IN SITU PHASE CHANGE GEL SUSTAINED-RELEASE SYSTEM FOR SMALL MOLECULE DRUG AND PREPARATION METHOD THEREOF

Abstract

An in situ phase change gel sustained-release preparation for a small molecule drug and a preparation method thereof. The in situ phase change gel sustained-release preparation comprises a small molecule drug comprising an active pharmaceutical ingredient, a phospholipid, Span, and an ethanol solution. The in situ phase change gel sustained-release preparation has a high concentration of phospholipids combined with Span, and is thus able to reduce the immediate-release of the small molecule drug and extend the release time, and is suitable for various administration routes, such as subcutaneous injection and external administration.

Claims

1. An in-situ gel carrier, wherein it comprises a phospholipid, a Span, and an ethanol solution.

2. The in-situ gel carrier according to claim 1, wherein it comprises, in parts by weight, 30-60 parts of phospholipid, 10-40 parts of Span, and 7-30 parts of ethanol solution, wherein the ethanol solution has a concentration range of 70-100% (v/v).

3. The in-situ gel carrier according to claim 1, wherein the phospholipid is selected from one or more of a natural phospholipid, a semisynthetic phospholipid, and a synthetic phospholipid.

4. The in-situ gel carrier according to claim 3, wherein the natural phospholipid is selected from egg yolk lecithin and soybean lecithin; the semisynthetic phospholipid is selected from hydrogenated egg yolk lecithin and hydrogenated soybean lecithin; and the synthetic phospholipid is selected from dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidic acid, dipalmitoyl phosphatidylglycerole, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, preferably soybean lecithin S100.

5. The in-situ gel carrier according to claim 1, wherein the Span is selected from one or more of Span80, Span85, Span60, Span40, and Span20, preferably Span80.

6. The in-situ gel carrier according to claim 1, wherein the ethanol solution is selected from anhydrous ethanol, ethanol-water solution, ethanol-normal saline solution, ethanol-phosphate buffer solution, ethanol carbonate buffer solution, ethanol-succinate buffer solution, ethanol-citrate buffer solution, and ethanol-lactate buffer solution.

7. An in-situ gel preparation, wherein it comprises a phospholipid, a Span, an active pharmaceutical ingredient, and an ethanol solution.

8. The in-situ gel preparation according to claim 7, wherein it comprises, in parts by weight, 0.01-20 parts of active pharmaceutical ingredient, 30-60 parts of phospholipid, 10-40 parts of Span, and 7-30 parts of ethanol solution, wherein the ethanol solution has a concentration range of 70-100% (v/v).

9. The in-situ gel preparation according to claim 7, wherein the phospholipid is selected from one or more of a natural phospholipid, a semisynthetic phospholipid, and a synthetic phospholipid.

10. The in-situ gel preparation according to claim 9, wherein the natural phospholipid is selected from egg yolk lecithin and soybean lecithin; the semisynthetic phospholipid is selected from hydrogenated egg yolk lecithin and hydrogenated soybean lecithin; and the synthetic phospholipid is selected from dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidic acid, dipalmitoyl phosphatidylglycerole, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, preferably soybean lecithin S100.

11. The in-situ gel preparation according to claim 7, wherein the Span is selected from one or more of Span80, Span85, Span60, Span40, and Span20, preferably Span80.

12. The in-situ gel preparation according to claim 7, wherein the ethanol solution is selected from anhydrous ethanol, ethanol-water solution, ethanol-normal saline solution, ethanol-phosphate buffer solution, ethanol carbonate buffer solution, ethanol-succinate buffer solution, ethanol-citrate buffer solution, and ethanol-lactate buffer solution.

13. The in-situ gel preparation according to claim 7, wherein the active pharmaceutical ingredient is a fat-soluble drug.

14. The in-situ gel preparation according to claim 7, wherein the active pharmaceutical ingredient is selected from one or more of 2,4-dinitrophenol, dabigatran etexilate, aspirin, ridogrel, ticlopidine, clopidogrel, heparin, logiparin, lomoparin, warfarin, dicoumarol, theophylline, aminophylline, choline theophyllinate, salbutamol, clenbuterol, terbutaline, ipratropium bromide, sodium tryptophan, ketotifen, sodium valproate, carbamazepine, phenytoin sodium, ethosuximide, primidone, chloral hydrate, zopiclone, zaleplon, phenobarbital, amobarbital, sodium thiopental, diazepam, oxazepam, clonazepam, nitrazepam, triazolam, alprazolam, estazolam, glipizide, diltiazem, tramadol, morphine, pethidine, fentanyl, methadone, pentazocine, buprenorphine, codeine, naloxone, diclofenac, diclofenac sodium, ibudilast, ambroxol hydrochloride, oxycodone, chlorpromazine, trifluoperazine, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, perphenazine enanthate, perphenazine, thioridazine, chlorprothixene, flupentixol decanoate, clopenthixlo, haloperidol, haloperidol decanoate, pipotiazine palmitate, trifluridol, pimozide, trichlorpromazine, fluspirilene, droperidol, clozapine, loxapine, clotiapine, olanzapine, quetiapine, sulpiride, sultopride, tiapride, penfluridol, risperidone, morpholone, oxypertine, clomacran, reserpine, imipramine, amitriptyline, maprotiline, clomipramine, mianserin, sertraline, fluoxetine, fluvoxamine, citalopram, moclobemide, trazodone, lithium carbonate, tolterodine, levodopa, ziprasidone, levetiracetam, retigabine, perampanel, brivaracetam, eslicarbazepine, oxcarbazepine, duloxetine, paroxetine, vortioxetine, desmethylvenlafaxine, escitalopram, agomelatine, reboxetine, cariprazine, paliperidone, pramipexole, rasagiline, ropinirole, opicapone, safinamide, alfacalcidol, eldecalcitol, edaravone, aripiprazole, brexpiprazole, carbidopa, benserazide, selegiline, amantadine, memantine, bromocriptine, trihexyphenidyl, galantamine, huperzine A, rivastigmine, xanomeline, citicoline, piracetam, pyritinol, venlafaxine, bupropion, fluvastatin sodium, gliclazide, metformin, acyclovir, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, niacin, allopurinol, magnesium valproate, vincamine, promethazine, diphenhydramine, tripelennamine, chlorpheniramine, buclizine, phenindamine, cyproheptadine, hydroxyzine, cyclizine, meclizine, loratadine, cetirizine, efletirizine, metronidazole, clemastine, azelastine, acrivastine, mizolastine, astemizole, pheniramine, brompheniramine, tolpropamid, pyrrobutamine, triprolidine, nefopam, indapamide, tamsulosin, emedastine, oxybutynin, buflomedil, propranolol, metoprolol, nadolol, pindolol, atenolol, alprenolol, acebutolol, bisoprolol, betaxolol, labetalol, carazolol, prazosin, captopril, enalapril, benazepril, fosinopril, cilazapril, trandolapril, alacepril, delapril, perindopril, quinapril, nifedipine, amlodipine, levoamlodipine, nimodipine, nicardipine, felodipine, lacidipine, nisoldipine, isradipine, verapamil, losartan, valsartan, telmisartan, irbesartan, candesartan, pomisaratan, terazosin, doxazosin, clonidine, moxonidine, reserpine, guanethidine, sodium nitroprusside, hydralazine, minoxidil, pinacidil, nicorandil, urapidil, piribedil, cicletanine, enalkiren, remikiren, hydrochlorothiazide, bendroflumethiazide, hydroflumethiazido, cyclopenthiazide, curcumin, tacrine, almitrine, platinum ligand, methotrexate, fluorouracil, thiopurine, tioguanine, hydroxyurea, cytarabine, everolimus, tacrolimus, acipimox, sirolimus, tegafur, pentostatin, gemcitabine, cyclophosphamide, busulfan, carmustine, dacarbazine, vinblastine, vincristine, vinorelbine, vindesine, paclitaxel, docetaxel, cabazitaxel, camptothecin, hydroxycamptothecin, teniposide, etoposide, irinotecan, topotecan, harringtonine, homoharringtonine, doxorubicin, pirarubicin, aclarubicin, idarubicin, epirubicin, daunorubicin, actinomycin D, plicamycin, clarithromycin, mitoxantrone, ibuprofen, acetaminophen, sulindac, fenoprofen, flurbiprofen, ketoprofen, meloxicam, piroxicam, nimesulide, rofecoxib, celecoxib, colchicine, probenecid, sulfinpyrazone, benzbromarone, phenylbutazone, mefenamic acid, clofenamic acid, naproxen, indomethacin, etodolac, magnesium salicylate, choline salicylate, salicylamide, salsalate, diflunisal, adrenocortical hormone, estrogen, androgen, tamoxifen, raloxifene, clomiphene, methyltestosterone, testosterone propionate, testosterone phenylacetate, medroxyprogesterone, megestrol, chlormadinone, hydroxyprogesterone acetate, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, flutamide, retinoic acid, imatinib, gefitinib, erlotinib, thalidomide, lenalidomide, procarbazine, chlorambucil, melphalan or a pharmaceutically acceptable salt of the above medicaments.

15. The in-situ gel preparation according to claim 14, wherein the active pharmaceutical ingredient is a fat-soluble drug.

16. A method for preparing the in-situ gel preparation according to claim 7, wherein the method comprises the following steps (1) dissolving an active pharmaceutical ingredient in an appropriate amount of ethanol solution, filtering and sterilizing by a microporous membrane to form a drug solution; and (2) mixing an injection grade phospholipid and a Span with the drug solution of step (1) under a sterile condition, stirring to completely dissolve the phospholipid, leaving to stand for a moment to remove bubbles in the preparation, and subpackaging and sealing.

17. A method for preparing the in-situ gel preparation according to claim 7, wherein the method comprises the following steps (1) subjecting an active pharmaceutical ingredient to a pharmaceutically common crystallization or pulverization under a sterile condition to prepare drug microparticles; (2) mixing a prescription amount of phospholipid and Span with an ethanol solution under a sterile condition, stirring to completely dissolve the mixture to prepare a carrier solution; and (3) mixing the drug microparticles of step (1) with the carrier solution prepared in step (2) uniformly under a sterile condition, leaving to stand for a moment to remove bubbles in the preparation, and subpackaging and sealing.

18. A method for inhibiting drug burst release and prolonging sustained release time, comprising using the in-situ gel preparation according to claim 7.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0052] FIG. 1 is a process diagram showing formation of a gel from a phospholipid Span sustained release preparation.

[0053] FIG. 2 shows an in vitro release profile of a phospholipid Span sustained release preparation (DNP-LC-gel) of 2,4-dinitrophenol.

[0054] FIG. 3 shows a drug concentration-time curve of a phospholipid Span sustained release preparation, a high-concentration phospholipid sustained release preparation, and a solution group of 2, 4-dinitrophenol.

[0055] FIG. 4 shows a drug concentration-time curve of a phospholipid Span sustained release preparation of 2,4-dinitrophenol for subcutaneous injection.

[0056] FIG. 5 shows a toxicity test of a phospholipid Span sustained release preparation of 2,4-dinitrophenol.

[0057] FIG. 6 shows a drug concentration-time curve of a phospholipid Span sustained release preparation, a high-concentration phospholipid sustained release preparation, and a solution group of dabigatran etexilate.

[0058] FIG. 7 shows a local irritation test of a phospholipid sustained release preparation of dabigatran etexilate.

[0059] FIG. 8 shows a drug concentration-time curve of a phospholipid Span sustained release preparation of brexpiprazole and F127 sustained release preparation.

DETAILED DESCRIPTION

[0060] The present disclosure discloses a small molecule drug in-situ phase change gel sustained release system and a preparation method thereof. Those skilled in the art can learn from the contents of the present disclosure and appropriately improve the process parameters. It is to be noted that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present disclosure. The method and the application of the present disclosure have been described by the preferred embodiments, and those skilled in the art can obviously modify or appropriately change and combine the method and application described herein without departing from the spirit and scope of the present disclosure, to implement and apply the techniques of the present disclosure.

[0061] The granule composition, and the raw material or excipients used in the preparation method or preparation thereof according to the present disclosure are commercially available.

[0062] The present disclosure is further illustrated below in conjunction with the examples.

Example 1

[0063] 50 mg of 2,4-dinitrophenol was dissolved in 2.0 g of 85% (v/v) ethanol-pH7.6 phosphate buffer. The mixture was then filtered by 0.22 m microporous membrane to obtain a drug solution. Then 4.5 g of injection grade soy lecithin S100 and 3.5 g of Span 80 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that S100 was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 2

[0064] 200 mg of dabigatran etexilate was dissolved in 1.0 g of anhydrous ethanol to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.0 g of injection grade egg yolk lecithin E80 and 4.0 g of Span 80 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that E80 was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 3

[0065] Under a sterile condition, an appropriate amount of brexpiprazole was ground and pulverized in a mortar to obtain a brexpiprazole powder. 1.5 g of anhydrous ethanol, 4.0 g of Span 80 and 4.5 g of injection grade soy lecithin S100 were magnetically stirred under the sterile condition for about 1 h, so that S100 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles. 200 mg of brexpiprazole powder was mixed uniformly under the sterile condition with the above liquid, which was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 4

[0066] 100 mg of theophylline was dissolved in 3.0 g of 80% (v/v) ethanol-pH7.6 phosphate buffer to obtain a drug solution, which was then filtered by 0.22 m microporous membrane. Then 4.0 g of injection grade hydrogenated egg yolk lecithin and 1.0 g of Span 80 and 1.0 g of Span 20 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that hydrogenated egg yolk lecithin was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 5

[0067] 10.0 mg of dexamethasone was dissolved in 0.7 g of anhydrous ethanol to obtain a drug solution which was filtered by 0.22 m microporous membrane. Then 6.0 g of injection grade dipalmitoyl phosphatidylethanolamine, 2.3 g of Span 20, and 1.0 g of Span 60 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that the dipalmitoyl phosphatidylethanolamine was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 6

[0068] 100 mg of aspirin was dissolved in 2.0 g of 80% (v/v) ethanol-pH7.6 phosphate buffer to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 4.0 g of injection grade egg yolk lecithin E80 and 3.9 g of Span 20 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that E80 was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 7

[0069] 200 mg of cimetidine was dissolved in 2.8 g of 90% (v/v) ethanol-pH7.6 phosphate buffer to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 6.0 g of injection grade soy lecithin S100 and 1.0 g of Span 20 were added under a sterile condition. The mixture was magnetically stirred for about 1 h under the sterile condition, so that S100 was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 8

[0070] 40 mg of donepezil hydrochloride was dissolved in 2.5 g of 70% (v/v) ethanol-water to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 6.0 g of injection grade soy lecithin S100, 1.0 g of Span 80, and 0.5 g of Span 40 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that S100 was completely dissolved to obtain a liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 9

[0071] Under a sterile condition, an appropriate amount of risperidone was ground and pulverized in a mortar to obtain a risperidone powder. 2.0 g of anhydrous ethanol solution, 3.5 g of Span 20 and 4.5 g of soy lecithin S100 were magnetically stirred under the sterile condition for about 0.5 h, so that 5100 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles. 150 mg of risperidone powder was mixed uniformly under the sterile condition with the above liquid, which was left to stand until the bubbles completely disappeared.

[0072] The liquid was subpackaged and sealed to obtain the product.

Example 10

[0073] 200 mg of captopril was dissolved in 1.5 g of 90% (v/v) ethanol-water solution to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.5 g of injection grade egg yolk lecithin E80 and 3.0 g of Span 85 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that E80 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 11

[0074] 100 mg of diazepam was dissolved in 2.0 g of 75% (v/v) ethanol-water to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.5 g of injection grade egg yolk lecithin E80 and 2.5 g of Span 20 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that E80 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 12

[0075] 80 mg of promethazine was dissolved in 2.0 g of 70% (v/v) ethanol-water to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.5 g of soy lecithin S100 and 3.5 g of Span 80 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that S100 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 13

[0076] 70 mg of aclarubicin was dissolved in 2.0 g of 80% (v/v) ethanol-water to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.5 g of egg yolk lecithin E80 and 2.5 g of Span 80 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that E80 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Example 14

[0077] 90 mg of carmustine was dissolved in 2.5 g of 80% (v/v) ethanol-water to obtain a drug solution, which was filtered by 0.22 m microporous membrane. Then 5.5 g of soy lecithin S100 and 2.0 g of Span 80 were added under a sterile condition. The mixture was magnetically stirred for about 0.5 h under the sterile condition, so that S100 was completely dissolved to obtain a creamy yellow liquid containing a large number of bubbles, and the liquid was left to stand until the bubbles completely disappeared. The liquid was subpackaged and sealed to obtain the product.

Experimental Example 1

[0078] The following test was carried out in accordance with the preparation method of Example 1, except that the Span in the prescription of Example 1 was replaced with glyceryl dioleate (Test Example 1), Tween (Test Example 2) and sucrose acetate isobutyrate (Test Example 3). At the same time, the original drug solution group was designed (Test Example 4, 50 mg of the drug was dissolved in 10 mL of phosphate buffer (pH=7.6), and a solution of the same concentration as in Example 1 was prepared).

[0079] 200-220 g of SD rats were randomly divided into five groups, 6 rats in each group, and were administered subcutaneously with 12.5 mg/kg dosage of 2,4-dinitrophenol (Example 1, Test Example 1, Test Example 2, Test Example 3 and Test Example 4). At the scheduled time point, blood was taken from the rat eye and placed in a heparin sodium anticoagulated test tube. After the sample was processed, the blood concentration was measured by LC-MS/MS. The results are shown in the following table:

TABLE-US-00001 Dosage Groups Surfactant (g) C.sub.max (g/mL) Example 1 Span 80 3.5 14.86 Test Example1 glyceryl dioleate 3.5 25.42 Test Example2 Tween 3.5 30.65 Test Example3 sucrose acetate isobutyrate 3.5 28.74 Test Example4 Original drug solution 54.48 (5 mg/mL)

[0080] Results: it can be seen from the above table that the Span, which is added to the phospholipid gel, is superior to other surfactants, and can effectively inhibit the burst release effect of 2,4-dinitrophenol.

Experimental Example 2

[0081] The following test was carried out in accordance with the preparation method of Example 1, except that the ethanol in the prescription of Example 1 was replaced with propylene glycol (Test Example 1) and glycerin (Test Example 2). The appearance of the preparation was examined and the viscosity was measured by a viscometer.

[0082] The results are shown in the following table:

TABLE-US-00002 Dosage Groups Solvent (g) Viscosity (cp) Example 1 ethanol 2.0 210 Test Example 1 propylene 2.0 S100 cannot be dissolved with glycol overnight stirring. Test Example 2 glycerin 2.0 S100 cannot be dissolved with overnight stirring and the mixture forms a semisolid.

[0083] Results: since ethanol can dissolve the largest amount of phospholipids, and the other two solvents can only dissolve a small amount of phospholipids, which shows that phospholipids cannot be dissolved with overnight stirring. The prepared preparation has a viscosity of more than 300 cp or it is even in a semisolid form, which cannot be injected. It can be seen that when the same amount of solvent is used, ethanol has a better dissolving property than other solvents, can better dissolve the components in the preparation, and is easy to be administered by injection.

Experimental Example 3

[0084] Different ratios of phospholipid Span 80 sustained release preparations were prepared. Local irritation experiments were carried out to investigate the irritating effects of different amount of anhydrous ethanol on the injection site, including phenomena such as red swelling and ulceration.

[0085] The results are shown in the following table:

TABLE-US-00003 Phospholipid Span S100 80 Ethanol Prescription (g) (g) (g) Results of local irritation experiments Prescription one 5.0 4.0 1.0 No obvious irritation at the site of injection Prescription two 5.0 3.0 2.0 No obvious irritation at the site of injection Prescription three 5.0 2.0 3.0 Slight red swelling at the site of injection, but it disappeared after 3-4 days. Prescription four 5.0 1.0 4.0 Red swelling at the site of injection, and skin ulcerated after 4-5 days.

[0086] Results: when the content of anhydrous ethanol in the preparation was less than 30%, the preparation was less irritating to the administration site. In theory, when the ethanol solution containing a certain amount of water is used instead of anhydrous ethanol, its toxicity should be lower.

Experimental Example 4

[0087] (1) Phospholipid Span Gel Phase Transition Process

[0088] The product of Example 1 was poured into water. The result is shown in FIG. 1. The phospholipid Span gel changed from a creamy yellow transparent liquid to a spherical semisolid state, indicating that a phase transition process occurred after the phospholipid Span gel was diffused.

[0089] (2) In Vitro Release Results

[0090] The product of Example 1 and solution group (Test Example 4 in Experimental Example 1) were separately placed in dialysis bags, and then they were placed in a 50 mL of PBS buffer solution (pH=7.4), and an in vitro release test was carried out in a constant temperature oscillator (37 C., 100 rpm). 5 ml of the buffer was taken at the setting time point and an equal volume of fresh PBS buffer was added. Calculate the cumulative release rate of 2,4-dinitrophenol. The results are shown in FIG. 2. The phospholipid Span gel group has the characteristic of inhibiting burst release.

[0091] (3) In Vivo Pharmacokinetic Results

[0092] The product of Example 1 was injected subcutaneously into male SD rats, whose blood was taken at regular intervals. The content of 2,4-dinitrophenol in plasma was determined by high-performance liquid chromatography-mass spectrometry (LC-MS/MS), thereby investigating the sustained release effect thereof.

[0093] 200-220 g of SD rats were randomly divided into three groups, solution group (Test Example 4 in Experimental Example 1), phospholipid Span gel group (Example 1), and high-concentration phospholipid gel group (prepared according to patent CN102526753A). There were 6 rats in each group and they were injected subcutaneously at the dosage of 12.5 mg/kg. At the scheduled time point, blood was taken from the rat eye and placed in a heparin sodium anticoagulated test tube. After the sample was processed, the blood concentration was measured by LC-MS/MS injection.

[0094] The fomulation of the high-concentration phospholipid gel sustained release preparation (patent CN102526753A) is as follows:

TABLE-US-00004 Medium chain triglyceride Ingredient DNP S100 (MCT) 85% ethanol Dosage 50 mg 7 g 1.5 g 1.5 g

[0095] The pharmacokinetic parameters of each group of preparations are as follows:

TABLE-US-00005 Cmax MRT AUC (0.fwdarw.) (g/mL) Tmax (d) t (d) (0.fwdarw.) (d) (mg/L * d) Solution group 54.48 5.12 0.02 0.02 0.11 0.01 0.17 0.01 10.19 1.11 High-concentration 33.56 4.11 0.04 0.03 0.2 0.33 0.24 0.11 11.33 0.78 phospholipid gel group Phospholipid Span 80 gel 14.86 2.12 0.07 0.02 3.72 1.87 3.61 0.97 13.37 0.99 group

[0096] The results showed that the sustained release property of phospholipid Span gel was significantly better than that of high-concentration phospholipid gel and solution, mainly showing in a decrease in Cmax and a prolongation in t.sub.1/2. As shown in FIGS. 3 and 4, the high-concentration phospholipid in-situ phase change gel sustained release preparation entrapping the small molecule drug DNP has a serious burst release, and the sustained release effect is not good, whereas the phospholipid Span gel preparation of the present disclosure can significantly reduce the burst release of the small molecule drug, and the sustained release effect is better.

[0097] (3) Toxicity Result

[0098] The product (B) of Example 1 and the drug solution (A) of the solution group (Test Example 4 in Experimental Example 1) in different drug doses were injected subcutaneously into male SD rats, and the death of the rats was observed and recorded. The results are shown in FIG. 5, the gel preparation of the present disclosure can significantly reduce its side effects, which is because that the preparation has a good property of sustained release and inhibiting burst release. Compared with the solution group, the preparation can significantly reduce the blood drug concentration of DNP in the body, thereby improving its safety.

Experimental Example 5

[0099] (1) In Vivo Pharmacokinetic Results

[0100] The product of Example 2 was injected subcutaneously into male SD rats, whose blood was taken at regular intervals, and the content of dabigatran etexilate in plasma was determined by high-performance liquid chromatography-mass spectrometry (LC-MS/MS), thereby investigating the sustained release effect thereof.

[0101] 200-220 g of SD rats were randomly divided into three groups, 6 rats in each group, and were administered subcutaneously with the following dosage: the solution group (11.4 mg/kg; 200 mg of dabigatran etexilate was dissolved in 10 mL of phosphate buffer (pH=7.6), to prepare a solution of the same concentration as in Example 2), the phospholipid Span 80 gel group (80 mg/kg) (Example 2), and the high-concentration phospholipid gel group (80 mg/kg, gel was prepared according to patent CN102526753A but DNP in the high-concentration phospholipid gel group in Experimental Example 4 was replaced with 200 mg dabigatran etexilate). At the scheduled time point, blood was taken from the rat eye and placed in a heparin sodium anticoagulated test tube. After the sample was processed, the blood concentration was measured by LC-MS/MS. The results showed that the sustained release ability of the phospholipid Span 80 gel group was significantly better than that of the high-concentration phospholipid gel and solution group, mainly showing in a prolongation in t.sub.1/2 and that dabigatran etexilate could maintain a high effective blood drug concentration. As shown in FIG. 6, the high-concentration phospholipid in-situ phase change gel entrapping the small molecule drug dabigatran etexilate has a poor sustained release effect, whereas the phospholipid Span gel preparation of the present disclosure can significantly reduce the burst release of small molecule drugs, and the sustained release effect is better.

[0102] The pharmacokinetic parameters of each group of preparations are as follows:

TABLE-US-00006 C.sub.max MRT.sub.0-t T.sub.max (h) (ng/mL) t.sub.1/2 (h) (h) AUC.sub.0-t (ng/mL .Math. h) Solution group 3.18 0.21 243.86 31.47 5.21 0.83 7.86 1.14 1966.75 473.82 High-concentration 5.56 4.11 25.262 9.13 7.21 163 11.56 0.34 200.33 50.69 phospholipid gel group Phospholipid Span 80 gel 48.21 3.56 131.95 22.56 96.14 8.72 138.42 26.93 10774.2 869.24 group

[0103] (2) Local Irritation Experiment

[0104] The product of Example 2 was injected subcutaneously into male SD rats, and on days 1, 14, and 21, the rats were sacrificed. The skin tissues were taken for HE staining. The results in FIG. 7 indicate that the gel preparation has less irritation and good biocompatibility.

Experimental Example 6

[0105] The product of Example 3 was injected subcutaneously into male SD rats, whose blood was taken at regular intervals. The content of brexpiprazole in plasma was determined by high-performance liquid chromatography-mass spectrometry (LC-MS/MS), which was compared with the F127 thermosensitive gel with significant sustained release effects (Lin Z, et al. Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: High drug-loading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity, Journal of Controlled Release 28 (2014) 161-70).

[0106] The formulation of the F127 thermosensitive gel is as follows:

TABLE-US-00007 Ingredient Brexpiprazole F127 Water Dosage 200 mg 2 g 10 g

[0107] 200-220 g of SD rats were randomly divided into two groups, 6 rats in each group, and were injected subcutaneously with the following dosage: a phospholipid Span 80 gel group (50 mg/kg) and a 20% F127 thermosensitive group (50 mg/kg). At the scheduled time point, blood was taken from the rat eye and placed in a heparin sodium anticoagulated test tube. After the sample was processed, the blood concentration was measured by LC-MS/MS. The results showed that the sustained release ability of the phospholipid Span 80 gel group was significantly better than that of the F127 thermosensitive gel, mainly showing a prolongation in t.sub.1/2. The brexpiprazole can maintain a highly effective blood drug concentration. As shown in FIG. 8, although the F127 thermosensitive gel can sustained release for more than 100 hours, it was metabolized quickly and showed an obvious burst release, whereas the phospholipid Span gel preparation of the present disclosure had almost no drug burst release, and the sustained release effect was better, being able to continuously release for 25 days.

TABLE-US-00008 T.sub.max C.sub.max t.sub.1/2 MRT.sub.0-t AUC.sub.0-t (h) (ng/mL) (h) (h) (ng/mL .Math. h) F127 thermosensitive gel 12 215.7 22.4 14.8 51253.6 group Phospholipid Span 80 24 74.9 66.5 31.0 91803.5 group

Experimental Example 7

[0108] The sustained release properties of the phospholipid Span sustained release preparations for other small molecule drugs.

[0109] In vivo experiments in animals were used to investigate the effects of other small molecule drugs on inhibiting burst release. The drugs in the following table were used to prepare the preparations according to the prescription amount and the preparation method of Example 1. The obtained phospholipid Span sustained release preparation and original drug solution of the other small molecule drugs (each drug was formulated with water, ethanol or DMSO for injection, depending on the specific solubility) were injected subcutaneously into male SD rats, whose blood was taken at regular intervals. The C. of the small molecule drugs in plasma was determined by high-performance liquid chromatography-mass spectrometry (LC-MS/MS), thereby investigating the effect on inhibiting burst release. The results are shown in the following table:

TABLE-US-00009 Phospholipid Span sustained Original drug Drug release preparation C.sub.max (g/mL) C.sub.max (g/mL) Aspirin 14.56 3.12 52.24 5.08 theophylline 1.54 0.32 5.78 1.23 Carbamazepine 4.46 0.57 53.21 6.75 Phenobarbital 2.51 0.68 23.61 4.91 Risperidone 0.34 0.04 3.21 0..25 Huperzine A 1.33 0.22 13.87 2.86 Metformin 0.82 0.09 2.71 0.45 hydrochloride Loratadine 0.02 0.01 0.24 0.05 Nimodipine 1.51 0.67 10.21 1.14 Hydroflumethiazido 0.87 0.52 5.78 2.06 Doxorubicin 0.03 0.01 2.83 0.14 Naproxen 6.17 1.29 24.17 5.36 Dexamethasone 0.13 0.05 0.53 0.12

[0110] The results indicated that the phospholipid Span gel preparation of the present disclosure can significantly reduce the burst release of small molecule drugs.

[0111] In summary, the phospholipid Span in-situ phase change gel can significantly inhibit the burst release of small molecule drugs, prolong the release time, reduce the toxicity of small molecule drugs, and has good biocompatibility.

[0112] The above descriptions are only preferred embodiments of the present disclosure, and it should be noted that those skilled in the art can also make several improvements and modifications without departing from the principles of the present disclosure. These improvements and modifications should be considered to fall within the scope of protection of the present disclosure.