Biosoluble pharmaceutical gels for drug delivery

Abstract

To provide a drug with an effective time course of drug availability that provides for the maintenance of a stable, long-term administration of a therapeutically effective amount of drug, while reducing the tendency to cause side effects and reducing the frequency of administration for patient convenience and improved compliance. The present invention provides a biodegradable / bioerodible aqueous gel system for pharmaceutical use, optionally containing an active pharmaceutical ingredient, that transitions from a liquid to a gel at or near mammalian body temperature. These compositions may contain a reversible gelling material, such as methylcellulose, and a rheology modifier, such as citrate.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Application No. 62 / 771,529, filed on Nov. 26, 2018, which is hereby incorporated by reference in its entirety.

[0002] (Technical Field) The present disclosure relates to a pharmaceutical lytic / erosive aqueous gel system for drug delivery. More particularly, the present disclosure relates to a lytic aqueous gel system for treating, modifying, and / or preventing local diseases. Characteristics such as the solubility, injectability, and drug release rate of the system can be controlled by the components and their concentrations.

Background Art

[0003] One important issue in the development of drug delivery systems is the long - term maintenance of bioavailability at the intended site of action. Depending on the nature of the drug and the route of administration, bioavailability may not be optimal, for example, due to degradation by first - pass metabolism in the hepatogastrointestinal tract of orally administered drugs and / or rapid excretion of the drug from the site of administration. As a result, higher doses and more frequent administrations than necessary are required to obtain a therapeutic effect, while undesirable side effects occur. Thus, it is desirable to be able to administer a drug with an effective time - course of drug availability that reduces the tendency to cause side effects and maintains a stable long - term administration of a therapeutically effective amount of the drug while reducing the frequency of administration for improved patient convenience and compliance.

Summary of the Invention

Means for Solving the Problems

[0004] Some embodiments include a pharmaceutical composition comprising a reverse thermogelation material that transitions from a liquid to a gel near the body temperature of a mammal, such as human body temperature.

[0005] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, wherein the pharmaceutical composition transitions from a liquid to a gel at mammalian body temperature, more preferably near human body temperature.

[0006] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, and a citrate.

[0007] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, a citrate, and a phosphate.

[0008] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, and a phosphate.

[0009] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, a citrate, and dimethyl sulfoxide.

[0010] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, a phosphate, and dimethyl sulfoxide.

[0011] Some embodiments include a pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, a citrate, a phosphate, and dimethyl sulfoxide.

[0012] Some embodiments include a method of treating a disease, comprising administering the pharmaceutical composition described herein to a mammal in need of treatment.

[0013] Some embodiments include a method of using the pharmaceutical composition described herein in the manufacture of a medicament for treating a disease.

[0014] Some embodiments include methods of delivering an active pharmaceutical ingredient that include administering the pharmaceutical compositions described herein to a mammal in need of the active pharmaceutical ingredient, the method providing a therapeutic effect with a reduced frequency of administration of the active pharmaceutical ingredient. Active pharmaceutical administration involves administration that involves an action on the part of the patient or the person administering the agent. For example, injection, application of a topical composition, swallowing of an oral dosage form, etc. are examples of active pharmaceutical administration. Thus, reducing the frequency of administration of the active pharmaceutical ingredient will reduce the frequency of injection, oral administration, topical administration, etc. Some administrations are not active, such as the sustained release delivery of dosage forms.

[0015] Some embodiments include methods of delivering an active pharmaceutical ingredient that include administering the pharmaceutical compositions described herein to a mammal in need of the active pharmaceutical ingredient, wherein a single administration of the active pharmaceutical ingredient provides a therapeutically effective concentration of the active pharmaceutical ingredient to the mammal for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 12 months, or longer.

[0016] Some embodiments include a step of placing and mixing a polymeric agent into a suspension comprising a gelling regulator and an active pharmaceutical ingredient, the mixing being carried out at a temperature of about 60°C to about 80°C, the suspension being formed by a method comprising precipitating the active pharmaceutical ingredient in an aqueous liquid and adding the gelling regulator to the suspension. A method of preparing a pharmaceutical composition having inverse thermogelation properties is included. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

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Mode for Carrying Out the Invention

[0018] Topically administered pharmaceutical gels are thought to have the potential to acquire the desirable drug delivery properties described above. However, most approved gel products are not injectable and / or impossible to inject via the parenteral route, and also cannot be instilled via the topical route. Furthermore, commercially available ophthalmic or dermatological gel products do not provide reduced dosing frequency and long-term exposure compared to conventional ophthalmic / dermatological dosage forms such as solutions, suspensions, emulsions, lotions, creams, ointments, etc. When long-term release is required in the parenteral, topical, and local areas, people have often had better success with multi-particle systems, devices, implants, and / or inserts rather than gels.

[0019] Inverse thermogelation systems, e.g., systems that increase in fluidity with decreasing temperature, are effective in regulating the maintenance and release of drugs after administration. To enable the use of these systems in therapy, some of the challenges to be overcome include ease of administration, dose stability, and local and systemic toxicity.

[0020] Generally, the present disclosure relates to pharmaceutical compositions (optionally containing an active pharmaceutical ingredient) having specific rheological properties. The pharmaceutical compositions described herein are generally referred to as "subject compositions". The subject composition is a reversible gelation composition having specific properties. For example, the subject composition may transition from a liquid to a gel near the body temperature of a mammal, e.g., near the body temperature of a human, e.g., between about 0°C and about 40°C. For example, the subject composition may be liquid at about 2 - 8°C, e.g., 7°C, and solid at a higher temperature, e.g., about 30 - 40°C, e.g., 37°C. The subject composition can be used by any route of administration, but the properties of the subject composition may provide advantages in parenteral and topical routes over other dosage forms currently in use (inserts, implants, transdermal / topical patches, etc.) for the intended purpose of the subject composition.

[0021] The subject composition may include a gelling material that forms a three-dimensional network.

[0022] The subject composition has many potential advantages that can overcome the limitations of existing gel technologies as follows.

[0023] 1) Gel compositions that become semi-solid near body temperature may not be able to pass through the thin needles or long catheters required for administration. To address this challenge, the subject composition has properties related to appropriate viscosity and elasticity before and during administration.

[0024] 2) Gel compositions that become semi-solid near body temperature may not undergo phase transition in vivo in a timely manner after administration into the body, tissue, or body cavity if the gelation rate is too slow or too fast. Some of the subject compositions have a kinetically favorable, e.g., sufficiently fast, gel-sol transition to ensure timely gel formation for the intended indication.

[0025] 3) When a gel is formed in vivo, the formed gel may be fragile and may not persist for a sufficient period to exhibit an effective drug release effect. On the other hand, an overly durable gel may remain in the body for a long time even after all the drug has been released from the gel, leaving an empty gel mass in the body, which may be undesirable. Some of the subject compositions have appropriate elasticity and viscosity to allow for proper formation after administration, and the gel dissolves at a rate corresponding and comparable to the rate of drug release.

[0026] The viscoelastic properties of the subject compositions can be adjusted such that the subject compositions are administered via a thin needle, catheter, and / or device, form a gel after administration, and have an appropriate solubility to provide the desired residence time required for the therapeutic effect.

[0027] The subject compositions enable targeted drug delivery to local tissues, which is preferred over systemic drug administration. Targeted drug delivery has been employed to maximize local drug exposure and minimize systemic side effects. However, for successful local drug delivery, the acquisition of several characteristics may be required, such as ease of administration, appropriate local tolerance and safety, delivery at an appropriate volume and dose to the target tissue, and effective disease management. To reduce the need for frequent administration, such as frequent injections, release of the drug over an appropriate period may be desirable. An increase in the residence time at the target tissue can reduce the frequency of repeated administrations and improve local treatment methods. Also, to improve the desirability and effectiveness of some local drug deliveries, it is desirable to improve the ease of administration of pharmaceutical compositions such as the subject compositions.

[0028] Surprisingly, many of the subject compositions provide extended or controlled "residence times" of the active agent in sufficient amounts in the target tissue upon local administration, as compared to conventional formulations such as injectable aqueous solutions, suspensions, and topical dosage forms. Some of the subject compositions can be administered to a patient using a conventional syringe and needle, while others can be administered using a catheter or applicator.

[0029] Unless otherwise specified, a reference to a compound such as an active pharmaceutical ingredient, or any other formulation ingredient, includes alternative solid forms such as pharmaceutically acceptable salts, acid forms, base forms, prodrugs, polymorphs, solvates, hydrates, tautomers, or other chemical species that may be rapidly converted to the compounds described herein under the conditions in which the compounds described herein are used.

[0030] As noted above, some subject compositions include an active pharmaceutical ingredient in an inverse thermogelling material, such as an inverse thermogelling polymer, e.g., an inverse thermogelling polymer dissolved or dispersed in water or an aqueous solution.

[0031] Any suitable polymer with reverse thermogelling properties may be used in the subject composition. US4474752, US4478822, and CA1072413, which are incorporated herein by reference, provide examples of polymers that can impart reverse thermogelling properties to the subject composition. BASF Wyandotte Corporation's "Tetronic®" polyols and Pluronic® poloxamer polymers may also be used to provide reverse thermogelling properties.

[0032] In some embodiments, the subject compositions include at least one polymeric agent. Preferably, the polymeric agent includes an alkyl cellulose, such as methyl cellulose, ethyl cellulose, etc. (C 1-6 alkyl)cellulose.

[0033] In some embodiments, the subject compositions comprise: 1-6It contains (alkyl) cellulose.

[0034] In some embodiments, the target composition contains ethyl cellulose.

[0035] In some embodiments, the target composition contains methyl cellulose. In some embodiments, the methyl cellulose has a viscosity of about 1,000 - 2,000 mPas, about 1,400 - 1,600 mPas, or about 1,500 mPas.

[0036] In a target composition containing methyl cellulose (such as methyl cellulose A15LV), for example, any suitable concentration of methyl cellulose such as about 0.1 - 20% (w / w), about 2 - 10% (w / w), about 3 - 4% (w / w), about 4 - 5% (w / w), about 5 - 6% (w / w), about 6 - 7% (w / w), about 7 - 8% (w / w), about 8 - 9% (w / w), about 4 - 6% (w / w), about 6 - 8% (w / w), about 8 - 10% (w / w), about 4.6 - 4.8% (w / w), about 4.8 - 5% (w / w), about 5 - 5.2% (w / w), about 5.2 - 5.4% (w / w), about 5.4 - 5.6% (w / w), about 5.6 - 5.8% (w / w), about 6.6 - 6.8% (w / w), about 6.8 - 7% (w / w), 7 - 7.2% (w / w), about 7.2 - 7.4% (w / w), about 7.4 - 7.6% (w / w), about 7.6 - 7.8% (w / w), about 4.5 - 5.5% (w / w), about 4.8 - 5.2% (w / w), about 6.8 - 7.2% (w / w), about 6.5 - 7.5% (w / w), about 3 - 9% (w / w), or 3 - 12% (w / w) may be used.

[0037] In a target composition containing methyl cellulose, the degree of methoxylation of the methyl cellulose may be, for example, about 10 - 50%, about 10 - 15%, about 15 - 20%, about 20 - 25%, about 25 - 30%, about 30 - 35%, about 35 - 40%, about 40 - 45%, about 45 - 50%, about 20 - 22%, about 22 - 24%, about 24 - 26%, about 26 - 28%, about 28 - 30%, about 30 - 32%, about 32 - 34%, about 34 - 36%, about 36 - 38%, about 38 - 40%, or about 20 - 35%, etc.

[0038] The methylcellulose solution has inverse thermogelation properties. However, among methylcellulose solutions, there are those with a gelation temperature outside the body temperature range. In addition, in methylcellulose solutions, its viscoelastic properties are often not suitable for large-scale pharmaceutical manufacturing and administration to patients in a clinical setting.

[0039] The subject composition may include at least one gelation regulator. The gelation regulator may alter properties such as the gelation start temperature, gelation rate, gelation temperature, and elastic profile as a function of temperature. The gelation regulator may be a substance such as a salt, buffer, solvent, surfactant, another substance, or a combination thereof. In some embodiments, multiple gelation regulators (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) can be used in one formulation to produce a formulation capable of enabling delivery of an active pharmaceutical agent.

[0040] Examples of suitable gelling regulators include phosphates, dihydrogen phosphates, hydrogen phosphates, tris(hydroxymethyl)aminomethane, borates, histidine, carbonates, bicarbonates, citrates, citrate acetates, tartrates, fumarates, lactates, formates, sulfaminates, oxalates, malonates, succinates, maleates, adipates, benzoates, o-toluylates, benzene tetracarboxylates, glutamates, e-aminocaproates, aspartates, glycineates, alginates, lysinates, taurinates, ethanol, dimethyl sulfoxide, glycerin, dimethylformamide, propylene glycol, polyethylene glycol, vegetable oils, corn oil, olive oil, castor oil, vitamin E, phospholipids, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, monosaccharides, disaccharides, dextrose, sucrose, sugar alcohols, mannitol, sorbitol, antioxidants, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfate, sodium sulfite, disodium sulfite, EDTA, sodium carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose, carbomer, hyaluronic acid, hyaluronate, etc., or combinations thereof. In some embodiments, the gelling regulator includes a phosphate. In some embodiments, the gelling regulator includes dimethyl sulfoxide. In some embodiments, the gelling regulator includes a citrate.

[0041] Suitable buffers (for use as gelling regulators or for buffering purposes unrelated to gelling regulation) may include phosphates, dihydrogen phosphates, hydrogen phosphates, tris-(hydroxymethyl)aminomethane, borates, histidine, carbonates, bicarbonates, citrates, acetates, tartrates, fumarates, lactates, formates, sulfaminates, oxalates, malonates, succinates, maleates, adipates, benzoates, o-toluylates, benzene tetracarboxylates, glutamates, e-aminocaproates, aspartates, glycylates, alginates, lysinates, taurinates, etc., or combinations thereof. In some embodiments, the pharmaceutical composition comprises a citrate, including citric acid, any salt of citric acid, or a combination thereof. In some embodiments, the pharmaceutical composition comprises a phosphate, including phosphoric acid, any salt of phosphoric acid, or a combination thereof. In some embodiments, multiple buffers can be used in combination in a single formulation.

[0042] For a pharmaceutical composition containing citrate, for example, any suitable citrate concentration (including citric acid, salts of citric acid, combinations of salts of citric acid, or combinations of one or more salts of citric acid and citric acid) may be, for example, 1 - 200 mmol / kg, about 25 - 200 mmol / kg, about 50 - 100 mmol / kg, about 100 - 150 mmol / kg, about 80 - 100 mmol / kg, about 100 - 120 mmol / kg, about 120 - 140 mmol / kg, about 96 - 98 mmol / kg, about 98 - 100 mmol / kg, about 100 - 102 mmol / kg, about 102 - 104 mmol / kg, about 104 - 110 mmol / kg, about 110 - 112 mmol / kg, about 112 - 114 mmol / kg, about 114 - 116 mmol / kg, about 116 - 118 mmol / kg, about 118 - 120 mmol / kg, about 120 - 122 mmol / kg, about 97 - 99 mmol / kg, about 99 - 101 mmol / kg, about 101 - 103 mmol / kg, about 103 - 108 mmol / kg, about 108 - 113 mmol / kg, about 113 - 115 mmol / kg, about 115 - 117 mmol / kg, about 117 - 119 mmol / kg, about 90 - 110 mmol / kg, or about 110 - 130 mmol / kg, etc.

[0043] Regarding a pharmaceutical composition containing phosphate, for example, any appropriate concentration of phosphate such as 1 - 200 mmol / kg, about 50 - 100 mmol / kg, about 100 - 150 mmol / kg, about 80 - 100 mmol / kg, about 100 - 120 mmol / kg, about 120 - 140 mmol / kg, about 96 - 98 mmol / kg, about 98 - 100 mmol / kg, about 100 - 102 mmol / kg, about 102 - 104 mmol / kg, about 110 - 112 mmol / kg, about 112 - 114 mmol / kg, about 114 - 116 mmol / kg, about 116 - 118 mmol / kg, about 118 - 120 mmol / kg, about 120 - 122 mmol / kg, about 97 - 99 mmol / kg, about 99 - 101 mmol / kg, about 101 - 103 mmol / kg, about 113 - 115 mmol / kg, about 115 - 117 mmol / kg, about 117 - 119 mmol / kg, about 90 - 110 mmol / kg, or about 110 - 130 mmol / kg, etc., may be used.

[0044] A hydrophilic solvent or a hydrophobic solvent may also be used as a gelling modifier or for other purposes. Suitable hydrophilic solvents include ethanol, dimethyl sulfoxide, glycerin, dimethylformamide, propylene glycol, and polyethylene glycol. Suitable hydrophobic solvents include vegetable oils (such as corn oil, olive oil, castor oil, etc.), vitamin E, and phospholipids.

[0045] For pharmaceutical compositions containing dimethyl sulfoxide, for example, any suitable concentration of dimethyl sulfoxide such as about 0.1 - 50% (w / w), about 0.1 - 20% (w / w), about 0.1 - 10% (w / w), about 0.1 - 1% (w / w), about 1 - 10% (w / w), about 10 - 20% (w / w), about 20 - 30% (w / w), about 30 - 40% (w / w), about 40 - 50% (w / w), about 0.1 - 8% (w / w), about 1 - 2% (w / w), about 2 - 3% (w / w), about 3 - 4% (w / w), about 4 - 5% (w / w), about 5 - 6% (w / w), about 6 - 7% (w / w), about 4 - 6% (w / w), about 6 - 8% (w / w), about 8 - 9% (w / w), about 9 - 10% (w / w), about 10 - 12% (w / w), about 4.8 - 5% (w / w), about 5 - 5.2% (w / w), about 5.2 - 5.4% (w / w), about 4.5 - 5.5% (w / w), about 4.8 - 5.2% (w / w), about 3 - 9% (w / w), about 9 - 11% (w / w), or about 3 - 12% (w / w) etc. may be used.

[0046] Other materials that may be used as gelling regulators include surfactants (such as polysorbate 20, 40, 60, 80, and phospholipids), monosaccharides or disaccharides (such as glucose, sucrose, etc.), sugar alcohols (such as mannitol, sorbitol, etc.), antioxidants (such as vitamin E, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfate, sodium sulfite, disodium sulfite, etc.), chelating agents such as EDTA, suspending agents (such as sodium carboxymethyl cellulose, sodium alginate, etc.), and viscosity increasing agents (such as hydroxypropyl methylcellulose, carbomer, hyaluronate, etc.).

[0047] The pharmaceutical composition may have any suitable pH, for example, about 4 - 9, about 5 - 9, about 6 - 8, about 6 - 7, about 7 - 8, about 7 - 7.3, about 7.3 - 7.6, about 7.6 - 7.9, about 7.2 - 7.6, or about 7.4 etc.

[0048] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, or less than 0.5% polyethylene glycol, or may be substantially free of or completely free of polyethylene glycol.

[0049] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% dimethyl sulfoxide, or may be substantially free of or completely free of dimethyl sulfoxide.

[0050] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% glycerin, or may be substantially free of or completely free of glycerin.

[0051] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% sucrose, or may be substantially free of or completely free of sucrose.

[0052] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% polysorbate 80, or may be substantially free of or completely free of polysorbate 80.

[0053] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% polysorbate 60, or may be substantially free of or completely free of polysorbate 60.

[0054] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% of polysorbate 40, or may be substantially free of or completely free of polysorbate 40.

[0055] In some embodiments, the composition may contain less than 20%, less than 10%, less than 5%, less than 2.5%, or less than 0.5% of polysorbate 20, or may be substantially free of or completely free of polysorbate 20. Also, salts such as NaCl, KCl, Na2SO3, MgC l2 、FeC l3 、Na3PO4, etc. may also be used as gelling regulators or for other purposes.

[0056] The subject composition can further contain tonicity agents such as sodium chloride, glycerin, mannitol, glucose, potassium chloride, etc.

[0057] The subject composition can contain any desired active pharmaceutical ingredient or drug, for example, an anti-angiogenic agent, an antibiotic, an antifungal agent, an antihistamine, an anti-inflammatory agent, an anti-tumor agent, an antiviral agent, a biological preparation, a blood pressure lowering agent, a urinary system preparation, a hormonal agent, or a steroid agent, or drugs for dermatology, gastroenterology, nasal cavity, oncology, ophthalmology, otolaryngology, analgesia, respiratory system, urinary system, but is not limited thereto.

[0058] The subject composition may offer advantages compared to water-insoluble drugs. For this purpose, the subject composition may contain solid particles in which the water-insoluble drug is dispersed. The solid particles can be the drug itself, microspheres or microcapsules of the active pharmaceutical ingredient, nanoparticles of the active pharmaceutical ingredient, or a drug bound / associated with a polymer via a covalent or ionic bond. The subject composition may additionally or alternatively contain dispersed spheres of a hydrophobic solvent in which the water-insoluble drug is dissolved. Water-insoluble drugs that benefit from being used in the subject composition include steroids, NSAIDs, tyrosine kinase inhibitors, anti-cancer agents, antibiotics, prostaglandins, immunomodulators, hormones (and their agonists and antagonists), and the like.

[0059] In some embodiments, the active pharmaceutical ingredient includes, for example, multi-kinase inhibitors such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, pazopanib, and the like.

[0060] The subject composition may have temperature-dependent rheological properties. Examples of the subject composition and rheograms are shown in Examples 1-17 and Figures 1-4. Recording the phase angle δ as a function of temperature describes the gelation rate and shows the gelation onset temperature and the gelation rate with increasing temperature. The phase shift δ is inversely proportional to the gelation rate at a specific temperature and is used to determine the gelation rate at a specific temperature. In the case of intravitreal injection, a delayed gelation onset with sudden and rapid gelation is more desirable than an early gelation onset with slow gelation. Recording the storage modulus (G’) shows the increase in solid properties (elasticity) with increasing temperature. The G’ value near body temperature reflects the gel strength, and the gel strength is related to gel durability. The higher the G’ value of the composition near body temperature, the higher the gel durability.

[0061] Recording of the G’ slice suggests injectability. Slice values close to or less than about 0.1, such as about 0.05 - 0.07, about 0.07 - 0.1, about 0.1 - 0.3, or about 0.3 - 0.5, etc., are more preferred for administration requiring a thin needle. The same principle applies to the recording of complex viscosity as a function of temperature, i.e., slice values close to or less than about 0.1, such as about 0.05 - 0.07, about 0.07 - 0.1, about 0.1 - 0.3, or about 0.3 - 0.5, etc., are more preferred for administration requiring a thin needle.

[0062] Recording of the slope of G’ as a function of temperature suggests the tendency of the composition to solidify. A negative slope in the cold temperature range is more preferred for administration requiring the use of a long catheter. In some embodiments, G’ has a slope of about -0.001 - 0.003, about -0.003 - 0.007, about -0.007 - 0.01, about -0.01 - 0.015, or about -0.012 - 0.02 at about 2 - 8°C, about 5 - 15°C, about 5 - 20°C, or about 5 - 25°C.

[0063] In some embodiments, the subject composition has a first storage modulus (G’) at about 37°C and a second G’ at about 5°C, and the first G’ is, for example, at least about 5 times higher, at least about 8 times higher, at least about 10 times higher, at least about 20 times higher, at least about 50 times higher, at least about 100 times higher, at least about 500 times higher, or at least about 1000 times higher than the second G’.

[0064] In some embodiments, the subject composition has a first complex viscosity at about 37°C and a second complex viscosity at about 5°C, and the first complex viscosity is, for example, at least about 1.5 times higher, at least about 2 times higher, at least about 5 times higher, at least about 10 times higher, at least about 20 times higher, at least about 50 times higher, or at least about 100 times higher than the second complex viscosity.

[0065] In some embodiments, the subject composition has a first loss modulus (G”) at about 37°C and a second G” at about 5°C, and the first G” is higher than the second G”.

[0066] In some embodiments, the subject composition has a gelation rate at about 37 °C of at least 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%.

[0067] In some embodiments, the subject composition has a gelation rate between about 30 °C and 40 °C of at least 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%.

[0068] In some embodiments, the subject composition has a gelation rate between about 2 °C and about 8 °C of about 20% or less, about 10% or less, about 5% or less, about 3% or less, or about 1% or less.

[0069] The subject composition may be administered to a mammal in need of such an active pharmaceutical ingredient in order to deliver the active pharmaceutical ingredient to the mammal. In some embodiments, the composition may reduce the dosing frequency of the active pharmaceutical ingredient. In some embodiments, a single administration of the active pharmaceutical ingredient results in a therapeutically effective concentration of the active pharmaceutical ingredient in the mammal for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 12 months, or longer. Such administration may be by any route of administration, including topical administration, intralesional injection, perilesional injection, intraprostatic injection, intravitreal injection, intramuscular injection, subcutaneous injection, intradermal injection, intra-tissue injection, or eye drops.

[0070] In some embodiments, the target composition is obtained by mixing methylcellulose having an appropriate molecular weight and viscosity with a buffering agent and / or an isotonic agent. Not all methylcelluloses have the viscoelastic properties most desirable for pharmaceutical manufacturing and the properties most suitable for administration to patients in a clinical setting. Figure 4 is a temperature sweep rheogram at 5% of two types of methylcelluloses (A15LV and A15C). A15C has a higher molecular weight than A15LV. This temperature sweep rheogram shows that 5% concentration of A15LV is recognized to have viscoelastic properties suitable for formulation into parenteral preparations. Furthermore, methylcellulose A15C may be too viscoelastic at 5% to be injectable with a syringe or injection.

[0071] Furthermore, in order to cause a gel-sol phase transition near body temperature, a methylcellulose A15LV concentration exceeding 3% may be required.

[0072] Some gelling regulators have been found to be more effective than others (Figures 2 and 3). A citrate buffer at 116 mmole / kg was surprisingly found to enable a significant improvement in gel elasticity at 37°C. As a result, a significant decrease in gel solubility in vivo (i.e., an increase in gel residence time) is expected. Furthermore, a citrate buffer at 116 mmole / kg was surprisingly found to be able to change the slope of the elasticity profile from positive to negative in the temperature range from 5°C to 25°C compared to the elasticity profile without a citrate buffer or with only 75 mmole / kg (Figure 3). The negative slope in the temperature range from 5°C to 25°C suggests that formulations containing 116 mmole / kg of citrate will reduce the risk of coagulation when administered through a needle or catheter.

[0073] In some target compositions, the desired particle size of the poorly water-soluble drug is generated / regulated / influenced via a controlled precipitation process before being dispersed in a methylcellulose solution having the desired gelling temperature, pH, and osmotic tension. The precipitation may be caused by changes in pH, solubility, osmotic tension, or temperature. The precipitate has crystallization properties different from those of commercially available raw materials, and as a result, the drug release rate may be different. Table 3 shows four methods of incorporating a water-insoluble drug into the target composition. The influence of gel strength and controlled precipitation on the drug release rate in vitro is shown in Figure 5.

[0074] In some target compositions, the methylcellulose solution is formulated with appropriate buffering agents and tonicity agents so that it can have a pH value and osmotic tension suitable for the intended pharmaceutical use.

[0075] A target composition comprising a methylcellulose solution having the desired gelling temperature, pH, and osmotic tension, in which one or more active pharmaceutical ingredients are dispersed, may be administered to a patient by intravitreal, intramammary, intramuscular, subcutaneous, or intradermal injection for the treatment / prevention / manage ment of local diseases.

[0076] The target composition can be administered locally (via injection with a needle or an applicator) to target tissues such as the eye (ocular surface, anterior segment, and posterior segment of the eye), prostate, bladder, uterus, vagina, skin, tongue, gingiva, oral cavity, nose, paranasal sinuses, joints, and various solid tumors. When formulated with one or more drugs, the target composition can transport an active agent for treating local diseases in the aforementioned target tissues. The drug can be water-soluble or water-insoluble. The gel composition can be designed under relatively wide conditions so that it is liquid at low temperature or room temperature and can undergo a phase transition to a semi-solid state when warmed to body temperature, which is particularly preferred.

[0077] The target composition has advantages when used as a product that can be dropped, dripped, or injected because it is fluid during dropping or injection, and it is a gel when it touches the body. The target composition also has advantages in that it can control the delivery of active pharmaceutical ingredients and / or diagnostic agents to local tissues.

[0078] Some target compositions may be used for the prevention or treatment of diseases or disorders characterized by chronic inflammation, with accompanying angiogenesis and fibrosis. In some embodiments, the diseases or disorders include skin-related disorders, benign prostatic hyperplasia-related disorders, eye-related disorders, alcohol-related disorders, uterine fibroids and related diseases, neoplastic diseases, and adhesion-related disorders. In some embodiments, the pharmaceutical biocompatible / biodegradable aqueous gel system may include at least one active pharmaceutical ingredient dispersed therein, such as an active pharmaceutical ingredient designed for anti-angiogenesis, including a multi-kinase inhibitor such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, or pazopanib.

[0079] In some embodiments, a multi-kinase inhibitor such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, or pazopanib is present in the subject composition at a concentration of about 0.01 - 5% (wt / wt), about 0.1 - 1% (wt / wt), about 1 - 2% (wt / wt), about 2 - 3% (wt / wt), about 3 - 4% (wt / wt), about 4 - 5% (wt / wt), about 0.01 - 0.5% (wt / wt), about 0.5 - 1% (wt / wt), about 1 - 1.5% (wt / wt), about 1.5 - 2% (wt / wt), about 2 - 2.5% (wt / wt), about 2.5 - 3% (wt / wt), about 3 - 3.5% (wt / wt), about 3.5 - 4% (wt / wt), about 4 - 4.5% (wt / wt), about 4.5 - 5% (wt / wt), 0.01 - 0.1% (wt / wt), about 0.1 - 0.2% (wt / wt), about 0.2 - 0.3% (wt / wt), about 0.3 - 0.4% (wt / wt), about 0.4 - 0.5% (wt / wt), about 0.5 - 0.6% (wt / wt), about 0.6 - 0.7% (wt / wt), about 0.7 - 0.8% (wt / wt), about 0.8 - 0.9% (wt / wt), about 0.9 - 1% (wt / wt), about 1 - 1.1% (wt / wt), about 1.1 - 1.2% (wt / wt), about 1.2 - 1.3% (wt / wt), about 1.3 - 1.4% (wt / wt), about 1.4 - 1.5% (wt / wt), about 1.5 - 1.6% (wt / wt), about 1.6 - 1.7% (wt / wt), about 1.7 - 1.8% (wt / wt), about 1.8 - 1.9% (wt / wt), about 1.9 - 2% (wt / wt), about 2 - 2.2% (wt / wt), about 2.2 - 2.4% (wt / wt), about 2.4 - 2.6% (wt / wt), about 2.6 - 2.8% (wt / wt), about 2.8 - 3% (wt / wt), about 3 - 3.3% (wt / wt), about 3.3 - 3.6% (wt / wt), about 3.6 - 3.9% (wt / wt), about 3.9 - 4.3% (wt / wt), about 4.3 - 4.7% (wt / wt), about 4.7 - 5.1% (wt / wt), about 0.9 - 1.1% (wt / w), or about 1% (wt / wt).

[0080] In some embodiments, administration is by topical formulation, intralesional injection, perilesional injection, ophthalmic instillation, or intratissue injection.

[0081] The terms "treating" or "treatment" are broadly construed to include any kind of treatment activity for diagnosing, curing, alleviating, or preventing diseases in humans or other mammals, or any other activity that affects the structure or any function of the body of a human or other mammal.

[0082] The terms "agent" and "active pharmaceutical ingredient" may be used interchangeably.

[0083] Agent-free target compositions / gel formulations can be prepared as follows. This method is an example and can be modified by those skilled in the art.

[0084] 1. Mix a given amount of components other than methylcellulose (buffers, salts, solvents, etc.) in an appropriate amount of water according to the formulation composition. While mixing constantly, heat the mixture to about 60 - 80 °C, preferably 67 - 70 °C.

[0085] 2. Accurately weigh an appropriate amount of methylcellulose and add the powder to the hot mixture while mixing constantly. Once the cellulose is well dispersed, remove the heat source, adjust the batch to the target weight with water, and continue mixing until the dispersion cools to room temperature. Cool the dispersion overnight to fully hydrate the cellulose and produce the final agent-free target composition / gel formulation that exhibits appropriate / desirable inverse thermogelation properties.

[0086] 3. The cooled bulk gel formulation is filled into type 1 glass serum vials and sealed with a silicon-coated stopper and an aluminum crimp cap. The filled and sealed vials are finally sterilized.

[0087] Target compositions containing water-insoluble drugs can be prepared as follows. This method is an example and can be modified by those skilled in the art.

[0088] 1. Preparation of a high-concentration drug stock solution using an appropriate solvent Mix the correct amount of the drug with an appropriate solvent to newly prepare a high-concentration drug stock solution. After dissolving the drug in the solvent, the resulting solution may be filtered through a sterilized filter before use.

[0089] 2. Preparation of the Phase 1 drug suspension by controlled precipitation Dropwise add an accurate amount of the drug stock solution into an appropriate and accurate amount of water according to the formulation composition while performing constant mixing to precipitate the drug. Homogenize the resulting suspension with a homogenizer for an appropriate time at an appropriate speed.

[0090] 3. Preparation of the final target composition / gel formulation containing the drug Accurately weigh an appropriate amount of the Phase 1 drug suspension and mix it with an appropriate amount of solvents other than methylcellulose, buffers, salts, etc. While mixing constantly, heat the mixture to about 60 - 80 °C, preferably 67 - 70 °C. Accurately weigh an appropriate amount of methylcellulose and add the powder to the hot suspension while mixing constantly. Once the cellulose is sufficiently dispersed, remove the heat source, adjust the batch to the target weight with water, and continue mixing until the dispersion cools to room temperature. Cool the dispersion overnight to fully hydrate the cellulose and produce a final target composition / gel formulation containing the drug that exhibits appropriate / desirable inverse thermal gelation properties.

[0091] 4. Filling and final sterilization The cooled bulk gel formulation containing the drug is filled into type 1 glass serum vials and sealed with a silicone-coated stopper and an aluminum crimp cap. The filled and sealed vials are finally sterilized.

[0092] (Examples 1 - 20) Composition Examples 1 - 17 were prepared as described above with the formulations shown in Tables 1 to 6 below.

[0093] Appended Table 1: Single gelation regulator formulation system containing citrate [Table 1]

[0094] Appendix Table 2: Double Gelation Regulator Formulation System, Triple Gelation Regulator Formulation System [Table 2] Note: Examples 3 and 4 have the same formulation composition, but different methods of composing the suspension of the active pharmaceutical ingredient (API).

[0095] Appendix Table 3: Single Gelation Regulator Formulation System Containing Dimethyl Sulfoxide (DMSO) [Table 3]

[0096] Examples 9, 10, 11, 12, and 13 were prepared according to the final bulk gel formulation process without the drugs described in this specification, and then tested for gelation at 37°C. In this test, 1 mL of Examples 8, 9, 10, 11, and 12 was placed in a 2 mL glass vial, capped, and placed in a water bath at 37°C. After 0.5 hours, 1 hour, and 2 hours, the vials were taken out of the water bath, and the formation of the gel was confirmed using the inverted flow test method. In this test, the vial was taken out of the water bath and inverted for 5 - 6 seconds. If the solution did not flow and remained inverted, the term "gel" indicating the formation of "gel" was used, and if it flowed, the term "none" indicating no gel formation / gelation was used. Table 4 shows that DMSO functions as a gelation regulator for methylcellulose at all three DMSO concentrations (2.5%, 5%, and 10%) examined.

[0097] Appendix Table 4: Gel Formation Results at 37°C by the Inverted Flow Test Method for the Newly Adjusted Examples [Table 4]

[0098] Appendix Table 5: Examples of Compositions Containing Active Pharmaceutical Ingredients [Table 5]

[0099] Examples 14 - 16 were prepared by the method described in this specification. In Example 14, a gel was formed at 37°C and there was no fluidity. In Examples 15 and 16, no gel was formed at 37°C and there was fluidity.

[0100] Appendix Table 6: Examples of Compositions Containing Axitinib as the Active Pharmaceutical Ingredient [Table 6]

[0101] Example 17 contained axitinib as the active pharmaceutical ingredient and was prepared by the same method as that used in Examples 3 - 8. In Example 17, a gel was formed at 37°C and there was no fluidity.

[0102] Example 18 The characteristics of finally sterilized Example 5 are shown in Example 18. Shown in Table 7 below are the physical appearance, resuspensibility, fluidity, injectability and assay data, and in - vitro drug release data of finally sterilized Example 5. Figure 5 shows the in - vitro drug release of some different lenvatinib formulations described in Table 2.

[0103] Appendix Table 7: Finally Sterilized Example 5 [Table 7] Note: Using United States Pharmacopeia Apparatus 2 (paddle method)

[0104] Example 19 To evaluate the residence time of lenvatinib in three gel formulations, a test using rabbits was conducted. Each group of rabbits (the formulations described as Examples 3, 6, and 4 for the first, second, and third groups respectively) was administered 0.5 mg of 1% lenvatinib gel formulation to both eyes by intracameral injection once.

[0105] In all groups, as expected, over time, the highest concentration of ranibizumab was detected in the vitreous humor, retina, and choroid. In the vitreous humor, retina, and choroid of the first and third groups, the ranibizumab concentration gradually decreased, but in the second group, it remained relatively stable even 20 weeks after intravitreal administration. The concentration of ranibizumab in the eye tissues of the first group decreased to a level where ranibizumab could not be quantified by 12 weeks. The ranibizumab concentration in all measured eye tissues of the second group remained generally stable until the 20th week. The ranibizumab concentration in the eye tissues of the third group remained generally stable until the 12th week, but the quantifiable concentration was sporadic by the 20th week.

[0106] Appendix Table 8: Plasma Concentrations after Single Intravitreal Injection of 1% Ranibizumab Gel in Dutch Belted Rabbits [Table 8] Note: Lower limit of quantification = 0.2 ng / mL

[0107] Since the vitreous humor was the rate-limiting part, the plasma concentration was thought to be similar to the concentration in the eye tissues, but it was much lower. The ranibizumab concentration in plasma was quantifiable until the 6th week in the first group, until the 20th week in the second group, and was quantifiable at the 12th week in the third group but not quantifiable at the 20th week (Table 8).

[0108] Appendix Table 9: Residence Time and Residual Rate of Ranibizumab after Single IVT Injection in Vitreous Humor [Table 9]

[0109] Table 9 shows the recovery rates of the amount of ranibizumab remaining in the vitreous humor after a single IVT injection of different formulations. The ranibizumab recovery rate in the first group was approximately 28% at week 2 and then decreased to a small percentage by week 20. The ranibizumab recovery rate in the second group was approximately 58% at week 2 but decreased to approximately 8% by week 20. The formulation administered to the second group had the longest retention time in the vitreous humor. The ranibizumab recovery rate in the vitreous humor of the third group was approximately 36% at week 2 but decreased to a small percentage by week 20.

[0110] Fundus images of the formulation dispersion were continuously taken for each eye at day 0 (after administration), day 3, day 7, day 14, day 28, day 42, day 84, and day 140. The results of the fundus images and the eye tissue concentrations were similar to each other. The first group and the third group released the drug more rapidly compared to the second group. The second group released ranibizumab in a sustained-release manner throughout the 20-week test period, and it was shown that the ranibizumab concentrations in the eye tissue and plasma were stable over time (Figures 6 - 8).

[0111] (Example 20) A test in rats was conducted to evaluate the retention time of the ranibizumab gel after a single intraprostatic injection.

[0112] Twelve rats in each group (the first, second, and third groups) were administered three different 1% ranibizumab gel formulations (Examples 3, 4, and 6) at two doses (0.2 mg and 2 mg). Plasma samples were collected on test days 3, 7, 14, 21, 28, 42, and 60 after administration. After the test ended on day 60, the prostate glands were collected from these rats.

[0113] After a single administration of 0.2 mg of lenvatinib, the mean maximum plasma concentrations in the animals of the first, second, and third groups were 9.15, 12.0, and 5.24 ng / mL, respectively. The maximum administration concentration was on the third day. The lenvatinib concentration in plasma was detectable up to 14 days, 42 days, and 60 days after administration in the first, second, and third groups, respectively. The lower limit of quantification was 0.100 ng / mL (Table 10)

[0114] Supplementary Table 10: Mean plasma concentrations after single intraprostatic injection of different formulations of 1% lenvatinib into rats

Table 10

[0115] After delivering 2 mg of lenvatinib to rats, the maximum prostate concentration of lenvatinib 60 days later was in the third group, with the highest mean concentration (494,000 ng / g) in the ventral lobe. The mean concentration in the dorsal lobe was 127,000 ng / g. In the third group administered 0.2 mg / animal, the mean concentration in the ventral lobe was 13,500 ng / g and the mean concentration in the dorsal lobe was 2,450 ng / g. The tissue concentrations in the first and second groups were basically undetectable or very low 60 days later compared to the animals in the third group. The general data of the prostate are shown in Table 11

[0116] Supplementary Table 11: Mean prostate concentrations of lenvatinib on day 60 after single intraprostatic injection of different formulations of 1% lenvatinib into Sprague-Dawley rats

Table 11

[0117] In each of the three formulations, a dose-dependence was observed in the plasma concentration-time profile (Table 10). In all three formulations, a slow release of the drug from the prostate, the administration site, to the plasma compartment was observed, and on the third day, Cmax was observed. The "half-life" of drug release was approximately 6 days, 8 days, and 43 days in the first, second, and third groups, respectively. In the first and second groups, higher C max was observed, but in the third group, a much longer plasma concentration maintenance was observed compared to the first and second groups.

[0118] Table 11 shows a controlled drug delivery system in the prostate. That is, the third group in Table 11 had the highest remaining percentage in the prostate on the 60th day, which was approximately 2.7% and 12.7% in the dosage groups of 0.2 mg and 2 mg, respectively.

[0119] Specifically, the following embodiments can be considered.

[0120] (Embodiment) (Embodiment 1) A pharmaceutical composition containing a reverse thermogelation material, wherein the pharmaceutical composition transfers from a liquid to a gel near the body temperature of a mammal.

[0121] (Embodiment 2) The pharmaceutical composition according to Embodiment 1, wherein the mammal is a human.

[0122] (Embodiment 3) The pharmaceutical composition according to Embodiment 2, further comprising at least one active pharmaceutical ingredient.

[0123] (Embodiment 4) The pharmaceutical composition according to Embodiment 2 or 3, wherein the pharmaceutical composition is liquid at about 5°C.

[0124] (Embodiment 5) The pharmaceutical composition according to Embodiment 1, 2, 3, or 4, wherein the pharmaceutical composition is a gel between about 35°C and 40°C.

[0125] (Embodiment 6) 6. The pharmaceutical composition of embodiment 1, 2, 3, 4, or 5, further comprising methylcellulose, dimethyl sulfoxide, and citrate.

[0126] (Embodiment 7) A pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, dimethyl sulfoxide, and citrate.

[0127] (Embodiment 8) 8. The pharmaceutical composition of embodiment 6 or 7, comprising the methylcellulose in a concentration of about 2% (w / w) to about 10% (w / w).

[0128] (Embodiment 9) 9. The pharmaceutical composition of embodiment 6, 7, or 8, comprising the citrate salt in a concentration of about 25 mmole / kg to about 200 mmole / kg.

[0129] (Embodiment 10) 10. The pharmaceutical composition of embodiment 1, 2, 3, 4, 5, 6, 7, or 9, wherein the pH is from about 5.0 to about 9.0.

[0130] (Embodiment 11) 11. The pharmaceutical composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, having a first storage modulus (G') at about 37°C and a second G' at about 5°C, wherein the first G' is higher than the second G'.

[0131] (Embodiment 12) 12. The pharmaceutical composition of embodiment 11, wherein the first G' is at least about 10 times higher than the second G'.

[0132] (Embodiment 13) 13. The pharmaceutical composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, having a first complex viscosity at about 37°C and a second complex viscosity at about 5°C, wherein the first complex viscosity is higher than the second complex viscosity.

[0133] (Embodiment 14) The pharmaceutical composition according to embodiment 13, wherein the first complex viscosity is at least twice as high as the second complex viscosity.

[0134] (Embodiment 15) The pharmaceutical composition according to embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, having a first loss modulus (G”) at about 37° C. and a second G” at about 5° C., wherein the first G” is higher than the second G”.

[0135] (Embodiment 16) The pharmaceutical composition according to embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, having a gelation rate of at least 70% at about 37° C.

[0136] (Embodiment 17) The pharmaceutical composition according to embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, having a gelation rate of 10% or less at about 5° C.

[0137] (Embodiment 18) A method for treating a disease, comprising administering the pharmaceutical composition according to embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 to a mammal in need of said pharmaceutical composition.

[0138] (Embodiment 19) The method according to embodiment 18, wherein the mammal is a human.

[0139] (Embodiment 20) Use of the pharmaceutical composition according to embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 in the manufacture of a medicament for treating a disease.

[0140] (Supplementary Note) (Supplementary Note 1) A pharmaceutical composition comprising a reverse thermogelation material, wherein the pharmaceutical composition transitions from a liquid to a gel near the body temperature of a mammal.

[0141] (Appendix 2) The pharmaceutical composition according to Appendix 1, wherein the mammal is a human.

[0142] (Appendix 3) The pharmaceutical composition according to Appendix 1 or 2, further comprising an active pharmaceutical ingredient.

[0143] (Appendix 4) The pharmaceutical composition according to Appendix 3, wherein the active pharmaceutical ingredient is designed for anti-angiogenesis.

[0144] (Appendix 5) The pharmaceutical composition according to Appendix 3, wherein the active pharmaceutical ingredient is a multi-kinase inhibitor.

[0145] (Appendix 6) The pharmaceutical composition according to Appendix 3, wherein the active pharmaceutical ingredient includes axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, pazopanib, or a combination thereof.

[0146] (Appendix 7) The pharmaceutical composition according to Appendix 1, 2, 3, 4, 5, or 6, wherein the pharmaceutical composition is liquid at a temperature of about 2°C to about 8°C.

[0147] (Appendix 8) The pharmaceutical composition according to Appendix 1, 2, 3, 4, 5, 6, or 7, wherein the pharmaceutical composition is a gel at a temperature of about 30°C to about 40°C.

[0148] (Appendix 9) The pharmaceutical composition according to Appendix 1, 2, 3, 4, 5, 6, 7, or 8, further comprising a polymer agent and a gelation regulator.

[0149] (Appendix 10) 10. The pharmaceutical composition of claim 1, wherein the polymeric agent comprises an alkylcellulose.

[0150] (Appendix 11) 11. The pharmaceutical composition of claim 10, wherein the polymeric agent is methylcellulose.

[0151] (Appendix 12) The gelation modifier may include phosphate, dihydrogen phosphate, hydrogen phosphate, tris(hydroxymethyl)aminomethane, borate, histidine, carbonate, bicarbonate, citrate, citrate acetate, tartrate, fumarate, lactate, formate, sulfamate, oxalate, malonate, succinate, maleate, adipate, benzoate, o-toluate, benzenetetracarboxylate, glutamate, e-aminocaproate, aspartate, glycinate, alginate, lysine, taurate, ethanol, dimethyl sulfoxide, glycerin, dimethylformamide, propylene glycol, polyethylene glycol, vegetable oil, corn oil ... 12. The pharmaceutical composition of claim 9, 10, or 11, comprising: reeve oil, castor oil, vitamin E, phospholipids, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, monosaccharides, disaccharides, dextrose, sucrose, sugar alcohols, mannitol, sorbitol, antioxidants, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfite, sodium sulfite, sodium disulfite, EDTA, sodium carboxymethylcellulose, sodium alginate, hydroxypropyl methylcellulose, carbomer, hyaluronic acid, hyaluronate, or the like, or a combination thereof.

[0152] (Appendix 13) 13. The pharmaceutical composition of claim 12, wherein the gelation modifier comprises a phosphate, dimethyl sulfoxide, citrate, or a combination thereof.

[0153] (Appendix 14) A pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, dimethyl sulfoxide and citrate.

[0154] (Appendix 15) The pharmaceutical composition according to Appendix 14, further comprising phosphate.

[0155] (Appendix 16) The pharmaceutical composition according to Appendix 11, 14 or 15, comprising the methylcellulose at a concentration of about 2% (w / w) to about 10% (w / w).

[0156] (Appendix 17) The pharmaceutical composition according to Appendix 16, comprising the citrate at a concentration of about 25 mmol / kg to about 200 mmol / kg.

[0157] (Appendix 18) The pharmaceutical composition according to Appendix 17, having a pH of about 5.0 to about 9.0.

[0158] (Appendix 19) The pharmaceutical composition according to Appendix 17, having a pH of about 6.0 to about 8.0.

[0159] (Appendix 20) A pharmaceutical composition comprising an active pharmaceutical ingredient, methylcellulose, dimethyl sulfoxide, and citrate, wherein the pharmaceutical composition has a first storage modulus (G') at about 37°C and a second G' at about 5°C, and the first G' is higher than the second G'.

[0160] (Appendix 21) The pharmaceutical composition according to Appendix 20, wherein the first G' is at least about 10 times higher than the second G'.

[0161] (Appendix 22) The pharmaceutical composition according to Appendix 21, having a first complex viscosity at about 37°C and a second complex viscosity at about 5°C, and the first complex viscosity is higher than the second complex viscosity.

[0162] (Appendix 23) The pharmaceutical composition according to Supplementary Note 22, wherein the first complex viscosity is at least twice as high as the second complex viscosity.

[0163] (Supplementary Note 24) The pharmaceutical composition according to Supplementary Note 23, having a first loss modulus (G”) at about 37 °C and a second G” at about 5 °C, wherein the first G” is higher than the second G”.

[0164] (Supplementary Note 25) The pharmaceutical composition according to Supplementary Note 24, wherein the gelation rate at about 37 °C is at least 70%.

[0165] (Supplementary Note 26) The pharmaceutical composition according to Supplementary Note 25, wherein the gelation rate at about 5 °C is 20% or less.

[0166] (Supplementary Note 27) The pharmaceutical composition according to Supplementary Note 20 or 26, further comprising a phosphate.

[0167] (Supplementary Note 28) A method for treating a disease, comprising administering the pharmaceutical composition according to Supplementary Note 26 or 27 to a mammal in need of said treatment.

[0168] (Supplementary Note 29) The method according to Supplementary Note 28, wherein the disease is characterized by chronic inflammation accompanied by angiogenesis and fibrosis.

[0169] (Supplementary Note 30) The method according to Supplementary Note 28, wherein the disease includes skin-related diseases, prostate hyperplasia-related diseases, eye-related diseases, rosacea-related diseases, uterine fibroids or related conditions, neoplastic diseases, or adhesion-related diseases.

[0170] (Supplementary Note 31) The method according to Supplementary Note 30, wherein the pharmaceutical composition is administered locally by intralesional injection, perilesional injection, intravitreal injection, intraprostatic injection, intramuscular injection, subcutaneous injection, intradermal injection, intra-tissue injection, or eye drops.

[0171] (Appendix 32) 32. The method of claim 28, 29, 30, or 31, wherein the mammal is a human.

[0172] (Appendix 33) 28. A method for delivering an active pharmaceutical ingredient, comprising administering a pharmaceutical composition of claim 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, or 27 to a mammal in need of said active pharmaceutical ingredient, wherein said composition provides a therapeutic effect with a reduced frequency of administration of the active pharmaceutical ingredient.

[0173] (Appendix 34) 34. The method of claim 33, wherein the pharmaceutical composition is administered locally by intralesional injection, perilesional injection, intravitreal injection, intraprostatic injection, intramuscular injection, subcutaneous injection, intradermal injection, intratissue injection, or eye drops.

[0174] (Appendix 35) 35. The method of claim 33 or 34, wherein the mammal is a human.

[0175] (Appendix 36) 36. The method of claim 33, 34, or 35, wherein a single administration of the active pharmaceutical ingredient provides a therapeutically effective concentration of the active pharmaceutical ingredient to the mammal for at least 5 days.

[0176] (Appendix 37) 37. The method of claim 36, wherein a single administration of the active pharmaceutical ingredient provides a therapeutically effective concentration of the active pharmaceutical ingredient to the mammal for at least 6 weeks.

[0177] (Appendix 38) mixing a polymeric agent into a suspension containing a gelation modifier and an active pharmaceutical ingredient, said mixing being carried out at a temperature of about 60°C to about 80°C; The suspension is formed by a process comprising precipitating the active pharmaceutical ingredient in an aqueous liquid and adding the gelation modifier to the suspension. A method for preparing a pharmaceutical composition having inverse thermogelling properties.

Claims

1. A pharmaceutical composition comprising a reverse thermogelation material, wherein the pharmaceutical composition transitions from a liquid to a gel near the body temperature of a mammal, the pharmaceutical composition further comprises a multi-kinase inhibitor, methylcellulose, and citrate, the methylcellulose is methylcellulose A15LV, and the methylcellulose is present at a concentration of 4% (w / w) to 6% (w / w), the citrate is present at a concentration of 25 mmol / kg to 200 mmol / kg, the multi-kinase inhibitor includes axitinib, lenvatinib, or a combination thereof, pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the mammal is a human.

3. the pharmaceutical composition is liquid at a temperature of about 2°C to about 8°C, the pharmaceutical composition is a gel at a temperature of about 30°C to about 40°C, The pharmaceutical composition according to claim 1 or 2.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pH is about 5.0 to about 9.

0.

5. having a first storage modulus (G') at about 37°C and a second G' at about 5°C, the first G' is at least about 10 times higher than the second G', The pharmaceutical composition according to any one of claims 1 to 4.

6. having a first complex viscosity at about 37°C and a second complex viscosity at about 5°C, the first complex viscosity is at least 2 times higher than the second complex viscosity, The pharmaceutical composition according to claim 5.

7. having a first loss modulus (G") at about 37°C and a second G" at about 5°C, the first G" is higher than the second G", The pharmaceutical composition according to claim 6.

8. the gelation rate at about 37°C is at least 70%, the gelation rate at about 5°C is 20% or less, The pharmaceutical composition according to claim 7.

9. A medicament for treating a disease characterized by chronic inflammation accompanied by angiogenesis and fibrosis, the medicament comprises the pharmaceutical composition according to any one of claims 1 to 8, the medicament is administered to a human in need of the treatment, medicament.

10. The medicament according to claim 9, wherein the diseases include skin-related diseases, prostate hyperplasia-related diseases, eye-related diseases, alcoholic cirrhosis-related diseases, uterine fibroids or related conditions, neoplastic diseases, or adhesion-related diseases.

11. The agent according to claim 9 or 10, wherein the pharmaceutical composition is administered locally by intralesional injection, perilesional injection, intravitreal injection, intraprostatic injection, intramuscular injection, subcutaneous injection, intradermal injection, intra-tissue injection, or eye drop.

12. The agent according to any one of claims 9 to 11, wherein the pharmaceutical composition provides a therapeutic effect at a reduced administration frequency of the multi-kinase inhibitor as compared with a conventional dosage form.

13. The agent according to claim 11 or 12, wherein the multi-kinase inhibitor is provided to the human for at least 5 days by a single administration of the pharmaceutical composition.

14. A method for preparing a pharmaceutical composition according to any one of claims 1 to 8, comprising the step of mixing methylcellulose into a suspension containing a citrate and a multi-kinase inhibitor, the mixing being carried out at a temperature of about 60 °C to about 80 °C, wherein the suspension is formed by a method comprising precipitating the multi-kinase inhibitor in an aqueous liquid and adding the citrate to the suspension. A method for preparing a pharmaceutical composition having inverse thermogelation properties.

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