A composition capable of in-situ phase transition to form a gel and its uses

Abstract

This invention belongs to the field of pharmaceutical technology and relates to a composition that can undergo an in-situ phase transition to form a gel upon contact with water, and the application of this composition in gel formulations. The composition of this invention consists of a polyethylene glycol difatty acid graft compound and a non-aqueous solvent, wherein the molecular weight of the polyethylene glycol in the polyethylene glycol difatty acid graft compound is no greater than 2000. In this invention, the polyethylene glycol difatty acid graft compound is dissolved in a non-aqueous solvent to form the composition, which undergoes a phase transition upon contact with water to form a gel. This phase transition gel can be widely used in pharmaceutical formulations.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a composition capable of forming a gel in situ when coming into contact with water, and application of the composition in gel preparations. BACKGROUND

[0002] The prior art discloses that in-situ gels refer to a kind of preparation which can quickly change phase at the administration site from a liquid state to a semi-solid gel state after being administered in a solution state. Solution-gel transition is a response of a high molecular material to external stimuli, causing the material to change from a solution to a gel. A pharmaceutical in-situ gel needs to respond to stimuli under physiological conditions, and the stimuli under physiological conditions can be derived from temperature change, pH change, specific ions or molecules, solvent exchange, etc.

[0003] Research shows that temperature-sensitive in-situ gels are composed of hydrophilic homopolymers or block copolymers, and are characterized by being in a liquid state at room temperature and quickly changing into a semi-solid gel at body temperature after administration. Materials that can be used for temperature-sensitive in-situ gels include poloxamer 407, poly-N-isopropyl acrylamide and its derivatives, beta-glycerophosphate sodium derivatives of chitosan, xyloglucan, triblock polyethylene glycol-poly-lactic acid copolymer (PLA-PEG-PLA), triblock polyethylene glycol-poly-lactic acid-glycolic acid copolymer (PLGA-PEG-PLGA), triblock polyethylene glycol-poly-caprolactone copolymer (PCL-PEG-PCL), etc.

[0004] pH-sensitive in-situ gels are gelled by ionization due to release or reception of protons by acidic groups (carboxyl or sulfonic acid groups) or basic groups (amine groups) contained in the high molecular material in the pH environment of the body fluid. Commonly used materials include carbomer, chitosan and its derivatives, cellulose acetate phthalate, etc.

[0005] Ion-sensitive in-situ gels are gelled by phase transition after reaction of polysaccharide derivative solutions with K + , Na + , Ca 2+ , etc. contained in the body fluid. Commonly used materials include sodium alginate, deacetylated gellan gum, carrageenan, etc.

[0006] Solvent exchange type in situ gel is to dissolve water insoluble biodegradable polymer in a suitable non-aqueous solvent to form a solution. When injected into subcutaneous or muscle, the solvent migrates to the surrounding tissue, while the surrounding water penetrates into it, causing the polymer to phase separate and precipitate at the injection site to form a gel. Commonly used materials include polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polylactic-co-caprolactone, polyanhydride, polyorthoester, polyurethane, polyethylene carbonate (PEC), sucrose acetate isobutyrate (SAIB) and lecithin, etc. The non-aqueous solvent used in this type of in situ gel should have certain biocompatibility, and commonly used ones include N-methyl pyrrolidone (NMP), ethanol, 2-pyrrolidone, ethyl lactate, dimethyl sulfoxide, propylene carbonate, ethyl acetate and glycerol triacetate, etc.

[0007] Studies have also shown that in addition to the above several types of in situ gels, a lyotropic liquid crystal precursor can also be used as an in situ gel. The principle is to prepare a solution of liquid crystal material with a suitable solvent to form a lyotropic liquid crystal precursor; adding an appropriate amount of water to the precursor solution can convert it into a high-viscosity liquid crystal as a gel. Materials used to prepare the liquid crystal system include glyceryl monooleate, glyceryl dioleate, oleyl glycerate, sorbitan monooleate, phytantriol, phytantriol glycerate and phospholipids, etc.

[0008] In situ gels, as a new type of drug delivery system, have the advantages of easy use, long retention time at the drug application site and effective drug release, and have wide application in the pharmaceutical field, such as gel injection, implant, oral gel, skin gel, cavity gel and joint cavity gel, etc.

[0009] However, in situ gels still have certain limitations, the most prominent of which is the burst release of drugs during phase transition to form a gel. If the gel formation process is slow and the preparation enters the body in the form of a liquid, the drug will be released quickly, which is a risk for drugs with a narrow safety range and large adverse reactions. In addition, the polymer and the solvent used may cause certain body irritation and adverse reactions; the types of polymer materials are few, the price is high, the production of the preparation is difficult, and the cost is high.

[0010] Based on the current status of the prior art, the inventors of the present application propose a new in situ gel composition to solve the above technical problems. Specifically, it relates to a composition capable of forming a gel in situ by phase transition and its use. SUMMARY

[0011] The present application aims at providing a composition capable of forming gel in situ based on the current situation of the prior art. The composition is composed of polyethylene glycol double fatty acid graft and non-aqueous solvent, in particular, the composition is obtained by dissolving polyethylene glycol double fatty acid graft in non-aqueous solvent, and the composition is capable of forming gel in situ when meeting water.

[0012] Specifically, the present application provides a new in-situ gel composition, in particular, a composition capable of forming gel in situ when meeting water, which is composed of polyethylene glycol double fatty acid graft and non-aqueous solvent, in particular, the composition is obtained by dissolving polyethylene glycol double fatty acid graft in non-aqueous solvent, and the composition is capable of forming gel in situ when meeting water.

[0013] In the present application, the molecular weight of polyethylene glycol in the polyethylene glycol double fatty acid graft should be no more than 2000, preferably no more than 1000.

[0014] In the present application, the number of carbon atoms of fatty acid in the polyethylene glycol double fatty acid graft ranges from 10 to 22, preferably from 16 to 18.

[0015] In the present application, the carbon chain of fatty acid in the polyethylene glycol double fatty acid graft can contain or not contain unsaturated bond, i.e. it can be saturated fatty acid or unsaturated fatty acid.

[0016] In the present application, the saturated fatty acid can be decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, etc.

[0017] In the present application, the unsaturated fatty acid can be oleic acid, linoleic acid, linolenic acid, arachidonic acid, docosahexaenoic acid, etc.

[0018] In the present application, the fatty acid in the polyethylene glycol double fatty acid graft can be connected to the two sides of polyethylene glycol in any suitable chemical manner (as shown in formula 1), or connected to the same side of polyethylene glycol (as shown in formula 2).

[0019]

[0020] In the formula, PEG represents polyethylene glycol, R represents the carbon chain of fatty acid, and L represents the linking group.

[0021] In the polyethylene glycol double fatty acid graft, the fatty acid chain R1 = R2 or R1 ≠ R2.

[0022] In the present application, when the fatty acid is on both sides of polyethylene glycol, the fatty acid can be connected to PEG through ester bond or amide bond, i.e. the linking groups L1 and L2 can be any of the following.

[0023]

[0024] The ester bond is formed by the reaction of fatty acid with the hydroxyl group on PEG; the amide bond is formed by the reaction of fatty acid with amino-PEG.

[0025] When the fatty acid is on the same side of the polyethylene glycol, one end of the polyethylene glycol is a non-reactive methoxy group, and the other end can be a hydroxyl group, a carboxyl group, an amino group, an acyl halide, an aldehyde group, etc., i.e., mPEG-OH, mPEG-COOH, mPEG-NH2, mPEG-X, mPEG=O, etc. The mPEG is connected to the carbon chain of the two fatty acid chains through L3. L3 can be any of the following

[0026]

[0027] In the present application, when the fatty acid is on the same side of the polyethylene glycol, the chemical structure of the polyethylene glycol double fatty acid grafting product is as shown in the following formula

[0028]

[0029] In addition to the polyethylene glycol double fatty acid grafting product, the composition also contains a non-aqueous solvent. The non-aqueous solvent can be a solvent used in pharmacy other than water and having a certain solubility for the polyethylene glycol double fatty acid grafting product, for example, one or more of ethanol, 1,2-propanediol (PG), glycerol, 1,3-butanediol, polyethylene glycol (PEG), benzyl alcohol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), dimethyl acetamide, N-methyl pyrrolidone (NMP), glyceryl triacetate, ethyl lactate, ethyl oleate, isopropyl myristate, benzyl benzoate, and medium-chain fatty acid triglyceride (MCT).

[0030] When the non-aqueous solvent in the composition is a water-miscible solvent, such as ethanol, 1,2-propanediol, glycerol, 1,3-butanediol, polyethylene glycol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, glyceryl triacetate, etc., the speed of phase transition of the composition into a gel upon contact with water can be accelerated, and the gel can even be formed immediately upon contact with water.

[0031] When the non-aqueous solvent in the composition is a water-immiscible solvent, such as benzyl alcohol, ethyl lactate, ethyl oleate, isopropyl myristate, benzyl benzoate, medium-chain fatty acid triglyceride, etc., the rate of phase transition of the composition into a gel upon contact with water is slower.

[0032] In the composition, water-soluble and water-insoluble non-aqueous solvents can be used in combination.

[0033] In the composition, the polyethylene glycol double fatty acid grafting product is dissolved in the non-aqueous solvent to form a solution. The solution undergoes phase transition to form a gel upon contact with water.

[0034] The mass ratio of the polyethylene glycol double fatty acid grafting agent to the non-aqueous solvent in the composition is 1:10 to 10:1.

[0035] The composition can also be added with drugs for treatment, diagnosis, or imaging contrast for treatment or diagnosis.

[0036] The composition can be widely used in the field of pharmacy, including but not limited to: gel injection, implant, hemostatic agent, oral gel, cavity gel (rectum, vagina, nasal cavity).

[0037] The composition can be subcutaneously or intramuscularly injected, and a gel can be quickly formed at the injection site, which can be used as a gel injection or an implant.

[0038] The composition can be dropped or applied on the bleeding site, and the composition can quickly gel when it meets blood, and can be used as a hemostatic agent.

[0039] The composition can be dropped, applied or sprayed on the mucosa surface of the oral cavity, and the composition can quickly change into a gel on the wet mucosa surface, which can be used as an oral gel.

[0040] The composition can be injected into the rectum or vagina, and the composition can absorb water in the cavity and change into a gel, which can be used as a rectal or vaginal gel.

[0041] The composition can be dropped or sprayed into the nasal cavity, and the composition can quickly change into a gel on the wet mucosa surface, which can be used as a nasal gel.

[0042] The composition has the following advantages:

[0043] 1. The composition can quickly change into a gel when it meets water, which can significantly reduce the burst release of drugs.

[0044] 2. The rate of phase transition to form a gel can be adjusted. When a water-miscible non-aqueous solvent is used, the composition can instantly change into a gel when it meets water; when a water-immiscible non-aqueous solvent is used, the rate of gel formation is slow; when a water-miscible and water-immiscible non-aqueous solvent is used, the rate of gel formation can be adjusted.

[0045] 3. The optional non-aqueous solvent is various, from a strong hydrophilic non-aqueous solvent to a hydrophobic non-aqueous solvent, so that some non-aqueous solvents with low irritation to the body can be selected to reduce the incidence of adverse reactions.

[0046] 4. The polyethylene glycol double fatty acid grafting agent is simple to synthesize and has low cost.

[0047] 5. The polyethylene glycol double fatty acid grafting agent is biodegradable, and the degradation product is non-toxic and physiologically tolerable, which has good safety

[0048] 6. The composition can withstand autoclaving and can also be sterilized by aseptic filtration. Detailed Implementation

[0049] The present invention will now be described in detail with reference to specific embodiments. These specific embodiments are provided only to help those skilled in the art understand the present invention and are not intended to limit the scope of the invention.

[0050] Example 1: Polyethylene glycol difatty acid grafts with fatty acids attached to both sides of polyethylene glycol (as shown in Formula 1)

[0051] In this embodiment, polyethylene glycol with a molecular weight of 750 (HO-PEG) is selected. 750 -OH), both R1 and R2

[0052] The carbon chain of palmitic acid (PA) is shown, with L1 and L2 being... This embodiment demonstrates the attachment of fatty acids to polyethylene glycol.

[0053] Structural characteristics and synthesis process of polyethylene glycol difatty acid grafts on both sides.

[0054] Take HO-PEG 750 -OH 7.5g (10mM, containing 20mM hydroxyl group) was dissolved in 30ml of dichloromethane. 2.5ml of pyridine was added, and the mixture was kept in an ice bath. 6.1ml (20mM) of palmitoyl chloride was added dropwise, and the mixture was reacted in an ice bath for approximately 30 minutes after the addition was complete. The reaction mixture was then allowed to warm to room temperature and reacted for another 12 hours. The reaction solution was filtered, and excess pyridine was removed by washing with water. The organic layer was evaporated to dryness, and the product was extracted with acetonitrile and evaporated to dryness to obtain the final product, with the following structural formula, abbreviated as PA-PEG. 750 -PA.

[0055] .

[0056] Example 2: Preparation of PA-PEG-PA with different molecular weights

[0057] HO-PEG-OH with molecular weights of 200, 400, 600, 1000, and 2000 were selected to synthesize PA-PEG-PA with different molecular weights according to the method in Example 1, and these were labeled as PA-PEG. 200 -PA, PA-PEG 400 -PA, PA-PEG 600 -PA, PA-PEG 1000 -PA and PA-PEG 2000 -PA.

[0058] Example 3: Polyethylene glycol di-fatty acid grafts with fatty acids attached to one side of polyethylene glycol (as shown in Formula 2).

[0059] In this embodiment, the polyethylene glycol is selected from polyethylene glycol monomethyl ether (mPEG) with a molecular weight of 600 600 -OH), R1and

[0060] R2are both carbon chains on stearic acid (SA), and L3is This embodiment shows the structural characteristics and synthesis process of the polyethylene glycol double fatty acid grafting product with fatty acid attached to one side of the polyethylene glycol.

[0061] Take mPEG 600 -OH 3.0g (5mM) into a 100ml flask, add dichloromethane 40ml, stir to dissolve, add N,N'-carbonyldiimidazole (CDI) 4.9g, stir at room temperature for 3h. Wash the excess CDI with water by shaking, remove the dichloromethane solution, and evaporate to dryness to obtain CDI-activated mPEG 600 .

[0062] Take (R)-3-amino-1,2-propanediol (APD) 1.45g and add DMSO 6ml to stir to dissolve; take another CDI-activated mPEG 600 3.67g, add dichloromethane 25ml, stir to dissolve, and then gradually add to the APD solution, stir at room temperature for 12h. Wash with water to remove excess APD, remove the organic layer, evaporate to dryness to obtain mPEG 600 -APD.

[0063] Take mPEG 600 -APD 1.8g (2.5mM, containing 5mM of hydroxyl), add dichloromethane 9ml to dissolve. Add pyridine 0.6ml, ice bath. Drop stearoyl chloride 1.82ml (5.4mM), after adding, ice bath for 30min, continue to react for 12h after warming. Filter the reaction solution, wash with water to remove excess pyridine, take the organic layer, evaporate to dryness, extract the product with acetonitrile, evaporate to dryness to obtain the product, the structural formula is as follows, which is abbreviated as mPEG 600 -DSA.

[0064]

[0065] Preparation of mPEG-DSA with different molecular weights

[0066] Select mPEG with molecular weights of 200, 400, 750, 1000 and 2000, and synthesize mPEG-DSA with different molecular weights according to the method of Example 3, which are marked as mPEG 200 -DSA, mPEG 400 -DSA, mPEG 750 -DSA, mPEG 1000 -DSA, and mPEG 2000 DSA.

[0067] Example 5: Solubility of polyethylene glycol difatty acid grafts in non-aqueous solvents

[0068] Take the polyethylene glycol di-fatty acid grafts synthesized in Examples 1 to 4, add 3 times the amount (by mass) of non-aqueous solvent, vortex mix at room temperature, and observe the dissolution. The results are shown in Table 1.

[0069] Table 1. Solubility of polyethylene glycol difatty acid grafts in non-aqueous solvents

[0070]

[0071] Note: * indicates partial dissolution; ** indicates complete dissolution.

[0072] Example 6: The composition undergoes a phase transition upon contact with water to form a gel.

[0073] Take about 0.5 ml of the solution from Example 5. If it is not completely dissolved, centrifuge and take 0.5 ml of the supernatant. Add it dropwise to water and observe the state of the precipitate. The results are shown in Table 2.

[0074] Table 2. State of the composition after contact with water.

[0075]

[0076] Note: imG represents an immediate phase transition forming a gel; imG→S represents an immediate phase transition forming a gel, which then gradually disappears.

[0077] S is a homogeneous solution; L is an immiscible solution; L→G is initially an immiscible solution, then gradually transforms into a gel. It is initially an immiscible liquid, which then rapidly transforms into a gel.

[0078] Example 7 Composition for Gel Injection

[0079] Take mPEG600-DSA, add twice the amount (by mass) of NMP, shake to dissolve, and filter sterilize using a 0.22μm microporous membrane. Inject 0.5ml of the composition intramuscularly into the hind leg of a rabbit. Five minutes after injection, collect muscle tissue from the injection site, cut it open, and observe the formation of a gel-like reservoir. The advantages of this gel injection solution are low viscosity, ease of sterilization and injection, and rapid gel formation, thereby reducing drug burst release.

[0080] Example 8: Composition for Hemostasis

[0081] Take PA-PEG 400 Add PA to twice the amount (by weight) of 1,2-propanediol, shake to dissolve, and autoclave. Make an incision on the central artery of the rabbit ear, then insert PA-PEG. 400When a propylene glycol solution of PA is applied to the incision, the composition rapidly forms a gel upon contact with blood, thus stopping the bleeding. The advantages of this hemostatic agent are its ease of use and rapid hemostasis.

[0082] Example 9: Composition for Implantation

[0083] Take mPEG400-DSA, add twice the amount (by weight) of NMP, shake to dissolve, then add 10% palmitic acid (by total weight), shake to dissolve, and autoclave. Inject 1 ml subcutaneously into a rabbit; after 5 minutes, incision of the skin reveals the formation of a gel-like reservoir at the injection site, indicating that the composition can be used as an implant. The advantage of this implant is its ease of administration; it can be injected directly using a standard injection needle.

[0084] Example 10 Composition for use in oral gel

[0085] Take mPEG750-DSA, add 4 times the amount (by mass) of 1,2-propanediol, shake to dissolve, pour into a small vial, and drop onto the oral mucosa of anesthetized rats. A gel is observed to form rapidly at the application site and adhere to the mucosa. The advantages of this oral gel are its low viscosity, ease of administration, and rapid gel formation.

[0086] Example 11 Composition for use in rectal and vaginal gels

[0087] Take PA-PEG600-PA, add twice the amount (by mass) of polyethylene glycol 200, shake to dissolve, and fill a small syringe. Inject the solution into the rectum and vagina of anesthetized female rats. After 5 minutes, dissection reveals that a gel has formed within the cavities. The advantage of this gel is its low viscosity, making it convenient for administration.

[0088] Example 12 Composition for use in nasal gel

[0089] Take PA-PEG750-PA, add 4 times the amount (by mass) of polyethylene glycol 200, shake to dissolve, pour into a spray bottle, and spray into the nasal cavity of anesthetized female rats. After 5 minutes, dissection reveals the formation of a gel-like film in the nasal cavity. The advantages of this gel are its low viscosity, convenient administration, and rapid formation of a gel film in the nasal cavity.

Claims

1. A composition which is in situ gellable in the presence of water, characterized in that, The composition is composed of a double fatty acid grafted polyethylene glycol and a non-aqueous solvent, the double fatty acid grafted polyethylene glycol is dissolved in the non-aqueous solvent, and the composition is phase transitioned into a gel when water is added; The mass ratio of the double fatty acid grafted polyethylene glycol to the non-aqueous solvent in the composition is 1:10-10:1; The non-aqueous solvent in the composition is one or more of ethanol, 1,2-propanediol, glycerol, 1,3-butanediol, polyethylene glycol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, and glyceryl triacetate; The molecular weight of the polyethylene glycol in the double fatty acid grafted polyethylene glycol is not more than 1000; The fatty acid in the double fatty acid grafted polyethylene glycol is connected to both sides of the polyethylene glycol, as shown in formula 1, or connected to the same side of the polyethylene glycol, as shown in formula 2, Formula 1 Formula 2 wherein, PEG represents polyethylene glycol; R1 and R2 represent the carbon chain of the fatty acid, the number of carbon atoms ranges from 14 to 18; L1, L2 and L3 represent the linking group, the linking groups L1 and L2 are any one of the following, ； L3 is one of the following, 。 2. The in-situ water geltable composition according to claim 1, wherein The fatty acid chain R1 = R2 or R1 ≠ R2 in the double fatty acid grafted polyethylene glycol.

3. Use of the in-situ hydrogelable composition of claim 1 in the preparation of a gel preparation.

4. Use according to claim 3, characterised in that The gel preparation is prepared into a gel injection, an implant, a hemostatic agent, a gel for oral use, and / or a gel for rectal, vaginal or nasal cavity.

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