water.

[0903] The following examples are intended to illustrate the invention but do not limit the invention in any way, shape or form (explicitly or implicitly). Examples

[0904] Solvents, reagents and starting materials were purchased from commercial suppliers and used as received, unless otherwise described. 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.

[0905] Abbreviations

[0906] DC: Dendritic cell

[0907] DSS: Dextran sulfate sodium

[0908] h: Hour

[0909] H: Hexagonal phase

[0910] H&E: Hematoxylin and eosin

[0911] HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

[0912] HPLC: High performance liquid chromatography

[0913] L: Lamellar phase

[0914] LMP: Lipid mesophase

[0915] LVR: Linear viscoelastic region (regime)

[0916] min: minute

[0917] MLO: Monolinolein

[0918] PBS: Phosphate Buffered Saline

[0919] Q: Cubic phase

[0920] SAXS: Small Angle X-ray Scattering

[0921] TAC: Tacrolimus

[0922] TIF-gel: Temperature-triggered in-situ formed adhesive lipid gel

[0923] TOFA: Tofacitinib

[0924] UC: Ulcerative Colitis

[0925] WAXS: Wide Angle X-ray Scattering

[0926] Materials

[0927] Monolinolein (MLO) was purchased from NU-Check Prep, Inc. (MN, USA). Ultrapure water with a resistivity of 18.2 MΩ.cm was produced by Barnstead Smart2pure (Thermo scientific) and used as the aqueous phase. Methanol, acetonitrile, and tetrahydrofuran were analytical grade substances provided by Fisher Scientific (Schwerte, Germany). Ethanol with an absolute purity > 99.5 wt% was obtained from VWR chemicals BDH (London, UK). Tofacitinib citrate (TOFA) was purchased from LClaboratories (Woburn, MA), and tacrolimus (TAC) was obtained from R&S Pharmchem Co., Ltd (Shanghai, China). Clotrimazole and mesalazine 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 (European Pharmacopoeia quality) was purchased from Hanseler Swiss Pharma. HEPES salt was obtained from Carl Roth (Karlsruhe, Germany).

[0928] Analytical methods

[0929] Small Angle X-ray Scattering (SAXS)

[0930] SAXS measurements were used to determine the phase identity and symmetry of the resulting LMP. Measurements were carried out on a Bruker AXS Micro instrument equipped with a microfocus X-ray source operating at a voltage and filament current of 50 kV and 1000 μA, respectively. Cu Kα radiation was collimated by a 2D Kratky collimator and data were collected by a 2D Pilatus 100K detector. The scattering vector Q = (4π / λ)sinθ was calibrated using silver behenate, where 2θ is the scattering angle. Data were collected and azimuthally averaged using Saxsgui software to yield a relationship of 1D intensity versus the scattering vector Q, where Q ranges from 0.001 to For all measurements, the sample was placed inside a stainless-steel container located between two replaceable thin mica sheets and sealed with an O-ring, with a sample volume of 10 μL and a thickness of approximately 1 mm. Measurements were carried out at 25 °C, 30 °C, 34 °C, 36 °C, and 38 °C. The sample was equilibrated for 10 min prior to measurement, while the scattering intensity was collected over 30 min and, in the case of the lamellar phase, over 60 min. On the other hand, for kinetic studies, the sample was pre-equilibrated at 25 °C and inserted into a sample holder maintained at 38 °C, and the scattering intensity was collected over 5 min. To determine structural parameters such as water-channel dimensions, the SAXS data information on the lattice was combined with the composition of the sample (R. Mezzenga, et al., Shear rheology of lyotropic liquid crystals: a case study, Langmuir 21, 3322 - 3333 (2005)).

[0931] SAXS spectra obtained on gels containing 10% w / w TOFA and 10% w / w TAC at different temperatures

[0932] MLO was used as the lipid component of the mesophase and mixed with a weighed amount of the drug (10% w / w) in a sealed Pyrex tube and centrifuged alternately at room temperature (10 min, 5000 g) several times until a homogeneous mixture was obtained. The mesophase was then equilibrated at room temperature in the dark for 48 h (see,[[]]END]] Figure 1A and 1B )

[0933] rheological experiments

[0934] A stress-controlled rheometer (modular compact rheometer MCR 72, obtained from Anton Paar, Graz, Austria) with a cone-and-plate geometry, an angle of 0.993°, and a diameter of 49.942 mm was used. The temperature was controlled at 25 °C or 38 °C. First, a strain sweep was performed between 0.002 and 100% strain at 1 Hz to determine the linear range, the linear viscoelastic regime (LVR), the yield point, and the low point. Then, an oscillatory frequency sweep was performed at 0.1% strain between 0.1 and 100 rad / s. Frequency sweep measurements were performed at constant strain in the linear viscoelastic regime (LVR), which was determined by oscillatory strain sweep (amplitude sweep) measurements performed on each sample. In fact, within the linear viscoelastic region, the material response is independent of the magnitude of the deformation, and the material structure remains intact; this is a necessary condition for accurately determining the mechanical properties of the material.

[0935] Release experiments of TAC and TOFA: in vitro and ex vivo setups and HPLC drug quantification

[0936] A 3000 nm polycarbonate membrane (Sterlitech Corporation, USA) was used to conduct in vitro and ex vivo tests on the formulations and free drug enemas through a vertical diffusion cell (PermeGear, Pennsylvania, USA). HEPES buffer (8 mL) at pH 7.4 was used as the release medium, and the device was placed in an oscillating incubator at 100 rpm and 37 °C. To study the effect of lipase on drug release, porcine pancreatic lipase (1000 U / mL) was added to the samples in the donor chamber. Ex vivo experiments using rat intestinal tissue were conducted to evaluate the drug release of TIF-gel. Briefly, fresh intestinal tissue was obtained and cut into samples (2 mm * 1 mm * 1 mm) suitable for the Franz cell device. The tissue was placed on the polycarbonate membrane for tensile loading. At specified time points (0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 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 in the mobile phase together with an internal standard and then analyzed for drug content by HPLC. The same experimental design was used for TIF-gel loaded with TOFA and TAC. In addition, samples of TIF-gel containing the drug were 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 TIF-gel loaded with TOFA and TAC.

[0937] HPLC method: Tofacitinib citrate

[0938] Tofacitinib citrate was detected by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 column (4.0 x 250 mm; 5.0 μm particle size). The mobile phase consisted of acetonitrile / methanol / water (13:13:74 v / v) + 0.1% trifluoroacetic acid, the flow rate was 1 mL / min, the temperature was 25 °C, and UV detection was performed at λ = 278 nm. An internal standard (caffeine, 20 μg / mL) was added to each sample to correct for inter-injection variation, and UV detection was performed at λ = 278 nm. Data were collected and analyzed using Chromeleon 7 software (Thermo Fisher).

[0939] HPLC method: Tacrolimus

[0940] Tacrolimus was detected by reversed-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 column (4.0 x 250 mm; 5.0 μm particle size). The mobile phase consisted of methanol / water (80:20 v / v) + 0.1% trifluoroacetic acid, the flow rate was 1 mL / min, the temperature was 50 °C, and UV detection was performed at λ = 214 nm. An internal standard (ketoconazole, 20 μg / mL) was added to each sample to correct for inter-injection variation, and UV detection was performed at λ = 278 nm. Data were collected and analyzed using Chromeleon 7 software (Thermo Fisher).

[0941] Release experiments of clotrimazole, budesonide and mesalazine: in vitro setup and HPLC drug quantification

[0942] Release experiment: Clotrimazole

[0943] Prepare a 5% w / w clotrimazole preparation according to the preparation method described in Example 1. Briefly, the TIF-gel composition comprises: a) a carrier, which comprises: a1) water in an amount of 16% by weight of the carrier; and a2) 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 free clotrimazole solution was also prepared using 2% w / v Tween 80 as a solvent. The drug release characteristics were 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 a 2% w / v Tween 80 release medium. The loaded Franz cell was placed in an oscillating incubator at 100 rpm and 37 °C. For free clotrimazole and 5% w / w TIF-gel, 300 μL and approximately 40 mg were placed directly into the donor chamber, respectively. At predetermined time points 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8 h, the release medium was completely replaced and an aliquot was lyophilized. Each sample was resuspended in a solution of acetonitrile / water (70:30 v / v) and the clotrimazole content was analyzed by HPLC.

[0944] HPLC method: Clotrimazole

[0945] The concentration of clotrimazole was determined by reverse-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 x 250 mm; 5.0 μm particle size) column. The mobile phase consisted of acetonitrile / water (70:30 v / v) + 0.1% trifluoroacetic acid, the flow rate was 0.5 mL / min, the temperature was 40 °C, and UV detection was carried out at λ = 200 nm.

[0946] Release experiment: Budesonide

[0947] Prepare a 5% w / w budesonide formulation according to the preparation method described in Example 1. Briefly, the TIF-gel composition comprises: a) a carrier, which comprises: a1) water in an amount of 16% by weight of the carrier; and a2) 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 free budesonide solution was also prepared using Tween 80 (2% w / v) as a solvent. Then, the drug release characteristics were 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 a 2% w / v Tween 80 release medium. The loaded Franz cell was placed in an oscillating incubator at 100 rpm and 37 °C. For free budesonide and 5% w / w TIF-gel, 300 μL and approximately 40 mg were placed directly into the donor chamber, respectively. At predetermined time points of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8 h, the release medium was completely replaced and an aliquot was lyophilized. Each sample was resuspended in a solution of acetonitrile / water (70:30 v / v) and the content of clotrimazole was analyzed by HPLC.

[0948] HPLC method: Budesonide

[0949] The concentration of budesonide was determined by reverse-phase liquid chromatography using a Macherey-Nagel Nucleosil 100-5 C18 (4.0 x 250 mm; 5.0 μm particle size) column. The mobile phase consisted of acetonitrile / water (70:30 v / v) + 0.1% trifluoroacetic acid, the flow rate was 0.5 mL / min, the temperature was 40 °C, and UV detection was performed at λ = 260 nm.

[0950] Release experiment: Mesalazine

[0951] Prepare a 5% w / v mesalazine preparation according to the method described in Example 1. Briefly, the TIF-gel composition comprises: a) a carrier, which comprises: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) mesalazine in an amount of 5% by weight of the composition. A solution of 1 mg / mL free mesalazine in HEPES (10 mM, pH 7.4) was also prepared. The drug release characteristics were 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 an oscillating incubator at 100 rpm and 37 °C. For free mesalazine and 5% w / w TIF-gel, 300 μL and approximately 40 mg were placed directly into the donor chamber, respectively. At the predetermined time points 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8 h, the release medium was completely replaced. 200 μL aliquots were analyzed directly by absorbance.

[0952] HPLC method: Mesalazine

[0953] The mesalazine concentration was determined by absorbance using a microplate reader (Spark 10M, Tecan, Switzerland). At 20 °C, for mesalazine in HEPES (10 mM, pH 7.4), the maximum absorbance wavelength of mesalazine was 298 nm.

[0954] Drug uniformity in the gel structure

[0955] To determine whether TOFA and TAC are uniformly distributed in the gel matrix, gels (loaded with TAC or TOFA) were prepared as described herein and transferred into 2 mL Eppendorf tubes. The tubes were centrifuged and left standing for 24 hours. Subsequently, the gels were divided into 3 different layers (top layer, middle layer and bottom layer), and the drug content in each layer was evaluated by HPLC.

[0956] LC-MS / MS analysis

[0957] Samples, standards, and QCs were extracted by protein precipitation and analyzed by LC-MS / MS using the method described below. For plasma samples, 10 μL of plasma was mixed with 25 μL of precipitation solution (80:20 acetonitrile:methanol + 0.1 μM loperamide). The samples were centrifuged at 10,000 g for 10 minutes, and 20 μL of the supernatant was diluted with 40 μL of H2O + 0.1% FA. The samples were centrifuged at 3400 rpm for 10 minutes, and 50 μL of the supernatant was diluted with 100 μL of H2O + 0.1% FA. All samples were analyzed by LC-MS / MS (Shimadzu prominence HPLC coupled with AB / SCIEX 4000 QTRAP) in positive MRM mode. Samples were separated on a Cortecs RP shield column (3 x 50 mm 2.6 μ) using a rapid gradient of 10 mM ammonium formate in water (A) and methanol (B). The gradient started at 20% B and increased to 98% B in 2 minutes, held for 0.5 minutes, and equilibrated for 1.4 minutes. MRM parameters were optimized for each analyte; an MRM transition of 313. to 149.3 was selected for tofacitinib, an MRM transition of 822.3 to 770.1 was selected for tacrolimus, and an MRM transition of 477.1 to 266.0 was selected for loperamide (internal standard). Samples were quantified using the area ratio of the analyte to the internal standard using a calibration curve prepared in matrix.

[0958] WAXS (Wide Angle X-ray Scattering)

[0959] WAXS measurements were performed on a Bruker AXS Micro, which was equipped with a microfocus X-ray source with a working voltage and filament current of 50 kV and 1000 μA, respectively. Cu Kα radiation was collimated by a 2D Kratky collimator and data were collected by a 2D Pilatus 100K detector. The scattering vector Q = (4π / λ)sinθ was calibrated using silver behenate, where 2θ is the scattering angle. Data were collected and azimuthally averaged using Saxsgui software to produce a relationship of 1D intensity versus scattering vector Q, where Q ranged from 13 to 18 nm -1 . For all measurements, the sample was placed inside a stainless-steel container between two replaceable thin mica sheets and sealed with an O-ring. The sample volume was 10 μL and the thickness was approximately 1 mm.

[0960] Method - In Vivo Studies

[0961] Chemically induced colitis based on DSS application

[0962] Female 6-8-week-old C57B / 6J mice (e.g., Charles River Deutschland) were maintained under specific pathogen-free (SPF) small-colony conditions in the animal facility of the University of Bern. Mice were ear-tagged, randomly assigned to different cages and treatment groups, and bedding was mixed between all cages to avoid potential cage effects on the small colony. All methods used were approved by the Bernese Animal Welfare Agency (permit number: BE 20 / 18). One day before starting DSS supplementation, mice were injected rectally with 100 μL of empty gel, TOFA in 1% methylcellulose, or TOFA-loaded gel (5 mg TOFA / 100 μL gel). The next day, mice were given drinking water supplemented with 2% w / v dextran sulfate sodium (DSS; MP Biomedicals, 160110). Every other day, different compounds were applied rectally until the end of the experiment. During the experiment, mice were continuously monitored, and weight and disease scores were recorded when appropriate. The disease score was determined by a 1-4 grading according to the following criteria (grade 4 corresponding to the most unhealthy / abnormal): posture, mobility, fur appearance, weight, fecal consistency, and fecal color (L.F. 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. Swiss rolls were prepared from the colon (C. Moolenbeek, et al., (1981) The “Swiss roll”: A simple technique for histological studies of the rodent intestine, Lab. Anim. 15, 57-59), fixed overnight in 10% formalin in PBS, then washed with PBS, embedded in paraffin, and sectioned and stained with hematoxylin and eosin. Histopathological scoring was performed blindly by board-certified pathologists using the following criteria: goblet cell loss, crypt abscess, epithelial erosion, congestion, mucosal thickness, and cellular infiltration (maximum score for each category: 3).

[0963] Flow cytometry and quantification of single cells

[0964] This gating strategy was adapted from the inventors' previously published work (S.E. Liyanage, et al., Flowcytometric 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, and thereafter 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) for 5 minutes at room temperature. Splenocytes were quantified using a CASY cell counter (Omni Life Sciences), and the following populations were quantified after single cell and live / dead selection (Thermofischer, L34961). T cells (defined as CD3ε+ cells; antibody 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 LSRII SORP flow cytometer.

[0965] T-cell transfer colitis

[0966] To induce T cell-mediated colitis, CD4+ T cells were isolated from the spleens of C57 / BL6 mice (strain number: 000664; RRID:IMSR_JAX:000664ex.Jackson laboratories) using a CD4 T cell isolation kit (#19852; Cologne, Germany) from Stemcell Technologies, and naive T helper cells (CD3+, CD4+, CD25low, CD6Lhigh, CD44low cells) were then sorted on a FACS AriaIII (Becton Dickinson; Eysins, Switzerland) as previously described (D.V. Ostanin, et al., T cell transfer model of chronic colitis: Concepts, considerations, and tricks of the trade Am. J. Physiol.-Gastrointest. Liver Physiol. 296, 135-146 (2009); M.R. Spalinger, et al., PTPN2 controls differentiation of CD4+ T cells and limits intestinal inflammation and intestinal dysbiosis, Mucosal Immunol. 8, 918-929 (2015); M.R. Spalinger, et al., Loss of PTPN22 Promotes Intestinal Inflammation by Compromising Granulocyte-mediated Antibacterial Defence, J. Crohn’s Colitis 15, 2118-2130 (2021)). Male and female Rag - / - mice (model RAGN12 (B6.129S6-Rag2 tm1Fwa N12)ex.Taconic) were injected intraperitoneally with 2.5x10 5Initial T helper cells (all methods used were approved under license number ZH043 / 2021). Starting from day 2 after T cell injection, mice received daily rectal instillations (100 μL) of empty TIF-gel, TAC-loaded TIF-gel, or a solution of TAC in vehicle (1% nitrocellulose in distilled water). Body weight development and disease activity scores were measured daily. On the last day of the experiment (day 18), mice were anesthetized using a mixture of ketamine 90 - 120 mg / kg body weight (Vétoquinol, Bern, Switzerland) and xylazine 8 mg / kg body weight (Bayer, Lyssach, Switzerland), and murine endoscopy was performed to evaluate the extent of endoscopic colitis using the following parameters (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)): 1) thickening of the colonic wall, 2) vascularization / bleeding, 3) degree of fibrin deposition, 4) granular appearance of the colonic wall, 5) fecal consistency. A score from 0 (normal) to 3 (most severe manifestation) was given for each parameter, with a maximum total score of 15. After colonoscopy, mice were sacrificed and colonic tissues were harvested for histological examination and isolation of lamina propria immune cells. Immune cells were isolated from the colon, mesenteric lymph nodes, and spleen, and immune cell subset analysis was performed (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).

[0967] Hematoxylin and eosin staining and histological analysis of colitis severity

[0968] To evaluate the microscopic degree of colitis, hematoxylin and eosin (H&E) staining was performed on formalin-fixed, paraffin-embedded sections of the most distal 1.5 cm of the colon using a standard protocol (M.R. Spalinger, et al. (2019)). Two blinded scientists analyzed the sections for the degree of epithelial damage (score 0 - 4) and immune cell infiltration (score 0 - 4), with a maximum possible score of 8. Images were taken using a Zeiss Axio Imager.Z2 microscope (Zeiss) equipped with an AxioCam HRc camera (Zeiss, Jena, Germany) and ZEN imaging software (Zeiss, Germany).

[0969] Phase transition identification after in vivo application

[0970] 100 mL of TIF-gel was administered to healthy animals, and the excreted gel (excreted with feces after 30 minutes) or the residual gel present in the colon after 6 hours was collected and analyzed by SAXS (the animals were sacrificed, the colon was harvested, and the residual gel was washed 3 times with PBS before analysis). As shown in Figure 2J , at 25 °C there were Bragg reflections characteristic of the L phase prior to administration, while the gel excreted with feces showed an L→Ia3d transition. In addition, the lamellar phase absorbed heat and water during the experiment, thus reaching the cubic (pn3m) phase, as has been observed in in vitro studies.

[0971] Analysis of cytokine levels in the colon

[0972] To analyze cytokine levels in the colon, colon fragments were lysed in PBS (1 ml PBS / 0.1 mg tissue) using a GentleMACS device obtained from Miltenyi Biotec (Miltenyi Biotec, Bergisch Gladbach, Germany). Then, cytokines in the lysate were analyzed using a Bio-Plex Pro mouse cytokine 23-plex assay obtained from Bio-Rad (Hercules, CA) according to the manufacturer's instructions.

[0973] Pharmacokinetics (PK)

[0974] PK studies in healthy animals were conducted by the Biopharmaceutics Platform of the University of Montreal according to the requirements of the local Animal Welfare Committee of the University of Montreal and according to the regulations of the Canadian Council on Animal Care (CCAC). Healthy female C57BL / 6 mice (5 animals per group) were anesthetized and received a single rectal administration (100 μL) of drug-loaded TIF-gel (TIF-gel-TOFA or TIF-gel-TAC) or free drug (TOFA or TAC in suspension). All formulations contained 5 mg of TOFA or 1 mg of TAC and were administered rectally once at t = 0. Plasma levels were measured at 0.25, 1, 2, 4, 6, 12, 24, and 48 h post-administration. After the last sampling point, the animals were euthanized with CO2. Blood was collected and stored in K2-EDTA BD-Microtainer TM (Fisher Scientific AG, Switzerland). The drug was extracted from plasma and its concentration was determined using LC-MS / MS analysis (see above). AUC was calculated according to the trapezoidal method 0-48h .

[0975] In vivo / ex vivo experiments to evaluate the adhesion of TIF-gel to the colon wall

[0976] For in vivo adhesion tests, healthy animals (n = 11) were anesthetized as described above and received an enema of 100 μl of DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide)-loaded gel (DiR-TIF-gel). The animals were sacrificed at 30 minutes (n = 3), 2, and 6 hours (n = 4). The distal 3 cm of the colon (including the rectum) was harvested and imaged fresh after gentle washing with PBS. Fluorescence signal intensity was measured using an IVIS SpectrumCT in vivo imaging system (PerkinElmer, MA, US). DiR fluorescence signals (excitation 754 nm, emission 778 nm) were detected in the distal part of the dissected colon at 3 time points after gel injection. An untreated control mouse (n = 3) was included in each measurement. Images obtained were analyzed using Living software (PerkinElmer, MA, US). Background (untreated tissue samples) was measured for each time point. The signals obtained were analyzed as radiant efficiency (RE), which is a calibration unit that compensates for device settings and non-uniform light excitation patterns

[0977] Example 1 - Preparation of TIF-gel

[0978] The 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). The lipid / drug mixture was prepared by dissolving appropriate amounts of the lipid and drug stock solutions together in ethanol. The solvent was then completely removed under reduced pressure (lyophilized at 0.22 mbar for 24 h), and the dried lipid mixture was hydrated as follows: an aliquot of water (16% w / w) was mixed in a sealed Pyrex tube and centrifuged alternately at room temperature (10 min, 5000 g) several times until a homogeneous mixture was obtained. The mesophase was then equilibrated at room temperature in the dark for 48 h. The final TIF-gel composition loaded with TOFA comprised: a) a carrier comprising: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TOFA in an amount of 5% by weight of the composition. The final TIF-gel composition loaded with TAC comprised: a) a carrier comprising: a1) water in an amount of 16% by weight of the carrier; and a2) 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 composition. The resulting TAC concentration was 1 mg / 100 mg composition. For in vivo studies, after 48 h equilibration (as described above), the formulation was loaded into 1 mL syringes (Injekt-F, Braun), and the dead volume of the animal feeding needle (20G, L × diameter 1.5 inches × 1.9 mm) for rectal administration was calculated such that 100 μL was applied precisely.

[0979] Example 2 - Physicochemical Characterization of TIF-Gels Loaded with TAC and TOFA

[0980] At 25 °C and in the presence of a low percentage of water, MLO forms a lamellar (L) phase, which has a lower structural strength than the cubic phase (Q), resulting in a formulation that is easier to administer and capable of treating distant tissue regions, as Figure 2A shown. Once applied rectally, the precursor L phase gradually absorbs heat (and the available amount of water) from the body and rapidly (<5 min) transforms into the cubic phase, thus facilitating the in situ formation of a depot, which locally releases the contained drug in a sustained manner.

[0981] First, small-angle X-ray scattering (SAXS) measurements were used to determine the optimal amount of water required to obtain the lamellar phase, which transforms into the cubic at 38 °C ( Figure 2B and 2C ). The X-ray beam incident on the gel produces a scattering pattern with a set of maxima, which corresponds to sharp Bragg reflections characteristic of long-range positional order. The sequence of Bragg reflections (and their ratios; listed in Figure 2Ain) will identify the symmetry of the mesophase under study (see also Figure 1A and 1B ).

[0982] As shown in Figure 2B and 2C , for 12% water, Bragg reflections characteristic of the L phase are present at 25 °C and 38 °C. Hydrating MLO with 14% water produces a lamellar structure at 25 °C and a coexistence of L and Q structures (with Ia3d geometry) at 38 °C, while increasing the water content to 18% w / w already induces an L→Q transition at 30 °C. On the other hand, the mesophase composed of 16% w / w water and 84% w / w MLO produces Bragg reflections characteristic of a lamellar structure at 25 °C and transforms into a Q structure (with Ia3d geometry) at 38 °C (i.e., rectal temperature).

[0983] After incubation at 38 °C for only 5 min, the reflections characteristic of the L phase adopt those characteristic of the Q phase ( Figure 2D ), indicating a rapid transformation of the lamellar precursor into an Ia3d cubic structure, which is particularly suitable for rectal administration. If the temperature is returned to 25 °C, the transformation is reversible ( Figure 2H ). Although this information itself is not relevant to rectal application per se, it is an important property for the storage conditions of the TIF-gel.

[0984] The different viscoelastic regimes identified by rheological (frequency sweep) measurements confirm the diverse topologies of the mesophases. Specifically, the precursor L phase has low structural strength, as indicated by lower storage modulus and loss modulus (G’ and G”, respectively) values relative to the viscoelastic Q phase, resulting in a less viscous pseudoplastic gel, which is characterized by a large number of energy dissipation mechanisms associated with slip parallel to the lamellae. Under simulated application conditions, an increase in temperature and increased water availability lead to structural swelling, which corresponds to the Q phase transition (where both G’ and G” are higher than the values obtained for the L phase; Figure 2E ). In addition, the flow point or yield point (both representing the shear limit beyond which the material starts to behave like a fluid) will better define the difference between our low-viscosity lamellar precursor and the highly viscoelastic cubic gel, and they may identify a threshold beyond which the formulation is too elastic to be rectally applied ( Figure 2G ). Since the slip of the lamellae can occur in any possible direction, a low shear force needs to be applied to the gel to make it start to behave like a fluid and it can be forced to easily pass through an enema cannula, syringe, or colon tube. This means that a low-viscosity material with low structural strength is more easily administered compared to a fully hydrated cubic gel due to its high flow and yield points ( Figure 2I ).

[0985] To demonstrate the occurrence of the expected transitions, a series of SAXS experiments were conducted. Thereafter, the gels were soaked in 1 mL of HEPES (alternatively, soaked in a buffer solution containing lipase) and incubated at 38 °C for 8 h. As shown in Figure 2F , the L phase present at the start of the release experiment at 25 °C absorbs heat (and water) during the release experiment, thereby reaching the cubic (pn3m) phase, whose lattice parameter (a = 8.7 nm) and water channels (d w = 4 nm) are comparable to the values obtained by the Pn3m phase at its maximum hydration level (43). These transitions were also confirmed in vivo, where after rectal application, the gels excreted and collected with feces after 30 min had an Ia3d phase identity, while the residual gels present in the colon after 6 h were determined to be in the pn3m cubic phase ( Figure 2J ).

[0986] The presence of lipase (1000 U / mL) hydrolyzes the ester groups of MLO, thereby inducing a transition from Q → hexagonal phase (H), which is not associated with any burst release phenomenon (Figure 3). Based on this initial key characterization, the inventors 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 small-diameter animal feeding needles (size 20G) in order to further expand into a sponge-like system once injected into the rectum.

[0987] Example 3 - Encapsulation of TOFA and TAC and Release from TIF-Gel

[0988] To evaluate the effect of the guest drugs on the phase identity, intermediate phases loaded with TOFA or TAC were prepared and analyzed by SAXS. The intermediate phase composition loaded with TOFA comprised: a) a carrier, which comprised: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TOFA in an amount of 5% by weight of the composition. The intermediate phase composition loaded with TAC comprised: a) a carrier, which comprised: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TAC in an amount of 1% by weight of the composition. Notably, the encapsulation of the drugs (5 mg of TOFA and 1 mg of TAC in 100 mg of gel - 5 or 1% w / w respectively) ( Figure 3A and 3D ) does not affect the phase identity and thermal behavior of the carrier gel, and the rectal temperature still induces the transition from L → Q phase. Both drugs are encapsulated in the TIF-gel with 100% encapsulation efficiency. In addition, once embedded in the 3D gel structure, the two drugs do not form crystals, as demonstrated by the absence of reflections associated with drug crystallization in the wide-angle X-ray scattering (WAXS) spectra at high q ( Figure 3H)。The drug is also evenly distributed in the gel matrix ( Figure 3H )。

[0989] When hydrated with water, the lipid / drug mixture forms a lamellar structure and all the drug is embedded in the gel. In in vitro release experiments, the drug-loaded TIF-gel formulation was placed in the donor chamber of a vertical diffusion cell (as Figure 3G shown), and separated from the receptor chamber by a polycarbonate membrane with a pore size of 3 μm, which only allows free drug to pass through.

[0990] Unlike the small intestine for which different in vitro models have been established, in the case of the rectum, only animal models are available, mainly used in preclinical studies. Therefore, to bypass this limitation, an ex vivo protocol was adopted to study the diffusion time of the drug through the rectal epithelium from the gel. Tissues isolated from the rectum of healthy rats were used as the native membrane, and the amount of drug diffused into the receptor chamber was quantified. The 3D gel network reduced the release rate of TOFA (a hydrophilic drug) in in vitro or ex vivo environments (respectively Figure 3B and 3C ). The same experimental set was also performed on gels loaded with TAC. Even in this case, the gels retained the drug and released it slowly in in vitro and ex vivo experiments (respectively Figure 3E and 3F ).

[0991] Notably, the presence of lipase under our experimental conditions did not induce the degradation of the gel and thus the burst release of the drug, as reported for another lipid-based gel, IT-hydrogel (developed for the topical treatment of UC). 41 The enzyme only induced a responsive release (release of +20% of the drug) in IT-hydrogel after 24 h, while TAC and TOFA were released from our TIF-gel within only 8 h, a time span more compatible with the retention time of dosage forms administered rectally. The Structure Control Efficiency Index (SCEI) can estimate the drug release kinetics of various phases. However, the phase identity of the gels described in this article changes dynamically during the release experiment. Therefore, SCEI cannot be used to describe the release curve. In fact, hydrophobic drugs do not follow Fickian diffusion curves and thus the Higuchi equation cannot be used to simulate the release curve. The inventors did not observe any gel erosion (no weight loss was recorded in in vitro or ex vivo experiments), and thus the hypothesis that the release process is driven by gel dissolution can be rejected. Interestingly, the presence of 10 mg of drug (10% w / w of TOFA and TAC) did not affect the phase identity and the transition temperature of the gel, which presented a lamellar phase at room temperature and a cubic (Ia3d) phase at 38 °C (see Figure 1A and 1B) This indicates that the administration of a small volume of TIF-gel can deliver a large amount of drug while alleviating the urgency associated with a high application volume.

[0992] Example 4 - Release of clotrimazole, budesonide, and mesalazine from TIF-gel

[0993] The drug-loaded TIF-gel formulations and free drug formulations were prepared according to the method described above in "Release experiments of clotrimazole, budesonide, and mesalazine: In vitro setup and HPLC drug quantification". When hydrated with water, the lipid / drug mixture forms a lamellar structure and all the drugs are embedded in the gel. In the in vitro release experiment, the drug-loaded TIF-gel formulations were placed in the donor chamber of a vertical diffusion cell and separated from the receptor chamber by a polycarbonate membrane with a pore size of 3 μm, which only allows free drug to pass through. The 3D gel network reduced the release rate of all the free drugs used, as shown in Figure 4A 、 4B and 4C.

[0994] Example 5 - Effect of TOFA / TIF-gel on dextran sulfate sodium (DSS)-induced acute colitis

[0995] To test the potential efficacy of the gel in treating acute UC flares, the inventors applied TOFA-loaded TIF-gel to a mouse model of acute colitis induced by dextran sulfate sodium (DSS). The TOFA-loaded TIF-gel contains: a) a carrier, which contains: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TOFA in an amount of 5% by weight of the composition. DSS is toxic to epithelial cells and its application impairs the integrity of the intestinal barrier, leading to the activation of submucosal immune cells by intestinal microbiota. It was determined experimentally that the twice-daily application of the gel effectively alleviated local and systemic inflammation.

[0996] Compared to the mice treated with empty TIF-gel, the mice treated with the TIF-gel-TOFA regimen showed reduced weight loss and disease severity ( Figure 5A and 5B ). In contrast, the drug (TOFA) in the vehicle solution, although it improved weight loss, did not improve the disease score in these mice ( Figure 5B ). Notably, the daily application of the compound did not produce such robust results and the difference between free TOFA and TIF-gel-TOFA was less obvious under this regimen.

[0997] In those mice treated twice daily with TIF-gel-TOFA, systemic inflammation signs determined by spleen size and cellular composition were also reduced ( Figure 5C and 5D ). Additionally, local pro-inflammatory cytokine levels were reduced in TOFA- and TIF-gel-TOFA-treated mice, and anti-inflammatory IL-10 levels were elevated only in the TIF-gel-TOFA group ( Figure 5E ). TIF-gel-TOFA also alleviated local inflammation, which was determined by colon shortening and reduction of pathology ( Figure 5F 、 5G and 5H). For colon shortening, TIF-gel-TOFA was more effective than the drug in vehicle, but not for histopathology. No differences were detected in immune cell populations of the spleen or mesenteric lymph nodes in different treatment groups. Overall, these data indicate that locally applied temperature-dependent in-situ forming gels carrying TOFA represent a valuable tool for alleviating acute intestinal inflammation.

[0998] Example 6 - Effect of TAC / TIF-gel on T-cell transfer colitis

[0999] TIF-gel serves as a platform capable of loading and releasing molecules with different polarities. Therefore, hydrophobic TAC was loaded into TIF-gel, 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 TIF-gel loaded with TAC contained a) a carrier, which included: a1) water, in an amount of 16% of the weight of the carrier; and a2) MLO, in an amount of 84% of the weight of the carrier; and b) TAC, in an amount of 1% of the weight of the composition. In this model, naive T cells were transferred into B- and T-cell-deficient Rag - / - recipient mice, which led to the generation of T cells that responded to luminal antigens and subsequently led to severe colonic inflammation. Three days after transferring naive T cells into Rag - / - hosts, mice were treated by daily rectal instillation with 100 μL of i) TIF-gel loaded with TAC (TIG-gel-TAC), ii) empty TIF-gel (TIF-gel), or iii) a solution of TAC in vehicle (TAC) ( Figure 6A ). Monitoring of body weight development and disease activity showed that mice receiving empty TIF-gel or a solution of TAC in vehicle began to show initial signs of colitis around day 10 after T-cell transfer, manifested as progressive weight loss and signs of diarrhea ( Figure 6B and 6C ). Notably, mice treated with TIF-gel loaded with TAC did not lose weight, and the diarrhea score was lower than the other two groups ( Figure 6Band 6C )。On day 19 after T cell application, all mice were subjected to colonoscopy to evaluate macroscopic signs of colitis, and the mice were sacrificed and colon tissues were collected for histological and molecular analysis of colitis severity. Interestingly, administration of TAC via TIF-gel and TAC administration in vehicle reduced endoscopic signs of colitis. Although there was a clear trend towards further reduction in the endoscopic score of mice receiving TAC in TIF-gel, it was not significant( Figure 6D )。However, in contrast, and consistent with the disease activity score, mice receiving TAC in TIF-gel showed not only significantly reduced colitis severity compared to mice treated with empty TIF-gel, but also compared to mice receiving a solution of TAC in vehicle( Figure 6D )。Notably, all mice receiving TAC (administered in TIF-gel or in vehicle) showed a longer colon and reduced spleen weight( Figure 6E ), indicating reduced disease in these two groups compared to mice treated with empty TIF-gel. Collectively, these data clearly demonstrate that TAC administration via TIF-gel is superior to TAC administration in vehicle in reducing colitis severity.

[1000] Metastatic colitis is mainly mediated by abnormally activated T helper cells, and in particular IFN-γ+(Th1) and IL-17+(Th17) CD4+ T cells contribute to the disease. To test the effect of TAC administration in vehicle or TIF-gel, the inventors analyzed the proportion of T helper cells in the colonic lamina propria( Figure 7 A), mesenteric lymph nodes( Figure 7 B) and spleen( Figure 7 C). Notably, both forms of TAC administration reduced the relative abundance of T cells in the lamina propria, mesenteric lymph nodes and spleen( Figure 7 A to 7C). Among T helper cells, compared to mice receiving only empty TIF-gel, TAC in vehicle and TAC-loaded TIF-gel reduced Th1 and Th17 cells( 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 )。Overall, there was little effect on the abundance of FOXP3+ (regulatory) T cells( Figure 7 )。These findings were also reflected in cytokine measurements in colon tissues( Figure 7D), where reduced levels of IFN-γ and IL-17 were found in mice treated with the free drug. TIF-gel-TAC further reduced the levels of these two cytokines and, in addition, significantly reduced the level of TNF-α ( Figure 7 D), indicating that TIF-gel-TAC is more effective than the free drug alone in reducing the production of pro-inflammatory cytokines. Collectively, these results suggest that, in the case of T cell-induced colitis, administration of TAC in TIF-gel would effectively reduce disease-promoting T helper cells.

[1001] Example 7 - Stability study of TIF-gel loaded with TAC and TOFA

[1002] TIF-gel loaded with TAC and TOFA was prepared according to Example 1. Briefly, the final TOFA-loaded TIF-gel composition comprised a) a carrier comprising: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TOFA in an amount of 5% by weight of the composition. The TAC-loaded TIF-gel composition comprised a) a carrier comprising: a1) water in an amount of 16% by weight of the carrier; and a2) MLO in an amount of 84% by weight of the carrier; and b) TAC in an amount of 1% by weight of the composition. Long-term stability monitoring of TOFA loaded into the gels of the present invention and TAC loaded into the gels of the present invention was carried out at 4 °C and 25 °C for one month. At specific time points, aliquots of the formulation were analyzed by HPLC and the drug content was recorded. The data was expressed as a relative percentage with reference to day 0.

[1003] As seen in Figure 8, the gels loaded with TOFA ( Figure 8A ) and TAC ( Figure 8B ) remained stable at 4 °C and 25 °C over the one-month period.

[1004] Example 8 - Rectal drug delivery via TIF-gel reduces systemic drug exposure

[1005] To demonstrate that rectal TIF-gel application is indeed suitable for minimizing systemic drug release, in vivo drug release was analyzed by longitudinally monitoring the plasma drug levels in mice following colonic TIF-gel enema. For this purpose, healthy mice received a single enema of 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 9 A). The plasma concentration of mice receiving free TOFA reached an early peak at 0.25 h ( Figure 9B); thereafter, the TOFA plasma level rapidly declined 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) (an indicator of cumulative systemic drug absorption) was also significantly reduced in mice treated with TIF-gel-TOFA compared to the group treated with free TOFA ( Figure 9 D). Administration of TAC as a free drug or as a drug-loaded gel resulted in low (and negligible) systemic drug circulation ( Figure 9 C), and no difference was detected in its AUC ( Figure 9 E).

[1006] Example 9 - Evaluation of the Adhesion of TIF-Gel to the Colonic Wall

[1007] At 25 °C and 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 capable of reaching more distal regions of the colon. On the other hand, the pseudoplastic precursor has a higher viscosity than commercially available enemas (such as and and foams containing 5-ASA and budesonide). Therefore, once applied, the TIF-gel adheres to healthy colonic tissue and remains for at least 6 hours, which is the time required to avoid material loss (see, Figure 10 ).

[1008] Additional Embodiments

[1009] The present invention is further illustrated by the following numbered embodiments.

[1010] 1. A composition comprising:

[1011] a) A carrier comprising:

[1012] a1) Water in an amount of more than 10% to 30% by weight of the carrier; and

[1013] a2) Lipid in an amount of 70% to 90% by weight of the carrier; and

[1014] b) A pharmaceutically active agent,

[1015] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate, and

[1016] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C;

[1017] Preferably, the lipid is glyceryl mono-linoleate.

[1018] 2. The composition according to embodiment 1, wherein the carrier comprises 14% to 18% water, wherein the % is by weight of the carrier.

[1019] 3. The composition according to embodiment 2, wherein the carrier comprises 16% water; wherein the % is by weight of the carrier.

[1020] 4. The composition according to any one of embodiments 1 to 3, wherein the carrier comprises 80% to 90% lipid, wherein the % is by weight of the carrier.

[1021] 5. The composition according to embodiment 4, wherein the carrier comprises 84% glyceryl mono - linoleate, wherein the % is by weight of the carrier.

[1022] 6. The composition according to any one of embodiments 1 to 5, wherein the composition comprises a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition.

[1023] 7. The composition according to embodiment 6, wherein the composition comprises a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition.

[1024] 8. The composition according to any one of embodiments 1 to 7, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent.

[1025] 9. The composition according to any one of embodiments 1 to 8, wherein the pharmaceutically active agent is selected from: AbGn168H, ABT - 494, ABX464, apremilast, PF - 00547659, PF - 06687234, 6 - mercaptopurine, adalimumab, azathioprine, bavituximab, brexanolone (MEDI2070), cobitolimod, certolizumab pegol, CP - 690,550, corticosteroids (e.g., multimax budesonide, methylprednisolone), cyclosporine, E6007, itolimod, etrolizumab, filgotinib, guselkumab, golimumab, IL - 2, IMU - 838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS - 5745), mesalazine, mirikizumab (LY3074828), RPC 1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD - 1473, TJ301, tezepelumab (MK 3222), tacrolimus, Janus kinase inhibitors (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressants (e.g., sirolimus), antifibrotic agents (e.g., pirfenidone, nintedanib) and antifungal agents (e.g., clotrimazole, fluconazole).

[1026] 10. The composition according to embodiment 9, wherein the pharmaceutically active agent is tofacitinib or a pharmaceutically acceptable salt thereof.

[1027] 11. The composition according to embodiment 9, wherein the pharmaceutically active agent is tacrolimus.

[1028] 12. The composition according to any one of embodiments 1 to 11, wherein the composition has a lamellar phase structure at 25 °C, preferably wherein the composition is a lamellar gel at 25 °C.

[1029] 13. The composition according to any one of embodiments 1 to 11, wherein the composition forms a lipid cubic phase at a temperature of about 38 °C.

[1030] 14. The composition according to any one of embodiments 1 to 13, wherein the composition further comprises an additive.

[1031] 15. The composition according to any one of embodiments 1 to 14, wherein the composition is substantially free of organic solvents.

[1032] 16. The composition according to any one of embodiments 1 to 15, wherein the composition has a zero-shear viscosity of 1 x 10 -1 to 1 x 10 6 to 1 x 10 7 mPa·s measured at 25 °C and 0.01 s.

[1033] 17. The composition according to any one of embodiments 1 to 16, wherein the composition is an injectable formulation.

[1034] 18. The composition according to embodiment 17, wherein the injectable formulation is a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation.

[1035] 19. The composition according to any one of embodiments 1 to 16, wherein the composition is a topical formulation.

[1036] 20. The composition according to embodiment 19, wherein the topical formulation is an enema.

[1037] 21. The composition according to 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.

[1038] 22. A composition according to any one of embodiments 1 to 21 for use as a medicament.

[1039] 23. A composition according to any one of embodiments 1 to 21 for the treatment of lower gastrointestinal disorders.

[1040] 24. A composition for said use according to embodiment 23, wherein the disorder is selected from: inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colon polyps, proctitis, radiation-related colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis, colorectal cancer and adenocarcinoma, IBD-related perianal fistula, vaginal fistula, intestinal fibrosis and fungal colon infections (such as paracoccidioidomycosis, histoplasmosis and candidiasis).

[1041] 25. A composition for said use according to embodiment 24, wherein the disorder is ulcerative colitis.

[1042] 26. A composition for said 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.

[1043] 27. A composition according to any one of embodiments 1 to 16 or 19 to 21 for treating a disorder affecting the colon, wherein the composition is topically applied to the colon of a subject.

[1044] 28. A composition for said use according to embodiment 27, wherein the disorder 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 fistula, vaginal fistula, intestinal fibrosis and fungal colon infections (such as paracoccidioidomycosis, histoplasmosis and candidiasis).

[1045] 29. A composition for said use according to embodiment 28, wherein the disorder is ulcerative colitis.

[1046] 30. A composition for said 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.

[1047] 31. A composition for said use according to any one of embodiments 27 to 30, wherein the composition is administered rectally, preferably wherein the composition is administered as an enema.

[1048] 32. A composition for said use according to any one of embodiments 27 to 31, wherein the composition forms a controlled-release depot in situ after administration to the subject.

[1049] 33. Use of a preparation comprising from 10% w / w to 30% w / w water and from 70% w / w to 90% w / w lipid as a carrier for a pharmaceutically active agent,

[1050] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate.

[1051] 34. Use according to embodiment 33, wherein the pharmaceutically active agent is dispersed or dissolved in the carrier.

[1052] 35. Use according to embodiment 33 or embodiment 34, wherein the carrier provides a controlled release of the pharmaceutically active agent at a temperature of from 36 °C to 39 °C.

[1053] 36. 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 from 36 °C to 39 °C.

[1054] 36. Use according to any one of embodiments 33 to 36, wherein the carrier is administered as an enema.

[1055] 37. Use of a pre - formulated composition comprising a lipid and a pharmaceutically active agent for the preparation of a composition according to any one of embodiments 1 to 21,

[1056] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate.

[1057] 38. Use according to embodiment 37, wherein the pre - formulated composition is a lyophilized mixture.

[1058] 39. A method for preparing a composition according to any one of embodiments 1 to 21, the method comprising:

[1059] a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid - drug mixture; and

[1060] b) equilibrating the lipid - drug mixture to provide the composition,

[1061] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate.

[1062] 40. Method according to embodiment 39, wherein the mixture in step a) is a lyophilized mixture.

[1063] 41. Method according to embodiment 40, wherein the lyophilized mixture is obtained by:

[1064] i) dissolving the lipid and the pharmaceutically active agent in an organic solvent; and

[1065] ii) Freeze-dry the mixture of i) to provide the freeze-dried mixture.

[1066] 42. The method according to embodiment 41, wherein in step i), the organic solvent is selected from ethanol or methanol, preferably wherein the organic solvent is ethanol.

[1067] 43. A method for preparing a composition according to any one of embodiments 1 to 21, the method comprising:

[1068] a) Dissolve a pharmaceutically active agent in water to provide a drug mixture;

[1069] b) Hydrate the lipid with the drug mixture to provide a lipid-drug mixture; and

[1070] c) Equilibrate the lipid-drug mixture to provide the composition,

[1071] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[1072] 44. The method according to embodiment 43, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[1073] 45. A kit comprising:

[1074] a) A first container containing a lipid and a pharmaceutically active agent; and

[1075] b) Instructions for combining a) with water to provide a composition according to any one of embodiments 1 to 21,

[1076] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[1077] 46. The kit according to embodiment 45, the kit further comprising a second container, wherein the second container contains water.

[1078] 47. The kit according to embodiment 45 or embodiment 46, wherein the lipid and the pharmaceutically active agent in the first container are provided as a freeze-dried mixture.

[1079] 48. A kit comprising:

[1080] a) A first container containing a lipid; and

[1081] b) Instructions for combining a) with a solution containing a pharmaceutically active agent dissolved in water to provide a composition according to any one of embodiments 1 to 21,

[1082] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate.

[1083] 49. The kit according to embodiment 48, wherein the kit further comprises a second container, and the second container contains a pharmaceutically active agent dissolved in water.

[1084] 50. The kit according to embodiment 48 or embodiment 49, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[1085] The present invention is further illustrated by the following numbered embodiments.

[1086] P1. A composition, comprising:

[1087] a) a carrier, comprising:

[1088] a1) water in an amount of more than 10% to 30% by weight of the carrier; and

[1089] a2) lipid in an amount of 70% to 90% by weight of the carrier; and

[1090] b) a pharmaceutically active agent,

[1091] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate, and

[1092] wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C;

[1093] Preferably, the lipid is glyceryl mono-linoleate.

[1094] P2. The composition according to embodiment P1, wherein the carrier comprises 14% to 18% water, wherein the % is by weight of the carrier;

[1095] Optionally, the carrier comprises 16% water, wherein the % is by weight of the carrier.

[1096] P3. The composition according to embodiment P1 or embodiment P2, wherein the carrier comprises 80% to 90% lipid, wherein the % is by weight of the carrier;

[1097] Optionally, the carrier comprises 84% glyceryl mono-linoleate, wherein the % is by weight of the carrier.

[1098] P4. The composition according to any one of embodiments P1 to P3, wherein the composition comprises a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition;

[1099] Optionally, the composition comprises a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition;

[1100] Further optionally, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent.

[1101] P5. A composition according to any one of embodiments P1 to P4, wherein the pharmaceutically active agent is selected from: AbGn168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bavituximab, brodalumab (MEDI2070), cobitolimod, certolizumab pegol, CP-690,550, corticosteroids (e.g., multimax budesonide, methylprednisolone), cyclosporine, E6007, itraflimod, etrolizumab, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitor (e.g., GS-5745), mesalazine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK3222), tacrolimus, Janus kinase inhibitor (e.g., tofacitinib), ustekinumab, UTTR1147A, vedolizumab, immunosuppressive agents (e.g., rapamycin), antifibrotic agents (e.g., pirfenidone, nintedanib) and antifungal agents (e.g., clotrimazole, fluconazole),

[1102] Optionally, wherein the pharmaceutically active agent is:

[1103] (i) tofacitinib or a pharmaceutically acceptable salt thereof; or

[1104] (ii) tacrolimus.

[1105] P6. A composition according to any one of embodiments P1 to P5, wherein:

[1106] (i) the composition has a lamellar phase structure at 25 °C, preferably wherein the composition is a lamellar gel at 25 °C; and / or

[1107] (ii) the composition forms a lipid cubic phase at a temperature of about 38 °C; and / or

[1108] (iii) further comprises an additive; and / or

[1109] (iv) is substantially free of organic solvents; and / or

[1110] (v) has a value measured at 25 °C and 0.01 s -1 of 1x 10 6 to 1x 107 zero-shear viscosity in mPa·s

[1111] P7. A composition according to any one of embodiments P1 to P6, wherein the composition:

[1112] (i) is an injectable formulation,

[1113] optionally wherein the injectable formulation is a subcutaneous, intramuscular or intradermal injectable formulation, preferably a subcutaneous injectable formulation; or

[1114] (ii) is a topical formulation,

[1115] optionally wherein the topical formulation is an enema; and / or

[1116] (iii) forms a bioadhesive controlled release depot at a temperature of 36°C to 39°C.

[1117] P8. A composition according to any one of embodiments P1 to P7 for use as a medicament.

[1118] P9. A composition according to any one of embodiments P1 to P7 for the treatment of lower gastrointestinal disorders,

[1119] optionally wherein the disorder is selected from: inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colon polyps, proctitis, radiation-related colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis, colorectal cancer and adenocarcinoma, IBD-related perianal fistula, vaginal fistula, intestinal fibrosis and fungal colon infections (such as paracoccidioidomycosis, histoplasmosis and candidiasis),

[1120] further optionally wherein the disorder is ulcerative colitis, for example, wherein 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.

[1121] P10. A composition according to any one of embodiments P1 to P7 for the treatment of a disorder affecting the colon, wherein the composition is topically applied to the colon and / or rectum of a subject,

[1122] optionally wherein the disorder 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 fistula, vaginal fistula, intestinal fibrosis and fungal colon infections (such as paracoccidioidomycosis, histoplasmosis and candidiasis),

[1123] Further optionally, wherein the disorder is ulcerative colitis, for example, wherein 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.

[1124] P11. A composition for the use according to embodiment P9 or embodiment P10, wherein the composition is administered rectally, optionally wherein:

[1125] (i) the composition is administered as an enema; and / or

[1126] (ii) the composition forms a controlled release depot in situ after administration to a subject.

[1127] P12. Use of a formulation comprising more than 10% w / w to 30% w / w water and 70% w / w to 90% w / w lipid as a carrier for a pharmaceutically active agent,

[1128] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate;

[1129] Optionally wherein:

[1130] (i) the pharmaceutically active agent is dispersed or dissolved in the carrier; and / or

[1131] (ii) the carrier provides controlled release of the pharmaceutically active agent at a temperature of 36°C to 39°C; and / or

[1132] (iii) the carrier forms a controlled release depot for the pharmaceutically active agent at a temperature of 36°C to 39°C; and / or

[1133] (iv) the carrier is administered as an enema.

[1134] P13. Use of a pre-formulated composition comprising a lipid and a pharmaceutically active agent for the preparation of a composition according to any one of embodiments P1 to P7,

[1135] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[1136] Optionally wherein the pre-formulated composition is a lyophilized mixture.

[1137] P14. A method selected from method A or method B:

[1138] Method A: A method for preparing a composition according to any one of embodiments P1 to P7, the method comprising:

[1139] a) hydrating a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and

[1140] b) balance the lipid-drug mixture to provide the composition,

[1141] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[1142] optionally wherein:

[1143] A1) the mixture in step a) is a lyophilized mixture; and / or

[1144] A2) the lyophilized mixture is obtained by:

[1145] i) dissolving the lipid and the pharmaceutically active agent in an organic solvent; and

[1146] ii) lyophilizing the mixture of i) to provide the lyophilized mixture; and / or

[1147] A3) in step i), the organic solvent is selected from ethanol or methanol, preferably wherein the organic solvent is ethanol; or

[1148] Method B: A method for preparing a composition according to any one of embodiments P1 to P7, the method comprising:

[1149] a) dissolving a pharmaceutically active agent in water to provide a drug mixture;

[1150] b) hydrating a lipid with the drug mixture to provide a lipid-drug mixture; and

[1151] c) balancing the lipid-drug mixture to provide the composition,

[1152] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[1153] optionally wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent.

[1154] P15. A kit selected from Kit A or Kit B:

[1155] Kit A: A kit comprising:

[1156] a) a first container containing a lipid and a pharmaceutically active agent; and

[1157] b) instructions for combining a) with water to provide a composition according to any one of embodiments P1 to P7,

[1158] wherein the lipid is selected from glyceryl mono-linoleate or glyceryl mono-oleate,

[1159] optionally wherein the kit further comprises a second container containing water,

[1160] Optionally further wherein the lipid and the pharmaceutical active agent in the first container are provided as a lyophilized mixture; or

[1161] Kit B: A kit comprising:

[1162] a) A first container comprising a lipid; and

[1163] b) Instructions for combining a) with a solution comprising a pharmaceutical active agent dissolved in water to provide a composition according to any one of embodiments P1 to P7,

[1164] wherein the lipid is selected from glyceryl mono - linoleate or glyceryl mono - oleate,

[1165] Optionally wherein the kit further comprises a second container, wherein the second container comprises a pharmaceutical active agent dissolved in water,

[1166] Optionally further wherein the pharmaceutical active agent is a hydrophilic pharmaceutical active agent.

[1167] References

[1168] 1. J. Meier, Inflammatory Bowel Disease Nursing Manual, (Springer International Publishing, Cham, 2019), pp. 11 - 14

[1169] 2. R. Ungaro, et al., Ulcerative colitis, Lancet 389, 1756 - 1770 (2017)

[1170] 3. S. Singh, et al., AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis, Gastroenterology 158, 1465 - 1496.e17 (2020)

[1171] 4. C. W. Ko, et al., AGA Clinical Practice Guidelines on the Management of Mild - to - Moderate Ulcerative Colitis, Gastroenterology 156, 748 - 764 (2019).

[1172] 5. M. Manz, et al., Treatment algorithm for moderate to severe ulcerative colitis, Swiss Med. Wkly. 141(2011), doi:10.4414 / smw.2011.13235

[1173] 6. J. Wehkamp, et al., Recent advances and emerging therapies in the non-surgical management of ulcerative colitis, F1000Research 7, 1207(2018)

[1174] 7. R. Khanna, et al., Ustekinumab for Ulcerative Colitis, Gastroenterology 160, 2184 - 2186(2021)

[1175] 8. W. J. Sandborn, et al., Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis, N. Engl. J. Med. 385, 1280 - 1291(2021)

[1176] 9. G. D’Haens, Risks and benefits of biologic therapy for inflammatory bowel diseases, Gut 56, 725 - 732(2007)

[1177] 10. S. Ben-Horin, et al., Optimizing biologic treatment in IBD: objective measures, but when, how and how often?, BMC Gastroenterol. 15, 178(2015)

[1178] 11. J. Kirchgesner, et al., Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases, Gastroenterology 155, 337 - 346.e10 (2018)

[1179] 12. G. Mocci, et al., Dermatological adverse reactions during anti - TNF treatments: Focus on inflammatory bowel disease, J. Crohn’s Colitis 7, 769 - 779 (2013)

[1180] 13. F. Hoentjen, et al., Safety of anti - tumor necrosis factor therapy in inflammatory bowel disease, World J. Gastroenterol. 15, 2067 - 2073 (2009)

[1181] 14. S. Danese, et al., JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines, Am. J. Physiol. Liver Physiol. 310, G155 - G162 (2016)

[1182] 15. S. Bonovas, et al., Systematic review with network meta - analysis: comparative assessment of tofacitinib and biological therapies for moderate - to - severe ulcerative colitis, Aliment. Pharmacol. Ther. (2018), doi:10.1111 / apt.14449

[1183] 16. S. Singh, et al., Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis, Aliment. Pharmacol. Ther. (2018), doi:10.1111 / apt.14422

[1184] 17. H. Ogata, et al., A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis, Gut 55, 1255 - 1262 (2006)

[1185] 18. G. Rogler, Gastrointestinal and liver adverse effects of drugs used for treating IBD, Best Pract. Res. Clin. Gastroenterol. (2010), doi:10.1016 / j.bpg.2009.10.011

[1186] 19. R. Westhovens, Clinical efficacy of new JAK inhibitors under development. Just more of the same?, Rheumatol. (United Kingdom) 58, i27 - i33 (2019)

[1187] 20. K. Haga, et al., Effec...

Claims

1. A composition for treating lower gastrointestinal disorders, wherein the composition comprises: a) a carrier, which comprises: a1) water in an amount of more than 10% to 30% by weight of the carrier; and a2) monoacylglycerol lipids in an amount of 70% to 90% by weight of the carrier, wherein the monoacylglycerol lipids comprise glyceryl mono-linoleate or glyceryl mono-oleate 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, and wherein the composition is administered rectally; preferably wherein the monoacylglycerol lipids are glyceryl mono-linoleate.

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

3. The composition for the use according to claim 1 or claim 2, wherein the carrier comprises 80% to 90% monoacylglycerol lipids, wherein the % is by weight of the carrier; optionally wherein the carrier comprises 84% glyceryl mono-linoleate, wherein the % is by weight of the carrier.

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

5. The composition for the use according to any one of claims 1 to 4, wherein the pharmaceutically active agent is selected from biopharmaceuticals (such as anti-TNF antibodies, IL-23 inhibitors, IL-12 inhibitors, TLR9 agonists, anti-MAdCAM antibodies, human IL-22Fc fusion proteins, interleukins, anti-β7 integrin antibodies, matrix metalloproteinase 9 (MMP9) inhibitors), JAK inhibitors, PDE4 inhibitors, sphingosine-1-phosphate receptor modulators, anti-inflammatory agents, corticosteroids, immunosuppressants, antifungal agents, antibiotics, anti-fibrotic agents, and anti-cancer agents, optionally wherein the pharmaceutically active agent is selected from: (i) ABT-494, ABX464, apremilast, 6-mercaptopurine, azathioprine, CP-690,550, multimaxbudesonide, methylprednisolone, cyclosporine, E6007, itraflimod, filgotinib, IMU-838, mesalazine, RPC1063, sulfasalazine, TD-1473, TJ301, tacrolimus, tofacitinib, sirolimus, pirfenidone, nintedanib, clotrimazole, and fluconazole; and / or (ii) AbGn168H, PF-00547659, PF-06687234, adalimumab, brolimumab, brodalumab (MEDI2070), cobitolimod, certolizumab, etrolizumab, guselkumab, golimumab, IL-2, infliximab, GS-5745, mirikizumab (LY3074828), risankizumab (BI 6555066), SHP647, tildrakizumab (MK 3222), ustekinumab, UTTR1147A, and vedolizumab, further optionally wherein the pharmaceutically active agent is: (a) tofacitinib or a pharmaceutically acceptable salt thereof; or (b) tacrolimus.

6. The composition for the use according to any one of claims 1 to 5, wherein: (i) the composition has a lamellar phase structure at 25 °C, preferably wherein 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 has a zero-shear viscosity measured at 25 °C and 0.01 s -1 of 1 x 10 6 to 1 x 10 7 mPa·s.

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

8. The composition for the use according to any one of claims 1 to 7, wherein the disease is selected from: inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, colorectal polyps, proctitis, radiation-related colitis, pseudomembranous colitis, diverticulosis, diverticulitis, collagenous colitis, colorectal cancer and adenocarcinoma, IBD-related perianal fistula, vaginal fistula, intestinal fibrosis, and fungal colon infection (such as paracoccidioidomycosis, histoplasmosis, and candidiasis), optionally wherein the disease is ulcerative colitis, for example, wherein 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 composition comprising: a) a carrier, which comprises: a1) water in an amount of 14% to 18% by weight of the carrier; and a2) monoacylglycerol lipid in an amount of 82% to 86% by weight of the carrier, wherein the monoacylglycerol lipid comprises at least 50% by weight of glyceryl monooleate; and b) a pharmaceutically active agent in an amount of 0.1% to 10% by weight of the composition, wherein the composition forms a lipid cubic phase at a temperature of 36 °C to 39 °C.

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

11. The composition according to claim 9 or claim 10, wherein: (i) The composition comprises a pharmaceutically active agent in an amount of 1% to 5% by weight of the composition; Optionally, wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent or a hydrophobic pharmaceutically active agent; and / or (ii) The pharmaceutically active agent is selected from biopharmaceuticals (such as anti-TNF antibodies, IL-23 inhibitors, IL-12 inhibitors, TLR9 agonists, anti-MAdCAM antibodies, human IL-22Fc fusion proteins, interleukins, anti-β7 integrin antibodies, matrix metalloproteinase 9 (MMP9) inhibitors), JAK inhibitors, PDE4 inhibitors, sphingosine-1-phosphate receptor modulators, anti-inflammatory agents, corticosteroids, immunosuppressants, antifungal agents, antibiotics, antifibrotic agents, and anticancer agents, Optionally, wherein the pharmaceutically active agent is selected from: (I) ABT-494, ABX464, apremilast, 6-mercaptopurine, azathioprine, CP-690,550, multimaxbudesonide, methylprednisolone, cyclosporine, E6007, itraflimod, filgotinib, IMU-838, mesalazine, RPC1063, sulfasalazine, TD-1473, TJ301, tacrolimus, tofacitinib, rapamycin, pirfenidone, nintedanib, clotrimazole, and fluconazole; and / or (II) AbGn168H, PF-00547659, PF-06687234, adalimumab, brazikumab, brepocitinib (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, Further optionally, wherein the pharmaceutically active agent is: (a) tofacitinib or a pharmaceutically acceptable salt thereof; or (b) tacrolimus.

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

13. Use of a pre-formulated composition comprising a monoacylglycerol lipid and a pharmaceutically active agent for the preparation of a composition according to any one of claims 9 to 12, Optionally, wherein the pre-formulated composition is a lyophilized mixture.

14. A method selected from method A, method B, or method C: Method A: A method for preparing a composition for the use according to any one of claims 1 to 8, or a composition according to any one of claims 9 to 12, the method comprising: a) Hydrate a mixture comprising a lipid and a pharmaceutically active agent with water to provide a lipid-drug mixture; and b) Equilibrate the lipid-drug mixture to provide the composition, Optionally wherein: A1) The mixture in step a) is a lyophilized mixture; and / or A2) The lyophilized mixture is obtained by: i) Dissolve the lipid and the pharmaceutically active agent in an organic solvent; And ii) Lyophilize the mixture of i) to provide the lyophilized mixture; and / or A3) In step i), the organic solvent is selected from ethanol or methanol, preferably wherein the organic solvent is ethanol; or Method B: A method for preparing a composition for the use according to any one of claims 1 to 8, or a composition according to any one of claims 9 to 12, the method comprising: a) Dissolve the pharmaceutically active agent in water to provide a drug mixture; b) Hydrate the lipid with the drug mixture to provide a lipid-drug mixture; and c) Equilibrate the lipid-drug mixture to provide the composition, Optionally wherein the pharmaceutically active agent is a hydrophilic pharmaceutically active agent; or Method C: A method for preparing a composition for the use according to any one of claims 1 to 8, or a composition according to any one of claims 9 to 12, the method comprising: a) Heat the lipid to provide a molten lipid; b) Mix the molten lipid with the pharmaceutically active agent to provide a lipid-drug mixture; c) Mix the lipid-drug mixture with water; And d) Equilibrate the lipid-drug mixture and water to provide the composition, Optionally wherein: C1) Mix the molten lipid and the pharmaceutically active agent in step b) at a temperature of about 30 °C to 70 °C, preferably about 40 °C to 60 °C; and / or C2) Mix the lipid-drug mixture in step c) with water in a dual syringe.

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

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